APPROACHES TO THE SYNTHESIS OF GNIDIDIONE

by

RONALD HARTWIGK ERICKSON, B.A.

A DISSERTATION

IN

CHEMISTRY

Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for

the Degree of

DOCTOR OF PHILOSOPHY

Approved

May, 1983

/ ^

>

IcfO;^^ TABLE OF CONTENTS

LIST OF TABLE^ iv

LIST OF FIGURES v

INTRODUCTION 1

S asquitarpenes 1

Gnididiona 2

Guaianes and Guaianolides , 5

Biosynthesis of Guaianes and Guaianolides, ,,, 7

Synthesis of Guaianolides 9

Proposed Route to Gnididiona/lsognididiona 17

RESULTS AND DISCUSSION 25

Synthesis of the Kay Intermediate ^ . .,, 25

A ttempt to Prepare the Butenolide 10^ 3^

Alternate Routes to the Butenolide 10^ 39

Second Attempt to Prepare 104 43

Model Studies for the Introduction of the G-8 Garbonyl 46

GONCLUS ION 50

EXPERIMENTAL SECTION , 51

General 5^

0_-Acatyl Isophotosantonic Lactone (^) 51

Isophotosantonic Lactone (^) .52

Cyclization of 89. to 53

Dehydration of to 53

Hvdro^enation of _^. ...•,• 53

Hydrogenation of 6l_ 5^

Reduction of 60_ with 9-BBN 5^

Protection of the Alcohol 98 55

Formation of the a-Mathylane Lactone 103. , ,, • ,55

Reduction of 1 ^ by LAH 56

Oxidation of 134 by Manganese Dioxide 56

Preparation of Activated Manganese Dioxide 51

Preparation of the Enamines 138a and 138b. 51

ii

Alkylation of I38a 58

Alkylation of 138b 58

Hydrolysis of the Esters I39a and 139b 59

Cyclization of the Acids 140a and 140b 59

DIBAL Reduction of 108 60

Oxidation of 76b with Selenium Dioxide 60

Oxidation of 108_ with Selenium Dioxide 61

REFERENCES 62

APPENDIX: IR AND "'•H NMR SPECTRA 68

IR and H NMR Spectra of ^ 69 1

IR and H NMR Spectra of ^ 70

IR and •'•H NMR Spectra of 82. 71

IR and ^H NMR Spectra of ^ , 72

IR and " H NMR Spectra of 60 » 73

IR and "'"H NMR Spectra of 62 » o .. 0 74

IR and " H NMR Spectra of 10^. 15

IR and " H NMR Spectra of lO;^ 76

IR and ^H NMR Spectra of 1 ^ 11

IR and "''H NMR Spectra of ^08 , 78

IR and H NMR Spectra of 148.. .., 79

IR and ^H NMR Spectra of 149 80

IR Spectra of 147 and jj4 81

IR Spectra of 99 and 1 ^ 82

IR Spectra of 98 and ^ 83

111

LIST OF TABLES

1. Spectral Data on Gnididione , 3

2. Photochemical Rearrangements of Cyclohexadienones 11

3. Cyclization of Germacrenes.., 15

IV

LIST OF FIGURES

1 • Guaianolides , . . . . . . . • . . , . • , 6

2, Apparatus for the Dehydration of ^ , . . • 30

INTRODUCTION

Sesquiterpenes

The sesquiterpenes are a class of compounds that have 15

carbon atoms that are formally assembled from 3 isoprene (2-methyl-

butane) units. The members of this class are biosynthesized via

the mevalonate-isopentenyl pyrophosphate-famesyl pyrophosphate

pathway (vide infra). Historically, three other characteristics

have served to distinguish this class of natural products.

One characteristic was that sesquiterpenes were only found in

plants0 However, this is no longer true. Sesquiterpenes have now

been found in a number of marine animals and in insects in addition

to plants,

A second characteristic is the great diversity of the carbon

skeleton that is possible, including all ring sizes from 3 to 12,

and up to tetracyclic structures. Today, there appear to be more

different arrangements with the sesquiterpenes than with the di-,

tri-, and higher terpenes which have more isoprene units to work

with.

The third characteristic of sesquiterpenes was that they were

all believed to be biologically inactive. For many years no

activity or use could be seen for these compounds in nature and

much speculation existed to explain why there were so many of these

compounds. Some people believed that sesquiterpenes were just

waste products in the plants while others thought that "...we may

be examining today either the distorted descendants of simpler

sesquiterpenes which functioned in geological times perhaps as

repellants to now extinct herbivores, or the diverse products

resulting ftom a^es of random search by plants for a useful 1

sesquiterpene."

Today researchers are finding a great number of sesquiterpenes

that are biologically activeo In nature, the activities found

2

include antifeedant and antifungal properties. In addition, man

has found that some sesquiterpenes have medicinal value. Mention

should be made of the large number of antitumor agents and also of

the dimeric sesquiterpene, gossypol, which appears to be a leading

candidate for a male birth control agent. Still, the great majority

of this large class of compounds exhibit no apparent function in

nature.

Gnididione

Gnididione (l_) is a sesquiterpene of the guaiane class. It

was isolated from the stem wood and stem bark of the Kenyan shrub

Gnidia latifolia by the late S, Moirris Kupchan and his co-workers,

Although the compound was isolated during a search for tumor inhibi­

tors, the interest in gnididione was not in its biological properties

(no activity studies are reported by Kupchan), but instead its rather

unique structure . This is the first (and so far, only) member of

the guaiane family that contains a furan ring. The structure was 13 1

proposed on the basis of ^C NMR, H NMR, and chemical transformations

(spectral data are summarized in Table 1). 1

The stereochemistry at C-1 was assigned by H NMRo Kupchan

found that treating gnididione with hydrochloric acid isomerizes

the molecule at position 1 and the resulting mixture could be separ­

ated to give gnididione (l_) and isognididione (Z) (Fig, l). He

found that the C-15 methyl- of gnididione gave a signal at 6 1.12,

and that the methyl of isognididione gave a signal at 6 0.80.

He reasoned that this was because the methyl of isognididione was

in close proximity to the 6,1 double bond, and is therefore subject

to anisotrophic shielding by the if system.

These assignments assume that gnididione exists in the confor­

mation shown as and that isognididione exists as (Scheme 1).

However, examination of molecular models shows that neither gnidi­

dione nor isognididione is conformationally locked and that they

could also adopt the reasonable conformations 4 and , respectively.

What these drawings are intended to show is that either stereo­

isomer at C-1 would allow the molecule to adopt a conformation in 1

which the methyl is close to a rr system and that H NMR information

Table 1 Spectral Data on Gnididione

13 *C NMR

.6

206 0 3

195.8

154o0

153.6

142 0 2

137.9

126.5

123,4

54.1

40o7

46.4

32o8

21,8

l O o l

9c8

multiplicity s s s s d s s s t

t

d

d

q

q

q

type of carbon

carbonyl

double bond

•t

•I

methylene

methine

methyl

H NMR (CDCI3) 6 1.12 (3 H, d, J=7 Hz, I5-CH3), 2.02 (3 H, d, J=2 Hz, I4-CH3), 2.15 (3 H, d, J=l Hz, I2-CH3), 2.30-3.00 (6 H, m, 1-, 2-, 9-, and lO-H), 7.35 (l H, q, J=l Hz, 13-H).

IR- 3.22, 6,331 and 6.69 |i- indicates a furan ring,

UV- 338nm- indicates that the carbonyl groups, furan ring, and

double bond axe conjugated.

0 y/^'' \2

H ^

.X ' ^

J ^ V

Scheme 1

alone is not enough to unambiguously assign the relative stereo­

chemistry of gnididione.

The work described in this dissertation was initiated to provide

the first synthesis of this rather unique highly-functionalized ,

sesquiterpene and, more importantly, to determine its stereochemistry

unambiguously. By synthesizing intermediates whose stereochemistry

can be produced in a predictable manner, a synthetic final product

would be obtained which could be compared with natural gnididione.

Since the molecule has only two chiral centers, either gnididione

or isognididione would have to result from the synthesis and thus the

stereochemistry of both would be established. In addition, a synthesis

by the route proposed below would establish the absolute configuration

of gnididione (which is not known) since the absolute configuration

of a-santonin, the starting material, is known. Therefore, by

comparing the optical rotations of gnididione with that of the

synthetic product, the configuration could be established.

Before discussing the proposed route to gnididione/isognididione,

an examination of some of the known chemistry of the related

compounds, the guaianes and especially the guaianolides, would be

helpful.

Guaianes and Guaianolides

Among the diverse structural types found in the sesquiterpenes

are those of the guaianes and guaianolideso The basic carbon

skeleton of a guaiane is shown as structure 2 - d. that of a guaian-

olide is shown as compounds 8 and 2<. The "olide" ending refers

to the presence of the lactone ring which can be fused to either

the C-6 and C-7 carbons as in 8_ or to the C-7 and C-8 carbon atoms

as in 2o Several representative guaianolides are shown in Fig, 1. .

12 Forelladiollde^

V OH

11 Artabsin' 4-8

12 Zaluzanln C 12 Axivalin^°'^^

14 Geigerln 12-14 1^ Keli3plendiollde^5

T—0

16 Arctolide^^ 17 Hymen osignin'

--OAe

18 Handelin 18

Fig. 1 Guaianolides

While the biological activity of many of the guaianolides is

unknown, some of the examples shown do have activity. Porella-

diolide (lO) , isolated from a species of liverwort, inhibits the 4 / \

germination and growth of roots of rice in the husk, zaluzanln C (12; 19 / \

has been shown to have antitumor properties, and geigerin (1^) is a toxin isolated from species of Geigeria that caused poisoning of

12-13 sheep in Africa, ^ Of the remainder of the compounds shown, many of them have been isolated from species of the Compositae,

members of which have been used for various folk medicine preparations.

Biosynthesis of Guaianes and Guaianolides

The biosynthetic pathways leading to guaianes and guaianolides

have been studied; however, they are not completely understood and

there are some exceptions to the proposed pathways. The biosynthesis

has been extensively reviewed and the following discussion has been

summarized from these reviews.

An outline of the biosynthesis of a guaianolide from trans,

trans-farnesyl pyrophosphate (l£) is shown in Scheme 2. Trans,

trans-farnesyl pyrophosphate itself is synthesized from isopentenyl

pyrophosphate (for a review of the biosynthesis of famesyl pyro­

phosphate see ref, 22 and 26-28), The biosynthesis is believed to

occur by the cyclization of fajrnesyl pyrophosphate (l .) to give

the intermediate 20,

The exact route from 20 to the germacrolide precursor of the

guaianolides 21 is not known; however, two possible intermediates

have been proposed. These are germacrene A (2j) and germacrene B

(24)o Of these two, germacrene A is the preferred intermediate

because biogenetic pathways can be drawn from it which lead to the

a-methylene lactone function which is common in guaianolides. (See

ref. 20 for a more complete discussion of these pathways.)

Evidence against germacrene A as an intermediate is that

germacrene A does not seem to explain the occurence of C-7» C-8

fused lactones such as geigerin (l^). Examination of germacrene

A's structure reveals that every carbon except C-8 is allylically

activated for oxidation. Germacrene B's structure does allow for

the activation of C-3 and furthermore, it has C-6 doubly acti-

8

vated. This may explain why C-6, C-7 lactones predominate in

nature. However, a pathway to an a-methylene lactone is harder

to imagine.

In any event, the cyclodecadiene system next undergoes a

cationic-initiated cyclization to give either the hydronapthalene

(two fused six-membered rings) found in the large eudesmsme class

or the hydrozaulene (fused five and seven-membered rings) found

in the guaiane class. The latter cyclization requires an initiation

OPP

19 t r a n s , t r a n s -f a m e s y l pyrophosphate

-?

20

V

23 Germacrene A 2+ Germacrene B

\^

^

Scheme 2

step that is formally an anti-Markovnikov addition to a double bond.

Exactly where gnididione with its furan ring fits into the

biosynthetic scheme is less clear. It is possible that the lactone

ring is eventually transformed into a furan ring. However, it is

also possible that the furan ring is the precursor of the lactone.

This situation occurs in the related family of compounds known as

the eremophilanelideso In this class, sesquiterpene lactones

such as 26 commonly co-occur with furanosesquiterpenes such as 2^.

The furan 2^ could be autoxidized to the butenolide 26, These

oxidations probably involve hydroperoxide intermediates—as has

been suggested by in vitro photosensitized oxygenations^^'-^^

(see ref, 31 for a recent review of the other evidence that exists

for this route).

21

OX

26

It is clear that much mere work needs to be done in this area

before these questions can be answered.

Synthesis of Guaianolides

The guaianes and guaianolides have been popular synthetic

targets in recent years. This is primarily a consequence of chemists'

desire to explore synthetic and conformational principles in the

less common 5 -nd. 7 membered rings these compounds contain. Many

different approaches to this carbon skeleton have been devised;

however, by far the most common route involves the photochemical

rearrangement of cross-conjugated cyclohexadienones, such as

a-santonin (29).

10

The entry to the guaianolide system by the photolysis of

a-santonin to give JO. has several advantages. First, a-santonin

is commercially available in high purity and at moderate cost.

Second, it is a natural product and therefore, no resolution is

needed. Third, a-santonin and its photoproduct have been

thoroughly investigated and the absolute stereochemistry of them 32-34 35 36

is known both by x-ray analysis- ^ "^ and by synthesis. * The natural products synthesized by this route have included

14 37 geigerin (14) by Barton, estafiatin (jl_) by Crabb^ and Greene,- ' amboresceln (j^) by Sorm,- dihydroarbiglovin (^) by Marx,^

/ \ 40 41 and achillin (34) and desacetoxymatricarin (35) ly White. '

In addition to a-santonin, other cross conjugated cyclo­

hexadienones have been photolyzed to give the guaiane skeleton

These are listed in Table 2 along with the yields of the products.

Other rearrangement routes to the guaiane system have been

devised. Buchi has carried out the pinacol rearrangement of the 47

decalin to give (+)-apoaromadendrene (j^) in 8dfo yield.

Compound ^ was prepared in 6 steps from (-)-perillaldehyde,

J4 R=Me, R'=H J^ R=H, R'«Me

Scheme 3

11

Table 2

Photochemical Rearrangements of Cyclohexaxiienones

Startirvsc Material Photoproduct Solvent Yield Reference

6-epl-o-santonin

HOAc ZlV^o 42,43

g-santonin

6-epi-0-'5antonln

OH

artemisin acetate

Ufa H(3Ac

HOAc

4 5 ^ HOAc

191; 42,43

2 ^ 4 ^

b%

42,43

42,43

OH

8-epiartemisin acetate

6-epi-8-epiarteniisin acetate

OH

OAc HOAc

4 5 ^ HOAc

Z^fr

11^,

42,43

42,43

Table 2 (con t . )

12

starting Material Photoproduct Solvent Yield Rpference

CO2CH]

45^ HOAc

45/» HOAc

4 5 ^ HOAc

50^

not repor ted

modest yield

kh

45

45

CO2CH,

4 5 ^ HOAc

low yie ld

45

45?g HOAc

60^ 45

--M

anhydrous dioxane 60^ 46

13

^

J6 J8

Another rearrangement approach has been reported by Heathcock,

This involves the Wagner-Meerwein rearrangement of another decalin

^ yielding a-bulnesene (4o). The starting material was prepared

in 11 steps from the Wieland-Miescher diketone.

KQAc HOAc

>

21 40

Still another rearrangement route was used by Marshall in the 49 50

synthesis of bulnesol. ^*^ In this route, the stereochemistry of

the final product was controlled by controlling the stereochemistry

during the synthesis of the bicycle Q4,3.1 decane intermediate 41 .

This compound upon solvolysis rearranges to give the compound 42

which was then transformed into bulnesol (43)»

AcOHjC

41

NaOAc

HOAc • >

AcOH2C

42

Posner et al. has provided another total synthesis route

— . 51 which has been summarized in Fig. 5o

u

/44

_12 steps • >

14

steps

H ;

Schema 4

One other total synthesis approach is outlined in Scheme 5, This 52 53

route by Vandewalle '^^ is similar to a route taken by Liu and T 54 Lee.

Another approach which has been used by several research

groups is a biomimetic approach. These routes use germacrene

intermediates similar to 21_ (p. 8) --usually a compound with one of

the double bonds functionalized as an epoxide, an alcohol, or

similar group. The various cyclizations by this route have been

summarized in Table 3- Most of the starting materials used for

these routes are either natural products or have been derived

from natural products in a few steps.

There have been some other syntheses, but the ones shown above

show the various elegant and ingenious approaches that have been

used in this area. Through this work much stereochemical knowledge

of the guaianolides has been acquired and many synthetic techniques

have been made available to other researchers.

MljSIO,

MtjSIO »

48 m

OSIMt,

io

V

OSiMt,

OH

x ^ ; OH OH

n Pb(0Ac)4/H0Ac

->

Scheme 5

15

Table 3 Cyclization of Germacrenes

starting Material Product Conditions Yield Reference

hv 254nm

10^ xylene-isopropanol

hv 254nm

21'« 55

56

16

Table 3 (cont.) starting Material

Product Conditions Yield Reference

HVH^ 57

HO

BF3 ether

or

HCl gas ether

58,59

BF3 ether or HCl ether

5B,59

silica gel 1 week

60

mesyl chloride/ pyridine

0°

•yzU 61

3 compounds

a R=OH, R'=CH3 b R=<:H3, R'=0H

c.R=CH3, R'=OMS

15"«

17

Proposed Route to Gnididione/isognididione

An outline of the proposed route is shown in Scheme 6. The

synthesis starts with the photolysis of a-santonin (22) to give

0-acetyl isophotosantonic lactone (_20). As stated before, the

stereochemistry of both the starting material and the photoproduct 32-34

are known from x-ray analysis,^ -^ Compound _20 has all the requisite

carbon atoms for a synthesis of gnididione or isognididione. A

number of modifications of functionality are required however, and

the order in which they are carried out is crucial.

The logical first step would seem to be to replace the acetate

group in _20. stereospecifically by an H atom, followed by protection

of the ketone group to give the key intermediate a The next major

transformation would be to convert the lactone ring into a furan

ring, giving , Finally, oxidation at the somewhat activated

"benzylic-llke" methylene group should give either the required

ketone or some group which can be converted into a ketone, Depro-

tection would then give the final objective, compound 2 . This syn­

thetic product would be compared with natural gnididione, to see if

it corresponds to the natural product or to isognididione, as

required if Kupchan's stereochemical assignments are correct. In

either event, since the stereochemistry of the synthetic product

OAc

Scheme 6

18

would be unambiguously known, the stereochemistry of gnididione

would be established.

Details of the individual steps required for the proposed

synthesis are discussed below.

The transformation of into has been carried out by

previous workers except for the last step—the protection of the

ketone. Still, the work has not been carried out under optimum

conditions and neither has it been completely described in the 64

literature. The transformation requires four steps, as shown in

Scheme 7. First, the acetate croup is hydrolyzed to the alcohol 58. 62-65

This step has been carried out by a number of workers, ~ - This

is followed by an elimination reaction using thionyl chloride in

pyridine to give the exocyclic double bond in , This step requires

very careful control of reaction conditions to give the kinetically-'4 6? 6* 6*

controlled product," * t Jt J Then, catalytic hydrogenation can be

->

<-

Nl/"

Scheme 7

19

carried out selectively and stereospecifically to give the 3-roethyl

compound 60,

Biichi - has investigated the dehydration reaction of with

acid, as shown in Scheme 8, This gives the thermodynamically-

controlled product 61 which hydrogenates predominantly from the

3-face of the molecule to give 62_, which has inverted stereochemistry

at both stereocenters. This product would presumably be a precursor

to the enantiomer of gnididione or isognididione.

pd

pd

Scheme 8

For further transformations of 6Q, it will be necessary to

protect the ketone group, as in ^ (PG=protecting group). This

normally trivial procedure could cause problems here, since simple

derivatives of ketones, such as ethylene ketals, are not very

stable for a,3-unsaturated ketones, and the allylically-placed oxygen

of the lactone ring could cause problems for any acid-catalyzed

reaction required to put on a protecting group. Furthermore, the

protecting group will be required to remain in place during a number

of different types of reactions, involving strong bases, vigorous

reducing and oxidizing conditions, and mildly acidic conditions„

It seemed to be more feasible to reduce the ketone to an alcohol

group and then protect that,, though it was anticipated that much

20

experimentation might be necessary in order to find a suitable

protecting group.

The next major sta^e, the transformation of the lactone of

56 into the furan ring of 57 has been mapped out in our laboratories 66

previously by Herman Ramsey. This work is summarized in Scheme 9.

Compound 6^ (prepared for a synthesis of a different compound) was

•treated with lithium diisopropylamide (LDA) followed by phenyl

selenenyl chloride, followed by hydrogen peroxide. This sequence

of reactions introduced the double bond a to the lactone carbonyl.

This selenoxide elimination is a standard method for this type 67

of transformation. It was required that the double bond be

endocyclic rather than exocyclic; however, from the work of Grieco

it was known that trans-fused lactones of the type 22. give only

exocyclic product.^^ Therefore, it was necessary to treat the

compound 66_ with a catalyst to migrate the double bond within the

1; \.rjp\\

>

2) PhS.-CJ . J ) 11,0,,

-V^

1 /

. - " N • • ^ ^

Schema 9

21

ring. This was accomplished by the use of rhodium trichloride 69

trihydrate ^ to give the butenolide 680 The butenolide was reduced

using diisobutylaluminum hydride (DIBAL) to give the furan 6^,

This reduction of butenolides is well known, and is a standard 70-75

method to make furan rings,

Compound 6^ would also seem to be a possible precursor to

gnididione/isognididione, and was indeed synthesized for this

purpose. The single double bond in the five-membered ring, while

in principle convertible to the required a,3-unsaturated ketone,

would add several steps to the synthesis. Also, it required

several extra steps to produce the precursor 6^ as compared to 60.

This approach was terminated when the previous worker ran out of

material.

Presumably, the chemistry shown in Scheme 9 to make the furan

ring will be applicable to the present case. The analogous

sequence of reactions to make the required key furan compound ^

is summarized in Scheme 10.

1 . LDA 2 . PhSeCl

3. H^2

DIBAH

->

RhCla'HsO

Scheme 10

22

There now remain only two steps to get to Z^ These are an

oxidation of the "allylic/benzylic" methylene group to give a

carbonyl at position 8 and deprotection of the C-3 carbonyl group

(Scheme 11).

The first step, the oxidation of the C-8 to a carbonyl, could

present a problem. Although the position is formally like an

allylic or benzylic position and therefore, activated towards

oxidation, furan rings are known to be sensitive towards oxidation.

The difficulty will be to find an allylic oxidant that will not

attack the furan ring, A fairly extensive literature search could

find no good analogy for this step. There appear to be no allylic-

type oxidations which have been performed on furans. Therefore, it

will be necessary to do some model studies directed toward this end.

Two compounds, 76a and 76b were chosen as the model compounds. They

have the same substitution pattern around the furan ring as does

57, but of course lack the other functionality.

After introduction of the C-8 carbonyl, the C-3 carbonyl will

be deprotected (22—^ ^) "to give isognididione/gnididione (Z),

ox depro-

tect • >

n Scheme 11

If no oxidation reagent can be found that will introduce the

carbonyl without attacking the furan, an alternate route has been

considered. This is outlined in Scheme 12. Here, the carbonyl will

be formally introduced before the reduction of the butenolide to

the furan. Allylic oxidation of the butenolide 71. would lead to

23

-^ pa

Scheme 12

the allylic alcohol i* The most likely reagent here would be 1 38

selenium dioxide, as fairly close analogies exist, -^ This would

then be followed by the reduction with DIBAL to give the furan 21»

Then the C-8 alcohol would be oxidized to the carbonyl followed by

deprotection of the C-3 carbonyl to give .

In the remote possibility that neither of the above approaches

succeed in introducting the carbonyl, it will still be possible

to confirm the stereochemistry of gnididione. Preliminary work in

our lab has shown that treatment of natural gnididione with

tosylhydrazide yields compound 22 with little or none of 2.8 being

formed (Scheme I3). Treatment of XL ^^"^^ sodium cyanoborohydride

would then be expected to produce a methylene group at C-8, without

reducing the ketone at C-3. This sequence should give 79* On the

other hand, regeneration of the ketone group on C-3 of our synthetic

intermediate should give either the same product, 22» o^ " he C-1

H—NHT$

24

epimer of 22. (i*©* "the product that would be obtained if the C-8

carbonyl group of isognididione were removed). By comparing the two

compounds, the stereochemistry of gnididione would be established.

Of course, it is preferred to compare the synthetic and natural

products at the end of the synthesis . Therefore, this route should

not be investigated unless it proved necessary.

RESULTS AND DISCUSSION

Synthesis of the Key Intermediate 56

The first step in the synthesis generates the basic guaianolide

skeleton (as described before) via the photochemical rearrangement

of a-santonin. The photorearrangement of santonin has been known 78

since I83O. Since that time, structural and mechanistic work on

santonin and its photoproducts has been carried out by an impressive 70 f\C) PA

group of chemists which include S, Cannizzaro, R, B. Woodward, *

E, J, Corey, and Sir Derek Barton, While a variety of products

can be obtained depending upon the choice of solvent, the use of

glacial acetic acid results in the formation of 0-acetyl isophoto­

santonic lactone (30) as the major product. The mechanism of this 84-87

transformation has been studied by Kropp and his co-workers and

their results and results from other groups point to the mechanism

shown in Scheme 14 (see ref. 88-91 and references therein for more

information on these rearrangements).

hv n—rr*

'OAc

intersystem

crossing

Scheme 14

25

26

In our work, santonin was photolyzed by dissolving 30 g of

santonin in 275 mL of glacial acetic acid and irradiating this with

a 250 watt Hanovia Hg lamp in a water-cooled quartz immersion well

for 24 hours. Three photolysis runs were combined and the acetic

acid was removed in vacuo and the product was obtained in 35^ yield

by recrystallization of the oil from methanol (2 crops). For the

purposes of this study, I5 batches of santonin were photolyzed.

The next step in the synthesis of was to hydrolyze the

acetate group in ^ to an alcohol. Two problems have been encountered 66

by researchers on this step. In our own laboratory, Ramsey

found that when he hydrolyzed the related compound 8^ using potassium

^-butoxide in jt-butanol he obtained not only the desired 86 but also

87> the C-11 epimer, and separation of the two epimers was difficult.

Conditions were found to minimize the epimerization, but it could

not be avoided altogether.

t-BuO"K*

t-BuOH +

64 Italian chemists have reported the hydrolysis of compound J ,

Their procedure involved stirring ^ with aqueous KOH until

solution was complete, then acidifying to regenerate the lactone

from the salt of the hydroxy acid. This procedure gave not only

the desired but also the C-1 epimer 8§, which required chroma­

tography to separate,

OAe . OH

1 ^ 1 . ^ a q . KOH

2 . H2SO4 > 0 -H

° N / i8 " Y ' "' 88 °-0 0 0

We reasoned that the epimerization at C-1 was probably occuring

after the hydrolysis, while the compound is in solution. If so, 64 \

minimizing the reaction time (three hours in the original work )

27

might minimize the epimerization reaction. It was hoped that simply

grinding JO to a very fine powder would increase the surface area

enough to aj?fect appreciably the rate of solution into the aqueous

base. Indeed, this proved to be the case. Solution could now be

effected in about one hour and the C-1 epimer was virtually elim­

inated. Also, no epimerization occurred at C-11. This is presumably

because the carboxylate ion in the basic solution decreases the

acidity of the C-11 proton dramatically, thus "protecting" it from

the epimerization reaction.

A surprise occured however, when the basic solution was acidified.

At pH 3 a white precipitate formed (in highly varying yields—in most

runs little or none formed) and remained even after the solution was

stirred for one hour. Based upon its IR, NMR, and solubility in

bicarbonate solution, the compound was identified as the hydroxy

acid 89. Ordinarily, this would be no surprise that an opened lactone

was obtained; however, in the guaianolide system, trans lactones are

very stable and the equilibrium lies very much in favor of the closed

lactone rather than the opened hydroxy acid. How much the equilibrium

favors the lactone is shown by the fact that 89 is believed to be the

only example of an opened trans lactone in the guaianolide system.

In our lab, Ramsey tried unsuccessfully to obtain 91 from 90.

Careful acidification yielded only the regenerated lactone under all

conditions investigated. The instability of the hydroxy acids in 105 these systems has also been reported in the literature and in

private communications from other workers in the field (to Dr. Marx).

1. base

2. controlled acidification

CO,H

0

OH

21

Compound 89. is unstable. Even the pure crystalline compound,

upon sitting at room temperature for several weeks, underwent some

decomposition. In an attempt to characterize the compound, 89_ was

stirred with an ethereal solution of diazomethane; however, what was

obtained was not the methyl ester 9±, but instead the closed lactone

^ . Upon attempting to take a melting point of 89, it was found

that 89 decomposed at 120° C to give the lactone . Therefore,

heating in an oven at 120° C is one way to obtain more 58 .

The easiest method found to cyclize 89 to the lactone was to stir

89 with absolute ethanol (it dissolves in about 2 or 3 min.)

followed by removal of the solvent. This gave as an off-white

solid. • OH

28

CH^N.

ether

CO:H

* 0

CO:Me

The remainder of the product from the original hydrolysis

reaction was , which could be obtained by ethyl ace Late extraction

of the acidic solution after 89. was filtered off. Removal of the

ethyl acetate also gave as a solid—though not quite as pure as

that obtained from the cyclization of 8^ in ethanol.

It should be noted that it is possible to obtain directly from

a-santonin by using aqueous acetic acid as the solvent in the photolysis 4?

reaction instead of glacial acetic acid. " (Generally 45^ acetic acid

is used. See the entries in Table _2, p 11.) This method, however,

gives a more complex mixture than that obtained when glacial acetic

acid is used. As a result, the product can only be obtained pure by

extensive chromatography. This alternative was investigated in our 141

lab, but was judged to be completely impractical for largo scale

work. Thus, isolation of the acetate and hydrolysis as described

above is the preferred route to 58,

The next step was the elimination of the alcohol iproup in to

give the exocyclic alkene 59_' '^ described earlier, this can be done

29

using thionyl chloride in pyridine. This step has been carried

out by a number of workers;^^'^^'^^»^^ but, the yields have

ranged from fair to poor or else have yielded mixtures requiring

chromatography. The best procedure to date has been that of Greene^^'^^

using low temperature, which gave yields of about 60-65^. OH

H V H

SOCI2 ^ ^ y

py

i3 ^ i i

0 66 ° Again, from the work of Ramsey on compound 86, it is known that

the longer the reaction mixture remained in contact with the thionyl

chloride/pyridine, the more of the endocyclic isomer 4 was obtained. OH

H

30G1. '

py

0 ^ 0

As the contact time for this reaction was just a few seconds, it was

thought that perhaps the use of a flow system (which would decrease

the contact time even more) might result in higher yields.

The simple flow system shown in Fig, 2 was designed for this

purpose. Through one of the septums a solution of in pyridine was

injected while simultaneously through the other septum a solution of

thionyl chloride/pyridine was introduced. The reaction took place as

a stream of nitrogen forced the solutions down the tube into a mixture

of ice and ether, to quench the reaction. The exact reaction time is

not knownr but, it is less than 0,5 sec, and is probably around

0,1-0.3 sec. (The reaction times can be varied easily by lengthening

or shortening the bottom portion of the tube.) This procedure, after

workup, results in the desired as a crude solid in about 90^ yield.

A few comments about the reaction and the properties of should

be made. Difficulties in repeating the work (a few months later)

were traced to the quality of the thionyl chloride and pyridine used.

,"J 30

ilcohol , py

s i p t u m

SOCI, , py

septum

:om m " - ^ N^ /^ '

I I

• 150 mm /

I I

i ! ' J [ 1

Co i c e - e c i i e r quencu

Fig. 2 Apparatus for the Dehydration of ^

Both should be purified before use. Thionyl chloride was distilled 139 from quinoline and pyridine was distilled from sodium hydroxide

pellets. While both reagents may be handled in air, it is recommended

that they be transferred by syringes. The thionvl chloride/pyridine

mixture should be mixed just before using in the following manner.

The pyridine should be transferred to a flask first. Then, the

thionyl chloride should be injected under the surface of the pyridine.

When the needle was not immersed, or when the thionyl chloride was

poured instead, a cloud formed above the liquid in the flask. The

resulting thionyl chloride/pyridine mixture gave increased amounts

of the endocyclic product. Therefore, care should be excercisad in

handling the thionyl chloride.

It was also found that was sensitive to work up conditions.

Compound 59_ appears to be sensitive to acid, heat, and to chroma­

tography on silica gel. For our purposes, we found that if some

endocyclic product was present, it was best to submit the mixture

to the next reaction (a hydrogenation of the double bond) and then

separate the hydrogenation products.

Poisoning of the hydrogenation catalyst in the following reaction

31 often occurred with the crude alkene. This appeared to be due to

trace amounts of some impurity in the crude product. The most

likely impurity seems to be pyridine—which cannot be removed in

the usual manner (by aqueous HCl extraction) due to the acid

sensitivity of the molecule. In any case, the impurity could

usually be removed by stirring a solution of the alkene, at room

temperature, with 2 or 3 portions of activated charcoal.

The next step vias the catalytic hydrogenation of the exocyclic

double bond in , using the procedure of Buchi.^ The result

of this hydrogenation was the compound 60. It is known that

60 (the result of addition of hydrogen from the bottom of the .aole-

cule) is the product rather than 9^ (the result of top-side addition)

0. / 0.

o o

because the product gives a methyl doublet at 6 O.67. This upfield

shift of the C-10 methyl group in is caused by shielding by the

C-4,5 double bond, which is in close proximity only in this isomer,

as judged by molecular models. Without this shielding, the signal

would be expected at 6 0.9-1.0.

In a few hydrogenation runs, a second product with a methyl

doublet at 6 1.03 was isolated in small amounts as a crystalline

solid. This product proved to be 62, the product of the hydrogenation

of the double bond of the endocyclic, conjugated alkene (see Fig. 9»

p. 19). Apparently, a small amount of 59 had been isomerized by the

catalyst before it was hydrogenated. That this product was indeed

62 and not the 21 discussed above, was proven by comparison to a

sample of 6Z prepared by hydrogenation of the conjugated isomer

61 (isolated by column chromatography as a by-product of some of

the poorer dehydration runs).

Next came the protection of the C-3 carbonyl CT:OUP. It was

hoped that it could be protected at the carbonyl oxidation stage.

32

rather than having to reduce it and protect it as an alcohol; however,

no method was found to protect it as a carbonyl—although a variety

of methods were tried.

First, attempts were made to protect the carbonyl as the ethylene

ketal 96. The first method used the standard conditions which

consist of the use of ethylene glycol with p-toluenesulfonic acid I —

as a catalyst. The H NMR spectrum of the product of this reaction

indicated that starting material was not obtained. In addition, it

showed that an ethylene ketal was not present. It also showed that

the C-6 lactone proton was not present. It is known that under these

conditions double bond migration (to the 3,Y position) usually accom­

panies protection under these conditions."'^ Therefore it was decided

to try again using milder conditions. A milder method that is reported to prevent this migration,

yet still give the desired ketal in good -yields has been reported 93 94

by De Leeuw et al.^-^'^ De Leeuw investigated the formation of

ketals with ethylene glycol using different acids as catalysts, and

found that the use of an acid catalyst with a pK^ of 3 or more would

give the ketal without double bond migration. However, to get an

acceptable reaction rate, it was necessary to keep the pK^ between

3 and 4. Fumaric acid has a pKa of 3.03 and they reported up to 90^ 93 94 yields using it as a catalyst. -* When this method was tried with

compound 60_, only starting material was obtained.

Another mild procedure which appeared to be promising was that

of Noyori. This procedure uses the trimethylsilyl ethers of

1 . CHa-CHa, 2-TsOH

HO OH

2 . CH2-CH2, fumaric a c i d

HO OH

3 . QHa-CHa, THSOTf

MegfliO OSLMea

. 33

ethylene glycol and trimethylsilyl triflate as a catalyst. For

simple unsaturated ketones, this procedure usually gives yields in

excess of 90%, and the double bond remains at the a,3 position.

Unfortunately, application of this method to compound 60 also gave only

starting material.

Rather than pursue the ketal protection any further (since it was

also suspected that an ethylene ketal may not have withstood all of

the reaction conditions that would follow), attempts were made to

protect the ketone as the thioketal 97» a- group which is much more

stable to hydrolysis. Here, when the standard conditions of ethane-

dithiol with boron trifluoride etherate as a catalyst were used, the

H NMR of the product mixture was much different from that of the

starting material. The most noticeable feature of the spectrum was the

absence of a signal for the C-6 proton—indicating that the lactone

was no longer intact.

A milder procedure and one that is reported to protect an a,3-

unsaturated ketone in the presence of a saturated ketone has been

developed by Evans.°^*^ This method uses the trimethylsilyl ether

derivative of ethanedithiol with zinc iodide as a catalyst.

When this was tried, it was found that the C-6 proton signal had

disappeared again. Exactly what the product was, was not determined.

However, the opening of lactones by other Lewis acids in the presence 97

of thiols has been reported.^^ Apparently the zinc iodide is assist­ing in the opening of the lactone here also.

1 . CHa-CHa, BFa^OEta

H3 SH

2. CHa-CHa, Znis

MegSiS SiMea

3 . GKg-CHa, TMSOTf

34 Since protection of 60 as a ketone appeared to be impossible, the

decision was made to reduce the ketone to an alcohol and protect

the alcohol. Ordinarily, a reduction of a ketone to an alcohol is no

problem. Numerous reagents are now available for such reductions.

However, three features of the molecule greatly limit the choice of

reagent. First, the ketone is a,3-unsaturated. It is known that

besides 1,2 addition of hydrogen (reduction of the carbonyl), 1,4

addition (reduction of the double bond) can also occur, and will

predominate with many reagents (Scheme 15). Unfortunately, cyclo-

pentenone systems (of which the C-3 carbonyl of 60 is a part) are prone

to give 1,4 addition with many of the standard ketone reducing: 101 102

reagents, ' For example, sodium borohydride, which is one

of the most selective reagents for reduction of simple ketones, when

applied to compound 60 gave only the product which results from

1,4 addition. Other reagents have also been found to give large

amounts of 1,4 addition to cyclopentenone (sea ref. 102 and refer­

ences therein).

OH

1.4 <f ^ hZ ..

Scheme 15

The choice of reagent is further limited by the presence of a

lactone ring in the molecule. The reagent chosen must therefore be

selective enough to reduce the ketone without reducing the lactone.

This eliminates the use of reagents such as diisobutylaluminum

hydride (DIBAL) and lithium aluminum hydride. While these reagents

are known to give high yields of 1,2 addition, they also will

reduce lactones and esters rapidly.

Finally, since the molecule is already chiral, it was desired

that the reduction give only one of the two possible isomers for the

resulting alcohol . This would avoid the separation of diastereomers

or the annoyance of having to carry mixtures of both products through

to the end.

The initial survey of the literature indicated that several

35 reagents could meet the first two requirments, but that few, if

any, reagents could meet all three. The reagent finally chosen for 1 n?

the reduction was 9-'borabicyclononane (9-BBN). Brown has reported

that this reagent will reduce a,P-unsaturated ketones, including

cyclopentenone, to allylic alcohols in quantitative yields. In

addition, he reports that ketones can be reduced selectively in the

presence of many functional groups—including nitro, epoxide, amide,

nitrile, carboxylic acid, and ester. Therefore, it appeared to meet

the first two requirements. It was also expected that it would meet

the third requirement for the following reasons. First, 9-BBN is a

bulky reagent, and should therefore be influenced in its approach to

the molecule by steric factors. Since it is known that the methyl

attached to C-IO is in close proximity to the C-4,5 double bond

(vide supra), the methyl could provide enough hindrance to prevent

transfer of the hydride by the bulky 9-BBN to the top side of the

molecule. Therefore, the product arising from bottom-side attack

by 9-BBN was expected to be the major, if not only, product. 102

Following the procedure of Brown, 60 was reduced using one

equivalent of 9-BBN. Thin layer and column chromatography of the

reaction mixture resulted in the isolation of three major components

and one minor component^ The minor component was not identified.

The major product was the desired alcohol 98 (although it was only

present in 50-60% yield). One of the other major components proved

to be starting material. The IR spectrum of the third major com­

ponent showed the presence of an aldehyde functional group, as well

as an alcohol group. This compound is believed to be 99• which results

from the reduction of both the C-3 ketone and the C-6,7 lactone ring

by 9-BBN. While it has not been reported that 9-BBN reduces lactones

readily, it is known that the closely related reag;ent, diisoamyl-

borane, can reduce lactones to give hydroxy-aldehydes.

9-BBN ^ HO 4- HO

36

Fortunately, the reagent did appear to give only one stereoisomer

in the reduction. The alcohol isolated gave a single spot in TLC

and, after protection as the jt-butyldimethylsilyl ether (vide infra),

the protecting group gave only .one signal in the H NMR. It was

thought that if both the a and P alcohols had been formed, two

signals would have been seen due to the different environments they

would be in.. Therefore, since a further survey of the literature

did not find any reagent that was likely to give any better

results for all three requirements, we decided to accept the losses

for the moment, and continued to use 9-BBN for the following studies.

Happily, the protection step was uneventful. The protecting

group chosen was the tert-butyldimethylsilyl ether (TBDMS). The 104 TBDMS ether protecting group was developed by Corey and it is

known to be stable to strong bases, reducing agents, many oxidizing

reagents, organometallics such as Grignards and organolithiums, and

is stable down to ca. pH 4. The group is introduced by stirring a

DMF solution of the alcohol, t^-butyldimethylsilyl chloride, and

imidazole at 35° for ca. l6 h. The yields obtained were comparable

to those of Corey (80-85%). The group can be selectively removed 104

by treatment with tetrabutylammonium fluoride. The result of

the protection step was our first key intermediate 100.

TBDMSO

Attempt to Prepare the Butenolide 104

For reasons discussed in the section describing the model studies

for the introduction of the C-8 carbonyl group (vide infra), the key

intermediate chosen for the oxidation of C-8 was the butenolide 1^,

and not the furan as was discussed in the introduction.

After the alcohol was protected as its TBDMS ether, the route

37

to the butenolide was explored. Treatment of 100 with one equivalent

of lithium diisopropyl amide (LDA) in dry THF at -78° C resulted in

the formation of the enolate of the lactone. Reaction of this enolate

with phenylselenium chloride resulted in the formation of the selenide

101. The formation of the selenide was confirmed by the collapse of

the C-11 methyl doublet (in H NMR) to a singlet and by the fact that

the compound eliminated after treatment with H2O2 to give an alkene

(vide infra). The selenide was isolated as an oil in ca. 70% yield,

after chromatography over silica gel, and was used directly in the

next reaction. No attempt was made to get it crystalline. Also,

the yield was not optimized because this route to the butenolide

developed problems (vide infra). It should be possible to increase

the yield on this step to over 85% with practice and more careful

exclusion of moisture.

To effect elimination, the selenide was treated with HgOg at 0° C

to form the selenoxide 102, which spontaneously eliminated PhSeOH to

give the a-methylene lactone 103. The presence of the a-methylene

lactone was shown in the H NMR by the characteristic signals for

the two vinyl protons at 6 5.43 and 6,15. (Ha is shifted upfield

relative to Hb by interaction with the rr-system of the lactone

carbonyl group,)

TBDMSO 1 . LDA 2 . PhSoCl

TBDMSO • TBDMSO

HhCl30":P ^ ^3P„S0

38

The fact that the a-methylene lactone was the only elimination

product isolated (none of the butenolide W^ was found) establishes

the stereochemistry at C-11 in the selenide. As selenoxide elimina­

tions are known to require a syn arrangement of the selenoxide and 67

the leaving hydrogen and, since no butenolide was found, the -SePh

group in 10l_ had to be 3, since the C-7 proton is a.

In order to obtain the desired butenolide, 1_0 was stirred in

dioxane with RhClgO H2O for 24 hours at room temperature. While

this procedure succeeded in migrating the double bond from the

exo to the endo position for Ramsey in fairly good yield in a related

compound (see Fig, 10, p, 20), it did not work here. The H NMR

spectrum of the total product was difficult to interpret; however, it

was clear that some major changes in the molecule had taken place.

The a-methylene lactone signals were gone, indicating that no starting

material remained. Further, no signals could be found for the C-3

or C-6 methine protons. In addition, the signals of the methyl

group protons of the TBDMS protecting group were nearly gone.

In the hope of finding some of the butenolide, the mixture was

chromatographed over a silica gel column. The reaction mixture

proved to be very complex. Small amounts of material were eluted

in nearly every fraction; however, none of the desired butenolide

could be found.

The mechanism of double bond migration of simple olefins by 106 124

rhodium catalysts has been studied by Cramer * and by Harrod 122 123

and Chalk, * Their work, plus that from other groups, indicates

that these migrations involve a transition metal-olefin complex.

However, a mechanism has not been established. In fact, it is

possible that different substrates or different solvents may cause 123

a change in mechanism for the same metal-ion catalyst.

In addition to multiple bond migrations, transition metal-olefin

complexes can undergo three other principal types of reactions:

polymerization, molecular addition to a multiple bond, and group 122

substitution in the vicinity of multiple bonds. Usually one

of these reactions will predominate, but frequently several may be 122

observed to occur simultaneously. The complexity of the reaction

39

mixture obtained from the reaction of 103 indicates that more than one

process is operating here, also. Group substitution could result

from the attack of the catalyst on the C-4,5 double bond, or the

allylic, protected alcohol on C-3, or the allylic oxygen of the

lactone ring on C-6,

In addition to the above processes, it is possible that some

redox reactions between the catalyst and the substrate are also 143

occuring. Researchers ^ have found that when rhodium trichloride

trihydrate is used to migrate double bonds using ethanol as the

solvent, the catalyst oxidizes some of the ethanol to give a rhodium

hydride complex (of unknown composition) plus some HCl, Perhaps

the use of the less easily oxidized solvent, dioxane, resulted in

the oxidation of the substrate in this reaction, too.

Since a clear reason for the failure of the reaction could not

be found, alternate routes to the butenolide were investigated.

Alternate Routes to the Butenolide 104

Three things became clear from the above research. One was that

competition between attack of the catalyst on the C-4,5 double bond

and attack on the a-methylene lactone was more of a problem than had

been anticipated. Another was that a better solvent for the migration

using RhClgO H2O would have been ethanol. However, it was also clear

that the catalyst may be prone to give many side reactions, and that

even the use of ethanol might not give a successful reaction. It

would be better to look for a different migration catalyst.

The best choice might be hydridocarbonyltris(triphenylphosphine)-

rhodium (l), RhH(PPh3)3C0, which has recently been shown to isomerize 11 R 11 Q

the compounds 10^ and I06 to the butenolides 107 and 108, *

RhH(PPh3)3C0

(CHP. I r ^ (CH:)

105 n=l 107 n=l

106 n=2 108 n-Z

Another possibility would be Wilkinson's catalyst, RhCl(PPh3)3,

which gave large amounts of the butenolide Ij^ in the hydrogenation

of the exo double bond of the pseudoguaianolide IC19. However,

40

RhCKPPha):

° - 0. 0 uo 0

neither of the above examples has. an additional double bond, such

as our compound 10^ does. Of course, the additional steric hindrance

provided by the triphenylphosphine groups may prevent the attack

on the C-4,5 double bond—although this would not guarantee it. Still

it appears that such a catalyst might be the answer.

If either of these catalysts would still give appreciable attack

on the C-4,5 double bond, one method to decrease the attack would be to

deprotect the C-3 alcohol and oxidize the alcohol to a ketone. Then,

the migration would be attempted on the resulting compound 111_, The

now conjugated C-4,5 double bond would be more stable, and would be

less likely to undergo undesirable reactions with the catalyst.

o. Ill O 112

However, this idea suffers from a serious drawback. The next

reaction in the proposed sequence is an allylic oxidation at C-8

using selenium dioxide (see model studies below). Unfortunately,

compound 112 now has another functional group , the C-3 carbonyl group

which is susceptible to reaction with selenium dioxide. Oxidation

with selenium dioxide adjacent to a carbonyl (in this case the C-2

methylene group) is a standard method of producing 1,2-dicarbonyl

compounds, » -'» » - Therefore, to go this route would involve

deprotection and oxidation of the C-3 alcohol, a more favorable

double bond migration, and then the reprotection of the ketone,

presumably as the protected alcohol again. This would greatly

lengthen the route to gnididione. In any case, the use of a

different catalyst was not tried because another route (already in

progress and outlined at the end of this section) was showing more

41

promise.

The use of other migration catalysts than rhodium was also

considered. Both of the rhodium catalysts above are homogenous

catalysts. Another possibility would be to use a heterogeneous

catalyst. It is well known that heterogeneous hydrogenation catalysts

often will migrate double bonds, as well as hydrogenate them, *

However, Ramsey tried to migrate the exo double bond on 66 (Fig, 10,

p 20) without success using Pd/C catalysts,

Ramsey also tried to migrate the double bond of 66^ using acid

catalysis (^-toluene sulfonic acid) without success. Thus, the

more complex compound at hand seemed unlikely to undergo the desired

reaction by these methods.

Another approach considered was to find some method to make the

selenoxide elimination reaction go endocyclic rather than exocyclic, Co

and produce the butenolide directly. For selenoxides, Grieco

found that selenation of the fused lactones 113 and 117 proceeded

stereospecifically (Scheme 16). This was proven by the subseauent

eliminations. The trans-fused lactone 113 eliminated to give only

the product with an exocyclic double bond. However, it was found

that elimination from the cis-fused lactone 117 gave the butenolide

120 as the major product. Therefore, for our purposes, if we could

epimerize the lactone 100 at the C-6 position, the following elimina­

tion reaction would result in the desired butenolide (Scheme 17).

i iz

t . LPA

Z.CFK^e),

1 . LDA ^

Mf StP* 11'*

PllSt XX^l

J b O j 90-99<

ICK " •

112

Scheme 16

120

Since the lactone ring is destined to become .a furan, the stereo­

chemistry at C-6 is unimportant. However, this approach was not

pursued because any reasonable (i.e. short) method to epimerize at

C-6 seemed highly likely to cause concmrrent epimerization at C-1.

42

TllfMM«;o, -> TMUmo 1 . IJW

7. r«?«!i TMOMSO- » , 2 ». teoMso-

s,ni

Scheme 17

This could not be allowed, since it would destroy the stereochemistry

in the crucial part of the molecule, and invalidate the entire

synthesis as a method to establish the stereochemistry of gnididione.

The use of a different leaving group is possible. The best

choice here would seem to be to introduce a halogen a-to the carbonyl.

Greene, Muller, and Ourisson have found that the trans elimination of 120 HBr from a trans lactone leads to the double bond being endocyclic.

However, when this elimination was performed on 124, the product found

was not 125i "but instead, 126, which is obtained from 125 hy removal

of the now doubly activated C-6 proton by the base present to effect 120

the elimination. Since it is quite possible for this type of

double bond migration to occur in our molecule also (both molecules

have a C-4,5 double bond), this route was not pursued.

12i^

The route that was finally chosen, and had already shown some

encouraging results, was based upon work done by Indian chemists.

They succeeded in making a guaianolide butenolide by the route shown

in Scheme 18. Unfortunately, their route involves a verv low yield

step, the Jones oxidation (chromium trioxide in sulfuric acid) of

the diol 128 to the keto-acid 129. They found that the major product

LIA.llt4 Jon<!s* ox

6-10* AccO

reflux

120 122 CO,H

Scheme 18

43

of this reaction was the initial starting material of the sequence,

the lactone 127, This product probably arises as is shown in Scheme 19

The Jones reagent attacks the primary alcohol first, oxidizing it to

an aldehyde. The aldehyde then cyclizes with the C-6 alcohol to form

the lactol I33t which is then oxidized to the lactone. Simple primary

alcohols often give substantial yields of esters as by-products by a

similar mechanism (through a hemiacetal intermediate) when they are 110 111

oxidized by Jones reagent, * In addition, diol oxidations using

silver carbonate on celite result in lactones, and these reactions axe 112

reported to preceed through a lactol intermediate.

jji CHsOH

1:22 CHO

Scheme 19

We decided to investigate this route because we felt that we

could overcome the problem through a two-step oxidation. It was

thought that if the C-6 alcohol could first be oxidized to a ketone,

then, oxidation of the primary alcohol to give the keto-acid V^

should give high yields. In our molecule, the C-6 alcohol is allylic

and therefore, the use of manganese dioxide (which can oxidize

allylic alcohols specifically in the presence of non-allylic

alcohols)-'-^^*^^^ would allow the oxidation of the C-6 alcohol to a

ketone without affecting the primary alcohol. This route is outlined

in Scheme^ 20 and the results are described below.

Second Attempt to Prepare 104

The first step was the reduction of the lactone in 100 by lithium

aluminum hydride. This was accomplished by stirring 100, overnight,

in dry ether with an excess of lithium aluminum hydride. The excess

hydride was destroyed by the careful addition of water, as described

by Fieser and Fieser.^^^ This provided the diol 1J4 in nearly

quantitative yield.

TBDMSO LUIH4 -*• TBDMSO MnOs

CH^OH

-*• TBDMS

H2OH

Jones ox • TBDMSO

U6 COjH

AcgO

reflux -• TBDMSO

Scheme 20

Next, the diol was stirred in benzene with a five-fold excess of

manganese dioxide. Although the reaction with allylic alcohols is 140

normally over in a few minutes, the reaction here proved to be

quite sluggish. It was necessary to resubmit the diol twice to

increased amounts of manganese dioxide. The slowness of the reaction

may be due to the conformation of the molecule. There is evidence

from work in the steroid and in the carbohydrate fields that an

axial allylic alcohol is oxidized much slower than one that is equa­

torial. This evidence is summarized in the two-part review on Mn02

by Fatiadi (ref. l4o). (Patiadi comments that the evidence is not

conclusive.) In 134, if the bulky isopropyl group attached to C-7 is

equatorial, then the C-6 allylic alcohol would have to be axial, and

therefore, this may be the reason the reaction is so slow. Alterna­

tively, the slowness may be due to either the particle size of the

manganese dioxide (This is a heterogeneous reaction. Therefore, the

total surface area of the Mn02 will affect the rate.) 'or to the method

of preparation since the way it is made can have a signigicant

affect upon its activity. However, the method used to prepare

the Mn02 for this experiment ^ is reported to be very dependable

and has been used by a number of workers. In any case, since this

reaction has only been tried once, and since no standardization of

the catalyst activity was done, the exact reason for the sluggishness

can not be stated with certainty.

^5 In any case, a small sample of 135 was obtained. This was then

subjected to a Jones oxidation (Cr03 in H2SO4) of the primary alcohol

in order to obtain the keto-acid lj6. The results of this reaction

were confusing. Almost no bicarbonate soluble material could be

found, indicating that very little lj6 was present. Further, the

product mixture still showed a significant alcohol signal in the IR—

even after prolonged treatment with the reagent. Further examination

of the Ir and H NMR spectra showed that the TBDMS protecting group

had come off and that the C-3 alcohol had been oxidized to a ketone.

Additionally, some carbonyl «:roup signals renresentative of lactones

were found in the IR spectrum.

This reaction has only been run once. Clearly, a mixture of

products has been formed. The most reasonable interpretation of the

results is shown in Scheme 21. It appears that the Jones reagent has

oxidized the primary alcohol of 135 to a carboxylic acid, but further

reactions have occurred in the acidic medium. Addition of the car­

boxylic acid to the ketone would give the lactol 142, which would

explain the OH signal in the IR and its inertness towards further

oxidation. Acid-catalyzed dehydration of this could give slowly the

product 143, which would isomerize to the more stable butenolide 144.

Thus, these preliminary results suggest that the Jones reagent has

TBDMSO

135 CH2OH

- • o

COOH

Scheme 21

46

given the elusive butenolide 144, and no deliberate cyclization react­

ion is required.

The mixture was chromatographed on silica gel, and a small amount

of a material was obtained which did show a carbonyl and a double bond

stretch in the IR, very similar to that of the model compound 108.

At this point, all available material was used up. The reaction

needs to be repeated and improved, of course. It would be desirable

to retain the TBDMS protecting group, or replace it with one which is

more stable to acidic conditions. It is known that the TBDMS group is

moderately stable to Jones reagent, usually surviving up to an hour at

room temperature. It is unknown how fast the oxidation and cycliza­

tion reactions are to give the butenolide 144, but they could be fair­

ly fast. If so, it may be possible to carry out the Jones oxidation

for a shorter time period ( 6 hours was used in the described run )

and obtain the desired butenolide 104.

Model Studies for the Introduction of

C-8 Carbonyl Group

As stated in the Introduction, problems were anticipated in the

introduction of the C-8 carbonyl. The plan called for an allylic

oxidation on either a furan compound or a butenolide. Literature

searches for these types of transformations are often difficult.

Reactions such as these are often buried in papers and are generally

not abstracted. Therefore, review articles were relied upon in the

search for a procedure for allylic oxidation of these compounds. In

addition, a search of Chemical Abstracts using DIALOG (from 1967-May

1982) was done to see if any references could be found on the use of

selenium dioxide on furans.

The reviews searched included several detailed ones on furan

chemistry," ^ " - ^ on butenolide chemistry, * one on eremopho-

lane chemistry"'' ^ (The eremophilanes are sesquiterpenes with similar

structures to our compound—see compounds 2^ and 26., page 9, for

examples. Fused butenolides and furan rings abound in this class of . 1 3 7

compounds.), and a large review on the synthesis of sesquiterpenes.

In all this literature, it appeared clear that selenium dioxide is the . . 125,128,129,130

most commonly used reagent for allylic oxidations.

47

Even then, no examples of its use on furans was found, and only one

reference was found for an allylic oxidation on a butenolide. Sond-

heimer has reported the oxidation of the butenolide 14^ to give

146. Since this was not considered to be a very good model for

our system, we decided to investigate the oxidation of lO^ and 10^

(see Fig. 24), which are more closely related to our molecule.

Furans are very electron-rich molecules, and are thus, subject

to attack by oxidizing agents at the ring positions and not the

allylic position. Since there seems to be no systemmatic study of

possible methods to oxidize adjacent to a furan ring, investigation

of the action of some oxidizing agents on the model furans 76a and

76b was also studied, although the likelihood of a successful allylic

oxidation appeared to be remote.

The compounds for the model study were synthesized as shown in

Scheme 22. The synthesis starts with cyclohexanone and cycloheptanone, 99 The enamines of the ketones were prepared by the method of Stork.

Next, the enamines were alkylated by refluxing the enamines and

ethyl 2-bromopropionate in either dry methanol or dry acetonitrile.

After the appropriate reaction time, addition of water and a further

short reflux hydrolyzed the enamines to give the keto-esters 139a

and 139b. The esters were then hydrolyzed using 5% aq KOH to give

the keto-acids I40a and I40b. Then, to obtain the desired butenolides,

the keto-acids were refluxed in acetic anhydride (a standard method

of synthesizing butenolides:i -* ^* The furans could be obtained

by treating the butenolides with diisobutylaluminum hydride.

Three different reagents for allylic oxidations were examined as

potential candidates for the introduction of a carbonyl functionality

allylic to the butenolide double bond. These were selenium dioxide

48

't»^

137a r.=l

137b -11=2

pyrrolidine r 11 !• GH3CH3rG0:St . i r " ^ ( C H ^ 2. HaO » ( C H J V J L C C R

^ ^ 3. ^ KOH vCV'^^COjR

138a n=l 1 138b n=2 lJ2a,_.i_=L, a=Ke

139b n=2, R=St

l ^ a n= l , R=H

AcaO ref lux (CHj),

107 n=l

108 n=2

DIBAL

0

heme 22

- > r T°> ^ (CHjJsX/

76a n=l

76b n=2

Collin's reagent (Cr03«2 pyridine), and lead tetraacetate. Lead

tetraacetate is a good reagent for introducing an acetate (-OAc) 147

group, which could be hydrolyzed and oxidized to a ketone. Collin's 1 48

oxidations can introduce a carbonyl group directly/ and selenium"

dioxide can introduce an acetate, a carbonyl group, or an alcohol

function, depending on the conditions used.

Both Collin's reagent and lead tetraacetate failed to give pro­

ducts of allylic oxidation. For the Collin's oxidation, the butenolides

were added to an 11-fold excess of the preformed reagent in methylene

chloride and stirred for 12 h. For the lead tetraacetate, the buten­

olides were stirred in acetic acid at 80° with 2.5 equivalents of

lead tetraacetate. In both cases, only starting material was found

after work-up.

The oxidation with selenium dioxide proved to be interesting. In

an attempt to introduce an acetate group, the butenolide was refluxed

with Se02 in acetic anhydride and in acetic anhydride/acetic acid

(1:1), Both of these solvent systems are reported to give acetates

as the products. However, while selenium did precipitate out in the

reaction flask, only starting material was obtained. Exactly what

was reducing the selenium is not known. When the reaction was tried

49

in a different solvent system though, (dioxane/acetic acid/water)

it was found that both 107 and 108 were oxidized to give an alcohol

in the allylic position (compounds 147 and 148); however, while 108

oxidized in three days, it took nearly five weeks for 107 to oxidize.

The exact reason for this strange rate difference is not known. In

any case, it appears that selenium dioxide is the reagent of choice

for our oxidation.

(CHg)

107 n=l

108 n=2

Selenium dioxide was tried on a furan to see if it could be

oxidized in the allylic position. Using the same conditions as

were used for the butenolides, 76b was treated with Se02. Not

surprisingly, no allylic oxidation took place. After chromatography,

compound 149 was isolated from the reaction mixture. Compound 1 ^

is also believed to be a product of this reaction, since the H NMR

of the total reaction product showed a clear triplet at 6 5.89

(J= 4 Hz); however, this compound did not survive the chromatography.

+

26b lk9 150

CONCLUSION

The work described the attempted synthesis of gnididione to deter­

mine its stereochemistry. The synthesis started with the photolysis of

santonin to give 0-acetylisophotosantonic lactone (^). From four

things were required to obtain gnididione. The first was the replace­

ment of the acetate group on C-10 with a hydrogen. This has been

accomplished in three steps to give the first key intermediate 60.

The second goal was the transformation of the lactone ring of 60

into butenolide 104. The first approach, the introduction of an exo

double bond a to the lactone carbonyl, followed by the migration of the

double bond to the endo position, proved to be quite difficult. However,

with the appropriate catalyst this approach may still work. The alter­

nate route, the transformation of the lactone to a keto-acid and cycli­

zation to a butenolide appears to have worked. However, lack of enough

material prevented complete proof of structure.

The third goal was introduction of a ketone at C-8, allylic to the

butenolide ring. This type of transformation has been accomplished

in a model compound, 108, using selenium dioxide. Once butenolide

104 is made in quantity, this reaction will be applied to it.

The last goal is to convert the oxidized butenolide into a furan.

This type of reaction has been accomplished with DIBAL in related

molecules. Then, simple functional group transformations should give

synthetic gnididione, which will be compared with the natural product

to determine stereochemistry.

50

EXPERIMENTAL SECTION

General

Melting points were determined on a Laboratory Devices Mel-

Temp apparatus and are reported uncorrected. Infrared spectra were

taken on a Perkin-Elmer 457, or a Beckman Acculab 8, or a Nicolet

MX-S FT spectrophotometer, either neat, in chloroform solution, or

in KBr pellets. Nuclear magnetic resonance spectra were obtained on

either a Varian XL-100-15 or a Varian EM-360 spectrometer. UV spectra

were obtained on either a Cary-17 or a Gary 219 spectrophotometer.

Optical rotations were taken on a Perkin Elmer l4l polarimeter.

Thin layer chromatography was done on Eastman Chromagram Sheets

(#13181 silica gel with fluorescent indicator~#6060), Unless

specified, column chromatography was done on silica gel (60-200 mesh)

using mixtures of petroleum ether and ether. Pyridine was dried by

distillation from sodium hydroxide pellets. THF was dried by

distillation from calcium hydride followed by distillation from

sodium and benzophenone.

0-Acetyl Isophotosantonic Lactone, (30)

The procedure followed was similar to that of White, Eguchi, 4o 41 / \ /

and Marx, * A solution of 30,0 g (122 mmol) of a-santonin (Sigma

Chemical Co,) in 285 inL of glacial acetic acid was irradiated for

24 h under a slow stream of nitrogen using a 250 watt Hanovia mercury

arc lamp in a water-cooled quartz immersion well. Three photolysis

rains were combined and the acetic acid was removed on a rotary

evaporator to give a heavy brown oil. Next, 50 mL of methanol was

added and the oil dissolvedo Then the flask was cooled and the

solution seeded and placed in the freezer overnight. This afforded

2908 g {Zl%) of crystals. The solvent was removed from the filtrate

and 15 mL of methanol was added to the warm oil. The solution was

cooled and seeded and 4 days later a second crop of crystals was

51

52 collected (7.1 g, 6%). The crystals were washed with cold methanol and

used in the next step.

"P ^2-183° C (lit. 175-177,^^ 182-182.5,^^ 176-177,^^ 183,^^ 180-

181, °' ^ ) ; IR (KBr) 1772, 173^, 1701, 1647 cm"^ [ lito^^ (Nujol 1775,

1730, 1700, 1645 cm"^]; ^H NMR (CDCI3) 6 1.10 (s, 3H) , 1.28 (d, J=6 Hz,

3H), 1.90 (t, J=2 Hz, 3 H), 2.01 (s, 3 H), 4.85 (hr d, J=7-8 Hz, 1 H) 0

Isophotosantonic Lactone (58)

To 500 mL of 5% aq KOH, 10,0 g of finely ground was added

and the mixture stirred at 25° C until solution was obtained (ca,

1-1,5 h), A small amount of insoluble material was filtered off

and the solution was acidified to ca, pH 3 with concentrated H2SO4,

At pH 3 the white precipitate of the hydroxy acid formed. After

stirring for 30 min,, the hydroxy acid was collected by filtration

and dried at about 60° C, (The yield of 82. in this reaction was

0,5 g; however, the yields of varied greatly from reaction to

reaction,) Compound 89. decomposes at about 120° to give 58,

IR (KBr) 3445, 3151, 2980, l693j 1653, I63I cm"^, ^H NMR (DMSO^d^)

6 0,63 (s, 3 H), 0,98 (d, J=8 Hz, 3 H ) , 1,71 (s, 3 H) ,

The filtrate was allowed to stir for another hour and then

extracted with three 100 mL portions of ethyl acetate and one 100 mL

portion of ether. The combined extracts were washed with 50 mL of

brine and then dried with MgS04, The solvent was removed by rotary

evaporator to give 8,1 g (93%) of as an oil which solidified

upon standing. Another 0,46 g of was obtained by cyclization

of the hydroxy acid 82 by the procedure described below to give

98^ over-all yield,

A sample was recrystallized from absolute ethanol: mp 167.5-

168,5° G (lit, 166-168^^); IR (KBr) 3750, 1782, I689, 1643 cm'S

^H NMR (CDCI3) 6 0,96 (s, 3 H), 1,30 (d, J=6 Hz, 3 H) , 1,87 (t, J=2 Hz,

3 H), 4,88 (br d, J=9 Hz, 1 H ) .

53 Cyclization of 89 to 68

The hydroxy acid 82 (0.98 g) was stirred with 50 mL of absolute

ethanol until solution occur ed (ca, 5 mimj). Then the solution was

filtered and the solvent was removed by rotary evaporator to give

58 as an oil which solidified upon standing (0.88 g, 96^; mp 97-

104°).

Dehydration of 58 to 59

The reaction was run through the simple flow system shown and

described on p, 28, For the run described here, two 5 niL syringes

fitted with 21 ga, needles were used to inject the two solutions.

In one syringe was placed a solution of 300 mg of dissolved in

3.0 mL of dry pyridine. In the other syringe a mixture of 2.5 mL

of dry pyridine and 2.5 mL of thionyl chloride was placed. The

reaction was quenched into a mixture of 25 mL ether and 50 mL ice.

The quenched reaction mixture was transferred to a separatory funnel

and the layers separated. The water layer was extracted with two

25 mL portions of ether. The combined ether layers were then washed

with two successive 15 mL portions of water, 5% sodium bicarbonate,

water, and brine, followed by drying with MgS04. Removal of the sol­

vent by rotary evaporator at 25° gave as a crude solid (yield-260 mg,

93%; "mp 80-85° C, recrystallization from ether gave mp 113-114°—lit,

113.5-11^.5,^-^ 113-115^^). IR (KBr) 3086, 1776, 1705, 1689, 1645 cm"^

^H NMR (CDCI3) 6 1.29 (d, J=6 Hz, 3 H) , 1,99 (t, J=2 Hz, 3 H) , 3.54

(m, 1 H), 4.85 (s, 1 H), 4,93 (m, 1 H ) , 5.03 (s, 1 H),'

Hydrogenation of 59

Compound was hydrogenated using the procedure of Buchi.

Compound was dissolved in ethyl acetate (1,0 g into 35 mL EtOAc)

and hydrogenated on a sloping manifold hydrogenation apparatus using

a 10% Pd/C catalyst (60 mg catalyst per 1,0 g of ^ ) . Following the

completion of hydrogen uptake, the catalyst was filtered off through

a pad of celite. The solvent was removed by a rotary evaporator to

give an oil which was chromatographed over silica gel to give 60

(ether/pat ether; 40:6o) as an amorphous lactone. Further elution

(ether/pet ether; 45:60) gave 62 as an oil which was recrystallized

from ether. The exact yield of each compound was variable (usually

5^

62 was isolated in ca. 0-10% yield).

60: IR (film between salt plates) 296O, 2924, 2876, I778, I697,

and 1645 cm- ; H NMR (CDCI3) 6 O.67 (d, J=7 Hz, 3 H), 0.86-2.93 (m,

9 H), 1.26 (d, J=6.5 Hz, 3 H), 1.88 (t, J=2 Hz), 3.17 (br m, 1 H),

^.88 (br d, J=lo Hz, 1 H).

62: mp 152-153° (lit^^ 153-153.5°); IR (KBr) 2964, 2920, 2866,

1784, 1697, and 1645 cm"S ^H NMR (CDCI3) 6 I.03 (d, J=7 Hz, 3 H),

0.92-2.66 (m, 9 H), 1.28 (d, J=6.5 Hz, 3 H), I.87 (s, 3 H), 3.II '

(br m, 1 H), 4.86 (d, J=10 Hz, 1 H).

As was discussed in the body of the paper, sometimes poisons were

present in ^ . Usually they could be removed by stirring a solution

of with two or three portions of activated charcoal; however,

there were times when this would not work. In those cases, it was

necessary to resort to chromatography over silica gel.

Hydrogenation of 6I

The conjugated alkene (l.10 g, slightly impure) was dissolved in

50 mL of ethanol and hydrogenated on a sloping manifold hydrogenation

apparatus using 60 mg of 10% Pd/c catalyst. After hydrogen uptake

was complete (ca. 1 h), the solution was filtered through celite and

the solvent removed by rotary evaporator to give 0.92 g of a solid

that proved to be compound 62.

Reduction of 60 with 9-BBN 102

The procedure of Brown was used. Compound 60 (l.lO g) was

dissolved in ca. I5 mL of dry THF at 0°. Then, with stirring, 9 mL

of a 0.5 M solution of 9-BBN was added over ca. 30 min. Then, the

solution was stirred at 0° for 4 h and at 25° for 2 h. A small

amount of methanol was then added to destroy any unreacted 9-BBN.

The solvent was removed and replaced by ether. Then, 0.24 mL of

ethanolamine was added with stirring and the precipitate of the 9-BBN

complex formed immediately. After 10 min. of stirring, the solution

was filtered through celite and the solvent was removed to give an oil

which was chromatographed over silica gel. Elution with ether/pet

ether (1:1) gave the desired alcohol 28 (0.47 g) as an oil which was

submitted to the protection step without further purification.

55 Protection of the Alcohol 98

The alcohol 28 (0.79 g) was dissolved in 25 mL of DMF and stirred

with 1.2 eq of TBDMS-Cl and 2.5 eq of imidazole at 25° for 24 h, as 104

recommended by Corey. The solution was poured into ca. 250 mL of

ether and the ether washed with five 50 mL portions of water. Then,

the solution was dried over magnesium sulfate and the solvent removed

to give an oil. Chromatography over silica gel gave 0.92 g of the

protected alcohol as an oil. (ether/pet ether; 15:85).

IR (neat between salt plates) 2957, 2928, 2856, 1778, and 1672 cm"- .

H NMR (CDCI3) 6 0.07 (s, 6 H), O08O-3.IO (br, I3 H ) , 0.87 (s, 9 H) ,

1.20 (d, J=10 Hz, 3 H), 1.82 (s, 3 H ) , 4,21-5.05 (br, 2 H),

Formation of the a-Methylene Lactone 103

The procedure for selenation and elimination was the same as 68

that developed by Grieco for lactones except that PhSeCl was used

rather than PhSeSePh, All glassware, syringes, and stirbars were

dried in an oven at 150° C for ca, 8 h and cooled in a desiccator

before use,

A 25 mL round-bottomed flask containing a stirbar was fitted

with a septum and flushed with nitrogen. Then, 3 mL of dry THF and

0,1 mL of diisopropylamine was added and, with stirring, the solution

was cooled to -78° C, Then, 0,5 mL of 1,5 M methyllithium (in THF)

was added to generate the LDA, This solution was allowed to stir

for 10 min, at -78°, Then, 5 mL of THF containing 0.222 g of the

lactone 100 was added by syringe over 20 min. The solution was

allowed to stir for 20 min. at -78° in order to form the enolate.

Then, 1.0 mL of dry THF containing 0.14 g of PhSeCl and 0.I3 mL of

hexamethylphosphoric triamide (HMPA) was added rapidly and the solution

kept at -78° for 50 more min. Then, the solution was warmed to -45°

and kept at -45° C (chlorobenzene slush bath) for 1.5 h. The reaction

was then quenched by the addition of 0.1 N HCl. Following the quench,

the solution was extracted with three portions of ether. The

combined ether layers were washed with water, 5% aqueous sodium

bicarbonate, water, and brine. The solution was dried (MgS04) and

the solvent removed to give an oil which was chromatographed over

5(>

silica gel to give 0.222 g (70%) of the selenide 101 as an oil.

Compound 101 was then oxidized to the selenoxide without further

purification.

Compound 101 (0.222 g) was dissolved in 3 mL of THF containing

0.06 mL of acetic acid and was then cooled to 0° C. Then, 0.28 mL

of 30% hydrogen peroxide was added and the solution was then stirred

at 0° for 30 min. "The reaction mixture was then poured into a cold

saturated sodium bicarbonate solution. The aqueous solution was

extracted with ether three times and the ether layers were combined

and washed with water and brine. Then, the solution was dried with

magnesium sulfate and the solvent was removed. Chromatography of the

crude product gave the a-methylene lactone 10^ (0.138 g, 89%) as an

oil which was not purified further.

The presence of the a-methylene lactone was shown in the •''H NMR

by the two downfield signals of the vinyl protons (6 5.43, 6.I5).

Reduction of 100 by LAH

The lactone 100 (188 mg) was dissolved in dry ether and added to

50 mL of dry ether containing 250 mg of lithium aluminum hydride.

Then, the solution was stirred at room temp, for 10 h. Then, 0,25

mL of water was slowly added and followed by the addition of 0.40

mL of 5% NaOH. The solution was stirred for 1 h and then filtered

through a pad of sodium sulfate. The solvent was removed to give

163 mg of the diol as a clear oil. This was submitted to the man­

ganese dioxide reaction.

Oxidation of 134 with Manganese Dioxide

The diol 134 (I63 mg) was dissolved in 30 mL of benzene and 175 mg

of active manganese dioxide was added. The solution was then stirred

for 1 h at room temp. The mixture was filtered through celite and

the solvent removed. An IR of the oil showed that virtually no carbonyl

stretch was present. Therefore, the oil was resubmitted to Mn02

(200 mg for 24 h). Again, the IR showed that the reaction was not

complete, so the mixture was stirred with ca, 0,75 g of Mn02 for

three days. This time the carbonyl band was quite strong, so the

mixture was chromatographed to give 103 mg of 135 as an oil.

51

Preparation of Activated Manganese Dioxide

Manganese dioxide was prepared by a modified^^ Attenburrow^^^

procedure. The resulting manganese dioxide was activated by the

procedure of Goldman,"^^^

A solution of potassium permanganate (48 g in 3OO mL of water)

was heated to 85° C, Then, with stirring, 60 mL of 40% aqueous sodium

hydroxide and a solution of manganese sulfate monohydrate (42 g in

75 mL of water) were added simultaneously over about 30 min. The

resulting solution was allowed to stir at 85-90° for one hour. Then,

the solution was filtered in three portions through a 6OO mL coarse

glass-sintered funnel. Each portion of filter cake was washed with

water until it was neutral to pH paper. Then, the wet filter cake

was stored until it was activated, 109

The activation consisted of refluxing the wet filter cake with

benzene into a Dean-Stark trap until no more water separated—usually

about one hour. The amount of water distilled off was usually 50-

60% of the weight of the wet filter cake. The resulting, activated

manganese dioxide was stored under benzene until it was needed.

Preparation of the Enamines 138a and 138b 99 The procedure used was similar to that of Stork, In a 5OO mL

round-bottomed flask fitted with a Soxhlet extractor containing

magnesium sulfate, the appropriate ketone was refluxed with two

equivalents of pyrrolidine and 3OO mL of solvent per mole of ketone.

For cyclohexanone, benzene was the solvent. For cycloheptanone,

toluene with a small amount of -toluene sulphonic acid added was

used, as recommended by Stork. Reflux times were 12 h for I38a and

48 h for 138b. Following the reflux, the mixtures were distilled

through a short, ."sracuum-jacketed Vigreux column to give the enamines

138a and 138b.

138a; bp 147-149° C, 89 mm ( l i t . 105-107°, 13 mm^^); ^H NMR (CDCI3)

6 1.30-2.40 (m, 12 H), 2.98 (m, 4 H), 4.25 (m, 1 H).

138b: bp 155-158°, 155 mm; ^H NMR (CDCI3) 6 1.30-2.60 (m, 14 H)

2.93 (m, 4 H), 4.40 (m, 1 H ) .

58

Alkylation of 138a

The procedure of Stork^^ was used. In a 500 mL round-bottomed

flask fitted with a condenser fitted with a calcium chloride drying

tube, 65 g of the pyrrolidine enamlne of cyclohexanone, 65 mL of

ethyl a-bromo protionate, and I50 mL of dry MeOH were refluxed for

24 h. Then 20 mL of water was added through the condenser and the

reflux continued for one h. The solvent was removed by a rotary

evaporator. The resulting oil was extracted with ether three times.

The ether layers were washed with water and then brine. Drying of

the ether layers with magnesium sulfate and removal of the ether

gave a liquid which was vacuum distilled through a short, vacuum-

jacketed Vigreux column to give 40 g (51%, bp 160-162° C, 58 mm; QQ

lit. 130-131°, 10 mm ^) of 139a as a 1:1 mixture of diastereomers

that was not separated.

• ^H NMR (CDCI3) 6 0.90-3.00 (m, 12 H ) , 3-58 (s, 3 H ) , Alkylation of 138b

In a 250 mL round-bottomed flask fitted with a calcium chloride

drying tube, 18.4 g of the pyrrolidine enamlne of cycloheptanone,

100 mL of dry acetonitrile, and 14.5 mL of ethyl 2-bromopropionate

were refluxed for 72 h. Then, 25 mL of water was added through the

condenser and the solution refluxed for another hour. The solvent

was removed by a rotary evaporator. The resulting oil was extracted

with ether three times. The ether layers were washed with water and

then brine. Drying of the ether layers with magnesium sulfate and

removal of the ether gave a liquid which was vacuum distilled through

a short, vacuum-jacketed Vigreux column to give 13.4 g of the keto

ester I39b (bp 168-170°, 45 mm).

^H NMR (CDCI3) 6 0.98-3.00 (m, 18 H) , 4.05, 4.08 (2 q, J=7 Hz, 2 H).

59

Hydrolysis of the Esters 139a and 139b

The esters were stirred with 5% aqueous KOH at 25° until complete

solution was obtained. Then the basic solution was extracted with

one portion of ether. This was followed by acidification to a.

pH 3 with HCl. The aqueous solution was extracted with ether and

the ether layers combined and dried with ma^esium sulfate. The

solvent was removed to give an oil which solidified upon standing.

Both l40a and I40b were used in the next step without further

purification.

Cyclization of the Acids I40a and 140b

The appropriate acid was refluxed in acetic anhydride (50 mL

per 50 mM of acid) for 48 h. Then the acetic anhydride was

distilled away and the remainder distilled through a short, vacuum-

jacketed Vigreux column to give 102 (clear liquid, bp 124-125°, 1.75

mm; lit. 133-134°, 3 mm''- ) or 108 (clear yellow liquid, bp 120-122°,

0.25 mm).

107: IR (neat between salt plates) 293^, 2858, 1743, and 1680 cm"

^H NMR (CDCI3) 6 0.94-2.98 (m, 8 H ) , 1.80 (s, 3 H) , 4.60 (m, 1 H).

108: IR (neat between salt plates) 2932, 2858, 1743, and I67O cm"

^H NMR (CDCI3) 6 1.05-2.74 (m, 10 H) , 1.79 (s, 3 H) , 4.85 (m, 1 H) .

The compounds proved to be > ^7fo pure by capillary GLPC (Varian

3700 FID gas chromatograph operating 200-250° C; 0.20 mm X 25 m

vitreous silica column with 25QC2/SE-30 stationary phase from S. G.

E.). Product yields are reported uncorrected for molar response.

60

DIBAL Reduction of 108

To a solution of 108 (450 mg) in dry THF (5 mL) was added 2 mL of

25 weight % DIBAL (in toluene) with stirring at -24° C. The mixture

was stirred at -24° for 1.5 h. Then, 5.5 mL of 2 N sulfuric acid was

added and the mixture stirred at 0° for 0.5 h. The mixture was then

added to ice water and the water extracted with ether. The ether

layers were combined and washed with 5% aqueous sodium bicarbonate,

water, and brine. The solution was dried with magnesium sulfate and

the solvent removed to give an oil which was chromatographed to give

215 mg of 76b and I52 mg of starting material. The presence of the

furan ring was shown in the H NMR by the aromatic proton signal at

6 7.18.

Oxidation of 76b with Selenium Dioxide

The furan (215 mg) was dissolved in 7 mL of a solution of dioxane/

acetic acid/water (15:4:1) and refluxed with I50 mg of selenium

dioxide for 11.5 h. The solution was decanted from the precipitated

selenium and the flask rinsed with ether. The solutions were combined

and the solvents were removed by rotary evaporator. The resulting

solids were extracted with ether. The ether layers were combined and

washed with 5% aqueous sodium bicarbonate, water and brine. The

solution was dried over magnesium sulfate and the solvent removed to

give an oil which was chromatographed over silica gel. Elution with

ether/pet ether (15:85) gave a solid which was recrystallized (ether)

to give 59 mg of 149.

149: mp 109.5-110,5° G; IR (film between salt plates) 3375, 2932,

2858, 1739, and 1674 cm""'"; "H NMR (CDCI3) 6 1.04-2.68 (br, 10 H), 1.77

(s, 3 H), 4.54 (br, 1 H).

61 Oxidation of 108 with Selenium Dioxide

Selenium dioxide was prepared by sublimation. Selenous acid was

heated in a beaker on a hot plate until the water was driven off. Then,

a watch glass was placed on top of the beaker and the selenium dioxide

formed as thin needles on the watch glass and the upper portions of the

beaker. These needles were collected and stored in a bottle in a

desiccator until needed.

Compound 108 (414 mg) was dissolved in a solvent mixture of dioxane/

acetic acid/water (15:4:1) and refluxed with 277 mg of selenium dioxide

for 66 h. The solution was decanted from the solids in the flask and

the solids were washed with a portion of ether. The solutions were

combined and evaporated on a rotary evaporator. This caused more

material to precipitate. The solids were extracted with three portions

of ether and the three portions were combined and washed with several

portions of 5% aqueous sodium bicarbonate, one portion of water, and

one of brine. The solution was dried over magnesium sulfate and the

solvent removed to give 383 mg of an oil which was chromatographed

over silica gel. Elution with ether/pet ether (25:75) gave 115 mg

of a crude solid which proved to be 148.

148: mp 68-69° C; IR (film between salt plates) 3423, 2930, 2858,

1730, and 1672 cm"-'-; H NMR (CDCI3) 6 1,20-2,92 (br, 9 H), 1,87 (s, 3 H ) ,

4,88 (br t, J ca, 4 Hz, 1 H ) , 5.01-5.21 (br, 1 H).

REFERENCES

lo Sutherland, M,D,; Park, R.J, In "Terpenoids in Plants"; Pridham, J.Po, Ed,; Academic Press: New York, 1967; p 147,

2, Kupchan, S,M,; Shizirri, Y,; Baxter, R.L,; Haynes, H,R,, J_, Org, Ghem. 1977. 42, 3^o

3, The numbering system used here is taken from Kupchan's paper (ref, 2), This appears to be the most common system of numbering the guaianolides; however, in some papers and reviews the C-14 and C-15 methyls will be reversed,

4, Asakawa, Y.; Toyota, M,; Takemoto, T, Phytochem. 1981, 20, 257.

5, Herout, V,; Sorm, F, Collecto Czech, Ghem, Commun, 1953, 18, 854,

6, Geisman, T,A.; Winters, T,E. Tet, Lett, 1968, 3145,

7, Herout, V,; Sorm, F. Collect. Czech, Chem, Commun. 1954, 19, 792.

8o Vokac, K,; Samek, Z,; Herout, V.; Sorm, F. ibid. 1969, , 2288.

9„ Vokac, K.; Samek, Z.; Herout, V.; Sorm, F. ibid, 1£72, J2, 1346,

10. Romo, J,A.R, de V,; J.-Nathan, P. Tetrahedron 1967, |^, 29.

11. Herz, W.; Sudarranam, V.; Schmid, J.J. J. Or^. Chem. 1966, , 3232,

12. Anderson, G.D.; McEwen, R.S.; Herz, W. Tet. Lett, 1972, 4423.

13. Barton, D,H,R,; Pinhey, J,T, Proc, Ghem, Soc, I960, 279.

14. Barton, D,H,R,; Pinhey, J,T,; Wells, R,J, J, Chem, Soc, 1964, 2518,

15. Hamilton, J,A.; McPhail, A.T.; Sim, G.A. Proc. Chem. Soc. I960 278.

16. Bohlmann, F.; Suwita, A. Phytochem. 1979, 1^, 885.

17. Samek, Z.; Holub, M.; Drozdz, B,; Grabarczyk, H, Collect, Czech, Chem. Commun, 1977, 42, 2217.

18o Herz, W.; Govindan, S,V,; Bierner, M.W,; Blount, J,F, J, Org., Ghem,

1980. 4^, 493.

19, Herout, V. In "Aspects of Terpenoid Chemistry and Biochemistry (Proceedings of the Phytochemical Society Symposium, Liverpool, April, 1970)"; Goodwin, T.W., Ed.; Academic Press: 1971; P 53-94 and references therein.

20. Geismann, T.A.; Grout, D.H.G. "Organic Chemistry of Secondary Plant Metabolism"; Freeman, Cooper, and Co.: San Francisco; I969.

62

63

21. Fischer, N.H.; Olivier, E.J,; Fischer, H.D. In "Progress in the Chemistry of Organic Natural Products, #38"; Herz, W.; Grisebach, H.G.; Klrby, G.W., Eds.; Springer Verlag: New York; 1979; P 47-390.

22. Cordell, G.A. Ghem. Rev, 1976. 6, ^25.

23. Geissman, T,A, In "Recent Advances in Phytochemistry, V,6"; Runechler, V.C; Mabry, ToJ., Eds,; Academic Press: New York; 1973; P 65.

24. Richards, J.H,; Hendrickson, J.B. "The Biosynthesis of Steroids Terpenes, and Acetogenins"; W.A, Benjamin, Inc: New York; 1964,

25. Herz, W. Isr. J. Chem. 1977, 1^, 32.

26. Hanson, J.R. In "Comprehensive Organic Chemistry, V.5"; Barton, D.H.R., Ed,; Pergammon Press: New York; 1979; P 989-1023,

27. Nes, W,R,; McKean, M,L. "Biochemistry of Steroids and Other Isopentenoids"; University Park Press: Baltimore, London, Tokyo; 1977.

28. "Biosynthesis of Isoprenoid Compounds, V,I"; Porter, J,W,; Spurgeon, S,L,, Eds,; Wiley: New York; 1981,

29. Naya, K,j Kanazawa, R,; Sawada, M, Bull, Chem, Soc. Jap, 1975, ^ , 3220.

30. Naya, K,; Nogi, N,; Makiyama, Yo; Takashina, H,; Imagawa, T, Bull, Chem, Soc. Jap. 1977, ^ t 3002,

31. Pinder, A.R. In "Progress in the Chemistry of Organic Natural Products, #34"; Herz,W.; Grisebach, H.; Kirby, G.W., Eds.; Springer Verlag: New York; 1977; P 81-186.

32. Archer, J.D.; Sim, G.A. Proc. Chem. Soc. 1962, 111,

33o Barton, D.H.R.; Miki, T.; Pinhey, J.T.; Wells, R.J, Proc. Chem. Soc. 1962, 112.

34, Barton, D.H.R.; Levisalles, J.E.B.; Pinhey, J.T. j;. Ghem. S^c. 1962. 3^72.

35, Marshall, J.A.; Wuts, P.G.M. j;. Or^. Ghem. 1978, 4^, IO86.

36, Abe, Y.; Harukawa, T,; Ishikawa, H.; Miki, T.; Sumi, M,; Toga, T, J, Am, Chem, Soc. 12^6, 21 1^22.

37, Edgar, M.T.; Greene, A.E.; Crabb^, P. J, Or£, Chem, 1^79, , 159.

38, Suchy, M,; Herout, V.; Sorm, F, Collect, Czech, Chem, Commun,

1964, 29, 1829.

39, Marx, J,N.; McGaughy, S,M, Tetrahedron 19.72, 28, 3583.

40, White, E,H,; Eguchi, S,; Marx, J,N, Tetrahedron 1262, 2^, 2099.

41, White, E,H,; Eguchi, S,; Marx, J,N, Tetrahedron I969, 2^, 2117.

42, Barton, D,H.R, ; Levisalles, J,E,D, ; Pinhey, JoT, J, Ghem Soc. * 1962, 3^72.

43, Kropp, P.J. In "Organic Photochemistry V.l"; Chapman, O.L., Ed.; Marcel Dekker: New York; I967.

^ . Caine, D.; Gupton, J . T . , I I I J , Or^, Chem. 1975. 40, 809„

^ 5 . P i e r s , E„; Cheng, K.F. Can. J . Chenio 1970. 48, 2234.

46. Caine, D.; Ingwalson, P.F. J . Or^. Chem. 1972. ^ , 3751.

" ^ 1969!'9l''64f^^^''^' '' ^^""^^^^^^^^ J-V- I' Am7chem. Soc.

48. Heathcock, C.H.; Ratcliffe, R. J. Am, Chem. Soc. 122L» 21, 17^6,

49. Marshall, J.A. ; Partridge, J.J. J. Am. Chem. Soc, 1968,^, 1090,

50. Marshall, J.A.; Partridge, J.J. Tetrahedron 1969, 2^, 2159.

510 Posner, G.H., Babiak, K.A., Loomis, G.L., Frazee, W7J.; Mittal, R,D.i Karle, I.L. J. Am. Chem. Soc. I98O, 102. 7498.

52. Termont, D,; De Clerq, P.J.; De KeukeleireT^,; Vandewalle, M. S.ynthesis. I977. 46.

53. Deveresse, A.A.; De Clerq, P.J.; Vandewalle, M. Tet. Lett. 1980. 21_, 4767.

54. Liu, H.J.; Lee, S.P. Tet. Lett. I977, 3699.

55* Winter, R.E.K.; Lindauer, R.F. Tetrahedron 1976. J^, 955,

56, Yoshioka, H.; Mabry, T.J.; Hlgo, A. J. Am. Chem. Soc. 1970. 22, 923.

57o Brown, E.D.; Sutherland, J.K. Chem, Commun, I968. IO60,

58, Govindachari, T,R,; Joshi, B.S,; Kamat, V.N. Tetrahedron 1965. 11,1509.

59, Ogura, M.; Cordell, G.A.; Farnsworth, N.R. Phytochem. 1978. 17. 957. =^

60, Fukui, T. Yakugaku Zasshi I958, 78, 712.

61, Gonz^ez, A,G,; Galindo, A,; Mansilla, H, Tetrahedron, 1980, J6, 2015.

62, Greene, A.E. Tet. Lett. 1978, 85I.

63o Greene, A.E. J , Am. Chem. Soc. 1980, 102, 5337.

64. Corbella, A,; Gariboldi, P.; Jommi, G.; Orsini, F.; Ferrari, G. Phytochem. 1974, 1 » 59»

65* Biichi, G.; Kaufman, J.M.; Loewenthal, H.J.E. J.. Am, Ghem. Soc. 1966. 88, 3^03.

66, Ramsey, H.D. "Synthetic Approaches Toward Dihydrodamsin and Gnididione"; Ph.D. Dissertation, Texas Tech University, 1980.

6I0 Clive, D.L.J. Tetrahedron 1978, J4, 1049.

68, Grieco, P.A.; Miyashita, M. J, Or^, Chem, 1974. J2» 122,

69, Andrieurx, J,; Barton, D.H.R.; Patin, H. iJ, Ghem, Soc,. Perk, Trans, 1977. 4, 359.

70. Minato, H,; Nagasaki, T. J, Chem, Soc, (C.) I966, 1866,

71. Minato, H,; Nagasaki, T, Chem, Ind, I965, 899.

65

72, Minato, H.; Nagasaki, T. J. Chem. Soc. Ghem, Commun. I965, 377.

73, Minato, H,; Nagasaki, T. J, Chem. Soc. (C_) I966, 377,

74, MinatOj H„; Nagasaki, T. J, Chem. Soc. (c) I968, 621. 750 "The Use of Aluminum Alkyls in Organic Synthesis''; Brochure

review published by the Ethyl Corporation| Baton Rouge; 1971} P 23, 31.

16. Winterfeldt, E. Synthesis 1975, 617.

77. Danieli, N.; Mazur, Y.; Sondheimer, F. Tet. Lett. I962, 1281.

78. Kahler.Arch. Pharm. I83O. j^, 3I8.

79. Cannizzaro, S.; Fabris, G. Ghem. Ber. 1886, l£, 2260.

80. Woodward, R,B.; Yates, P. Chem. and Ind. I954. I3I9.

81. Woodward, RoB.; Brutschy, F,J.; Baer, H. J, Am. Chem, Soc. 1948, 20, 4216. " •" " ^

82. Corey, E.J. J_. Am. Chem. Soc, 1955. 2Z» 1 0 ^ .

83. Barton, D.H.R.; de Mayo, P.; Shafiq, M. J. Chem. Soc. 1957, 929.

84. Kropp, P.J.; Erman, W.F. J_. Am. Ghem. Soc. I963, 8^, 2456.

85. Kropp, P.J. J. Am, Ghem. Soc. I963. 8|, 3779.

860 Kropp, P.J, j;. Am, Ghem. Soc. 1964, 86, 4053.

87. Kropp, P.J. J. Org. Chem. 1964, 22, 3110.

88. Kropp, P.J. In "Organic Photochemistry"; Chapman, O.L., Ed,; Marcel Decker: New York; I967.

89. Shaffner, K, In "Advances in Photochemistry, V. 4"; Noyes, W.A., Jr.; Hammond, G.S.; Pitts, J.N., Eds.; Interscience; New York; 1966.

90. Zimmerman, H.E. In "Advances in Photochemistry, V. 1"; Noyes, W.A., Jr.; Hammond, G.S.; Pitts, J.N., Eds.; Interscience: New York; 1963.

91. Cowan, D.O.; Drisko, R.L. "Elements of Organic Photochemistry"; Plenum Press: New York, London; 1976.

92. Loewenthal, H.J.E. In "Protective Groups In Organic Chemistry"; McOmie, J.F.W., Ed,; Plenum Press: New York and London; 1973; PP 323-402.

93. De Leeuw, J.W,, et. al. Reel. Trav. Chim. Pays-Bas 1973, 2|» 1047.

94. Meskens, A.J. Synthesis 1981, 501.

95o Evans, D.A.; Truesdale, L.K.; Grimm, K.G.; Nesbitt, S.L. J. Am. Chem. Soc. 1977, 22» 5009.

96. Greene, T.W. "Protective Groups in Organic Synthesis"; John Wiley & Sons: New York; I98I.

97. Node, M.; Nishide, K.; Ochiai, M.; Fujita, E. J. Or^. Chem. ' 1981, , 5163.

66 98. Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, , 3899.

99. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. I963, 8^, 207.

100. Noyori, R.; Tsunoda, R.; Suzuki, M. Tet. Lett. I98O, 21, 1357.

101. Krishnamurthy, S,; Brown, H,C, j;. Org, Ghem. I975, 40, 1864.

102. Krishnamurthy, S.; Brown, H.C. £. Org. Chem. I977, 42, 1197,

103. Cocker, W,; Homsby, S. J, Ghem, Soc, 1947, 1157,

104. Corey, E,J.; Venkateswarlu, A. J. Am, Chem, Soc, 1972, 2^, 6I9O,

105. Karwe, M,V, ; Deshpande, N,R.; Hiremath, S,V,; Kulkami, G.H.; Kelkar, G.R. Ind. J. Chem. (B) 1978, 1^, 539.

106. Cramer, R. Ace. Chem. Res. I968, 1, 186.

107. Brown, H.C. "Boranes in Organic Chemistry"; Cornell University Press: Ithaca and London; 1972; p 240.

108. Carruthers, W, "Some Modem Methods of Organic Synthesis, 2nd Ed,"; Cambridge University Press: London, New York, Melbourne; 1978; p 3^3.

109» Goldman, I,M, j;. Org. Ghem, I969, , 1979.

110. Craig, J,C, ; Homing, E.G. J, Org, Chem. I96O, 2^, 2098.

111. March, J. "Advanced Organic Chemistry, 2nd Ed."; McGraw-Hill: New York; 1977; P 1107.

112. McKillop, A.; Young, D.W. S.yn thesis 1979, 401.

113. Shaw, B.L.; Tucker, N.I. In "Comprehensive Organic Chemistry, V. 4"; Bailar, J.C. , Jr.; Emeleus, H.J.; Nyholm, Sir R.; Trotman-Dickenson, A.F., Eds.; Pergamon: Oxford, New York, Toronto, Sydney, Braunschweig; 1973; P 892.

114. ref. Ill, p 1101.

115. Rao, Y.S. Ghem. Rev. 1964, , 353-

116. Rao, Y.S. Chem. Rev. 1976, 26, 625.

117. ref. 108, p 272.

118. Murray, T.F.; Varma, V.; Norton, J.R. J_, Am. Chem. S_oc. 1977,

22, 8085. 119. Murray, T.F.; Norton, J.R. J_. Am. Chem. Soc. 1979, lOj, 4107.

120. Greene, A.E.; Muller, J.-C; Ourisson, G.; J. Org. Ghem. 1974,

J2, 186. 121. Nakazake, M.; Naemura, K. Tet. Lett. I966, 2615.

122. Harrod, J.F.; Chalk, A.J. J. Am. Chem. Soc. 1964, 86, 1776.

123. Harrod, J.F.; Chalk, A.J. J. Am. Chem. Soc. 1966, 88, 3491.

124. Cramer, R. J.. Am. Chem. Soc. I966, 88, 2272.

67 125. Trachtenberg, E.N. in "Oxidation, V. 1"; Augustine, R.L. , Ed.;

Marcel Dekker: New York; 1969; P 119.

126. ref. Ill, p 713.

127. ref. 108, p 424.

128. Rabjohn, N. Org. Reactions 1949, i, 331.

129. Rabjohn, N. Org. Reactions 1976, 24, 261.

130. Elderfield, R.C.; Dodd, R.N., Jr. in "Heterocyclic Compounds, V. 1"; Elderfield, R.C., Ed.; Wiley: New York; I95O; p 119.

131. Bosshard, P.; Eugster, G.H. in "Advances in Heterocyclic Chemistry, V. 7"; Katritzky, A.R.; Boulton, A.J., Eds.; Academic Press: New York and London; I966; p 377,

132. Dunlop, A,P,; Peters, F,N. "The Furans"; Reinhold Publishing Corporation: New York; 1953,

133. Livingstone, R, in "Rodd's Chemistry of CarbOn Compounds, V. IV, Part A"; Coffey, S,, Ed,; Elsevier Scientific Publishing Company: Amsterdam, London, New York; 1973; p 83.

134. Sargent, M.V.; Cresp, T.M. in "Comprehensive Organic Chemistry, V. 4"; Barton, D.; Ollis, W.D., Eds.; Pergammon Press: New York; 1979; P 693.

135. Pinder, A.R. in "Progress in the Chemistry of Organic Natural Products, #34"; Herz, W.; Grisebach, H.G,; Kirby, G.W., Eds,; Springer Verlag; New York; 1977; P 81.

136. Jerussi, R,A, in "Selective Organic Transformations"; Thya-garajan, B.S,, Edl; Wiley-Interscience: New York; 1970; p 301.

137. Heathcock, G.H. in "The Total Synthesis of Natural Products, V. 2"; ApSimon, J., Ed.; John Wiley & Sons: New York; 1973; P 197.

138. Danieli, N.; Mazur, Y.; Sondheimer, F. Tetrahedron I967, 2^, 715.

139. Vogel, A.I. "Practical Organic Chemistry, 3rd ed."; Longman: London; 1956; p 189.

140. Fatiadi, A.J. Synthesis 1976, 65 and 133.

141. Unpublished results of D. Lundberg.

142. Brown, J.M. Chem. and Ind. 1982, 737.

143. Trebellas, J.C; Olechowski, J.R.; Johassen, H.B.; Moore, D.W. J. Organometallic Chem. 1967, 2» 153.

144. Pratt, E.F. ; Van De Castle, J.F. £. Org. Chem. I961, 26, 2973-

145. Attenburrow, J.; Cameron, A.F.B.; Chapman, J.H.; Evans, R.M.; Hems, B.A.; Jansen, A.B.A.; Walker, T. J. Chem. Soc. 1952, 1094.

146. Fieser, L.F.; Fieser, M. "Reagents for Organic Synthesis, V. 1"; Wiley: New York; I968; p 583.

147. Rawlinson, D.J,; Sosnovsky, G. Synthesis 1973, 567.

148. ref. 108, p 335.

APPENDIX: IR AND "H NMR SPECTRA

68

69

IR and H NMR Spectra of 30

/\ /V h

JL

^600 4000 S^OO 2800 2200 1800 ISOO 1200 dOO 600 tQO WpVENUMBERS f Crl-11

IR and ^H Nm Spectra of 58 70

OH

i i

I J^ A_J ' ^ w ^ J U — * -^

• I I ' ' • • • I • • • • ' • ' • • • • • • • • • ' ' • • • I • • ' • T I • I . . • 1 . I • T 1 • T • I I • I I • • . I I i • • • 1 • 1 1 T • ' • • • • « . . 1 - — - • ' • • • • • • • • j _ ^ _ . I . . • • • • • . . I . .——~-i-

CD .

UJ CVI . o —• <c tZ a x: — % t— CD

U>

<«•

CVi

.

\

'

• > • >

r\ \

'

1

'

1

» » 1 1 '

°4600 -lOOO 9400 E800 ESOO 1800 iSOO I ZOO 900 600 -lOO

wfiVENuneeos ccn-ii

IR and H NMR Spectra of 89 71

' • ' • 1 • • • •, . ' • • • > ' ' I ' i' * •' 'i' '' M ' I ' • ; ' ' ' 'i' ' * ' 'i ' * ' ' I ' * ' 'I'.'.'.'.'i','.'.! I !.',',' i' .'.'.'I'l'AA-'. H'. I ! •' f f* . I I I i I • 1 I 1 . I I • 1 I . I I 1 I I t • I I • • I I • I 1 I • I I I 1 I 1 I I I 1 1 r i I I I I I I I I I I I 1 I I I I I I I I I I I I I I I I 1 I

«4600 ^OOO a^OO 2BOO Z200 1800 ISOO 1200 900 600 -lOO KiavENunaens c en-11

72

1

IR and H NMR S p e c t r a o f 59

% 6 0 0 -4000 3 4 0 0 2800 E200 1800 ISOO 1200 800 600 -IQO wpveNuriBEfis (cti-11

73

IR and H NMR Spectra of 60

ii P •iMiiiW>> mm*i'm^»t0m09»'i\/\»t,ftm»%P' V-O

••600 40QO 3400 280Q 2200 1800 ISOO 1200 SOO 600 400

wpivENUneens (en-11

74

IR and -H NMR Spectra of 62

«46ao' 4Doa 3400 zeao 2200 looo isao 1200 SOD SQO IQO WpV£NU{18£PS C C n - 1 1

.. 1 15

IR and H NMR Spectra of 1 ni

TBDMSO

4600 4000 3400 2800 2200 1800 tSOO 1200 800 600 •«nn kif^VENUriaEBS (CM-11

IR and ^H NMR Spectra of 103 16

TBDMSO

i<.VI>, >M'**>'

Q

N W * * N H M I ^

4600 4000 3400 2800 2200 1800 tSOO 1200 800 600 400 Wf^VENUMBEftS CCn-l)

77

IR and ^H NMR Spectra of 10 7

J f.

_rv.

J 1

Q Q NICQLET S-tlX 1/ 1/80 Os 0» O

°4600 4000 340Q 2800 220Q ISOO ISOQ 1200 30O 600 ^OQ WPVENUMBEPS (CM-I^

78

IR and H NMR Spec t ra of lOS

___i. „__! I L_

•4S00 40nrj 3400 20no 22nn lent i i^-Lin ic-.tji' H'.ll o l ) » i , . l l

79

•I

IR and ^H NMR Spec t ra of 148

A/L * I i I . i . i . A A. A i i i t I t t- i. A. i . I • I I . i . . • , . . . T • t „ • * f

*^4SOO 4QOO 3 4 0 Q 2 8 0 0 2 2 0 0 1SDO ISDQ \Zaa 9 0 0 SCO ^QQ

80

IR and - H NMR Spec t ra of 149

lil9

i<t>y>»v^^vy>VV«^A/V^^t*'*'w

_L I u. _ l ^ I ^ .i i.^ L i J i l i t i i l i ' t i - . - . - i l

^4600 4000 3-100 2800 2200 1800 ISOO 1200 SOO 600 400

4BUU 4UU wf,vENUneEns (cn-t)

IR Spectra of 147 and 134

81

4 6 0 0 4 0 0 0 S 4 0 0 2 8 0 0 2 2 0 0 ISOO ISOO 1 2 0 0 BOO Wp»VENUt1BEBS CCtl-11

BOO 400

= 4600 4000 34DO 2800 2200 18DO ISDO 1200 SOO 6DO 400 WpVENUtlBERS f Cti-11

IE Spectra of 99 and 100 82

-I600 4000 3400 2800 2200 ISOO ISOO 1200 BOO 600 400 WftVENUMBEBS CCM-l)

O NICOLET S-nX X/" 1/80 0» Os O

to .. to

C\J . . to

y

CD

in

in

V v w " - ^ " ^ ^

£ in "f

a:.

S5 "

C<J .

CD CO

CO

O < I I » . I t > I I I I « I ' « ' ' t »l I I

4600 4000 3400 2800 2200 I SOO ISOO 1200 SOO 600 400 WpiVENUMBEPS (CM-H

IR Spectra of 98 and 61

33

•4600 4000 3400 2800 2200 1800 ISOO 1200 BOO 60O 400 WPVENUMBEPS (CM-11

*^4600 4000 3400 2800 2200 1800 ISOO 1200 900 SOO 400 WnVENUhBEBS C Cti-11