chapter-i - inflibnetshodhganga.inflibnet.ac.in/bitstream/10603/8220/9/09_chapter 1.pdf · such...

Chapter-I

A Flexible Enantioselective Total Synthesis of Diospongins A, B and their

Enantiomers Using Catalytic Hetero-Diel-Alder/Rh-catalyzed 1,4-Addition

and Asymmetric Transfer Hydrogenation Reactions as Key Steps.

Chapter I: A Flexible Enantioselective Total Synthesis of Diospongins A, B

and their Enantiomers Using Catalytic Hetero-Diels-Alder/Rh-catalyzed

1,4-Addition and Asymmetric Transfer Hydrogenation Reactions as Key

Steps.

Introduction

Cyclic ethers are a distinct class of molecules that are highly prevalent in nature. Many

such compounds, specifically those containing 2,6-disubstituted terahydropyran ring systems,

have been produced by microscopic living organisms.1 A variety of terahydropyran ring

systems have been isolated, slightly modified, and recognized as potential aids in the clinical

world. 2,6-disubstituted THPs are also synthetically useful intermediates in the production of

polysubstituted tetrahydropyran ring systems, such as those found in the pseudomonic acids

which are commonly used in skin antibiotics to fight infections including Staphylococcus

epidermidis.2 The wide variety of important applications of tetrahydropyran scaffolds

3 in the

biomedical world has made their synthesis a widely explored topic of research. Hence,

considerable attention has been focused on development of an efficient and stereocontrolled

synthetic routes to these key structural fragments.

Our group has embarked on the total synthesis of the substituted tetrahydropyran motif

containing natural products. It is worthwhile at this juncture to look briefly at a few

substituted tetrahydropyran molecules, which have been of paramount importance due to

their significant biological activity and also to the researchers who have been actively

involved in the synthesis of these natural products.

Phorboxazoles:

Phorboxazole A and B are the marine natural products isolated from a species of Indian

Ocean sponge (genus Phorbas sp.). Searlae and co-workers reported the isolation,

preliminary structural assignments and the results of initial bioassay of the phorboxazoles in

1995.4 Phorboxazole A is a C13 epimer of phorboxazole B. The complete structural

assignments for phorboxazoles A and B have resulted from the extensive NMR studies,

derivatisation and degradation-correlation studies. These substances were reported to be

extremely cytostatic towards the 60 tumor cell lines and having potent in vitro anti-fungal

activity against C. albicans and S. carlsbergensis. The complex and unique structures make a

distinction the phorboxazoles as a new class of natural products and they contain

unprecedented array of oxane, oxazole, polyene and macrolide moieties. The broad range of

activity against human cancer cell lines combined with cytostatic activity, structural novelty,

and limited availability make the phorboxazoles as important and challenging synthetic

targets (Figure 1).

O

OHMe

OMe

Br

OMe

O

NMe

O

Me

O

Me

N

O

O

X

Y

O

O

OH

Phorboxazole A: X = OH, Y = H Phorboxazole B: X = H, Y = OH

Figure 1, Phorboxazole A and B

(-)-Ratjadone:

In 1994, the polyketide ratjadone was isolated from cultures of Sorangium cellulosum strain

Soce360.5 Ratjadone displays potent in vitro antifungal activity with MIC values in the range

from 0.004 to 0.6 g/mL for Mucor hiemalis, Phytophthora drechsleri, Ceratocystis ulmi and

Monilia brunnea. Additionally, significant cytotoxicity in mammalian L929 cell lines (IC50

= 0.005 ng/mL) and Hela cell line KB3.1 (IC50 = 0.04 ng/mL) has been demonstrated6

(Figure 2).

O

OHO O

OH

Figure 2, (-)-Ratjadone

(-)-Zampanolide and (-)-Dactylolide:

In 1996 Higa and co-workers,7 isolated zampanolide (Figure 3) a novel macrolide that

exhibited significant activity against a variety of tumor cell lines. In particular, zampanolide

has proven to be active against the P388, A549, HT29 and MEL 28 cell lines with IC50

values ranging from 1 to 5 ng/mL.7 However, extensive biological tests have not been

performed because of the lack of material, as only 3.9 mg were isolated from 0.480 kg (wet

weight) of the marine sponge Fasciospongia rimosa. Riccio isolated a structurally related

compound, dactylolide (Figure 4) from the marine sponge Dactylospongia.8 However,

dactylolide only displayed a modest biological profile (63% and 40% inhibition of L1210 and

SK-OV-3 tumor cell lines at 3.2 g/mL) with respect to that of zampanolide, thus suggesting

that the N-acyl hemiaminal side-chain resident in zampanolide is required for the impressive

biological activity.

O

OO

OH

NH

OO

O

OO

OO

Figure 3, (-)-Zampanolide Figure 4, (-)-Dactylolide

(-)-Lasonolide A:

Lasonolide A, was isolated from shallow water Caribbean sponge; species of Forcepia.9 It

shows a potent activity against A-549 human lung carcinoma. Lee’s seminal synthetic work

included a correction of the structure and a reassignment of the absolute configuration.10

Lee

prepared the tetrahydropyran scaffold of lasonolide through a cyclisation with silyl ether.

Later, several other groups have synthesized the tetrahydropyran core of lasonolide A.11

Lasonolide A’s interesting structure, potent anticancer-activity and natural scarcity have

made it an attractive target for synthetic chemists (Figure 5).

O

OH

O

O

HO

OO

O

OH

Figure 5, (-)-Lasonolide A

(-)-Kendomycin:

(-)-Kendomycin, a novel macrocyclic polyketide first isolated in 1996 from Streptomyces

violaceoruber, possesses potent activity as both an endothelin receptor antagonist and an anti-

osteoporotic agent.12

Reisolation by the Zeeck group13

revealed, in addition, significant

antibacterial activity against multiresistant bacteria, including vancomycin–resistant strains

and remarkable cytotoxicity against a series of human tumor cell line (GI50 < 0.1 M). The

impressive biological profile, in conjunction with the challenging architecture, defined by X-

ray and Mosher ester analysis, triggered considerable synthetic efforts,14

culminating in 2004

with the first total synthesis.15

The structure of kendomycin comprises a unique quinone-

methide-lactol chromophore, attached to a densely substituted tetrahydropyran ring in

addition to an aliphatic ansa ring (Figure 6).

HO

O

O

O

HO

OH

Figure 6, (-)-Kendomycin

Polycarvernoside A:

Polycarvernoside A, a toxin isolated from the red alga Polycavernosatsudai.16

It is an unusual

13-membered macrolactone disaccharide assembled on a tetrahydropyran core bearing four

substituents each in an equatorial position (Figure 7). Three total syntheses of

polycarvernoside A have been achieved which utilize either a 6-epoxy cyclization of

protected trihydroxy-α,β-unsaturated esters17

or manipulation of a δ-lactone to construct the

THP core.18

A further valuable approach for the preparation of variously substituted THPs is

the acid-promoted Prins-type cyclization of an oxycarbenium ion generated in situ, from the

reaction of a homoallylic alcohol with an aldehyde or from a homoallylic acetal or α-acetoxy

ether. A number of reaction conditions have been employed to prepare C4 oxygenated THP

ring.19

O O

O

OO

O

HO

O

OMe

O

MeO

OMeOMe

OMe

Figure 7, Polycavernoside A

(+)-Neopeltolide:

(+)-Neopeltolide, is a marine macrolide belongs to the family Neopeltidae, and was isolated

by Wright et al. from a deep-water sponge collected off the northwest coast of Jamaica.20

Neopeltolide exhibits highly potent in vitro anti-proliferative activity against several cancer

cell lines with nano molar concentration (IC50 = 1.2, 5.1, and 0.56 nmol L-1

against the A-549

human lung adenocarcinoma, the NCI-ADR-RES human ovarian sarcoma, and the p388

murine leukaemia cells, respectively). Additionally, it also shows as potent antifungal activity

against pathogenic yeast Candida albicans. Kozmin and co-workers reported that

neopeltolide targets cytochrome bc1 complex and may inhibit mitochondrial ATP syntheses.21

The key structural features of neopeltolide include a 14-membered macrolactone ring,

containing a trisubstituted tetrahydropyran ring, and an oxazole-bearing unsaturated side

chain appended at C5 through an ester linkage. The complex macrolide structure and potent

biological activity of neopeltolide have stimulated a flurry of synthetic interest; as a result a

number of total syntheses 22

have been reported (Figure 8).

O

O

OO Me

OMe

Me

O

N

O

H H

HN

OOMe

1

5

9

13

Figure 8, (+)-Neopeltolide

(+)-Ambruticin:

Ambruticin is a novel antifungal agent that was isolated from fermentation extracts of the

myxobacterium Ployangium celluosum by Warner-lambert et. al. in 1977.36

It exhibits

pronounced activity against systemic medical pathogens such as Coccidioides immitis,

Histoplasma capsulatum, and Blastomyces dermatitidis.23

It is also displays potent inhibitory

activity against the yeast strain Hansenula anomala with an MIC of 0.03 µg/mL.24

The

relative stereochemistry of ambruticin have been established through a combination of

spectroscopic studies,25

chemical degradation, and single-crystal X-ray analysis.26

This

structurally intriguing molecule incorporates 10 stereocenters and 3 E-olefins within a

relatively small framework bearing a dihydropyran, a tetrahydropyran diol, and a

trisubstituted divinylcyclopropane unit unique to this family of natural products (Figure 9).27

The important structural features and potentially valuable biological activities have

stimulated considerable interest in the synthetic community28

and to date three total syntheses

have been reported.20-31

O

OH

OH

MeMe Me

O

Me

MeCO2H1

5

8

12 15

24

Figure 9, (+)-Ambruticin

(-)-Centrolobine:

(-)-Centrolobine, 6[β(p-hydroxyphenyl) ethyl]-2-(p-methyoxyphenyl) tetrahydropyran is a

crystalline substance isolated from the heartwood of Centrolobium robustum32

and from the

stem of Brosinum potabile33

in the amazon forest. (-)- Centrolobine is a 2,6-disubstituted

tetrahydropyran with antibiotic properties. Recently, (-)-centrolobine and related natural

products have been shown to be active against leishmania amazonenis promastigotes, a

parasite associated with leishmaniasis, a major health problem in Brazil. The basic structure

was elucidated in 1964 by total synthesis of the racemic methyl ether.32

The first

enantioselective total synthesis of (-)-centrolobine (Figure 10), which also served to elucidate

its absolute configuration by Colobert et. al.34

was appeared followed by several other

syntheses.35

O

MeO OH

Figure 10, (-)-Centrolobine

(-)-Diospongins:

(-)-Diospongin A and B are cyclic 1,7-diarylheptanoids, and they possess 2,6-cis and 2,6-

trans tetrahydro-2H pyran rings, respectively, and these rings are assumed to be formed by an

intramolecular cyclization of 5,7-dihydroxy-1,7-diphenyl-2-hepten-1-one, in their

biosynthesis (Figure 11).

Isolation & Biological activity:

Diospongin A and B (2 & 1) are isolated36

in 2003 from the rhizomes of Dioscorea spongiosa

along with Diospongin C 3 and three known lignans, piperitol 4, sesaminone 5 and (+)-

syringaresinol 6 (Figure 11). The water extracts of rhizomes of Dioscorea spongiosa was

chromatographed with a diaion HP-20 column, using a H2O-EtOH solvent system, to give

four (H2O and 30%, 60%, and 90% H2O-EtOH) fractions. They showed 11.2, 14.7, 86.7, and

89.5% stimulation of the proliferation of osteoblast-like UMR106 cell line at a concentration

of 200µg/mL, and all showed 100% inhibition of the formation of osteoclast-like

multinuclear cells at the same concentration. On the other hand, only the 90% H2O-EtOH

fraction inhibited the bone resorption induced by parathyroid hormone (PTH) in a bone organ

culture system at a concentration of 440µg/mL (82.8% inhibition). Thus this fraction was

further separated by a combination of normal and reversed-phase column chromatography

and preparative TLC, to afford 1 to 6 compounds.

O

O

O

O

HH

OCH3

OH

OO

O

CH2OHO

O

OO

O

HH

OCH3

OH

H3CO

HO

OCH3

OCH3

OR1 OR2 OR3 OR4

3, R1, R2, R3, R4 = H

3a, R1, R2 = H, R3, R4= C(CH3)3

3b, R1, R2, R3, R4 = C(CH3)3

O

N(CH3)2

3c, R3, R4 =

R3, R4 = C(CH3)3

O

OH

O

O

OH

O

(-)-Diospongin B, 1

(-)-Diospongin A, 2

4

5 6

7

5

3 1

7

5

3 1

Figure 11

Osteoporosis, the most frequent bone remodelling disease, is defined by a low bone mass

and high risk of fractures. It is caused by relative increase of osteoclastic bone resorption over

osteoblastic bone formation.37

Since ipriflavin (Figure 12) was approved for the treatment of

osteoporosis in the 1980’s, natural plants have been researched.

O

O

O

Figure 12, Ipriflavin

In traditional Chinese medicine, herbs that strengthen the kidney and bone can be used for

the treatment of bone diseases with the same symptoms as osteoporosis.38

The currently

available treatment, e.g., estrogen replacement treatment, is based on inhibition of bone

resorption to prevent further bone loss. Many osteoporotic patients, however, have already

lost a substantial amount of bone, and thus a method to increase bone mass by stimulating

new bone formation is needed.39

It is known that in bone formation, osteoblasts are the key

cell in bone matrix formation and calcification.40

Kadota and co-workers36

have screened

water and methanol extracts from 30 Chinese herbs that have effects on kidney and bone to

determine whether they influence the proliferation of the osteoblast like UMR 106 cell line.

As the excellent osteoporotic therapy should act on both formation and bone resorption, they

have also examined the effect of active extracts against the formation of tartrate-resistant acid

phosphatase (TRAP)-positive osteoclast-like multinucleated cells. Based on results of both

assays, the water extracts of rhizomes of Dioscorea spongiosa showed the strongest in vitro

antiosteoporotic activity. The same extract is used in traditional Chinese medicine for the

treatment of rheumatism, urethra, and renal infection.

Structural Elucidation:

OH

H

H

H

HO

H

Ph

H

H

7

6eq

6ax

5

4ax

4eq 3O H2'

H6'

Diospongin A, 2

Diospongin A, 2 showed a quasi-molecular ion, corresponding to the molecular formula

C19H20O3 on HR-FAB-MS. Its IR spectrum displayed the absorption of hydroxy (3450 cm-1

),

conjugated carbonyl (1695 cm-1

) functionalities including an aromatic ring (1610, 1495 cm-1

).

The 1H and

13C NMR spectra of 2 revealed the presence of three oxymethine, three

methylenes, two phenyl rings and a ketone carbonyl carbon. Extensive analysis of the 2D

NMR spectra suggested that 2 should be diarylheptanoid. The location of carbonyl carbon

was determined to be C-1 by the HMBC correlations between the aromatic protons H-2`, 6`

and the carbonyl carbon (δc = 198.4), while the HMBC correlations H-7 / C-2, 6 and H-2,

6/C-7 confirmed the other phenyl ring at C-7. The correlations H-3/C-7 and H-7 / C-3

indicated the presence of an ether linkage between C-3 and C-7. Thus, the structure of 2 was

determined as 1, 7-diphenyl-3, 7-epoxy-5-hydroxy-1-heptanone. The large coupling constants

between H-3 and H-4ax at δH = 1.67 (J = 11.2 Hz) and between H-7 and H-6ax at δH = 1.75

(J = 12.0 Hz) indicated that these protons should be axial while, H-5 was considered to be

equatorial form the small coupling constants with H2-4 and H2-6 (each J = 3.0 Hz). The

ROESY correlations H-3 / H-7, H-3/H4eq and H-4ax / H-6ax indicated that the pyran ring

had a chair conformation that H-3, H-4eq and H-7 are cis and that H-4ax and H-6ax are also

cis. Finally the absolute configuration at C-5 was determined to be S by the advanced Mosher

method. Thus the structure of diospongin A was established as (3R, 5S, 7S)-1,7-diphenyl-3,7-

epoxy-5-hydroxy-1-heptanone.

O

H

H

H

H

Ph

OH3

H

Ph

OH

H5

6eq

6ax 4ax

4eq

1

1

1

72

Diospongin B, 1

Correspondingly, the molecular formula of diospongin B, 1 was determined to be the same as

that of 2 by HR-FAB-MS. The 1H- and

13C-NMR spectra of 1 were very similar to those of 2,

except for slight differences in splitting patterns of H-4ax, H-5, H-6ax and H-7. Thus, 1 was

considered to be a diastereomer of 2, which was confirmed by the analysis of its 2D NMR

spectra. The coupling patterns of H-3, H-5 and H-7 indicated H-3 and H-5 to be axial and H-

7 to be equatorial. While the ROESY correlations H-3 / H-5, H-5 / H-6eq revealed that the

pyran ring should have a chair conformation. The analysis of the 1H-NMR spectra of its α-

methoxy- α-trifluoro methylphenylacetyl (MTPA) derivatives indicated the absolute

configuration at C-5 to be S. Thus, the structure of diospongin B, 1 was established as (3S,

5S, 7S)-1,7-diphenyl-3,7-epoxy-5-hydroxy-1-heptanone.

Contemporary works:

Jennings et al.41

not only achieved unambiguous total syntheses of both (-)-diospongins A, 2

and B, 1 but also validated the structures proposed by Kadota et. al..36

The synthetic protocol

along with preparation of key intermediate δ-lactone 11 is highlighted in Scheme 1. They

initially focused on the introduction of the bromoacetate functionality and consequently,

examined the stereoselective intramolecular Reformatsky lactone formation reaction

sequence. Thus, esterification of the free secondary hydroxyl of 742

(derived via a Keck

allylation of benzaldehyde in 92% ee) with bromoacetyl bromide in the presence of pyridine

provided 8. Ensuing oxidative cleavage via the modified Johnson-Lemieux protocol of the

terminal alkene in 8 furnished the extremely labile α-bromo acetyl aldehyde 9. Then, the

stage set for the intramolecular SmI2-mediated Reformatsky reaction.43

Accordingly, using

SmI2 generated Sm(III) enolate, which subsequently underwent an intramolecular aldol

reaction with a pendent aldehyde via a double six-membered transition state to furnish

selectively a β-hydroxylactone with exceptional diastereoselectivity44

in a low 32% yield

(Scheme 1).

OH

a) Br

O

Br

pyridine

O

O

Br

b) OsO4, NaIO4CHO

O

O

Br

c) SmI2

CHO

O

OSm(III)

O

O

OH

7 8 9

1011

OOSmIII

H

H

H

H

Scheme 1

Alternatively, a high yield synthetic strategy for the synthesis of the desired β-hydroxy

lactone 11 was developed based on their previous approach using same starting meterial.45

The alcohol 12 was coupled with acrylyl chloride under the standard protocol afforded the

dienic ester 13. Treatment of acrylate ester 13 with Grubbs catalyst 14 readily allowed for the

formation of lactenone 15 via a ring-closing olefin metathesis with a combined yield of 61%

over two steps from 12. An ensuing stereoselective epoxidation of the corresponding

lactenone intermediate 15 with basic hydroperoxide provided the epoxy-lactone 16 followed

by subsequent regioselective opening of the oxirane 16 with in situ generated PhSeH

provided the required intermediate 7 on a multigram scale (Scheme 2).

OHa) Cl

O

Et3N

O

O

O

O

O

O

O

N N

Ru

PCy3

Cl

ClPh

12 13

14

15

16

b) 18

c) H2O2

NaOH

d) PhSeH

11

a) TESCl, imid. O

O

OTES

O

OAc

OTES

b) DIBAL

c) Ac2O, Pyr.

d) BF3.OEt2

OTMS

O

O

OH

1

17 18

11

Scheme 2

Jennings and co-workers initially chose to investigate the synthesis (-)-diospongin B 1. As

delineated in Scheme 4, initial protection of the free hydroxyl moiety of 7 was with TESCl

and reduction of lactone 17 with DIBAL resulted in the formation of the lactol and

subsequent acetylation with Ac2O and pyridine gave 18.46

Treatment of intermediate 18 with

BF3.OEt2 generated oxocarbenium cation which was trapped with TMS enol ether (derived

from acetophenone) and concomitant removal of the TES group led to the target (-)-

diospongin B, 1 (Scheme 2).

The diastereomer (-)-diospongin A, 2 was synthesized using the same the lactone 11. The

reaction of lactone 11 with excess of allyl magnesium bromide furnished the lactol 19 as a

mixture of diastereomers which was readily reduced (TFA / Et3SiH) via the oxocarbenium

intermediates.

O

O

OH

a) allylMgBr O

OH

O

OH

TFA

H

O

OTES

H

+

HO

H

TESO+

X

11 19 18

OH+

Et3SiH

H-

H-

O

OTES

O

OTES

O

b) O3

c) PhMgBr

d) Dess-Martin O

OTES

O e) HCl

O

OH

O

20

21 22 2

Scheme 3

Ozonolysis of the alkene 20 followed by phenyl Grignard addition afforded the

corresponding secondary alcohol as a mixture of diastereomers, which was subsequently

oxidized to the ketone intermediate 22 by means of the Dess-Martin periodinane reagent.

Finally, deprotection of the TES ether furnished the diospongin A, 2 (Scheme 3).

Cossy’s Approach:

In 2006, Cossy and co-workers47

have reported the synthesis of (-)-diospongin A, 2 using two

enatioselective allylation to control the formation of two out of three steoreogenic centers

present in the molecule, followed by a cross-metathesis reaction and an intramolecular oxy-

Michael reaction. Thus, benzaldehyde was treated with allyltitanium complex (R, R)-Ti to

afford the corresponding allylic alcohol 23 with high enantioselectivity. After the protection

of 23 with TBSCl and was subsequent oxidative cleavage of terminal olefin produced the

corresponding aldehyde which is directly treated with titanium complex to afford 1, 3-syn

diol 24. The diol was then subjected to a cross-metathesis reaction with unsaturated ketone 25

in presence of Grubb’s catalyst furnished the desired 1,7-diarylheptanoid 26 with a E/Z ratio

95/5. Finally, cleavage of silylether and subsequent inramolecular oxy-Michael addition was

successfully achieved in one pot with TBAF to furnish (-)-diospongin A, 2 with an overall

yield of 29% (Scheme 4).

H

O

a) (R,R)-Ti, -78oC

OH

b) TBSCl, imid

c) OsO4, NaIO4

d) (R,R)-Ti, -78oC

OTBSOH

e) G II 5 mol %

23 24

O

25

OTBSOH O

O

OH

O

2

f ) TBAF, THF

26

Ti

O

O

PhPh

PhPh

O

O

(R,R)-Ti

N N

Ru

PCy3

Cl

ClPh

G II

Scheme 4

Uenishi’s Approach:

Uenishi and co-workers48

have synthesized both diospongins B, 1, A, 2 and their C5 epimers

using highly stereoselective Pd(II)-catlysed cyclization of chiral 1, 5, 7-trihydroxy-2-heptenes

and a regioselective Wacker oxidation as strategic reactions. The key intermediate 28 was

synthesized form the known aldehyde 27, which was readily derived from ethyl (R)-(-)-

mandelate (Scheme 5). Diastereoselective reductions of α, β-unsaturated ketone 28 with an

(S)-CBS reagent,49

at 0 oC gave the corresponding (R)-allylic alcohol 29a, followed by

deprotection with TBAF in THF afforded triol 30a in 90% yield. Meanwhile, the reduction of

28 with a (R)-CBS reagent49

gave 29b with 85% de and the deprotection of silyl ether

generated triol 30b in 94% yield (Scheme 5).

OTBS

CHO

OTBSOTBS O

27 28

OTBSOTBS OH

OTBSOTBS OH

OH

OH

HO

OH

OH

HO

29a

29b

30a

30b

a ,b, c, d

e

f

g

h

a) (+)-Ipc2Ballyl, E2tO, -78 oC, 62% b) O3, CH2Cl2, -78

oC 10 min then PPh3, rt c)

Ph3P=CHCOPh, THF, 80% (2 steps) d) TBSOTf, 2,6-lutidine, CH2Cl2, 86% e) (S)-CBS,

BH3.THF, THF, 0 oC, 1h, 92%, 87% de f) (R)-CBS, BH3.THF, THF, -40

oC, 1h, 98%, 85%

de g) TBAF, THF, rt, 3h, 90% h) TBAF, THF, rt, 3h, 94%

Scheme 5

The triol 30a containing 7% of 30b was treated with 10 mol% of PdCl2(CH3CN)2 in THF at 0

oC, the desired cis-tetrahydropyran 31a was obtained in 92% yield along with 31b in 6%

yield. Meanwhile, under the same conditions, triol 30b containing 8% of 30a gave the desired

trans-tetrahydropyran 31b in 86% yield and 31a in 5% yield. Treatment of alkene 31a with

50 mol% PdCl2 and CuCl under the microwave irradiation led to target 2 in moderate 57%

yield (Scheme 6).

OH

OH

HO

OH

OH

HO

30a

30b

O

OH

31a

O

OH

O

O

OH

31b

2

PdCl2(CH3CN)2

THF, 0 oC

PdCl2(CH3CN)2

THF, 0 oC

PdCl2, CuCl, O2

DMF+H2O

Scheme 6

The alcohol 31b was protected with MOMCl resulted in the compound 32 which was

subjected to Wacker oxidation led to the trans-hydropyran 33 in 55% yield under

conventional conditions. Final deprotection of MOM-ether with aq. HCl gave the desired 1 in

91% yield (Scheme 7).

O

OH

31b

O

OMOM

32

O

OMOM

O

O

OH

O

133

MOMCl, iPr2NEt

NaI, THF

PdCl2, CuCl

DMF+THF

HCl/THF

rt

Scheme 7

Ming Xian’s Approach:

Ming Xian and co-workers50

have reported the synthesis of diospongins A and B (1&2) using

a strategy which is based on the Smith-Tietze three-component linchpin coupling.51

The

syntheses started from the construction of the dihydropyranone intermediates 38 and 40

(scheme 8). The linchpin coupling of TBS-dithiane 34 with known epoxides (+)-35 and (+)-

36 provided alcohol (-)-37. Switching the order of epoxide addition under the same protocol

led to product (-)-39. Oxidative cleavage of dithiane group in (-)-37 and (-)-39 followed by

Dess-Martin oxidation, and acidic cyclization gave (+)-38 and (+)-40.

S S

TBS

t-BuLi

Et2O, -40 oC

a)O

Ph(+)-35

34

b) OOBn

(+)-36

TBSOSS

OBn

OH

(-)-37

c) HgCl2,CaCO3, H2O-MeCN, 60 oC

d) DMP, CH2Cl2, rt

e) TFA, CH2Cl2, rt

73% (for 3 steps)

O OBn

O

(+)-38

S S

TBS

t-BuLi

Et2O, -40 oC

a)

O

Ph(+)-35

34

b)

OOBn

(+)-36 SS

OBn

OTBS

(-)-39

c) HgCl2,CaCO3, H2O-MeCN, 60 oC

d) DMP, CH2Cl2, rt

e) TFA, CH2Cl2, rt

70% (for 3 steps)

O OBn

O

(+)-40

75%

74%

OH

Scheme 8

The key intermediate (+)-38 was on stereoselective Luche reduction provided alcohol (-)-41

(Scheme 9). The olefin hydrogenation and benzyl group deprotection of (-)-41 gave (-)-42 as

a single isomer. Next, the primary alcohol of (-)-42 was oxidized to aldehyde and addition of

PhMgBr furnished the compound 43. Then, the selective benzylic oxidation in 43 led to 5-

epi-diospongin A, (-)-44. Finally, the R-hydroxy group of (-)-44was converted into the S-

configuration under Mitsunobu conditions to complete the synthesis of diospongin A 2. The

Luche reduction of (+)-40 provided alcohol (+)-45 and hydrogenation with

Chlorotris(triphenylphosphine)rhodium(I) [Ph3P)3RhCl] under high pressure provided (+)-46

in modest yield along with stereoisomer (+)-47. Compound (+)-46 was then subjected the

same set of reactions as above afforded the diospongin B, 1 (Scheme 10).

O OBn

O

(+)-45

O OBn

OH

O OH

OH

O

OH

OH

O

OH

O

O

OH

O

(-)-2

(-)-48

(-)-4950

(-)-51

NaBH4, CeCl3, MeOH

-78 oC

H2, Pd(OH)2

72%

a) TEMPO, NaClO2, KBr

b) PhMgBr, THF, -78 oC

92%

DMP, CH2Cl2, rt

82%

1) DEAD, Ph3P,

4-bromobenzoic acid

2) K2CO3, MeOH

99%

Scheme 9

O OBn

O

(+)-40

O OBn

OH

O OBn

OH

O

OH

OH

O

OH

O

(-)-45

(-)-46

(-)-1

NaBH4, CeCl3, MeOH

-78 oC

b) TEMPO, NaClO2

c) PhMgBr

64%

DMP, CH2Cl2, rt

82%

(Ph3P)3RhCl

H2

200 psi

+

O OBn

OH

(-)-47

(-)-46

a) Pd/C, H2

Scheme 10

PRESENT WORK

While 1,7-diarylheptanoids are relatively simple molecules, they exhibit various

biological and pharmacological activities, such as anti-oxidant activity, anti-cancer activity,

inhibitory activity on nitric oxide production, anti-inflammatory activity, and DPPH-radical

scavenging activity. Particularly, cyclic 1,7-diarylheptanoids have been receiving

considerable attention. Among them, the intriguing C-aryl glycoside natural products

diospongins A, 2 and B, 1 contains six-membered cyclic ether structural unit with 2-aryl and

6-phenacyl substitution (Figure 11). Despite the fact that the both compounds indicate an

inhibitory activity against bone resorption induced by parathyroid hormone in a bone organ

culture, diospongin B shows more potent antiosteoporotic activity than that of diospongin A

due to their sterogenic variations at C3 and C7. Due to their antiosteoporotic activity coupled

with unique structure the diospongins have stimulated considerable interest in the synthetic

community.

Although considerable efforts has been devoted to the development of synthetic routes to

diospongins, there still exists a great need for a synthetic approach to these classes of

molecules that enables rapid and easy access to substrates, proceeds with excellent

stereosectivity in excellent yield, and requires mild reaction conditions compatible with

various functional groups. To date, most strategies rely on asymmetric induction resulting

from either chiral auxiliaries or resident chirality or enzymatic kinetic resolution of racemic

mixtures. Consequently, a synthetic sequence is preferred in which optical isomers are

excluded at the earliest possible stage through creation of chiral centers. A branch of

chemistry that has recently received much attention is that of organometallic catalysis. In a

view to develop a concise and viable route to this class of compounds, we have evaluated

organometallic catalytic processes. Organometallic catalysis is the acceleration of chemical

reactions with a sub-stoichiometric amount of an organic chiral compound which contain a

metal atom.

Keeping in mind all the valuable resources and with our continued interest in developing

catalytic routes to bioactive small molecules,52

we envisaged a flexible route for the

synthesis of the diospongins based on three catalytic steps: (a) catalytic asymmetric hetero-

Diels-Alder reaction, (b) diastereoselective rhodium(I)-catalyzed 1,4-addition, and (c)

catalytic asymmetric transfer hydrogenation (CATHy) reaction (Scheme 11).

+

O

OH

O

7

Keckhetero-Diels-Alder reaction

Rh-catalyzed1,4-addition

Catalytic Noyori's reduction

Diospongin B (1)

Me3SiO

OMe

+O

O

H

O

OPMB

O

O

OPMB

O

48 4950

5152

PO(OMe)2

OMe

3

5

Retrosynthetic analysis of Diospongin B, 1

Scheme 11

At the outset, we envisioned that this strategy in turn could be used to generate a library of

small molecules, in principle, by varying chirality inducing ligands of the above pivotal

reactions with perfect stereocontrol and a predictable absolute stereochemistry and

subsequently varying substitutions in the aromatic nucleus.

Results and Discussions:

In principle, the stereogenic center 3 in diospongin B 1 could be accessed through a catalytic

enantioselective hetero-Diels-Alder reaction that are either R or S selective by using

BINOL/Ti(OiPr)4 derived catalyst. The intermediate 52 would be equivalent to a masked

phenacyl moiety as well as we chose furyl moiety of 50 as a masked carboxaldehyde.

Further, the stereogenic center 7 could be realized through a rhodium (I)-catalyzed

stereoselective 1,4-addition of an arylboronic acid to a cyclic enone (Scheme 11).

Accordingly, the synthesis of diospongins initiated using catalytic asymmetric hetero-Diels-

Alder reaction between Danishefsky’s diene 48 and furfuraldehyde 49 with 10 mol % of the

(S)-BINOL / Ti(OiPr)4 derived catalyst, L1. A mixture of (S)-(+)-BINOL, Ti(OiPr)4 (1M),

CF3CO2H and 4Ao molecular sieves in ether was refluxed for 1 h. The aldehyde 49 and diene

48 was added successively at -78 oC, and the reaction mixture was stirred for 40 h at -20

oC.

After work up, and purification generated dihydropyranone 53 with 96% enantiomeric

excess.53

Further, single recrystallization of 53 from hexane:ether (2:1) solvent mixture

resulted in 99.9% enantiomeric excess with 60% yield (Scheme 12). The 1H NMR spectrum

of compound showed characteristic peaks as two doublets at δ 7.38 (J = 6.6 Hz), δ 5.47 (J =

3.6 Hz) integrating for one proton each and a triplet was appeared at δ 5.51 (J = 5.8 Hz)

integrating for one proton which can be assigned to furan attached carbon proton. Two sets of

doublet of doublet at δ 3.10 (J = 13.1, 16.8 Hz), 2.74 (J = 3.6, 16.8 Hz) integrates for one

proton each along with other peaks in their respective positions confirmed the desired

dihydropyranone formation. The required transformation also supported ESI spectral analysis

showing m/z peak at 165 [M + H]+. Similarly, 10 mol % of the (R)-BINOL / Ti(OiPr)4

derived catalyst, L2 generated ent-53 under otherwise identical conditions with the same

enantioselectivity and yield. The enantioselectivity and absolute configuration was assigned

based on optical rotation reported in the literature 53

and advanced further (Scheme 12).

O

O

O+48 49

53

10 mol% L1

-78 0C, 42h

CH2Cl2

60%

(96%ee)

(after recrstallization >99%ee)

O

O

O+48 49

ent -53

10 mol% L2

-78 0C, 42h

CH2Cl2

60%

(96%ee)

(after recrstallization >99%ee)

O

OTi

OiPr

OiPr

O

OTi

OiPr

OiPr

(S)-BINOL/Ti(OiPr)4 L1 (R)-BINOL/Ti(OiPr)4 L2

Scheme 12

The postulated mechanism for the proposed catalytic cycle is shown in scheme 13. Initially,

the silyoxydiene 48 on reaction with titanium complex L1 results the Ti-diene complex by

liberating TMSisoprpyl ether. Then, the Mukaiyama aldol53

adduct II was obtained through a

six-membered cyclic transition state I which involves the diene linked to the Ti-BINOL by

the C-3 oxygenated substituent and the aldehyde 49 associated to the metal by the carbonyl

oxygen followed by exchange of trimethylsilyl group from Danishefsky’s diene substrate to

the Mukaiyama aldol adduct II furnish the intermediate III and the Ti(IV) complex. Upon

treatment with trifluoroacetic acid generates the desired dihydropyranone.

TiLn-2O

O O

O

O

MeO

MeO

O OTiLn

O

OTiLn

OMe

BINOL_Ti(OiPr)2

48

TMSOiPr

OTMS

OMe

MeO

O OTMS

O

TFA

O

O

O

I

II

III*

Scheme 13: Mechanism of the Ti-BINOL catalyzed hetero-Diels-Alder reaction

With enantioenriched 53 in hand, we sought a flexible and appropriate means for introducing

a C-aryl group into the pyranose ring. To this end, we have examined the rhodium(I)-

catalyzed stereoselective 1,4-addition of an arylboronic acid to a cyclic enone, a protocol

developed by Miyaura,54a

Hayashi,54b

and Maddaford.55

Primarily, we have explored

Maddaford conditions. Accordingly, the reaction of 53 with phenylboronic acid in the

presence of 5 mol % of Rh(cod)2BF4 in dioxane/water was heated to 100 oC for 2 h.

Surprisingly, after workup, only a trace amount of the expected 1,4-addition product 54 was

isolated. However, the addition of 5 mol% of KOH to the reaction, under otherwise identical

conditions, furnished the product 54 in 70% yield. In another set of reactions, when the molar

ratio of the Rh catalyst was reduced to 2.5 mol% and the KOH loading was increased 2-fold

(1:2 catalyst:KOH), the reaction proceeded smoothly to yield the required product in 98%

(Scheme 14).55

2.5 mol% Rh(I)(cod)2BF4

PhB(OH)2

5 mol% KOH

Dioxane/H2O100 0C, 2h

98%(de = >99.9%)

54

O

O

O

53

2.5 mol% Rh(I)(cod)2BF4

PhB(OH)2

5 mol% KOH

Dioxane/H2O100 0C, 2h

98%(de = >99.9%)

ent-54

O

O

Oent-53

Scheme 14

The 1H NMR spectrum of product showed a doublet at δ 7.44 with a coupling constant 1.4 Hz

integrating for one proton which can be assigned for proton related to furan moiety. The

aromatic peak at δ 7.40-7.25 as multiplet integrating for five protons and a triplet at δ 4.74 (J

= 7.5 Hz) integrated for one proton could be attributed to phenyl attached carbon proton

proving the assigned structure of the product formation. The peak obtained in the ESI mass

spectra at m/z 243 (M + H)+

was an additional evidence for assigned structure. The de was

determined to be >99.9% by chiral HPLC (ODH column, 2% isopropanol in hexane, flow

rate 0.5 mL/min).

The highly diastereoselctive addition could be rationalized on the basis of proposed catalytic

cycle. As proposed,55

primarily, the pre-catalyst hydroxyl-Rh was generated by cataionic Rh

with KOH. Then, phenylboronic acid transmetallation resulted in organometallic species

ArRh(cod)2 II which inturn, proceeded from the less hindered Re-face addition of the enone

double bond and subsequent hydrolysis of Rh-O, III bond in the presence of H2O led to high

diastereoselective trans 2,6-disubstituted pyranone, 54 (Scheme 15).

Rh(cod)2BF4-

PhRh(cod)2

H2O

HORh(cod)2

PhB(OH)2

III

KOH

II

O

O

O

O

O

O

O

O

OPh

[Rh]

O

O

OPh

[Rh]

PhI

54

Scheme 15: Catalytic cycle

The stereochemistry of 54 was assigned α configuration at the anomeric center based on 1H

NMR data reported in the literature. Then, ent-53 was converted to ent-54 following the same

sequence of reaction conditions and the product ent-54 was characterized by 1H NMR, IR,

and Mass and corresponding data are placed under experimental section (Scheme 15). Under

anhydrous conditions, a low yield (<5%) of the 1,4-addition product was obtained, suggesting

need for H2O. Presumably, water serves to protonate the Rh-O bond. The role of hydroxide

(KOH which is added in the reaction mixture) could be facilitate the transmetalation, or it

could react with Rh(cod)2BF4 to generate precatalyst HORh(cod)2 or a combination of both.

Next, we focused on the reduction of the keto group of 54 (Scheme 16).

0.5 mol% cat. A

Et3N:HCO2H (5:2)

EtOAc, 50 0C, 3h

OO

OH

96%de = >99.9%

54

55

N

Ru

HNPh

PhTos

cat. A

N

Ru

HNPh

PhTos

cat. B

Scheme 16

Arrays of achiral and chiral reducing agents were screened for this transformation (Scheme

16) and the results are shown in Table 1. The achiral catalysts NaBH4 and DIBAL-H led to a

diastereomeric mixtures (entry 1 & 2, Table 1). Corey-shibaka chiral catalyst also furnished

55:45 diastereomeric mixture (entry 3, Table 1). While Noyori’s56

catalyst i.e., R,R-diamine-

Ru catalyst A, catalysed the reaction in high enantioselectivity with stable organic hydrogen

donor Et3N:HCO2H (entry 4, Table 1).

entry Reducing agent dr

ratio

%yield

1 NaBH4 55:45 90

2 DIBAL-H 60:40 92

3

N

B O

ArAr

Me

s

10mol% ; BH3.DMS

55:45

93

4

NRu

HNPh

PhTos

0.5mol% cat. A

>99.9

96

5

NRu

HNPh

PhTos

0.5mol% cat. B

60:40

94

Table 1: Reduction of ketone 54 with various reducing agents

The postulated mechanism is described in scheme 17. Initially, the [{RuCl2(p-cymene)}]

reacts with (S,S) or (R,R) TSDPEN ligand in the presence of KOH in CH2Cl2 at room

temperature to form orange colored catalyst precursor I. The precursor-I has acidic NH2

protons which undergoes facile elimination of HCl on treatment with 1eq of KOH to afford

the true catalyst II. This complex is a deep purple monomeric 16e-

species, which takes two

hydrogen atoms from a donor such as 2-propanol to produce yellow ruthenium hydride

species III by a rate-limiting step. The Ru-hydride in turn reduces the prochiral ketone via a

six-membered cyclic transition state to form highly enantioenriched product. This process

generates the catalyst which then re-enters the catalytic cycle to forward the reaction (Scheme

17).

Ph

Ph

N

NH2

Ru KOH, CH2Cl2 -H2O

-HCl

Ph

Ph

N

NH2

Ru

H

Ts

Cl

Ts

Ph

Ph

N

N

H

Ru

Ts HO H O

R1

HO H

R1

O

SubstrateProduct

Catalyst precursor-ITrue catalyst-II Hydride species-III

Scheme 17

Catalyst A (0.5 mol %) with the Et3N.HCO2H azeotropic mixture and heating at 50 oC for 3 h

afforded the alcohol 55 in 96% isolated yield with >99.9% diastereoselectivity The

diastereomeric ratio analyzed on chiral HPLC, ODH column, 10% isopropanol in hexane as

mobile phase at a flow rate of 0.5 mL/min (Scheme 16). The 1H NMR spectra showed a

characteristic peak of -CHOH at δ 4.03 ppm as multiplet and the furan attached carbon

proton appeared as triplet at δ 5.21 (J = 4.5 Hz). The aromatic protons appeared as multiplet

at δ 7.37-7.21 integrating for five protons confirming the product formation. The peak

obtained in the ESI mass spectra at m/z 267 (M + Na)+

was also corroborated the assigned

structure. The relative configuration of the hydroxyl group was assigned as R based on single

X-ray crystallography of 55 (Figure 18).

Figure 18: ORTEP representation of 55 with 50% probability

Our efforts to synthesize the C4 epimer of 55, by using substrate 54 employing S,S-diamine-

Ru catalyst B (0.5 mol %), under otherwise identical conditions resulted in a lower level of

diastereoselectivity (entry 5, Table 1). The R,R-diamine-Ru catalyst/ substrate 54 appears to

be a matched combination, which has overcome the inherent substrate bias, thus resulting in

high diastereoselectivity. On the other hand, S,S-diamine-Ru catalyst/substrate 54 is a

mismatched combination as evidenced by the modest level of diastereoselctivity. However,

the reduction of the keto group of ent-54 with R,R-diamine-Ru catalyst A (0.5 mol %), using

a Et3N.HCO2H azeotropic mixture, smoothly furnished the alcohol ent-55 in 98% yield.

Further, the optical rotation of ent-55 was found to be approximately equal in magnitude to

that of 55 but opposite in sign, indicating an enantiomeric relationship. Consequently, the

newly formed chirogenic center absolute configuration was assigned as S (Scheme 18). In

principle, the ent-55 should be achieved by employing the catalyst B. To our surprise, two

enantiomeric ketones 54 and ent-54 are reduced with the same enantiomer of catalyst A

leading to a pair of enantiomers, i.e., 55 and ent-55. These findings suggest that the

enantiomeric Ru-template catalyst A is efficiently differentiating diastereofaces of pro-chiral

ketone 54 and ent-54. However, these findings warrant a detailed investigation to establish

the plausible mechanism.

0.5 mol% cat. AEt3N:HCO2H (5:2)

EtOAc, 50 oC, 3hent -54

OO

OH

98%

(de = >99.9%)

ent-55

N

Ru

HNPh

PhTos

cat. A

Scheme 18

Having prepared the two enantiomeric tetrahydropyryl alcohols 55, ent-55 we next

proceeded to synthesise diospongin B 1 and its enatiomer ent-1. Proceeding further, the

hydroxy group of 55 was converted to PMB ether 50 by treating with 5.0eq of NaH and 4.0eq

of PMBCl at 0 oC to rt in THF for 6h in 98% yield. The product formation confirmed by

1H

NMR spectrum. In 1H NMR spectrum, the PMB protons appeared at δ 7.28 as a doublet (J =

8.0 Hz) and at 6.90 doublet (J = 8.8 Hz). The rest of the characteristic peaks showed at their

respective places. Then, the furyl group of 50 was oxidatively cleaved to acid (O3, 15 min,

DCM/MeOH, [1:1]), and the resulting acid on esterification with diazomethane (CH2N2,

ether, 0 oC to rt) gave methyl ester. The

1H NMR spectrum showed a peak at δ 3.81 as a

singlet integrated for three protons ensured the product formation. Then, the methyl ester was

subjected to reduction with 1.5eq of DIBAL-H at -78 oC for 1h lead to 51 in 88% yield (after

3 steps). The 1H NMR spectrum showing a peak corresponding to –CHO group at δ 10.01

ppm as a singlet and presence of all other proton signals in their respective positions

confirmed the compound 51 formation. The aldehyde 51 was then treated with the anion

derived from Horner-Emmons reagent 52 and subsequent hydrolysis of intermediate enol

ether resulted in 56 (75%).57

The presence of two doublet of doublets for each methylene

proton adjacent to keto group at δ 3.43 (dd, J = 6.6, 16.1 Hz), 3.27 (dd, J = 5.8, 16.1 Hz) in

the 1H NMR spectrum proved the product formation. Further evidence has come from ESI

spectrum exhibiting peak at m/z 439 [M+Na]+. Finally, compound 56 was exposed to 1.2eq of

DDQ in DCM/H2O (9:1) at 0 oC to rt for 1h furnished the target compound 1 in 92% isolated

yield (Scheme 19). The 1H NMR spectrum of 1 provided sample evidence for the formation

of product, with the devoid of PMB protons. A triplet at δ 5.19 (J = 4.4 Hz) integrated for one

proton corresponding to the carbon atom attached directly to phenyl group and the peaks at δ

2.51 (J = 3.8, 5.1, 13.4 Hz ) as doublet of doublet of doublet, δ 2.05 (J = 4.4, 8.9, 14.6 Hz) as

doublet of doublet of doublet, δ 1.92 (J = 5.0, 9.7, 13.5 Hz ) as doublet of doublet of doublet,

and δ 1.50 (J = 9.3, 12.3 Hz) as doublet of triplet integrating for one proton each indicating

the presence of two methylene groups adjacent to secondary hydroxyl carbon along with

other protons integrating at their respective values ensured the product formation. The ESI

mass spectral analysis, showing peak at m/z 319 [M+ Na]+ also supported the formation of

product 1 without any ambiguity. The chirooptical data of 1 were in full agreement with that

reported in the literature54

([α]23

D – 22.5, (c 0.2, CHCl3) {lit. 54

([α]23

D – 22.6, (c 0.0114,

CHCl3}).

OO

OPMB

DCM:MeOH (1:1)

ii) CH2N2, Et2O

0 oC to rt, 1hiii) DIBAL-H

toluene, -78 oC, 1h

O CHO

OPMB

Ph PO(OMe)2

OMe

n-BuLi, THF

-78 oC to rt, 3hO

OPMB

O

Cl3CCO2H/acetone

rt, 6h

50

5156

1

DDQ

DCM:H2O (9:1)

98%

88%( over 3 steps)75%

92%

i) O3, 15min.

PMBClNaH

THF, 0 oC to rt6h

55

60

0 oC to rt, 1h

Scheme 19

The 2, 6-trans enantiomer ent-1 was synthesized in 67% yield (over 6 steps) from ent-55

following the above mentioned conditions (Scheme 20). The corresponding experimental

data is all compounds are given in the experimental section.

ent-55

67%

OO

OH

(over 6 steps)

ent -1

O

O

OH

Scheme 20

Initially, the hydroxyl group of 55 was protected with TBDPS and carried out a

complete sequence. To our surprise, the final product 1H NMR and

13C data did not match to

reported data of 1. Consequently, changing the protecting group TBDPS to PMB followed by

the same set of reactions resulted in the expected product 1. The TBDPS protected 55 also

exposed to TBAF (10 equiv) but only deprotected compound 55 was recovered. To evaluate

the product formed from TBDPS, the C-5 hydroxyl group of diospongin B, 1 was converted

as TBDPS ether 57 (tBu(Ph)2SiCl, Et3N, DCM, 0 °C to rt, 6h). While subjecting deprotection

of the TBDPS group of compound 57 with 10eq of TBAF in THF at ambient temperature,

unexpectedly, furnished the product 2 in 86% yield. It was also noticed that the reaction did

not proceed with less than 10 equiv of TBAF. Using Aldrich supplied TBAF, reaction did not

initiate whereas, addition of 5 mol equiv of H2O (based on TBAF mole equivalent) to the

reaction under otherwise identical conditions yielded the expected product 2. However,

TBAF supplied by Spectochem.Pvt.Ltd., India without addition of H2O resulted in 2.

Further, the product 2 was unambiguously characterized by means of 1H NMR, IR and Mass

spectra. In 1H NMR spectrum, the peak at δ 4.90 (J = 1.5, 11.3 Hz) as doublet of doublet

integrating for one proton which can be assigned to phenyl attached carbon proton found to

characteristic. Two doublet of doublets at δ 3.39 (J = 5.3, 15.9 Hz), 3.04 (J = 7.5, 16.6 Hz)

accounting for one proton each of carbon atom directly attached to keto group, the peaks at δ

1.95 as multiplet, 1.67 as multiplet and absence of TBDPS and appearance of all other peaks

gave additional proof for the formation of the target molecule. Moreover, the optical data of 2

were in full agreement with that of diospongin A reported in the literature54

([α]23

D – 19.2, (c

1.2, CHCl3) {lit.54

([α]23

D – 19.6, (c 0.0084, CHCl3}). Also the 1H NMR and

13C NMR data

were in full accord with those reported for the natural product.

Under identical conditions ent-57 also resulted in ent-2. The structure of ent-2 was confirmed

by 1H and

13C NMR data. Furthermore, the optical rotation of ent-2 was found to be equal in

magnitude to 2, but opposite in sign and hence, was considered as enantiomer to 2 (Scheme

21).

ent -1 O

O

ent-2

O

OTBDPS

O

Et3N, DCM

i) tBu(Ph)2SiClexcess TBAF(10 equiv.)

THF, rt

57

ent-57

OTBDPS

0 oC to rt, 6hdiospongin B

1

diospongin A

2

92%

86%

O

O

OH

Scheme 21

The reaction could be rationalized on the basis of retro-Michael opening of pyran ring and the

subsequent intramolecular Michael reaction of the hydroxy nucleophile to the enone leads to

the thermodynamically more stable cis-conformer (Scheme 22).

O

H

Ph

H

H

H

Ph

O

OPH

H O

H

Ph

H

HPh

O

OHH

H

O

H OH

H

H

HPh

Ph

O

H

P = TBDPS

Scheme 22

In conclusion, we have accomplished the total synthesis of diospongins A, 2 and B, 1 and

their enantiomers employing achiral starting materials. To the best of our knowledge, the

synthesis of 2, 6-trans isomer ent-1 and 2, 6-cis isomer ent-2 are described here for the first

time. All three stereocenters are introduced by means of catalytic reactions and this strategy

in turn could be used to generate a library of small molecules with varying substitutions in

aromatic nucleus.

EXPERIMENTAL SECTION

(S)-2-(Furan-2-yl)-2, 3-dihydropyran-4-one (53):

O

O

O

A mixture of (S)-(+)-BINOL (0.276 g, 0.96 mmol), 1M Ti(OiPr)4 in CH2Cl2 (0.48 mL, 0.48

mmol), CF3CO2H (0.028 mL, 0.5 M in CH2Cl2), and flame dried powdered 4Ao molecular

sieves (1.86 g) in ether (20 mL) was heated at reflux for 1 h. The red-brown mixture was

cooled to room temperature, and furfuraldehyde 49 (0.460 g (0.39 mL, 4.83 mmol) was

added. The mixture was stirred for 5 min and cooled to -78 oC, Danishefsky’s diene 48 (1.0 g,

5.80 mmol) was added, and the reaction mixture was stirred for 10 min and then placed in a -

20 oC bath. After 40 h, saturated NaHCO3 (0.5 mL) was added, and the reaction mixture was

stirred for 1 h and then filtered through a plug of celite. The organic layer was separated, and

the aqueous layer was extracted with ether (3 x 20 mL). The combined organic layers were

dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product

was dissolved in CH2Cl2 (60 mL) and cooled to 0 oC. To this solution was added CF3CO2H

(0.25 mL) and stirred for 1 h, saturated NaHCO3 (30 mL) was added, the reaction mixture

was stirred for 10 min, and the layers were separated. The aqueous layer was extracted with

CH2Cl2 (3 x 50 mL), and the combined organic layers were dried over anhydrous Na2SO4 and

concentrated under reduced pressure. The residue was purified by column chromatography on

silica gel (10% acetone in hexane), to afford product 53 as a crystalline solid. A single

recrystallization from 1:2 Et2O: hexanes gave white needle like crystals.

Yield : 1.05 g, 60 %.

M. P : 73-75 oC

[α]23

D : + 359.0 (c = 1.2, CH2Cl2).

IR (KBr) : 2923, 2852, 1724, 1595, 1268, 1114, 1039, 747 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 7.48 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 6.6 Hz, 1H),

6.46 (d, J = 3.6 Hz, 1H), 6.42 (t, J = 1.4 Hz, 1H), 5.51

(t, J = 5.8 Hz, 1H), 5.47 (d, J = 3.6 Hz, 1H), 3.10 (dd,

J = 13.1, 16.8 Hz, 1H), 2.74 (dd, J = 3.6, 16.8 Hz, 1H).

13C NMR (100 MHz, CDCl3) : δ 191.3, 162.4, 149.9, 143.5, 110.5, 109.6, 107.3, 73.5,

39.4.

MS (ESI) : m/z 165 (M + H)+.

(2S, 6S)-2-(Furan-2-yl)-6-phenyl-tetrahydropyran-4-one (54):

O

O

O

A mixture of 53 (1.05 g, 6.40 mmol), phenyl boronic acid (1.56 g, 12.8 mmol),

Rh(I)(cod)2BF4 (0.052 g, 0.16 mmol), 1.0 mL of H2O, KOH (0.018 g, 0.32 mmol) and 20 mL

of dioxane was heated at reflux for 4 h. The reaction mixture was cooled to room temperature

and diluted with ethyl acetate (40 mL) and filtered through a pad of silica gel. The filtrate was

concentrated in vacuo and the residue was subjected to silica gel flash column

chromatography (5% EtOAc in hexane) to afford product 54 as a crystalline solid.

Yield : 1.51 g, 98 %.

M. P : 84-86 oC

[α]23

D : –10.0 (c = 0.5, CHCl3).

IR (KBr) : 2923, 2853, 1721, 1458, 1255, 1064, 1016, 752 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 7.44 (d, J = 1.5 Hz, 1H), 7.40-7.25 (m, 5H), 6.36 (t, J

= 5.3 Hz, 2H), 5.44 (dd, J = 3.0, 6.8 Hz, 1H), 4.74 (t,

J = 7.5 Hz, 1H), 2.96 (dd, J = 6.8, 15.1 Hz, 1H),

2.87 (dd, J = 3.02, 15.1 Hz, 1H), 2.72 (d, J = 7.5

Hz, 2H).

13C NMR (100 MHz, CDCl3) : δ 191, 151.1, 143.2, 140.2, 128.6, 128.1, 126.1, 110.2,

73.2, 69.0, 48.5, 43.4.

MS (ESI) : m/z 243 (M + H)+.

HRMS (ESI) : m/z 243.1026 (calcd for C15H15O3: 243.1016).

(2S, 4R, 6S)-2-(Furan-2-yl)-6-phenyl-tetrahydro-2H-pyran-4-ol (55):

O

OH

O

To a solution of 54 (1.51 g, 6.24 mmol) in anhydrous EtOAc (12 mL) under argon was added

Et3N: HCOOH (5:2) mixture (0.90 mL) followed by the addition of Ru-catalyst A (0.019 g,

0.031 mmol, 0.5 mol %) which was pre-dissolved in CH2Cl2 (2 x 1 mL). The resulting

reaction mixture was heated to 50 oC for 3 h. After cooling the reaction mixture to room

temperature diluted with ethyl acetate (20 mL) and filtered through a pad of silica gel. The

filtrate was concentrated in vacuo and the residue was subjected to silica gel flash column

chromatography (25% EtOAc in Hexane) to afford compound 55 as a crystalline solid.

Yield : 1.46 g, 96 %.

M. P : 65-68 oC

[α]23

D : –17.0 (c = 0.5, CHCl3).

IR (KBr) : 3404, 2925, 2856, 1451, 1366, 1060, 1011, 738 cm-1

.


= 3.0 Hz, 1H), 6.29 (d, J = 3.7 Hz, 1H), 5.21 (t, J = 4.5

Hz, 1H), 4.66 (dd, J = 3.7, 9.0 Hz, 1H), 4.03 (m, 1H),

2.48 (dt, J = 4.5, 13.5 Hz, 1H), 2.13 (dt, J = 3.7, 12.8

Hz, 1H), 2.02-1.95 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 154.3, 142.2, 140.1, 128.6, 127.2, 126.3, 110.2,

106.9, 72.3, 65.8, 64.1, 37.4, 36.8.

MS (ESI) : m/z 267 (M + Na)+.

HRMS (ESI) : m/z 267.1000 (calcd for C15H16O3Na: 267.0997).

(2S, 4R, 6S)-2-(Furan-2-yl)-4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran

(50):

O

OPMB

O

To a solution of 55 (1.46 g, 5.98 mmol) in DMF (30 mL) was added 60 % dispersion sodium

hydride (0.718 g, 29.9 mmol) at 0 oC. After the solution was stirred for 30 min at the same

temperature, 4-Methoxybenzyl chloride (3.74 g, 23.9 mmol) was added. The resulting

reaction mixture was stirred for 12 h at room temperature under argon. The reaction mixture

was quenched with water and extracted with EtOAc (3 X 30 mL). The organic layers were

dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue

was purified by flash chromatography (10% EtOAc in hexane) to afford product 50 as a

colourless oil.

Yield : 2.13 g, 98 %.

[α]23

D : –36.5 (c = 0.7, CHCl3).

IR (KBr) : 3448, 2929, 2860, 1612, 1513, 1248, 1089, 1035, 816,

737 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 7.46-7.34 (m, 6H), 7.28 (d, J = 8.0 Hz, 2H), 6.90 (d, J

= 8.8 Hz, 2H), 6.36 (t, J = 3.6 Hz, 1H), 6.34 (d, J = 3.6

Hz, 1H), 5.29 (t, J = 4.4 Hz, 1H), 4.65 (dd, J = 3.6,

10.2 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.51 (d, J =

11.7 Hz, 1H), 3.82 (s, 3H), 3.78 (m, 1H), 2.59 (m, 1H),

2.23 (m, 1H), 2.07 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 159.2, 154.2, 142.1, 140.2, 130.5, 129.2, 128.6,127.1,

126.4, 113.8, 110.1, 106.6, 72.8, 70.4, 69.6, 65.9, 55.2,

34.9, 33.8.

MS (ES) : m/z 387 ( M + Na)+.

HRMS (ES) : m/z 387.1588 (calcd for C23H24O4Na: 387.1572).

(2S, 4R, 6S)-Methyl 4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-

carboxylate:

O

OPMB

OMe

O

Ozone was passed for 10 min through a cooled (-78 oC) solution of 50 (2.13 g, 5.85 mmol) in

150 mL MeOH:CH2Cl2 (1:1), Me2S (0.725 g, 11.7 mmol) was added to the reaction mixture

and further stirring was continued for 30 min at -78 oC and 1 h at room temperature. The

solvent was removed under reduced pressure. The crude residue was dissolved in diethyl

ether (10 mL) and cooled to 0 oC in an ice bath. To this, etheral solution of diazomethane (10

equiv) (Caution: Liquid diazomethane is an explosive compound and explosions may occur

in the gaseous state if the substance is dry and undiluted) was added and resulting reaction

mixture stirred for 1 h (the reaction progress was monitored by TLC). Then, the reaction

mixture was allowed to stand overnight to escape the left over diazomethane in a well

ventilated fuming cupboard. The residual solvent was removed under reduced pressure and

the crude residue was purified by column chromatography (15% EtOAc in hexane) to yield

methyl ester as a colourless oil.

Yield : 1.79 g, 86 %.

[α]23

D : –32.1 (c = 0.7, CHCl3).

IR (KBr) : 2923, 2853, 1746, 1512, 1246, 1173, 1034, 819,

755 cm-1

.


= 8.8, 2H), 5.38 (dd, J = 2.2, 10.2 Hz, 1H), 4.54 (d, J =

11.7 Hz, 1H), 4.50 (dd, J = 0.7, 2.2 Hz, 1H), 4.40 (d, J

= 11.7 Hz, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.67 (s, 3H),

2.52 (m, 2H), 2.06 (m, 1H), 1.89 (m, 1H).

13C NMR (100 MHz, CDCl3) : δ 172.9, 158.9, 141.8, 128.8, 128.3, 127.4, 126.2,

113.7, 113.6, 70.4, 70.0, 69.8, 69.6, 55.2, 51.9, 36.8,

30.4.

MS (ESI) : m/z 379 (M+Na)+.


(2S,4R,6S)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-carbaldehyde

(51):

O

OPMB

CHO

To a solution of methyl ester (1.79 g, 5.02 mmol) in CH2Cl2 (20 mL) was added DIBAL-H

(1.07 g, 7.54 mmol, 1M solution in toluene) at -78 oC. The reaction mixture was stirred for 1

h at the same temperature and then quenched with saturated sodium potassium tartarate

solution. The aqueous layer extracted with CH2Cl2 (3 x 25 mL). The combined organic layers

were washed with brine solution, dried over anhydrous Na2SO4, and concentrated under

reduced pressure. The residue was purified by silica gel column chromatography (10%

EtOAc in hexane) to yield product 51 as a colourless oil.

Yield : 1.47 g, 90 %.

[α]23

D : –86.5 (c = 1.0, CHCl3).

IR (KBr) : 3444, 2929, 1729, 1610, 1512, 1248, 1089, 1034, 822,

757, 700 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 10.01 (s, 1H), 7.41- 7.24 (m, 7H), 6.89 (d, J = 8.2 Hz,

2H), 5.23 (dd, J = 3.0, 11.2 Hz, 1H), 4.48 (d, J = 11.2

Hz, 1H), 4.33 (d, J = 11.2 Hz, 1H), 4.28 (dd, J = 2.2,

6.7 Hz, 1H), 3.89 (m, 1H), 3.81 (s, 3H), 2.42 (m, 1H),

2.01 (m, 2H), 1.83 (m, 1H).

13C NMR (100 MHz, CDCl3) : δ 203.3, 159.1, 141.7, 130.1, 129.2, 128.4, 127.7,

126.0,113.8, 76.8, 70.4, 69.6, 69.4, 55.2, 36.9, 29.5.

MS (ESI) : m/z 349 ( M + Na)+.


(2-((2S, 4S, 6S)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-

phenylethanone) (56):

O

OPMB

O

To a -78 oC stirred solution of 52 (1.14 g, 4.96 mmol) in THF (40 mL) was slowly added n-

BuLi (0.316 g, 4.96 mmol, 3.0 mL, 1.6 M solution in hexane). After stirring the solution for

15 min, a solution of 51 (1.47 g, 4.50 mmol) in THF (25 mL) was added, then stirred for 1 h.

The reaction mixture was warmed to room temperature, and resulting solution was carefully

concentrated to 1/3 of original volume under reduced pressure. To the resulting reaction

mixture, acetone solution (0.8 M) of Cl3COOH (25 mL) was added and resulting reaction

mixture stirred at room temperature for 6 h. The reaction mixture was neutralized by addition

of saturated aq NaHCO3 until gas evolution subsides and extracted with EtOAc (3 x 50 mL).

The combined organic layers were washed with brine solution and dried over anhydrous

Na2SO4, then concentrated under reduced pressure. The crude residue was purified by flash

column chromatography over silica gel (10% EtOAc in hexane) to afforded product 56 as

colourless oil.

Yield : 1.40 g, 75 %.

[α]23

D : –45.5 (c = 1.0, CHCl3).

IR (KBr) : 3061, 2926, 2854, 1683, 1598, 1513, 1448, 1250,

1068, 755, 698 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 7.96 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H),

7.45 (t, J = 7.3 Hz, 2H), 7.31-7.21 (m, 7H), 6.86 (d, J =

8.8 Hz, 2H), 5.14 (t, J = 5.1 Hz, 1H), 4.50 (m, 2H),

4.28 (m, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 3.43 (dd, J =

6.6, 16.1 Hz, 1H), 3.27 (dd, J = 5.8, 16.1 Hz, 1H), 2.39

(ddd, J = 3.6, 8.0, 13.2 Hz, 1H), 2.05 (ddd, J = 3.6, 8.0,

13.2 Hz, 1H), 1.95 (m, 1H), 1.58 (m, 1H).

13C NMR (100 MHz, CDCl3) : δ 198.4, 140.6, 137.2, 133.1, 130.6, 129.2, 128.5,

128.4, 128.2, 127.1, 126.3, 126.1, 113.8, 71.9, 70.7,

69.8, 67.3, 55.3, 44.4, 36.4, 34.4.

MS (ESI) : m/z 439 (M+Na)+.


Diospongin B (1):

O

OH

O

To a stirred solution of 56 (1.40 g, 3.37 mmol) in CH2Cl2:H2O (9:1) (70 mL) was added DDQ

(0.919 g, 4.05 mmol) at 0oC and the reaction mixture was stirred at room temperature for 1 h.

The reaction mixture was quenched with saturated NaHCO3 solution and extracted with

EtOAc (3 x 20 mL). The combined organic layers were washed with H2O followed by brine

solution and dried over anhydrous Na2SO4, then concentrated under reduced pressure. The

crude residue was purified by flash column chromatography (30% EtOAc in hexane) to

afford the product 1 as an amorphous solid.

Yield : 0.91 g, 92 %.

[α]23

D : –22.5 (c = 0.2, CHCl3).

IR (KBr) : 3624, 2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174

753 cm-1

.


7.47 (t, J = 8.2 Hz, 2H), 7.34 (m, 5H), 5.19 (t, J = 4.4

Hz, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 3.45 (dd, J = 7.0,

15.7 Hz, 1H), 3.17 (dd, J = 5.9, 15.7 Hz, 1H), 2.51

(ddd, J = 3.8, 5.1, 13.4 Hz, 1H), 2.05 (ddd, J = 4.4, 8.9,

14.6 Hz, 1H), 1.92 (ddd, J = 5.0, 9.7, 13.5 Hz, 1H),

1.50 (dt, J = 9.3, 12.3 Hz, 1H).

13C NMR (100 MHz, CDCl3) : δ 198.3, 140.2, 137.2, 133.2, 128.6, 128.5, 128.3,

127.1, 126.3, 72.3, 66.9 64.2, 44.6, 40.1, 36.7.

MS (ESI) : m/z 319 (M + Na)+.


[2-((2S, 4S, 6S)-4-(tert-Butyldiphenylsilyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-

phenylethanone] (57):

O

OTBDPS

O

To a stirred solution of 1 (0.5 g, 1.68 mmol) in CH2Cl2 (15 mL) was added Et3N (0.341 g,

3.37 mmol) at 0 oC. After stirring the solution for 15 min, tert-Butyldiphenylsilyl chloride

(0.927 g, 3.37 mmol) and DMAP (0.020 g, 0.16 mmol) was sequentially at the same

temperature. The resulting reaction mixture was stirred at room temperature for 6 h,

quenched with saturated NH4Cl solution and extracted with CH2Cl2 (3 x 20 mL). The

combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced

pressure. The crude residue was purified by flash column chromatography (10% EtOAc in

hexane) to afford the product 57 as a colourless oil.

Yield : 0.853 g, 95 %.

[α]23

D : –31.0 (c = 0.25, CHCl3).

IR (KBr) : 3068, 2927, 2855, 1681, 466, 1215, 1110, 760,

701 cm-1

.


7.62 (m, 3H), 7.47-7.36 (m, 8H), 7.05 (d, J = 4.8, Hz,

3H), 6.71 (t, J = 4.8 Hz, 2H), 4.97 (t, J = 3.7 Hz, 1H),

4.03 (m, 1H), 3.94 (m, 1H), 3.37 (dd, J = 7.0, 15.7 Hz,

1H), 3.01 (dd, J = 5.9, 15.7 Hz, 1H), 2.11 (m, 1H),

2.00 (m, 1H), 1.86 (m, 1H), 1.65 (m, 1H), 1.05 (s, 9H).

13C NMR (100 MHz, CDCl3) : δ 198.3, 139.8, 137.0, 135.9, 135.7, 134.0, 133.7,

133.0, 129.7, 129.6, 128.5, 128.2, 128.1, 127.7, 127.6,

126.6, 126.1, 72.2, 66.8, 65.4, 44.7, 40.2, 36.5, 26.9.

19.0.

MS (ESI) : m/z 557 (M + Na)+.

HRMS (ES) : m/z 535.2692 (calcd for C35H39O3 Si: 535.2668).

Diospongin A (2):

O

OH

O

To a stirred solution of 57 (0.853 g, 1.59 mmol) in THF (15 mL) was added TBAF

(Specrochem Pvt.Ltd., India) (15.7 mL 15.9 mmol, 1M solution in THF) at 0 oC and the

reaction mixture was stirred at room temperature over night. The reaction mixture was

quenched with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers

were washed with brine solution and dried over anhydrous Na2SO4, then concentrated under

reduced pressure. The crude residue was purified by column chromatography over silica gel

(26% EtOAc in hexane) to afford product 2 as an amorphous solid.

Yield : 0.238 g, 86 %.

[α]23

D : –19.2 (c = 1.2, CHCl3).

IR (KBr) : 3624, 2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174,

753 cm-1

.


7.43 (t, J = 7.5 Hz, 2H), 7.22 (m, 5H), 4.90 (dd, J = 1.5,

11.3 Hz, 1H), 4.60 (m, 1H), 4.34 (t, J = 2.3 Hz, 1H),

3.39 (dd, J = 5.3, 15.9 Hz, 1H), 3.04 (dd, J = 7.5, 16.6

Hz, 1H), 1.95 (m, 2H), 1.67 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 198.3, 142.8, 137.5, 133.0, 128.5, 128.3, 128.2,

127.2, 125.8, 73.8, 69.1, 64.7, 45.2, 40.4, 38.8.

MS (ESI) : m/z 319(M + Na)+.


(R)-2-(Furan-2-yl)-2, 3-dihydropyran-4-one (ent-53):

O

O

O

Same procedure was used for preparation of compound ent-53 as used for 53 by using (R)-

(+)-BINOL catalyst gave white needle like crystals. [a single recrystallization from 1:2

Et2O:hexanes].

[α]23

D : –352 (c = 1.0, CH2Cl2).

IR (KBr) : 2923, 2852, 1724, 1595, 1268, 1114, 1039, 747 cm-1

.


6.46 (d, J = 2.9 Hz, 1H), 6.42 (dd, J = 2.2, 3.6 Hz, 1H),

5.50 (dd, J = 5.8, 7.3 Hz, 1H), 5.47 (d, J = 4.39 Hz,

1H), 3.10 (dd, J = 12.4, 16.8 Hz, 1H), 2.74 (dd, J = 3.6,

16.8 Hz, 1H).

13C NMR (100 MHz, CDCl3) : δ 191.4, 162.4, 149.4, 143.5, 110.5, 109.6, 107.3, 73.5,

39.4.

MS (ESI) : m/z 165 (M+H)+.

(2R, 6R)-2-(Furan-2-yl)-6-phenyl-tetrahydropyran-4-one (ent-54):

O

O

O

Same procedure was used for preparation of compound ent-54 as used for 54.

[α]23

D : + 10.9 (c = 0.5, CHCl3).

IR (KBr) : 2923, 2853, 1721, 1458, 1255, 1064, 1016, 752 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 7.44 (d, J = 1.5 Hz, 1H), 7.39-7.29 (m, 5H), 6.37 (d, J

= 3.5 Hz, 1H), 6.36 (t, J = 1.4 Hz, 1H), 5.44 (dd, J =

3.5, 7.1 Hz, 1H), 4.74 (dd, J = 5.6, 7.8 Hz, 1H), 2.96

(dd, J = 6.3, 14.8 Hz, 1H), 2.87 (dd, J = 2.8, 15.5 Hz,

1H), 2.72 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 205.5, 151.9, 143.2, 140.2, 128.6 128.1, 126.1, 110.2,

73.2 68.9, 48.4, 43.4.

MS (ESI) : m/z 243 (M + H)+.

HRMS (ESI) : m/z 243.1009 (calcd for C15H15O3: 243.1016).

(2R, 4S, 6R)-2-(Furan-2-yl)-6-phenyl-tetrahydro-2H-pyran-4-ol (ent-55):

O

OH

O


[α]23

D : +18.5 (c = 1.0, CHCl3).

IR (KBr) : 3404, 2925, 2856, 1451, 1366, 1060, 1011, 738 cm-1

.


= 1.5 Hz, 1H), 6.34 (d, J = 2.9 Hz, 1H), 5.26 (t, J = 4.4

Hz, 1H), 4.72 (dd, J = 3.6, 8.7 Hz, 1H), 4.10 (m, 1H),

2.53 (dt, J = 4.4, 13.1 Hz, 1H), 2.19 (dt, J = 4.4, 13.2

Hz, 1H), 2.02 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 154.3, 142.2, 140.2, 128.7, 127.3, 126.4, 110.4,

107.0, 72.2, 65.8, 64.2, 37.4, 36.9.

MS (ESI) : m/z 267 (M + Na)+.


(2R,4S,6R)-2-(Furan-2-yl)-4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran (ent-

50):

O

OPMB

O


[α]23

D : +37.0 (c = 0.9, CHCl3).

IR (KBr) : 3447, 2927, 2865, 1611, 1514, 1248, 1035, 816 cm-1

.


= 8.8 Hz, 2H), 6.35 (t, J = 2.9 Hz, 1H), 6.32 (d, J = 2.9

Hz, 1H), 5.28 (t, J = 3.6 Hz, 1H), 4.63 (dd, J = 2.9,

10.2 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.50 (d, J =

11.0 Hz, 1H), 3.81 (s, 3H), 3.78 (m, 1H), 2.58 (m, 1H),

2.24 (m, 1H), 2.05 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 159.1, 154.5, 142.1, 142.0, 130.5, 129.1, 128.6,127.2,

126.4, 113.8, 110.2, 108.2, 72.6, 71.4, 69.5, 65.9,

55.3, 34.9, 33.8.

MS (ESI) : m/z 387 (M + Na)+.


(2R,4S,6R)-Methyl-4-(4-methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-

carboxylate:

O

OPMB

OMe

O

[α]23

D : + 2.4 (c = 0.3, CHCl3).


= 8.8 Hz, 2H), 5.38 (dd, J = 2.9, 11.0 Hz, 1H), 4.54 (d,

J = 11.7 Hz, 1H), 4.50 (dd, J = 0.7, 2.2 Hz, 1H), 4.40

(d, J = 11.0 Hz, 1H), 3.88 (m, 1H), 3.81 (s, 3H), 3.67

(s, 3H), 2.52 (m, 1H), 2.06 (m, 2H), 1.91 (m, 1H).

13C NMR (100 MHz, CDCl3) : δ 173.1, 159.0, 141.8, 128.8, 128.4, 127.5, 126.2,

113.8, 113.7, 70.5, 70.0, 69.8, 69.7, 55.2, 51.9, 36.8,

30.4.

MS (ESI) : m/z 379 (M + Na)+.


(2R,4S,6R)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-carbaldehyde

(ent-51):

O

OPMB

CHO


[α]23

D : + 74.3 (c = 1.5, CHCl3).

IR (KBr) : 3443, 2928, 1728, 1611, 1512, 1245, 1034, 822 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 9.98 (s, 1H), 7.37-7.25 (m, 5H), 7.19 (d, J = 8.3 Hz,

2H), 6.83 (d, J = 9.1 Hz, 2H), 5.18 (dd, J = 2.3, 10.6

Hz, 1H), 4.45 (d, J = 11.3 Hz, 1H), 4.26 (d, J = 11.3

Hz, 1H), 4.20 (dd, J = 2.3, 6.8 Hz, 1H), 3.84 (m, 1H),

3.79 (s, 3H), 2.40 (m, 1H), 1.96 (m, 2H), 1.76 (m, 1H).

13C NMR (100 MHz, CDCl3) : δ 203.4, 159.2, 141.7, 130.2, 129.2, 128.4, 127.6,

126.0, 113.9, 77.5, 70.5, 69.7, 69.5, 55.3, 37.0, 29.6.

MS (ESI) : m/z 349 (M + Na)+.


2-((2R,4R,6R)-4-(4-Methoxybenzyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-

phenylethanone (ent-56):

O

OPMB

O


[α]23

D : + 47.2 (c = 0.8, CHCl3)

IR (KBr) : 3061, 2926, 2854, 1683, 1598, 1513, 1448, 1250, 1068,

755, 698 cm-1

.


7.45 (t, J = 6.6 Hz, 2H), 7.31-7.22 (m, 7H), 6.86 (d, J =

8.8 Hz, 2H), 5.14 (t, J = 5.1 Hz, 1H), 4.50 (m, 2H),

4.28 (m, 1H), 3.80 (s, 3H), 3.73 (m, 1H), 3.43 (dd, J =

6.6, 16.1 Hz, 1H), 3.27 (dd, J = 5.8, 16.1 Hz, 1H), 2.43

(ddd, J = 3.6 8.0, 13.2 Hz, 1H), 2.10 (ddd, J = 6.3, 8.0,

13.2 Hz, 1H), 1.97 (m, 1H), 1.63 (m, 1H).

13C NMR (100 MHz, CDCl3) : δ 198.4, 140.6, 137.2, 133.0, 130.5, 129.2, 128.5,

128.4, 128.2, 127.0, 126.3, 126.1, 113.8, 71.9, 70.7,

69.8, 67.3, 55.2, 44.4, 36.4, 34.4.

MS (ESI) : m/z 439 (M + Na)+.


2-((2R,4R,6R)-4-hydroxy-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-phenylethanone (ent-

1):

O

OH

O


[α]23

D : + 23.3 (c = 0.2, CHCl3).

IR (KBr) : 3624, 2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174,

753 cm-1

.


7.49 (t, J = 8.8 Hz, 2H), 7.38-7.23 (m, 5H), 5.18 (t, J =

4.4 Hz, 1H), 4.22 (m, 1H), 4.00 (m, 1H), 3.45 (dd, J =

6.6, 15.4 Hz, 1H), 3.16 (dd, J = 5.9, 16.1 Hz, 1H), 2.15

(ddd, J = 3.7, 7.3, 13.2 Hz, 1H), 2.04 (m, 1H), 1.91

(ddd, J = 3.7, 5.1, 8.8 Hz, 1H), 1.50 (dt, J = 9.5, 12.4

Hz, 1H).

13C NMR (100 MHz, CDCl3) : δ 198.4, 140.2, 137.1, 133.1, 128.5, 128.4, 128.2,

127.0, 126.3, 72.3, 66.9, 64.0, 44.6, 40.0, 36.6.

MS (ESI) : m/z 319 (M + Na)+.


2-((2R, 4R, 6R)-4-(tert-Butyldiphenylsilyloxy)-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-

phenylethanone (ent-57):

O

OTBDPS

O


[α]23

D : + 36.0 (c = 0.25, CHCl3)

IR (KBr) : 3068, 2927, 2855, 1681, 1466, 1215, 1110, 760,

701 cm-1

.

1H NMR (400 MHz, CDCl3) : δ 7.94 (d, J = 6.6 Hz, 2H), 7.72 (t, J = 6.7 Hz 4H), 7.65

(d, J = 6.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44-

7.36 (m, 7H), 7.05 (t, J = 2.9 Hz, 2H), 6.71 (t, J = 2.9

Hz, 2H), 4.97 (t, J = 3.7 Hz, 1H), 3.98 (m, 2H), 3.39

(dd, J = 7.4, 15.5 Hz, 1H), 3.05 (dd, J = 5.9, 16.2 Hz,

1H), 2.15 (m, 2H), 1.74 (m, 2H), 1.07 (s, 9H).

13C NMR (100 MHz, CDCl3) : δ 198.3, 142.9, 135.8, 35.7, 134.1, 132.9, 130.3, 129.8,

129.7, 128.5, 128.4, 128.3, 128.1, 127.6, 127.0, 126.4,

125.7, 73.9, 69.6, 66.1, 45.3, 40.6, 38.4, 27.0, 19.3.

MS (ESI) : m/ 557 (M + Na)+.

HRMS (ESI) : m/z 535.2685 (calcd for C35H39O3 Si: 535.2668).

2-((2R,4R,6S)-4-Hydroxy-6-phenyl-tetrahydro-2H-pyran-2-yl)-1-phenylethanone (ent-

2):

O

OH

O


[α]23

D : +18.9 (c = 1.8, CHCl3).

IR (KBr) : 3622, 2922, 2854, 1681, 1598, 1452, 1058, 751 cm-1

.


7.43 (t, J = 7.7 Hz, 2H), 7.26-7.22 (m, 5H), 4.90 (dd, J

= 1.9, 12.0 Hz, 1H), 4.60 (m, 1H), 4.34 (t, J = 3.0, 1H),

3.39 (dd, J = 5.7, 16.0 Hz, 1H), 3.04 (dd, J = 6.8, 16.0

Hz, 1H), 1.94 (m, 2H), 1.75-1.60 (m, 2H).

13C NMR (100 MHz, CDCl3) : δ 198.3, 142.5, 137.0, 133.1, 128.5, 128.2, 127.2,

125.8, 73.7, 68.9, 64.6, 45.0, 39.8, 38.3.

MS (ESI) : m/z 319 (M + Na)+.


REFERENCES

1. (a) Westly, J. W. Ed.; Polyether Antibiotics; Marcel Dekker: New York, 1983; Vols.

I and II. (b) Dobler, M. Ionophors and Their Structures; Wiley- Interscience: New

York, 1981. (c) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7-55.

2. Sutherland, R.; Boon, R. J.; Griffin, K. E.; Masters, P. J.; Slocombe, B.; White,

A. R. Antimicrobial Agents and Chemotherapy. 1985, 27, 495-498.

3. Biovin, T. L. B. Tetrahedron, 1987, 43, 3309.

4. Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc.

1995, 118, 9422.

5. Schummer, D.; Gerth, K.; Reichenbach, H.; Hofle, G. Liebigs Ann. 1995, 685.

6. Gerth, K.; Schummer, D.; Hofle, G.; Irschik, H.; Reichenbach, H. J. Antibiot.

1995, 48, 973.

7. Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.

8. Cutignano, A; Brujno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-

Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775.

9. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J. Am. Chem.

Soc. 1994, 116, 6015.

10. a) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D. S.; Jung, C. K.; Joo, J. M. J. Am.

Chem. Soc. 2002, 124, 384. b) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D. S.;

Jung, C. K.; Hong, C. Y.; Jeong, S.; Jeon, K. Bioorg. Med. Chem. Lett. 2002,

12, 3519.

11. a) Gurjar, M. K.; Kumar, P.; Rao, B. V. Tetrahedron Lett. 1996, 37, 8617. b)

Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron Lett. 1997, 38, 1001.

12. Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L. U.S. Patent 5728727

[A 9803317], 1998; Chem. Abstr. 1998, 128, 239489.

13. Bode, H. B.; Zeeck, A. J. Chem. Soc. Perkin, Trans. 1 2000, 323.

14. Sengoku, T.; Arimoto, H.; Uemura, D. Chem. Commun. 2004, 1220. b) White,

J. D.; Smits, H. Org. Lett. 2005, 7, 235.

15. Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 104, 2199.

16. Yamashita, Y, M.; Haddock, R. L.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,

1147.

17. a) Fujiwara, A.; Murai, M.; Yamashita, Y. M.; Yasumoto, T. J. Am. Chem.

Soc. 1998, 120, 10770. b) White, J. D.; Blakemore, P. R.; Browder, C. C.;

Hong, J.; Lincoln, C. M.; Nagorrnyy, P. A.; Robarge, L. A. Wardrop, D. J. J.

Am. Chem, Soc. 2001, 123, 893.

18. Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J. Am. Chem. Soc.

2000, 122, 619.

19. a) Zhang, W. C.; Li, C. J. Tetrahedron 2000, 56, 2403. b) Rechnovsky, S. D.;

Thomas, C. R. Org. Lett. 2000, 2, 1217. c) Kozmin, S. A. Org. Lett. 2001, 3,

755.

20. Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley, P.;

McCarthy, P. J.; Pitts, T. P.; Pomponi, S.A.; Reed, J. K. J. Nat. Prod. 2007, 70,

412

21. Ulanovskaya, O. A.; lanjic, J.; Suzuki, M.; Sabharwal, S.S.; Schumacker, P. T.;

Kron, S. J.; Kozmin, S. A. Nat. Chem. Biol. 2008, 4, 418.

22. a) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S. Angew.

Chem. 2007, 119, 9371; Angew. Chem. Int. Ed. 2007, 46, 9211. b)

Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130,

804. c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem. 2008, 120, 3286;

Angew. Chem. Int. Ed. 2008, 47, 3242. d) Paterson, I.; Miller, N. A. Chem.

Commun. 2008, 4708. e) Vintonyak, V. V.; Kunze, B.; Sasse, F.; Maier, M. E.

Chem. Eur. J. 2008, 14, 11132. f) Custar, D.W.; Zabawa, T. P.; Hines, J.;

Crews, C. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 12406.

23. Ringel, S. M.; Greenough, R. C.; Roemer, S.; Connor, D.; Gutt, A. L.; Blair, B.;

Kanter,G.; von Strandtmann, M. J. Antibiot. 1977. 30, 371.

24. Gerth, K.; Washausen, P.; Hofle, G.; Irschik, H.; Reichenbach, H. J. Antibiot.

1996, 49, 71.

25. Connor, D. T.; von Strandtmann, M. J. Org. Chem. 1978, 43, 4606.

26. (a) Connor, D. T.; Greenough, R. C.; von Strandtmann, M. J. Org. Chem. 1977,

42, 3664. (b) Just, G.; Potvin, P. Can. J. Chem. 1980, 58, 2173.

27. Hofle, G.; Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs Ann. Chem. 1991,

941.

28. For earlier synthetic studies on ambruticin, see: (a) Michelet, V.; Adiey, K.;

Bulic, B.; Geneˆt, J.-P.; Dujardin, G.; Rossignol, S.; Brown, E.; Toupet, L. Eur.

J. Org. Chem. 1999, 64, 2885. (b) Wakamatsu, H.; Isono, N.; Mori, M. J.

Org. Chem. 1997, 62, 8917. (c) Liu, L.; Donaldson, W. A. Synlett 1996,

103. (d) Marko´, I. E.; Bayston, D. J. Synthesis 1996, 297. (e) Marko´,

I. E.; Bayston, D. J. Tetrahedron 1994, 50, 7141. (f) Marko´, I. E.;

Bayston, D. J. Tetrahedron Lett. 1993, 34, 6595. (g) Nagasawa, T.;

Handa, Y.; Onoguchi, Y.; Ohba, S.; Suzuki, K. Synlett 1995, 739. (h)

Davidson, A. H.; Eggleton, N.; Wallace, I. H. J. Chem. Soc., Chem. Commun.

1991, 378. (i) Burke, S. D.; Armistead, D. M.; Schoenen, F. J.; Fevig, J. M.

Tetrahedron 1986, 42, 2787. (j) Barnes, N. J.; Davidson, A. H.; Hughes,

L. R.; Procter, G. J. Chem. Soc., Chem. Commun. 1985, 1292. (k)

Barnes, N. J.; Davidson, A. H.; Hughes, L. R.; Procter, G.; Rajcoomar, V.

Tetrahedron Lett. 1981, 22, 1751. (l) Sinay¬, P. In Bioorganic

Heterocycles 1986: Synthesis, Mechanism and BioactiVity; Elsevier:

Amsterdam, The Netherlands, 1986; pp 59.

29. (a) Kende, A. S.; Fujii, Y.; Mendoza, J. S. J. Am. Chem. Soc. 1990, 112, 9645.

(b) Kende, A. S.; Mendoza, J. S.; Fujii, Y. Tetrahedron 1993, 49, 8015.

30. Martin has presented a total synthesis of ambruticin, see: Kirkland, T.A.;

Martin, S. F.; Colucci, J.; Marx, M.; Geraci, L. Paper Abstracts; 220th

National

Meeting of the American Chemical Society, 2000; American Chemical Society:

Washington, DC, 2000; ORGN-126.

31. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.

32. (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C, G.; Marini-Bettolo, G. B.

Gazz. Chim. Ital. 1964, 287. (b) Galeffi, C.; Casinovi, C, G.; Marini-Bettolo,

G. B. Gazz. Chim. Ital. 1965, 95. (c) Aragao Craveiro, A.; da Casta Prado, A.;

Gottlieb, O. R.; Welerson de Albquerque, P. C. Phytochemistry 1970, 9, 1869.

33. Alcantara, A. F. de C.; Souza, M. R.; Pilo-Veloso, D. Fitoterapia 2000, 71,

613.

34. Colobort, F.; Des Mazery, R.; Solladie, G.; Carreno, M. C. Org. Lett. 2002, 4,

1723.

35. a) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D.; Org. Lett. 2002,

4, 3919. b) Evans, P. A.; Cui, J.; Gharpure, S. J. Org, Lett. 2003, 21, 3883. c)

Lee, E; Kim, H, J; Jang, W. S. Bull. Korean Chem. Soc. 2004, 25, 1609. d)

Boulard, L.; BouzBouz, S.; Cossy, J.; Franck, X.; Fifadere, B. Tetrahedron

Lett. 2004, 45, 6603. e) Clarke, P. A.; Martin, W. H. C. Tetrahedron Lett.

2004, 45, 9061. f) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005, 46,

2021. g) Chandrasekhar, S.; Prakash, S. J.; Shyamsunder, T. Tetrahedron Lett.

2005, 46, 6651.

36. Yin, J.; Kouda, K.; Tezuka, Y.; Tran, Q. L.; Miyahara, T.; Chen, Y.; Kadota, S.

Planta Med. 2004, 70, 54.

37. Frost, H. M. Bone Minor. Res. 1992, 7, 253.

38. Wu, J. H.; Zhao, G.; Zhong Yi Zheng Gu 1996, 8, 30.

39. Mohan, S.; Kutilek, S.; Zhang, C.; Shen, H. G.; Kodama, Y.; Srivastava, A. K.;

Weredal, J. E.; Bermer, W. G.; Baylink, D. J. Bone 2000, 27, 471.

40. Duncan, R.; Misler, S. FEBS Lett. 1989, 251, 17.

41. Jennings, M. P.; Sawant, K. B. J. Org. Chem. 2006, 71, 7911.

42. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.

43. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.

44. Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J. J. Am. Chem. Soc.

1991, 113, 8036.

45. Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321.

46. Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.

47. Bressy, C.; Allais, F.; Cossy, J. Synlett. 2006, 3455.

48. Kawai, N.; Hande, S.-M.; Uenishi, J. Tetrahedron. 2007, 63, 9049.

49. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.

50. Wang, H.; Shuhler, B. J.; Xian, M. Synlett. 2008, 2651.

51. (a) Smith, A. B.; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis, C.;

Moser, M. H. J. Am. Chem. Soc. 2003, 125, 14435. (b) Tietze, L. F.; Geissler,

H.; Gewert, J. A.; Jakobi, U. Synlett. 1994, 511. (c) Fisher, M. R.; Kirschning,

A.; Michel, T.; Schaumann, E. Angew. Chem. Int. Ed. Engl. 1994, 33, 217.

52. (a) Kumaraswamy, G.; Sadaiah, K.; Ramakrishna, D. S.; Naresh, P.; Sridhar, B.;

Jagadeesh, B. Chem. Commun. 2008, 5324. (b) Kumaraswamy, G.; Padmaja,

M.; Markondaiah, B.; Jena, N.; Sridhar, B.; Udaya Kiran, M. J. Org. Chem.

2006, 71, 337. (c) Kumaraswamy, G.; Padmaja, M. J. Org. Chem. 2008, 73,

5198. (d) Kumaraswamy, G.; Markondaiah, B. Tetrahedron Lett. 2007, 48,

1707. (e) Kumaraswamy, G.; Markondaiah, B. Tetrahedron Lett. 2008, 49, 327.

53. Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998.

54. (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics. 1997, 16, 4229. (b)

Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579.

55. Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Maddaford, S. P. Org.

Lett. 2001, 3, 2571.

56. a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.

1997, 119, 8738. b) Haack, K.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.

Angew. Chem., Int. Ed .Engl. 1997, 36, 285.

57. Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.; Tamber, U. K.;

Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745.

chapter-i - inflibnetshodhganga.inflibnet.ac.in/bitstream/10603/8220/9/09_chapter 1.pdf · such...

Documents