CHAPTER IV

SYNTHESIS OF (4S1 5S)-4-(2-HYDROXY-2,2-DlARYL ETHYL)-2,2-DIMETHYL-aIaIawIa'-TETRLL ARYL-1,3-

DIOXOLANE-4,5-DIMETHANOLS AND THEIR CATALYTIC STllDlES

IV.l Introduction

One of the most important breakthroughs in chemical technology in the last

few decades is the enantioselective synthesis of chiral organic compounds via

asymmetric catalytic reaction. Many recent synthetic applications of asymmetric

synthesis are linked to asymmetric catalysis.z In the field of asymmetric catalysis

spectacular progress has been made by using homogeneous catalysts based on

transition metal complexes modified by chiral ligands. Homogeneous

organometallic catalysts can function with ligands like phosphines, alcohols,

amines, arnides, sulphoxides and cyclopentadienyl groups. Examples of reactions

that are successfully investigated in the recent past are hydrogenation, double-

bond migration, hydrosilylation, hydroformylation, olefin codimerisation,

hydrocyanation, coupling between a Grignard reagent and vinylic halide, allylic

alkylation, Diels-Alder reaction, epoxidation and cyclopropanation.

Although acid and base catalysts are widely used to accelerate organic

reactions, the development of chiral base and acid catalysts was a relatively

unexplored area in organic synthesis. However in the last few years, remarkable

progress has been observed in this area. Typial examples are the Sharpless

asymmetric epoxidation,'41 the ketene addition reaction,'42 phase transfer

catalysis143 and proline-catalysed intramolecular aldol c~ndensa t ion . '~~ The

development of chiral Lewis acids and bases is now the subject of intense

research.

IV.1.1 Chiral Hydroxy Compounds used as Iigands or chiral precursors in Asymmetric Synthesis

It is evident from the review (Chapter 1) that, a number of monodentate,

bidentate and polydentate alkoxide ligands have been developed in recent years.5

The most successful strategy for preparing metal alkoxides for use as asymmetric

catalyst has been to employ diols or polyols, so that the metal centre is stabilised

vla chelation. Some of the frequently used alkoxide ligands are listed below

(FigIV. 1).

Fig IV.l

Chiral hydroxy acids such as Tartaric acid, Malic acid, Lacticacid etc

present an attractive source from the chiral pool for the preparation of chiral

synthons (Scheme IV. 1). loo, 145.148

0 HOOC COOH R,o'p; ::- tartaric acid

R2O J \ Ts 0 --OTs

0

Scheme IV.l

A variety of chiral agents derived from hydroxy acids have been widely

used in asymmetric reactions such as Diels-Alder reaction, 2+2 cycloaddition

reactions, Sharpless asymmetric epoxidation, Addition of EtzZn to aldehydes etc.

In many cases only the backbone is left unchanged while the OH andlor the

COOH groups are protected or transformed to give efficient ligands. Some

homogeneous chiral catalysts derived from tartaric acid are listed below

(Fig 1v.21.~

Diels-Alder reaction Epoxidation of ally lic alcohols Oxidation of sulphides

Hy drosily lation of ketones Hy drobomtion of olefms

Use of chiral amino diols as ligands in various asymmetric catalytic

reactions have been reported recently (Fig IV.3). 149-151

M e ... I MC / Ti p h y N ~ f" \,,.ph /sm

OH OH 01 OH

Asymmetric epoxidation of Asymmetric MPV reduction substitutd ally1 alcohol of q l methyl ketones

Stereovelective reduction of prochiral ketones

Fig IV.3

Recently this laboratory has established chiral triesters prepared from

Garcinia acid 156 and Hibiscus acid 157 as efficient chiral diol ligands in

asymmetric Sharpless epoxidation reaction (Scheme 1 v . 2 ) ' ~ ~

Garcinia acid triester ,,:::o -

(CH,),COOH, T(OiPr), (S,S)-Epoxygeraniol

CH2C12, - 2 0 ' ~

:ti: Hibiscus acid tries ter J ..'.,,,/OH

Scheme IV.2

Chiral acetals and ketals act as efficient chiral auxiliaries in asymmetric

synthesis by influencing the face selectivity of a proximal prochiral centre. In the

pharmaceutical, phytopharmaceutical, fragrance and lacquer industries, acetals are

used both as intermediates and as end products.'52

A large array of chemical transformations have been investigated with the

acetal auxiliary in various relative positions to the prochiral centre, either on the

nucleophile or on the electrophile. Perhaps, the most simple conceptual approach

to reaction where the chiral acetal is on the electrophile is the attack of a carbonyl

group next to a chiral acetal (Scheme I V . ~ ) . " ~

R=MeorPh L W 83

LiAM4~gSr2 9

R = -CH20Me L I A h Y 9

Scheme IV.3

The diastereoselective reaction of a chiral nucleophile having an acetal

appendage are very scarce. Thus ketene acetals have been used in asymmetric

synthesis, with diphenyl 1,2-ethane dial seeming to be the best auxiliary in

cycloaddition reactions, as well as in conjugate addition-enolate trapping reactions

(Scheme IV.4).

Ph 1) EtLi -

Ph

1 10

Scheme IV.4

N. 1.2 Asymmetric Diels-Alder Reactions

Efficient synthesis of enantiomerically pure and structurally complex

molecules by inducing asymmetry in carbon-carbon bond forming reactions has

been a great challenge for organic chemists. Among the several methods available

for asymmetric induction during such carbon-carbon bond forming reactions, the

Diels -Alder reaction deserve special mention. After its discovery in 1928, the

Diels-Alder transformation was often said to be the most powerful tool in the

carbon-carbon bond forming reactions in organic synthesis. This transformation

formally belongs to the general class of pericyclic reactions and is a [ 4 ~ + 2 ~ ]

cycloaddition of an electron-rich diene to an electron-poor dienophile. The

importance and usefulness of Diels-Alder reaction arises from the high regio and

stereoselectivity, as well as from the possible use of numerous dienes and

dienophiles bearing a large number of functional groups.

A useful development became possible when it was found that Lewis acids

catalyse the Diels-Alder reaction, allowing to run it in very mild conditions, even

below o'c. '~~ The activation process occurs by coordination of the carbonyl group

of dienophile to the Lewis acid. Chiral auxiliaries of various kinds have been

subsequently developed for thermal or catalytic Diels-Alder reactions, and some

of them are now commercially available. The development of asymmetric Diels-

Alder reaction using metal alkoxide as a catalyst has attracted attention in the

recent literature. The enantioselection of the products depends on the absolute

configuration of the chiral auxiliary residing either in the substrate or in the ligand

on the catalyst. In the substrate control method, the chiral auxiliary is a part of the

diene or dienophile and this method needs separate steps for incorporation and

subsequent removal of chiral auxiliary. These factors can be overcome by

employing chiral catalysts. In metal catalysed asymmetric Diels-Alder reaction,

the source of chirality is manifested by the ligand. This approach not only

eliminates the need for incorporation and removal of the chiral auxiliary, requires

only catalytic amount of the chiral source.

Lewis acids

Frontier Molecular Orbital theory, in addition to predicting endoiexo

selectivity can also explain the role of Lewis acid as a catalyst in Diels-Alder

r e a ~ t i 0 n . l ~ ~ Interaction of chiral lewis acid with a dienophile lowers the energy of

both LUMO and HOMO of the reactant resulting in lower activation energy for

the reaction. In majority of Diels-Alder reactions, the addition of Lewis-acid also

results in maximum selectivity which can be explained as follows. Increase in

reation rate that allows the reaction to be run at lower temperatures and this in turn

allows for differentiation in the diastereomeric transition states. The increase in the

selectivity also depends on the type of complex formed between the Lewis acid

and the dienophile prior to cycloaddition. Often times, bare Lewis acids like TiCI,

or A1C13 can induce polymerisation, react with functional groups andlor accelerate

substrate decomposition. To avoid such undesirable side reactions, sometimes the

metal chlorides have been replaced by the corresponding alkoxides.

In 1979, Koga first reported the use of optically active Lewis acids in

organic reaction^.^ Since then this exciting field of reagent controlled asymmetric

process has shown impressive development and several comprehensive reviews

have been published recently. 153,155

Though it is possible to develop effective chiral Lewis acid catalysts for the

Diels-Alder reaction, simple application of the chiral Lewis acids itself only

achieved moderate asymmetric i n d ~ c t i o n . ' ~ ~ Hence it is necessary to design chiral

auxiliaries that will interact with the Lewis acid to realize high asymmetric

induction.

Chiral Titanium Reagents

Chiral alkoxy titanium complexes prepared from chiral diols have been

used as chiral Lewis acids for the Diels-Alder reaction. Stochiometric amounts of

titanium complexes were first utilised, enantiomeric excesses in the range of

90-95% have been achieved in the condensation of cyclopentadiene and some

specific acrylamides and crotonamides.

Seebach et at and Narasaka et a1 24 found that a class of crotonam~des

(3-acyl-l,3-oxazolidin-2-ones) reacts wtth cyclopentadiene to give cycloadducts in

presence of some titanium complexes (Scheme IV.5). The titanium complexes

(2 mol equiv) were prepared from equimolar amounts of a chiral 1,4-diol

(TADDOL) derived from diethyl tartrate and TiC12(0i-Pr)2 The 3-acyl-1,3-

oxazolidin-2-one have been chosen because they should form a bidentate complex

with chiral titanium complex, resulting in increased stereoselectivity during the

Diels-Alder reaction. Indeed the major product (endo isomer) was obtained with

92% ee. . -'

Scheme IV.5

Narasaka et a1 made the interesting observation that 4 ~ " molecular sieves

allow the use of catalytic amounts of a dialkoxy dichloro titanate, keeping the

enantioselectivity at the level of 90% (close to the ee of the stoichiometric

reaction) (Scheme IV.6). 157, 158

Scheme IV.6

The beneficial effect of molecular sieves was ascribed in part to the

removal of water from the reaction mixture. The same authors found that alkyl

benzenes are excellent solvents for enhancing stereoselectivity of cycloadducts.

Mechanistic Aspects

It is well known that enone dienophiles can be activated by Lewis acids in

catalytic asymmetric Diels-Alder reactions, with improved regio and

stereoselectivity, when compared to that of uncatalysed reactions. The reason for

achieving high enantioselectivity in chiral Lewis acid catalysed Diels-Alder

reaction are not well studied. So, in order to understand the mechanism of

asymmetric induction, the conformational relationship between the chiral auxiliary

and the reaction site as well as the solution structure of Lewis acid-carbonyl

complexes must be elucidated.

Narasaka el al. studied the structure of the titanium complex involved in

scheme 1 v . 6 . ' ~ ~ The 'H NMR investigation gave some structural information on

the single species formed by mixing of the chiral diol and TiClz(Oi-Pr)2. However

it could not be decided if the complex is monomeric or dimeric. The chiral

titanium complex is in equilibrium with the chiral diol, TiC12(Oi-Pr)2 and

2-propanol. It could be seen that addition of molecular sieves (MS 4A) shifts the

equilibrium to the side of the chiral titanium complex. The simultaneous increase

in enantioselectivity comes from a decreased concentration of TiC12(Oi-Pr)2 which

can by itself catalyse the Diels-Alder reaction. It was also found that the

dienophile (3-acyl-l,3-oxazolidin-2-one) and the chiral titanium complex has been

isolated and seems to be the key intermediate in the cycloaddition. Corey et al.

investigated modified titanium catalysts for elucidating the origin of the high

enant iose le~t iv i t~ .~~ A strong influence of groups in meta position of aromatic

rings led the authors to propose the transition state represented in fig. IV.4.

Attractive a-a interactions between a donor aromatic group and the double bond

of the dienophile protects one face and provides high ee.

Fig. IV.4

With this background, preparation of optically pure (4S,5S)-4-(2-hydroxy-

2,2-diary1 ethyl)-2,2-dimethyl-a,aCLa',a'-tetraaryl-l,3-dioxolane-4,5-dimethanols,

which resemble very much with TADDOL have been carried out starting from

trimethyl ester of Garcinia acid. 1,2-Diol moiety of trimethyl ester is protected and

the resulting ketal on Grignard reaction with appropriate reagents furnished the

corresponding -4-(2-hydroxy-2,2-diary1 ethyl)

compounds have been used as efficient chiral iigands i

Diels-Alder reaction of 3-crotonyl oxazolidinone and cyclopentadiene.

IV.2 Results and discussion

N.2.1 Preparation of Trimethyl Ester and Ketal from Garcinia acid

Having two chiral centres and a vicinal diol moiety triesters of Garcinia

acid are expected to find extensive application in asymmetric reactions. The

procedure developed by Ibnusaud and co-workers has been followed for the

preparation of triester.I6O

Treatment of 156 with aqueous sodium hydroxide under refluxing

conditions, followed by the addition of alcohol furnished the highly hygroscopic

trisodium salt 166 (Scheme IV.7).

NaOH 156 - NaO2C

MeOH HO OH

166

Scheme IV.7

A suspension of 166 in appropriate alcohol on refluxing with thionyl

chloride, readily furnished the corresponding triester in good yield and purity

(Scheme IV.8).

SOClz 166 - Mc0,C

MeOH HO OH

167

Scheme IV.8

Protection of vicinal diol moiety of the triester is necessary for further

transformations like Grignard reaction, alkylation etc. Attempts to prepare ketal of

triester following conventional procedures161 were futile as the molecule

underwent lactonisation. This could be due to the fact that conditions for ketal

formation are ideally suited for lactonisation also. The difficulty for the

preparation of acetonide was overcome by following a reported modified

procedure.'62 A solution of triester in acetone is refluxed in the presence of

anhydrous copper sulphate and catalytic quantity of concentrated sulphuric acid.

Workup of the reaction after about four hours, furnished the acetonide 168

(Scheme IV.9).

M a 2 c p e pa..... Anhyd CuS 0,

M a 2 C - Me0,C + HO OH Acetone, H

168

Scheme IV.9

In the case of 168 the yield obtained was very poor (22%) and to improve

the yield, the acetonide formation was tried with 2,2-dimethoxy propane and

catalytic amount of p-toluene sulphonic acid in dry benzene. Even then the

hydrolysis of the triester followed by regular lactonisation was observed.

Protection of vicinal hydroxyl groups of triester using acetophenone dimethyl

acetal also was attempted. However, the ketal formed was found to be

decomposing during isolation.

N.2.2 Preparation of (4S,5S)-4-(2-hydroxy-2,2-diaryl ethyl)- 2,2-dimethyl-a,a,a9,a'-tetraaryl-1 ,3-diawo lane-4,5- dimethanols

Starting from optically active dialkyl tartrates, Seebach and co-workers

have prepared a,a,a',a'-tetra aryl-1,3-dioxolane-4,5-dimethanols (TADDOLs,

169) and used them as efficient chiral ligands in various asymmetric reactiom5

The ketd of diethyl tartrate on Grignard reaction with appropriate aryl magnesium

halide furnished the corresponding TADDOL (Fig. IV.5, Scheme IV. 10).

Scheme IV.10

With the objective of obtaining (4S,SS)-4-(2-hydroxy-2,2-diaryl ethyl)-2,2-

dimethyl-a,a,a',a'-tetraaryl-1,3-dioxolane-4,5-dimethanols, 170a-c, Grignard

reactions on 168 have been carried out following the general method developed by

Seebach et a1 for the preparation of TADDOL using diethyl tartrate. By refluxing

a solution of ketal (168) with appropriate aryl Grignard reagent in dry

tetrahydrofuran furnished 170a-c as oily mass (Scheme IV. 1 1). The formation of

these compounds are thoroughly confirmed by IR, 'H NMR, I3c NMR and Mass

spectra (Fig IV.6, IV.7 & IV.8).

170a : AF pheny I 170b : Ar=4-methy 1 pheny 1

Scheme IV.l l 17Uc : AFI-naphthy 1

The IR,'H NMR and I3c NMR data clearly reveal the absence of carbonyl

group. "C NMR spectra show the expected signal characteristic of the C-2 carbon

of the 1,3-dioxolane ring at -1 15 ppm. Peaks at 6 1.25-1.55 ppm in the 'H NMR

and at -23 ppm in the I3c NMR indicate the methyl groups attached to the

dioxolane ring. The AB pattern in the 'H NMR at 6 3.3 ppm and 3.1 ppm confirms

the presence of methylene group. Peaks around 77-80 ppm indicates the tertiary

carbon atoms as well as C-4 and C-5 of the dioxolane ring. Aromatic protons give

peaks at 7.6-7.23 and aromatic carbon atoms are confirmed by peaks 127-146 in 13 C NMR. These molecules show corresponding molecular ion peaks in the fast

atom bombardment mass spectra at mlz, 662,746 and 962 respectively.

4;s 1:s i j r &it ;b" '4ao' 450 "' rbo 350 E i - % h o o

Fig. IV.6a

Fig. IV.6b

Fig. IV.6c

Fig. IV.6d

- -- -.--.-. ~ ,--- r ---

* / -

-7 cc ,~~ 2 c I

I

L . - L , . L -c u 170b I>

d O O 0 2 0 0 0 1 6 0 0 1 2 0 0 8 0 0 100

W A V E NUMBER I C ~ - I I 1 Fig. IV.7a

, .? -- , -- Fig. IV.7c

.ear--- ib5 -n . . 1 1

d l * , - !

cr___? ..--- 488 U 5 l 582 SUil 6ZB 78P 756 I,L

, Fig. lV.7d

Fig. IV.8a 170c

Fig. IV.8b

Fig. IV.8c

Fig. lV.8d

N.2.3 Asymmetric Diels-Alder reaction employing (45, 5s)-4- (2-hydrawy-2,2-diaryI ethyl)-2,2-dimethyZ-aya,ay,a'- tetraawl-1,3-diarolane-4,5-dimethanols as chiral Zigands

Although large number of asymmetric Diels-Alder reactions are known,

greater degree of asymmetric induction can occur with chiral Lewis acids having

Cz-symmetric diols as chiral ligands. To explore the efficiency of (4S,5S)-4-(2-

hydroxy-2,2-diarylethyl) - 2, 2 - dimethyl - a, a, a', a' - tetraaryl -1,3-dioxolane-

4,5-dimethanols as chiral ligands, asymmetric Diels-Alder reactions using these

ligands which lacks Cz- symmetry have been considered.

An examination of the structure of these triols show that the molecular

topology matches with TADDOL derived from dialkyl tartrate except the fact that

C-4 hydrogen is replaced by CHZ-C(Ar)Z-OH. Therefore these triols are nothing

but -4-(2-hydroxy-2,2-diarylethyl) TADDOLs. Hence it is a curiosity to study the

employment of 170a-c as chiral ligands in asymmetric organic reactions.

Therefore a preliminary study was undertaken to assess the influence of

chiral ligands 170a-c derived from 156 on chiral induction in asymmetric Diels-

Alder reaction of 3-crotonyl oxazolidinone and cyclopentadiene. 170a-c are used

as chiral ligands for the preparation of titanium complexes which were used as

catalysts in place of TADDOL-titanium complex. Chiral titanium reagents are

prepared insitu by mixing chiral triols 170a, 170b or 170c and

dichlorodiisopropoxy titanium in toluene at room temperature. Diels-Alder

reaction was carried out using catalytic amount of the titanium reagent. The best

solvents for the Ti-TADDOLate-mediated Diels-Alder reactions are those with

poor donor ability, such as toluene, petroleum ethers, methylene chloride or

mixtures thereof, For the addition of 3-crotonyl oxazolidinone to cyclopentadiene

toluene is the solvent of choice. Hence the reaction is carried out in toluene in

presence of 4 ~ ' molecular sieves.

Scheme IV.12

Fig. IV.9

The reaction proceeded smoothly leading to the formation of endo and exo

cyclo adducts, 171 (Scheme IV.12). The major endo adduct was purified by silica

gel chromatography. The adduct has shown optical activity in each case ( [aID = -

22.96, -16.05 and -13 respectively). This indicates a feasibility of using (4S,5S)-4-

(2-hydroxy-2,2-diary1ethyl)-2,2-dimethyl-a,a,ct',a'-tetraaryl-1,3-dioxolane-4,5-

dimethanols 170a-c as chiral ligands in place of TADDOL. The possible transition

state complex involving 170 is shown in Fig.IV.9. A control Diels-Alder reaction

using TADDOL 169 as chiral ligand was also carried out under identical

laboratory conditions.

Enantiomeric excesses of the endo products were calculated from the

maximum specific rotation values available in the 1 i te ra t~re . l~~

The recorded [a] 0 values and the calculated enantiomeric excesses (ee) of

the endo adducts are given in Table IV.1. The adducts were identified using 'H

and "C NMR spectra (Fig IV. 10, IV. 1 1 &IV. 12).

Table IV.1

Enantiomeric excess (%)

170b

1 7 0 ~

~ e ~ o r t e d ' ~ ~ [ a ] ~ value of 171 when TADDOL (169)

was used as ligand: -191'

-16.058 ~-rL‘%7 -13.000 6.80

171

Ligand used 170a

Fig. IV.l Oa -. . . , . .-.

>"

, . . . . - , , - .~ - .- . -. r- . , --.-- 2 ° C 18,; 16. 140 12. 10. 8 : 3 4. ,3 A ppi ~ Fig. IV.lOb

-.---. --,.-.T.--.-- -. , . .- --.- I 0 6 I I 0 pvm Fig. IV. l la

Fig. IV.1 I b

Ligand used 170c

Fig. IV.12a

Fig. IV.12b

In conclusion novel triols 170a, 170b and 170c derived from (2S,3S)-

tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid, 156, (Garcinia acid) have

been used as chiral ligands in asymmetric Diels-Alder reactions. The enantiomeric

excesses observed are significant as these chiral ligands are devoid of Cz-

symmetry. However a detailed investigation on the feasibility of using these

ligands in various catalytic systems is required.

IV.3 Experimental

Trisodium (1S,2S)-1,2-dihydroxy-1,2,3-propanetricarboxylate (166)

To an aqueous solution of 156 (1.0 g, 5.25 mmol, in 5 ml water), 2N of

sodium hydroxide solution was added at about 80" C, till reaction mixture is

alkaline (- pH = 9.0). The residue obtained after evaporation under reduced

pressure, was triturated with dry methanol (5 x 25 ml). The solid obtained was

finally dried under vacuum.

Yield : 1.1 g(76.5%)

'H NMR (DzO) : 6 4.08 (s, lH), 3.36 (s, lH), 2.82(d, J = 15.9 Hz, lH), 2.71 (d, J = 15.9Hz, 1H)ppm.

Trimethyl (1S,2S)-1,2-dihydroxy-l,2,3-propanetricarboxylate (167)

To a suspension of 166 (1.0 g, 3.65 mmol) in dry methanol (I0 ml), thionyl

chloride (1.5 ml, 20 mmol) was added at O'C. After refluxing for two hours, the

reaction mixture was cooled and neutralised with saturated aqueous solution of

sodium bicarbonate. The residue obtained upon concentration under reduced

pressure was extracted with chloroform (3 x 20 ml). The combined extract was

dried and concentrated to furnish 167 as yellow oil

Yield : 0.5 g (50 %).

lalo : +22.14 O (c 0.52, CHCl3)

IR (film) : 3494,3009,2969, 1748, 1452, 1128, 1081, 1013 cm-'

'H NMR (CDCI3) : 6 4.98 (s, lH), 3.84 (s, 6H), 3.68 (s, 3H); 3.2 (d, J = 18.0 Hz, lH), 2.80 (d, J = 18.0 Hz, 1H) ppm.

Mass spectrum : ndz 251 (M+l) (loo), 219 (23), 191 (32), 159 (SO), 143 (3), 13 1 (4.5), 99 (lO.S), 90 (IS), 59 (6), 43 (15).

dicarboxylate (168)

To a solution of 167 (1.0 g, 4 mmol) in dry acetone (25 ml), anhydrous

copper sulphate (0.5 g) and a few drops of conc. Sulphuric acid were added. After

refluxing for four hours, the reaction mixture was concentrated followed by

extraction with hexane (3 x 25 ml). The combined extract was dried and

evaporated to yield 168 as a yellow liquid

Yield : 0.25 g (22 %).

lalo : +29.5 O (c 0.95 %, CHC13)

Ill (film) : 2950, 1740, 1440, 1370, 1200, 1080, 1000 cm-'

'H NMR(CDC13) : 6 4.9 3 (s, lH), 3.86 (s, 3H) 3.81 (s, 3H), 3.68 (s, 3H), 2.98 (d, J = 16.04 Hz, lH), 2.85 (d, J = 16.04 Hz, lH), 1.58 (s, 3H), 1.48 (s, 3H) ppm.

13CNMR(CDC13) :6170.6,169.3,167.8,112.8,82.5,78.8,52.9,52.3,51.7,38.9, 27.4,25.5 ppm.

Mass spectrum : ndz 290 (M') (1.0), 274 (19.8), 230 (36.4), 214 (64.4), 198

(19.4), 180 (1 1.2), 172 (loo), 156 (16.4), 144 (29.2), 113

(51.5), 105 (14.2), 73 (41.0), 59(43.3), 43 (92.5).

Prepared by following the reported procedure of Seebach et ~ 1 . ~ Phenyl

magnesium bromide is prepared by adding bromobenzene (3.6 ml, 5.4 g,

34.34 mmol) dissolved in 10 ml dry THF to stirred magnesium turnings (1 g,

41.1 1 mmol). The resulting mixture is heated to reflux for 30 minutes. It is cooled

to O'C and ketal of diethyltartrate (1 .O g, 2.14 mmol) dissolved in 10 ml dry THF

is added dropwise. The reaction mixture is stirred at room temperature overnight

and then heated to reflux for 2 hours. To the chilled reaction mixture saturated

ammonium chloride solution (15ml) was added carefully and the organic phase

was separated. The aqueous phase was further extracted with ether. Combined

organic phase is dried over magnesium sulphate and concentrated under vacuum.

The product is separated by column chromatography using 100% hexane as eluent.

It is obtained as a white solid.

Yield : 0.84 g (85 %).

Melting point : 1 9 2 ' ~ Reported: 1 9 2 ' ~

ID : -73 (c 1.1 %, CHC13) Reported: -68.5'

'H NMR (CDC13) : 6 7.59-7.24 (m, 20H), 4.61 (s, lH), 4.4 (s, lH), 1.1 (s, 6H) PPm.

13cNMR(CDC13) :6145.87,142.56,128.61,128.03,127.60,127.47,127.19,

109.45, 80.86, 78.11, 27.06 ppm

Phenyl magnesium bromide is prepared in the usual manner by adding

Bromobenzene (5.4 ml, 8.11 g, 51.67 mmol) dissolved in 20 ml of dry THF

dropwise to stirred magnesium turnings (1.2g, 49.34 mmol). The resulting mixture

is heated to reflux for 30 minutes. The mixture is cooled to O'C and the ketal 168

(1 .O g, 3.44 mmol) dissolved in 10 ml of dry THF is added dropwise. The reaction

mixture is stirred at room temperature overnight and then heated to reflux for 2

hours. To the chilled reaction mixture saturated aqueous ammonium chloride

solution (20 ml) was added dropwise. The organic phase was collected and the

aqueous layer was further extracted with ether (5x10 ml). The combined organic

phase was dried over MgS04. The solvent was removed under reduced pressure

and the residue is purified by column chromatography over silicagel using hexane

and hexane, chloroform (8:2) as eluents. The pure product is obtained as an yellow

oil.

Yield : 1.0 g (44 %).

ID : -32.56 IJ (c 2.5, CHCI,)

IR (film) : 3400,3056,2912, 1952,1881, 1590, 1488, 1446, 755, 700cm-'

' H N M R ( C D C ~ ~ ) :67.6-7.23(m,30H),5.86(s,lH)3.3(d,J=17.3Hz,lH),3.1 (d, J = 17.3 Hz, lH), 1.25-1.55 (m, 6H) ppm.

' 3 ~ N M ~ ( ~ ~ ~ b ) : 6 146.92, 143.65, 133.58, 132.37, 129.99, 129.49, 129.21,

128.60, 128.39, 128.13, 127.83, 127.24, 127.15, 115.22. 80.53, 78.24, 77.24, 37.12, 31.80,31.56, 29.59,22.58 ppm

Mass spectrum : m/z 662 (M+) (2.2), 658 (2.6), 634 (2.7), 478 (3.0), 415 (5.4),

Following previous procedure 1.0 g of 168 (3.44 mmol) in 10 ml THF is

added to 21 mmol 4-methyl phenyl magnesium bromide (prepared from 4 ml p-

bromo toluene and 1.2 g magnesium turnings) in 10 ml THF. After work-up 170b

was isolated as yellow liquid. It is purified by column chromarography using

hexane chloroform (8:2) as eluent

Yield : 1.2 g (46.7 %).

[al~ : -7.1581J(c 1.2, CHCI,)

IR (film) : 3360, 2928, 1692, 1606, 1510, 1443, 1356, 857, 819,758 cm"

'H NMR (CDC13) : 6 7.75-6.75 (m, 24H), 5.15 (s, 1H) 3.3 (d, J = 17.3 Hz, lH), 3.1 (d, J = 17.3 Hz, 1H),2.48-2.28(m, 18H) 1.3 (s, 6H)ppm.

129.69, 128.94, 127.85, 127.47, 126.73, 126.51, 115.88, 80.09, 79.12, 78.09, 32.65, 30.76, 30.42, 30.07, 23.40, 22.33, 21.73, 21.15, 20.47 ppm.

Mass spectrum : m/z 746 (M') (2), 661 (4), 553 (6), 447 (20), 386 (26), 309 (30), 243 (loo), 183 (48), 167 (70), 136 (34), 105 (loo), 91 (34), 77 (38), 57 (28), 43 (14).

The procedure adopted for 170a was followed using 168 (1.0 g, 3.44

mmol) in 10 ml THF and 21 mmol I-naphthyl magnesium bromide (prepared

from 3.2 ml 1-naphthyl bromide and 0.58 g magnesium turnings) in 10 ml THF.

The crude product was purified by column chromatography using hexane,

chloroform (8:2) as eluent

Yield : 1.5 g (45.8 %).

[a ln : -27.03 (c 2.2, CHC13)

IR (film) : 3392, 2960, 1689, 1603, 1510, 1363, 1164, 1014, 860, 819, 758 cm"

'H NMR (CDC13) : 6 8.2-6.8 1 (m, 42H), 5.57 (s, IH), 2.2 (s, 2H) 1.7 (s, 6H) ppm.

I 3 c NMR(CDCI~) : 6 152.12, 135.47, 128.37, 127.13, 126.54, 125.94, 125.08, 122.25, 121.35, 109.31, 81.09, 80.05, 78.04, 39.55, 25.51 ppm.

Mass spectrum : m/z 962 (M') (2), 911 (2), 781 (2.1), 716 (4.4), 638 (13.3), 570 (6.6), 391 (11.1), 287 (66.6), 232 (44.4), 222 (loo), 157 (loo), 127 (100).

Preparation of diisopropoxy titanium (IV) dichloride

To a solution of titanium (IV) isopropoxide (2.98 ml, 10 mmol) in

dichloromethane (10 ml) was added titanium tetrachloride (1.10 ml, 10 mmol)

slowly at room temperature. On addition of titanium (IV) chloride heat was

evolved. After stirring for 10 minutes, the solution was allowed to stand for 6 hrs

at room temperature and the precipitate was then collected. The precipitate was

washed with hexane (2x5 ml), dried under reduced pressure and then dissolved in

toluene to get 2.5M solution.

Preparation of 3- ((E)-2-butenoyl)-l,3-oxazolidin-2-one

3-((E)-2-butenoyl)-1,3-oxazolidin-2-one was prepared according to the

procedure of ~ v a n s . ' ~ ~

To a solution of 1,3-oxazolidinone (5g, 57.47 mmol) in anhydrous THF

(150 rnl) at - 7 8 ' ~ was added n-butyl lithium (5.4 ml, 1 eqiv). After 15 minutes

freshly distilled 3-(E)-2butenoyl chloride (6.5 ml) was added. The mixture was

stirred at - 7 8 ' ~ for 30 min. and at O'C for 15 min. The reaction was quenched

with excess saturated aqueous ammonium chloride, and the resultant slurry is

concentrated in vacuo. The residue was extracted with ether. Ether layer was

washed successively with saturated aqueous sodium bicarbonate and then with

saturated aqueous sodium chloride. It is dried over magnesium sulphate, filtered

and concentrated in vacuum to yield the product.

3-(((I'S, 2's' 3'R, 4'R)-3'-methyl bicyclo [2.2.1] hept-Sen-2'-y1)-carbony1)-

1,3-oxazolidin-2-one (171): (Employing 170a as chiral ligand)

To a toluene suspension of powdered molecular sieves (4A,lg) added

toluene solution of diisopropoxy titanium (IV) dichloride (1 rnl, 2.5 M), cooled to

- 7 8 ' ~ and added toluene solution of polyol(170a) (200 mg) slowly for a period of

30 min. Slowly warmed to room temperature and stirred for 2 hours. The reaction

mixture was then cooled to -78'~, 3((E)-2-butenoyl)-l,3-oxazolidin-2-one

(388 mg, 2.5 mmol, 1 equiv.w.r.t polyol) in toluene (10 ml) was added, stirred for

15 min. followed by the addition of freshly distilled cyclopentadiene (4.4 ml,

55 mmol) and further stirred for 2-4 hours at - 7 8 ' ~ . The complex was decomposed

by adding a saturated solution of sodium hydrogen carbonate, filtered through

sintered crucible over ceiite bed and extracted with dichloromethane. The organic

layer was washed twice with saturated sodium chloride solution and dried over

anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave a

crude resin, which on silica gel chromatography gave the pure endo adduct 171.

Yield : 250 mg (45.2 %)

'H NMR (CDCb) : 6 1.50 (d, 3H, J=7.05 Hz), 1.82-2.08 (m, 3H), 2.46 (br, lH), 3.65 (br, lH), 3.91 (dd, lH), 4.27-4.46 (m, 2H), 4.75-4.89 (m, 2H), 6.15 (dd, lH, P 2 . 4 Hz, 5.4 Hz,), 6.53 (dd, lH, J=2.3Hz, 5.4 Hz) ppm.

13cNMR(CDC13) :6174.77,153.37,140.04,131.28,62.20,51.64,49.87,47.81, 47.46, 43.35, 36.82, 20.73 ppm.

1,3-oxazolidin-2-one (171): (Employing 170b as chiral ligand)

The procedure adopted for 170a was followed using powdered, activated

molecular sieves (1 g), diisopropoxy titanium (IV) dichloride in dry toluene (1 ml,

2.5 M), 170b (200 mg), 3((E)-2-butenoyl)-l,3-oxazolidin-2-one (388 mg) and

cyclopentadiene (4.4 ml). Work up of the reaction followed by silica gel

chromatography furnished pure endo adduct 171

Yield : 230 mg (41.62 %).

[ a l D : -16.05 ' (c 1.5, CHCI,)

'H NMR (CDCb) : 6 1.50 (d, 3H, J=7.05 Hz), 1.82-2.09 (m, 3H), 2.47 (br, lH), 3.69 (br, lH), 3.84 (dd, lH), 4.28-4.43 (m, 2H), 4.71-4.82 (m, 2H), 6.16 (dd, lH, J=2.6 Hz, 5.4 Hz,), 6.74 (dd, lH, J=2.3Hz, 5.5 Hz) ppm.

l 3 ~ N M ~ ( ~ ~ ~ 1 3 ) :6174.78,153.37,140.04,131.28,62.20,51.64,49.87,47.81, 47.47,43.35, 36.83, 20.73 ppm.

3-(((17S, 2'S, 3'R, 4'R)-3'-methyl bicyclo [2.2.1] hept-5'en-2'-yl)-carbony1)-

1,3-oxazolidin-2-one (171): (Employing 170c as chiral ligand)

The reaction was performed as described in the case of 170a using

powdered, activated molecular sieves (1 g), diisopropoxy titanium (1V) dichloride

in dry toluene (1 ml, 2.5 M), 170c (200 mg), 3((E)-2-butenoy1)-l,3-oxazolidin-2-

one (388 mg) and cyclopentadiene (4.4 ml). Work up of the reaction followed by

silica gel chromatography furnished the pure endo adduct 171

Yield : 200 mg (36.19 %).

[alo : -13.00 O (c 1.5, CHCI,)

'H NMR (CDCb) : 6 1.50 (d, 3H, J=7.0 Hz), 1.8-2.1 (m, 3H), 2.46 (br, IH), 3.65 (br, lH), 3.84 (dd, lH), 4.29-4.48 (m, 2H), 4.75-4.83 (m, 2H), 6.15 (dd, lH, J=2.8 Hz, 5.3 Hz,), 6.75 (dd, lH, J=3.2Hz, 4.9 Hz) ppm.

"C NMR (CDC13) : 6 174.77, 153.84, 140.03, 131.29, 62.24, 51.65, 49.88, 47.82,

47.47, 43.35, 36.83, 20.73 ppnl.