Tc!nhedron Letters, Vol.32, No.51, pp 7517.7520. 1991 Printed in Great Britain

Ow-4039191 $3.00 + .oo Pw&imcm Rev. p!c

Catalytic Enantios&ctive Synthesis of a Key Intermediate for the Synthesis of

Prostanoids

E. J. Corey, Nobuyuki Imai and Stanislaw Pikul

Summary: A route has been demonstrated for the enantioselective synthesis of prnstanoids from achiral starting materials by the use qf chiral catalysts of the molecular robot class.

Some years ago we reported the first general synthesis of prostanoids from bicyclo[2.2.l]heptenone

intermediates (1)’ which were synthesized as racemates by a Diels-Alder addition of a 5-(alkoxymethyl)-l,3-

cyclopentadiene with a ketene equivalent such as 2-chloroacrylonitrile (Cu+z catalysis)*a or Z-chloroacrylyl

chloride.lC Chiral prostanoids were obtained by conversion of 1 to acid 2 and resolution.lb Subsequently,

chlral 1 was prepared enantioselectively by AlCls-catalyzed IX&-Alder reaction of the reactive species 3,

involving the 8-phenylmenthol controller grou~,~ and transformed into the enantiomerically pure iodo lactone 4

after recrystallization, We now report a further evolution of this approach which takes advantage of a catalytic

endntioselective Diels-Alder reaction as the initial step for the synthesis of enantiomerically pure 4 from achiral

reactants,

The use of chiral catalysts such as 5 for enantioselective Diels-Alder reactions has been described

rec:cntly.3 ‘I’bus, reaction of 5-(benzyloxymcthyl}-l$cyclopentadiene (6) and 3-acrylyl-1,3-oxazolidin-2-one

(7) in the presence of 10 mole % of the (S,S)-catalyst 5 in CH2C12 at -78 “C for 18 h afforded the adduct 8 in

93% yield and > 95% ee. The chiral bis-sulfonamide from which catalyst 5 was made was recovered for reuse.

The adduct 8 was converted to the crystalline, enantiomerically pure iodo lactone 4 by the following sequence.

Treatment of 8 with aqueous lithium hydroxide-H2024 provided the corresponding acid (100%) which was

transformed into the ethyl ester (9) by reaction with &OH-HC(OEt)3 McS&H (95%). a Dcprotonation of 9

(LDA) and reaction with MeSSMe gave the ester 10, R=Et, (lOO%), and this was cleaved to the acid 10, R=H,

using KOt-Bu-DMSO (87%). The ketone 1, R-CHzPh, was obtained from this acid by oxidative

decarboxylations in 78% yield (93% corrected for recovered acid 10). Baeyer-Villiger oxidation of 1,

R=CH$h, basic hydrolysis of the resulting lactone and iodolactonation provided after recrystallization the iodo

lactone 4, in 83% yield overall from 1, and 100% ee.6

7517

(-j-HI, R=Et. To a solution of 1.69 g (5.10 mmol, 1 equiv) of this ester in 30 ml of dimethylsulfoxide was

added 1.71 g (15.3 mmol, 3 equiv) of potassium terr-butoxide. After stirring for 4 h at 110 ‘C, the reaction

mixture was acidified with 20 ml of 1N aq. HCl, stirred for 30 min at 23 ‘C, and extracted with 200 ml of

EtOAc. After washing with brine and drying, the crude product was chromatographed on s.g. with 1 : 1 EtOAc-

hexane to afford 1.35 g (87%) of acid 10, R=H.

7-Benzyloxymethylbicyclo[2.2.l]hept-5en-2-one (1, R=CHzPh). To a solution of 252 mg

(0,832 mmo!, 1 equiv) of 10E R=H in 7 ml of 1% trimethyl orthofomrate in anhydrous methanol was added 405

pl(O.832 mmol, 1 equiv) of 40% benzyltrimethylammonium methoxide in anhydrous methanol. After stirring

for 3 h at 23 ‘C, a solution of 117 mg (0.874 mmol, 1.05 equiv) of N-chlorosuccinimide in 0.7 ml of anhydrous

acctommle was added dropwise to the solution at 0 “C. The reaction mixture was stirred for 1.5 h at 0 “C,

quenched at 0 “C with 2 ml of 1N aq. HCl, and evaporated. The aqueous solution was dissolved in 4 ml of

THF, stirred for 16 h at 23 “C, and evaporated and the residue was extrxctcd with EtOAc; The ethyl acctatc

layers were combined and dried over MgS04. The crude product was chromatographed on silica gel with 1 : 4

EtOAc-hexane to afford 148 mg (78%) of 1, R=CHzPh, as a colorless oil and 40.4 mg (16%) of recovered 10,

R=Hq for 1, R=CHzPh: Lo]: _ 46Q,O”(c 2.28, CHC13). IR (neat): 1745 (CO) cm-l; 1H NMR (CDC~J) S 1.95 (1

H, d, J= 16.5 Hz), 2.06 (1 H, dd, J= 3.0, 16.5 Hz), 2.74 (1 H, t, J= 7.1 Hz), 3.01 (1 H, br), 3.15 (1 H, br),

3.53 (2 I#_, d, J-7.1 Hz), 4.48 (2 H, s), 5‘94 (1 H, dd, J= 2.4, 5,l Hz), 6.40 (1 H, dd, J= 2.4, 5.1 Hz), 7.23

(5 H, m). The enantiomeric purity of ketone 1 is determined by HPLC analysis using a Daicel AD column with

1% isopropyl alcohol in hexane for elution.

6-Benzyloxymethyl-7-hydroxy-8-iodo-2-oxabicyclo[3.3.O]octan-3-one (4). To a solution of

105 mg (0.461 mmol, 1 equiv) of 1. R=CHzPh, in 5 ml of CHzCl2 were added at 0 ‘C 95 mg (0.553 mmol,

1.2 equiv) of m-chloroperoxybenzoic acid (55%) and 105 mg (1.24 mmol, 2.7 equivj of NaHC03. After

stirring for 39 h at 0 ‘C, the mixture was quenched at 0 *C with 369 ~1 (0.553, 1.2 equiv) of 1.5N aq. Na2S03,

diluted with 1 ml of brine and extracted with CHzC12. After drying and removal of the solvent, 112 mg (100%)

of Baeyer-Villiger lactone was obtained and this was dissolved in 800 N of a 3 : 1 mixture of THF and methanol

and treated with 277 ml (O,SS3 mmol, 1.2 equiv) of 2N aq, KOH, After stirring for 2 h at 23 ‘C, CO2 was

passed in and THF and methanol were removed. To the aqueous solution were added 55 mg (0.553 mmol, 1.2

equiv) of KHCO3 and at 0 ‘C. 234 mg (0.922 mmol, 2 equiv) of iodine, 168 mg (1.01 mmol, 2.2 equiv) of

potassium iodide, InO p1 of ‘T’PIF, and ZOO ~1 of CH2C12. The mixture was stirred at 24 h at 0 “C, decolorized

at 0 “C with 256 mg (2.03 mmol, 4.4 equiv) of Na2S03, and extracted with 4 : 1 EtOAc-CH2Cl2. The crude

product was chromatographed on s.g. using 1 : 1 EtOAc-hexane. The organic layers were combined and dried

over MgS04. The crude product was chromatographed on s.g. with 1 : 1 EtOAc-hexane to afford 160 mg

(89%) of 4 as a pale yellow solid ([a] *; - 24.1°(c 1.38, CHC13)), which was recrystallized from CHZC12-ether-

hexane to afford 150 mg (83% yield, 100% ee) of (-j-4 as colorless prisms: m.p. 119121”, [a]‘: - 35.8’(c 1.1,

CHC13), identical with an authentic sample. I,2 The enantiomeric purity of iodolactone 4 was determined by

HPLC analysis using a Daiccl OD column with 20% isopropyl alcohol in haxane for elution.*

fS20

0 AICl,

OCH,Ph

Ph Ph

0CH2Ph

PhCH,O

Me

5

phcH20~,..-E, phcH20&?y-; Arco&mC5~ll 0

9

Reference and Notes

1.

2.

3.

4.

5.

6.

7.

8.

10 11

{a) Corey, E. J.; Weinschenker, N.M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Sot. 1969,91, 5675-

5677; (b) Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.; Weinschenker, N. M. J. Am. Chem. Sot.

1970, 92, 397-398; (c) Cnrg_jr, E. J.; Ravindranathan, T,; Terashima, S. J. Am. Chcm. Sot. 1971,9.5,

4326-4327; (d) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley Inc. 1989; pp.

250-264.

Corey, E. J.; Ensley, H. E. J. Am. Chem. Sot. 1975,97, 6908-6909.

Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Sot.. 1989,111, 5493-5495. Very

pure catalyst 5 can be obtained by recrystallization from CH2C12-heptane (dry). Using very pure 5 ee’s as

high as 98% have been obtained for 8.

Evans, I). A.; Britton, T. C: Ellmtn, J, A.; T~rmhcdmn Lets. 1987.28, 6141-6144. i ------4

(a) van Tamelen, E. E.; Haarstad, V. B.; Orvis, R. L.; Terrahedron Lett., 1968, 24, 687-704; (b) Trost,

B. M.; Tamaru, Y. J. Am. Chem. Sot. 1977,99,3101-3113.; 1975,97, 3528-3530.

We have also succeeded in the conversion ester 9 to 1, R=CH#h, using the u-hydroxylation methodology

of Wasserman, H, H.; Lipschutz, B. H. Tetrahedron Lett. 197.5, 1731-1734.

Corey, E. 1.: Bakshi, R. K.; Shiharn, S.; Ohen, C.-F.; Singh, V. K. J, Am. Chem Sm, 1987, I&Y, 7925-

7926.

This research was assisted by grants from the National Institutes of Health and the National Science

Foundation.

(Received in USA 13 March 1991; accepted 16 October 1991)