J. Org. Chem. 1991,56,2468-2476 3600-3300, ~ 2 8 0 0 , 1 3 5 0 , 1 ~ 1 1 0 0 , 1 0 7 ‘H 5 ; NMR (250MHz, CDClS) S 4.05 (d, J 8.3 Hz, 1H), 3.80 (d, J = 5.6 Hz, 1H), 3.48 (d, J = 7.0 Hz, 1 HI, 3.45-3.10 (m, 4 H), 2.80 (d, J = 6.7 Hz, 1 H), 2.20-1.65 (series of m, 12 H), 1.60-1.5 (m, 2 H), 1.32 (s,6 H), 1.30-1.15 (m, 1 H), 1.17 (s,3 H), 1.16 (s,3 H); ‘9C NMR (62 MHz, CDClJ ppm 102.64,91.81,80.80,75.64,72.07,65.76,57.65,49.98, 45.62, 42.27, 40.29, 38.77, 35.33, 32.66, 31.82, 30.73, 28.28, 27.50, 26.51, 22.34,. 20.67, 19.81, 17.15; MS m / z (M+) calcd 442.2211, obsd 442.2190; [aImD +10.9’ (C 0.22, CHClJ. Anal. Calcd for C,H,O& C, 62.40; H, 8.65. Found: C, 62.48; H, 8.67. (3’aS ,6‘S ,7’S ,8‘S ,8‘aR ,12’aR ,13’aS )-Decahydro8’a,l4’,14’-trimethyl-2’-phenylspiro[l93-dithiolane-2,12’(9’H)-[4H-3a,6]methanobenzo[4,5]cyclodeca[ 1,2-d]dioxole]-7’,8’-diol Diacetate (23a). A solution of 21a (13 mg, 2.85 x mol) in pyridine (1 mL) was treated with a solution of osmium tetroxide in pyridine (0.17 mL of 0.25 g of OsO, per 5 mL, 1.2 equiv), stirred at room temperature overnight, and processed as described above. The significant insolubility of the diol prompted direct conversion in unpurified form to the diacetate. The crude diol 22b in anhydrous pyridine (0.6 mL) containing acetic anhydride (0.3 mL) and DMAP (3 crystals) was stirred under argon at room temperature overnight. The mixture was diluted with ethyl acetate (5 mL), washed in turn with water (5 mL), 0.12 N HCl(2 X 5 mL), saturated NaHCO, solution (2 X 5 mL), and brine ( 5 mL), and then dried and evaporated. Purification by silica gel chromatography gave 23a (1 mg, unoptimized): IR (CHC13,cm-’) 3020-2800, 1730,1370, 1270-1150, 1095,1050,1025; ‘H NMR (300 MHz, CDCIS)6 7.50-7.40 (m, 2 H), 7.40-7.30 (m, 3 H), 5.76 (8, 1 H), 5.22 (9, 1H), 5.19 ( 8 , 1 H), 4.28 (d, J = 9.6 Hz, 1 H), 3.45-3.15 (m, 5 H), 2.13 (s,3 H), 2.04 (s,3 H), 2.50-1.00 (series of m, 13 H), 1.35 (s,3 H), 1.26 (s,3 H), 1.20 ( ~ , H); 3 ‘9C NMR (125 MHz, CDCla) 6 170.59, 169.36, 139.07, 128.93,128.25,126.81,100.20,91.82,84.11,74.87,73.42,68.41,56.10, 50.24, 46.51,43.12, 40.41, 38.67, 35.91, 32.96, 32.61, 30.77, 29.71, 22.38, 21.33, 20.94, 20.58, 20.48, 17.54; MS m / z (M+) calcd 574.2423, obsd 574.2416; [aImD -41.7’ (c 0.35, CHCI,).
(3’aS ,6’S ,7‘S ,8‘S ,8’aR ,12’aR ,13‘aS )-Decahydro2’,2’,8’a, 14’, 14’-pentamet hy lspiro[ 1,3-dithiolane-2,12’(9’H)[4H-3a,6]methanobenzo[4,5]cyclodeca[1,2-d][ 1,3]dioxole]7’,8’-diol Diacetate (23b). A solution of 22b (23 mg, 5.2 X l@ mol) in dry pyridine (2 mL) containing acetic anhydride (1mL) was stirred at room temperature under argon in the presence of DMAP (3 crystals) for 24 h. The usual workup and chromatographic purification gave 23b (20 mg, 73%) as a white solid mp 226-228 OC; IR (CHCI,, cm-’) 3030-2800, 1730, 1460, 1375, 1280-1200, 1140, 1075-1000,955; ‘H NMR (300 MHz, C&) S 5.64 (br s, 1H), 5.51 (br s, 1H), 4.53 (d, J = 9.4 Hz,1H), 2.85-2.60 (m, 5 H), 2.60-1.00 (series of m, 13 H), 1.81 (8, 3 H), 1.75 (8, 3 H), 1.60 (8, 3 H), 1.52 (8, 3 H), 1.46 (8, 3 H), 1.44 (8, 3 H), 1.30 (8, 3 H); “C NMR (75 MHz, c&) ppm 169.86, 168.67, 103.11, 92.04, 81.46, 75.43, 73.77,68.75,56.47,50.81,46.74,43.65,40.37, 39.01, 35.74, 33.26, 32.21, 30.90, 28.24, 27.82, 26.88, 22.92,20.99, 20.92, 20.48, 20.42, 18.18; MS m / z (M+) calcd 526.2323, obsd 526.2364; [almD-17.5’ (C 0.2, CHCl3). Anal. Calcd for CnHuOBS2: C, 61.57; H, 8.04. Found: C, 61.75; H, 8.24. Deuterium Labeling Studies. The preparations of 25-27 were carried out along lines entirely parallel to those outlined above. The chemical shift effects and NOE data of greatest relevance are provided in the illustrated formulas.
Acknowledgment. We thank the National Institutes of Health for financial support (Grant CA-12115),Robin D. Rogers (Northern Illinois University) for the X-ray crystallographic analysis of 11, George D. Maynard for molecular mechanics calculations, and Kurt Loening for assistance with nomenclature. Supplementary Material Available: Tables of X-ray crystal data, bond distances and angles, final fractional coordinates, and thermal parameters for 11 as well as the 300-MHz ‘H NMR spectra of those compounds for which elemental analyses are not available (11pages). Ordering information is given on any current masthead page.
(2)-a-(Trimethylsilyl)a,@-UnsaturatedEsters. Their Stereoselective Conversion into a,@-and @,r-UnsaturatedEsters and @,r-Unsaturated Ketene Acetals M. Ramin Najdi, Mei-Ling Wang, and George Zweifel* Department of Chemistry, University of California, Davis, California 95616 Received September 6,1990
Deprotonation of methyl (2)-a-(trimethylsilyl) a,,%unsaturated esters with lithium diisopropylamide (LDA)
or with lithium hexamethyldisilazide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) ae an
activator, followed by protonation of the intermediate dienolates with methanol, produces stereoselectively the desilylated (E)-3-alkenoic esters. Trapping the dienolates with chlorotrimethylsilane instead of methanol and then treatment of the resultant ketene acetals with aqueous hydrochloric acid affords (E)-a-(trimethylsily1)esters B,y-alkenoicesters in 98% isomeric purities. In the absence of HMPA, (2)-a-(trimethylsily1)-a,@-alkenoic undergo a Michael-typeaddition with LDA to &ish, after methanol-mediated elimination of the diisopropylamine moiety, (E)-a-(trimethylsily1)-a,B-alkenoic esters. In contrast to the behavior with the corresponding 2 esters, deprotonation of the E esters with LDA does not require an activator. Treatment of the dienolate intermediatas formed with chlorotrimethylsilaneyields 0-methyl-C,O-bis(trimethylsily1)ketene acetals, and alkylation furnishes (%a-alkyl B,y-unsaturated eaters. Protodesilylation of the latter compounds with tetra-n-butylammoniumfluoride followed by hydrolytic workup provides trisubstituted 2-alkenoates.
The protonative deconjugation of a,&unsaturated esters has been extensively investigated and represents an im0022-3263/91/1956-2468$02.50/0
portant method for preparing stereodefined B,y-unsaturated esters.’ It thus occurred to us that subjecting t h e 0 1991 American Chemical Society
J. Org. Chem., Vol. 56, No. 7, 1991 2469
(2)-a-(Trimethylsilyl) a,p-Unsaturated Esters readily accessible (2)-a-silyl a,P-unsaturated esters l2to a sequence of deprotonation-protonation reactions might provide a convenient route to the a-silyl &-punsaturated esters 3. These contain the synthetically exploitable and 1a-c
2 H
H
versatile allylsilyl and alkoxycarbonyl moieties and hence should be amenable to a variety of interesting synthetic transformation^.^ Although methods for preparing the esters 3 have been reported$5 a general, stereoselective, and high-yield method for their synthesis is lacking. In this paper, we report the results of a study of deprotonation of (2)-a-silyl esters 1 under various conditions and the conversion of the resultant dienolates into a variety of synthetically attractive intermediates. In a preliminary experiment, the (Z)-cy-silylester la was added to a solution of LDA (lithium diisopropylamide, 1.1 equiv) in THF containing HMPA (hexamethylphosphoramide, 3 equiv) at -78 "C. Protonation with methanol at -78 "C followed by pouring the reaction mixture into aqueous ammonium chloride and workup, however, did not provide the &y-unsaturated silyl ester 3a, but instead the corresponding desilylated E ester 4a in 98% isomeric purity? Under similar experimental conditions, the ester IC also furnished, after protonative deconjugation, the ester 4c. However, deprotonation of the cyclohexyl-substituted ester lb did not proceed to completion unless lithium hexamethyldisilazide (LHMDS) in HMPA was used.' (1) For the preparation of &y-unsaturated esters via deconjugative protonation of dienolates derived from E and Z a,b-unsaturated esters, see: (a) Rathke, M. W.; Sullivan, D. Tetrahedron Lett. 1972,4249. (b) Hermann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H. Tetrahedron Lett. 1973,2433. (c) Hase, T. A.; Kukkola, P. Synth. Commun. 1980,10, 451. (d) Krebs. E.-P. Helu. Chim. Acta 1981, 64, 1023. (e) Kende, A.; Toder, B. H. J. Org. Chem. 1982,47,163. (f) Ikeda, Y.; Yamamoto, H. Tetrahedron Lett. 1984,25,5181. (g) Tsuboi, S.; Muranaka, K.; Sakai, T.; Takeda, A. J. Org. Chem. 1986, 51,4944. (h) Ikeda, Y.; Ukai, L.; Ikeda, N.; Yamamoto, H. Tetrahedron 1987,43,743 and references cited therein. (i) Hudlicky, T.; Fleming, A.; Radesca, L. J . Am. Chem. SOC. 1989,111,6691. (k) Piers, E.; Gavai, A. V. J. Org. Chem. 1990,55,2374. (2) Lewis, W. Ph.D. Thesis, University of Califomia, Davis, CA, 1979. Dansheimer, R. L.; Sard, H. J. Org. Chem. 1980,45,4810. Miyaura, H.; Suzuki, A. Chem. Lett. 1981,879. Cooke, M. P. J. Org. Chem. 1987,52, 5729. Sato, Y.; Takeuchi, S. Synthesis 1983,734. For nonsterecaelective syntheses of a-silyl a,&unsaturated esters, see: Hartzell, S. L.; Rathke, M. W. Tetrahedron Lett 1976, 2737. Sato, Y.; Takeuchi, S. Synthesis
3
414
R- a IFGH,; b oC6Hl1; c &H5
Previous investigators have shown that kinetically controlled deprotonation of (E)-Zalkenoates with LDAHMPA followed by protonation of the resultant dienolates affords the corresponding (2)-3-alkenoates.' The observed inversion of stereochemistry was rationalized in terms of deprotonation occurring from a conformation that leads directly to the minimum energy The stereoselective conversion of the ester 1, in which the alkyl and COzMe substituents are also in a trans relationship, into the trans ester 4 may be rationalized similarly, but with the alkyl-SiMe3 rather than the alkyl-C02R' steric interactions dictating the stereochemical outcome of the reaction. Thus, deprotonation of the 2 esters 1 with LDA-HMPA or with LHMDS-HMPA from a conformation in which the R and the Me3Si groups are anti leads to the dienolates 2. Protonation of 2 with methanol gives 3 which is, however, susceptible to nucleophilic attack on silicon by the lithium methoxide formed in the course of the reaction to furnish the desilylated esters 4.8 To ascertain that formation of 4a had indeed proceeded via an initial protonation of the dienolate 2a, the reaction mixture was stirred with excess MeOD at -78 "C for 15 min, allowed to warm to 25 "C, maintained a t this temperature for 30 min, and then poured into a mixture of saturated aqueous ammonium chloride-n-pentane-ice. 'H NMR examination of the resulting B,y-unsaturatedester revealed incorporation of 1.8 deuteriums (f0.05 D) at the C-2 carbon. Hence initial protonation of 2a with MeOD must have occurred chemoselectively at the a-position followed by desilylation of the intermediate monodeuterated ester by the MeOLi formed.* Deuteration of the resultant monodeuterated dienolate furnished the dideuterated &y-unsaturated ester.
1983,734. (3) Weber, W. P. Silicon Reagents for Organic Synthesis; Springer Verlag: Berlin, 1983. Colvin, E. Silicon in Organic Synthesis; Butterwortha. London, 1983, Fleming, I. In Comprehensive Organic Chemistry; Barton, D. H. R., Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 3.
Magnus, P. D.; Sakar, T.; Djiuric, S. In Comprehensiue Organometallic Chemistry; Wilkinson, G. W., Stone, F. G. A., Abel, F. W., Eds.; Pergamon: Oxford, 1982; Vol. 7. (4) (a) Albaugh-Robertaon, P.; Katzenellenbogen, J. A. Tetrahedron Lett. 1982,23,723. (b)Albaugh-Robertson, P.; Katzenellenbogen, J. A. J . Org. Chem. 1983,48,6288. (5) Millard, A. A.; Rathke, M. W. J. Am. Chem. SOC.1977,99,4833. Naruta, Y.; Uno, H.; Maruyama, K . Chem. Lett. 1982,609. Morizawa, K.;Kanemoto, S.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982,23, 2953. Mamyama, K.; Uno, H.; Namk, Y. Chem. Lett. 1983,1767. Uno, . H. Bull. Chem. SOC.J D ~1986.59.2471. (6) The E esters 4a% could not be separated from the corresponding 2 isomers on various silica caDillarv columns. Hence. the ratios of the (E)- and (Z)-3-alkenoiceaters formed were determined by 'H NMR,since the allylic protons of each pair of the isomeric esters exhibited different chemical shifta. (7) Methyl (Z)-2-(trimethylsilyl)-3-~yclohexylpropenoate, which contains a tertiary allylic hydrogen, could not be deprotonated with LDAHMPA under the experimental conditions used for 1. This was evidenced by the absence of deuterium incorporation when the reaction mixture was quenched with deuterated methanol. Attempts to deprotonate the ester with LHMDS-HMPA led to a mixture of products. A similar reluctance for deprotonation haa been reported for the corresponding ethyl (E)-3cyclohexylpropenoate: Haw, E. T.; Kukkola, P. Chem. Commun. 1980, 10, 451.
H
H
@.Me
In an attempt to avoid the loss of the trimethylsilyl moiety at C-2 in 3, the dienolates 2 derived from la-c were trapped at -78 "C with chlorotrimethylsilane, a reaction which does not form lithium methoxide. Although isolation of the unsaturated ketene acetals 5 formed by aqueous workup resulted in considerable desilylation, hydrolysis of the crude silyl ketene acetals 5 with aqueous 5% HCl (8) Oxygen nucleophiles such aa alkoxidea are known to attack a-silyl esters at silicon rather then at the a-hydrogen atoms to give the desilylated enolate ions. On the other hand, nitrogen baaes such as LDA usually attack the a-hydrogen a t o m to give silicon-eubaituted enolatee. Fleming, I. In Comprehensiue Organic Chemistry; Barton,D. H. R, Ollis, W. D., EMS.; Pergamon: Oxford, 1979; Vol. 3, p 657. Brooks, A. G.; Duff, J. M.; Anderson, D. G. J. Am. Chem. SOC. 1970,92,7667. Chvalovsky, V. Orgummet. React. 1972,3,191. Pandy-Szekere, D.; Deleris, G.; Picard, J.-P.; Callas, R. Tetrahedron Lett. 1980,21,4267.
Najafi et al.
2470 J. Org. Chem., Vol. 56, No. 7, 1991
yielded the corresponding esters 3a-c in 96-9890 isomeric p u r i t i e ~ . ~ JThe ~ trans stereochemistry of the esters is consistent with the large vicinal coupling constants ( J > 15 Hz) observed for the vinylic protons in the 'H NMR spectra.
should proceed via rotamer 9 to furnish the E ester 6, in agreement with the experimental result. R i-PrzNU x L
e
-
18,b
Me- 5% HCI R&iMe3
2- W C I R f l
fle
Me, 5
3r-c
I
We next investigated the reaction of 1 with LDA in the i-Pr,h. 'Li' b H
