J . Org. Chem. 1992,57,2937-2941 pounds 7, 10, and 12. General procedure: A solution of 3-(diethylamino)-2(vl)-pyazinone(1mmol) in freshly dried toluene (10 mL) containing 3 equiv of dienophile was heated at 60 "C until all starting material had disappeared. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (ethyl acetate-chloroform) on a silica gel column. The product was then recrystallized from hexane-chloroform. Dimethyl 2-Cyano-5-(diethylamho)-1,6-dihydro-6-oxo-1phenyl-3,4-pyridinedicarboxylate(7a). After reaction for 3 h followed by chromatographythis compound was obtained from 5a and dimethyl butynedioate in a yield of 363 mg (95%): mp 118-119 O C ; IR (KBr) 2230 (CN), 1720 (eater), 1665 (lactam)cm-'; 'H NMR 6 1.3 (t, 6 H, NCHZCH,), 3.45 (q,4 H, NCHZCH,), 4.0 (s,6 H, COZCH3),7.4 (m, 5 H, ArH); MS ( m / z )383 (M+,54), 368 (M+ - CH3, 100),351 (M+ - CH,OH, 65)) 322 (91); HRMS calcd for C&21Ns06 (M+),383.1481, found 383.1490. Anal. Calcd for CdZlN305: C, 62.66; H, 5.52; N, 10.96. Found: C, 62.28; H, 5.43; N, 10.71. Dimethyl 2-Cyano-5-(diethy1amino)-1,6-dihydro-1methyl-6-oxo-3,4-pyridinedicarboxylate (7b). After reaction for 3 h this compound was obtained from 5b in a yield of 299 mg (93%): mp 87-88 "C; IR (KBr) 2220 (CN), 1740 (ester), 1720 (ester), 1665 (lactam) cm-'; 'H NMR 6 1.3 (t, 6 H, NCHzCH3), 3.3 (q,4 H, NCHZCH,), 3.8 (8, 3 H, CH3), 3.9 ( 8 , 3 H, COZCH,), 3.95 (8, 3 H, COZCH,); 13C NMR 6 13.7 (9, NCHZCH,), 35.3 (4, NCH3),46.3 (t,NCHzCH3),52.6 (q, OCH3),53.1 (q, OCHJ, 111.8 (s,CN), 116.8 (9, C-2,3J = 4), 118.3 (8, C-3), 132.0 (9, C-4), 143.6 (m, C-5, 3J = 3), 159.8 (q, C-6,3J = 2), 163.0 (q, C=O, 3J = 5 ) , 165.6 (q, C 4 , 3J = 5 ) ;MS ( m / z )321 (M+,301,306 (M+ - CH3, loo), 290 (M+ - OCH3, 26), 260 (46), 246 (39); HRMS calcd for C15HlsN305(M+) 321.1325, found 321.1322. Anal. Calcd for c1&1&305: C, 56.07;H, 5.96; N, 13.08. Found: C, 55.76; H, 5.87; N, 13.00. Ethyl 6-Cyano-3-(diethylamho)-I,2-dihydro-2-oxo-1phenyl-4-pyridinecarboxylate(7c). After reaction for 8 h this compound was obtained from Sa and ethyl propynoate in a yield of 288 mg (85%): mp 84 "C; IR (KBr) 2230 (CN), 1735 (ester), 1665 (lactam) cm-'; 'H NMR 6 1.25 (t, 6 H, NCHzCCH3),1.4 (t, 3 H, COZCHzCH3), 3.6 (4, 4 H, NCHZCH,), 4.3 (9, 2 H, COZCHzCH3),7.1 (8, 1 H, H-5), 7.4 (m, 5 H, ArH); 13C NMR 6 13.5 (NCHZCH,), 14.1 (OCHZCH,), 46.4 (NCHZCH,), 61.4 (OCHZCH,), 109.4 (d, (2-6, 2J = 3), 113.2 (d, CN, 3J = 51, 117.8 (d, C-5, ' J = 174), 120.6 (8, C-4), 127.5, 128.3, 129.5 (C-Ar), 137.8 (C-ipso), 146.3 (m, C-3),160.1 (C-2), 164.7 (M); MS ( m / z )339 (M+, 43), 324 (M+ - CH3, 56), 310 (M+ - CzH5, loo), 264 (73); HRMS calcd for C ~ & H , N ~(M+) O ~ 339.1583, found 339.1586. Anal. Calcd for Cl&&03: C, 67.24; H, 6.24; N, 12.38. Found C, 67.20; H, 6.22; N, 12.40. 5-(Diethylamino)-1,6-dihydro-6-oxo-l,4-diphenyl-2pyridinecarbonitrile(7d). After reaction for 12 h this compound was obtained from 5a and phenylacetylene in a yield of 305 mg (89%): mp 140-141 OC; IR (KBr) 2220 (CN), 1660 (lactam) cm-'; 'H NMR 6 1.0 (t,6 H, NCHZCHS), 3.05 (q,4 H, NCHZCHJ, 6.85 (8, 1 H, H-3), 7.6-7.15 (m, 10 H, ArH); 13C NMR 6 13.6 (q, NCHzCH3), 45.9 (t,NCHZCHJ, 112.4 (d, C-2,'5 = 2.6), 113.5 (d, CN, 3J = 5 ) , 120.3 (d, C-3, ' J 171), 127.7, 127.8, 128.6, 129.3, 129.5, 129.6 (m, CAr), 136.7 (m, C-4), 138.0, 138.3 (2 X C-ipso), 143.1 (m, C-5), 161.1 (8, (2-6); MS ( m / z )343 (M', 551,328 (M+ - C H , 59), 314 (M+ - CzH5, 100), 299 (73); HRMS calcd for CzzHz1N30(M+) 343.1685, found 343.1686. Anal. Calcd for CZH21N30 C, 76.94; H, 6.16; N, 12.24. Found: C, 76.64; H, 6.02; N, 11.93. Methyl 3-(Diethy1amino)-1f-dihydro-6-methyl-2-oxo-1phenyl-4-pyridinecarboxylate(10). After reaction of compound 9 with methyl propynoate for 8 h, this compound was isolated in a yield of 47 mg (15%): mp 85-86 "C; IR (KBr) 1740 (ester), 1665 (lactam) cm-'; 'H NMR 6 1.05 (t, 6 H, NCHzCH3),1.95 (8, 3 H, CH3), 3.15 (q,4 H, NCHZCH,), 3.9 (8, 2 H, COZCHJ, 6.1 ( 8 , 1 H, H-5), 7.4 (m, 5 H, ArH); 13CNMR 21.2 (qd, 6-CH3), 103.5 (dq, C-5, 'J = 168) MS ( m / z )314 (M+,loo), 299 (M+- CH3,971, 285 (M+ - CzH5,85), 271 (35); HRMS calcd for C1&22NzO3 (M+) 314.1630, found 314.1627. Dimethyl 5-(Diethylamino)-1,6-dihydro-6-oxo-l-phenyl3,4-pyridinedicarboxylate(12). After reaction of 11 with dimethyl butynedioate for 3 h, this compound was isolated in a yield of 305 mg (85%): mp 89-90 OC; IR (KBr) 1730 (ester), 1665
2937
(lactam) cm-'; 'H NMR 6 1.0 (t, 6 H, NCHzCH3),3.1 (9,4 H, NCHzCH3),3.75 (8, 3 H,COzCH3),3.9 (e, 3 H, CO2CH3),7.4 (m, 5 H, ArH), 8.2 (8, 1 H, H-2); MS ( m / z )358 (M', 89), 329 (M+ CZH5,21), 327 (M+- OCH3, 47), 299 (M+ - C02CH3,lOO); HRMS calcd for CJIZNZO5 (M+)358.1529, found 358.1533. Anal. Calcd for C1sHz2N205:C, 63.68; H, 6.19; N, 7.82. Found: C, 63.51; H, 6.15; N, 7.75. Reactions of 5-Chloro-3-(diethylamino)-2H-l,4-oxazin-2one 6 with Acetylenic Compounds: Generation of Compounds 8. General procedure: A solution of compound 6 (1 mmol) in neat acetylenic compound (3 mL) was stirred at room temperature until compound 6 had disappeared. Workup and purification of compounds 8 was done as for compound 7 using silica gel plates and chloroform as eluent. Methyl 6-Cyano-3-(diethylamino)-2-0~0-2H-pyran-4carboxylate (sa). After reaction for 1 h compound 8a was obtained as an oil from 6 and methyl propynoate in a yield of 188 mg (75%): IR (KBr) 2225 (CN), 1740 (CO) cm-'; 'H NMR 6 1.2 (t,6 H, NCHZCHJ, 3.5 (q,4 H, NCHZCH,), 3.9 (s,3 H, COZCHJ, 7.2 (8, 1H, H-5); 13CNMR 6 13.4 (CHZCHJ, 47.4 (CHZCH,), 52.5 (OCH3),112.4 (d, CN, 3J = 4), 116.4 (8, C-41, 118.3 (d, (3-5, ' J = 175), 121.6 (d, C-6,zJ = 4), 141.8 (m, C-3), 158.1 (C-2), 163.6 (COzCH3);MS ( m / z )250 (M+,100); HRMS calcd for Cl2Hl4N2O4 (M+) 250.0954, found 250.0950. 3-(Diethylamino)-4-phenyl-2-oxo-2H-pyran-6-carbonitrile (8b). After reaction for 40 h compound 8b was obtained from compound 6 and phenyl acetylene in a yield of 91 mg (34%): mp 84 OC; IR (KBr) 2218 (CN), 1724 (CO) cm-'; 'H NMR 6 1.0 (t, 6 H, NCHZCHJ, 3.0 (q, 4 H, NCHZCHJ, 6.8 ( 8 , l H, H-5), 7.5-7.3 (m, 5 H, ArH); '3c NMR6 13.4 (q, NCHzCHJ, 46.0 (t,NCHzCH$ 112.6 (d, CN, 'J = 4), 121.1 (d, C-5, 'J = 171), 125.0 (d, (2-6, J = 4), 127.5, 128.8 (C-Ar), 135.0 (m, C-4), 136.5 (C-ipso), 137.3 (m, C-3), 159.3 (8, (2-2); MS ( m / z ) 268 (M+, 100); HRMS calcd for C16H1602N2 (M+) 268.1212, found 268.1207.
Acknowledgment. The authors are indebted to the F.K.K.O. and the "Ministerie vmr Wetenschapsbeleid" for financial support. They wish to thank the K. U. Leuven (M.G.T.) and the IWONL (S.M.V. and K.J.V.A.) for a fellowship and the Janssen Pharmaceutica company for elementalanalysis. They are also grateful to Dr.S. Toppet, Dr. F. Compernolle, R. De Boer, and P. Valvekens for technical assistance. Registry No. 1 (R' = Ph, R3 = Cl), 87486-37-1; 1 (R' = Me, R3 = Cl),87486-33-7; 2 (R3 = Cl), 125850-02-4;5a, 139706-32-4; 5b, 139706-33-5;6,139706-346; 7a, 139706-35-7; 7b, 139706-36-8; 7c, 139706-37-9;7d, 139706-380;8a,139706-391;8b, 139706-40-4; 9,139706-43-7;10,139706-41-5; 11,139706-44-8; 12,139706-42-6; diethylamine, 109-89-7; dimethyl acetylenedicarboxylate,762-42-5; ethyl propiolate, 623-47-2; phenylacetylene, 536-74-3. Supplementary Material Available: 'H and 13C NMR spectra of 8a and 8b (9 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information.
An Asymmetric Synthesis of Crobarbatic Acid Ming-Yi Chen and Jim-Min Fang*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 10764, Republic of China Received July 9, 1991
The knowledge that pyrrolizidine alkaloids are highly biologically active' has ensured that the synthesis2of such (1)For recent reviews, see: (a) Robins, D. J. In Fortsch. Chem. Org. NaturstoffelProgr. Chem. Org. Nat. Prod.; Herz, W., Grieebach, H., Kirby, G. W., Eds.;Spring-Verb: Vienna, 1982;Vol. 41. (b) Robins, D. J. Nat. Prod. Rep. 1989,221.
0022-3263/92/ 1957-2937$03.O0/0 0 1992 American Chemical Society
2938
J. Org. Chem., Vol. 57, No. 10, 1992
Notes
compounds continues to be the goal of much effort. Crobarbatine (1) is an 11-membered dilactone which incorporates a necine base (retronecine, 2) and 2-hydroxy2,3-dimethylglutaric acid (3).3 The hydrolysis of crobarbatine yields retronecine and crobarbatic acid (4), the product of the spontaneous lactonization of 2-hydroxy2,3-dimethylglutaric acid. Crobarbatic acid has been shown to bear two trans methyl groups;h however, its absolute configuration is still u n k n ~ w n . ~ % ~ H
\
O
b1
5
g N
2
H
fl 0
OH Ho
3
We have already described4 an efficient method for preparing racemic crobarbatic acid via the reaction of ethyl pyruvate with the 2-propenyl-l,3-dithian-2-ylzinc reagent derived from 5 (Scheme I). The involvement of a chelate transition state (A) was hypothesized to account for the stereochemistry that is generated in the product. In addition to being a masked form of the dicarboxylic acid 3, the ketene dithioacetal6 has the potential for regioselective elaborationto crobarbatineby esterification of retronecine at the allylic hydroxyl grouph and macrocyclization subsequent to hydrolysis of the ketenedithioacetal m ~ i e t y . ~ Prior to the pursuit of this project, we investigated preparation of crobarbatic acid in optically pure form. Attempts to kinetically resolve the ethyl ester 6 via enzymatic hydrolysis were unsuccessful. Treatment of 6 with a protease (Amanon) or any of nine lipases (AK, Ap 6, FAP 15, M-AP 10, N Conc, OF, P-Amano, Poncreo, and R-Amano 10) in phosphate buffer (pH 6.9) for as long as 1 week failed to effect any appreciable hydrolysis. The reluctance of 6 to undergo enzymatic hydrolysis is believed to be a consequence of the presence of the 3-methyl group for the structurally similar esters ethyl 2-methyl-3-(1,3dithian-2-y1)propanoateand methyl 2-methyl-2-(benzyloxy)-Cpentenoate are readily hydrolyzed under the conditions described. Since the first report' of its use in such a role, the (-)-8-phenylmenthoxy group has found wide employment as a chiral auxiliary.8 Therefore, we decided to attempt an asymmetric synthesis of crobarbatic acid starting from (-)-&phenylmenthyl pyruvate (7). Whitesell et aLEb showed that Grignard reagents attack the chiral pyruvate 7 at its si-diastereotopic face when the oxygen atoms of the two carbonyl groups are synclinally coordinated with the Mg2+ion. From this observation and the inspection of molecular models, it was concluded that the addition to the ester 7 of a crotylmetal generated from 2propenyl-1,3-dithiane5 would proceed by way of a chelate transition state similar to A and would furnish a product (2) For leading references to the total synthesisof pyrrolizidine alkaloids, see: (a) Huang, J.; Meinwald, J. J. Am. Chem. SOC.1981,103,861. (b) Brown, K.; Devlin, J. A.; Robins, D. J. J.Chem. SOC.,Perkin Trans. 1 1983, 1819. (c) Narasaka, K.; Sakakura, T.; Uchimura, T.; GuedinVuong, D. J. Am. Chem. SOC.1984,106, 2954. (d) White, J. D.; Ohira, S. J. O g . Chem. 1986,51,5492. (e) Vedejs, E.; Ahmad, S.;Larsen, S. D.; Westwood, S. J. Org. Chem. 1987,52,3937. ( f ) Niwa, H.; Okamoto, 0.; Yamada, K. Tetrahedron Lett. 1988,29, 5139. (3) Puri, R. L.; Sawhney,R. S.;Atal, C. K. Experientia 1973,29,390. (4) Fang, J. M.; Hong, B. C. J. Org. Chem. 1987,52, 3162. (5) (a) Corey, E. J.; Beams,D. J. J. Am. Chem. SOC.1973,95,5829. (b) Seebach, D.; Kolb, M. Liebigs Ann. Chem. 1977, 811. (c) Suzuki, K.; Masuda, T.; Fukazawa, Y.; Tsuchihashi, G.-I. Tetrahedron Lett. 1986, 27,3661. (d) Fang, J. M.; Hong, B. C.; Liao, L. F. J. Org. Chem. 1987, 52, 855. (6) (a) Gu,
R. L.; Sih, C. J. Tetrahedron Lett. 1990, 31, 3283. (b) Sugai, T.; Kakeya, H.; Ohta, H. J. Org. Chem. 1990,55, 4643.
Scheme I
A
6
4
Table I. Results of the Addition of the Crotyllithium Jhrived from 2-Propenyl-1,i-dithme (5) to the (-)-Phenylmenthyl Pyruvate 7 in the Presence of Various Additives product total ratio" total yield of additive reactn 8a:8b8c: yield of 9a-db entry (1equiv) temp ("(2) 8d 8a-d (%) (%) 1 -78 30203020 82 68 -78 2 MgC12' 30351025 78 65 3 ZnC1, -78 20303020 68 4 ZnClp -78 to -4od 25:38:12:25 76 62 5 ZnCl2J3 -78 to-40 23341627 57 equiv) 6 ZnCl, -100 26:351821 84 70 7 MgC12; -78tort 28f BF3. OEg' "The ratio was calculated from the results of lH NMR analysis of the mixture of crude products. Both 8a and 8d could be isolated in pure form; however, 8b and 8c formed an inseparable mixture. The 8b:8c ratio was calculated from that of the corresponding hydrolysis products, 9b and 90. bOverall yield (two steps) based on the dithiane 5. 'Attempted direct deprotonation by treatment with MeMgCl at -30 "C was unsuccessful. The pyruvate 7 was added at -78 "C. The mixture was then allowed to warm to -40 OC. The reaction was quenched 30 min later. eMgC12 (1 equiv) and BF,.OEh (1 equiv) were added in that order. The pyruvate 7 was added at -78 OC. The mixture was then allowed to warm to rt. The reaction was quenched 2 h later. f N o reaction occurred at -78 OC. When the reaction temperature was raised to rt, the products 8 (28%),5 (42%), and (-)-&phenylmenthol(33%) were isolated.
which displays the desired stereochemistry. To our disappointment, the reaction of the pyruvate 7, unlike that of ethyl pyruvate, was not stereoselective (Table I). The reaction mediated by a divalent counterion such as Mg2+ or Zn2+ only showed a modest preference for the 2Sproducts (8a + 8b) and the relative 2,3-threo configuration (8b + & The I) relative . configurations of the four addition products, 8a-d (R* = (-)-Bphenylmenthyl), were established by 'HNMR analysis of the correspondingy-lactones (Sa-d, respectively) as well as by an X-ray crystallographic analysis of 9a. The 'H NMR spectra show that the protons of the 2-methyl group of both Sb (the 2S,3S-isomer) and Sd (the 2R,3R-isomer) are diamagneticallyshielded by the adjacent 3-methyl group because they absorb at higher fields than the corresponding protons of Sa (the 2S,3RLikewise, diaisomer) and 9c (the 2R,3S-i~omer).~*~ (7) Corey, E. J.; Ensley, H. E. J. Am. Chem. SOC.1975, 97, 6908. (8) For example, see: (a) Oppolzer, W. Angew, Chem. 1984,96,840; Angew. Chem., Znt. Ed. Engl. 1984,23,876 and references cited therein. (b) Whitesell,J. K.; Bhattacharya,A,; Henke, K. J. Chem. SOC.,Chem. Commun. 1982, 988. (c) Grossen, P.; Herold, P.; Mohr, P.; Ta", C. Helu. Chim. Acta 1984 67,1625. (d) Weuthen, M.; Scharf, H.-D.; Runsink, J.; Vden, R. Chem. Ber. 1988,121,971. (e) Ihara, M.; Takahashi,
M.; Nitsuma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K. J. Org. Chem. 1989,54,5413. ( f ) Hubscher, J.; Barner, R. Helu. Chim. Acta 1990, 73, 1068. (9) Solladie-Cavallo, A. Tetrahedron 1991,47, 249.
J. Org. Chem., Vol. 57, No. 10,1992
Notes magnetic shielding by the 2-methyl group causes the protons of the 3-methyl group of both 9b and 9d to resonate at higher fields than the correspondingprotons of 9a and 9c.
n. p.3 H
Scheme I1 1 ) LDA, MF,-78 'C
H+CO?Et
2) 1 q u i v MgC12
-b o p
C02Et + Rdiastereomer
3) R'OfXOMe (7)
R.o/.,(o
OH
8. (2s.3R)
7 H
OH
8b (25,35)
H
R'O 9a (ZS, 3R)
bo bo -.,, R'O2C
R'02C
9c (2R, 3s)
9b (25, 3s)
R*O2C" $& -*.o
Y-Co2Et
R'02Cd OH
R'02C +.,A0 15
16
Thus, an expeditious synthesis of the crobarbatic acid ester 9a (Scheme 11),which involved (1)addition to the (9) Yamamoto, Y.; Mnruyama, K.; Komateu, T.; Ito, W. J. Org. Chem.
1986.51. - - - -, - - , IIFl(i. - - -.
MeZCuLi,Et20
H,I Pd-C. EtOH
-30"c; 70% 9s
chiral pyruvate 7 of an alkynylmetal generated from ethyl propiolate, (2) addition to the alkynoate of lithium dimethylcuprate, and (3) the catalytic hydrogenation of the unsaturated lactone product, was achieved. Efforts directed toward a total synthesis of crobarbatine are now under way. Experimental Section
9d (2R, 3R)
At this point, a different route to derivatives of crobarbatic acid was investigated. This first step involved the nucleophilic addition of the alkynyllithium generated from ethyl propiolate (10) to the chiral pyruvate 7. In the presence of Mg2+,the addition occurred stereoselectively to afford a 70% isolated yield of the (2S)-alcohol lla.8b To convert l l a to crobarbatic acid, it was necessary to reduce the triple bond to a cis double bond and to introduce a methyl group at the 3-position. The hydrogenation of l l a in the presence of Lindlar catalyst gave only 12, a product of overreduction, which has served as an intermediate in a synthesis of (-)-frontalin.lo Compound l l a was not reduced at all when 5% Pd/CaC03 poisoned with quinoline was the catalyst. However, upon treatment with P ~ ( O A C ) ~ ( P P ~ ~ ) ~ / H C1 la O ~gave H , "the furanone 13. The addition of lithium dimethylcuprate to 13 yielded a 1:l mixture of desired crobarbatate (9a)and ita C-3epimer (9b).I2 On the other hand, treatment of the aUrynoate l l a with lithium dimethylcuprate gave the furanone 14, hydrogenation (10% Pd/C, EtOH) of which afforded, exclusively, the crobarbatate 9a. In contrast, the reduction of 14 by treatment with magnesium13was less stereoselective than catalytic hydrogenation and gave a 1:2 mixture of 9a and 9b. Interestingly, if oxygen is not completely excluded during treatment of lla with lithium dimethylcuprate, only the methoxylated compounds 15 (27%) and 16 (32%) are isolated.
R'O2C
