J. Org. Chem. 1991,56,5196-5202
5196
11 = 3 Hz, H-b), 2.57 (tt, 1 H, lu 0 11 Hz, 'J(h)Hz, 'J(w ,= 3 Hz, ' J ( w 2 % z , H-(9a)ax), 1.5-1.9 (m, 4 154.5 (C-ipso), 129.5.128.9, H, H-8,9)>b N M R 6 165.9 (c--O), 1!28.7,120.8,112 (C-Ar), 105.3 (C-7), 64.8,64.5 (OCH&H20), 60.2 (a), 58.4 (C-4), 55.8 (C-k), 55.4 (C-OCH& 54.6 (Cl),32.5 (C-8), 26.5 (C-9); exact mass calcd for C17HaN204 318.1577, found 318.1573. 7-(Ethylenedio~y)-2-~henyloctahyd~2~-pyrido[ 1,2-a 1pyrazine (15a). To a stirred solution of 14a (293 mg, 1.02 "01) in 20 mL of anhydrous ether was added LiAlH4 (100 mg, 2.64 "01) portionwise. After 1h, the excess of hydride was destroyed by dropwise addition of methanol followed by addition of CH2C12 (200mL), K&Oa (100 mg), and water (2 mL). The organic solvent was evaporated, and the residue was chromatographed on a silica column (gradient elution 5-20% EtOAeCHClJ to give 15a (200 mg, 72%) as a yellow oil: 'H NMR (CDCl') 6 7.3 (dd, 2 H, Ph), 6.9 (dd, 2 H, Ph), 6.89 (tt, 1H, Ph), 4 (m, 4 H, OCH2CH20),3.63 (dd, 1 H, 2J = 12 Hz, 8Jlu,(h)u= 10 Hz, H-lax), 3.5 (dm, 1 H, ?J = 12 Hz, H-le), 3.5 (dm, 1H, 2J = 11 Hz, H-3e), 3.05 (td,1 H, 'J 11Hz, ' J p h = 11Hz, 'JWk 3 Hz, H-Ba), 2.89 (at, 1 H, ?J = 11Hz, J = 3 Hz, 'Jk = 2.5 Hz, H-4e), 2.8 (dd, 1H, 2J = 11.5 Hz, = 2.5 Hz, fisc), 2.4 (M, 1H, 2J = 11 Hz, ' J 11Hz, J h s , 3 Hz, H-4=), 2.22 (d, 1 H, ' J 11.5 HZT&x),2.15 (m, 1k,H-(Sa)ax), 1.87 (m, 1H, H-8e), 1.65 (m, 3 H, H-9,8ax); exact mass calcd for C16HaN202 274.1680, found 274.1677. 2-Phenyloctahydro-2H-pyrido[lf]pyrazin-7one ( 16a). A mixture of 15a (500mg, 1.82 mmol) and 6 M HCl(20 mL) was refluxed for 2 h. The solution was evaporated, and the residue was diesolved in water (10 mL). The aqueous solution was cooled to 0 OC and made alkaline with K2COs&r the addition of CH2C12 (100 mL). The aqueous layer was further extracted with CH2Clz (50 mL), and the combined organic layers were evaporated. Column chromatography of the residual oil on silica (gradient elution 5 1 5 % EtOAeCHCl') afforded pure 16a (395 mg, 94%) as a yellow oil (stored as the HC1 salt since it was oxidized in ita basic form): IR Y 1730 cm-l; 'H N M R (CDCl' C&) 6 7.22 (dd, 2 H, Ph), 6.85 (t, 1H, Ph), 6.75 (ad, 2 H, Ph), 3.38 (dt, 1H, 2J = 11.3 Hz, *Jle,(9m= 2.5 Hz, 'J = 2.5 Hz, H-le), 3.32 (dq, 1 H, 2J = 11.5 Hz, Jh, = 3 Hz, = 2.5 Hz, 4Ja,1e= 2.5 Hz, H-3e), 3.17 (ad, 1 H, F J = 14 Hz, 'jqa = 2 Hz, H-6e), 2.71 (td, 3 Hz, H - 3 4 , 2.56 1H, 'J 11.5 Hz, ' j 3 p = 11.5 Hz, J-k (dt, 1H, 2J = 11Hz, Jh,& = 3 Hz, 'Jhh = 2.5 Hz, H-4e), 2.54 (dd, 1H, 2J = 14 Hz, 'Jk& = 1Hz, I-f-Sax), 2.35 (dd, 1 H, 2J 10.2 HZ,Helm), 2.21 (td,1H, 'J = 11Hz, = 11.3 Hz, 'J1, 'JWau = 11.5 8JIuc = 3 Hz, H-4ax), 2.12-2.38 (m, 2 H, H-Be,(ga)ax), 2.04 (dddd, 1H, 2J = 15 Hz, ' J V 13Hz, 'J1Hz, H - k ) , 1.57 (ddt, 1H, J 13 HZ,'Je, 7 HZ,'J= 7 Hz, *Jo.(h)u= 3 Hz, *J3. = 2.5 Hz, H-ge), 1.45 (tdd, 1 2J = 13 Hz, $J= 13 Hz, Jg~q(h)= = 10.5 Hz, 'J- = 5 Hz);
pqa
+
xl,
kz,
e
exact mass calcd for C14H&O 230.1419, found 230.1417. 2- (2-Met hoxyphenyl)octahydro-2H-pyrido[ 1,2-a 1pyrazin-7-0110 (16b). To a stirred solution of 14b (200 mg, 0.63 mmol) in 15 mL of anhydrous ether was added LiAlH4 (50 mg, After 1h, the excess of hydride was destroyed wlth 1.32 "01). MeOH and the mixture worked up as for 15a to give the crude product 15b (176 mg, 92%) as an oil, which was wed directly in the next step: MS mlz 304 (M+). A mixture of the crude product 15b (176 mg) and 6 M HCl(10 mL) was refluxed for 2 h. After workup as described for 16a, column chromatography using silica gel with EtOAc as eluent afforded pure 16b (107 mg,65% from 15b) as a pale yellow crystalline product, mp 106-108 "C: IR Y 1725 cm-l; lH NMR (CDCld 6 6.85-7.1 (m, 4 H, Ar),3.9 (s,3 H, OCH3),3.49 (dt, 1H, 2J = 11Hz,BJle(wu= 3 Hz, 'Jlec = 3 Hz, H-le), 3.43 (dq, 1 H, 2J = 12.5 Hz, 'jkh = 3 Hz, 'Jal, = 3 Hz, 'Jal. = 3 HZ,H-3e),3.33 (dd, 1H, 2J = 14 I&, 'Jw = Z'HZ, H-6e), 2.84-2.9 (m, 1 H, H-4e), 2.88 (d, 1 H, 2J = 14 Hz, H-Gax), 2.84 = 12.5 Hz, ' J W h 3 Hz, H - 3 4 , (td, 1H, 2J 12.5 Hz, 'J2.46-2.7 (m, 3 H, H-(Sa)ax,de,riax), 2.47 (t, 1 H, 2J = 10.5 Hz, 3J1a(h)m= 10.5 Hz, H-lax), 2.38 (ddd, 1H, 2J = 15 Hz, 'JWs, = 11.7 HZ,' J M = 7 HZ,H - k ) , 1.95 (ddt, 1H, ' J = 13 HZ," J g 9 = 7 Hz, 3Jo.,(h))u = 3 Hz, = 3 Hz, H-ge), 1.7 (tdd, 1H, J = 13 Hz, 'J = 11.7 Hz, JW(h)u = 10 Hz, ' J u = 5.5 Hz, H-Sax); 6 205.8 (C-O),152.3 (C-2' Ar), 140.8 (C-1' Ar), 123.1, 121, 118.2, 111.4 (C-3',4',5',6' Ar), 65.3 (C-6),58.6 (C-ga), 56.1 (C-l), 55.4 (OCHd, 55 (C-4), 49.9 (C-3), 38.3 (C-8),28.4 ((3-9); exact maas calcd for Cl&,JU202 260.1523, found 260.1525. Anal. Calcd for C15H&J202:C, 69.21; H, 7.74; N, 10.76. Found C, 69.25 H, 7.70; N, 10.80.
IJ,,,,
%%
Acknowledgment. We are indebted to the F.K.F.0 and the 'Ministerie voor Wetenschapsbeleid" for financial support. We thank the K.U.Leuven (M. A. Saleh) for a fellowship and the firm Janssen Pharmaceutica for elemental analyses. We are also grateful to R. De Boer for high-resolution mass spectra. R e d s t v NO.1, 132462-23-8; 2,134334-33-1; 3,134334-34-2; 4a, 134334-35-3;5, 134334-36-4;7, 134334-37-5;8, 134334-38-6; ,12a, 134334-41-1; 12b, 134334-42-2; 9,134334-39-7; 11,134334-40-0. 13a, 134334-45-5; 13b, 134334-46-6; 14a, 134334-43-3; 14b, 134334-44-4; 15a, 134334-47-7; 15b, 134334-488; 164 134334-49-9; 16b, 13433450-2; LiAl(OEt),H, 17250-30-5;ClCH2COC1,79-069; C6HsCH2Br,100-39-0; C6HsNH2,62-53-3; 2-MeOC6H4NH2,9004-0; 2-fluoropyridine, 372-48-5.
Supplementary Material Available: 'H and/or '*C NMR spectra for compounds 2,3,11,12a, 12b, 14a, 14b, 15a, and 16a (10 pages). Ordering information is given on any current masthead PWe.
+
Asymmetric Total Synthesis of ( )-Jasplakinolide Kent S. Chu, George R. Negrete, and Joseph P. Konopelski+*' Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064
Received February 6, 1991
A convergent synthesis of the marine cyclodepsipeptide (+)-jasplakinolide has been realized. The synthesis of the required (R)-@-tyrosineunit is accomplished via the stereospecific palladium-catalyzed arylation of an enantiomerically pure dihydropyrimidinone. The overall yield of the synthesis, based on the longest linear sequence, ie 6.6%.
In 1986,two papere documenting the isolation, structure, and biological activity of a novel cyclodepsipeptide of marine origin appeared in the literature.' This metabolite, which is composed of both peptide and polypropionate portions, was named jasplakinolide (1) by t h e Crews American Cancer Society Junior Faculty Research Awardee, 1987-90. 0022-3263/91/1956-5196$02.50/0
groupla and jaspamide by the Ireland-Faulkner team.Ib Along with the common acid (8-alanine, jasplakinolide contains two unusual amino acids, @-tyrosine2 and 2(1) (a) Crews, P.; Manes, L. V.;Boehler, M. Tetrahedron Lett. 1986, 27,2797-2800. (b)Zebriekie, T. M.; Klocke, J. A,; Ireland, C. M.; Marcue, A. H.;Molinski, T. F.;Faulkner, D. J.; Xu, C.; Clardy, J. J. Am. Chem. SOC.1986,108,3123-4. (c) Braekman, J. C.; Daloze, D.; Moueeiaux, B. J. Nat. Prod. 1987,50, 994-6.
0 1991 American Chemical Society
J. Org. Chem., Vol. 56, No. 17,1991 8197
Asymmetric Total Synthesis of (+)-Jasplakinolide
the starting point for production of 5: while lactone 7" can be elaborated into fragment 3. Our plan was to prepare the tripeptide and polypropionate segments, joining the C-1,N-19amide bond prior to the ester linkage. Ester formation was chosen as the last step to avoid racemization in the ring closure. 1
2
Ho*
R1=
7
3
+ X = 1; gcodimolideA X = Br; gcadimolideB
bromoabrine, both possessing the less common R absolute configuration. The nonenoic acid fragment contains three chiral centers and had also not been described previously in the literature. Initially, our attention was drawn to the tryptophantyrosine portion of the molecule, undoubtedly an important aspect of the structureactivity relationship? Work by the Crews' group' on the solution conformation of the molecule indicated that the B-tyrosine unit has more conformational mobility than the other portions of the ring. As shown below, synthesis of the desired 2-bromoabrine molecule is straightforward. However, the lack of general enantioselective approaches to the synthesis of &aryl B-amino acids prompted us to investigate new routes to this class of compound6within the context of a total synthetic venture. The combination of a wide range of biological activity (including cytotoxic, anthelminthic, insecticidal, and specific antifungal against Candida albicam) with its unique structural aspects has made jasplakinolide an attractive target for total synthesis. To date, one completed synthesis has appeared! as well as reporta of the synthesis of both the peptide' and polypropionate* sections. In addition, several published reporta of the synthesis of the structurally related, but inactive, marine cyclodepsipeptides geodiamolide A and B (2)gJ0have appeared. Below we report our own efforts in this area, which have culminated in the total synthesis of (+)-jasplakinolide.
Results and Discussion Retrosynthetically, 1 can be divided into protected hydroxy acid 3 and the protected constituent amino acid fragments 4-6. protected (Sl-alanine6 and (R)-tryptophan 8 fragments are commercial products. Dihydropyrimidinone 9, prepared from (8)-asparagine, provides (2)Parry, R. J.; Kurylo-Boroweka, 2.J. Am. Chem. SOC.1980,102, 836-7. (3)Kahn, M.; Su, T. In Peptides, Chemistry and Biology, ESCOM Leiden, 1988,pp 109-11. (4)Inman, W.; Crews, P. J. Am. Chem. SOC.1989,111,2822-9. (6) A preliminary discloewe of this work has appeared. Konopelski, J. P.; Chu, K. 5.;Negrete,G.R.J. Org. Chem. 1991,56,1365-6. (6)Crieco, P. A.; Hon, Y. S.; Perez-Medrano, A. J. Am. Chem. SOC. 1988,110,1630-1. (7)Kato, 5.;Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1988,29, 6466-6. (8)Schmidt, U.;Siegel, W.; Mundinger, K. Tetrahedron Lett. 1988, 29,1269-70. (9) Isolation: Chan, W. R.; Tinto, W. F.; Manchand, P. S.;Tadaro, L. J. J. Org.Chem. 1987,52,3091-3. (10) Synthesk (a) Crieco, P. A,; Perez-Medrano, A. Tetrahedron Lett. 1988,29,422E-8.(b)White, J. D.;Amedio, J. C., Jr. J. Org.Chem. 1989,54, 736-8. (c) Hirai, Y.; Yokota, K.; Sakai, H.; Yamazaki, T.; Momow, T. Heterocycles 1989,29,1886-9.
4 1-
t
9
5
+
6 N-r-BOC-(S)-ddne
Our independent routeI2to (E)-(28,6R,8S)-a[(tert-b~tyldimethylsilyl)oxy]-2,4,6-trimethyl-4-nonenoic acid (3) is similar to that completed by Grieco? Enantiomeridy pure lactone 7 is catalytically dehalogenated and subsequently reduced with DIBAL prior to treatment with 2lithio-2-propene. The resultant mixture of diol isomers 10 (73% yield from 7) is directly subjected to the Ehchenmoser variation of the Claisen rearrangementla and affords, after base hydrolysis, the desired hydroxy acid along with starting diol. Recycling of the recovered diol through the Claisen protocol allows for a 75% isolated yield of hydroxy acid. Protection of the secondary hydroxy functionality as ita tert-butyldimethylsilyl derivative 11 is uneventful (94% yield). Use of the Evans auxiliarylC1* (S)-4-isopropyl-4-oxazolidinoneallows asymmetric methylation to proceed in 88% yield as a 3 1 mixture of isomers, separable by HPLC. The major isomer 12, obtained in 62% yield, is transformed to the corresponding carboxylic acid 3 by treatment with LiOH/H20217in 86% yield (9steps, 25% yield from 7). (11) Corey, E. J.; Haee, T. Tetrahedron Lett. 1979, 336-8. h Q pointed out in ref 6,(4-7is obtained via the rseolution of the cormsponding fll7-uneatwated acid with (S)-(-)-a-methylbenzylamine,fob lowed by cyclization. (12)Konopelsk$ J. P.;Negrete,G. IL,Chu, S. 196th American Chemical Society Meet-, Loa Angeles, CA, Se tember, 1989; American Chemical Society: Washington, DC, 1989; Aktract ORGN 139. (13) von Dorthee Felix, K. G.; Wick, A. E.: &henmaser. A. Helu. Chim. Acta l969,52,103W2. (14)Evans, D.A.: Ennia. M. D.;Mathre. D.J. J. Am. Chem. Soc. lW, 104,11371). (16)In independent studies, we have established that 9 functions in an analogous fashion to the Evans reagent.'@In a single, unoptimised experiment, substitution of 9 into the methylation sequence of thin acheme allows for a 60%yield of product ae a 2 1 diantemmeric m h along with a 60% yield of starting material. (16)Negrete,G. R.;Konopelski,J. P. Tetmhedrom Asymmetry 1991, 2. 106-8. (17)Evans, D.A.; Britton, T. C.;Ellman, J. A. Tetrahedron Lett. lW7, 29,6141-4.
Chu et al.
1198 J. Org. Chem., Vol. 56, No.17, 1991 X
7
hkL'
10
11 X = O H , R - H 12 X=Dxrmlidaw.R=Mc 55% 3 X = O H , R = M c 86%
(a) 10% Pd/C, Hp, N(Et)a, MeOH, rt, 30 min; OC,
(b) DIBAL, -78 30 min; (c) CHp4XLi)CHa; (d) CHaC(OCH&N(CH&, reflux;
OH-; (e) TBDMSCI, imidazole, DMF; (0KOH, ClCOCOCl, lithium salt of (S)-4-isopropyl-2-oxazolidinone;(g) NaN(TMS)*, MeI; (h) LiOH, Hoop
The preparation of the tripeptide portion of jasplakinolides begins with treatment of (R)-tryptophan methyl ester (8)with acetic formic anhydride,l*followed by borane reduction to afford N-methyl-(R)-tryptophanmethyl ester (13)in 56% yield.19 Coupling of 13 to N-BOC-(8-alanine (DCC/HOBt, 90%) gives desired dipeptide 14 with little (
