3402
J. A m . Chem. SOC.1987, 109, 3402-3408
C22H36Br2).An analytical sample was prepared by recrystallization from hexane. Anal. Calcd for C,,H,,Br,: C , 57.39; H , 7.83; Br, 34.78. Found: C, 57.97; H , 7.96; Br, 34.35. The product mixture (rf values 0.5 (2a) and 0.4 (2b) by analytical TLC, eluent hexane) was subjected to HPLC, using 3% ethyl acetatehexane (v/v) as eluent. This procedure resulted in the isolation of pure 2a in addition to unidentified decomposition products of the other isomer. After recrystallization from benzene, 2a had mp 203-205 “ C dec. ‘ H NMR 6 1.04-1.47 (multiplet of doublets, 24 H, CH(CH,)J, 2.06 (d, 3 H , J = 6.98 Hz, CHBrCH,), 2.15 (d, 3 H , J = 7.35 Hz, CHBrCH,), 3.62-3.79 (m, 3 H , CH(CH,)*), 4.46 (septet, 1 H , J = 7.19 Hz, CH(CH3)2), 6.07 (q, I H , J = 7.32 Hz, CHBrCH,), 6.89 (q, I H, J = 6.99 Hz, CHBrCH,). See also Figure 6. I3C NMR 6 21.50, 22.49, 22.59, 22.71, 22.77, 23.16, 23.37 (CH(CH,),), 26.17, 26.71 (CHBrCH,), 27.81, 28.19 (CH(CH,),), 47.49, 47.73 (CHBrCH,), 139.04, 140.41, 144.67, 147.81, 148.1I , 149.23 (aromatic carbons). Both diastereomers decompose slowly in CHCI, or CH,Cl, solutions, and more rapidly in tetrachloroethene or on exposure to light. They are
relatively stable in CCI4 or hydrocarbon solutions, but repeated recrystallization of the mixture invariably resulted in preferential decomposition of 2b. Dipole moments were determined for two solutions of mixtures of 2a and 2b in benzene at room t e m p e r a t ~ r e . ~ Mixtures ~ containing 64 and 84% of 2a had = 2.92 and 2.81 D, respectively. The calculated dipole moments of 2a and Zb are therefore 2.72 and 3.25 D, r e ~ p e c t i v e l y . ~ ~
Acknowledgment. We t h a n k M a r y W. Baum for technical assistance, Albert0 Gutierrez and Roman Gancarz for stimulating discussions, t h e Grace Chemical Company for a Fellowship t o J.S., the National Science Foundation for s u p p o r t of this work. (42) We thank Professor E. N. DiCarlo for these measurements. (43) Dipole moments calculated by the empirical force field method (MM2) are 1.71 and 3.45 D for (I’RS,Z’SR)- and (l’RS,2’RS)-2, respectively.
Total Synthesis of ( f)-Granaticin Keiichi Nomura, Kousuke Okazaki, Kozo Hori, and Eiichi Yoshii* Contribution from the Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-01, Japan. Received October 21, 1986
Abstract: A 20-step total synthesis of (f)-granaticin from tetralone 8 is described. Conversion of 8 to allylic alcohol 15 followed by a catalytic osmylation afforded triol 16 in a highly stereoselective manner, which was then cyclized t o benzooxabicycle 18 through the agency of benzylic bromination with NBS. T h e intermediate 18 was efficiently converted t o cyanophthalide 22, and its annulation with 5-tert-butoxy-2-furfurylideneacetone afforded naphthyl ketone 25. Reduction of 25 to a carbinol and subsequent pyranocyclization provided a diastereomeric mixture of hexacyclic compounds, 26a,b and 27a,b, which could be separated by HPLC. T h e predominant isomers 26a and 26b, whose structures were determined by X-ray crystallography a n d N M R spectroscopy, were subjected to two-step O-demethylation (oxidation with ceric ammonium nitrate t o dimethoxy-1,4-naphthoquinones a n d subsequent treatment with A1CI3-Et2S) to provide (f)-granaticin (1) and its diastereomer 30, respectively.
The antibiotic g r a n a t i c i n (1) was first isolated in 1 9 5 7 from the culture of Streptomyces olivaceuslaand since has been detected in a number of other actinomycetes along with granaticin B (2),lb the a-L-rhodinoside of 1, and dihydrogranaticin (3).’c-e,2 Granaticin is highly active against Gram-positive bacteria and protozoa and exhibits some activity a g a i n s t P-388 lymphocytic leukemia in mice (T/C 166% a t 1.5 m g / K g ) and cytotoxicity against KB cells (EDSo 1.6 pg/mL).’di3 The glycoside 2 shows a distinct inhibition of various transplanted t u m o r s in rodents after intraperitoneal a p p l i ~ a t i o n . ~G r a n a t i c i n h a s been reported t o inhibit RNA synthesis in bacteria by the failure t o charge I e ~ c y l - t R N A . ~ ~ The cytotoxicity of 1 is attributed to inhibition of ribosomal RNA mat~ration.~~ A novel feature of the molecular structure of 1, which had been d e t e r m i n e d by a combination of chemical degradations and an X - r a y crystallographic analysis in 1968,6 is the a t t a c h m e n t of t w o ( 1 ) (a) Corbaz, R.; Ettlinger, L.; Gaumann, E.; Kalvoda, J.; KellerSchierlein, W.; Kradolfer, F.; Manukian, B. K.; Neipp, L.; Prelog, V.; Reusser, P.; Zahner, H. Helv. Chim. Acta 1957, 40, 1262-1269. (b) Barcza, S.; Brufani, M.; Keller-Schierlein, W.; Zahner, H. Ibid. 1966, 49, 1736-1740. (c) Pyrek, J . St.; Mordarski, M.; Zamojski, A. Arch. Immunol. Ther. Exp. 1969, 17, 827-832. (d) Chang, C.-j.; Floss, H. G.; Soong, P.; Chang, C.-t. J . Antibiot. 1975, 28, 156. (e) Pyrek, J. St.; Achmatowicz, O., Jr.; Zamojski, A. Tetrahedron 1977, 33, 673-680. (2) The Merck Index, 10th ed.; Windholz, M.; Budavari, S.; Blumetti, R. F.; Otterbein, E. S., Eds.; Merck & Co., Inc.: NJ, 1983; p 4408. (3) Krzywy, T.; Mordarski, M.; Orlowska, B.; Tkaczowa, A. Arch. Immunol. Ther. Exp. 1969, 17, 63-71, (4) Sethi, M. L. J . Pharm. Sci. 1977, 66, 130-132 (footnote I ) . ( 5 ) (a) Ogilvie, A.; Wiebauer, K.; Kersten, W. Biochem. J. 1975, 152, 51 1, 517. (b) Heinstein, P. J . Pharm. Sci. 1982, 71, 197-200.
0 0 0 2 - 7 8 6 3 / 8 7 / 1509-3402$01.50/0
3
4
5
oxygen-containing heterocycles a t each side of t h e naphthazarin ring. T h e s e residues, t h e 2-oxabicyclo[2.2.2]oct-5-enes y s t e m (6) (a) Keller-Schierlein, W.; Brufani. M.; Barcza, S. Helv. Chim. Acta 1968, 51, 1257-1268. (b) Brufani, M.; Dobler, M. Ibid. 1968,5/, 1269-1275.
0 1 9 8 7 American C h e m i c a l Society
J . Am. Chem. SOC.,Vol. 109, No. 11, 1987 3403
Synthesis of (&)-Granaticin Scheme
Scheme 11'
I
b
Hwo -
HO 12
O M e CN
o''"
o"" H
OMeo
OH
\
OH
10
-
Br
CONEt,
Br
/
0 WOBU'
H
13
C
OMeOMe 11
1
derived from a C-glycoside' and the pyrano-y-lactone ring, are the same as those found with sarubicin A (U 58431) (4)8 and nanaomycin D9a(5, the enantiomer of kalafungin'O), respectively. Our own interest in 1 as a synthetically challenging target led us to embark on a program directed toward its total synthesis in mid 1981. To date we have developed a highly stereoselectivesynthetic method for construction of the oxabicyclic ring system" and achieved the first total synthesis of (*)-4.l* We then progressed very recently to a synthesis of the granaticin analogue 613 from
&
f
18
R
I
___)
0 6
Me
0
the anthracenone 7 which was prepared from 1,8-dihydroxyanthraquinone (chrysazin). However, all attempts at the transformation of 6 into 1 were unsuccessful due to sensitivity of the oxabicycle to conventional O-demethylation methods. Our continued efforts focussed on a modified strategy have now yielded the first total synthesis of (&)-l, which is the subject of this article. The synthetic plan, which utilizes the tetralone 8 as starting material, involves the key transformations outlined in Scheme I: (1) a highly stereoselective synthesisll of the 5,6-benzo-2-oxabicyclo[2.2.2]oct-5-ene derivative 9; (2) transformation of 9 into (7) Investigations on the biosynthesis of granaticin: (a) Snipes, C. E.; Chang, C.-j.; Floss, H. G. J . Am. Chem. Soc. 1979, 101,701-706. (b) Snipes, C. E.; Chang, C.-j.; Floss, H. G. J . Nat. Prod. 1979, 42, 627-632. (c) Arnone, A.; Camarda, L.; Cardillo, R.; Fronza, G.; Merlini, L.; Mondelli, R.; Nasini, G.; Pyrek, J. St. Helo. Chim. Acta 1979, 62, 30-33. (d) He, X. G.; Chang, C.-C.; Chang, C.-j.; Vederas, J. C.; McInnes, A. G.; Walter, J. A,; Floss, H. G. 2.Naturforsch., C: Biosci. 1986, 41, 215-221. (8) (a) Reinhardt, G.; Bradler, G.; Eckardt, K.; Tresselt, D.; Ihn, W. J . Antibiot. 1980, 33, 787-790. (b) Slechta, L.; Chidester, C. G.; Reusser, F. Ibid. 1980, 33, 919-923. (c) Tresselt, D.; Eckardt, K.; Ihn, W.; Radics, L.; Reinhardt, G. Tetrahedron 1981, 37, 1961-1965. (d) Eckardt, K.; Tresselt, D.; Ihn, W.; Kajtar, M.; Angyan, J.; Radics, L.; Hollosi, M. J . Antibiot. 1983, 36, 976-979. (9) (a) Omura, S.; Tanaka, H.; Okuda, Y.; Marumo, H. J . Chem. SOC., Chem. Commun.1976, 320-321. (b) Synthesis of optically active nanaomycin D and kalafungin: Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. Bull. Chem. SOC.Jpn. 1985, S8, 1699-1706. (IO) (a) Bergy, M. E. J . Antibiot. 1968, 21, 454. (b) Hoeksema, H.; Krueger, W. C. Ibid. 1976, 29, 704-709. ( 1 1) (a) Sudani, M.; Takeuchi, Y.; Yoshii, E.; Kometani, T. Tetrahedron Lett. 1981,22,4253-4256. (b) Yoshii, E.; Takeuchi, Y.; Nomura, K.; Takeda, K.; Odake, S.; Sudani, M.; Mori, C. Chem. Pharm. Bull. 1984, 32, 4767-4778. (12) (a) Takeuchi, Y.; Sudani, M.; Yoshii, E. J . Org. Chem. 1983, 4151-4152. (b) Semmelhack, M. F.; Appapillai, Y.; Sato, T. J . Am. Chem. SOC.1985. 107. 4577-4579. ( I 3) Nomura, K.; Hori, K.; Ishizuka, M.; Yoshii, E. Heterocycles 1987, 25, 167-173.
1
CONEt, I
OCH,OMe
7
0
OMe
HO"*
OH
H
21
22
'(a) CH2=C(OMe)Li, T H F , -60 'C; HCI-MeOH (90%); (b) NaBH,, 2-propanol (ca. 100%); (c) Ac20, pyridine; S O U 2 , pyridine; KOH-MeOH (65%); (d) Me3N(0), catalytic Os04, terf-butyl alcohol-H20, 60 O C (65%); (e) NBS, CCI,, AIBN, 40 OC; (f) AgCIO4, T H F (65% from 16); (8) CH2=C(OMe)Me, camphorsulfonic acid, T H F , room temperature (97%); (h) n-BuLi, T H F , -100 "C; CICONEt2, -70 O C (90%); (i) t-BuLi, T H F , -75 OC; DIMF, 0 " C (96%); 6) Me3SiCN, KCN-I 8-crown-6, CH2CI2; HOAc, room temperature: CH2=C(OMe)Me, camphorsulfonic acid, T H F , room temperature (84%).
the tetracyclic cyanophthalide 10 and subsequent a n n ~ l a t i o n l ~ , ' ~ ~ leading to the interwith 5-tert-buto~y-2-furfurylideneacetone'~ mediate 11; (3) formation of the pyrano-y-lactone ring according to the method of Kraus.15 Results and Discussion Reaction of 8'' with lithiated methyl vinyl etherI8 followed by brief acid-treatment of the reaction product afforded 0-keto1 12 in 90% yield (Scheme This material was then reduced with sodium borohydride to afford diol 13 as a 1:9 mixture of diastereomew20 Regioselective dehydration of 13 to allylic alcohol (14) (a) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 2263-2266. (b) Li, T.; Wu, Y. J . Am. Chem. SOC.1981, 103, 7007-7009. (c) Li, T.; Walsgrove, T. C. Tetrahedron Lett. 1981,22, 3741-3744. (d) Keay, B. A,; Rodrigo, R. Can. J . Chem. 1983, 61, 637-639. (e) Chenard, B. L.; Dolson, M . G.; Sercel, A. D.; Swenton, J. S. J . Org. Chem. 1984, 49, 318-325. (0 Freskos, J. N.; Swenton, J. S. J . Chem. SOC.,Chem. Commun. 1985,658-659. ( 1 5 ) (a) Kraus, G. A.; Roth, B. J . Org. Chem. 1978,43, 4923-4924. (b) Kraus, G.A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. Ibid. 1983. 48. 3439-3444. (16) Nomura, K.; Okazaki, K.; Hori, K.; Yoshii, E. Chem. Pharm. Bull. 1986, 34, 3175-3182. (17) Braun, M. Tetrahedron Lett. 1980, 21, 3871-3874. (18) Baldwin, J. E.; Hofle, G. A.; Lever, 0. W., Jr. J . A m . Chem. SOC. 1974, 96, 7125-7127. (19) All compounds are racemic. One enantiomer corresponding to l 6 is depicted for graphic simplicity. ~~
~i~
~
~
3404 J. Am. Chem. Soc.. Vol. 109, No. 11, 1987 15 was first attempted by use of acid catalysts ( e g , trifluoroacetic acid or camphorsulfonic acid in dichloromethane or benzene).Ilb However, the yields of 15 were unacceptable (
