4494 J. Am. Chem. Soc. 1981, 104, 4494-4496
of the 2Hj1H ratios is by complete combustion of the organic resonance lines to specific molecular sites was accomplished from matter to C02 and H20 and rcduction to H 2 in a uranium fumace analysis of the corresponding 500-MHz proton spectra or from and mass spcctroscopic analysis of the isotropic ratio of the whole associating the protons with a specific carbon peak by using compound without any indication of isotopic ratios as a function selective proton decoupling. of site within the molecule. Some effort has been made to be more selective in analysis of 2Hj1H ratios. In particular, work has been Acknowledgment. This work was supported in part by the done on tbe nonexchangable hydrogens of cellulose."J While these National Institutes of Health under Grant GM 08521 from the studies focused on one type of sitc by eliminating the hydroxyl Institute of General Medical Sciences. Spectra were obtained hydrogens, the 2Hj1H ratios were not site specific for the C-H at the Southern California Regional NMR Facility, supported hydrogens. Rauschenbach et al.6 compared 2H/1H ratios for by the National Science Foundation on Grant CHE 79-16324. synthetic and fennented ethanols and also detcnnined the isotopic Reaistry No. Methylcyclohexane, 108-87-2; 1,1 ,3-trimethylcyclo ratio in the mcthyl group of the ethanol by oxidation to acetic hexane, 3073-66-3; d-camphor, 464-49-3. acid and analysis of the corresponding acetate salt. Martin and Martin7•8 recently have used 2H NMR to show that the isotopic distribution of 2H in ethyl and vinyl groups varies from molecule to molecule. The full significance of observing site-specific isotopic effects Tricyclo[ S.l.O.Ol.l]octa-3,5-diene ( Octavalene) upon the 2Hj1H ratio is emphasized when it is realized that such information is not readily available from the traditional mass Manfred Christi* and Reinhard Lang spectrometric methods of measuring isotope ratios. Although mass spectral methods are much more sensitive than NMR techniques Institut für Organische Chemie and have a much larger dynamic rangc, such methods can only der Universität Würzburg, Am Hubland measure the averagc molecule 2H/1H isotope ratio because of the D-8700 Würzburg, Federal Republic of Germany 1 2 facile scrambling of the molecular hydrogens (both H and H) Received April 22, 1982 in the typical mass spectrometric ion. Futhennore, these hydrogen 5 rearrangements can be isotopic selectivities as large as 10 in somc 1 9 The unique properties of the (CH)8 hydrocarbons have at instanccs. Such large isotope effects would completely mask tracted the attention of many organic chemists. As a member thc significant but still smaller intramolecular ratios that we have of this series the title compound (8) enjoys special interest. Tbc been recently observing. Thus, high-field deuterium magnetic 2 butadiene bridge should substantially widen the dihedral angle resonance, H NMR, techniques provide a unique method for of the bicyclo[ 1.1.0] butane system from the normal value of about detcrmining this potentially valuable information. 122 o, 2 resulting in an increased strain energy. T~is, as weil as Site-specific isotopic ratios have the potential for more complete the electronic interaction of the 'II" system and the stramed " system, characterization of the rate-controlling processes in rather complex Ieads one to anticipate that 8 will exhibit unusual chemical and chemical and biosynthesis processes. Detailed information on 2 1 spectroscopic properties. Furthermore, the Woodward-Hoffmann mechanistic steps should be available from variations in the H/ H rules allow a thermally induced [1,5] carbon shift. Repetition ratio as a function of molecular site. This technique, applicable of this degenerate rearrangement would finally equilibrate all CH at natural abundance, allows analysis without destruction of the groups. Thus, 8 could be te bullvalene equivalent of the (CH)s sample and removes the possibility of artifical inhibition of a family. metabolic system by excess deuterium present in Iabel~ ~om Interested in such prospects, several research groups have un pounds. Finally, as found in our two camphors, one may anttCJpate dertaken to synthesize 8. When 8,8-dibromobicyclo[S.l.O]octa- the opportunity of observ!ng the chemical history of !w~ ide~tical 2 4-diene was treated with methyllithium, the resulting carbene molecules derived from dtfferent precursors from vanattons m the 3 4 2 1 r~rranged to a dihydropentalene • instead of inserting into the intramolecular Hf H ratios stampled into the molecule by al syn-6-CH bondas intended. Likewise, the tricarbonyl iron com ternative synthetic pathways. With improved sensitivity and 2 plex of the dibromide with methyllithium failed ~o give the desired spectral dispersion at very high fields, proton-decoupled H NMR 5 1 insertion product. In analogy to the preparatton of benzvalene can now realize its full potential. The significant isotope effects 6 2 via cyclopentadienylcarbene the intramolecular [~ + 1] or [6 + observed herein further enhance the importance of H NMR 1) cycloaddition of cycloheptatrienylcarbene to gtve 8 has been techniques. 2 attempted. However, only cyclooctatetraene, heptafulvene, Experimental Section. Tbc 76.77-MHz H spectra were re benzene, and acetylene could be identified as reaction products.' corded on a Bruker WM500 spectrometer operating in Fourier Also, the disrotatory opening of the cyclobutene portion in tet transform mode. Methylcyclohexanc and 1,1,3-trimethylcyclo racyclo[ 4.2.0.02•4.03.s]oct-7-ene, which shoul~ produce 8, could hexane were run as neat liquids, and d-camphor was prepared as not be achieved without rearrangement of the btcyclo[l.l.O]butane a nearly saturated solution in chloroform. Each sample contained system.8 In addition, a Straightforward route to prepare ~ 1O% tetramethylsilane as a chemical shift reference. Spectra bromooctavalene by cyclopropane ring enlargement of the dt requiring about 400 scans were acquired at 8-s intervals by utilizing bromocarbene adduct of homobenzvalene and subsequent hy a 90° pulse and a 2-s data aquisition of 2048 points. Broad-band drogen bromide elimination failed because under all conditions decoupling at 5 W of power was used with the power reduced to tried a trans-bis(homobenzene) derivative was formed in the first 0.4 W during the interval between accumulations to allow the step,9· 10 most probably in an acid-catalyzed process. 10 Here, we nuclear magnetization of the sample to recover under redu~ed dielectric heating. Free induction decays were filtered by usmg a Lorentzian to Gaussian line-shape transformation and zero ftlled (1) Smith, L. R. J. Chem. Educ. 1978, 55, 569-510 and Iiterature cited to 8192 points before Fourier transformation. Assignment of ~~ . (2) Cox, K. W.; Harmony, M. 0.; Nelson, G.; Waberg, K. 8. J. Chem. Phys. 1969, 50, 1976-1980. (3) Smitb, B. N.; Jacoblen, B. S. plant Cell PhyJtol. 19'76, 17, 1089-1092. (3) Van Vuurcn, P. J. Ph.O. Thesis Cornell Univenity, Ithaca, NY, 1970; (4) Epstcin, S.; Yapp, 0. J.; Hall, J. N. Earth Planet Sei. Lm. 1976, 30, Diss. Abstr. B 1971, 31B, 7201. 241-251. (4) Baird, M. S.; Reese, C. 8. Tetrahedron Lett. 1976, 2895-2898. (5) Epstcin, S.; Tbornaon, P.; Yapp, C. J. Science (Washington, D.C.) (5) Van Vuuren, P. J.; Fletterick, R. J.; Mcinwald, J.; Hughes, R. E. J. 1977, 198, 1209-1215. Am. Chem. Soc. 1971, 93, 4394-4399. (6) RaUJChenbach, P.; Simon, H.; Stichler, W.; Maser, H. Z. Naturforsch, (6) Katz, T. J.; Wang, E. J.; Acton, N. J. Am. Chem. Soc. 1971, 93, C 1979, 34C, 1-4. 3782-3783. (7) Marti.n, G. J.; Martin, M. L. Telrahedran Lett. 1981, 22, 3525-3528. (7) Zimmerman, H. E.; Sousa, L. R. J. Am. Chem. Soc. 1972, 94, (8) Martin, G. J.; Martin, M. L. Compt. Rend. Acad. Sei., Ser. 1/1981, 834-842. 293, 31-33. (8) Smith, L. R.; Gream, G. E.; Meinwald, J. J. Org. Chem. 1977, 42, (9) Futrell, J. H., private consultation. 927-936.
0002-7863/82/1504-4494$01.25/0
characterized by analytical and spectral data. Scheme I Aeknowledgment. We thank the Deutsche Forschungsge· meinschaft and thc Fonds der Chemischen Industrie for generous )~ ~ )~ ~ ~OH support. UCHO 0ycN ~COOH Repstry No. I, 35618·58· 7; l, 82248-46-2; 3, 82309· 70-4; 4, 82248· O....,..OBn H o....,..oen 47-3; !, 82309·71-5; 6, 82248-48-4; 7, 82248-49-5; 8, 35438-35-8; cy 6 7 clooctatetraene, 629-20-9.
Total Synthesis of ( +)- Phyllanthocin 8 R•CH20H 10 Paul R. McGuirk and David B. Collum• 9 R• COOH a, KeN/HOAc/diethyl ether/25 oe (95% yield); Department of Chemistry, Baker Labaratory b, PbeH 0CH eVe,H,N/60 oe (51% yield); c, thexylborane/ Corne/1 University, lthaca, New York 14853 2 2 THF/-40 oe H2 0/Na0Ac (83% yield); d, KOH/ethanol/100 oe Received February 8, 1982 (95% yield); e, EtOOCN=NeOOEt/PPh,/TIIF/-20 °e; f, Jones' / reagent/acetone 0 oe (81% yield from 7); g, Ph(OAc) 4 /eu(OAc)2 C5H5 N/benzene/80 oe (82% yield); h, LDA/THF/-78 oe The crude ethanol extract obtained from the root of Phyllanthus PheH 0eH Cl/THF/HMPA/-60 °C (71% yield) acumlnatus VahJI.2 was found to inhibit growth in thc P388 2 2 leukemia system in mice. Kupchan and co-workers traced the H interesting pharmacological properlies to a bisabolane sesqui terpene glycoside, ( + )·phyllanthoside (1).1 Although the structure ~~., ROOC H O..._...oen
4 oxidation of 6 was modeled after the totally stereoselective hy droboration of Iimonene by Brown.6 Analogous to this is the stereocontrol derived from cyclic borane II. Phosphonium salt
of the corresponding aglycone, ( + )·phyllanthocin (2), was elu cidated by single-crystal X-ray diffraction, the exact nature of the sugar moiety in I and thc absolute configurations of 1 and t(CN 2 remained unknown. Recently Pettit and co-workers determined o....,....oen the structure of phyllanthose, the novel disaccharide portion of I, as weil as the structures of several closely related tumor in· II 12 II R•CH20H hibitory sesquiterpene glycosides. 3 Sturlies pertaining to phyll· 14 R•COCH3 anthoside's pronounced activity against the NCI murine B 16 7 4 induced lactonization proceeded with the anticipated complete melanoma have reached the Ievel of advanced preclinical trials. inversion of configuration at the alcohol center as shown by We report herein the first synthesis and the absolute configuration comparison of 8 with a sample of the corresponding trans-fused of (+)-phyllanthocin (2). Iactone prepared by acid-catalyzed closure. Oxidative decar· The spiroketal moiety of 2 readily lent itself to the retrosynthetic boxylation of 9 by the method of Kochi8 produced 10 as a readily dissection illustrated in eq 1. Although the convergency of such separable mixture of epirners free of regioisomeric impurities LI corresponding to 12. Although a preference for the formation H of thc desired terminal alkene was expected,9 this exclusive M•OO~O '"OP Hofmann orientation was not. Highly stereoselective (~95%) 2 + >:,,,cH (1) benzyloxymethylation10 of the Iithium enolate derived from 10 afforded 3 as a white, crystalline solid (mp 5G-51 °C). High Ho~ 3 OP stereoselectivities in the alkylations of similar systems have been an approach seemed attractive, several problems pertaining to observed. 11 stereocontrol remaincd. Notably, since the absolute configuration Throughout the sequence depicted in Scheme I there are a of 2 was unknown, entry into either enantiomeric series was variety of intermediates that contain one or two random asym essential. We settled on 3 and 4 as our two pivotal intermediates. metric centers. Although the eventual destruction of these centers We prepared Iactone 3 starting with (S)-(-)-perilla aldehyde made them inconsequential to the final outcome, they made (5) in eight steps as illustrated in Scheme I. Several features product analyses in the developmental stages problematic. warrant comment. The thexylborane-mediated hydroboration- However, through exhaustive searches for isomeric products and
(6) Brown, H. C.; Pfaffcnbergcr, C. D. J. Am. Chem. Soc. 1967, 89, 5475. (1) Kupchan, S. M.; LaVoie, E. J.; Branfman, A. R.; Fei, 8. Y.; Bright, For cxcellent leading refcrences to cyclic hydroborations see: Still, W. C.; W. M.; Bryan, R. F. I. Am. Chem. Soc. 1977, 99, 3199. Darst, K. P. J. Am. Chem. Soc. 1980, 102, 7385. (2) The plant collection providing tbe original sample of phyllanthosidc was (7) Fora comprchcnsive review, see: Mitsunobu, 0. Synthesis 1981, 1. incorrectly believcd tobe P. brasiliensis. Subsequently, this was shown tobe (8) Bacha, J. 0.; Kochi, J. K. Tetrahedron 1968, 24, 2215. an crror (ref 3). (9) Review: Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279. (3) Pettit, G. R.; Cragg, G. M.; Gust, D.; Brown, P. Can. I. Chem. 1981, (10) McQuillin, F. J.; Simpson, P. L. I. Chem. Soc. 1963, 4726. Caine, 60, S44. D.; Smith, T. L., Jr. 1. Am. Cllem. Soc. 1980, 102, 7568. (4) We thank Dr. Matthew Suffncss of the National Cancer Institute for (11) Bartlett, P. A.; Pizzo, C. F. J. Org. Chem. 1981, 46, 3896. Smith, this information. Phyllanthocin (l) has been shown to exhibit no antitumor A. 8., Jr.; Richmond, R. E. lbid. 1981, 46, 4816. Welch, S. C.; Gruber, J. activity (ref 1, 3). M.; Chou, C.-Y.; Willcott, M. R. lbid. 1981, 46, 4816. Gricco, P. a.; Mi· (S) Either antipode of perilla aldchydc can be purchascd from Research yashita, M.lbid. 1974, 39, 120. Grcene, A. E.; Muller, J.-C.; Ourisson, G. Oraanics Inc., Bcllcvillc, NJ. lbtd. 1974, 39, 186.
0002· 7863/82/1504-4496$01.25/0 © 1982 American Chemical Society