J. Org. Chem. 1989,54, 3236-3239
3236
that they could be kairomones which induce settling a n d metamorphosis in larvae of the dorid nudibranchs known t o be associated with the genus Dysidea.s-ll T h e presence of both the 5a,6@and 5@,6ahydroxylated sterol series in t h e same sponge suggests a 5q6a epoxide precursor to both groups. Such a compound could undergo either electrophilic or nucleophilic ring opening t o give rise to both sets of steroids. Since Djerassi has suggested4 that 5P-stanols are most likely the product of bacterial conversion of 5a-stanols in P. ficiformis, it is possible that 2-4 are derived from bacterial conversion of appropriate precursors in D. etheria. This sponge does contain a substantial community of bacteria.12 Although the trans-AB steroid 1 was moderately cytotoxic,2 t h e 5@steroid 3 was inactive (ICso = 26 p g / m L in t h e KB assay, >10 p g / m L PS). Neither group of steroids elicited any reproducible effect upon larvae of the tobacco hornworm, Manduca sexta, whether incorporated into an agar-based diet (250 ppm) or injected subcutaneously (100-pg dose).
Experimental Section General. One-dimensional NMR spectra were recorded on a Bruker WM-250 spectrometer; COSY and HMQC 2D experiments were done on a Varian VXR-500 instrument; chemical shifts are reported in 6 units relative to tetramethylsilane (6 = 0) with pyridine-d, as the solvent and internal standard. 13CNMR and 'H NMR assignments were made by using 2D COSY and 2D HMQC sequences and by comparison of chemical shift data with those in the literature. Mass spectra were determined on a VG7070 EHF mass spectrometer in the fast atom bombardment (FAB) mode, using a 0.14 M RbI in glycerol matrix to obtain (M Rb)+ adduct ions. Optical rotations were obtained on a Perkin-Elmer 241 MC polarimeter. All HPLC separations were carried out on a Perkin-Elmer series 3B liquid chromatograph. A Knauer differential refractometer was used for detection in all HPLC steps. Collection, Extraction, and Initial Fractionation. The collection, extraction, partitioning, and initial chromatographic separations of D. etheria have been reported in detail.2 Isolation of 2-4. The third fraction from an isocratic LPLC silica gel column (Whatman LPS-2, 2.5 X 25 cm), using CHC13-iPrOH-MeOH (155:l) as eluent, was dissolved in MeOH and subjected to semipreparative HPLC on a Hamilton PRP-1 (CI8)column (30 X 0.7 cm) using CH3CN-H20 (1:l)as the mobile phase. Further purification of the three major fractions from this separation was achieved by HPLC on an analytical /3-cyclodextrin HPLC column (ASTEC, 250 X 4.6 mm), with different mixtures of CH3CN-HzO (4:1, 2), (l:l,3 and 4). 5j3-Cholest-7-ene-2i3,3a,5&6a,9a,lla,l9-heptol (2): yield, 1 X dry wt; mp 230-250 dec; [a]%D +23.1° ( c 0.78, EtOH); 'H NMR (250 MHz, pyridine-d6,exchanged with MeOH-d4)6 0.75 (3 H, S, H-18), 0.84 (6 H, d, J = 6.6, H-26,27), 0.92 (3 H, d, J = 5.3, H-21), 1.08 (3 H, m, H-23,24),1.28 (6 H, m, H-16,17,20,22,23), 1.52 (3 H, m, H-15,25), 1.83 (1 H, m, H-16), 2.10 (1 H, t, J = 11.6, H - ~ c Y2.55 ) , (2 H, m, H-lP, H-4P), 2.76 (1 H, dd, J = 11.9, 23.9, H-12a),2.85 (1 H, m, H-14), 2.99 (1H, m, H-l2j3), 3.20 (1H, dd, J = 2.7, 10.0, H-la), 4.69 (3 H, m, H-6, and H-19 methylene protons-coalesced AB pattern), 4.82 (2 H, m, H-2,3), 5.38 (1 H, dd, J = 4.1, 11.9,H-ll), 5.71 (1H, s, H-7); FAJ3-MS, m / z 567 (M Rb+, 1.7). 24-Methy l-58-c holest-7-ene-2&3a,5/3,6a,9a,1la,19-heptol(3): dry wt, mp 240-260 "C dec; [ a ] %+18.2' ~ (c 0.28, yield, 1 X EtOH); 'H NMR 6 0.75 (3 H, S, H-18), 0.78 (3 H, d, H-27), 0.79 (3 H, d, H-28), 0.82 (3 H, d, J = 6.9, H-26), 0.92 (3 H, d, J = 4.4,
+
"c
+
(8)Grade, S.H.; Cardellina, J. H., I1 J.Nut. Prod. 1984,47,76. (9)Schulte, G.; Scheuer, P. J.; McConnell, 0. J. Helu. Chim. Acta 1980,63,2159. (10) Hochlowski, J. E.; Walker, R. P.; Ireland, C.; Faulkner, D. J. J . Org. Chem. 1982,47,88. (11) Karuso, P. In Bioorganic Marine Chemistry; Scheuer, P. J., Ed.; Springer-Verlag: Berlin, 1987;Val. 1, pp 31-60. (12)Cardellina, J. H., 11; Stierle, A. C.; Dillman, R., unpublished data.
0022-3263/89/1954-3236$01.50/0
H-21), 1.0-1.6 (11H), 1.84 (1H, m, H-16), 2.10 (1H, t, J = 11.7, H - 4 4 , 2.57 (2 H, m, H-lP, H-4P), 2.82 (1 H, dd, J = 11.9, 23.9, H-12~42.86(1 H, m, H-14), 2.99 (1H, m, H-12/3),3.20 (1 H, dd, J = 3.0, 13.1, H-la), 4.68 (3 H, m, H-6, and H-19 methylene protons-coalesced AB pattern), 4.83 (2 H, m, H-2,3), 5.38 (1H, dd, J = 4.7,12.1, H-ll), 5.71 (1H, s, H-7); FAB-MS, m / z 581 (M Rb', 0.7). 24-Ethyl-5&cholest-7-ene-2&3a,5&6a,9a,lla,lg-heptol (4): yield, 1 X lo-'% dry Wt, mp 235-245 "c dec; [a]%D+17.7" (c 1.3, EtOH); 'H NMR 6 0.75 (3 H, s, H-18),0.8124 (9 H, m, H-26,27,29), 0.94 (3 H, d, J = 4.1, H-21), 1.0-1.6 (13 H), 1.83 (1 H, m, H-16), 2.11 (1H, t, J = 11.7, H - 4 4 , 2.56 (2 H, m, H-lP), 2.76 (1 H, dd, J = 12.0,23.8, H-12a),2.86 (1H, m, H-14), 2.98 (1H, m, H-12@), 3.20 (1 H, dd, J = 3.0, 13.2, H-la), 4.67 (3 H, m, H-6, and H-19 methylene protons-coalesced AB pattern), 4.82 (2 H, m, H-2,3), 5.37 (1 H, dd, J = 4.4, 12.2, H-11), 5.71 (1H, S, H-7); FAB-MS, m / z 595 (M + Rb+, 1.1).
+
Acknowledgment. This work was supported by t h e Office of Sea Grant, Department of Commerce, and, in part, by a grant (CA 35905) from the National Cancer Institute. We are grateful to L. J. Sears for assistance with t h e mass spectral analyses. Registry No. 2, 120711-48-0;3, 120711-49-1;4,120711-50-4.
A Subtotal Synthesis of Methynolide via an Electrophilic Spirocyclization Reaction Paul A. Bartlett,* Ichiro Mori, and Judith A. Bose
Department of Chemistry, University of California, Berkeley, California 94720 Received January 23, 1989
As the aglycon of the simplest member of the macrolide class of antibiotics, methynolide, 1, has served as a proving ground in the development of stereochemical methods for synthesis of this family of natural products.l+ Most routes to methynolide involve the assembly of two optically active fragments in order to control t h e relationship between the stereocenters in the right half of t h e molecule (C-2 to C-6) and those in the left ((3-10and C-11). Exceptions are t h e synthesis reported by Vedejs et al.! in which the C-10 and C-11 stereocenters are introduced on a macrocyclic intermediate, and the formal synthesis by Ireland e t a1.,4 in which they are assembled on t h e rigid, spirocyclic framework of intermediate 2. We have developed a number of methods for t h e stereocontrolled construction of cyclic ethers via electrophilic cyclization of unsaturated alcohols and derivatives."l' (1)Masamune, S.; Kim, C. U.; Wilson, K. E.; Spessard, G. 0.; Geroghiou, P. E.; Bates, G. S. J.Am. Chem. SOC.1975,97,3512-3513. Masamune, s.;Yamamoto, H.; Kamata, s.;Fukuzawa, A. Ibid. 1975,97, 3513-3515. (2)Nakano, A.; Takimoto, S.; Inanaga, J.; Katsuki, T.; Ouchida, S.; Inoue, K.; Okukado, N.; Yamaguchi, M. Chem. Lett. 1979,1019-1020. Inanaga, J.; Katsuki, T.; Takimoto, S.; Ouchida, S.; Inoue, K.; Nakano, A,; Okukado, N.; Yamaguchi, M. Ibid. 1979,1021-1024. (3)Grieco, P. A.;Ohfume, Y.; Yokoyama, Y.; Owens, W. J. Am. Chem. SOC.1979,101,4749-4752. (4)(a) Ireland, R. E.; Daub, J. P. J. Org. Chem. 1983,48,1303-1312. (b) Ireland, R. E.; Daub, J. P.; Mandel, G. S.;Mandel, N. S. Ibid. 1983, 48, 1312-1325. (5) White, J. D. Strategies and Tactics in Organic Synthesis; Lindberg, T., Ed.; Academic Press: Orlando, 1984;pp 347-366. (6)Vedejs, E.; Buchanan, R. A.; Connard, P.; Meier, G. P.; Mullins, M. J.; Watanabe, Y. J . Am. Chem. SOC. 1987,109,5878-5880. (7)Tanaka, T.; Okawa, Y.; Nakajima, N.; Hamada, T.; Yonemitsu, 0. Chem. Pharm. Bull. 1987,35,2203-2208. (8) For a recent review of macrolide antibiotic synthesis, see: Paterson, I.; Mansuri, M.M. Tetrahedron 1985,41,3569-3624. (9)Rychnovsky, S. D.; Bartlett, P. A. J . Am. Chem. SOC.1981,103, 3963-64.
0 1989 American Chemical Society
J. Org. Chem., Vol. 54, No. 13, 1989 3237
Notes
Scheme I
%
X+
2
1
The fundamental principle in these transformations has been the transmission of stereochemical information from the carbinol (or related) stereocenter to the newly generated stereocenter(s1 because of the conformational preference of the nascent ring.12 If an anomeric hydroxyl group were to function in a similar fashion, a concise synthesis of the Ireland spiroketal, 2, could be envisaged as outlined in Scheme I. Both the stereo- and regiochemical course of the proposed cyclization and ring expansion had been demonstrated in our previous ~ o r k . ~ J l The key questions to be answered with the present system were (1)whether the anomeric effect could be utilized to relay the stereochemicalinformation from the substituents on one ring to the other and (2) whether participation of the ketal oxygen in the solvolysis process, presumably via the oxiranium ion 5, would lead to the desired ring expansion or cleavage of the ketal bond. This report describes the successful resolution of both of these questions. A latent form of the Prelog-Djerassi lactone, 9,13 was selected as the precursor to the C-1 C-7 fragment. The remaining carbons were introduced via the unsaturated lithium reagent, 8, which was prepared from the corresponding bromide 7 as shown in Scheme 11. Cyclopropanation14 of 2-methyl-1-penten-3-o1l5 provides the cyclopropyl carbinol 6, which undergoes rearrangement in the presence of PBr3 and zinc bromide16to give the homoallylic bromide 7 as a 94:6 ratio of E2 isomers. Addition of the lithium reagent 8 to lactone 9 at -78 OC affords hemiketal 10 in 57% yield (30% recovery of lactone). 'H and 13CNMR analyses indicate that 10 exists predominantly in the cyclic form as a 1O:l mixture of anomers. The predominant isomer is assigned the axial hydroxyl configuration in view of the anomeric effect and the clear preference for equatorial disposition of the alkyl substituents. Treatment of 10 with N-iodosuccinimidein CH2C1, at 0 "C gives a mixture of spirocyclic iodides in the approximate ratio of 1Ol:l:l by lH NMR; the major isomer is isolated by chromatography in 61% yield. That this material is 11, the product of Markovnikov cyclization, rather than the spiro[5.5] isomer, is demonstrated by the 'H NMR resonance at 6 4.06 ppm (dd, J = 2.1, 11.5 Hz) for the proton adjacent to the iodide; in the ring-expanded alcohol 12 (see below), the corresponding hydrogen resonates at 6 3.28 (dd, J = 1.7, 10.6 Hz).l'
-
(10)Bartlett, P. A.; Adams, J. L. J . Am. Chem. SOC.1980, 102, 337-342. (11)Michael, J. P.; Ting, P. C.; Bartlett, P. A. J. Org. Chem. 1985,50, 2416-2423. Bartlett, P. A.; Ting, P. C. J. Org. Chem. 1986,51,2230-2240. (12)Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press, Inc.: New York, 1984;Vol. 3, pp 411-454. (13)Yamamoto, Y.; Yatagi, H.; Ishihara, Y.; Maeda, N.; Maruyama, K. Tetrahedron 1984,40,2239. Compound 9 is reported to be formed in a highly stereoselective manner. However, after considerable experimentation, we were only able to obtain a 3:l ratio of 9 and its diastereomer; the desired isomer wm isolated in pure form by chromatography. (14)Smith, R.D.;Simmons, H. E. Organic Syntheses; Wiley: New York, 1973;Collect. Vol. V, pp 855-858. (15)Overman, L. E.; Lin, N.-H. J. Org. Chem. 1985,50, 3669-3670. (16)Brady, S.F.;Ilton, M. A.; Johnson, W. S. J. Am. Chem. SOC.1968, 90,2882. (17)A O.&ppm difference in chemical shift is predicted by the method described by: Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identification of Organic Compounds, 4th ed.; John Wiley & Sons: New York, 1981;p 225.
I
-x+
H-0
Iodo ether 11 undergoes solvolysis and ring expansion on treatment with silver tetrafluoroborate in wet acetone at room temperature.'O lH NMR analysis of the crude product indicates that the anticipated spiroketal 12 and an isomer are formed in a 1O:l ratio; the desired isomer is isolated in 75% yield after chromatographicpurification. The ketal oxygen thus participates normally in the cyclization/ring expansion sequence. The "subtotal" synthesis18 of methynolide is completed by oxidative cleavage of the vinyl group (RUC~~-N~IO:~) and esterification with diazomethane, which provides ester 2 in 77% yield. The 'H NMR spectrum of our racemic material indicates that it has the same relative stereochemistry as the optically active form described by Ireland et al.4b,20 A fairly concise route to methynolide has therefore been established in which all of the stereocenters are generated with relative asymmetric induction.
Experimental Section General. All reactions were perforqed under a dry nitrogen
atmosphere. THF, diethyl ether, and benzene were dried by distillation from sodium benzophenone ketyl immediately prior to use; CH2C12and acetonitrile were distilled from CaH2and DMF from CaS04. Unless otherwise indicated, reaction workups culminated in washing the organic layer with brine, drying over MgSO,, and removal of the solvent on a rotary evaporator under reduced pressure and finally under vacuum. Chromatography was performed on Silica Gel 60, 100-120 mesh (E. Merck, Darmstadt),with the indicated eluting solvent. 'H NMR spectra were acquired at 500 MHz in CDCl, solvent and are reported as (18)While we doubt that this usage will gain acceptance, we think it appropriate to refer to a route that starts with one person's intermediate and ends with someone else's as a "subtotal synthesis" of the ultimate target. (19)Sharpless, K. B.;Carlsen, P. H. J.; Kabuki, T.; Martin, V. S. J. Og. Chem. 1981,46,3936-3938. (20)All chemical shifts agreed within 0.03 ppm, with the exception of the resonance for the C-13methyl group, which appeared at 1.03 ppm in our spectrum of 2 rather than 1.09 ppm as rep~rted.'~As additional confirmation of the indicated structure, in initial work we had prepared the model compound i using the same iodocyclization/ring expansion sequence; the configuration of this material was conclusively demonstrated by observation of the indicated NOE interactions.
