Enantioselective total synthesis of the marine alkaloid Lepadin B

Full text of DOI:10.1021/jo990141n

2182
J . Org. Chem. 1999, 64, 2182-2183
lecular aldol type of cyclization of the functionalized piperi-
dine (ii) accompanying the epimerization at the C-3 position.
It also seemed likely that this hexahydroquinolinone would
lead to desired trisubstituted decahydroquinoline core for
the synthesis of lepadins with correct stereochemistry at the
C-5 position using the conjugate addition.
We have previously shown that the efficient synthesis of
the piperidone 4 as a chiral building block for alkaloid
synthesis5 and its application to the synthesis of the marine
alkaloid clavepictines A and B.6 Herein, we describe the first
enantioselective total synthesis of lepadin B (2) starting from
4 using the novel strategy mentioned above as the key step
and the determination of its absolute stereochemistry.
Debenzylation of the enantiopure lactam 5,5 obtained from
4 in four steps, under Birch condition followed by protection
of the resulting amide with methyl chloroformate gave the
carbamate 6,7 which was converted to vinyltriflate 78 using
Comins’ reagent (Scheme 1).9 Palladium-catalyzed carbonyl-
En a n tioselective Tota l Syn th esis of th e
Ma r in e Alk a loid Lep a d in B
Naoki Toyooka,* Maiko Okumura, and
Hiroki Takahata*
Faculty of Pharmaceutical Sciences, Toyama Medical and
Pharmaceutical University, Sugitani 2630,
Toyama 930-0194, J apan
Received J anuary 26, 1999
The decahydroquinoline alkaloids continue to be of inter-
est as synthetic targets due to their intriguing biological
properties,1 and several methods for the enantioselective
construction of this ring system have been reported.2 The
structurally interesting decahydroquinoline alkaloids lepa-
dins A (1), B (2), and C (3), isolated from the tunicate
Clavelina lepadiformis by Steffan3 and Andersen and co-
workers,4 showed significant cytotoxic activity toward a
variety of murine and human cancer cell lines.4 Although
their relative stereochemistry has been determined by the
extensive NMR studies, the absolute stereochemistry is still
unknown.
Sch em e 1a
a
Key: (a) 85% overall yield from 4; see ref 5; (b) Na, liquid, NH3-
THF (91%), then n-BuLi, ClCO2Me, THF, -78 °C to rt (77%); (c)
LiHMDS, N-(chloro-2-pyridyl)trifimide,9 THF, -78 to -50 °C (80%);
(d) Pd(PPh3)4, Et3N, Ph3P, MeOH, CO balloon, DMF, rt (74%); (e) vinyl
lithium, CuI, Et2O, -78 to -30 °C (89%) and 8 (7% recovered); (f)
LiOH‚H2O, MeOH-H2O (3:1), 60 °C; ClCO2Et, Et3N, THF, 0 °C;
CH2N2, Et2O; PhCO2Ag, Et3N, Et2O (71% in four steps); (g) LiOH‚H2O,
MeOH-H2O (3:1), 60 °C; 1,1′-carbonyldiimidazole, Et3N, O,N-dimethyl-
hydroxylamine‚hydrochloride, CH2Cl2, 0 °C to rt (83% in two steps);
(h) MeMgBr, THF, 0 °C to rt (97%); (i) OsO4, NaIO4, dioxane-H2O
(1:1), rt (84%).
We planed a new strategy for the construction of the cis
hexahydroquinolinone ring system (i) based on an intramo-
ation of 7 using Cacchi’s procedure10 afforded the enecar-
bamate 8, which was subjected to conjugate addition of in
situ generated divinylcuprate to give the 2,3,4,6-tetrasub-
stituted piperidine 9 as a single isomer.11 Carbon-chain
(1) Daly, J . W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1993; Vol. 43, pp 185-288. Daly, J .
W. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998;
Vol. 50, pp 141-169.
(2) Several strategies for the chiral synthesis of the cis-decahydroquino-
line alkaloid pumiliotoxin
C have been reported; see: Oppolzer, W.;
Flaskamp, E. Helv. Chim. Acta 1977, 60, 204-207. Royer, M. B. J .; Grierson,
D. S.; Husson, H.-P. Tetrahedron Lett. 1986, 27, 1569-1572. Schultz, A.
G.; McCloskey, P. J .; Court, J . J . J . Am. Chem. Soc. 1987, 109, 6493-6502.
Murahashi, S.; Sasao, S.; Saito, E.; Naota, E. J . Org. Chem. 1992, 57, 2521-
2523; Tetrahedron 1993, 49, 8805-8826. Comins, D. L.; Dehghani, A. J .
Chem. Soc., Chem. Commun. 1993, 1838-1839. Naruse, M.; Aoyagi, S.;
Kibayashi, C. Tetrahedron Lett. 1994, 35, 9213-9216; J . Chem. Soc., Perkin
Trans. 1 1996, 1113-1124. Toyota, M.; Asoh, T.; Fukumoto, K. Tetrahedron
Lett. 1996, 37, 4401-4404. Davies, S. G.; Bhalay, G. Tetrahedron: Asym-
metry 1996, 7, 1595-1596. Riechers, T.; Krebs, H. C.; Wartchow, R.;
Habermehl, G. Eur. J . Org. Chem. 1998, 2641-2646. Two strategies for
the construction of trans-decahydroquinoline ring system have been re-
ported; see: McCloskey, P. J .; Schultz, A. G. J . Org. Chem. 1988, 53, 1380-
1383. Comins, D. L.; Dehghani, A. J . Org. Chem. 1995, 60, 794-795.
(3) Steffan, B. Tetrahedron 1991, 47, 8729-8732.
(5) Toyooka, N.; Yoshida, Y.; Momose, T. Tetrahedron Lett. 1995, 36,
3715-3718.
(6) Toyooka, N.; Yotsui, Y.; Yoshida, Y.; Momose, T. J . Org. Chem. 1996,
61, 4882-4883.
(7) Satisfactory analytical and spectral data were obtained for all new
compounds.
(8) Recently, this type of vinyltriflate has been used as a tool for the
synthesis of several types of compound; see: Okita, T.; Isobe, M. Tetrahedron
1995, 51, 3737-3744. Foti, C. J .; Comins, D. L. J . Org. Chem. 1995, 60,
2656-2657. Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett.
1996, 37, 8257-8260; J . Org. Chem. 1997, 62, 3592-3596. Ha, J . D.; Lee,
D.; Cha, J . K. J . Org. Chem. 1997, 62, 4550-4551. Ha, J . D.; Kang, C. H.;
Belmore, K. A.; Cha, J . K. J . Org. Chem. 1998, 63, 3810-3811.
(9) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-6302.
(10) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109-
1112.
(4) Kubanek, J .; Williams, D. E.; de Silva, E. D.; Allen, T.; Andersen, R.
J . Tetrahedron Lett. 1995, 36, 6189-6192.
10.1021/jo990141n CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/12/1999

Communications
J . Org. Chem., Vol. 64, No. 7, 1999 2183
Sch em e 3a
elongation at C-2 position on 9 was performed by an Arndt-
Eistert sequence to provide the homologated ester 10. This
ester was transformed into ketone 12 via Weinreb’s amide12
11, and subsequent oxidative cleavage of the terminal alkene
in 12 yielded the aldehyde 13.
With the requisite aldehyde in hand, the stage was now
set for the key intramolecular aldol cyclization. The stere-
ochemistry of C-3 position in 13 was unfavorable for the
synthesis of target alkaloid; however, we expected that the
epimerization of the C-3 position would be possible during
the aldol cyclization step. It is anticipated that the confor-
mation of 13 is restricted to comformer 13-A owing to A(1,3)
strain and the appendages on C-2 and C-3 in 13-A lie in no
cyclizable trans diaxial relationship. Consequently, this
epimerization will proceed first to give 13′-A, which will
cyclize easily to afford the desired 4a,8a-cis-hexahydroquino-
linone 14.
a
Key: (a) PhSCH2SO2Ph, n-BuLi, THF, -78 to -10 °C (78%, 14%
recovered of 14); (b) n-Bu3SnH, AIBN, benzene, reflux (85%); (c)
NaBH4, CH2Cl2-MeOH (10:1), 0 °C; (d) 1,1′-thiocarbonylimidazole,
ClCH2CH2Cl, reflux (75% in two steps); (e) n-Bu3SnH, toluene, reflux
(84%); (f) n-PrSLi, HMPA-THF, rt; (g) (Boc)2O, benzene, reflux (59%
in two steps); (h) n-BuLi, THF, -78 to -70 °C then 2-heptenal, -78 to
-50 °C; (i) Na-Hg, Na2HPO4, MeOH, rt (49% in two steps); (j) concd
HCl, MeOH, reflux (85%).
product. Thus, the 1,4-addition at the C-5 position of 14
proceeded in a highly stereoselective manner.14 Deoxygen-
ation of 16 was performed in a three-step sequence. Reduc-
tion of 16 with NaBH4 afforded the alcohol, which was
deoxygenated with n-Bu3SnH via Barton’s ester15 to give the
product 17. Deprotection at the methoxycarbonyl group in
17 with n-PrSLi in HMPA,16 followed by treatment of the
resulting amine with (Boc)2O, furnished the Boc derivative
18. Construction of the octadienyl moiety was accomplished
by means of J ulia coupling to give diene 19. The synthesis
of 2 was completed by cleaving both the methoxymethyl and
Boc protecting groups with acid. The spectral data for
Thus, the treatment of 13 with 4 equiv of DBU in refluxing
benzene gave the cyclized product in a ratio of 14:1 (in the
1H NMR spectrum of the crude product), and fractionation
by chromatography on silica gel furnished the major product
in 60% isolated yield (Scheme 2). The stereochemistry of the
Sch em e 2
trifluoroacetate salt of synthetic 2 [[R]26 -92.6 (MeOH)]
D
were identical with those for trifluoroacetate salt of natural
lepadin B [[R]D -96 (MeOH)].
In summary, the first total synthesis of lepadin B (2) was
accomplished by using the intramolecular aldol cyclization
of the tetrasubstituted piperidine 3 as the key step, and the
absolute stereochemistry of (-)-2 was verified to be 2S,3S,-
4aS,5S,8aR by the present chiral synthesis.
major product was determined to be that of the desired cis-
hexahydroquinolinone 14 on the basis of the observation of
NOEs between Ha and Hb, Ha and Hc on the NOESY
experiment.
This enone 14 was subjected to conjugate addition of the
anion generated from phenylthiomethyl phenyl sulfone13
with n-BuLi at -78 to 0 °C to afford the ketone 15 as a 2:1
mixture of the diastereomers (Scheme 3). Radical reduction
of the phenylthio group in 15 gave the sulfone 16 as a sole
Ack n ow led gm en t. We are grateful to Professor Ray-
mond J . Andersen, University of British Columbia, for
kindly providing us with 1H and 13C NMR spectra of
trifluoroacetate salt of natural lepadin B.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for all new compounds.
J O990141N
(11) The stereochemistry of the newly formed C-2 and C-3 positions in 9
was anticipated to be 2S,3R according to our previous investigation on the
Michael addition reaction of the similar system; see: Momose, T.; Toyooka,
N. J . Org. Chem. 1994, 59, 943-945. Toyooka, N. Tanaka, K. Momose, T.;
Daly, J . W.; Garraffo, H. M. Tetrahedron 1997, 53, 9553-9574.
(12) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(13) Bordwell, F. G.; J arvis, B. B. J . Org. Chem. 1968, 33, 1182-1185.
(14) Highly stereoselective 1,4-addition of this type of enone has been
reported; see: Polniaszek, R. P.; Dillard, L. W. J . Org. Chem. 1992, 57,
4103-4110. Ibuka, T.; Masaki, N.; Saji, I.; Tanaka, K.; Inubushi, Y. Chem.
Pharm. Bull. 1975, 23, 2779-2790.
(15) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans. 1
1975, 1574-1585.
(16) Corey, E. J .; Yuen, P. Tetrahedron Lett. 1989, 30, 5825-5828.