Enantioselective total synthesis of the marine alkaloid clavepictines A and B

Full text of DOI:10.1021/jo9608174

4882
J . Org. Chem. 1996, 61, 4882-4883
Sch em e 1a
En a n tioselective Tota l Syn th esis of th e
Ma r in e Alk a loid Cla vep ictin es A a n d B
Naoki Toyooka, Yasuhito Yotsui,
Yasuko Yoshida, and Takefumi Momose*
Faculty of Pharmaceutical Sciences, Toyama Medical and
Pharmaceutical University, Sugitani 2630,
Toyama 930-01, J apan
Received May 7, 1996
Clavepictines A (1) and B (2), isolated from the tunicate
Clavelina picta, are the first quinolizidine alkaloids from
a tunicate and possess a substantial cytotoxic activity
against human solid tumor cell lines.1 Although their
relative stereochemistry has been determined on the
basis of extensive NMR studies for 1 in conjunction with
an X-ray diffraction analysis for 2, the absolute stereo-
chemistry is unknown.1 Pictamine (3) has been isolated
from the same marine species, and its gross structure
has been determined to be a bis-nor analog of 1.2
a
Key: (a) Ac2O, pyridine (88%); (b) Lawesson’s reagent, THF,
reflux (99%); (c) BrCH2CO2Me then Ph3P, Et3N, MeCN, reflux
(92%); (d) NaBH3CN, TFA, 0 °C (84% combined yield); (e) LiAlH4,
THF, reflux; 2,2-dimethoxypropanone, p-TsOH, MS (5A), CH2Cl2,
room temperature (75%); (f) Swern oxidation; (EtO)2P(O)CH2CO2Et,
NaH, THF (80%); (g) H2, Pd(OH)2, EtOH; LiAlH4, THF, reflux;
TrocCl, K2CO3, CHCl3-H2O ) 10:1 (65%); (h) Swern oxidation;
(EtO)2P(O)CH2SO2Ph, NaH, THF (80%).
mixture with LiAlH4 followed by treatment of the result-
ing triol with 2,2-dimethoxypropane in the presence of
p-TsOH and molecular sieves (5A) afforded the diaste-
reomerically pure acetonide (-)-6 ([R]26 -20.9). Swern
D
oxidation of (-)-6 and Wittig-Horner reaction of the
resulting aldehyde provided the homologated ester (+)-7
([R]26D +62.6). Catalytic hydrogenation of (+)-7 over Pd-
(OH)2, LiAlH4 reduction, and protection of the amine with
TrocCl yielded alcohol (-)-8 ([R]26D -9.3), which on Swern
oxidation and subsequent Wittig-Horner reaction gave
Although a notable progress toward access to the deoxy
core of the above cis-quinolizidine alkaloids via reduction
of the corresponding iminium salt has been made by
Hart,3 the total synthesis has not been achieved to date.
Herein we disclose the first enantioselective total
synthesis of (+)-1 and (-)-2 and determination of the
absolute configuration of the natural products. The
synthetic strategy involved is based on an intramolecular
ring closure4 of the functionalized piperidine (i) to form
a cis-quinolizidine (ii) bearing all the chiral centers and
appropriate functionality needed for the synthesis of 1
and 2.
ester (-)-9 ([R]26 -3.77) (Scheme 1).
D
With the requisite ester (-)-9 in hand, we next focused
our attention on the construction of the cis-quinolizidine
core by using the intramolecular Michael reaction as the
key step. Deprotection of the Troc group in (-)-9 with
10% Cd-Pb8 at room temperature took place smoothly,
and subsequent intramolecular cyclization proceeded
nicely to afford the quinolizidine (-)-10 ([R]26 -44.5)9
D
in 94% yield as the only cyclized product (eq 1).
The enantiopure diol (-)-45 was converted to the
The stereochemistry of (-)-10 was initially assigned
on the basis of the following NMR argument. The
observation of an NOE between Ha and Hb on the NOESY
experiment for (-)-10 suggested a cis relation between
the substituents at the C4- and C6-position. Moreover,
analysis of the coupling pattern (doublet of multiplets)
vinylogous urethane (+)-5 ([R]26 +70.2)6 by the Eschen-
D
moser’s sulfide contraction reaction via the diacetate
([R]26D -55.0) and the thiolactam ([R]26D -137.0). Reduc-
tion of (+)-5 with NaBH3CN under an acidic condition
at 0 °C gave a ca. 11:1 diastereomeric mixture of the
trans-2,6- and cis-2,6-piperidines.7 Reduction of the
(7) The trans(2,6)-selectivity based on the A(1,2) strain, and
a
stereoelectronic effect has been reported for the reduction of an
iminium salt of this type of piperidine; see: Cook, G. R.; Beholz, L. G.;
Stille, J . R. J . Org. Chem. 1994, 59, 3575-3584.
(1) Raub, M. F.; Cardellina, J . H., II; Choudhary, M. I.; Ni, C.-Z.;
Clardy, J .; Alley, M. C. J . Am. Chem. Soc. 1991, 113, 3178-3180.
(2) Kong, F.; Faulkner, D. J . Tetrahedron Lett. 1991, 32, 3667-3668.
(3) Hart, D. J .; Leroy, V. Tetrahedron 1995, 51, 5757-5770.
(4) The intramolecular conjugate addition reaction with nitrogen
nucleophiles has been recognized as a powerful tool for construction
of piperidine ring systems; see: Akiyama, E.; Hirama, M. Synlett 1996,
100-102 and references cited therein.
(5) Toyooka, N.; Yoshida, Y.; Momose, T. Tetrahedron Lett. 1995,
36, 3715-3718. An alternative stereoselective chiral synthesis of the
dibenzyl ether of (-)-4 from D-serine was reported; see: Campbell, J .
A.; Lee, W. K.; Rapoport, H. J . Org. Chem. 1995, 60, 4602-4616.
(6) Satisfactory analytical and spectral data were obtained for all
new compounds. Optical rotations were taken in chloroform unless
otherwise stated.
(8) Dong, Q.; Anderson, C. E.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 5681-5682.
(9) Fixation of the ring conformation (i.e., presence of the acetonide
protecting group) was indispensable for exclusive formation of 10. For
example, cyclization of 17 resulted in the formation of a ca. 4:1 mixture
of trans- and cis-quinolizidines (eq 2).
S0022-3263(96)00817-1 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 15, 1996 4883
Sch em e 2a
and the coupling constant (J ) 12.2 Hz) of the bridgehead
proton (Hc) indicated that Hc was situated axially with
respect to the ring bearing the (benzenesulfonyl)methyl
and equatorially to the second ring, implying a cis ring
fusion.10 This assignment was confirmed by an X-ray
diffraction analysis,11 and the result suggested that the
absolute configuration of (-)-10 was 3R,4S,6S,10S.
This high-kinetic stereoselectivity on the Michael cy-
clization can be rationalized as shown below. Compari-
son of two kinds of folded chairlike transition states (A
and B) leading to (-)-10 and its C6-epimer, respectively,
reveals a potential steric repulsion involving the Ha and
Hb protons for B. Therefore, the cyclization occurs via
the transition state A to give the desired product (-)-10.
a
Key: (a) 10% HCl, EtOH, reflux; TBDPSCl, imidazole, DMF,
80 °C (85%); (b) MOMCl, Hu¨nig base, CHCl3, reflux (93%); (c) 40%
HF, pyridine, THF (95%); (d) I2, Ph3P, imidazole, benzene (89%);
(e) n-Bu3SnH, AIBN, toluene, reflux (94%); (f) n-BuLi, trans-2-
nonenal, -80 to -50 °C; 5% Na-Hg, Na2HPO4, MeOH, rt (53%);
(g) concd HCl, MeOH, reflux (82%); (h) Ac3O, pyridine (90%).
([R]26 +30.9) and radical reduction of (+)-14 afforded
D
quinolizidine (-)-15 ([R]26 -10.95). Finally, the deca-
D
dienyl moiety was installed by the J ulia coupling. Thus,
treatment of (-)-15 with n-BuLi at -80 °C followed by
addition of trans-2-nonenal to the resulting anion at -80
to 50 °C gave the â-hydroxy sulfone, which on sodium
Completion of the synthesis of 1 and 2 is shown in
Scheme 2. Treatment of (-)-10 with 10% HCl in EtOH
followed by TBDPSCl and imidazole gave alcohol (-)-11
amalgam reduction provided the diene (-)-16 ([R]26
D
-20.7). Deprotection of the MOM protecting group with
concentrated HCl in refluxing MeOH resulted in (+)-
clavepictine B (2) [[R]26D +25.7 (c 0.61, CH2Cl2) (lit.1 [R]D
+27.1 (c 0.03, CH2Cl2))], and acetylation of (+)-2 afforded
([R]26 -1.01). Protection of the secondary hydroxyl in
D
(-)-11 with MOMCl afforded ether (-)-12 ([R]26D -4.58),
and deprotection with HF-pyridine provided alcohol (-)-
(-)-clavepictine A (1) [[R]26 -74.5 (c 0.55, CH2Cl2) (lit.1
D
13 ([R]26 -3.06). Iodination of (-)-13 to give (+)-14
[R]26 -75.6 (c 0.7, CH2Cl2))]. The spectral data for
D
D
synthetic (-)-1 and (+)-2 were identical with those for
natural products.1
(10) We have investigated the alternative construction of a cis-
quinolizidine according to the Hart protocol,3 and as in the case of the
reduction of an iminium ion generated from 18 with NaB(OAc)3H,
undesired trans-quinolizidine 19 was formed exclusively in quantitative
yield. Comparison of the coupling pattern (triplet of triplets) and
coupling constant (11.0, 3.0 Hz) of the bridgehead proton of 19 to (-)-
10 revealed the trans ring juncture of 19 (eq 3).
In summary, the first total synthesis of (-)-1 and (+)-2
was accomplished by using the intramolecular Michael
reaction as a crucial step that enabled us to construct
the cis-quinolizidine ring having correct chiral centers
of the above alkaloids. Furthermore, the absolute ster-
eochemistry of both alkaloids was verified to be 3R,4S,6S,-
10S by the present synthesis; pharmacological studies
on the alkaloids and congeners synthesized are now being
conducted concurrently at the NCI, and the results will
be described in due course.
Ack n ow led gm en t. We are grateful to Doctor J ohn
H. Cardellina, II, National Cancer Institute, for kindly
providing us with 1H and 13C NMR spectra of natural
(-)-1 and (+)-2.
(11) Crystallographic data for (-)-10: orthorhombic, space group
P212121, with a ) 14.160(3) Å, b ) 15.825(3) Å, c ) 8.616(3) Å, V )
1930.5(9) Å3, and Z ) 4 (Dcalcd ) 1.306 g cm-3), µ (Mo KR) ) 1.92 cm-1
absorption corrected by ω scans; 966 with I > 3.00σ(I) were used in
refinement; R ) 5.2%, Rw ) 6.4%. The authors have deposited the
atomic coordinates for (-)-10 with the Cambridge Crystallographic
Data Centre. The coordinates can be obtained, on request, from the
Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and compound characterization data (9 pages).
J O9608174