Total synthesis of clavepictines A and B. Cross-coupling of an acylenamino triflate and cyclization of a δ-aminoallene

Full text of DOI:10.1021/jo970788c

4550
J . Org. Chem. 1997, 62, 4550-4551
Communications
Tota l Syn th esis of Cla vep ictin es A a n d B.
Cr oss-Cou p lin g of a n Acylen a m in o Tr ifla te
a n d Cycliza tion of a δ-Am in oa llen e
Sch em e 1
J ae Du Ha, Dongha Lee, and J in Kun Cha*
Department of Chemistry, University of Alabama,
Tuscaloosa, Alabama 35487
Received May 5, 1997
Three new quinolizidine alkaloids, clavepictines A and
B (1a ,b) and pictamine (1c), which showed antimicrobial,
antifungal, and antitumor activity, were recently isolated
from the tunicate Clavelina picta.1,2 The structures of
these alkaloidal homologs were determined on the basis
of spectroscopic data and X-ray diffraction analysis, while
their absolute configuration remained undefined. Key
structural characteristics include a rare cis-ring-fused
quinolizidine nucleus with axially disposed methyl and
acetoxy (or hydroxy) groups (presumably to avoid the
otherwise severe 1,3-diaxial interaction) and an (E,E)-
deca- or octa-1,3-diene side chain. Recently, Momose and
co-workers disclosed the first enantioselective total syn-
thesis of clavepictines A and B (1a and 1b).3,4 Herein,
we report our own synthesis of 1a and 1b.
The 5,6-disubstituted lactam 4 was readily prepared
starting from the known and enantiopure diol 5 (Scheme
1).7,8 Hydrogenation afforded (92% yield) γ-lactone 6,
which allowed the regioselective introduction of the
amino group at C-2 (clavepictine numbering system).1 By
means of the azide intermediate, lactam 7 was prepared
in 81% overall yield.
Reductive alkylation of lactams, thiolactams, or imino
ethers to amines with concomitant attachment of the
alkyl side chain was previously achieved by Eschenmoser
sulfide contraction9 or by addition of organometallic
reagents.10 Unfortunately, most of the known methods
proved unsuitable for the subsequent introduction of the
allene functionality. We were thus prompted to develop
cross coupling of vinyl triflates derived from lactams with
a suitable nucleophile under mild conditions.11 Toward
(6) For cyclization of allenes bearing an internal nitrogen nucleo-
phile, see: (a) Prasad, J . S.; Liebeskind, L. S. Tetrahedron Lett. 1988,
29, 4253. (b) Arseniyadis, S.; Gore, J . Tetrahedron Lett. 1983, 24, 3997.
(c) Arseniyadis, S.; Sartoretti, J . Tetrahedron Lett. 1985, 26, 729. (d)
Lathbury, D.; Gallagher, T. J . Chem. Soc., Chem. Commun. 1986, 114.
(e) Kinsman, R.; Lathbury, D.; Vernon, P.; Gallagher, T. J . Chem. Soc.,
Chem. Commun. 1987, 243. (f) Shaw, R. W.; Gallagher, T. J . Chem.
Soc., Perkin Trans. 1 1994, 3549.
(7) (a) The Sharpless asymmetric dihydroxylation of ethyl sorbate
was shown to give the diol 5 in excellent ee: Kolb, H. C.; VanNieu-
wenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (b) For
regioselective osmylation of dienoates, see also: Whang, K.; Cooke, R.
J .; Okay, G.; Cha, J . K. J . Am. Chem. Soc. 1990, 112, 8985.
(8) As the absolute configuration of these alkaloids was unknown
at the outset, we arbitrarily chose (DHQD)2-PHAL for asymmetric
dihydroxylation.
(9) (a) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. Helv. Chim.
Acta 1971, 54, 710. (b) Shiosaki, K. In The Eschenmoser Coupling
Reaction; Trost, B. M., Fleming, I., Ed.; Comprehensive Organic
Synthesis; Heathcock, C. H., Vol. Ed.; Pergamon: Oxford, 1991; Vol.
2, Chapter 3.7. (c) Gugelchuk, M. M.; Hart, D. J .; Tsai, Y.-M. J . Org.
Chem. 1981, 46, 3671. (d) For a recent modification, see: Kim, G.; Chu-
Moyer, M. Y.; Danishefsky, S. J .; Schulte, G. K. J . Am. Chem. Soc.
1993, 115, 30.
(10) See inter alia: (a) LaLonde, R. T.; Muhammad, N.; Wong, C.
F.; Sturiale, E. R. J . Org. Chem. 1980, 45, 3664. (b) Hwang, Y. C.;
Chu, M.; Fowler, F. W. J . Org. Chem. 1985, 50, 3885. (c) Yamaguchi,
M.; Hirao, I. Tetrahedron Lett. 1983, 24, 1719. (d) Hua, D. H.; Miao,
S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo, A. A. J . Org. Chem. 1990,
55, 3682. (e) Tominaga, Y.; Kohra, S.; Hosomi, A. Tetrahedron Lett.
1987, 28, 1529. (f) Takahata, H.; Takahashi, K.; Wang, E.-C.; Yamaza-
ki, T. J . Chem. Soc., Perkin Trans. 1 1989, 1211. (g) Zezza, C. A.; Smith,
M. B.; Ross, B. A.; Arhin, A.; Cronin, P. L. E. J . Org. Chem. 1984, 49,
4397.
(11) In marked contrast to the widely utilized vinyl triflates from
ketone or ester enolates, the corresponding vinyl triflates of lactams
have received surprisingly little attention. While our synthetic studies
were in progress, Comins and Foti reported their preparation and
reactions: (a) Foti, C. J .; Comins, D. L. J . Org. Chem. 1995, 60, 2656.
For more recent examples, see also: (b) Okita, T.; Isobe, M. Tetrahe-
dron 1995, 51, 3737. (c) Luker, T.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1996, 37, 8257 and references cited therein. (d)
Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1997, 62,
3592.
Subsequent to several unsuccessful approaches, we
ultimately chose the electrophilic cyclization of the δ-al-
lenic amine 2 for the stereoselective construction of the
requisite quinolizidine system.5 In contrast to the oxygen-
containing heterocycles, the intramolecular cyclization of
ω-aminoallenes has been limited to a handful of mono-
cyclic ring formations; to our knowledge, only a single
application was reported for the stereocontrolled synthe-
sis of nitrogen-containing bicyclic rings.6 The requisite
allene 2 could be prepared diastereoselectively by elabo-
ration of alcohol 3. Finally, our plan called for the
stereoselective installation of the 2,6-trans side chain
onto the monocyclic lactam 4.
(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.
(2) Kong, F.; Faulkner, D. J . Tetrahedron Lett. 1991, 32, 3667.
(3) Toyooka, N.; Yotsui, Y.; Yoshida, Y.; Momose, T. J . Org. Chem.
1996, 61, 4882.
(4) There also appeared a synthetic study toward clavepictine A:
Hart, D. J .; Leroy, V. Tetrahedron 1995, 51, 5757.
(5) As also noted by the Momose group,3 an intramolecular conjugate
addition to the corresponding δ-amino R,â-unsaturated ester was found
to afford predominantly the undesired C-10 epimer: Ha, J . D.; Cha,
J . K. Unpublished results.
S0022-3263(97)00788-3 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 14, 1997 4551
Sch em e 2
Sch em e 3
Silver nitrate-mediated cyclization of 2 produced (54%)
a 7:1 mixture of the desired quinolizidine 14 (containing
the correct C-10 stereochemistry and the E-double-bond
geometry) and its C-10 epimer 15 (Scheme 3). It is
noteworthy that a ca. 1:2 mixture of 14 and 15 was
obtained from the otherwise identical cyclization of the
1:1 diastereomeric allenes in place of diastereomerically
pure 2. Finally, selective deprotection of the triethylsilyl
group, followed by stepwise treatment with Martin
sulfurane15 and TBAF, afforded (+)-clavepictine B (1b).
For additional characterization, (-)-clavepictine A (1a )
was also prepared by acetylation.16 The spectroscopic
and physical properties of 1a and 1b were in excellent
agreement with the literature data.
this end, 4 (R2 ) TIPS) was prepared in 83% yield by
sequential protection. Subsequent treatment with LiH-
MDS, followed by Comins’ reagent, furnished the ami-
novinyl triflate 8 in excellent (88%) yield. Sonogashira-
type coupling with the enantiomerically pure acetylene
912 afforded the cross-coupling product 10 in 88% yield
(Scheme 2). Subsequent reduction with NaBH3CN-TFA
resulted in the stereoselective construction of the trans-
2,6-disubstituted piperidine 3 in 52% yield, along with
the corresponding desilylated diol in 17% yield.
Hydrogenation of the alkyne group, followed by straight-
forward functional group management in the carbamate
and alcohol protecting groups, furnished the allyl car-
bamate 11. In order to install the requisite allene
functionality, the propargyl alcohol 12 was first prepared
in three steps (74% overall yield): (1) Swern oxidation;
(2) the Seyferth-Gilbert homologation;13 (3) THP depro-
tection. Subsequent ortho ester-Claisen rearrangement
afforded diastereoselectively the allenic ester 13 (83%).
The remaining side chain was then introduced (86%) in
a one-pot operation by sequential treatment with DIBAL
and n-hexylmagnesium bromide.14 Subsequent alcohol
protection and removal of the allyl carbamate group by
standard methods provided the δ-allenic amine 2 (70%
overall).
In summary, we have unequivocally established the
absolute configuration of 1a and 1b by their stereocon-
trolled total synthesis. Key methods include cross-
coupling of vinyl triflates 8 of N-acyllactams and dia-
stereoselective cyclization of the δ-aminoallene 2. Both
transformations should be of general synthetic utility in
the stereoselective synthesis of quinolizidines, indoliz-
idines, and related aza-heterocylces. A more convergent,
second-generation synthesis of 1a ,b is currently under
way and will be reported in due course.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM35956) for generous financial
support and an NIH Research Career Development
Award (GM00575 to J .K.C.).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data (47 pages).
J O970788C
(12) Prepared from (S)-(-)-glycidol in three steps: 1. t-BuCOCl,
pyridine; 2. LiC≡CTMS, BF3.OEt; 3. TBAF.
(14) As expected, 2 was obtained as an inseparable 1:1 diastereo-
meric mixture at C-14. Since the C-14 stereocenter was destined to
undergo dehydration, lack of stereocontrol was inconsequential.
(15) Martin, J . C.; Franz, J . A.; Arhart, R. J . J . Am. Chem. Soc. 1974,
96, 4604.
(16) Whereas (+)-clavepictine B (1b) is stable, (-)-clavepictine A
(1a ) is found to undergo slow decomposition in storage.
(13) (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. J . Org. Chem. 1971,
36, 1379. (b) Gilbert, J . C.; Weerasooriya, U. J . Org. Chem. 1982, 47,
1837. (c) Ohira, S. Synth. Commun. 1989, 19, 561. (d) Brown, D. G.;
Velthuisen, E. J .; Commerford, J . R.; Brisbois, R. G.; Hoye, T. R. J .
Org. Chem. 1996, 61, 2540.