Total synthesis of clavepictines A and B. Diastereoselective cyclization of δ-aminoallenes

Article abstract of DOI:10.1021/ja9925958

The stereocontrolled total synthesis of (-)-clavepictine A (1A) and (+)- clavepictine B (1B) has been accomplished in an enantioselective fashion, which has unequivocally established the absolute configuration of 1A and 1B. The pivotal step in the synthes

Full text of DOI:10.1021/ja9925958

10012
J. Am. Chem. Soc. 1999, 121, 10012-10020
Total Synthesis of Clavepictines A and B. Diastereoselective
Cyclization of δ-Aminoallenes
Jae Du Ha and Jin Kun Cha*
Contribution from the Department of Chemistry, The UniVersity of Alabama, Tuscaloosa, Alabama 35487
ReceiVed July 21, 1999
Abstract: The stereocontrolled total synthesis of (-)-clavepictine A (1A) and (+)-clavepictine B (1B) has
been accomplished in an enantioselective fashion, which has unequivocally established the absolute configuration
of 1A and 1B. The pivotal step in the synthesis is diastereoselective silver(I)-promoted cyclization of δ-amino
allenes. Another key method includes cross-coupling of enol triflates of N-acyl lactams, which allows
stereocontrolled functionalization of otherwise unreactive lactams under mild conditions. The utility of Beak’s
R-lithiation-substitution chemistry of N-BOC piperidines involving a functionalized aldehyde as the electrophile
is demonstrated in the preparation of highly substituted nitrogen heterocycles. These new synthetic strategies
should be of general synthetic utility in the stereoselective syntheses of quinolizidines, indolizidines, and related
aza-heterocylces. Also included is the unique conformational preference of the highly substituted cis-quinolizidine
core of clavepictines; the (superfluous) m-(trifluoromethyl)benzoate substituent has a surprisingly significant
influence on the relative energies of the two possible chair-chair conformations.
Introduction
Scheme 1
Clavepictines A and B (1A,B) were isolated in 1991 by
Cardellina and co-workers from the tunicate ClaVelina picta.1
A lower homologue 1C of clavepictine A was independently
isolated by the Faulkner group and named pictamine.2 These
new quinolizidine alkaloids have been reported to exhibit
antimicrobial, antifungal, and antitumor activity, but their
thorough biological evaluation was hampered primarily by
supply problems. The structures of these alkaloidal homologues
were determined on the basis of spectroscopic data and X-ray
diffraction analysis, while their absolute configuration remained
undefined. Key structural characteristics center around a rare
cis-ring fused quinolizidine nucleus bearing axially disposed
methyl and acetoxy (or hydroxy) groups (Scheme 1); this cis-
ring junction conformation I appears to be favored over the
alternative cis-conformation II, presumably because in the latter
isomer the bulky 1,3-dienyl side chain must be axial. Due to
severe 1,3-diaxial interactions among the ring junction hydrogen,
the methyl group, and the dienyl side chain, the otherwise
favorable trans-ring junction conformer III is of significantly
higher energy than the cis isomers.
The Hart group first reported a synthetic approach to a
3-desoxyquinolizidine skeleton 3 by reduction of the vinylogous
carbamate 2 via an iminium ion (Scheme 2).3a The stereochem-
ical outcome of reduction was found to depend on two possible
half-chair conformations of the iminium ion intermediate and
the effective size of the reducing agent. This approach was based
upon the previous syntheses of structurally related Lythraceae
alkaloids [e.g., Lythrancepine III (5)].3b Subsequently, two
groups have completed enantioselective syntheses of 1A and
1B: the first enantioselective total synthesis was reported by
Momose and co-workers,4 followed by our own work.5 These
total syntheses unequivocally established the absolute config-
uration of 1A and 1B as shown in Scheme 1. Herein we report
a full account of our first-generation and more convergent,
second-generation syntheses of 1A and 1B.
Results and Discussion
Conjugate Addition Approach. The initial synthetic plan
was based on an intramolecular conjugate addition6 of a
trisubstituted piperidine 8 to produce the requisite quinolizidine
6 in preference to the C-10 epimer 7 (Scheme 3). Subsequent
elaboration of the side chain of 6 would then afford the target
alkaloids. The stereochemical course of the intramolecular
(4) Toyooka, N.; Yotsui, Y.; Yoshida, Y.; Momose, T. J. Org. Chem.
1996, 61, 4882.
(5) For a preliminary account of part of this work, see: Ha, J. D.; Lee,
D.; Cha, J. K. J. Org. Chem. 1997, 62, 4550.
(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) (a) Hart, D. J.; Leroy, V. Tetrahedron 1995, 51, 5757. (b) Hart, D.
J.; Hong, W.-P.; Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665.
(6) For recent developments in conjugate additions, see: (a) Little, R.
D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. Org. React. 1997,
47, 315. (b) Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771. (c)
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon
Press: Oxford, U.K., 1992. (d) Akiyama, E.; Hirama, M. Synlett 1996, 100.
10.1021/ja9925958 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/15/1999

Total Synthesis of ClaVepictines A and B
J. Am. Chem. Soc., Vol. 121, No. 43, 1999 10013
Scheme 2
Scheme 4
conformer. At the same time, however, we were concerned that
the ring conformation of 1A-1C is identical with that of 8b
(and 8c), rather than that of 8a.
Two different approaches to piperidine 8 via alcohol 9 were
envisaged starting from a disubstituted piperidine derivative
(Scheme 4). Beak’s elegant diastereoselective deprotonation-
substitution sequence would provide a direct method for
introducing the required side chain.7 However, the known
sluggish reactivity of an R-carbamoylamino carbanion (e.g., 10)
toward SN2 alkylation with aliphatic halides prompted us to
explore another approach: reduction of 11 via the iminium ion
should be highly diastereoselective due to the A(1,2) strain and
axial addition of hydride should occur.8 The N-acyl enamine
11, in turn, could be available by cross-coupling of an enamide
triflate (e.g., 12) derived from an N-acyl lactam with a suitable
reaction partner (e.g., 13). In marked contrast to the widely
utilized enol triflates from ketone or ester enolates, the corre-
sponding triflates of lactams have received surprisingly little
attention. Prior to our own work, the literature had dealt only
with the preparation and coupling of triflates of heteroaromatics.9
While our synthetic studies were in progress, Comins and Foti
first reported the preparation and reactions of N-acylaminoene
triflates from alicyclic N-acyl lactams.10a Subsequently, Hiemstra
and Speckamp described syntheses and applications of pyrro-
lidinone- and piperidinone-derived triflates.10b-e
Scheme 3
Toward this end, our first task was to prepare the enantiopure
lactam 17. Our synthesis began with the known, enantiopure
diol 14, which was conveniently prepared by the Sharpless
asymmetric dihydroxylation of ethyl sorbate in excellent ee
(Scheme 5).11 As the absolute configuration of the target
(7) (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708. (b)
Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. (c) Beak, P.; Kerrick,
S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116, 3231. (d) Beak, P.;
Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res.
1996, 29, 552.
(8) Cf.: (a) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.;
Sakane, S.; Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 2831.
(b) Overman, L. E.; Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc. 1983,
105, 5373. (c) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983. (d) Cook, G. R.; Beholz, L. G.;
Stille, J. R. J. Org. Chem. 1994, 59, 3575.
(9) (a) Okita, T.; Isobe, M. Synlett 1994, 26, 589. (b) Okita, T.; Isobe,
M. Tetrahedron 1995, 51, 3737. See also: (c) Thomas, E. W. Synthesis
1993, 767.
(10) (a) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656. (b)
Bernabe´, P.; Rutjes, F. P. J. T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
Lett. 1996, 37, 3561 (c) Luker, T.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1996, 37, 8257. (d) Luker, T.; Hiemstra, H.; Speckamp,
W. N. J. Org. Chem. 1997, 62, 3592. (e) Luker, T.; Hiemstra, H.; Speckamp,
W. N. J. Org. Chem. 1997, 62, 8131. Cf.: (f) Jacobi, P. A.; Liu, H. J. Am.
Chem. Soc. 1999, 121, 1958.
conjugate addition should be governed by the relative energies
of the respective conformers of 8 and also the rates of their
cyclization reactions. Predominant formation of 6 is expected
from conjugate addition via the chair conformer 8a, as the
diastereomeric transition state derived from 8d suffers from the
severe repulsive interaction shown. In contrast, cyclization of
the alternative chair piperidine (i.e, 8b and 8c) could proceed
with poor selectivity or possibly favor the undesired epimer 7.
Thus, the stereochemistry of the intramolecular Michael reaction
would depend primarily on conformational energies of the two
ring-inverted chair conformations of the trisubstituted piperidine.
On the basis of cursory consideration of A values for the three
substituents, we surmised that 8a might be the most stable

10014 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Ha and Cha
Scheme 5
Scheme 6
alkaloids was unknown at the outset, we arbitrarily chose
(DHQD)2-PHAL for asymmetric dihydroxylation. Hydrogena-
tion of 14 afforded (92% yield) γ-lactone 15, which allowed
the regioselective introduction of the amino group at C-2
(clavepictine numbering system). By means of the azide
intermediate, lactam 16 was then prepared in 81% overall yield.
Following protection (83%), sequential treatment of 17 with
LiHMDS and Comins’ reagent12 furnished the aminovinyl
triflate 12 (R2 ) Cbz) in excellent (88%) yield. Sonogashira-
type coupling13 with 1-butyn-4-ol (13: R1 ) CH2OH), followed
by acetylation (to facilitate isolation and characterization),
afforded the cross-coupling product 11 (R1 ) CH2OAc; R2 )
Cbz) in 90% yield. Subsequent reduction with NaBH3CN-TFA
resulted in the stereoselective construction of the desired
piperidine 18 in 78% yield. Finally, removal of the acetate group,
followed by catalytic hydrogenation and reprotection of the
amine, gave the desired alcohol 9 in good yield.
As illustrated by the preparation of the piperidine 9 from the
piperidinone 16, coupling of enol triflates derived from N-acyl
lactams represents a new, convenient method for reductive
alkylation of lactams to prepare amines with the stereocontrolled
attachment of a functionalized alkyl group and complements
other currently available methods such as Eschenmoser sulfide
contraction of thiolactams14 or addition of organometallic
reagents to lactams, thiolactams, or iminoethers.15 As an aside,
enol triflates of N-acyl lactams should have wide applicability
in alkaloid synthesis. For example, triflate 12 smoothly under-
went Stille coupling with tributyl(vinyl)tin in the presence of
catalytic Pd(PPh3)4 to afford diene 19 in excellent yield (Scheme
6).16 Diels-Alder reaction with ethyl acrylate gave the abnormal
1,3-regioisomer 20 as a 1:1 mixture of endo and exo diastere-
omers (79% yield). Exo preference was amplified by use of
the dienophile 21 bearing (1R)-(+)-2,10-camphorsultam to
afford the exo cycloadduct 22, as a single isomer, with complete
reversal of regioselectivity.17
Returning to the clavepictine project, the alcohol 9 was
converted by standard methods (1. Swern oxidation; 2.
Ph3PdCHCO2Et) to the requisite R,â-unsaturated ester 8 in 88%
overall yield to set the stage for the pivotal intramolecular
Michael addition (Scheme 7). Removal of the BOC group,
followed by treatment with triethylamine, induced facile cy-
clization to give nearly exclusive formation of the undesired
epimer 7 (R1 ) TIPS) in 82% yield. The initial stereochemical
assignment rested upon diagnostic 1H NMR coupling con-
stants: the proton H6 appears as a triplet of triplets with coupling
constants 11.0 and 2.8 Hz at δ 2.26, which indicate the trans-
ring junction. The stereochemistry of 7 was further supported
by analysis of other protons [H2: δ 3.31 (dq, J ) 2.7, 6.8 Hz);
H3: δ 3.79 (q, J ) 2.7 Hz); H10: δ 3.09 (dddd, J ) 2.8, 4.8,
7.8, 10.6 Hz where J9ax,10 ) 10.6 Hz)]. This disappointing
stereochemical outcome was attributed to the preponderance of
the conformer depicted as 8c (in Scheme 3). As judged from
1
the H NMR spectrum, the free amine 26, as well as related
2,3,6-trisubstituted piperidine derivatives bearing a different side
chain, was indeed found to exhibit the preference for the
conformation 26a,a,e over 26e,e,a.18
(11) (a) Kolb, H. C.; VanNieuwenhze, 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.
(12) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(13) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(14) (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., Eds.; Heathcock, C. H., Vol. Ed.; ComprehensiVe
Organic Synthesis; 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.; Danishef-
sky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30.
(15) 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.; Yamazaki, 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.
(16) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha, J. K. J. Org. Chem.
1998, 63, 3810.
(17) For a recent example (24 f 25), see: Jiang, J.; DeVita, R. J.; Doss,
G. A.; Goulet, M. T.; Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593.

Total Synthesis of ClaVepictines A and B
J. Am. Chem. Soc., Vol. 121, No. 43, 1999 10015
Scheme 7
Scheme 9
research groups and us.19 By a minor modification of the
procedure outlined in Scheme 5 for the preparation of 9, the
benzyl carbamate 32 was readily prepared. DIBAL-H reduction
and subsequent Sharpless asymmetric epoxidation20 with diethyl
D-tartrate afforded the requisite epoxy alcohol 33 in 52%
(unoptimized) yield. Stereoselective ring closure was then
accomplished by catalytic hydrogenation to give the desired cis-
quinolizidine 34. Although elaboration of 34 (or structurally
related diols) to clavepictines (1A and 1B) would appear to be
straightforward, we chose to develop a new synthetic strategy:
electrophilic cyclization of chiral δ-amino allenes appeared well-
suited for the stereoselective construction of the requisite
quinolizidine system.
Scheme 8
δ-Amino Allene Electrophilic Cyclization Approach. In
contrast to the oxygen-containing heterocycles, the intra-
molecular cyclization of ω-amino allenes has been limited to a
handful of monocyclic ring formations;21 to our knowledge, only
a single application was reported for the stereocontrolled
synthesis of nitrogen-containing bicyclic rings.21a Particularly
relevant is Gallagher’s enantioselective synthesis of (R)-(-)-
coniine (35) (Scheme 9), in which silver(I)-catalyzed cyclization
of chiral allene 36 was demonstrated to take place with little
racemization (<4-10%) to produce 38.21d Exceptional chirality
transfer was rationalized in terms of the intermediacy of a
dissymmetric silver-allene complex 37. Surprisingly, no ex-
amples have appeared on similar exploitation of chirality of the
allene unit in electrophilic cyclization reactions to diastereo-
selectively form more highly substituted, enantiopure nitrogen
heterocycles. Attachment of the chiral allene unit in the correct
absolute (i.e, S) configuration to the side chain, as shown in 39
(Scheme 10), was predicted to impose an overriding influence
to direct the selective formation of the desired cis-quinolizidine
derivative. Among possible transition states, for example, the
transition structure 41, leading to the trans-quinolizidine 43, is
disfavored due to severe nonbonded interactions, and the cis-
Similar results were also documented by Momose and co-
workers: cyclization of 27 resulted in formation of a ca. 4:1
mixture of trans- and cis-quinolizidines 28 and 29.4 An
ingenious solution was devised by use of the acetonide group
as an anchor, which locks the conformation of the piperidine
ring into the framework 30 of the trans-decalin type. As
expected, upon removal (with 10% Cd-Pb) of the 2,2,2-
trichloroethyl carbamate protecting group, cyclization afforded
the desired quinolizidine 31 as the sole product, which was
ultimately converted to the target alkaloids, 1A and 1B.
Another solution of bypassing the unfavorable conformational
preference of the 2,3,6-trisubstituted piperidine derivatives was
found in ring opening of the epoxide 33 by the deprotected
amine function (Scheme 8). Related cyclizations of epoxy
amines have been used previously in alkaloid synthesis by other
(19) (a) Gutawiller, J.; Uskokovic, M. R. J. Am. Chem. Soc. 1978, 100,
576. (b) Adams, C. E.; Walker, F. J.; Sharpless, K. B. J. Org. Chem. 1985,
50, 420. (c) Pearson, W. H.; Bergmeier, S. C.; Williams, J. P. J. Org. Chem.
1992, 57, 3977 and references therein. (d) Kim, N.-S.; Choi, J.-R.; Cha, J.
K. J. Org. Chem. 1993, 58, 7096.
(20) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(21) For cyclization of allenes bearing a proximate nitrogen nucleophile,
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.
(18) The carbamates 8 and 9 and related compounds all adopt a
conformation in which the methyl group is axial to avoid allylic strain.

10016 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Ha and Cha
Scheme 10
Scheme 11
Scheme 12
product 42 is expected to form predominantly via the transition
structure 40. Although the olefin geometry of 43 is depicted as
Z for clarity, it might equally well adopt the E configuration as
a result of equilibration prior to protonolysis. While not shown
in Scheme 10, the identical analysis on the ring-inverted chair
conformers of 39 also predicts diastereoselective formation of
42.
At the outset, we decided to eschew use of a vinyl allene
side chain: although the successful cyclization of a δ-amino
vinyl allene would directly establish the requisite (E,E)-1,3-
diene side chain, we were concerned about the likelihood that
the known cyclopentenone-type annulation22 would take place
more rapidly than the desired electrophilic cyclization of the
aminoallene function (Scheme 11).23 Instead, our plan called
for the late construction of the (E,E)-1,3-decadiene moiety by
means of dehydration of the homoallyl alcohol.
To diastereoselectively install the requisite allene functional-
ity, we decided to rely on the orthoester-Claisen rearrangement
of a propargyl alcohol (Scheme 12). Toward this end, the
enantiopure propargyl alcohol 47 was first prepared from
commercially available (S)-(-)-glycidol by standard methods
(1. t-BuCOCl, pyridine; 2. LiCtCTMS, BF3‚OEt; 3. n-Bu4-
NF). Application of the previously developed sequential reaction
sequence involving cross-coupling of 47 and 12 and reduction
with NaBH3CN-TFA resulted in the stereoselective construc-
tion of the trisubstituted piperidine 49 in 52% yield, along with
the corresponding desilylated diol in 14% yield. Hydrogenation
of the alkyne group, followed by straightforward functional
group manipulation of the carbamate and alcohol protecting
groups, furnished the allyl carbamate 51 via 50. To introduce
the allene group, the propargyl alcohol 52 was then prepared
in 74% overall yield. Subsequent diastereoselective orthoester-
Claisen rearrangement afforded the allenic ester 53 (83%).
Prior to the key cyclization, the rest of the side chain was
(22) Formation of cyclopentenones from vinyl allenes has been achieved
by acetoxymercuration or acetoxythallation, as well as peracid oxidation,
although there exists no example of Ag+-mediated cyclopentenone annu-
lation: (a) Balme, G.; Malacria, M.; Gore´, J. Tetrahedron Lett. 1979, 7.
(b) Malacria, M.; Gore´, J. J. Org. Chem. 1979, 44, 885. (c) Dulcere, J. P.;
Grimaldi, J.; Santelli, M. Tetrahedron Lett. 1981, 22, 3179. (d) Kim, S. J.;
Cha, J. K. Tetrahedron Lett. 1988, 29, 5613 and references therein.
(23) In a model study with a piperidine bearing an allenyne pendant at
C-2, however, it was found that, upon treatment with AgNO3 (0.3 equiv)
in aqueous acetone, a δ-amino allenyl alkyne underwent cyclization without
complication.

Total Synthesis of ClaVepictines A and B
J. Am. Chem. Soc., Vol. 121, No. 43, 1999 10017
Scheme 13
To probe the origin of the observed diastereocontrol in the
key cyclization, the 1:1 diastereomeric allenes were also
prepared starting from the racemic alcohol 47. The otherwise
identical cyclization of these diastereomeric allenes in place of
55 produced a ca. 1:2 mixture of 56 and 57 in 48% yield. In
additional studies, poor selectivity was also observed in the
cyclization of several piperidines bearing structurally related,
racemic (i.e., 1:1 diastereomeric) allenes. It is, therefore, clear
that diastereofacial control generated by the allene functionality
is exceptionally high and overrides the inherent conformational
bias of the substituted piperidine ring.
Having demonstrated the utility of electrophilic cyclizations
of ω-amino allenes in the synthesis of multi-substituted quino-
lizidines, our next goal was to optimize the yield and diaste-
reoselectivity of the cyclization reaction. At the same time, we
sought to reduce the overall number of steps used in our first-
generation synthesis of clavepictines, most of which involved
diastereocontrolled installation of the allene function after the
cross-coupling reaction. Utilization of a prefabricated allene
would lend itself to a convergent, efficient synthesis, but is not
compatible (i.e., see 49 f 50 in Scheme 12) with the alkyne
group employed for Sonogashira coupling. In lieu of the
operationally simple Sonogashira reaction, cross-coupling of the
vinyl triflate 12 and a primary alkyl group was required: the
more challenging coupling reaction of this type has been
achieved by the Suzuki procedure involving use of alkylboranes
derived from hydroboration with 9-BBN or by action of
organozinc reagents.26 As summarized in Scheme 14,27 â-hy-
dride elimination proved to be the major pathway under several
reaction conditions. This unsatisfactory result prompted us to
explore Beak’s deprotonation-substitution chemistry for the
second-generation synthesis of 1A and 1B.
Second-Generation Synthesis. Beak and co-workers have
developed an efficient diastereoselective functionalization of
BOC-protected pyrrolidines and piperidines by R′-lithiation and
subsequent electrophilic substitution.7 Of particular relevance
is the highly diastereoselective preparation of trans-2,6-BOC
piperidines from N-BOC-2-methylpiperidine.28 However, elec-
trophilic substitution of the dipole stabilized carbanion inter-
mediates is limited to acylation, condensation with aldehydes,
or methylation. Indeed, lithiation (sec-BuLi/TMEDA) of the
N-BOC-piperidine 62 and subsequent alkylation with a simple
alkyl iodide [e.g., (E)-6-iodo-2-hexene] proved to be diastereo-
selective (∼5:1 ds), but sluggish, affording up to 45% of the
correct alkylation product, along with recovered starting material
(45%) (Scheme 15). In contrast, use of alkyl iodides bearing
an allene gave none of the alkylation product, presumably
because of the presence of relatively acidic protons associated
with the allene functionality. We subsequently employed an
aldehyde bearing an enantiopure allene unit as the electrophile,
since the alcohol function of the resulting adduct should be
readily reduced at an appropriate stage.
then introduced (86%) in a one-pot operation by sequential
treatment of 53 with DIBAL-H and n-hexylmagnesium bromide
to afford alcohol 54 (Scheme 13). Not surprisingly, 54 was
obtained as an inseparable 1:1 diastereomeric mixture of the
C-14 alcohols, but since the alcohol was destined to undergo
dehydration, lack of stereocontrol here was inconsequential.
Subsequent alcohol protection and removal of the allyl carbam-
ate group by standard methods provided the δ-allenic amine
55 (70% overall). Silver nitrate-mediated cyclization of 55
produced a 7:1 mixture of the desired cis-quinolizidine 56 and
its C-10 epimer 57 in 54% yield. Selective removal of the
triethylsilyl group, followed by treatment with the Martin
sulfurane,25 gave a 10:1 mixture of TIPS-protected clavepictine
and the corresponding E,Z-isomer. Finally, separation and
treatment with n-Bu4NF afforded (+)-clavepictine B (1B). (-)-
Clavepictine A (1A) was then prepared by acetylation of 1B.
The spectroscopic and physical properties of 1A and 1B were
in excellent agreement with literature data;1 the 1H and 13C NMR
spectra of 1A and 1B were found to be identical with those of
authentic samples which were kindly provided by Professor
Momose.4 For additional characterization, the trans-quinolizidine
57 was converted to epi-clavepictine B, which exhibits drasti-
cally different spectra from 1B.
(26) (a) Miyaura, N.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1992,
33, 2571. (b) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58,
2201. (c) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (d) Oh-e, T.; Miyaura, N.;
Suzuki, A. Synlett 1990, 221. (e) Kobayashi, M.; Negishi, E. J. Org. Chem.
1980, 45, 5223. (f) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (g) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida,
Y. Angew. Chem., Int. Ed. Engl. 1987, 26, 1157. (h) Stadtmu¨ller, H.; Lentz,
R.; Tucker, C. E.; Stu¨demann, T.; Do¨rner, W.; Knochel, P. J. Am. Chem.
Soc. 1993, 115, 7027. (i) Organocopper Reagents; Taylor, R. J. K., Ed.;
Oxford University Press: Oxford, UK, 1994.
(24) (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.
(25) Martin, J. C.; Franz, J. A.; Arhart, R. J. J. Am. Chem. Soc. 1974,
96, 4604.
(27) Yields given in Scheme 14 are based on recovered starting triflate
(13-18%).
(28) (a) Reference 7b. (b) Chackalamannil, S.; Davies, R. J.; Asberom,
T.; Doller, D.; Leone, D. J. Am. Chem. Soc. 1996, 118, 9812.

10018 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Ha and Cha
Scheme 14
Scheme 16
Scheme 15
Following reduction with DIBAL-H, the alcohol 68 was
subjected to one-carbon chain elongation by displacement of
the bromine in 69 with cyanide to produce nitrile 70 in 75%
overall yield. The requisite aldehyde 71 was then readily
prepared (95%) by reduction with DIBAL-H.
As outlined in Scheme 17, coupling of the two fragments 62
and 71 was achieved according to Beak’s procedure: lithiation
(sec-BuLi/TMEDA) of the N-BOC-piperidine 62, followed by
addition of the aldehyde 71, produced, with 80% conversion,
an inseparable 3:1 mixture (75%) of alcohol epimers, anti 72
and syn 73, along with trans-oxazolidinone 74 (9%). Preferential
cyclization of the syn isomers to the corresponding bicyclic
carbamates was also previously noted by Beak.7b None of the
undesired stereoisomer at the piperidine ring center was found
in inspection of the crude reaction mixture. The stereochemical
assignments of 72-74 rested on analysis of proton coupling
constants and was confirmed by conversion to the respective
oxazolidinones (vide infra). Upon treatment with methane-
sulfonyl chloride, a 3:1 mixture of 72 and 73 underwent facile,
stereospecific cyclization to afford the identical ratio of the two
bicyclic carbamates, 74 and 75. Preparation of both oxazolidi-
none isomers allowed the unequivocal stereochemical assign-
ment: cis-oxazolidinone 75 shows a larger coupling constant
(J2,3) of 8.1 Hz (δ 3.73; ddd, J ) 11.8, 8.1, 3.5 Hz) in
comparison to a J2,3 of 6.4 Hz (δ 3.35; ddd, J ) 10.6, 6.4, 3.4
Hz) in trans-oxazolidinone 74. Although the inseparable mixture
of 72 and 73 was suitable for subsequent transformations, for
ease of characterization we chose to separate them after
acylation. For example, anti and syn m-(trifluoromethyl)-
benzoates, 76 and 77, were readily obtained in pure form by
silica gel column chromatography.
Moreover, we placed an alkoxy substituent, which was to be
eliminated to give the E-olefin moiety at C-13 and C-14 of 1A
and 1B, adjacent to the allene group, rather than at the previously
utilized â-position (cf. 55 in the first-generation synthesis): this
additional substituent was anticipated to raise the diastereo-
selectivity of the key cyclization step. On the basis of inspection
of molecular models, the (S)-configuration of the alkoxy
substituent at C-13 was chosen in an attempt to maximize
diastereofacial selectivity.
The enantiopure aldehyde partner 71 was first prepared
starting from ethyl (E)-2-decenoate (Scheme 16). Sharpless
asymmetric dihydroxylation, followed by treatment of the
resulting diol 64 with TIPSOTf, resulted in regioselective
protection of the â-alcohol to afford 65 in 74% yield. Following
protection of the remaining alcohol, the ester functionality was
converted by standard methods to the acetylene group, via the
dibromoolefin, to provide propargyl alcohol 66 (60% overall).
Subsequent orthoester-Claisen rearrangement took place smoothly
with excellent diastereocontrol to give allene 67 in 71% yield.
Cleavage of the BOC group of 76 and 77 by TMSOTf-
lutidine29 gave the free amines 78 and 79 in 95% and 90%
yields, respectively (Scheme 18). Subsequent treatment of 78

Total Synthesis of ClaVepictines A and B
J. Am. Chem. Soc., Vol. 121, No. 43, 1999 10019
Scheme 18
Scheme 17
with silver nitrate in an aqueous acetone solution afforded the
desired cis-quinolizidine 80, as a single isomer, in 94% yield.
Similarly, 81 was obtained in 91% yield as the sole product
from 79. It was gratifying to find that cyclization of both 78
and 79 took place with exceptional selectivity and excellent
yield, which represents a significant improvement over that of
55 which proceeded with 7:1 diastereoselectivity in 54% yield
(see Scheme 13). Because both C-7 epimers stereoselectively
give the respective cyclization product, the presence of an extra
(i.e., OTIPS) substituent at the C-13 position must be largely
responsible for enhanced selectivity. Particularly noteworthy are
the preferred conformations of cis-quinolizidines 80 and 81, in
which the epimeric m-(trifluoromethyl)benzoate substituent
occupies the equatorial position in each compound, as shown
in Scheme 18. Interestingly, 82, which was prepared by
DIBAL-H reduction of 80, adopts the ring-inverted chair, i.e.,
the framework identical with that of the alcohol 83, presumably
due to intramolecular hydrogen bonding of the alcohol to the
ring junction nitrogen.
The remaining tasks were deoxygenation of the superfluous
alcohol functionality in 82 and 83, followed by conversion of
the allyl alcohol in the side chain to the requisite E,E,-1,3-diene
to complete the total syntheses of clavepictines. The m-
(trifluoromethyl)benzoyl protecting group was originally chosen
with an eye toward chemoselective deoxygenation of the
secondary alcohol by electron-transfer reaction with N-meth-
ylcarbazole as the photosensitizer.30 Unfortunately, this photo-
sensitized deoxygenation by Saito’s method resulted only in
decomposition under several conditions. This failure might be
attributed to the interference of the tertiary amine, even in the
presence of buffer solutions of low pH, with the electron-transfer
process. Ultimately, an efficient solution was found using the
mesylate 85 (Scheme 19). Treatment of the R-alcohol 83 with
methanesulfonyl chloride, followed by LiAlH4 reduction of the
resulting mesylate 85, resulted in clean deoxygenation and
attendant, selective removal of one of the TIPS protecting groups
to afford alcohol 86 in 88% overall yield. Acetylation and
subsequent desilylation gave the alcohol 88. In contrast, when
the epimeric â-alcohol 82 was subjected to the identical mesylate
formation-LiAlH4 reduction sequence, the rearrangement prod-
uct 89 (17%), as well as 86 (28%), was obtained. Anchimeric
assistance by the tertiary quinolizidine nitrogen atom could
account for the unexpected lability of the mesylate 84 and also
the formation of 89. It should be noted that the preferred
conformation of the mesylate 84 is conducive for backside attack
at the mesylate-bearing carbon by the nitrogen lone pair.
Similarly, the desired inversion of configuration of the C-7
alcohol in 82 by the Mitsunobu reaction was foiled due to facile
neighboring group participation: exclusive formation (76%) of
the ring-rearranged benzoate 90 was obtained instead. The
requisite conversion of 82 to 83 was achieved in 86% yield by
Swern oxidation, followed by NaBH4 reduction (MeOH, 0 °C).
With the stereoselective preparation of 88 achieved, the only
remaining task was dehydration to complete the total synthesis
of clavepictine A (1A) (Scheme 20). It was disappointing to
find that dehydration of the allyl alcohol 88 by the Martin
sulfurane was nonselective and produced a ca. 1:1 mixture (44%;
unoptimized) of 1A and 91, which is in sharp contrast to that
(10:1) of the corresponding homoallyl alcohol 58 (Scheme 13).
Action of the Burgess reagent also resulted in the nonselective
(29) Sakaitani, M.; Ohfune, Y. Tetrahedron Lett. 1985, 26, 5543.
Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870. Sakaitani, M.;
Ohfune, Y. J. Am. Chem. Soc. 1990, 112, 1150.
(30) (a) Saito, I.; Ikehira, H.; Kasatani, R.; Watanabe, M.; Matsuura, T.
J. Am. Chem. Soc. 1986, 108, 3115. Cf.: (b) Myers, A. G.; Condroski, K.
R. J. Am. Chem. Soc. 1993, 115, 7926.

10020 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Ha and Cha
Scheme 19
Scheme 20
tion with Oxone and thermal syn elimination gave 1A in 80%
yield.32 Finally, basic hydrolysis (K2CO3, MeOH) of 1A afforded
clavepictine B (1B) in quantitative yield.
Conclusion
The stereocontrolled total synthesis of (-)-clavepictine A
(1A) and (+)-clavepictine B (1B) was accomplished in an
enantioselective fashion, which allowed the unequivocal deter-
mination of the absolute configuration of 1A and 1B. The pivotal
step in the synthesis is diastereoselective cyclization of δ-amino
allenes. Another key method includes cross-coupling of enol
triflates of N-acyl lactams, which allows stereocontrolled
functionalization of otherwise unreactive lactams under mild
conditions. The utility of Beak’s R-lithiation-substitution
chemistry of N-BOC piperidines involving a functionalized
aldehyde as the electrophile is demonstrated in the preparation
of highly substituted nitrogen heterocycles. These new synthetic
strategies should be of general synthetic utility in the stereo-
selective syntheses of quinolizidines, indolizidines, and related
aza-heterocylces. Also included is the unique conformational
preference of the highly substituted cis-quinolizidine core of
clavepictines, where the m-(trifluoromethyl)benzoate substituent
plays a surprisingly significant role in determining the relative
populations of the two possible chair-chair conformations.
Acknowledgment. This work is dedicated to Professor Drury
S. Caine, III on the occasion of his retirement. We thank the
National Institutes of Health (GM35956) for generous financial
support. We are grateful to Professor T. Momose for providing
1
the H and 13C NMR spectra of clavepictines A and B.
Supporting Information Available: Experimental proce-
dure and the 1H and 13C NMR spectra of synthetic (-)-
clavepictine A and (+)-clavepictine B, and also key synthetic
intermediates (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
coproduction of 1A and 91.31 However, stereoselective (7:1)
formation of 1A was achieved by way of the allyl sulfide, which
was readily prepared (74%) by treatment of 88 with N-
phenylthiophthalimide and tributylphosphine; subsequent oxida-
JA9925958
(32) (a) Reich, H. J.; Wollowitz, S. J. Am. Chem. Soc. 1982, 104, 7051.
(b) Use of the allylic o-nitrobenzeneselenoxide resulted in the [2,3]-
sigmatropic rearrangement to provide the 1,3-transposed allylic alcohol.
Lability of allylic selenoxides, even in the absence of trapping agents other
than adventitious moisture, was previously noted by Reich.
(31) (a) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26. (b) Wipf, P.; Venkatraman, S. Tetrahedron Lett. 1996, 37,
4659.