Formal total synthesis of (-)-lepadiformine

Article abstract of DOI:10.1021/ol053010j

A stereocontrolled approach to the preparation of the Weinreb intermediate 3 has been developed. The important features of this approach are the creation of stereogenic centers through a cyclic amino acid ester-enolate Claisen rearrangement and the use of

Full text of DOI:10.1021/ol053010j

ORGANIC
LETTERS
2006
Vol. 8, No. 4
745-748
Formal Total Synthesis of
)-Lepadiformine
(
−
Minhee Lee,† Taeho Lee,‡ Eun-Young Kim,‡ Hyojin Ko,‡ Deukjoon Kim,† and
Sanghee Kim*,†,‡
College of Pharmacy, Seoul National UniVersity, San 56-1, Shilim, Kwanak,
Seoul 151-742, Korea, and Natural Products Research Institute, College of Pharmacy,
Seoul National UniVersity, 28 Yungun, Jongro, Seoul 110-460, Korea
pennkim@snu.ac.kr
Received December 13, 2005
ABSTRACT
A stereocontrolled approach to the preparation of the Weinreb intermediate 3 has been developed. The important features of this approach
are the creation of stereogenic centers through a cyclic amino acid ester−enolate Claisen rearrangement and the use of ring-closing metathesis
for the construction of the azaspirocyclic skeleton.
Lepadiformine is a tricyclic perhydropyrrolo[2,1-j]quinolone
that was initially isolated from the tunicate ClaVelina
lepadiformis by Biard in 1994.1 This marine alkaloid exhibits
moderate cytotoxic activity against various tumor cell lines
in vitro,1 as well as high in vitro and in vivo cardiovascular
effects.2 The originally proposed structure 2 (Figure 1) for
synthesis. X-ray crystallographic analysis of synthetic lep-
adiformine hydrochloride verified the relative stereochemistry
unambiguously; it also indicated that the B ring of lepadi-
formine exists in an unusual twist-boat form.3 In 2002, the
Weinreb group determined the absolute configuration through
the first enantioselective total synthesis4 of the alkaloid and
the Kibayashi group reconfirmed this assignment shortly
thereafter.5
The significant amount of synthetic interest in lepadiform-
ine stems from its intriguing structural features and interesting
bioactivity. Before the correct structure of lepadiformine was
established, many efforts were directed toward the synthesis
of the incorrectly assigned structure and other possible
isomers.6 These efforts eventually resulted in the assignment
Figure 1. The revised structure 1 of lepadiformine and its originally
proposed structure 2.
(1) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.;
Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691-2694.
(2) Juge, M.; Grimaud, N.; Biard, J. F.; Sauviat, M. P.; Nabil, M.; Verbist,
J. F.; Petit, J. Y. Toxicon 2001, 39, 1231-1237.
(3) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122,
4583-4592.
this alkaloid was revised in 2000 by Kibayashi and co-
workers3 to the correct structure 1 through their first total
(4) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337-
4345.
† College of Pharmacy, Seoul National University.
(5) Kibayashi, C.; Aoyagi, S.; Abe, H. Angew. Chem., Int. Ed. 2002,
41, 3017-3020.
‡ Natural Products Research Institute, Seoul National University.
10.1021/ol053010j CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/25/2006

of the correct structure, which signified the pivotal role of
total synthesis in natural product structure determinations.7
Since the report of the first total synthesis of lepadiformine
in its correct form, several other elegant syntheses have been
reported.8
Scheme 2
In this paper, we report a novel formal stereoselective
synthesis of (-)-lepadiformine (1). Our strategy was based
on the use of an amino acid ester-enolate Claisen rear-
rangement and a ring-closing metathesis (RCM) reaction,
as presented in the retrosynthetic Scheme 1.9
Scheme 1. Retrosynthetic Analysis of (-)-Lepadiformine
glutamic acid 10, through a conventional seven-step se-
quence, according to Terashima and co-workers’ previously
reported procedure.11 Oxidation of the aldehyde group of 11
with NaClO2 gave the corresponding carboxylic acid 9 in
98% yield. Esterification of 9 with the known allylic alcohol
8 under Steglich’s DCC coupling conditions12 provided the
allylic ester 7 (88%).
With multigram quantities of the diastereoisomeric mixture
7 in hand, we explored the stereoselective Ireland-Claisen
rearrangement of the cyclic amino acid ester. To obtain the
desired stereoisomer, the selective formation of the (Z)-silyl
ketene acetal was a prerequisite prior to the Claisen rear-
rangement occurring via its well-established chairlike transi-
tion state (as indicated within the brackets). To the best of
our knowledge, however, there were no examples in the
literature describing selective ester enolate formation in cyclic
R-amino acid ester compounds possessing an exocyclic
N-carbonyl group.13 After several attempts, we found that
treatment of 7 with LHMDS and TBSCl in THF at -78 °C,
The tricyclic amino nitrile 3 (Scheme 1) was a key ad-
vanced intermediate in previous total syntheses of lepadifor-
mine.4,8a We envisioned that this intermediate 3 could be
synthesized from the cyclohexene 4. We envisaged that the
azaspirocyclic skeleton of 4 could be constructed through a
RCM of diene 5, which, in turn, would be accessible from
the densely functionalized cyclic amino acid 6. The presence
of the γ,δ-unsaturated carbonyl unit in compound 6 suggested
the use of a Claisen rearrangement of the cyclic amino acid
allylic ester 7. In this transformation, the relative stereo-
chemistry of three stereocenters could be determined by the
choice of the enolate geometry and the transition state geom-
etry. Further analysis indicated the known allylic alcohol 810
and the protected cyclic amino acid 9, as the source of
chirality, to be suitable synthetic precursors for the Claisen
rearrangement substrate 7.
(8) For synthesis of racemic 1, see: (a) Sun, P.; Sun, C.; Weinreb, S.
M. Org. Lett. 2001, 3, 3507-3510. (b) Greshock, T. J.; Funk, R. L. Org.
Lett. 2001, 3, 3511-3514. For the asymmetric synthesis of (-)-1, see: (c)
Liu, J.; Hsung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989-3992. (d) See
also refs 4 and 5.
(9) For the application of a similar strategy in the total synthesis of
perhydrohistrionicotoxin, see: Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org.
Chem. 2005, 70, 5756-5759.
(10) (a) Kim, D.; Jang, Y. M.; Kim, I. O.; Park, S. W. J. Chem. Soc.,
Chem. Commun. 1988, 760-761. (b) Murphy, J. A.; Rasheed, F.; Roome,
S. J.; Scott, K. A.; Lewis, N. J. Chem. Soc., Perkin Trans. 1 1998, 2331-
2340.
(11) Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.;
Terashima, S. Tetrahedron 1994, 21, 6221-6238.
(12) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522-524.
Our synthesis began by preparing the known amino alde-
hyde 11 (Scheme 2) from commercially available (S)-pyro-
(13) Chelation-controlled stereoselective ester enolate formation of
acyclic R-amino acid ester compounds having both N-carbonyl groups and
NH protons have been reported. See: (a) Kazmaier, U.; Maier, S.
Tetrahedron 1996, 52, 941-954. (b) Miller, J. F.; Termin, A.; Koch, K.;
Piscopio, A. D. J. Org. Chem. 1998, 63, 3158-3159. (c) Kazmaier, U.;
Maier, S. Chem. Commun. 1998, 2535-2536. (d) Kazmaier, U.; Zumpe,
F. L. Angew. Chem., Int. Ed. 1999, 38, 1468-1470. (e) Qiu, W.; Gu, X.;
Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett. 2001,
42, 145-148. (f) Morimoto, Y.; Takaishi, M.; Kinoshita, T.; Sakaguchi,
K.; Shibata, K. Chem. Commun. 2002, 42-43. (g) Ndungu, J. M.; Gu, X.;
Gross, D. E.; Cain, J. P.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett.
2004, 45, 4139-4142.
(6) For syntheses of the originally proposed structure 2, see: (a) Werner,
K. M.; de los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem.
1999, 64, 686-687. (b) Werner, K. M.; de los Santos, J. M.; Weinreb, S.
M.; Shang, M. J. Org. Chem. 1999, 64, 4865-4673. (c) Abe, H.; Aoyagi,
S.; Kibayashi, C. Tetrahedron Lett. 2000, 41, 1205-1208. (d) See also ref
3. For syntheses of the other three diastereomers of 2, see: (e) Pearson, W.
H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett. 1997, 38, 3369-3372. (f)
Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688-689.
(7) Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59-65.
746
Org. Lett., Vol. 8, No. 4, 2006

followed by gradual warming to room temperature, afforded
predominantly the desired rearrangement product 6, along
with a minor amount of its stereoisomer, in 79% combined
yield and 8:1 diastereoselectivity. We established the relative
stereochemistry of the two newly generated stereocenters of
6 ultimately through its conversion to 3. This relative
stereochemistry suggests that chelation control might have
existed between the enolate oxygen atom and the heteroatom
of the N-Boc group, which influenced the stereochemistry
of enolate formation and, hence, the stereochemical course
of the rearrangement.
The crucial ring-closing metathesis of 14 was successfully
performed with a second-generation Grubbs’ catalyst 1715
in CH2Cl2 at 40 °C, to produce the desired azaspiro-cyclo-
hexene derivative 18 in 98% yield (Scheme 4). Hydrogena-
Scheme 4
Next we turned our attention to the conversion of the
carboxylic acid group of 6 into a homoallyl group for the
preparation of the metathesis precursor 5 (Scheme 3). Thus,
Scheme 3
tion of the olefinic bond of 18 with H2 and 10% Pd/C in the
presence of Et3N as a catalyst poison afforded 19 without
effecting hydrogenolysis of the O-benzyl protecting group.16
Next, we directed our efforts toward the construction of
the cyano group-functionalized lepadiformine B-ring to
complete the formal synthesis. Toward that end, deprotection
of the silyl ether 19 with TBAF and oxidation of the resulting
alcohol 20 with the Dess-Martin periodinane17 led to the
isolation of the aldehyde 21 in 95% overall yield. Upon
treatment with p-TsOH in aqueous acetone under reflux, the
Boc-protected amino aldehyde 21 cyclized to the known
tricyclic enamine 22, which was unstable, as reported
previously.4,8a Without purification, we employed reaction
conditions analogous to those described by Weinreb et al.4,8a
to convert 22 into the more-stable R-amino nitrile 3 in 70%
overall yield. Our 1H and 13C NMR spectroscopic data for 3
were identical with those reported previously.
methylation of the carboxylic acid 6 with MeI/K2CO3 in
acetone afforded the ester 12 (93%), which we then reduced
with LiAlH4 to the corresponding primary alcohol 13 (94%).
Unfortunately, all of our attempts to convert the primary
alcohol group in 13 to the homoallyl group in 5 were
unsuccessful, presumably because of the high degree of steric
hindrance. This failure led us to devise an alternative RCM
substrate 14 for construction of the azaspirocyclic skeleton.
Thus, as a first step we converted the terminal olefin of 12
to the two-carbon-atom-homologated terminal olefin. Hy-
droboration of the olefin 12 with 9-BBN gave the alkyl
borane; a subsequent in situ B-alkyl Suzuki-Miyaura
reaction with vinyl bromide provided 15 in 73% yield.14
Treatment of 15 with LiAlH4 effected the reduction of the
hindered ester to afford the alcohol 16 in 91% yield. Swern
oxidation of 16, followed by a Wittig reaction of the resulting
aldehyde with methylidene triphenylphosphorane, provided
the desired RCM substrate 14 in 84% overall yield.
In summary, we have accomplished a formal stereoselec-
tive synthesis of (-)-lepadiformine from readily available
starting materials. Our strategy differs from those of previous
(14) Chemler S. R.; Danishefsky S. J. Org. Lett. 2000, 2, 2695-2698
and references therein.
(15) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(16) For examples of the use of amines as catalyst poisons, see: (a)
Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076-4078. (b) Sajiki,
H.; Hirota, K. Tetrahedron 1998, 54, 13981-13996. (c) Kadota, I.;
Takamura, H.; Sato, K.; Ohno, A.; Masayuki, M.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 11893-11899.
(17) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
Org. Lett., Vol. 8, No. 4, 2006
747

approaches in that we established the stereogenic centers of
lepadiformine through an amino acid ester-enolate Claisen
rearrangement and employed a ring-closing metathesis to
construct its azaspirocyclic skeleton.
Supporting Information Available: Full experimental
procedures and analytical data of compounds; copies of H
NMR and 13C NMR spectra of compounds 3, 12, 14, and
18. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
Acknowledgment. This study was supported by the
National Research Laboratory Program (2005-01319), NRDP,
Ministry of Science and Technology, Republic of Korea.
OL053010J
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Org. Lett., Vol. 8, No. 4, 2006