Total synthesis of the marine alkaloid (±)-lepadiformine via a radical carboazidation

Article abstract of DOI:10.1021/ol060083+

The total synthesis of lepadiformine has been achieved in 10 steps and 15% overall yield from cyclohexanone. The amino-substituted quaternary carbon center is created through a radical carboazidation reaction. The tricyclic core of lepadiformine is built via an efficient hydrogenation process, involving reduction of the azide and intramolecular reductive amination of a ketone, followed by lactamization of the intermediate γ-aminoester. The hydroxymethyl side chain is introduced according to a modified Takahata procedure after conversion of the lactam into a thiolactam.

Full text of DOI:10.1021/ol060083+

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1569-1571
Total Synthesis of the Marine Alkaloid
)-Lepadiformine via a Radical
Carboazidation
(±
Pascal Scha1r and Philippe Renaud*
Departement fu¨r Chemie und Biochemie, UniVersita¨t Bern,
Freiestrasse 3, CH-3012 Bern, Switzerland
philippe.renaud@ioc.unibe.ch
Received January 12, 2006
ABSTRACT
The total synthesis of lepadiformine has been achieved in 10 steps and 15% overall yield from cyclohexanone. The amino-substituted quaternary
carbon center is created through a radical carboazidation reaction. The tricyclic core of lepadiformine is built via an efficient hydrogenation
process, involving reduction of the azide and intramolecular reductive amination of a ketone, followed by lactamization of the intermediate
γ
-aminoester. The hydroxymethyl side chain is introduced according to a modified Takahata procedure after conversion of the lactam into a
thiolactam.
Lepadiformine is a marine alkaloid which was isolated in
1994 from the tunicate ClaVelina lepadiformis and later from
ClaVelina moluccensis.1 It showed moderate cytotoxic activ-
ity against several tumor cell lines as well as various
cardiovascular effects in vitro and in vivo. Its discovery
triggered a series of synthetic efforts. In several attempts
toward the total synthesis, it soon became obvious that the
structure originally proposed based on NMR experiments had
to be corrected. It was not until 6 years after its discovery
that the structure of lepadiformine was finally revised to 1
after the first total synthesis by Kibayashi.2a This process
has recently been reviewed by Weinreb, who emphasizes
the value of total synthesis for natural product structure
elucidation in this context.3 A number of syntheses for
racemic2 as well as for optically pure lepadiformine have
been reported.4
A key structural feature of lepadiformine is a trans-
azadecalin framework including an amino-substituted qua-
ternary carbon center (C10). We report here a very concise
synthesis of lepadiformine starting from cyclohexanone and
using a radical carboazidation step to create the quaternary
carbon center at C10.
Recently, we developed a radical carboazidation reaction
and applied it to the preparation of mono- and polycyclic
lactams such as indolizidinones and spirocyclic lactams.5 In
the latter case, the reaction proceeds via a tertiary alkyl
radical, which is particularly well suited to react with the
sulfonyl azide radical trap because of its nucleophilic
character. Therefore, this procedure is particularly efficient
(1) (a) Biard, J.-F.; Guyot, S.; Roussakis, C.; Verbist, J.-F.; Vercauteren,
J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691. (b) Juge´,
M.; Grimaud, N.; Biard, J.-F.; Sauviat, M.-P.; Nabil, M.; Verbist, J.-F.;
Petit, J.-Y. Toxicon. 2001, 39, 1231.
(2) (a) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122,
4583. (b) Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507. (c)
Greshock, T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511.
(3) (a) Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59. (b) Kibayashi, C.;
Aoyagi, S.; Abe, H. Bull. Chem. Soc. Jpn. 2003, 76, 2059. (c) Scha¨r, P.;
Cren, S.; Renaud, P. Chimia 2006, 60, 131.
(4) (a) Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem., Int. Ed. 2002,
41, 3017. (b) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67,
4337. (c) Liu, J.; Hsung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989. (d)
Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473.
10.1021/ol060083+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/17/2006

to prepare amino-substituted quaternary carbon centers, such
as C10 of lepadiformine. Our synthetic strategy to prepare
lepadiformine is depicted in Scheme 1. Tricyclic lactam 2
The tin-mediated carboazidation was carried out at 70 °C
with a 1:1 ratio of alkene 4 and ethyl iodoacetate and using
pyridine sulfonyl azide as the radical trap to facilitate
chromatographic separation of the product.9 This gave the
azidoester 3 in good yield as a 3:2 mixture of trans/cis
diastereomers (Scheme 3).
Scheme 1. Retrosynthetic Approach
Scheme 3. Radical Carboazidation
Attempts to run the reaction at lower temperature did not
enhance the diastereoselectivity.
Separation of the trans and cis diastereomers of 3 was
possible. However, the synthesis was carried on with the
mixture of diastereomers since an easier separation was
possible at a later stage.
To prepare cycle B, the azide moiety was reduced to an
amine by hydrogenation in the presence of palladium on
calcium carbonate. This catalyst was found to be superior
to Pd/C which led mainly to elimination of hydrazoic acid.
We later discovered that the minor azide cis-3 is much more
prone to elimination due to the anti arrangement of the proton
and the azide (Scheme 4). Thus, when the diastereomeric
will be obtained by two consecutive ring closures from
azidoketoester 3. The azidoester 3 will be prepared by
carboazidation of the methylenecyclohexane 4, easily pre-
pared from cyclohexanone 5.
Interestingly, 4 had already been reported as an intermedi-
ate in the total synthesis of 5,13-diepilepadiformine by
Pearson.6 The ketoester 6 was prepared according to a
literature procedure in 86% yield (Scheme 2).7 Methylenation
Scheme 2. Preparation of Methylenecyclohexane 4
Scheme 4. Formation of Tricyclic Lactam 2
of the ketone 6 was examined under several reaction
conditions. Wittig olefination gave the desired product in
moderate yield (60%). A better result was obtained with
Kauffmann’s tungsten carbene that gave the desired meth-
ylenecyclohexane 7 in nearly quantitative yield.8 The n-hexyl
side chain was then introduced by conversion of the ester 7
to the Weinreb amide 8 followed by reaction with n-
hexylmagnesium bromide as previously reported by Pearson.6
(5) (a) Panchaud, P.; Ollivier, C.; Renaud, P.; Zigmantas, S. J. Org. Chem.
2004, 69, 2755. (b) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005,
7, 2587. (c) Panchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.; Renaud,
P.; Zigmantas, S. Chem. Eur. J. 2004, 10, 3606. (d) Panchaud, P.; Renaud,
P. Chimia 2004, 57, 232. (e) Renaud, P.; Ollivier, C.; Panchaud, P. Angew.
Chem., Int. Ed. 2002, 41, 3460.
(6) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett. 1997,
38, 3369.
(7) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,
R. J. Am. Chem. Soc. 1963, 85, 207.
mixture of 3 was hydrogenated, the minor cis-3 was
completely converted to apolar products and trans-3 under-
went the desired reduction followed by a stereoselective
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Org. Lett., Vol. 8, No. 8, 2006

This simple transformation proved to be much more com-
plicated to run than expected since all methods involving
reduction of the lactam to a hemiaminal followed by reaction
with a nucleophile failed. Takahata reported that thioami-
dinium salts, formed by treatment of thiolactams with methyl
iodide, react with lithium acetylides to give propargylamines
after reduction of the intermediate N,S-acetal with lithium
aluminum hydride.10 By enforcing the reducing conditions,
a direct access to allylamines was envisaged. Conversion of
2 to the thiolactam 10 with Lawesson’s reagent11 was
straightforward. Treatment of thiolactam 10 with methyl
iodide and then with lithium 2-phenylacetylide followed by
heating with an excess of LiAlH4 afforded the allylic amine
11 as a single diastereoisomer. Conversion of 11 to (()-
lepadiformine was achieved by ozonolysis under acidic
conditions (AcCl in MeOH) followed by reductive treatment
with NaBH4 (Scheme 5).
Scheme 5. Conversion of Lactam 2 to (()-Lepadiformine 1
In conclusion, the total synthesis of (()-lepadiformine was
achieved in 10 linear steps from cyclohexanone with an
overall yield of 15%. This synthesis is expected to be easily
amenable to the preparation of the enantiomerically pure
natural product by preparing the methylenecyclohexane 4
in optically pure form. Work in this direction will be reported
in due course. The stereochemical outcome of the carboazi-
dation step is also under investigation and strategies to
achieve a high level of stereocontrol are being developed.
intramolecular reductive amination leading to the bicyclic
azadecaline 9. In analogy to lepadiformine, we assume that
the trans-azadecalin prefers an unusual boat conformation
as depicted in Scheme 4 and is reduced from the less
hindered face anti to the axial CH2CH2CO2Et. After filtration
of the catalyst, the crude amine was treated with Me2AlCl
to promote lactamization, and the tricyclic lactam 2 was
obtained in a respectable 43% yield for the mixture of trans-
and cis-3 (72% yield based on pure trans-3).
Acknowledgment. We thank the Swiss National Science
Foundation (Project No. 20-103627) and the State Secretariat
for Education and Research (COST Action D28, Project No.
C03.0047) for financial support.
Supporting Information Available: Experimental pro-
cedures and product characterization for all compounds
mentioned in this paper. This material is available free of
charge via the Internet at http://pubs.acs.org.
The last part of the synthesis concerned the conversion of
the γ-lactam into a hydroxymethyl-substituted pyrrolidine.
OL060083+
(10) Takahata, H.; Takahashi, K.; Wang, E.-C.; Yamazaki, T. J. Chem.
Soc., Perkin Trans. 1 1989, 1211.
(11) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. Org. Synth.
1984, 62, 158.
(8) Kauffmann, T.; Abeln, R.; Welke, S.; Wingbergmu¨hle, D. Angew.
Chem. 1986, 98, 927.
(9) Panchaud, P.; Renaud, P. AdV. Synth. Catal. 2004, 346, 925.
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