Total synthesis of the proposed structure of lepadiformine via intramolecular N-acylnitroso Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(99)02172-3

A stereocontrolled approach to the proposed structure of lepadiformine has been achieved employing an intramolecular hetero Diels-Alder reaction of an N-acylnitroso compound, in which syn-face selectivity was controlled. The NMR data of the product synthesized based on this approach is not identical with those reported for natural lepadiformine. Thus, the proposed structure for natural lepadiformine must be revised. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02172-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1205–1208
Total synthesis of the proposed structure of lepadiformine via
intramolecular N-acylnitroso Diels–Alder reaction
Hideki Abe, Sakae Aoyagi and Chihiro Kibayashi ∗
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 21 October 1999; revised 11 November 1999; accepted 12 November 1999
Abstract
A stereocontrolled approach to the proposed structure of lepadiformine has been achieved employing an
intramolecular hetero Diels–Alder reaction of an N-acylnitroso compound, in which syn-face selectivity was
controlled. The NMR data of the product synthesized based on this approach is not identical with those reported
for natural lepadiformine. Thus, the proposed structure for natural lepadiformine must be revised. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: alkaloids; cytotoxines; nitroso compounds; cycloaddition.
In 1994, Biard and co-workers1 published a report on the isolation and structure elucidation of
lepadiformine (1), a new marine alkaloid from the ascidian Clavelina lepadiformis collected in Tunisia.
It was found to be moderately cytotoxic toward various tumor cell lines in vitro. Its structure including
a unique zwitterionic form was assigned based on spectral analysis, though the absolute configuration
was still unknown. Lepadiformine and related marine alkaloids cylindricines (2–9),2 also isolated from
the ascidians, are azatricyclic compounds possessing a perhydropyrrolo[2,1-j]quinoline skeleton as a
common structural feature unprecedented among natural products. These alkaloids have attracted consid-
erable synthetic attention, and the development of new ring-forming reactions aimed at constructing the
pyrroloquinoline framework has been the major subject of recent synthetic efforts.3 In view of this, we
envisioned the stereoselective construction of the azatricyclic structure 1 proposed for lepadiformine by
employing the strategy involving an intramolecular hetero Diels–Alder cycloaddition of an N-acylnitroso
compound.4,5
∗
Corresponding author. Fax: +0081-426-764475; e-mail: kibayasi@ps.toyaku.ac.jp (C. Kibayashi)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02172-3
tetl 16100

1206
The ketone 10 was subjected to Horner–Emmons olefination followed by DIBALH reduction of the
cyano group to give the α,β-unsaturated aldehyde 11 in 86% yield as a 16:1 E/Z mixture favoring the
E-isomer (Scheme 1). Addition of bromine to this mixture and subsequent regioselective dehydrobro-
mination led to the α-bromo-α,β-unsaturated aldehyde, which underwent Horner–Emmons olefination
followed by DIBALH reduction and chromatographic separation to afford the (Z)-bromodiene 12 in 33%
overall yield. Conversion of 12 to the carboxylic acid 13 was carried out in 56% overall yield by the
Scheme 1.

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following four-step sequence: O-benzylation, removal of the MOM protective group, Swern oxidation,
and oxidation of the resulting aldehyde with sodium chlorite. Esterification of 13 with diazomethane
followed by treatment with hydroxylamine provided the hydroxamic acid 14 (66% yield), which was
treated with Pr4NIO4 in a CHCl3 solution at room temperature in order to allow the acylnitroso diene 15
generated in situ to undergo intramolecular cycloaddition; however, although the TLC analysis revealed
that the starting material disappeared within 20 min, the reaction produced only a poor yield (8%) of the
cycloadducts 18 and 19 in a 2.6:1 ratio, although the desired cis-fused cycloadduct 18 was predominantly
formed (Scheme 1). Neither prolonging the reaction time at room temperature nor heating at reflux
temperature improved the yield of the cycloadducts; in the latter case rapid decomposition of the substrate
resulted. The poor yield in this cyclization would be attributed to a significant decrease of the reactivity
of the acylnitroso compound 15 due to the attachment of an electron-withdrawing bromine atom to the
diene moiety. The sluggish nature of the cycloaddition reaction in this case would lead to decomposition
of the in situ generated 15 with properties associated with the RCO–N_O species, namely, they are
extremely labile and short-lived.5a To overcome these problems, including the inherent disadvantage
of the acylnitroso compounds, we sought to utilize the 9,10-dimethylanthracene adduct 16 which was
considered to be a stable acylnitroso equivalent.5a,6 Thus, upon exposure of 14 to the same oxidation
conditions in the presence of 9,10-dimethylanthracene, intermolecular cycloaddition reaction smoothly
proceeded to form the adduct 16 in 84% yield. Thermolysis of 16 in refluxing benzene caused a retro
Diels–Alder reaction to regenerate the intermediate acylnitroso diene 15, which immediately underwent
intramolecular cycloaddition under the reaction conditions, affording the cycloadducts 18 and 19 in 75%
yield and in a 5.5:1 ratio. The preference for the formation of the desired B/C cis-fused adduct 18 can be
rationalized on the basis of a syn-facial transition state 17A with a preferred adoption of an axial position
of the tethering 2-alkyl side chain, which avoids the 1,3-allylic strain with the bromine atom.7
After catalytic hydrogenation of the diastereomeric mixture of the cycloadducts 18 and 19 in the
presence of Et3N, the B/C cis-fused isomer 20 was chromatographically separated in 63% yield (Scheme
2). Reductive N–O bond cleavage of 20 using sodium amalgam to give the 1,2-diol 21 in excellent
yield, which was converted to the epoxide 22 in 65% yield via selective mesylation of the primary
hydroxyl group was followed by alkaline treatment. Treatment of 22 with NaH in refluxing THF
caused intramolecular epoxide opening, producing the perhydropyrroloquinolone 23 in 87% yield. After
protection of the hydroxyl group as a MOM ether, 24 underwent reductive ring-opening of the lactam
using LiH2NBH3,8 followed by N-protection to provide the azaspiro compound 25 in 78% yield from 24.
Swern oxidation of 25 and subsequent addition of hexylmagnesium bromide followed by PCC oxidation
afforded the ketone 26 in 66% overall yield. Cyclization of 26 could be successfully performed under
catalytic hydrogenation conditions (H2, Pd–C, EtOH) to produce 289 as a single isomer in 77% yield.
The preferential formation of this diastereomer can be explained by invoking an iminium intermediate
27 in which hydrogenation should occur on the less hindered α face.
Finally, removal of the MOM protecting group from 28 under methanolic HCl conditions provided the
aminoalcohol in 95% yield, possessing the stereostructure proposed for lepadiformine, which was found
to exist in a non-zwitterionic form as 29. The spectral properties (1H and 13C NMR) for both the free
base and hydrochloride salt of the synthetic material, however, were not identical with those reported1
for natural lepadiformine. While our work was in progress, Weinreb et al.10 reported the synthesis of
the putative structure 29 of lepadiformine and found their synthetic material to be different from natural
lepadiformine. At the same time, Pearson and Ren11 described the syntheses of the remaining three of
the four diastereoisomers of 29 at C-3 and C-5; however, none of these four compounds was found to
be compatible with lepadiformine. These findings as well as our result clearly suggest that the originally
proposed structure of natural lepadiformine requires revision.

1208
Scheme 2.
References
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nitrogen-containing natural products, see: Kibayashi, C.; Aoyagi, S. Synlett 1995, 873–879.
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7. When the cycloaddition was performed using the hydroxamic acid lacking a bromine atom, the preferential formation of the
B/C trans-fused adduct via an anti-facial transition state was observed (unpublished result).
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