Stereoselective formal synthesis of pseudodistomin C.

Article abstract of DOI:10.1021/ol010221p

[reaction: see text] Trisubstituted benzenesulfonylmethylpiperidine 4, in which the substituents are all cis to each other, is a direct synthetic precursor of the cytotoxic marine alkaloid pseudodistomin C; it has been synthesized with total diastereosele

Full text of DOI:10.1021/ol010221p

ORGANIC
LETTERS
2002
Vol. 4, No. 2
185-187
Stereoselective Formal Synthesis of
Pseudodistomin C
†
Nicole Langlois
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France
nicole.langlois@icsn.cnrs-gif.fr
Received October 4, 2001
ABSTRACT
Trisubstituted benzenesulfonylmethylpiperidine 4, in which the substituents are all cis to each other, is a direct synthetic precursor of the
cytotoxic marine alkaloid pseudodistomin C; it has been synthesized with total diastereoselectivities from (S)-pyroglutaminol.
Six members of the pseudodistomin family have been
described so far.1-3 Pseudodistomins A (1) and B (2) were
the first piperidine alkaloids isolated from marine organisms.
Pseudodistomin C (3) has been extracted from the Okinawan
tunicate Pseudodistoma kanoko along with 1 and 2 and was
shown to possess the absolute configuration 4S,5R, opposite
to those of 1 and 2.2 Pseudodistomin C exhibits in vitro
cytotoxicity against murine lymphoma L1210 and human
epidermoid carcinoma KB cells.4
Only one total synthesis of this biologically active product
has been achieved by Kobayashi et al. from D-serine derived
Garner’s aldehyde (Scheme 1).5 In this synthesis, however,
the key intermediates 4 and 5 are obtained with poor
diastereo- and enantioselectivities (dr 1.5:1 and ee 60%,
respectively), and only a few syntheses of all cis N-protected
2,4,5-trisubstituted piperidines have been reported.6
Thus, a diastereo- and enantioselective synthesis of either
4 or 5 was planned through 4-hydroxy-5-N-tert-butoxycar-
bonylaminopiperidin-2-one 6.7
Three different ways to this obviously promising inter-
mediate 6 were investigated from the bicyclic epoxide 7 or
Scheme 1
† Dedicated to the late Professor H. Nakamura.
(1) (a) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata,
Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450-453. (b) Ishibashi, M.;
Deki, K.; Kobayashi, J. J. Nat. Prod. 1995, 58, 804-806.
(2) Kobayashi, J.; Naitoh, K.; Doi, Y.; Deki, K.; Ishibashi, M. J. Org.
Chem. 1995, 60, 6941-6945.
(3) Freyer, A. J.; Patil, A. D.; Killmer, L.; Troupe, N.; Mentzer, M.;
Carte, B.; Faucette, L.; Johnson, R. K. J. Nat. Prod. 1997, 60, 986-990.
(4) (a) Kobayashi, J.; Ishibashi, M. Heterocycles 1996, 42, 943-970.
(b) Ninomiya, I., Kiguchi, T.; Naito, T. The Alkaloids 1998, 50, 317-342.
(5) Doi, Y.; Ishibashi, M.; Kobayashi, J. Tetrahedron 1996, 52, 4573-
4580.
(6) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009-6016.
10.1021/ol010221p CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/20/2001

from its derived secondary alcohol 8 prepared from (S)-
pyroglutaminol,8,9 as summarized in the Scheme 2.
Scheme 3a
Scheme 2
a (a) Me2C(OMe)2,TsOH, acetone (95%); (b) (Boc)2O, DMAP,
MeCN (82%); (c) Cp2Ti(Me)2, 99:1 toluene/pyridine (86%).
H-7 and H-4 (<3.3 Hz) are consistent with a boat conforma-
tion of the molecule which was confirmed by X-ray
analysis.14
Introduction of the hydroxymethyl group at C-6 present
in compound 5 was initially envisaged by submitting an
exomethylene derivative such as 15 to a diastereoselective
hydroboration-oxidation reaction.15 However, despite pre-
cautions to avoid isomerization of the created double bond,
treatment of lactam 13 with bis(cyclopentadienyl)dimeth-
According to the most efficient route (c), alcohol 8 was
converted first into methanesulfonate ester 9 as previously
described.10 Subsequent displacement of the mesylate by
sodium azide in DMF afforded 10 in 90% yield. The
reduction of the azido group (H2-Pd/C 10%) giving 11 was
followed by heating in methanol at 65 °C for 24 h. Under
these conditions, an intramolecular transamidation11 of the
primary amine was favored by the presence of the N-tert-
butoxycarbonyl group in pyrrolidinone 11. Indeed, N-
protecting carbamates are known to enhance the reactivity
of the lactamic carbonyl12 and translactamization occurred
quantitatively, leading to the stable piperidin-2-one 6. Thus,
an effective route to this cis-4,5-disubstituted piperidin-2-
one was established. With the key intermediate 6 in hand,
the introduction of suitable functionalization at C-2 in a cis
relationship with C-4 and C-5 substituents was attempted,
after convenient protections. Accordingly, the hydroxy and
N-tert-butoxycarbonylamino groups were simultaneously
protected as oxazolidine 12 in excellent yield (95%) with
2,2-dimethoxypropane and TsOH; then 12 was treated in
acetonitrile with di-tert-butyl dicarbonate in the presence of
DMAP,13 giving rise to (3aR,7aS)-2,2-dimethyl-6-oxoper-
hydrooxazolo[4,5-c]pyridine-3,5-dicarboxylic acid di-tert-
1
yltitanium16 provided only compound 14 (86%). The H
NMR spectrum of 14 is consistent with an endocyclic
unsaturated compound, and the easy formation of the endo-
enecarbamate prevented this synthetic route from being
carried out. As an alternative, the conversion of piperidinone
6 into the advanced phenyl sulfone precursor 4 was
investigated as shown in the Scheme 4.
Scheme 4a
1
butyl ester 13 (82%, Scheme 3). In the H NMR spectrum
of 13, the small vicinal coupling constants J7,7a and J3a,4 of
a (a) PhSO2CH2Li, THF; (b) H2/Pd(OH)2, MeOH; (c) (Boc)2O,
NaHCO3, THF-H2O.
(7) Preliminary communication: Langlois, N. 10th International Sym-
posium on Marine Natural Products, Nago, Okinawa, Japan, June 24-29,
2001.
(8) Panday, S. K.; Langlois, N. Synth. Commun. 1997, 27, 1373-1384.
(9) Langlois, N.; Calvez, O. Tetrahedron Lett. 2000, 8285-8288.
(10) Langlois, N. Tetrahedron Lett. 2001, 42, 5709-5711.
(11) (a) Holley, R. W.; Holley, A. D. J. Am. Chem. Soc. 1952, 74, 3069-
3074. (b) Kramer, U.; Guggisberg, A.; Hesse, M.; Schmid, H. Angew. Chem.,
Int. Ed. 1977, 861-862 and references therein. (c) Langlois, N. International
meeting, 40th Anniversary Faculty of Science, Antananarivo, Madagascar,
September 18-28, 2000.
The opening of N-alkoxycarbonyl or N-trimethylsilyl
lactams with organometallic reagents is well documented.17
(14) Chiaroni, A. et al., to be published.
(15) (a) Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1993, 4, 2085-
2094. (b) Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1997, 8, 1115-
(12) Langlois, N.; Moro, A. Eur. J. Org. Chem. 1999, 3483-3488.
(13) Hansen, M. M.; Harkness, A. R.; Loffey, D. S.; Bordwell, F. G.;
Zhao, Y. Tetrahedron Lett. 1995, 36, 8949-8952.
1121.
(16) Petasis, N. A.; Bzowej; E. I. J. Am. Chem. Soc. 1990, 112, 6392-
6394.
186
Org. Lett., Vol. 4, No. 2, 2002

Generally, pyrrolidin-2-one tert-butyl carbamates react with
Grignard reagents at low temperature, providing the corre-
sponding acyclic ketones or cyclic R-hydroxycarbamates in
good yields.17b However, few literature examples of the use
of (benzenesulfonyl)methylmagnesium bromide18 could be
found although effective nucleophilic additions to aldehydes
have been described.19 The experimentation started with
(benzenesulfonyl)methyllithium and with the N-benzyloxy-
carbonyl valerolactam 16 as a model. This N-protecting group
was chosen at this stage to allow a further selective
deprotection with polysubstituted piperidinone 6 derivatives.
Treatment of 16 with (benzenesulfonyl)methyllithium in THF
at -76 °C afforded 17 (68%) without attack of the benzyl-
oxycarbonyl group.20 Compound 17 was slowly but cleanly
converted under H2 (Pd/C 10%) into piperidine 18, which
was further protected (96%) as the known 1-tert-butoxycar-
bonyl-2-(benzenesulfonyl)methylpiperidine 19 for compari-
son purposes,21 and the same scheme was applied to 12
(Scheme 4). Accordingly, piperidinone 12 was N-protected
with benzylchloroformate to 20 (75%), which adopts the
same boat conformation as 13 according to the similarities
in their 1H NMR spectra. Treatment of 20 with PhSO2CH2-
Li at -76 °C afforded the corresponding ketone 21, in a
modest unoptimized 41% yield. In this case, the formation
of 12 (19%) by attack of the benzyloxycarbonyl group was
also observed. N-deprotection of 21, cyclization to the imine
intermediate, and subsequent reduction were performed in
one step with H2 in the presence of Pearlman’s catalyst,
which gave better results than Pd/C, affording the expected
all cis-trisubstituted piperidine 22 (76%) with total stereo-
selectivity. The previously described N-Boc derivative 4 was
obtained in 97% yield; it has been shown to lead to
pseudodistomin C 3, after Julia olefination and classical
deprotections.5
In conclusion, this work constitutes a valid completely
diastereoselective route, not only to natural pseudodistomin
C 3 itself but also to structural analogues containing other
olefinic side chains, to evaluate their biological activities.
Acknowledgment. The author is grateful to Professor
Jun’ichi Kobayashi for the MS and NMR spectra of 4, to
Jean-Franc¸ois Gallard for recording the NMR spectra, and
to Ange`le Chiaroni for X-ray analysis of 13.
(17) For selected references, see: (a) Street, J. D.; Harris, M.; Bishop,
D. I.; Heatley, F.; Beddoes, R. L.; Mills, O. S.; Joule, J. A. J. Chem. Soc.,
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S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo, A. A. J. Org. Chem. 1990,
55, 3682-3684. (e) Li, H.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett.
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Soc., Perkin Trans. I 1999, 1193-1200.
(18) Field, L. J. Am. Chem. Soc. 1956, 78, 92-97 and references therein.
(19) (a) Kim, K. S.; Ahn, Y. H.; Park, S. B.; Cho, I. H.; Joo, Y. H.;
Youn, B. H. J. Carbohydr. Chem. 1991, 10, 911-915. (b) Doi, T.;
Robertson, J.; Stork, G.; Yamashita, A. Tetrahedron Lett. 1994, 35, 1481-
1484.
Supporting Information Available: Experimental pro-
cedures for the synthesis of 4 and spectroscopic data for all
intermediates. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL010221P
(20) For ring opening of N-benzyloxycarbonyl-â-lactams, see: Baldwin,
J. E.; Adlington, R. M.; Russel A. T.; Smith, M. L. Tetrahedron 1995, 51,
4733-4762.
(21) (a) Ridley, D. D.; Simpson G. W. Austr. J. Chem. 1986, 39, 687-
698. (b) Hart, D. J.; Li, J.; Wu, W.-L.; Kozikowski, A. P. J. Org. Chem.
1997, 62, 5023-5033.
Org. Lett., Vol. 4, No. 2, 2002
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