Asymmetric Total Synthesis and Stereochemical Elucidation of the Antitumor Agent PM-94128

Article abstract of DOI:10.1021/ol035470n

(Equation presented) PM-94128, a novel depsipeptide antitumor agent, has been synthesized for the first time through a highly stereocontrolled route. The key steps for the synthesis of the dihydroxyamino acid moiety involve a diastereoselective addition of tert-butyl lithiopropiolate to a chiral nitrone and a 2,3-dihydro[1,2]oxazin-6-one dihydroxylation. The synthesis serves to define the relative as well as the absolute configuration of the natural product (bearing five stereogenic centers).

Full text of DOI:10.1021/ol035470n

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4081-4084
Asymmetric Total Synthesis and
Stereochemical Elucidation of the
Antitumor Agent PM-94128
Samir K. Patel, Karine Murat, Sandrine Py,* and Yannick Valle´e*
LEDSS, UMR 5616 CNRS, Institut de Chimie Mole´culaire de Grenoble - FR2607,
UniVersite´ Joseph Fourier, B.P. 53, 38041 Grenoble, France
sandrine.py@ujf-grenoble.fr
Received August 4, 2003
ABSTRACT
PM-94128, a novel depsipeptide antitumor agent, has been synthesized for the first time through a highly stereocontrolled route. The key
steps for the synthesis of the dihydroxyamino acid moiety involve a diastereoselective addition of tert-butyl lithiopropiolate to a chiral nitrone
and a 2,3-dihydro[1,2]oxazin-6-one dihydroxylation. The synthesis serves to define the relative as well as the absolute configuration of the
natural product (bearing five stereogenic centers).
In the course of a screening program for new antitumor
compounds, PM-94128 (1) was isolated in 1997 from the
culture broth of Bacillus sp. PhM-PHD-090, a bacterium
growing in marine sediment.1 This natural product, for which
neither the absolute nor the relative configuration was
elucidated, was shown to exhibit cytotoxic activity against
several tumor cell lines and to be an inhibitor of protein and
DNA synthesis.
As part of an ongoing program in our laboratories aimed
at designing stereocontrolled access to propargylic and allylic
amine derivatives,2 we became interested in synthesizing the
amino diol fragment 2 of PM-94128 from the propargylic
N-hydroxylamine 4 and coupling it with the aminodi-
hydroisocoumarin 3 in order to prepare the natural product
and determine its relative, as well as its absolute, configu-
ration (Scheme 1).
Aminodihydroisocoumarins have been reported to exhibit
a variety of biological activities.3 Among the most studied
of these natural products stands AI-77-B (5), a potent
gastroprotective agent for which several syntheses have been
described.4,5 As AI-77-B was also isolated from a bacterium
(3) See, for example: (a) Baciphelacin: Okazaki, H.; Kiski, T.; Beppu,
T.; Arima, K J. Antibiot. 1975, 28, 717-719. (b) Aminocoumacin: Itoh, J.;
Omoto, S.; Shomura, T.; Nishizawa, N.; Miyado, S.; Yuda, Y.; Shibata,
U.; Inouye, S. J. Antibiot. 1981, 34, 611-613. Itoh, J.; Omoto, S.; Shomura,
T.; Nishizawa, N.; Miyado, S.; Yuda, Y.; Shibata, U.; Inouye, S. Agric.
Biol. Chem. 1982, 46, 1255-1259. (c) Xenocoumacins: McInerney, B. V.;
Taylor, W. C.; Lacey, M. J.; Akhurst, R. J.; Gregson, R. P. J. Nat. Prod.
1991, 54, 785-795. (d) Y-05460M-A: Sato, T.; Nagai, K.; Suzuki, K.;
Morioka, M.; Saito, T.; Nohara, C.; Susaki, K.; Takebayashi, Y. J. Antibiot.
1992, 45, 1949-1952. (e) AI-77B: Shimojima, Y.; Hayashi, H.; Ooka, T.;
Shibukawa, M. Tetrahedron Lett. 1982, 23, 5535-5538. Shimojima, Y.;
Hayashi, H.; Ooka, T.; Shibukawa, M. Tetrahedron 1984, 40, 2519-2527.
(4) For total syntheses of AI-77-B, see: (a) Hamada, Y.; Kawai, A.;
Kohno, Y.; Hara, O.; Shioiri, T. J. Am. Chem. Soc. 1989, 111, 1524-1525.
(b) Broady, S. D.; Rexhausen, J. E.; Thomas, E. J. J. Chem. Soc., Chem.
Commun. 1991, 708-710. (c) Hamada, Y.; Hara, O.; Kawai, A.; Kohno,
Y.; Shioiri, T. Tetrahedron 1991, 47, 8635-8652. (d) Ward, R. A.; Procter,
G. Tetrahedron Lett. 1992, 33, 3359-3362. (e) Durgnat, J. M.; Vogel, P.
HelV. Chim. Acta 1993, 76, 222-240. (f) Ward, R. A.; Procter, G.
Tetrahedron 1995, 51, 12301-12318. (g) Broady, S. D.; Rexhausen, J. E.;
Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1999, 1083-1094. (h) Kotsuki,
H.; Tomohiro, A.; Miyazaki, A.; Datta, P. K. Org. Lett. 1999, 1, 499-502.
(i) Ghosh, A. K.; Bischoff, A.; Cappiello, J. Org. Lett. 2001, 3, 2677-
2680. (j) Ghosh, A. K.; Bischoff, A.; Cappiello, J. Eur. J. Org. Chem. 2003,
821-832.
(1) Canedo, L. M.; Fernandez Puentes, J. L.; Perez Baz, J.; Acebal, C.;
de la Calle, F.; Garcia Gravalos, D.; Garcia de Quesada, T. J. Antibiot.
1997, 50, 175-176.
(2) (a) Pandya, S. U.; Garc¸on, C.; Chavant, P. Y.; Py, S.; Valle´e, Y.
Chem. Commun. 2001, 18, 1806-1807. (b) Pinet, S.; Pandya, S. U.;
Chavant, P. Y.; Ayling, A.; Valle´e, Y. Org. Lett. 2002, 4, 1463-1466. (c)
Patel, S. K.; Py, S.; Pandya, S. U.; Chavant, P. Y.; Valle´e, Y. Tetrahedron:
Asymmetry 2003, 14, 525-528. (d) Pandya, S. U.; Pinet, S.; Chavant, P.
Y.; Valle´e, Y. Eur. J. Org. Chem. 2003, in press.
10.1021/ol035470n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/03/2003

Scheme 1. Retrosynthesis of PM-94128
of the Bacillus genus, we hypothesized that PM-94128 could
arise from a biogenetic process related to that for AI-77-B
and, hence, might likewise display “all (S)” configurations
at its stereogenic centers (Figure 1).
The synthesis of the proposed γ-amino-R,â-dihydroxy acid
fragment of PM-94128 was planned to involve direct
asymmetric addition of a 3C-synthon, such as a metallo-
propiolate, to a CdN bond, followed by transformation of
the adduct into a diol derivative. The synthesis of nitrone 9,
bearing a valinol-derived chiral auxiliary, started with
selective O-benzylation of valinol to give amine 7b (Scheme
2), which was oxidized to the corresponding hydroxylamine
8. This, in turn, condensed readily with isovaleraldehyde to
provide nitrone 9 in 49% overall yield (from (R)-valinol).
Although the addition of a variety of alkynes to chiral
nitrones had previously been successful using catalytic
Figure 1. Stereochemistry proposed for PM-94128.
Scheme 2
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Org. Lett., Vol. 5, No. 22, 2003

amounts of diethylzinc, the addition of propiolic esters to
nitrone 9 in this way failed.2c In searching for an effective
method to prepare the required γ-N-hydroxyamino-ynoate
with high diastereoselectivity, it was found that tert-butyl
lithiopropiolate smoothly added to nitrone 9 in THF at low
temperature (-78 °C) with excellent selectivity.6 Indeed, only
one diastereomer (10), displaying the desired 4S,2′R con-
figurations, was produced in this addition.
A single diol, 13, was obtained under these conditions in
83% yield. The configuration of the three new stereogenic
centers could be assigned from the X-ray analysis of the
protected diol 14.12 Starting from (R)-valinol, the obtained
oxazinone 14 was found to have the desired 2S, 3S, and 4S
stereocenters. The stereoselectivity of the dihydroxylation
is consistent with that previously reported with 1,2-oxazines
and results from reagent approach opposite to the isobutyl
group.8,5j
Controlled reduction of the triple bond to the correspond-
ing Z double bond was next necessary to set the stage for
dihydroxylation at C-2 and C-3. Selective hydrogenation of
the triple bond was performed using Pd/BaSO4 as the
catalyst, to yield exclusively the hydroxylamine 11a.7
The protected oxazinone 14 was next coupled with the
(3S,5′S)-aminodihydroisocoumarin hydrochloride salt 15
(Scheme 3), which was synthesized according to Kotsuki’s
Hydroxylamines are known to be highly sensitive to the
oxidants; thus, to avoid nitrone formation during the dihy-
droxylation step, protection was necessary.
Scheme 3
Cyclic protection could be conveniently realized in a two-
step sequence that involved acidic cleavage of the tert-butyl
ester,8 followed by dehydration-cyclization by refluxing the
resultant acid 11b in toluene.
Although dihydroxylation of 1,2-oxazines had previously
been described,5j,9 no examples were found involving the 2,3-
dihydro[1,2]oxazin-6-one system.10 To our delight, it was
found that Shing’s “flash dihydroxylation” conditions, using
a catalytic amount of ruthenium trichloride in the presence
of stoichiometric sodium metaperiodate, gave highly satisfac-
tory results in terms of both yield and diastereoselectivity.11
(5) For synthetic approaches to AI-77-B, see: (a) Kawai, A.; Hara, O.;
Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1988, 29, 6331-6334. (b) Gesson,
J. P.; Jacquesy, J. C.; Mondon, M. Tetrahedron Lett. 1989, 30, 6503-
6506. (c) Hamada, Y.; Kawai, A.; Matsui, T.; Hara, O.; Shioiri, T.
Tetrahedron 1990, 46, 4823-4846. (d) Kotsuki, H.; Miyazaki, A.; Ochi,
M. Chem. Lett. 1992, 1255-1258. (e) Kotsuki, H.; Iwasaki, M.; Ochi, M.
Heterocycles 1994, 38, 17-20. (f) Shinozaki, K.; Mizuno, K.; Masaki, Y.
Heterocycles 1996, 43, 11-14. (g) Superchi, S.; Minutolo, F.; Pini, D.;
Salvadori, P. J. Org. Chem. 1996, 61, 3183-3186. (h) Mukai, C.; Miyakawa,
M.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1997, 913-917. (i) Ghosh,
A. K.; Cappiello, J. Tetrahedron Lett. 1998, 39, 8803-8806. (j) Davies,
G.; Russell, A. T. Tetrahedron Lett. 2002, 43, 8519-8522.
(6) A full account on the asymmetric addition of metallopropiolates to
chiral nitrones will be published separately.
(7) Reduction of 10 was initially performed in the presence of Zn (MeOH/
AcOH, 9:1, 60 °C, see: Dagoneau, C.; Denis, J. N.; Valle´e, Y. Synlett 1999,
5, 602-604) to yield the corresponding Z-γ-amino enoate. However, no
dihydroxylation of the latter could be achieved using OsO4, or AD-Mix, or
KMnO4. Carbamoylation to reduce the coordinating ability of the nitrogen
(which was thought to be hampering the dihydroxylation) was attempted
but was unsuccessful.
(8) The use of Et3SiH in the tert-butyl ester acidolysis proved necessary;
complex mixtures were obtained in the absence of this hydride source. See:
Mehta, A.; Jaouhari, R.; Benson, T. J.; Douglas, K. T. Tetrahedron Lett.
1992, 33, 5441-5444.
method.4h The coupling was performed in the presence of
Me3Al with 3.5 equiv of the salt 15, in 62% yield.13 Attempts
to open oxazinone 14 with only 1.5 equiv of 15 in the
presence of sodium 2-ethylhexanoate14 gave only very poor
yields of the desired product.
Removal of the chiral auxiliary involved concomitant
hydrogenolysis of the O-benzyl and the N-O bonds,
followed by oxidative amino alcohol cleavage using Pb(OAc)4,
which provided the free amine.15
(9) (a) McClure, K. F.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 850-
853. (b) Defoin, A.; Pires, J.; Streith, J. HelV. Chim. Acta 1991, 74, 1653-
1670. (c) Defoin, A.; Pires, J.; Tissot, I.; Tschambert, T.; Bur, D.; Zehnder,
M.; Streith, J. Tetrahedron: Asymmetry 1991, 2, 1209-1221. (d) Behr, J.-
B.; Defoin, A.; Mahmood, N.; Streith, J. HelV. Chim. Acta 1995, 78, 1166-
1177. (e) Bach, P.; Bols, M. Tetrahedron Lett. 1999, 40, 3461-3464. (f)
Davies, G.; Russell, A. T.; Sanderson, A. J.; Simpson, S. J. Tetrahedron
Lett. 1999, 40, 4391-4394. (g) Zimmer, R.; Homann, K.; Angerrmann, J.;
Reissig, H.-U. Synthesis 1999, 1223-1235. (h) Arribas, C.; Carreno, M.
C.; Garcia-Ruano, J. L.; Rodriguez, J. F.; Santos, M.; Sanz-Tejedor, M. A.
Org. Lett. 2000, 2, 3165-3168.
(10) Model studies on dihydroxylation with N-benzyl-2,3-dihydro-3-
isobutyl[1,2]oxazin-6-one showed that typical conditions (cat. OsO4, NMO,
acetone/H2O, or KMnO4, 18-cr-6, CH2Cl2) gave unsatisfactory results.
(11) (a) Shing, T. K. M.; Tai, V. W. F.; Tam, E. K. W. Ang. Chem. Int.
Ed. 1994, 33, 2312-2313. (b) Shing, T. K. M.; Tam, E. K. W. Tetrahedron
Lett. 1999, 40, 2179-2180.
(12) See the Supporting Information.
(13) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am. Chem. Soc.
2000, 122, 2995-3000.
(14) Liu, W.; Xu, D. D.; Repic, O.; Blacklock, T. J. Tetrahedron Lett.
2001, 42, 2439-2441.
Org. Lett., Vol. 5, No. 22, 2003
4083

Deprotection of the vicinal hydroxyl groups was then
accomplished in 3% methanolic HCl to afford cleanly
compound 6 (mp 170-171 °C; [R]20D -90.1, c 2.00, CHCl3),
culins,16 which are potent phosphatase inhibitors that exhibit
antitumor activity.
Acknowledgment. We are grateful to Dr. L. M. Canedo
for kindly providing the NMR spectra of the authentic natural
product. Drs. C. Philouze and A. Durif are thanked for
performing the X-ray analysis of compound 14. This work
was supported by the CNRS and the Universite´ Joseph
Fourier.
1
which provided H and 13C spectra identical with those of
the naturally derived product (mp 172-173 °C; [R]25D -88.9,
c 2.00, CHCl3).1
In conclusion, an efficient and totally stereocontrolled
synthesis of PM-94128, the first of this natural product, has
allowed assignment of its stereochemistry. The method used
to prepare the dihydroxyamino acid part of PM-94128 can
also be applied for the synthesis of other γ-amino-R,â-
dihydroxy acid derivatives, such as AI-77-B or the caly-
Supporting Information Available: Experimental pro-
1
cedures and full characterization for compounds 6-16, H
NMR and 13C NMR spectra for compounds 6-16 and for
the naturally derived sample of PM-94128, and crystal-
lographic data for compound 14. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Gawley, R. E.; Rein, K.; Chemburkar, S. J. Org. Chem. 1989, 54,
3002-3004.
(16) Smith, A. B., III; Friestad, G. K.; Barbosa, J.; Bertounesque, E.;
Hull, K. G.; Iwashima, M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan,
J. J.-W. J. Am. Chem. Soc. 1999, 121, 10468-10477 and references therein.
OL035470N
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