Asymmetric synthesis of the C1-C6 portion of the psymberin using an Evans chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2013.05.153

The C1-C6 region of the potent cytotoxic agent psymberin has been synthesized. The key transformations of the synthesis are an auxiliary-controlled addition of a Sn(II)-glycolate enolate to an aldehyde to yield the anti-aldol product and transforming the

Full text of DOI:10.1016/j.tetlet.2013.05.153

Tetrahedron Letters 54 (2013) 5555–5557
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Tetrahedron Letters
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Asymmetric synthesis of the C1–C6 portion of the psymberin using
an Evans chiral auxiliary
⇑
Ashutosh Pal, Zhenghong Peng, Paul T. Schuber Jr., Basvoju A. Bhanu Prasad, William G. Bornmann
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The C1–C6 region of the potent cytotoxic agent psymberin has been synthesized. The key transformations
of the synthesis are an auxiliary-controlled addition of a Sn(II)-glycolate enolate to an aldehyde to yield
the anti-aldol product and transforming the primary alcohol into a terminal olefin utilizing organosele-
nium chemistry.
Received 16 May 2013
Accepted 29 May 2013
Available online 10 June 2013
Ó 2013 Published by Elsevier Ltd.
Keywords:
Psymberin
Pederin
Synthesis
Chiral
Auxiliary
Stereochemical
Introduction
the syntheses of all four stereoisomers of psymberic acid and com-
parison of the acid mediated cyclization products of these isomers
In 2004, two groups independently reported the isolation and
structural elucidation of a constitutionally identical acyl aminal 1
(Fig. 1). Pettit1 isolated the extremely potent toxin from the South
Pacific sponge Ircinia ramose whereas Crews2 and co-workers also
obtained the acyl aminal 1 from the crude extracts of an inconspic-
uous sponge, psammocinia sp., located from the waters of Papua
New Guinea. The Pettit group named the compound as irciniastatin
A and the Crews group named it as psymberin on the basis of its
proposed biogenesis from symbiotic bacteria.3
to the product of psymberin’s acidic methanolysis. Later De Brab-
ander and co-workers7 and Huang et al.8 synthesized and made a
complete stereochemical assignment of psymberin with an S-con-
figuration at C4 and they concluded that psymberin and irciniast-
atin A were structurally identical. Other synthetic approaches to
psymberin were attempted by Smith et al.,9 Crimmins10 as well
as an interesting approach to the amide side chain by Iwabuchi
and co-workers.11 Recently Smith and co-workers12 and De Brab-
ander and co-workers13 have also developed a second generation
synthesis of this family of natural products.
Psymberin also displays some unique biological activity which
was discovered at the SCI Development Therapeutic in vitro
Screening Program. Psymberin displayed exceptional cytotoxicity
below 2.5 nM against one colon cell cancer line (HCT-116) three
melanoma (MALME-3M, SK-MEL-5, and UACCC-62) and a breast
(MDA-MB-435) cancer cell line.2,14 Recently De Brabander has re-
vealed some fascinating structure–activity relationships (SAR) as
well as biochemical studies suggesting that psymberin may have
more than one biological function.15 These interesting structural
features as well as the interesting biological activity render this
compound a synthetic target.
Psymberin most closely resembles the pederin family4 of natu-
ral products defined by the presence of a functionalized cyclic
ether derivative, but psymberin is unique to the pederin family
(Fig. 1) because of the presence of a highly substituted dihydroiso-
coumarin moiety as well as a terminal six carbon amide append-
age. The configuration of the amide side chain of psymberin and
irciniastatin, was previously reported. Initially the stereochemical
assignment at the C4 position and the 5S configuration was pro-
posed based on the analogy to other natural products in the peder-
in family. Recently, William’s and co-workers5 reported the
stereochemical assignment of the C1–C6 region using 1H and 13C
NMR chemical shift homology and a corroborating X-ray crystal
structure. They postulated that the stereocenters at C4 and C5 have
an anti-relationship. Floreancig and co-workers6 established the
stereochemical configuration of this fragment to be the 4S, 5S by
Results and discussions
Here we report the synthesis of anti-isomer of methyl ester of
psymberic acid (C1–C6 fragment) 4 using the auxiliary-controlled
aldol addition of Sn(II)-glycolate enolate of 8 to aldehyde 7 as a
⇑
Corresponding author. Tel.: +1 713 563 0081; fax: +1 713 563 1878.
E-mail address: wbornmann@mdanderson.org (W.G. Bornmann).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.05.153

5556
A. Pal et al. / Tetrahedron Letters 54 (2013) 5555–5557
Me
OMe
O
OMe
O
10
13
OH
6
N
H
3
1
Me
Me
OH
Me
20
Me
OH
1
18
C1-C6 fragment
OH
16
25
O
24
O
OH
Psymberin
OMe
OMe
O
OH
Me
Me
Me
OH
O
OH
O
Me
H
N
H
N
MeO
O
MeO
O
Me
Me
Me
Me
OH
OMe
O
OMe
O
O
O
2
3
Theopederin A
Prderin
Figure 1. Structure of psymberin and representative acylaminal-containing cytotoxic agents.
O
OMe
OMe
O
Me
Me
controlled addition reaction between aldehyde 7 and
ated amide derivative 8.
The key bond forming reaction to obtain the anti-selectivity at
the C4 and C5 positions on the amide side chain was achieved by
an Evan’s aldol reaction. The acylated oxazolidinone 8 was sub-
jected to the Evans Sn(II) glycolate enolate protocol using aldehyde
a-oxygen-
OMe
OMe
OH
OH
OH
4
5
Me
N
Me
N
Me
Me
O
O
Me
OH
Me
7 and a-oxygenated amide derivative 8 to yield the anti aldol prod-
+
uct 6 in 60% yield (Scheme 2). The stereochemical rational for the
selectivity of the reaction remains to be unclear.17 However,
Mukaiyama et al. postulate that in this reaction the product equil-
ibration is slow. They assume the stereochemical outcome is deter-
mined by the possible binding of TMEDA to the divalent tin
enolate. This binding of TMEDA will change the coordination
geometry of tin from tetragonal to octahedral and possibly favor
a boat like transition state over the traditional chair transition
state.17,18
The aldehyde 7 was accessed from ozonolysis of alkene 11,
which was generated from ethyl-2-methyl 4-pentenoate 9 by a
LAH reduction followed by PMB protection of the resulting alcohol
10 by 4-methoxybenzyl chloride. The amide 6 was obtained by a
previously reported procedure by Evans et al. with benzyloxy acet-
yl chloride.19 Having the diastereomer 6 in hand, attention was
turned to implicate several methods to protect the free hydroxy
group in presence of the amide auxiliary. However, yields were
insufficient and the starting material could not be recovered.
Therefore, the chiral auxiliary was first removed with lithium
hydroxide and hydrogen peroxide to obtain the free acid. The acid
was immediately converted to methyl ester 12 by treating with
diazomethane, which was subsequently o-methylated with methyl
trifluoromethanesulfonate to provide methyl ether 13 (88% ee).
Deprotection of the benzyl and PMB protecting groups under pal-
ladium-catalyzed hydrogenation provided compound 5. The pri-
mary alcohol was selectively converted to the primary selenide
using the protocol developed by Grieco et al.16 in presence of the
secondary alcohol. Treatment of alcohol 5 with 2-nitrophenylse-
lenocyanate and tributyl phosphine gave the intermediate selenide
O
OBn
OBn
OPMB
OPMB
O
O
O
O
6
7
8
Scheme 1. Retrosynthetic analysis.
key reaction. Though psymberin belongs to the pederin family of
natural products, psymberin 1 has distinct structural features from
other members of the pederin family. For example, psymberin
contains a six carbon amide side chain and a dihydroisocoumarin
subunit and a structurally less-complex acyclic side chain. In this
work, our synthetic strategy was to prepare anti configuration of
methyl ester of psymberic acid and to compare methyl esters
spectral data with the reported spectral data for the amide side
chain of 1. Notable features of this synthetic strategy include the
implementing
a
modified protocol developed by Grieco17 to
transform the primary alcohol to an olefin in the presence of a
secondary alcohol as well as the application of Evans auxiliary-
controlled addition reaction to obtain the anti diastereoselective
fragment 6.
Retrosynthetically, psymberic ester 4 can arise from diol 5 by
selective elimination of the primary alcohol over the secondary
alcohol developed by Grieco et al.16 (Scheme 1). The diol can arise
from 6 through a three step reaction sequence which included: re-
moval of the chiral auxiliary, esterification followed by hydrogena-
tion. The anti diastereomer 6 is the predicted product of an
asymmetric aldol addition reaction using Evans auxiliary-

A. Pal et al. / Tetrahedron Letters 54 (2013) 5555–5557
5557
Me
Me
Me
O3, CH2Cl2, -78 °C, 3 h
then, Me2S, -78 °C to rt, 12 h
Me
NaH, PMBCl, THF
LiAlH4, Et2O
EtO
O
90 °C, 16 h
68%
0 °C- rt, 18 h
80%
O
OH
OPMB
11
OPMB
40%
9
10
O
7
1. LiOH, H2O2
THF:H2O (5:1), 0 °C, 3 h
2. CH2N2, Et2O, 0 °C, 1 h
Me
N
Me
O
8
Me
OH
O
, Sn(OTf)2, Et3N
CH2Cl2, TMEDA
Me
OH
12
MeOTf, 2,6-di-tert-butylpyridine
CH2Cl2, 0 °C, 12 h
OMe
-78 °C, 4 h
60%
OBn
OPMB
OBn
OPMB
62%
75%
O
6
1. o-NO2C6H4SeCN
n-Bu3P, 12 h
2. H2O2, THF, 12 h
O
O
Me
OMe
Me
OMe
OMe O
Me
10% Pd/C, H2
EtOAc, rt, 12 h
OMe
OMe
OMe
OBn
OH
OH
OPMB
OH
88%
64%
13
5
4
Scheme 2. Synthesis of C1–C6 portion of psymberin.
which was immediately oxidized with hydrogen peroxide to give
References and notes
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Conclusion
In conclusion, we have developed a viable strategy for the for-
mation of chiral C1–C6 region of the psymberin side chain using
Evan’s chiral auxiliary. The synthesis was completed in 10 linear
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Acknowledgments
This work was carried out with the startup funds to William G.
Bornmann from the University of Texas M D Anderson Cancer Cen-
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assistance and encouragement.
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Supplementary data
Supplementary data associated (1H and 13C NMR spectra of all
new compounds) with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.05.153.
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