An efficient total synthesis of the anticancer agent (+)-spisulosine (ES-285) from Garner's aldehyde

Article abstract of DOI:10.1016/j.tetlet.2010.05.146

An efficient total synthesis of (+)-spisulosine (ES-285) was completed in nine steps from (S)-Garner's aldehyde. The vicinal amino alcohol moiety with anti-configuration was achieved by a highly diastereoselective addition of vinyl magnesium bromide to Garner's aldehyde. The long hydrocarbon chain of the antitumor natural product was installed via olefin cross metathesis of the benzyl-protected allylic alcohol with an appropriate olefin counterpart followed by hydrogenation.

Full text of DOI:10.1016/j.tetlet.2010.05.146

Tetrahedron Letters 51 (2010) 4140–4142
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Tetrahedron Letters
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An efficient total synthesis of the anticancer agent (+)-spisulosine (ES-285)
from Garner’s aldehyde
*
Partha Ghosal, Arun K. Shaw
Division of Medicinal and Process Chemistry, Central Drug Research Institute (CDRI), CSIR, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient total synthesis of (+)-spisulosine (ES-285) was completed in nine steps from (S)-Garner’s
aldehyde. The vicinal amino alcohol moiety with anti-configuration was achieved by a highly diastereo-
selective addition of vinyl magnesium bromide to Garner’s aldehyde. The long hydrocarbon chain of the
antitumor natural product was installed via olefin cross metathesis of the benzyl-protected allylic alcohol
with an appropriate olefin counterpart followed by hydrogenation.
Received 28 April 2010
Revised 28 May 2010
Accepted 29 May 2010
Available online 2 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Natural products have played a prominent role in the history of
drug discovery and development process by providing novel, clin-
ically useful medicines having various biological activities such as
anticancer, antiprotozoal, antifeedant, anathematic, antiepileptic,
and antimicrobial activities, amongst others.1 In the last decades,
natural products, specially having anticancer activity received in-
creased attention from chemists because cancer is now the most
frequent disease and has got the first place in the order of causes
of deaths2 in the developed countries. So there is always an ever
increasing requirement of safe and effective antitumoral agents
to control cancer.
The influence of natural products upon anticancer drug discov-
ery and design is very impressive as about 75% of all drugs now in
clinical trials for cancer treatment are either natural products or
pharmacophores derived from natural products.3 (2S,3R)-2-Ami-
no-3-octadecanol (spisulosine or ES-285 1; Fig. 1) is a marine-de-
rived bioactive compound isolated by Rinehart et al.4 from the
North Arctic clam Spisula polynyma. (+)-Spisulosine is a sphing-
oid-type base which contains a long saturated C18 alkyl chain with
an erythro-1,2-amino alcohol. This naturally occurring substance
was found to exhibit potent cytotoxicity and morphological alter-
ation against L1210 leukemia cells. It also showed in vitro activity
a potential antitumoral agent. Owing to its simple structure and
potent biological activity it has garnered much attention from
the synthetic community. Several approaches for its synthesis have
been disclosed. The first total synthesis of (+)-spisulosine was re-
ported from L
-alanine methyl ester hydrochloride.4 A formal syn-
thesis of (+)-spisulosine was achieved by Lee and co-workers
from chiral 2-aziridine carboxylate.7 The asymmetric synthesis of
(+)-spisulosine from the N-benzylimine derived from D
-mannitol8
was completed by Allepuz et al. Later, Séguin et al. reported on
the total synthesis of the title natural product from enantiopure
N-tert-butylsulfinyl imine.9 Very recently in this year Coelho and
co-workers reported a total synthesis of ( )-spisulosine starting
from hexadecanal10 involving Morita–Baylis–Hillman (MBH)
chemistry. Our ongoing interest toward the total synthesis of bio-
active natural products and their analogues stimulated us to ex-
plore a convenient approach to the asymmetric synthesis of this
interesting natural product.11
Herein, we would like to report a new approach to the total syn-
thesis of (+)-spisulosine starting from easily available (S)-Garner’s
aldehyde. In our approach, the hydroxy group at C3 of the natural
product was introduced by highly diastereoselective nucleophilic
addition on Garner’s aldehyde resulting in a terminal allylic alco-
hol. Later, this intermediate was used in olefin cross metathesis
with 1-pentadecene to complete the synthesis of the title antican-
cer agent.
The retrosynthetic strategy for (+)-spisulosine (1) is delineated
in Scheme 1. We envisaged that 1 could be obtained from protected
amine C, a synthetic precursor of (+)-spisulosine, by hydrogenation
of the double bond and cleavage of protecting groups. The interme-
diate C could in turn be prepared by subjecting the functionalized
olefin B to coupling with a required long chain olefin counterpart
involving cross metathesis strategy. The fragment B could be
prepared from intermediate A involving a sequence of reactions.
Intermediate A, which contains the required erythro-1,2 amino
alcohol of the natural product, could be obtained by highly
against P-388 (0.01
(0.05
lg/ml); HT-29 (0.05 lg/ml) and MEL-28
l
g/ml) tumor cell lines.4
The great antiproliferative activity5 of (+)-spisulosine toward
advanced malignant solid tumors6 included it in clinical trials as
NH2
H3C
OH
Figure 1. Structure of (+)-spisulosine or ES-285 (1).
* Corresponding author. Tel.: +91 9415403775; fax: +91 522 2623405.
E-mail address: akshaw55@yahoo.com (A.K. Shaw).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.146

P. Ghosal, A. K. Shaw / Tetrahedron Letters 51 (2010) 4140–4142
4141
Table 1
NH2
NHR'
Optimization of cross metathesis reaction of 7 in DCM with 1-pentadecene in the
presence of 5 mol % Grubbs’ second generation catalyst
C14H27
C13H27
H3C
H3C
OH
OR
C
Entry
Equivalent of 1-pentadecene
Yield of 8 (%)
1
(+)-Spisulosine
1
2
3
4
1
2
3
5
70
79
87
89
NHR'
NR'
NR'
CHO
O
O
H3C
OR
OR
A
B
(S)-Garner's
aldehyde
With the assembly 7 with us, our next attempt was focused to-
ward the installation of appropriate long alkyl chain of the natural
product and this was done by adopting cross metathesis approach.
The cross metathesis11a reaction between olefin 7 and 1-pentade-
cene in the presence of Grubbs’ second generation catalyst
(5 mol %) gave the compound 8. It was observed that by increasing
the equivalents of 1-pentadecene the yield of cross metathesis
product was enhanced and therefore, when 3 equiv of alkene was
used in this reaction the cross metathesis product 8 was obtained
in 87% yield (Table 1).
In the next step, the hydrogenation of double bond and removal
of benzyl ether protection of compound 8 were carried out
smoothly in the presence of H2 atmosphere and 10% Pd/C in
MeOH/CHCl3 (2:1) to afford compound 9 as a white solid in 91%
yield.15
Now acidic hydrolysis of 9 in a solution of dioxane saturated
with HCl gas furnished the corresponding HCl salt of (+)-spisulo-
sine (ES-285ꢁHCl). The targeted natural product (+)-spisulosine 1
(ES-285) was finally obtained in 90% yield after neutralization of
the hydrochloride salt by aqueous NaOH solution (Scheme 2). All
the spectroscopic and physical data16 are identical to those re-
ported in the literature.4a,7,8
R, R' = Protecting group
Scheme 1. Retrosynthetic analysis of (+)-spisulosine 1.
NBoc
NBoc
CHO
NBoc
(b)
O
(a)
(c)
O
O
OBn
OH
4
2
3
NHBoc
NHBoc
NHBoc
(d)
(e)
TsO
HO
(f)
H3C
OBn
7
OBn
OBn
5
6
NHBoc
NHBoc
(g)
C13H27
C13H27
H3C
H3C
OBn
OH
9
8
NH2
In summary, we have achieved a convergent total synthesis of
(+)-spisulosine or ES-285 (1) by utilizing an olefin cross metathesis
reaction between long chain olefin 1-pentadecene and compound
7 with a terminal double bond followed by catalytic hydrogenation
of the resulting compound. The enantiomer of this natural product
could also be synthesized by using this approach. Since the title
natural product 1 was found to exhibit great antiproliferative
activity toward advanced malignant solid tumors and is now in
clinical trials, this class of compounds and their analogues thus
may deserve interest as potent and safe anticancer agents. There-
fore, one can install different cross olefin counterparts9 by adopt-
ing this flexible approach to facilitate the synthesis of various
analogues of the title natural product for improved antitumor
activity.
(h)
C13H27
H3C
OH
(+)-Spisulosine
1
Scheme 2. Synthesis of (+)-spisulosine (1). Reagents and conditions: (a) Vinyl
magnesium bromide, THF, ꢀ78 °C, 74%; (b) Benzyl bromide, NaH, DMF, 91%; (c)
PTSA, MeOH, 0 °C, 84%; (d) TsCl, Et3N, DCM, 25 °C, 73%; (e) LiAlH4, THF, ꢀ20 °C, 80%;
(f) Grubbs’ second generation catalyst (5 mol%), 1-pentadecene, DCM, reflux, 87%;
(g) H2, Pd/C, MeOHACHCl3, 91%; (h) (i) HCl-dioxane, rt; (ii) Aq. NaOH, DCM, rt, 90%.
diastereoselective Grignard addition to (S)-Garner’s aldehyde at
low temperature.
Thus, as per retrosynthesis shown above, the convergent total
synthesis of (+)-spisulosine (1) was commenced from (S)-Garner’s
aldehyde which could be easily prepared from commercially avail-
Acknowledgments
able inexpensive L
-serine.12 Stereoselective addition of vinyl mag-
nesium bromide to freshly prepared Garner’s aldehyde 2 at
ꢀ78 °C afforded a mixture of anti and syn allylic alcohols in 6:1 ra-
tio13a,13b from which the major anti isomer 3 was separated by col-
umn chromatography. It has already been reported that vinyl
magnesium bromide is a better Grignard species13 compared to
other Grignard reagents for asymmetric Grignard addition to Gar-
ner’s aldehyde. The alcohol functionality of compound 3 was pro-
We are thankful to Anup K. Pandey for technical assistance and
SAIF, CDRI, for providing spectral data. P.G. thanks CSIR, New Delhi,
for financial support. CDRI Communication No. 7941.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.146.
tected as O-benzyl ether to furnish
4 followed by smooth
isopropylidene opening with PTSA in MeOH at 0 °C to obtain inter-
mediate 5. Now to complete the synthesis of compound 7, the free
hydroxymethyl group at C1 in compound 5 had to be converted
into methyl group and this could be done in two steps, first by
tosylation13b of the primary alcohol followed by its replacement
by hydride. Thus, the tosylation of alcohol 5 with tosyl chloride
in the presence of triethylamine and subsequent treatment of the
tosyloxy derivative 614 with LiAlH4 afforded the desired olefin 7
in 80% yield (Scheme 2).
References and notes
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14. The tosylate 6 was not stable and it was used immediately for the next step,
that is, for its LiAlH4 reduction.
15. The physical and spectroscopic data of compound 9 are identical to those
reported in the literature except the specific rotation. The specific rotation of
the compound 9 {½a D28
= ꢀ8.54 (c 0.71, CHCl3)} does not match with that
ꢂ
reported by Lee and co-workers {Ref. 7 ½a D24
ꢂ
= +15.2 (c 1.00, CHCl3)} but closer
to the value reported by Allepuz et al. {Ref. 8 ½a D25
= ꢀ4.4 (c 1.00, CHCl3)}.
ꢂ
16. Physical and spectroctroscopic data of ES-285 or (+)-spisulosine 1: Yield: 90%;
white solid compound; Mp 65–67 °C {Ref. 8 Mp 64.5–66 °C}; ½a D28
ꢂ
= +25.3 (c
= +24.0 (c 1.00,
0.95, CHCl3){Ref. 4a ½a D26
ꢂ
= +24.9 (c 1.00, CHCl3), Ref. 8 ½a D25
ꢂ
CHCl3)}. 1H NMR (300 MHz, CDCl3): d = 0.84–0.88 (m, 3H), 0.99 (d, J = 6.4 Hz,
3H), 1.24–1.37 (br m, 27H), 1.46–1.48 (br m, 1H), 1.83 (br s, 3H), 2.94 (br m,
1H), 3.42 (br m, 1H). 13C (75 MHz, CDCl3): d = 14.5 (CH3), 17.3 (CH3), 23.1 (CH2),
26.6 (CH2), 29.7–30.2 (10 ꢃ CH2), 32.3 (CH2), 32.9 (CH2), 50.8 (CH), 75.1 (CH).
IR (neat, cmꢀ1): 3752, 3448, 2920, 2361, 1628, 771. DART–HRMS: m/z [M+H]+
calcd for C18H40N1O1 286.3110, found 286.3119.
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