Total synthesis of (+)-scyphostatin featuring an enantioselective and highly efficient route to the side-chain via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)

Article abstract of DOI:10.1039/b920261g

(+)-Scyphostatin (1) was synthesized via (i) construction of a side-chain 3b of ≥98% purity in 19% yield in eleven steps featuring ZACA reaction, Negishi coupling, and HWE olefination, (ii) an asymmetric synthesis of a fully protected core 4 from 10a, and (iii) a three-step assembly of 1 in 42% yield.

Full text of DOI:10.1039/b920261g

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Total synthesis of (+)-scyphostatin featuring an enantioselective and
highly efficient route to the side-chain via Zr-catalyzed asymmetric
carboalumination of alkenes (ZACA)w z
Emmanuel Pitsinos,*a Nikolaos Athinaios,a Zhaoqing Xu,b Guangwei Wangb and
Ei-ichi Negishi*b
Received (in Cambridge, UK) 29th September 2009, Accepted 9th February 2010
First published as an Advance Article on the web 23rd February 2010
DOI: 10.1039/b920261g
(+)-Scyphostatin (1) was synthesized via (i) construction of a
side-chain 3b of Z 98% purity in 19% yield in eleven steps
featuring ZACA reaction, Negishi coupling, and HWE olefination,
(ii) an asymmetric synthesis of a fully protected core 4 from 10a,
and (iii) a three-step assembly of 1 in 42% yield.
as a Z 98% isomerically pure compound in 19% yield over
eleven steps from allyl alcohol in the longest linear sequence.8
In that synthesis, TBS-protected (2R,4S)-5-iodo-2,4-dimethyl-
1-pentanol (5) was prepared from commercially available11
methyl (S)-3-hydroxy-2-methylpropionate of Z 98% isomeric
purity in 28% yield over six steps, and the ethyl ester of
(2E,4E)-6-diethylphosphono-2,4-hexadienoic acid (6) was
obtained by a literature method12 in 55% yield over four steps
from a commercially available11 ethyl (E)-4-bromocrotonate.
Thus, the total number of steps needed for the preparation of
3b was 21.
Scyphostatin (1) is a naturally occurring ceramide analogue
that potently and selectively inhibits the mammalian neutral
magnesium-dependent sphingomyelinase (N-SMase),1 a key
enzyme in the sphingomyelin signal transduction pathway2
and a promising pharmacological target for the treatment of
inflammation, immunological and neurological disorders.3
Scyphostatin has served as a prototype for the design of novel
N-SMase inhibitors,4 and its novel structure has attracted
considerable attention as a total synthesis target.5
With the goal of developing an enantioselective ZACA
route to 3b avoiding the use of an expensive chiral pool,
i.e., methyl (S)-3-hydroxy-2-methylpropionate, we opted for
applying our recent synthesis of TBS-monoprotected
(2S,4R)-2,4-dimethyl-1,5-pentanediol (7) of Z 98% ee in
31% yield (dr Z 40/1) in just three steps from allyl alcohol.10
It should be remembered that the high enantiomerical purity
stems from kinetic resolution in the second ZACA step
requiring only chromatographic diastereomeric separation
without any enantiomeric separation. Conversion of 7 into 5
was achieved in 95% yield. We believe that this four-step
synthesis of 5 of Z 98% ee in 29% yield is potentially more
economical, besides being more efficient, than that reported
previously.8 In this context, it should also be noted that a
pioneering work of Hoye9a reported a synthesis of 3b in 7%
Herein, we report an efficient and convergent total synthesis
of (+)-scyphostatin (1) incorporating some synthetically
important modifications of our recent syntheses of the core6,7
and side-chain8,9 of 1. As shown in Scheme 1, the high level
of convergency stems from the fact that only one step of
deprotection is required after union of the side-chain 3a and
the core 4a. It should be compared with 6,5a 5,5c and 2 steps5b
required in three previous syntheses. The higher efficiency of
the present synthesis relative to the previous syntheses mainly
lies in the use of recently developed Zr-catalyzed asymmetric
carboalumination of alkenes (ZACA reaction hereafter)10 in
place of conventional asymmetric methods, i.e., those based
on (a) preparation and desymmetrization of meso-2,4-
dimethyl-1,5-pentanediol used in all of the other scyphostatin
syntheses and (b) a chiral pool, such as triflate of methyl
(S)-lactate9a and methyl (S)-3-hydroxy-2-methylpropionate.8,9c
We have previously reported an efficient and selective
synthesis of the ethyl ester of the scyphostatin side-chain 3b
a Laboratory of Natural Products Synthesis & Bioorganic Chemistry,
Institute of Physical Chemistry, NCSR ‘‘DEMOKRITOS’’,
P.O. Box 60228, GR 153 10, Aghia Paraskevi, Greece.
E-mail: pitsinos@chem.demokritos.gr
b Herbert C. Brown Laboratories of Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907-2084, USA.
E-mail: negishi@purdue.edu
w This article is part of a ChemComm Catalysis in Organic Synthesis
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Spectral data
and experimental procedures for all new compounds reported herein.
See DOI: 10.1039/b920261g
Scheme 1 A three-step assembly of (+)-scyphostatin (1).
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2200 | Chem. Commun., 2010, 46, 2200–2202

Scheme 2 An enantioselective ZACA route to the side-chain 3b.
yield over twelve steps from meso-2,4-dimethyl-1,5-pentane-
diol, and all currently known syntheses of 3b except for those
reported by us8 employ this diol as a starting compound. To
our knowledge, however, this compound is not commercially
available, and it has been prepared from the ethyl ester of
a-bromoisobutyric acid and a-methylmalonic acid in 12%
yield in four steps,13 making the above-described synthesis of
3b a sixteen-step process of mere 1% overall yield. Another
modification was made in the synthesis of 6 according to a
recently reported Pd-catalyzed alkenyl–alkenyl coupling
procedure in 32% yield in four steps (Scheme 2).14
In 2005, we prepared a fully assembled and hydroxy-
protected core as a racemic palmitoylamide derivative 4b
from 3-amino-7-hydroxy-3,4-dihydro-2H-1-benzopyran (10).6a
With our more recent synthesis of enantiomerically pure
N-Boc-protected 10a in 36% yield over 11 steps from
L-tyrosine,6b the stage was set for the synthesis of enantio-
merically pure hydroxyl-protected core
4 en route to
(+)-scyphostatin (1). This has indeed been achieved, as
summarized in Scheme 3. After replacement of the Boc group
of 10a with the COCCl3 group to generate 10b in 95% yield
over two steps, its crucial oxidation with [bis(trifluoroacetoxy)-
iodo]benzene (PIFA)15 in CF3CH2OH and in the presence of
K2CO3, followed by hydrolysis afforded 12 via 11 in 40% yield
over two steps. After reduction of 12 with NaBH4–CeCl3
under Luche conditions16 to generate 13, its treatment with
p-MeOC6H4CH2OH (PMBOH), 10-camphorsulfonic acid
(CSA), and 4 A MS in THF proceeded with allylic rearrange-
ment to give stereoselectively 14. Without purification, 14 was
directly epoxidized17 to give 15 in 45% yield over three steps
from 12, and DDQ oxidation of 15 furnished 4 in 65% yield.
Thus, 4 of Z 98% ee was prepared from 10a in 11% yield over
eight steps.
Scheme 3 An asymmetric synthesis of 4 and 4a.
for its union with the core without further purification. In the
meantime, the fully protected core 4 was treated with iBu2AlH
in toluene at ꢁ92 1C to give free amine 4a. To a solution of the
crude amine in CH2Cl2–DMF (10 : 1) were added sequentially
i
at 0 1C the crude side-chain 3a obtained above, Pr2EtN, and
For the final assembly of scyphostatin (1), our main
attention was focused on minimizing the number of steps after
combining the core and side-chain, thereby maximizing the
yield of the final target 1. Conversion of the ethyl ester of the
fully assembled side-chain 3b into its free carboxylic acid 3a by
hydrolysis with LiOH (10 equiv.) in THF–MeOH (1/1)
proceeded quantitatively, and the crudely isolated 3a was used
PyBop. After the usual extractive workup, flash chromato-
graphy gave the desired 2 in 65% yield (90% based on
consumed 4) from 4 over two steps: [a]2D1 ꢁ70.6 (c 1.26,
CH2Cl2). After the core–side-chain union, hydrolytic conver-
sion of 2 (11 mg) to produce scyphostatin (1) was achieved by
using montmorillonite K 10.7d Extractive workup with acetone
followed by flash chromatography (10 : 1 CH2Cl2–MeOH)
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Chem. Commun., 2010, 46, 2200–2202 | 2201

furnished 4.1 mg of the desired scyphostatin (1) as a colorless
wax. A mixture containing the starting material 2 and
p-methoxybenzaldehyde was also obtained (6.6 mg). Its
resubmission to the same reaction conditions as above
provided an additional crop (1.6 mg) of 1 and unreacted 2
(2.2 mg). Thus, the total yield of 1 was 64% (80% based on the
consumed 2), and its spectral data are in good agreement with
those reported in the literature1,5: [a]D21 +61.0 (c 0.48, MeOH).
In summary, (+)-scyphostatin (1) has been synthesized in
1.7% yield over 22 steps in the longest linear sequence. We
believe that the above described synthesis (Scheme 2) of the
side-chain ester 3b in 19% yield over eleven steps in the longest
linear sequence from inexpensive starting compounds and only
catalytic amounts of Pd and chiral zirconocene complexes not
only is superior to that which we previously reported but
is also the currently most efficient and potentially most
economical. It should be remembered that 4a permits the
hitherto most convergent assembly of 1 requiring only one
step after linking the side-chain 3a and core 4a.
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The work at Purdue University was mainly supported by
National Institutes of Health (GM36792) and Purdue
University. Part of this work was performed in the frame of
COST Actions CM0602 ‘‘Inhibitors of angiogenesis: design,
synthesis and biological exploitation (ANGIOKEM)’’ and
CM0804 ‘‘Chemical biology with natural products’’.
N. A. thanks NCSR ‘‘D’’ for a Ph.D. scholarship and
Prof. A. Yiotakis for being the academic responsible for his
Ph.D. thesis. Prof. A. Giannis is gratefully acknowledged for
his assistance in obtaining HRMS spectra for the core inter-
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This journal is The Royal Society of Chemistry 2010
2202 | Chem. Commun., 2010, 46, 2200–2202