Applications of chiral allenylzinc additions and Noyori asymmetric reductions to an enantioselective synthesis of a C3-C13 precursor of the polyketide phosphatase inhibitor cytostatin

Article abstract of DOI:10.1016/j.tetlet.2003.12.067

A 12-step synthesis of a C3-C13 precursor of the protein phosphatase inhibitor cytostatin is described. Key stereocenters were introduced by a chiral allenylzinc addition and Noyori asymmetric-transfer hydrogenation.

Full text of DOI:10.1016/j.tetlet.2003.12.067

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1351–1353
Applications of chiral allenylzinc additions and Noyori asymmetric
reductions to an enantioselective synthesis of a C3–C13 precursor of
the polyketide phosphatase inhibitor cytostatin
James A. Marshall* and Keith Ellis
Department of Chemistry, University of Virginia, PO Box 400319, Charlottesville, VA 22904, USA
Received 4 December 2003; accepted 11 December 2003
Abstract—A 12-step synthesis of a C3–C13 precursor of the protein phosphatase inhibitor cytostatin is described. Key stereocenters
were introduced by a chiral allenylzinc addition and Noyori asymmetric-transfer hydrogenation.
Ó 2003 Elsevier Ltd. All rights reserved.
The polyketide cytostatin, a potent and selective inhib-
itor of protein phosphatase PP2A, was isolated from
a strain of Streptomyces in 1994 by Ishizawa and
co-workers.1 These investigators established the basic
constitution of the natural product, but did not elabo-
rate the stereochemistry. Some years later, Bialy and
Waldmann deduced a likelystereostructure byanalogy
with related natural products of established structure
O
ONa
HO
1
P
O
5
O
OH
O
13
3
9
cytostatin
OR2
5
OR2 OR3
9
R1O
3
1
and through analysis of H NMR coupling constants.
Theysubsequentlycompleted a total snythesis of a
13
H
1
compound with this proposed structure.2 The H, 13C,
and 31P NMR spectra of the synthetic and natural
material were comparable, but the presence of insepa-
rable impurities in the sample of the later prevented an
unambiguous confirmation (Fig. 1). However, the syn-
thetic material showed selective nanomolar in vitro
inhibition of serine–threonine phosphatase PP2A com-
parable to that reported for natural cytostatin in sup-
Proposed route
allenylzinc addition
Noyori reductions
Waldmann route
Evans aldol
Corey oxazabor-
olidene reductions
O
O
RO
3
5H
5
9
H
Figure 1. Alternative approaches to a C3–C13 precursor of cytostatin.
3
port of its identitywith the natural product.
In their synthesis, Bialy and Waldmann employed Evans
oxazolidinone-directed alkylation and aldol reactions to
introduce the stereocenters at C4–C6 and C9–C10 (Fig.
1). Enantioselective reduction of a C10 alkynyl ketone
with the Coreyoxazaborolidene reagent 4 established the
sixth and final stereocenter of their synthetic cytostatin.
Each of these methods is capable of introducing either
(R)- or (S)-chiralitythus providing flexibilityfor analog
synthesis.
In our approach, we utilize chiral allenylzinc method-
5
ologyto control the stereochemistryat C5 and C6. The
C4 and C10 stereocenters originate with (S)-3-hydroxy-
2-methylpropionic acid and the C9 and C11 hydroxyl
centers are introduced through Noyori asymmetric-
transfer hydrogenation of alkynone precursors.6;7 This
route is also capable of total stereochemical flexibility.
Keywords: Allenylzinc; Asymmetric reduction; Polyketide; Hydroge-
nation.
Our assemblage of the stereotriad homopropargylic
alcohol segment 2 was effected in 71% yield (>95:5
* Corresponding author. Tel.: +1-434-924-7997; fax: +1-434-924-7993;
e-mail: jam5x@virginia.edu
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.067

1352
J. A. Marshall, K. Ellis / Tetrahedron Letters 45 (2004) 1351–1353
O
OMs
O
O
OR
TBSO
Me(MeO)N
OBn
1.
TBSO
OMOM
TBSO
OBn
4
H
Pd(OAc)2, Ph3P,
Et2Zn (71%)
2. MOMCl (82%)
BuLi (92%)
5
2 R = H
3 R = MOM
1
OH
OMOM
OMOM
OR
TBSO
TBSO
i-PrOH
Ts
OBn
100psi H2/cat
OBn
H2/Pd-C
9
Ph
Ph
N
Ru
N
7 R = H
8 R = MOM
EtOAc (see Table)
EtOH (97%)
a
6
H
Noyori catalyst
Scheme 1. Reagents and conditions: (a) MOMCl, TBAI, (i-Pr)2NEt (91%).
anti:syn) from aldehyde 18 through addition of the all-
enylzinc reagent generated in situ from the mesylate of
(R)-3-butyn-2-ol9 and Et2Zn in the presence of a Pd(0)
catalyst (Scheme 1). The protected alkynyl adduct 3, was
next lithiated and treated with the Weinreb amide (4)
of (S)-3-benzyloxy-2-methylpropionic acid10 to afford
alkynone 5 in 92% yield. Reduction of this ynone with
the Noyori (R,R)-ruthenium/p-cymene catalyst pro-
ceeded in quantitative yield to afford the (R)-alcohol 6 as
the onlydetectable isomer.
under 100 psi of hydrogen afforded only the (Z)-dihydro
product (Table 1). Attempts to force this reaction by
increasing the catalyst ratio and/or the reaction time
caused extensive decomposition. The use of Pt-on-car-
bon effected partial cleavage of the MOM ether as well
as decomposition. A similar result was seen with
Pd(OH)2. However, when triethylamine was added to
this reduction, to neutralize what we presume to be
acidic by-products, the tetrahydro product 7 was ob-
tained in 97% yield.11
The next step of our synthesis, hydrogenation of the
internal triple bond of alcohol 6, proved surprisingly
difficult. Stirring 6 with 20 mol % rhodium-on-alumina
Protection of this alcohol as the MOM ether 8, then
hydrogenolysis of the benzyl ether over palladium-on-
carbon afforded the alcohol 9, which was converted to
aldehyde 10 with the Dess–Martin periodinane reagent
buffered with NaHCO3.12 Addition of lithio TMS
acetylene and a second Dess–Martin oxidation led to
alkynone 11. The Noyori transfer-hydrogenation meth-
odologywas again employed to reduce the alknyone
carbonyl, affording the (R)-propargylic alcohol 12 as the
sole isolable product in 62% yield (unoptimized). Pro-
tection of the alcohol as the DPS ether 13 and removal
of the TMS grouping afforded the terminal alkyne 14, an
intermediate in Bialyand Waldmann Õs synthesis of cy-
Table 1. Hydrogenation of Alkyne 7
OMOM
OMOM
100psi H2/cat
EtOAc
TBSO
OBn
Catalyst
Result
Rh–alumina (20 mol %)
Rh–alumina (100 mol %)
Pt–C
(Z)-Dihydro product
Decomposition
1
tostatin. Comparison of the optical rotation, H NMR,
and 13C NMR spectra of this sample to the reported
values confirmed the identityof the two substances
(Scheme 2).
Loss of MOM/decomposition
Loss of MOM/decomposition
Tetrahydro product 8 (97%)
Pd(OH)2
Pd(OH)2, Et3N
MOM
MOM
MOM
MOM
OMOM
O
OMOM
O
O
O
O
O
TBSO
TBSO
TBSO
b,c
a
OH
H
TMS
9
10
11
MOM
TBSO
MOM
MOM
TBSO
MOM
O
O
OR
O
O
ODPS
f
d,e
TMS
H
12 R = H
13 R = DPS
14
Scheme 2. Reagents and conditions: (a) Dess–Martin, NaHCO3 (ꢀ100%); (b) lithio TMS acetylene; (c) Dess–Martin, NaHCO3 (90%, two steps);
(d) Noyori reduction (62%); (e) DPSCI, Im, DMF (ꢀ100%); (f) K2CO3, MeOH (89%).

J. A. Marshall, K. Ellis / Tetrahedron Letters 45 (2004) 1351–1353
1353
A noteworthyfeature of the present snythesis is the
References and notes
seamless integration of the allenylmetal and Noyori
transfer-hydrogenation methodology to access relatively
complex polyketide structural segments. As was previ-
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Kinoshita, N.; Nishida, C.; Hamada, M.; Ishizawa, M.;
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5201.
7
ouslyshown, the Noyori methodology is remarkably
insensitive to the stereochemical environment of the
carbonyl group. Our route, like that of Bialy and
Waldmann, offers the potential for facile reversal of any
or all stereocenters of the natural product for possible
structure–activitystudies.
6. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
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Acknowledgements
10. Marshall, J. A.; Yu, R. H.; Perkin, J. H. J. Org. Chem.
1995, 60, 5550.
11. Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
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This studywas supported byresearch grant R01
CA090383 from the National Cancer Institute. We
thank Professor Herbert Waldmann for a copyof a
manuscript in press.