A novel, efficient, diastereo- and enantioselective mukaiyama aldol-based synthesis of a vinyl cyclopentanone core derivative of viridenomycin

Article abstract of DOI:10.1021/ol7025262

A strategy has been developed for a rapid seven-step construction of a chiral, nonracemic vinyl cyclopentanone building block as part of a synthetic approach to viridenomycin, using a diastereo- and enantioselective Mukaiyama aldol and intramolecular Knoe

Full text of DOI:10.1021/ol7025262

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5565-5568
A Novel, Efficient, Diastereo- and
Enantioselective Mukaiyama Aldol-Based
Synthesis of a Vinyl Cyclopentanone
Core Derivative of Viridenomycin
Andrei S. Batsanov,† Jonathan P. Knowles,† Andrew P. Lightfoot,‡ Graham Maw,§
Carl E. Thirsk,† Steven J. R. Twiddle,† and Andrew Whiting*,†
Department of Chemistry, Durham UniVersity, Science Laboratories, South Road,
Durham DH1 3LE, U.K., GlaxoSmithKline Pharmaceuticals, New Frontiers Science
Park, Third AVenue, Harlow, Essex CM19 5AW, U.K., and Pfizer Global Research &
DeVelopment, Sandwich, Kent CT13 9NJ, U.K.
andy.whiting@durham.ac.uk
Received October 16, 2007
ABSTRACT
A strategy has been developed for a rapid seven-step construction of a chiral, nonracemic vinyl cyclopentanone building block as part of a
synthetic approach to viridenomycin, using a diastereo- and enantioselective Mukaiyama aldol and intramolecular Knoevenagel condensation
as key steps.
Polyene macrolide viridenomycin 1 was first isolated from
a culture broth of Streptomyces Viridochromogenes1 and was
shown to have antibiotic and antitumor activity.2 Although
the relative stereochemistry of the cyclopentanone ring has
been assigned, the absolute stereochemistry of both this five-
ring section and the remote R-amide chiral center remains
unknown.3
Despite the efforts of several groups5 and ourselves,6
viridenomycin 1 has yet to succumb to total synthesis.
Several routes to the highly functionalized cyclopentanone
core have recently been published,5a-d and in this contribu-
tion, we report a concise asymmetric and highly diastereo-
selective assembly of a cyclopentenone derivatives related
to 4 and their Michael additions to access derivatives of 2
ready for elaboration to viridenomycin 1.
Viridenomycin 1 shares many similarities with hitachi-
mycin whose absolute stereochemistry has been assigned.4
(5) (a) Trost, B. M.; Jiang, C. Org. Lett. 2003, 5, 1563-1565. (b)
Mulholland, N. P.; Pattenden, G. Tetrahedron Lett. 2005, 46, 937-939.
(c) Pattenden, G.; Blake, A. J.; Constandinos, L. Tetrahedron Lett. 2005,
46, 1913-1915. (d) Arrington, M. P.; Meyers, A. I. Chem. Commun. 1999,
1371-1372. (e) Kruger, A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42,
4301-4304. (f) Waterson, A. G.; Kruger, A. W.; Meyers, A. I. Tetrahedron
Lett. 2001, 42, 4305-4308. (g) Ishihara, J.; Hagihara, K.; Chiba, H.; Ito,
K.; Yanigasawa, Y.; Totani, K.; Tadano, K. Tetrahedron Lett. 2000, 41,
1771-1774.
† Durham University.
‡ GlaxoSmithKline Pharmaceuticals.
§ Pfizer Global Research & Development.
(1) Hasegawa, T.; Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S.
J. Antibiot. 1975, 28, 167-175.
(2) Nakagawa, M.; Toda, Y.; Furihata, K.; Hayakawa, Y.; Seto, H. J.
Antibiot. 1992, 45, 1133-1138.
(3) Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron
Lett. 1991, 32, 659-662.
(6) (a) Batsanov, A. S.; Knowles, J. P.; Whiting, A. J. Org. Chem. 2007,
72, 2525-2532. (b) Maw, G. N.; Thirsk, C. E.; Toujas, J.-L.; Vaultier, M.;
Whiting, A. Synlett 2004, 7, 1183-1186.
(4) Smith, A. B. Pure Appl. Chem. 1989, 61, 405-408.
10.1021/ol7025262 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

Our initial retrosynthetic analysis of viridenomycin 1
assumes the absolute stereochemistry as drawn in Scheme 1
Scheme 2. Revised Retrosynthetic Analysis of â-Keto Ester
5a
Scheme 1. Retrosynthetic Analysis of Viridenomycin 1
Hence, TMS ketene acetal 11a11 (Scheme 3) was exposed
to oxazaborolidinone 8 promoted Mukaiyama aldol reaction.9
Scheme 3. Initial Examination of an Aldol-Claisen Sequence
to 5
and involves a potential Heck-Mizoroki coupling of 2 and
3 to assemble the northern hemisphere. In turn, cyclopen-
tanone 2 could be assembled via a stereoselective Michael
addition onto cyclopentenone 4, which could be further
disconnected through an intramolecular Knoevenagel con-
densation of methylketone 5a. The ketone 5a could be
obtained from oxidative cleavage of alkene 5b, potentially
available from a diastereo- and enantiocontrolled aldol
addition of a diene of type 7 (such as Brassard’s diene 7a7)
to methacrolein 6. Although asymmetric catalytic aldol
reactions of trimethylsilylketene acetals are well-known,8 the
application of such processes to dienolate equivalents might
be expected to follow syn-selectivity on the basis of
established models using asymmetric oxazaborolidinone
Lewis acid catalysis.9
However, this resulted in disappointing results: stoichio-
metric 8 being required and providing only 21% yield of
aldol adduct 12a with poor diastereoselectivity (syn:anti, 3:2).
It was also found that, after alcohol protection to give 13a,
the subsequent Claisen ester reaction to give 14 would not
proceed on the methyl ester. We, therefore, aimed to access
the more reactive phenol ester analogue 13b by an analogous
route (Scheme 3) with the expectation that the better leaving
group would enable the Claisen ester conversion (i.e., 13b
to 14). Thus, ketene acetal 11b was prepared in two steps
from methoxyacetyl chloride.12
Thus reactions of Brassard’s diene 7a and the correspond-
ing tert-butyl system 7b,10 using an oxazaborolidinone-
catalyzed Mukaiyama aldol9 with methacrolein 6, were found
to proceed smoothly, furnishing the desired adducts 9a and
9b in 66 and 76% yields, respectively (eq 1). However,
Initial attempts at this reaction using literature methods
based on tin(II) triflate and chiral diamine13 gave poor yields
and racemic product. Better results were obtained when
oxazaborolidinone 8 was employed, whereupon phenol ester
12b was obtained in 81% ee, albeit in low yield (Scheme
attempts at categorically determining the level of diastereo-
or enantioselectivity of systems 9 met with failure; these
compounds exist as a complex mixture of keto-enol
tautomers, which makes structural analysis difficult. Indeed,
attempts at derivatization and analysis were similarly unre-
warding.
Our inability to determine both relative and absolute
stereocontrol in the aldol addition of dienolate equivalents
7 led us to slightly revise our retrosynthetic analysis
employing a potentially more readily scrutinized aldol adduct
(i.e., 10), which could undergo a Claisen ester reaction to
give a system of type 5b (Scheme 2).
(8) For a review, see: Nelson, S. G. Tetrahedron: Asymmetry 1998, 9,
357-389.
(9) (a) Yokohawa, F.; Sameshima, H.; Shioiri, T. Tetrahedron Lett. 2001,
42, 4171-4174. (b) Kiyooka, S.; Hena, M. A. J. Org. Chem. 1999, 64,
5511-5523. (c) Kiyooka, S.; Hena, M. A.; Goto, F. Tetrahedron:
Asymmetry 1999, 10, 2871-2879.
(10) Diene 7b was prepared from methyl methoxyacetate using a
Claisen ester and double deprotonation-silylation sequences (see Supporting
Information).
(11) Wissner, A. J. Org. Chem. 1979, 44, 4617-4622.
(12) Commercially available methoxyacetyl chloride was converted to
the phenyl methoxyacetate, followed by conversion to the TMS-ketene acetal
(see Supporting Information).
(13) (a) Kobayashi, S.; Hayashi, T. J. Org. Chem. 1995, 60, 1098-1099.
(b) Kobayashi, S.; Uchiro, H.; Shina, I.; Mukaiyama, T. Tetrahedron 1993,
49, 1761-1772.
(7) Simoneau, B.; Brassard, P. Tetrahedron 1986, 42, 3767-3774.
5566
Org. Lett., Vol. 9, No. 26, 2007

3), and stoichiometric amounts of the oxazaborolidinone 8
were required. The low yields of the aldol reaction, together
with the moderate diastereoselectivity, led us to optimize the
aldol reaction to give 12b and subsequent secondary alcohol
protection and Claisen ester condensation to access 14, the
results of which are outlined in Scheme 4.
aldol reaction to provide 13b, assembly of the cyclopenten-
one ring was initiated by a Claisen reaction with lithium tert-
butyl acetate, which gave the desired â-keto ester 14 in high
yield. As expected from the previous results (vide supra),
the â-keto ester 14 showed significant keto-enol tautom-
1
erism in solution; a peak at 11.8 ppm in the H NMR
spectrum being assignable to the intramolecularly hydrogen-
bonded enol proton. Cyclization of protected â-keto ester
14 was accomplished as outlined in Scheme 4, that is, by a
one-pot ozonolysis in methanol followed by direct ozonide
reduction (solid supported triphenylphosphine) and Knoev-
enagel reaction in the presence of potassium carbonate
resulting in cyclopentenone 16 in 32% yield. This yield could
be increased to 46% using sodium triacetoxyborohydride as
reductant after ozonolysis, and no further base was required
for the Knoevenagel reaction as this was found to occur
spontaneously under these conditions. Despite the fact that
this step had considerable room for improvement, the desired
cyclopentenone 16 was prepared in sufficient quantity to
allow initial attempts to carry out a Michael addition of either
an acetylenic or a vinylic nucleophile. A wide variety of
conditions were attempted without success, and we surmised
that the tert-butyl ester may well be too sterically hindered
for an already highly substituted ring system. We therefore
turned to the preparation of nitrile analogue of ester 2
(Scheme 1), that is, via the sequence shown in Scheme 5.
Scheme 4. Diastereo- and Enantioselective Synthesis of
Cyclopentenone 16
By employing an alternative desilylation method14 after
the aldol reaction of 11b and reprotection of the alcohol (12b)
without actual isolation, the TBDMS ether 13b was isolated
in 71% yield and 81% ee. Importantly, good diastereose-
lectivity was also found, and the two diastereoisomers could
be separated by chromatography giving a syn:anti ratio of
92:8 (Scheme 4). Attempts to obtain a single-crystal X-ray
structure proved unsuccessful; however, reaction of the
phenol ester with 2,4-dinitroaniline and DBU provided
crystalline amide 15, which was amenable to X-ray analy-
sis.15 The absolute stereochemistry was as we had envisaged
(see Figure 1) based upon literature models for oxazaboro-
lidinone-mediated Mukaiyama aldol reactions.9
Scheme 5. Diastereo- and Enantioselective Synthesis of
Cyclopentanone 20
Reaction of phenyl ester 13b with the lithium anion of
acetonitrile provided ketone 17 in near quantitative yield.
Subsequent reaction with ozone gave two products which
could be separated by chromatography in high combined
yield. The main component was the desired cyclopentenone
18; however, the remaining component (single diastereo-
isomer) initially looked very similar to 18 by NMR but
appeared to have an additional oxygen atom present accord-
ing to MS. We surmised that it may be the result of
intramolecular trapping of the initial fragmentation product
(carbonyl oxide) upon transforming the primary ozonide
derivative of 17 into the secondary ozonide (by formaldehyde
elimination-recombination16) by the ketone function. The
structure of the endo-peroxide 19 was subsequently con-
Figure 1. X-ray structure of amide 15 (50% thermal ellipsoids).
Having ascertained that both the correct relative and
predicted absolute configuration had been obtained from the
(14) Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838.
(15) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876-881.
Org. Lett., Vol. 9, No. 26, 2007
5567

relative stereochemistry as shown by 20 (molecular mechan-
ics model shown in Supporting Information that supports
the nOe findings).
The nitrile analogue of cyclopentanone 2 (i.e., 20) has been
prepared in a highly efficient manner, requiring only seven
steps, and is the most efficient entry to the type of system
reported to date (46% overall yield). Importantly, this
synthesis is readily adaptable to access either the indicated
absolute stereochemistry or its enantiomer as required.
Further derivatization of 20 to access viridenomycin 1 is
underway.
Acknowledgment. We are grateful to the EPSRC for
CASE studentships (GR/99315155) to C.T. and for DTA
awards to J.P.K. and S.J.R.T., to Pfizer Global Research and
Development and GlaxoSmithKline Pharmaceuticals for
additional funding, and to the EPSRC mass spectrometry
service at the University of Wales, Swansea.
Figure 2. X-ray structure of endo-peroxide 19 (50% thermal
ellipsoids).
firmed by X-ray crystallography (Figure 2), which also
confirmed the relative and absolute stereochemistry of the
single diastereoisomer obtained. The endo-peroxide 19 could
be transformed to the desired cyclopentenone 18 using zinc/
HCl reasonably efficiently, and the final two carbons required
to access an equivalent of 2 were achieved on this highly
unreactive system using a stoichiometric trialkylphosphine
vinylcuprate procedure,17 which produced vinylcyclopen-
tanone 20 in 81% yield as the major diastereoisomer (10:1).
NOe studies (see Supporting Information) confirmed the
Supporting Information Available: General experimen-
tal methods, X-ray crystallographic data for compounds
1
15 and 19, and H and 13C spectra for all new compounds.
This material is available free of charge via Internet at
http://pubs.acs.org.
OL7025262
(17) (a) Cargill, R. L.; Bushey, D. F.; Ellis, P. D. J. Org. Chem. 1974,
39, 573-575. (b) Watanabe, H.; Mori, K. J. Chem. Soc., Perkin Trans. 1
1991, 2919-2934.
(16) Bunnelle, W. H. Chem. ReV. 1991, 91, 335-362.
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