Pd-catalyzed asymmetric allylic alkylation. A short route to the cyclopentyl core of viridenomycin

Article abstract of DOI:10.1021/ol0343515

(Matrix presented) A palladium-catalyzed asymmetric allylic alkylation effects a dynamic kinetic asymmetric transformation of racemic isoprene monoepoxide and a surrogate for Nazarov's reagent in which a quaternary center is created with exellent ee. The

Full text of DOI:10.1021/ol0343515

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1563-1565
Pd-Catalyzed Asymmetric Allylic
Alkylation. A Short Route to the
Cyclopentyl Core of Viridenomycin
Barry M. Trost* and Chunhui Jiang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received February 27, 2003
ABSTRACT
A palladium-catalyzed asymmetric allylic alkylation effects a dynamic kinetic asymmetric transformation of racemic isoprene monoepoxide
and a surrogate for Nazarov’s reagent in which a quaternary center is created with exellent ee. The resultant adduct allows easy access to
a substrate for ring-closing metathesis to form a cyclopentenone and sets the stage for an 11-step synthesis of the cyclopentyl core of the
antibiotic antitumor agent viridenomycin.
The actinomycete Streptomyces gannmycicus produced an
antitumor antibiotic designated AL081 that prolonged the
survival of mice suffering B16 melanoma.1 It was established
to be identical to viridenomycin.2 The structure was subse-
quently established as 1 solely on the basis of detailed NMR
structure provides a challenge for synthesis. First, the densely
functionalized cyclopentane ring core also contains a qua-
ternary center, always a formidable task. The high degree
of unsaturation of the macrocycle and the presence of an
enol ether also constitute difficult structural units. Two
groups have embarked upon the synthesis.3,4 The magnitude
of the challenge is highlighted by the fact that the successful
syntheses of the cyclopentane core required 20 steps by a
strategy utilizing a chiral auxiliary3 and 32 steps by one
employing a starting material from the “chiral pool”.4
We have recently disclosed a new approach to create
quaternary centers asymmetrically by utilizing dynamic
kinetic asymmetric transformations (DYKAT) of vinyl
epoxides as shown in eq 1.5 The high regio- (9:1) and
studies. Neither the stereochemistry of C-25 nor the absolute
configuration had been established. Synthesis provides a
strategy to clarify these structural points and provides access
to structural modifications in order to understand biological
mode of action of 1 and to design analogues that would have
more drug like structural features. Furthermore, the unusual
(1) Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron
Lett. 1991, 32, 659.
(2) Hasegawa, T.; Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S.
J. Antibiot. 1975, 28, 167.
enantioselectivity (99% ee, determined after dehydration) to
10.1021/ol0343515 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003

create a quaternary center using our standard ligand 2 in the
presence of a Pd(0) source 3 is remarkable. This result allows
the formulation of a synthetic strategy toward the cyclopentyl
core of viridenomycin as depicted in Scheme 1. The potential
Scheme 3. Diene Formation
Scheme 1. Retrosynthetic Analysis
give the desired enone in 60% yield.7 A significant amount
(30%) of sulfone 11 was also isolated. The latter presumably
derives from conjugate addition of phenylsulfinate anion,
which in turn was produced by disproportionation of the
phenylsulfenic acid byproduct of the sulfoxide thermolysis.
Addition of dihydropyran as a trap for sulfenic acid increased
the yield of the enone to 77% accompanied by only 6% of
the conjugate adduct 11. Ethyl vinyl ketone proved even
more effective, wherein enone 10 was isolated in 84% yield.
Ring-closing metathesis with the second generation Grubb’s
catalyst proved to be very slow, requiring 3.5 days to give
still only incomplete conversion (see Scheme 4).8 Fortunately,
availability of the trans-diol from an olefin sets the stage
for the synthesis of the requisite cyclopentenone via a ring-
closing metathesis. Thus, the problem simplifies to isoprene
monoepoxide (4) and the Nazarov reagent 56 as the starting
materials. Unfortunately, the Nazarov reagent kills the Pd(0)
catalyst. Believing the ability of this reagent to coordinate
Pd(0) was the source of the problem, we turned to a precursor
in our synthesis of this reagent7 that lacked the offending
double bond.
Scheme 4. Cyclopentene Synthesis
The â-thio derivative 6, derived by alkylation of the
dianion of ethyl acetoacetate, participated without incident
in the DYKAT as shown in Scheme 2. The initial adduct 7
Scheme 2. Dykat
the cyclopentenone 12 was isolated in a satisfactory yield
of 69%, 86% based upon recovered starting material. The
derived enol ether 13 of the â-ketoester underwent com-
pletely diastereoselective dihydroxylation9 to give the cis diol
14. The attack anti to the more bulky siloxymethyl group
was confirmed by a strong NOE between the methine ring
hydrogen and the hydrogens of the CH2OR group.
Completion of the synthesis requires inversion of the
allylic alcohol. It was envisioned that a Mitsunobu protocol10
may provide this chemoselectivity. If the two alkoxyphos-
phonium species A and B are in dynamic equilibrium through
is a mixture of diastereomers. Simple dehydration generates
a single dihydrofuran 8, which was shown to have 94% ee
by chiral HPLC analysis. Protection of the primary alcohol
derived from the lactol 7 fixed it in the keto form 9 to allow
easy elimination of the phenylthio group via sulfoxide
thermolysis (see Scheme 3). Oxidation to the sulfoxide with
sodium metaperiodate avoids overoxidation. The crude
sulfoxide was directly thermolyzed in benzene at reflux to
(3) Arrington, M. P.; Myers, A. I. Chem. Commun. 1999, 1371. Kruger,
A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4301. Waterson, A. G.;
Kruger, A. W.; Meyers, A. I. Tetrahedron Lett. 2001, 42, 4305.
(4) Ishihara, J.; Hagihara, K.; Chiba, K.; Ito, K.; Yanigasawa, Y.; Totani,
K.; Tadano, K. Tetrahedron Lett. 2000, 41, 1771.
(5) Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001, 123, 12907.
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Org. Lett., Vol. 5, No. 9, 2003

a hypervalent phosphorane, then it would be expected that
A would be more reactive because it is allylic and therefore
lead preferentially to product. In the event, under standard
Mitsunobu conditions (Ph3P, DEAD, 4-nitrobenzoic acid)
two products, 15 and 16, in addition to recovered starting
material were formed (eq 2). The best yield of the desired
which accounts for 20-40% of the crude mass, has been
tentatively identified as cyclopentenone 16 on the basis of
its spectral properties. This product presumably arises by an
intriguing skeletal rearrangement involving the homoallyl-
cyclopropylcarbinyl-cyclobutenyl cation manifold of the
alkoxyphosphonium salt at the neopentyl hydroxy group.12
The ability of the rearrangement, which involves highly
strained intermediates of the bicyclo[2.1.0]pentane and
bicyclo[1.1.0]butane type, to compete with an allylic dis-
placement is remarkable. Scheme 5 shows completion of the
synthesis which proceeded straightforwardly.
Scheme 5. Completion
p-nitrobenzoate 15a of 48% was obtained at 40 °C in toluene.
The yield increased slightly to 52% by using DIAD instead
of DEAD. Changing the acid to chloroacetic acid improved
the yield further to 57%. Several alternatives were explored
to improve the yield. For example, use of 9-phenyldibenzo-
phosphole as the phosphine for the Mitsunobu reaction led
to isolation of the cyclic phosphorane C, which unfortunately
would not react further. Reaction of the cyclic ortho-aminal
formed from diol 14 and the DMF dimethyl acetal11 also
did not lead to any successful reaction. The cyclic sulfite
from diol 14 and thionyl chloride also did not lead to any
desired product. The byproduct of the Mitsunobu reaction,
The successful use of a surrogate for the Nazarov’s reagent
in the Pd-catalyzed DYKAT reaction corresponds to the
introduction of an asymmetric alkyl group. The usefulness
of the reagent for subsequent annulations then makes this
asymmetric substituted building block a useful approach for
the asymmetric synthesis of cyclic structures. In this par-
ticular case, the presence of the two double bonds nicely
sets the stage for a ring-closing metathesis. The availability
of the heavily functionalized cyclopentyl core of virideno-
mycin in only 11 steps contrasts sharply with the two existing
routes, the shorter of which required nearly twice as many
steps. Efforts toward a total synthesis of viridenomycin and
to establish the unresolved stereochemical issues are under-
way.
(6) Zibuck, R.; Streiber, J. Org. Synth. 1993, 71, 236.
(7) Trost, B. M.; Kunz, R. A. J. Org. Chem. 1974, 39, 2648.
(8) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783. Also see: Aburel, P. S.; Romming, C.; Ma,
K.; Undheim, K. J. Chem. Soc., Perkins Trans. 1 2001, 1458, Gradl, S. N.;
Kennedy-Smith, J. J.; Kim, J.; Trauner, D. Synlett 2002, 411.
(9) Schroeder, M. Chem. ReV. 1980, 80, 187.
(10) Hughes, D. L. Org. React. 1992, 42, 335.
(11) Brechbuehler, H.; Bu¨chi, H.; Hatz, E.; Schreiber, J.; Eschenmoser,
A. HelV. Chim. Acta 1965, 48, 1746.
(12) A plausible mechanism for the formation of 16 follows.
Acknowledgment. We thank the National Institute of
Health, GM-33049, for their generous support of our
programs.
Supporting Information Available: Characterization
data for 7-10, 12-15, 17, and 18. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0343515
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