Enantiospecific and regioselective rhodium-catalyzed allylic alkylation: diastereoselective approach to quaternary carbon stereogenic centers.

Article abstract of DOI:10.1021/ol005953g

The enantiospecific and regioselective rhodium-catalyzed allylic alkylation of a series of chiral nonracemic allylic carbonates, followed by ozonolysis and reductive lactonization, provides a convenient route to optically active gamma-lactones. Sequential

Full text of DOI:10.1021/ol005953g

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2213-2215
Enantiospecific and Regioselective
Rhodium-Catalyzed Allylic Alkylation:
Diastereoselective Approach to
Quaternary Carbon Stereogenic Centers
P. Andrew Evans* and Lawrence J. Kennedy
Brown Laboratory, Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
paeVans@udel.edu
Received April 14, 2000
ABSTRACT
The enantiospecific and regioselective rhodium-catalyzed allylic alkylation of a series of chiral nonracemic allylic carbonates, followed by
ozonolysis and reductive lactonization, provides a convenient route to optically active γ-lactones. Sequential alkylation and reductive alkylation
furnished the r-quaternary-â-ternary substituted γ-lactone derivative as a g10:1 mixture of diastereoisomers.
The enantioselective construction of ternary and quaternary
carbon stereogenic centers continues to be the focus of
intense synthetic attention.1 This may be attributed to the
challenges associated with the design and implementation
of stereoselective methods, particularly for the formation of
quaternary carbon stereogenic centers. The enantiospecific
metal-catalyzed allylic alkylation provides a conceptually
useful method for the construction of vicinal ternary and
quaternary carbon stereogenic centers. However, this ap-
proach has been restricted to symmetrical substrates to
circumvent regiochemical problems, in which stoichiometric
metal is utilized to minimize the erosion of enantiospecificity
from metal-metal displacement reactions.2 We recently
demonstrated the first enantiospecific rhodium-catalyzed
allylic substitution reactions that furnish unsymmetrical
alkylation products with excellent regioselectivity.3 The
origin of the selectivity was attributed to the proposed
intermediacy of a distorted π-allyl or enyl (σ + π) organo-
rhodium intermediate.4
Herein, we describe the extension of this concept to a range
of chiral nonracemic acyclic carbonates,5 using the sodium
salt of methyl phenylsulfonylacetate.6 The mixed malonate
derivatives were expected to allow selective functionalization
of the allylic alkylation products and thus provide an
expeditious entry into a variety of useful synthons for
asymmetric synthesis. Furthermore, this study would also
address the effect of more sterically demanding carbon-
stabilized nucleophiles on the regiochemical outcome.
(3) (a) Evans, P. A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b)
Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121,
6761. (c) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929. (d) Evans,
P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012.
(4) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(5) The enantiomerically enriched allylic alcohol precursors of 1b-e and
1h were prepared using the Sharpless asymmetric kinetic resolution of the
racemates with dicyclohexyl tartrate; see: Gao, Y.; Hanson, R. M.; Klunder,
J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765. The enantiomerically enriched allylic alcohol precursors of 1a
and 1f/g were obtained from Fluka and D-mannitol, respectively.
(6) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 17, 3477.
(1) For recent reviews on asymmetric quaternary carbon construction,
see: (a) Fuji, K. Chem. ReV. 1993, 93, 2037. (b) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 388.
(2) For a recent review on the transition-metal-catalyzed allylic alkylation,
see: (a) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron:
Asymmetry 1992, 3, 1089. (b) Hayashi, T. In Catalytic Asymmetric Synthesis;
Ojima, I. Ed; VCH Publishers: New York, 1993; p 325. (c) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
10.1021/ol005953g CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/23/2000

the diene 2b with Grubbs’ catalyst10 furnished the cyclic
allylic alkylation product 4 in 92% yield (Scheme 2). The
Table 1. Regioselective and Enantiospecific
Rhodium-Catalyzed Allylic Alkylation of Chiral Nonracemic
Allylic Carbonates 1
Scheme 2. RCM Approach to Enantiomerically Enriched
allylic carbonate
ee
ratio
ee
cee yield
Cyclic Allylic Alkylation Products
entry
(R ))a
1
(%)b 2:3c,d (%)e (%)7 (%)f,g
1
2
3
4
5
6
7
8
Me
a
b
c
d
e
f
97
g99
94
36:1
26:1
9:1
95
98
92
95
92
98
98
98
97
98
86
91
86
87
86
86
78
97
CH2dCH(CH2)3
PhCH2
PhCH2CH2
BnOCH2
TBSOCH2
TPSOCH2
Ph
98
22:1
94 g99:1
g99
g99
98
18:1 g99 100
3:1 g99 100
61:1
g
h
advantage of this strategy is the ability to circumvent
regiochemical problems associated with the alkylation of
cyclic derivatives that proceed through unsymmetrical η3-
intermediates.11 Although stereoelectronics can often influ-
ence the regiochemical course of this type of allylic
alkylation, the ability to access unsymmetrical cyclic allylic
alkylation products in this manner is likely to have consider-
able synthetic utility.
96
98
a All of the rhodium-catalyzed allylic alkylation reactions were carried
out on a 0.5 mmol reaction scale using 2-3 equiv of the nucleophile.
b Enantiomeric excess of the allylic carbonates 1 or the allylic alcohols were
determined by chiral capillary GLC and HPLC. c Ratios of regioisomers
were determined by capillary GLC. d The primary products were prepared
independently Via Pd(0) catalysis.2 e The phenylsulfonyl group was
reductively removed, and the enantiomeric excess determined by chiral
capillary GLC and HPLC.6,9 f Isolated yields. g The allylic alkylation
products were formed as a ∼1:1 mixture of diastereoisomers.
The construction of ternary-quaternary substituted carbon
stereogenic centers was also examined using a γ-lactone as
a template for diastereoselective alkylation (Scheme 3).
Reductive ozonolysis of the allylic alkylation product 2a
furnished the γ-lactone 5 in 92% yield, as a single diaste-
reoisomer. Treatment of 5 with lithium hexamethyldisilazide
followed by methyl iodide resulted in the installation of the
R-methyl group. Reductive alkylation of the R-phenylsul-
fonyl γ-lactone under standard reaction conditions failed to
cleanly furnish the desired product 6a.13 Extensive investiga-
tion demonstrated that the nature of the electrophile was
crucial, in which alkyl iodides proved optimum. Hence,
reductive alkylation with lithium naphthalenide and allyl
iodide at -90 °C furnished the ternary-quaternary substituted
γ-lactone 6a/b in 78% overall yield, as a 10:1 mixture of
diastereoisomers favoring 6a. The ability to introduce various
groups at the â-position in the lactone provides a versatile
method for the construction of a variety of R-quaternary-â-
ternary carbon stereogenic centers, in which the diastereo-
selectivity is expected to improve (g10:1) with larger
â-substituents.
Table 1 summarizes the results of the rhodium-catalyzed
allylic alkylation, using the sodium anion of methyl phen-
ylsulfonylacetate, with a series of chiral nonracemic allylic
carbonates 1a-h (Scheme 1). The allylic alkylation reaction
Scheme 1. Regioselective and Enantiospecific
Rhodium-Catalyzed Allylic Alkylation
is both regioselective and enantiospecific (g97% cee).7 The
enantiospecificity is particularly significant for the substrates
that furnish alkylation products with modest regioselectivity
(entries 3 and 7). This observation presumably implies that
the organorhodium intermediate is not subject to π-σ-π
isomerization or metal-metal displacement as a means of
facial exchange.
Another significant aspect of this study was the tolerance
to other substituents; for example, aryl, alkyl, alkenyl, and
hydroxymethyl groups with various protecting groups may
be utilized. The benzyloxymethyl derivative is particularly
pertinent, since this functionality was expected to afford poor
secondary regiochemistry as a result of the propensity of this
group to competitively bind the metal-center and thus furnish
the alternative regioisomer.8
In conclusion, we have demonstrated that the rhodium-
catalyzed allylic alkylation may be expanded to include other
stabilized carbon-nucleophiles and combined with ring-
closing metathesis for the synthesis of enantiomerically
(9) The absolute configuration of allylic alkylation product 2a was
confirmed in the following manner. Reductive desulfonylation6 of 5
furnished (S)-â-methyl-γ-butyrolactone {[R]18D ) -20.9 (c ) 1.76, MeOH);
lit.12 {[R]21 ) -24.96 (c ) 1.77, MeOH)}.
D
(10) For recent reviews on ring-closing metathesis, see: (a) Randall, M.
L.; Snapper, M. L. J. Mol. Catal. A Chem. 1998, 133, 29. (b) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413. (d) Pandit, U. K.; Overleeft, H. S.; Borer,
B. C.; Bieraugel, H. Eur. J. Org. Chem. 1999, 959, 9.
The allylic alkylation products represent versatile synthons
for asymmetric synthesis, as outlined below. Treatment of
(11) Attempted rhodium-catalyzed allylic alkylation of the allylic carbon-
ate derived from cyclohexenol furnished rac-4 in 21% yield. This is
consistent with our findings that alkene substitution and geometry impact
the rates and selectivities.
(7) The term conservation of enantiomeric excess {cee ) (product ee/
starting material ee) × 100} provides a convenient method of describing
enantiospecificity.
(8) For an excellent review on substrate-directable chemical reactions,
see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(12) Mori, K. Tetrahedron 1983, 39, 3107.
(13) For a related example of a reductive alkylation from an R-cyano
ketone, see: Liu, H.-J.; Zhu, J.-L.; Shia, K.-S. Tetrahedron Lett. 1998, 39,
4183 and pertinent references therein.
2214
Org. Lett., Vol. 2, No. 15, 2000

Scheme 3. Diasteroselective Construction of Quaternary Carbon Stereogenic Centers
enriched unsymmetrical cyclic allylic alkylation products.
Faculty Grantee Award, and Glaxo Wellcome for a Chem-
istry Scholar Award. The Camille and Henry Dreyfus
Foundation is also thanked for a Camille Dreyfus Teacher-
Scholar Award (P.A.E.).
This is anticipated to circumvent some of the regiochemical
problems often encountered in unsymmetrical cyclic systems.
Finally, the allylic alkylation products can be transformed
into γ-lactones that serve as templates for the diastereo-
selective construction of R-quaternary-â-ternary carbon
stereogenic centers.
Supporting Information Available: Experimental pro-
cedures for the preparation of 6a and copies of proton spectra
for 2a-h, 4, 5, and 6a. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We sincerely thank the National
Institutes of Health (GM58877) for generous financial
support. We also thank Zeneca Pharmaceuticals for an
Excellence in Chemistry Award, Eli Lilly for a Young
OL005953G
Org. Lett., Vol. 2, No. 15, 2000
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