Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: Synthesis of (-)-sugiresinol dimethyl ether

Article abstract of DOI:10.1021/ja035983p

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alk

Full text of DOI:10.1021/ja035983p

Published on Web 07/04/2003
Regioselective and Enantiospecific Rhodium-Catalyzed Allylic Alkylation
Reactions Using Copper(I) Enolates: Synthesis of (-)-Sugiresinol Dimethyl
Ether
P. Andrew Evans* and David K. Leahy
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received May 6, 2003; E-mail: paevans@indiana.edu
Table 1. Scope of the Regioselective Rhodium-Catalyzed Allylic
The stereocontrolled construction of carbon-carbon bonds Via
Alkylation Reaction Using Copper(I) Enolates (eq 1; R′ ) Ph)a
transition metal-catalyzed allylic alkylation represents a fundamen-
tally important process for target-directed synthesis.1 Despite
significant advances with stabilized carbon nucleophiles, as exem-
plified by malonates, â-keto esters, etc., the analogous reactions
with enolates are limited to symmetrical or stereoelectronically
biased allyl fragments to circumvent problems associated with
regiochemical infidelity.2-4 Hence, the ability to facilitate a stereo-
specific allylic alkylation with an acyclic ketone enolate would
circumvent the need for further functionalization of the allylic
alkylation adduct, and thereby provide an important sp3-sp3 cross-
coupling protocol, which would expand the current repertoire of
unstabilized nucleophiles.
We envisioned that the rhodium-catalyzed allylic substitution
would facilitate the regio- and enantiospecific alkylation of ketone
enolates, owing to its propensity to undergo a selective alkylation
through a configurationally stable distorted π-allyl or enyl (σ + π)
organorhodium intermediate.5,6 The nature of the ketone enolate
was expected to be crucial in overcoming some of the inherent
limitations associated with this transformation, namely elimination
of the metal-allyl intermediate, polyalkylation, and poor regio-
and stereocontrol. In light of these concerns, we decided to examine
the transmetalation of the alkali metal enolate salt with a copper(I)
halide, with the expectation that this would soften the basic character
of the enolate.7 Herein, we now describe the rhodium-catalyzed
intermolecular allylic alkylation of enantiomerically enriched acyclic
unsymmetrical secondary alcohol derivatives 1, using a copper(I)
enolate, to afford the secondary allylic alkylation adducts 2 with
excellent stereospecificity (eq 1).
R in allylic carbonate
2°:1°
yield
(%)d
entry
rac-1
rac-2:3b,c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph(CH2)2
Me
a
b
c
d
e
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
19:1
g99:1
g99:1
g99:1
76:1
83
85
74
80
83
76
75
82
84
73
80
66
75e
78
nPr
CH2dCH(CH2)3
cHex
iPr
f
iBu
g
h
i
j
k
l
(CH3)2CH(CH2)2
Ph
Npth
Bn
CH2dCH
TBSOCH2
BnO(CH2)2
28:1
50:1
83:1
m
n
a All reactions were carried out on a 0.5 mmol reaction scale using 10
mol % RhCl(PPh3)3 modified with 40 mol % P(OMe)3.8 b Ratios of
regioisomers were determined by capillary GLC on the crude reaction
mixtures. c The primary products 3 were prepared for comparison using
the copper(I) cyanide to transmetalate the enolate, with the exception of 3j
and 3k, which were prepared using crossed metathesis. d Isolated yields.
e Reaction run at -10 °C.
Table 1 summarizes the application of the optimized reaction
conditions to a variety of racemic secondary allylic carbonates using
the copper enolate derived from acetophenone (Vide supra). The
alkylation is tolerant of linear and branched alkyl substituents (Table
1, entries 1-8), in which the excellent selectivity for the R-branched
derivatives is contrary to our previous studies. The allylic alkylation
is also feasible for aryl, benzyl, and vinyl substituents, providing
comparable results (entries 9-12). The benzyl-protected hydroxy-
methyl substituent proved unsatisfactory due to low chemical yield
and extensive side products. However, the tert-butyldimethylsilyl-
protected hydroxymethyl and benzyl-protected hydroxyethyl sub-
stituents afforded the alkylation products in excellent yield (entries
13 and 14). The excellent regioselectiVity and enantiospecificity,
coupled with the synthetic utility of enolates, makes this an
important method for the stereospecific allylic alkylation of acyclic
ketone enolates.
Encouraged by the results in Table 1, we anticipated that
the rhodium-catalyzed allylic alkylation could be extended to
R-substituted enolates, and thereby facilitate the introduction of
an additional stereogenic center.2,3 Interestingly, treatment of
the allylic carbonate 1o (R ) BnOCH2), which had proven
problematic in the previous study, under analogous reaction
conditions with the copper enolate derived from the ketone 4
furnished the R,â-disubstituted ketone, which was then subjected
to ring-closing metathesis to furnish the 1,2-cyclohexenes 5a/5b
in 75% overall yield, favoring the trans-diastereoisomer 5a
(eq 2, 2°:1° ) 30:1, ds ) 10:1).9 Overall, this reaction sequence
provides an alternative approach to an exo-selective Diels-Alder
Preliminary studies examined the effect of the transmetalation
of a lithium enolate with the requisite copper(I) halide salt. This
study demonstrated that although the transmetalation is crucial for
efficient conversion the nature of the copper(I) halide salt was
inconsequential to the stereospecificity (I ∼ Br ∼ Cl), which is in
sharp contrast to the previous studies with copper alkoxides.5f
Additional studies demonstrated that dialkylation could be mini-
mized at 0 °C (e5%), making this an extremely tolerant transfor-
mation. Hence, the treatment of the enantiomerically enriched
secondary allylic carbonate 1a (R ) Ph(CH2)2; g99% ee) with the
lithium enolate of acetophenone, transmetalated with copper(I)
iodide using trimethyl phosphite-modified Wilkinson’s catalyst at
0 °C, furnished the alkylation products 2a/3a in 87% yield, with
excellent regioselectivity and enantiospecificity (2°:1° g 99:1, cee
) 100%), favoring the secondary product 2a.
9
8974
J. AM. CHEM. SOC. 2003, 125, 8974-8975
10.1021/ja035983p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
cycloaddition, and indicates that substituted enolates are more
tolerant nucleophiles.
that copper(I) enolates may prove useful nucleophiles in related
metal-catalyzed reactions.
Acknowledgment. We sincerely thank the National Institutes
of Health (GM58877) and the donors of the Petroleum Research
Fund, administered by the American Chemical Society, for generous
financial support. We also thank Johnson and Johnson for a Focused
GiVing Award and Pfizer Pharmaceuticals for the Creativity in
Organic Chemistry Award. The Camille and Henry Dreyfus
Foundation is thanked for a Camille Dreyfus Teacher-Scholar
Award (P.A.E.) and the Department of Chemistry at Indiana
University for an E. M. Kratz Fellowship (D.K.L.).
Supporting Information Available: Experimental procedures for
5-9, and spectral data for 2a-n and 5-9 (PDF). X-ray crystallographic
file in CIF format for 5a. This material is available free of charge Via
the Internet at http://pubs.acs.org.
(-)-Sugiresinol, a norlignan isolated from heartwood of Cryp-
tomeria japonica by Funaoka et al., has potent antifungal activity
and inhibits cyclic AMP phosphodiesterase in addition to the growth
of C. shiitake hyphae.10 We envisioned that the rhodium-catalyzed
allylic alkylation, in combination with a reductive etherification,
would provide an expeditious synthesis of the dimethyl ether of
this biologically important agent.11 Preliminary studies demonstrated
that the allylic carbonate derived from (R)-6 was unstable due to
facile ionization. To circumvent this problem, an in situ activation/
allylic alkylation protocol was devised. Treatment of the allylic
alcohol with n-butyllithium followed by methyl chloroformate
furnished the allylic carbonate, which was then treated in a manner
analogous to that described earlier, to afford the â-substituted
ketone (R)-7 in 80% yield (2°:1° g 99:1, cee g 99%). Sharpless
asymmetric dihydroxylation, followed by a one-pot differential
protection, led to the cyclization precursor 8a/b in 60-71% yield
over two steps, albeit as a 4:1 mixture of diastereoisomers.12 The
mixture was separated, and the desired isomer 8a was subjected to
reductive etherification using bismuth bromide and triethylsilane,
followed by an in situ deprotection of the acetyl group, to afford
(-)-sugiresinol dimethyl ether 9 in 99% yield, with g19:1
diastereoselectivity.13 The combination of the rhodium-catalyzed
allylic alkylation with a diastereoselective reductive etherification
reaction provides the most expeditious asymmetric synthesis of
(-)-sugiresinol dimethyl ether developed to date, which was
accomplished in four steps in 45% overall yield from the enantio-
merically enriched allylic alcohol (R)-6.
References
(1) (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York, 1996;
Chapter 4, pp 290-404. (b) Trost, B. M.; Lee, C. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter
8, pp 593-649.
(2) For some examples of metal-catalyzed allylic alkylations using ketone
enolates, see: (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999,
121, 6759. (b) Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed.
2000, 39, 3494. (c) You, S. L.; Hou, X. L.; Dai, L. X.; Zhu, X. Z. Org.
Lett. 2001, 3, 149 and pertinent references therein.
(3) For examples of diastereoselective allylic alkylation reactions using ester
enolates, see: (a) Kazmaier, U.; Zumpe, F. L. Angew. Chem., Int. Ed.
2000, 39, 802. (b) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124,
7256.
(4) For an example of the challenges associated with the regioselective
rhodium-catalyzed allylic alkylation of unsymmetrical substrates, see:
Muraoka, T.; Matsuda, I.; Itoh, K. J. Am. Chem. Soc. 2000, 122, 9552.
(5) (a) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (b)
Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999,
121, 6761, 12214. (c) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000,
122, 5012. (d) Evans, P. A.; Kennedy, L. J. J. Am. Chem. Soc. 2001, 123,
1234. (e) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123,
4609. (f) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882.
(g) Evans, P. A.; Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158.
(6) For related rhodium-catalyzed allylic substitutions with silyl enol ethers,
see: (a) Minami, I.; Shimizu, I.; Tsuji, J. J. Organomet. Chem. 1985,
296, 269. (b) Muraoka, T.; Matsuda, I.; Itoh, K. Tetrahedron Lett. 2000,
41, 8807.
(7) For an example of the transmetalation of a lithium enolate with a copper-
(I) halide salt, see: Posner G. H.; Lentz, C. M. J. Am. Chem. Soc. 1979,
101, 934.
(8) RepresentatiVe experimental procedure: Trimethyl phosphite (24 µL, 0.20
mmol) was added directly to a suspension of Wilkinson’s catalyst (46.0
mg, 0.05 mmol) in anhydrous THF (2.0 mL) at 0 °C, and the mixture
then stirred under an atmosphere of argon. The catalyst was allowed to
form over ca. 15 min, resulting in a light yellow homogeneous solution.
Lithium hexamethyldisilazide (950 µL, 0.95 mmol, 1.0 M solution in THF)
was added dropwise to a suspension of copper(I) iodide (189.6 mg, 1.00
mmol, dried in Vacuo at 160 °C) and acetophenone (120 µL, 1.03 mmol)
in anhydrous THF (3.0 mL), and the anion was allowed to form over ca.
2 min until a light yellow homogeneous solution was obtained. The catalyst
and the enolate solutions were then cooled with stirring to 0 °C, and the
former was then added Via Teflon cannula to the copper enolate solution.
The allylic carbonate rac-1a (110.3 mg, 0.50 mmol) was then added via
a tared 500-µL gastight syringe to the catalyst/enolate mixture, and the
reaction was allowed to warm slowly to room temperature over ca. 4 h
(tlc control), resulting in a tan heterogeneous solution. The reaction mixture
was then quenched with NH4Cl solution (1 mL) and partitioned between
diethyl ether and saturated aqueous NH4Cl solution. The organic layers
were combined, dried (MgSO4), filtered, and concentrated in Vacuo to
afford a crude oil. Purification by flash chromatography (eluting with 1%
ethyl acetate/hexanes), followed by additional flash chromatography
(eluting with 15% methylene chloride/hexanes), furnished the â-substituted
ketone rac-2a (109.7 mg, 83%) as a colorless oil.
Scheme 1
(9) The relative configuration was proven through X-ray crystallographic
analysis of the 4-nitrobenzoate derived from 5a after debenzylation.
(10) Funaoka, K.; Kuroda, Y.; Kai, Y.; Kondo, T. Nippon Mokuzai Gakkaishi
1963, 9, 139.
In conclusion, we have developed a regioselective and enan-
tiospecific rhodium-catalyzed allylic alkylation of acyclic unsym-
metrical allylic alcohol derivatives using copper(I) enolates to
prepare â-substituted ketones. This protocol represents a convenient
asymmetric Claisen rearrangement surrogate in which substituted
enolates permit the introduction of an additional stereogenic center.
The synthetic utility of this transformation was highlighted in the
construction of a trans-1,2-disubstituted cyclohexene and the total
synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate
(11) For enantioselective total syntheses of (-)-sugiresinol dimethyl ether,
see: (a) Muraoka, O.; Zheng, B.-Z.; Fujiwara, N.; Tanabe, G. J. Chem.
Soc., Perkin Trans. 1 1996, 405. (b) Brown, E.; Dujardin, G.; Maudet,
M. Tetrahedron 1997, 53, 9679. (c) Matsuo, K.; Sugimura, W.; Shimizu,
Y.; Nishiwaki, K.; Kuwajima, H. Heterocycles 2000, 53, 1505.
(12) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 6D, pp 357-
398.
(13) Komatsu, N.; Ishida, J.-y.; Suzuki, H. Tetrahedron Lett. 1997, 38, 7219.
JA035983P
9
J. AM. CHEM. SOC. VOL. 125, NO. 30, 2003 8975