Copper-catalyzed enantioselective synthesis of trans -1-alkyl-2-substituted cyclopropanes via tandem conjugate addition-intramolecular enolate trapping

Article abstract of DOI:10.1021/ja105704m

Cu-TolBINAP-catalyzed conjugate addition of Grignard reagents to 4-chloro-α,β-unsaturated esters, thioesters, and ketones leads to 4-chloro-3-alkyl-substituted thioesters and ketones in up to 84% yield and up to 96% ee upon protonation of the correspondin

Full text of DOI:10.1021/ja105704m

Published on Web 09/23/2010
Copper-Catalyzed Enantioselective Synthesis of trans-1-Alkyl-2-substituted
Cyclopropanes via Tandem Conjugate Addition-Intramolecular Enolate
Trapping
Tim den Hartog, Alena Rudolph, Beatriz Macia´, Adriaan J. Minnaard,* and Ben L. Feringa*
Stratingh Institute for Chemistry, UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received June 29, 2010; E-mail: b.l.feringa@rug.nl; a.j.minnaard@rug.nl
To synthesize trans-cyclopropanes via tandem ACA-enolate
trapping, initially the ACA of Grignard reagents to 4-halocrotonates
Abstract: Cu-TolBINAP-catalyzed conjugate addition of Grignard
reagents to 4-chloro-R,ꢀ-unsaturated esters, thioesters, and ketones
leads to 4-chloro-3-alkyl-substituted thioesters and ketones in up to
84% yield and up to 96% ee upon protonation of the corresponding
enolates at low temperature. Tandem conjugate addition-enolate
trapping, however, yields trans-1-alkyl-2-substituted cyclopropanes
in up to 92% yield and up to 98% ee. The versatility of this reaction
is illustrated by the formation of key intermediates for the formal
was studied while varying the ligand (Table 1). The low yield
observed12 for the ACA to bromo-substituted thioester 6a (entry
1) prompted us to investigate the chloro-substituted analogue 6b
for this reaction (entry 2). Addition of hexylmagnesium bromide
to 6b using Cu-TolBINAP at -78 °C gave, after quenching at this
temperature, 4-chloro-3-hexyl thioester 7b in good yield (83%) and
excellent ee (94%). For 4-halo-R,ꢀ-unsaturated aliphatic ketones
and esters, similar results were obtained. For instance, reactions of
syntheses of cascarillic acid and grenadamide.
the bromo-substituted substrates 6c and 6d with Grignard reagents
The enantioselective Simmons-Smith cyclopropanation with a
stoichiometric amount of a chiral dioxaborolane, introduced by
Charette and co-workers,1 is currently the benchmark reaction for
the synthesis of trans-1-alkyl-2-substituted cyclopropanes. Only a
few catalytic2 asymmetric methods3,4 can compete with this
method1 in terms of efficiency and yield. This is in sharp contrast
to the well-known catalytic asymmetric synthesis of trans-1-aryl-
2-substituted cyclopropanes.5,6 Although Michael addition-initiated
ring-closure reactions (MIRCs) are well-known for the diastereo-
and enantioselective preparation of substituted cyclopropanes,5 to
the best of our knowledge the use of organometallic reagents for
the catalytic asymmetric6,7 preparation of trans-1,2-disubstituted
cyclopropanes6a,b,e,l via MIRC is unprecedented in the literature.8
Recently, we explored the asymmetric allylic alkylation9 of
4-halocrotonates using Grignard reagents for the preparation of
R-Me-substituted ester 2 in high yield and high regio- and
enantioselectivity (Scheme 1a, R1 ) OBn).10 Here we report the
Cu-catalyzed asymmetric 1,4-addition (ACA) of Grignard re-
agents9b,c,11 to 4-chlorocrotonates using the readily available
TolBINAP as ligand. This transformation provides a route to
4-chloro-3-alkyl-substituted thioesters and ketones (Scheme 1b, 4,
X ) Cl) and a general method to form trans-1,2-disubstituted
cyclopropanes (Scheme 1c, 5, X ) Cl) with excellent enantiose-
lectivities.
gave low yields of, respectively, cyclopropanes 8c and 8d (entries
3 and 4). In contrast, the reaction of the 4-chloro-substituted R,ꢀ-
unsaturated ketone 6e gave 7e in good yield (entry 5, 84%) and
excellent ee (96%). The Cu-catalyzed reaction of ester 6f with
phenethylmagnesium bromide at -40 °C gave cyclopropane 8f as
the main product, along with traces of 7f, in a reasonable yield
(65%, entry 6) and excellent ee (>95%). Already at -40 °C, the
enolate formed from 6f undergoes slow ring-closure to yield the
corresponding cyclopropane, 8f.
Table 1. Substrate Screening for ACA to 4-Halocrotonatesa
entry
LG
R1
R2
product
yield (%)
eeb (%)
1
2
Br
Cl
Br
Br
Cl
Cl
6a
6b
6c
6d
6e
6f
SEt
SEt
C11H23
OMe
C11H23
OMe
hexyl
hexyl
hexyl
BnCH2
BnCH2
BnCH2
8a
7b
8c
8d
7e
8ff
<20c
83
-
94
3
32d
<20c
84
n.d.
-
96
4e
5
6e
65g
>95
a Conditions: 6 (0.5 mmol) in CH2Cl2 added over 2 h to a solution of
CuI (1 mol %), TolBINAP (1.5 mol %), and Grignard reagent (1.2
equiv) in tBuOMe. b Determined by chiral GC or HPLC. c Based on
GC-MS. d 20% of 6c and 18% of (E)-pentadec-2-en-4-one obtained.
e Reaction performed at -40 °C, 4 h reaction time. f In addition, traces
(<10%) of 7f were obtained; in all other entries, exclusively 7 or 8 was
obtained. g Combined yield of 7f and 8f.
Scheme 1. Switch in Regioselectivity for the Reactions of
4-Halocrotonates with Grignard Reagents
The formation of cyclopropanes via tandem ACA-enolate
trapping was subsequently investigated. The reaction of hexyl-
magnesium bromide and 6b, after completion of the ACA and
warming to room temperature, afforded the diastereomerically
pure trans-cyclopropane 8b in high yield (Table 2, entry 1). Both
7b and 8b were obtained with 94% ee. However, precise control
of the amount of Grignard reagent is essential to obtain good
yields of the cyclopropanes. When less than 1.2 equiv of
hexylmagnesium bromide was used, a small but significant
9
10.1021/ja105704m  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 14349–14351 14349

C O M M U N I C A T I O N S
Table 2. Scope of Alkyl Grignard Reagents and
Electron-Withdrawing Groups for Tandem ACA-Enolate Trapping
toward trans-Cyclopropanesa
based on a commercial chiral ligand, CuI, and Grignard reagents.
Application of this methodology in natural product synthesis
and other ring structures will be reported in due course.
Acknowledgment. Dedicated to the memory of Dr. M. M.
Pollard. We thank M. Bastian for providing substrate 6b and T. D.
Tiemersma-Wegman and M. J. Smith for technical support (GC,
HPLC, MS). Financial support from NWO-CW is gratefully
acknowledged.
entry
R1
R2
product
yield (%)
eeb (%)
1
2
3
4
SEt
SEt
SEt
SEt
SEt
SEt
SEt
SEt
6b
6b
6b
6b
6b
6b
6b
6b
6b
6e
6e
6f
hexyl
Me
Et
iPr
8b
8g
8h
8i
8j
8k
8l
8m
8n
8e
8o
8f
87
56
67
89
91
88
>95d
92
50
75
87
68
94
87
95
70
84
94
96
84
26
96
98
>95
Supporting Information Available: Experimental details, data, and
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
5
iBu
6c
7d
8
but-3-enyl
(CH2)3OtBu
BnCH2
Ph
BnCH2
Me
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