Enantiomerically pure cyclopropenylcarbinols as a source of chiral alkylidenecyclopropane derivatives

Article abstract of DOI:10.1002/anie.200600556

(Chemical Equation Presented) The straightforward approach: The copper-catalyzed carbomagnesiation reaction of chiral cyclopropenylcarbinol derivatives, obtained through kinetic resolution of secondary allylic alcohols, leads to the preparation of enantio

Full text of DOI:10.1002/anie.200600556

Angewandte
Chemie
Synthetic Methods
path A).[1a] Herein, we document the first preparation of
racemic and then enantiomerically pure ACPs 2 from cyclo-
propenylcarbinol derivatives 1 (Scheme 1, path B) through a
copper-catalyzed addition of various Grignard reagents. In
our initial investigations, the regio- and stereochemistry of the
reaction was first checked on racemic cyclopropenylcarbinol
derivatives 1a–h, and the results reported in Table 1 fulfilled
our expectations.
DOI: 10.1002/anie.200600556
Enantiomerically Pure Cyclopropenylcarbinols as
a Source of Chiral Alkylidenecyclopropane
Derivatives**
Samah Simaan, Ahmad Masarwa, Philippe Bertus, and
Ilan Marek*
Table 1: Synthesis of ACP derivatives.
Entry Substrate R1
R2
R3
R4
R5
ACP E/Z[a] Yield [%][b]
Over the past few decades, racemic cyclopropene and
alkylidenecyclopropane (ACP) derivatives have been estab-
lished as powerful tools in synthetic chemistry. Indeed, on one
hand, cyclopropene derivatives can be readily transformed
into more complexmolecules by hydro- or carbometalation
reactions[1] on the strained internal double bond,[2] whereas
ACP derivatives have proven their usefulness by their unique
reactivity with transition-metal catalysts.[3] These catalyzed
transformations, also based on the release of the high level of
strain, can be performed either on the distal or proximal
bonds of the three-membered ring and the exo-alkylidene
moiety.[4] Despite this mounting interest, the synthesis of
enantiomerically pure cyclopropenes, particularly 1,2-disub-
stituted (internal) cyclopropenes and chiral ACPs are still in
their infancy.[5] In the course of our study on the functional-
ization of cyclopropenyl derivatives, we have recently shown
that cyclopropenylcarbinols (readily prepared in a one-pot
operation from 1,1,2-trihalogenocyclopropane[6]) are regio-
and diastereoselectively reduced with LiAlH4 in Et2O into
cyclopropylcarbinols as single trans isomers (Scheme 1,
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1e
1 f
1 f
1 f
1 f
1g
1h
CH3
CH3
CH3
C4H9
C4H9
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
C2H5 C2H5 C4H9 2a
C2H5 C2H5 C6H5 2b
C6H5 C6H5 C6H5 2c
C6H5 C6H5 C6H5 2d
–
–
-
76
81
61
62
–
iPr
H
H
H
H
H
H
H
H
CH3 2e 100:0 82
C4H9 2e 100:0 91
iPr
C6H5
C6H5
C6H5
C6H5
Ar[c]
C4H9 2 f
C6H5 2g
CH3 2h
C2H5 2i
C2H5 2j
CH3 2k
97:3 70
87:13 66
92:8 81
96:4 72
95:5 88
12:88 91
10
11
12
CH3 p-tol
[a] Determined on crude NMR spectroscopic and gas-chromatographic
analysis. [b] Yield of isolated product after purification by column chromatog-
raphy. [c] Ar=p-BrC6H4.
In all experiments, ACPs were obtained in good-to-
excellent yields which resulted from a formal copper-cata-
lyzed SN2’ reaction of alkyl and aryl magnesium halides
R5 MgX (X = Br, I) with the free allylic alcohol 1a–h. Tertiary
and secondary alcohol derivatives (Table 1, entries 1–4 and 5–
12, respectively) led similarly to ACP deriva-
tives. Substituents on the double bond of the
cyclopropenyl ring (R1) can be either alkyl
groups (entries 1–11) or a hydrogen atom
(entry 12). The same is true for substituent R2.
Substituents R3 and R4 can be either alkyl, aryl,
or hydrogen groups. When secondary alcohols
Scheme 1. Gen-
eral prepara-
were used (R3 = alkyl or aryl, R4 = H;
entries 5–12), the fate of the stereochemistry of the double
tion of
[*] Dr. S. Simaan, A. Masarwa, Prof. I. Marek
The Mallat Family Laboratory of Organic Chemistry
Department of Chemistry
bond was raised. In all these experiments, we always found
ACPs.
that the unique or major isomer was E configured (in
entry 12, the configuration of the double bond was identical
but the configuration of the product became Z because of the
interconversion of substituents R1 and R2).[7] Without a
copper salt, the reaction did not proceed.
Institute of Catalysis Science and Technology
The Lise Meitner-Minerva Center for Computational Quantum
Chemistry
Technion-Israel Institute of Technology, Haifa 32000 (Israel)
Fax: (+972)4-829-3709
With a straightforward method for the preparation of
ACPs from cyclopropenylcarbinol derivatives in hand, we
then turned our attention to their asymmetric synthesis.
Considering that cyclopropenylcarbinols are strained allylic
alcohols, we envisaged the enantiomerically enriched prepa-
ration of the ACPs to be through the Sharpless kinetic
resolution (Scheme 2).[8] When the racemic allylic alcohol 1 f
(Table 2, entry 1) was subjected to the epoxidation reaction
conditions using (R,R)-(+)-diethyl tartrate as the chiral
ligand, we were pleased to observe, despite the highly
reactive nature of the strained double bond, a very efficient
kinetic resolution at À208C. Only one enantiomer is epoxi-
E-mail: chilanm@tx.technion.ac.il
Dr. P. Bertus
UMR 6519
Reactions selectives et Applications
CNRS UniversitØ de Reims Champagne-Ardenne
BP 1039, 51687 Reims Cedex 2 (France)
[**] This research was supported by the German–Israeli Project
Cooperation (DIP-F.6.2), the Fund for the Promotion of Research at
the Technion, and a fellowship from the Lady Davis Foundation. The
authors thank Prof. Amnon Stanger for his great help in the
determination of absolute configuration by computational meth-
ods. I.M. is holder of the Sir Michael and Lady Sobell Academic
Chair.
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Scheme 3. Preparation of enantiomerically pure ACPs.
excellent transfer of chirality from chiral cycloprope-
nylcarbinol to ACP regardless of the nature of the alkyl
magnesium halides (R3 = aryl or alkyl; Table 3,
entries 1–4).
The absolute configuration of 2j was determined as
S by using both computational methods[11] and X-ray
analysis of functionalized 2j (see the Supporting
Information).
Scheme 2. Kinetic resolution of cyclopropenylcarbinol derivatives. TBHP=tert-butyl
hydroperoxide.
Table 2: Kinetic resolution of cyclopropenylcarbinol derivatives.
Entry R1
R2
R3
Products Yield [%][b] ee [%][a]
Table 3: Enantioselective preparation of ACPs.
Entry Substrate R1
R2
R3
Product E/Z
Yield ee
1
2
3
4
5
6
CH3
H
H
H
H
C6H5
p-BrC6H4
C6H5
1 f
1g
1i
46
44
44
42
47
40
99
99
99
96
99
95
[%][a] [%][b]
CH3
C4H9
CH3
CH3
CH3
1
2
3
4
1 f
1 f
1 f
1g
CH3 C6H5
CH3 C6H5
CH3 C6H5
C6H5 2g
C4H9 2 f
C2H5 2i
87:13 66
97
97
95
99
CH2CH2C6H5 1j
1k
CH3 CH2CH2C6H5 1l
97:3 70
96:4 72
97:3 88
CH3 C6H5
CH3 p-BrC6H4 C2H5 2j
[a] Yield of the isolated product after kinetic resolution and purification
by column chromatography. [b] Enantiomeric excess was determined by
gas-chromatographic analysis on chiral column (cyclodextrin B; see the
Supporting Information).
[a] Yield of isolated product after purification by column chromatog-
raphy. [b] Enantiomeric excess of the E isomer was determined by gas-
chromatographic analysis on chiral column (cyclodextrin B; see the
Supporting Information).
dized to lead to the putative unstable chiral 2-oxabicyclo-
[1.1.0]butane 3.
The absolute configurations of the starting cycloprope-
nylcarbinol 1g and the final ACP 2j imply an overall syn SN2’
displacement of the alcohol moiety. Starting at À508C, the
stirred mixture was slowly warmed to room temperature and
carefully followed by analysis of hydrolyzed aliquots. Under
these conditions, we were able to isolate the addition products
(after hydrolysis of aliquots of [Cu(6)]). These cyclopropyl–
metal complexes ([Cu(6)] or 6MgX) disappear in favor of the
ACP 2, which is obtained in good yield. As the deprotonation
of the alcohol precedes the addition, the most stable
conformer of the cyclopropenylcarbinolate is given in
Scheme 4, with the smallest substituent (hydrogen) at the
pre-existing orientation “inside” and the aryl group “out-
side”, away from the allylic methyl substituent (minimum 1,3-
strain). Thus, this catalytic reaction proceeds through a syn
addition/syn elimination mechanism (Scheme 4).
Two enantiomerically pure a,b-unsaturated ketols 4 and 5,
formed in equal amounts (each in 22–25% yield of isolated
product) as a result of the isomerization of the oxabicyclo-
butane by cleavage of the two pheripheral s bonds.[9] Oxabi-
cyclobutanes have been postulated several times to be
intermediates in various thermal[10a] and photochemical
reactions.[10b] In none of these cases, however, were oxabicy-
clobutanes detected. Although we were also not able to
isolate this intermediate, the Sharpless kinetic resolution
implies that the corresponding oxabicyclobutane was formed
as a reactive intermediate. The remaining non-oxidized
products, namely, the cyclopropenylcarbinols 1 were obtained
with very high enantiomeric excess and yields (95–99% ee
and 40–47% yield of isolated product). The scope of the
kinetic resolution is broad, as several different alkyl groups
can be present either on the double bond of the cyclopropenyl
unit (R1 = CH3 and C4H9) or on the cyclopropene ring itself
(R2 = H or CH3; Table 2, entries 1–4 and 5 and 6, respec-
tively).
Aryl and alkyl groups can be interchangeably used as
secondary substituents at the allylic position, although the
enantiomeric excess is slightly higher when R3 is an aryl group
(99% ee; entries 1–3 and 5) relative to an alkyl group
( ꢀ 95% ee; entries 4 and 6). Following the strategy we
described in Scheme 1, path B for the preparation of ACPs
from cyclopropenylcarbinols, alcohols 1 f,g were treated with
various Grignard reagents in the presence of 20 mol% of CuI
(Scheme 3 and Table 3). The reaction proceeds with an
Scheme 4. Mechanistic hypothesis for the overall syn SN2 process.
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reaction of chiral cyclopropenylcarbinol derivatives, obtained
through the kinetic resolution of secondary allylic alcohols,
leads to a straightforward, new preparation of enantiomeri-
cally pure alkylidenecyclopropane derivatives.
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Received: February 10, 2006
Published online: April 20, 2006
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