Palladium(II)-catalyzed dicarboxymethylation of chiral allylic alcohols: Chirality transfer affording optically active diesters containing three contiguous chiral centers

Article abstract of DOI:10.1016/j.tetlet.2010.04.105

This manuscript describes the extension of Stille's palladium-catalyzed olefin dicarbonylation reaction to chiral allylic alcohols with chirality transfer to afford the corresponding chiral alcohol functionalized with bis-carbomethoxy esters, containing three contiguous chiral centers, in good to excellent diastereoselectivities (78-98%).

Full text of DOI:10.1016/j.tetlet.2010.04.105

Tetrahedron Letters 51 (2010) 3514–3517
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Palladium(II)-catalyzed dicarboxymethylation of chiral allylic alcohols:
chirality transfer affording optically active diesters containing three
contiguous chiral centers
z
*
Othman Hamed, Patrick M. Henry , Daniel P. Becker
Department of Chemistry, Loyola University Chicago, 6525 N. Sheridan Road, Chicago, IL 60626, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This manuscript describes the extension of Stille’s palladium-catalyzed olefin dicarbonylation reaction to
chiral allylic alcohols with chirality transfer to afford the corresponding chiral alcohol functionalized with
bis-carbomethoxy esters, containing three contiguous chiral centers, in good to excellent diastereoselec-
tivities (78–98%).
Received 10 March 2010
Revised 22 April 2010
Accepted 23 April 2010
Available online 29 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tion reaction is catalyzed by a PdCl2–CuCl2 system in methanol un-
der basic conditions at low CO pressures (3 atm) to give diesters
Enantiopure chiral materials are of key importance, particularly
in the preparation of bioactive pharmaceuticals and more recently
in liquid crystals, and palladium catalysis can be used in the con-
struction of new asymmetric centers, either asymmetric catalysis
or through the intramolecular transfer of existing chirality within
a molecule. The directing influence of the hydroxyl group has been
demonstrated for a number of reactions of chiral allylic alcohols,1–9
and stereoselectivities of over 98% have been demonstrated for
some reactions.10–13 We presently wish to report the extension
of chirality transfer from chiral allylic alcohols utilizing Stille’s pal-
ladium-catalyzed olefin dicarbonylation reaction.14 In this context
is it noteworthy that a number of groups have explored the use of
chiral catalysts with the Stille bis-alkoxycarbonylation for the
asymmetric construction of chiral bis-esters. Inomata and co-
workers recently reported the palladium-catalyzed asymmetric
bis(alkoxycarbonylation) of cyclic olefins in the presence of copper
triflate.15 Liang et al. have described a palladium-catalyzed asym-
metric biscarbonylation of terminal olefins using chiral S,N-hetero-
bidentate ligands.16 Takeuchi described a palladium-catalyzed
asymmetric bis(alkoxycarbonylation) reaction of terminal olefins
in the presence of copper(I) triflate using a chiral bioxazoline li-
gand to give optically active mono-substituted succinates with
enantioselectivities up to 66% ee,17 while Sperrle reported the
enantioselective bis-alkoxycarbonylation of 1-olefins to substi-
tuted succinates using cationic palladium(II) complexes with C2
symmetric chelating ligands, and also the use of cationic palla-
dium(II) complexes to catalyze multiple carbonylation of 1-olefins
to 2-oxopentanedioates and to butanedioates.18 The dicarbonyla-
with an overall syn addition.19–27 While chirality transfer generally
involves transfer of optical activity from one carbon to another,
this allylic dicarbonylation that we now report involves a double
insertion of CO to give diesters containing three contiguous chiral
centers.
2. Results and discussion
The bis-carbonylation with chirality transfer was first tested
with the chiral cyclic allylic alcohol (R)-(+)-cyclopent-2-en-1-ol28
(1). Cyclopent-2-enone underwent clean 1,2-reduction to afford
compound (R)-(+)-1 in 78.3% isolated yield and 71% ee by reduc-
tion with chiral (R)-oxazaborolidine29–31 and borane. Kita reported
a similar asymmetric reduction of a cyclic enone with an oxaz-
aborolidine32 and Matusuo recently reported the oxazaboroli-
dine-catalyzed asymmetric reduction of
a-methylene ketones
using borane-diethylaniline as a stoichiometric reducing agent.33
The absolute configuration of 1 was determined based upon mea-
surement of rotation and comparison with literature values.34
Treatment of (R)-(+)-1 with PdCl2 and CuCl2 in methanol at room
temperature under an atmosphere of CO (3 atm) in the presence
of trimethyl orthoformate to remove adventitious water gave
two products in 65% and 35% relative yields as determined by
gas chromatography. The two products were identified by 1H and
13C NMR to be (1S,2S,3R)-dimethyl 3-hydroxycyclopentane-1,2-
dicarboxylate (2) and (S)-methyl 3-oxocyclopentanecarboxylate
(3), respectively (Scheme 1). The ee of 2 was established to be
69.7% as determined by 1H NMR in the presence of lanthanide shift
reagent Eu(hcf)3, thus the reaction proceeded in 98% diastereose-
lectivity (Table 1), representing the efficiency of chirality transfer
from the asymmetric carbinol center. As noted, allylic alcohol (R)-(+)-1
was utilized with 71% ee, such that complete diastereoselectivity
* Corresponding author. Tel.: +1 773 508 3089; fax: +1 773 508 3086.
E-mail address: dbecke3@luc.edu (D.P. Becker).
z
Deceased October 19, 2008.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.105

O. Hamed et al. / Tetrahedron Letters 51 (2010) 3514–3517
3515
CO (3 atm), PdCl2
CO2Me
CO2Me
2
CO2Me
HO
O
+
HO
NaOAc, HC(OMe)3
MeOH, rt, 72h
1
3
Scheme 1. Dicarbonylation of (R)-(+)-1.
Table 1
Stereochemistry of dicarbonylated products from various allylic alcohols
Substrate
%ee of substrate
Dicarbonylated product
%Yield
45
%ee of Dicarbonylated producta
Diastereo-selectivityb
H
HO
(R)-(+)-Cyclopent-2-en-1-ol (1)
71
69.7
98
96
MeO2C
CO2Me
-2
(1S,2S,3R)
OH CO2Me
R-(+)-(Z)-Pent-3-en-2-ol [(Z)-9]
86
52
82.7
CO2Me
(R,R,R)-10
OH CO2Me
(R)-(À)-(E)-Pent-3-en-2-ol [(E)-9]
83
29
41
36
64.7
80.7
64.7
78
93
86
CO2Me
(R,R,S)-10
OH CO2Me
Ph
CO2Me
(R,R,S)-14
OH CO2Me
(R)-(Z)-4-Phenyl-3-butene-2-ol [(R)-(Z)-13]
(R)-(E)-4-Phenyl-3-buten-2-ol [(R)-(E)-13]
87
Ph
75.3
CO2Me
(R,R,R)-14
a
Average of three ee values determined for each of the three asymmetric centers by 1H NMR using the chiral shift reagent Eu(hcf)3.
Diastereoselectivity (efficiency of chirality transfer) = product ee/ee of substrate  100%.
b
in the bis-alkoxycarbonylation would yield diester of ee identical
to the starting allylic alcohol. The relative stereochemistry of the
dicarbonylation product 2 was established by 1H NMR, and NOE
studies. The J values of Hb with Ha and Hc, respectively are 8.0 and
15.6 Hz. These values are consistent with the syn stereochemistry
between Ha, Hb and Hc. Since the absolute configuration at C-1 is
known to be R, the absolute configuration at C-1 and C-2, bearing
the carbomethoxy groups, must both be S. The relative stereochem-
istries of Ha, Hb and Hc were also confirmed on the basis of NOE
studies (Fig. 1). The all-syn relative stereochemistry evident by the
10.2% enhancement of the signal for Ha upon irradiation of Hb and
the 13.3% enhancement of the signal for Hc. The cis stereochemistry
is as predicted for the double-carbonylation reaction.35
dium(II)-catalyzed oxypalladation and 1,3-chirality transfer. Thus,
the hydroxyl group directs the palladium to the face that produces
the most stable p-complex 4, which in turn depends on the abso-
lute configuration of the starting allylic alcohol 1.4,10–13 Addition of
carbon monoxide to complex 4 followed by insertion of methanol
yields the olefin-carbomethoxypalladium intermediate 5, which
undergoes insertion of the carbomethoxy group to produce the
r
-complex 6.14,19 Adduct 6 then either undergoes further syn addi-
tion of CO to give desired 2, or loses a proton and eliminates palla-
dium yielding an enol which tautomerizes to ketone 3.
Next we examined the carbomethoxylation of (R)-(Z)-pent-3-
en-2-ol [(Z)-9] and (R)-(E)-pent-3-en-2-ol [(E)-9]. Both isomers
were prepared from the reduction of (R)-(+)-pent-3-yn-2-ol (8)
(Scheme 3). (R)-(+)-pent-3-yn-2-ol (8) was prepared in 85% yield
by the reduction of 3-pentyn-2-one 7 with chiral (S,S)-RuCl[N-(to-
syl)-1,2-diphenylethylenediamine)(p-cymene)] reagent in formic
acid/triethylamine isotropic mixture according to the general
method of Bogliotti.36 A sample of (R)-(Z)-9 was prepared in 86%
ee by reduction of the triple bond with Lindlar’s catalyst37 while
(R)-(E)-9 was prepared in 83% ee by reduction with LiAlH4.38 GLC
and 1H NMR analysis showed that each sample was greater than
95% of the desired double bond geometric isomer.
The product distribution and relative stereochemistries are con-
sistent with the proposed mechanism (Scheme 2), similar to the
mechanism proposed by Uenishi13 for an intramolecular palla-
MeO2C
MeO2C
OH
Ha
Hc
Hb
Dicarbomethoxylation of each geometric isomer of 9 indepen-
dently was carried out in the same manner as for the substrate
(R)-(+)-1 (Table 1). (R)-(Z)-9 afforded three products as shown by
GLC, which were identified by NMR spectroscopy to be the desired
(2R,3R)-dimethyl 2-((R)-1-hydroxyethyl)-3-methylsuccinate [(R,R,R)-
J = 15.6 Hz
J = 8.0 Hz
NOE = 13.3%
NOE = 10.2%
Figure 1. Confirmation of all-cis stereochemistry of dicarbonylated product 2 based
on vicinal coupling constants and NOE correlations.

3516
O. Hamed et al. / Tetrahedron Letters 51 (2010) 3514–3517
H
H
H
CO
O
-2Cl-
MeOH
MeOH
O
-2
H
+
+
CO
PdCl4
HO
H
- Cl-,
-H
+
Pd
Pd
Cl
CO2Me
Cl
Cl
(R)-(+)-1
4
5
H
CO
H
HO
MeO2C
-Pd0
-HCl
CO2Me
O
2
H
Pd
CO2Me
Cl
O
H
-Pd0
-HCl
H3C
O
6
CO2Me
3
Scheme 2. Proposed mechanism for the palladium-catalyzed bis-alkoxycarbonylation of allylic alcohols with chirality transfer.
OH
R
Ts
Ph
Ph
N
Lindlar
LAH
Ru
(Z)-9 R = CH3
(Z)-13 R = Ph
O
Cl
OH
N
Ts
H3C
H3C
HCO2H, Et3N
R
R
OH
8
R = CH3
R = Ph
7
R = CH3
R = Ph
12
11
R
(E)-9 R = CH3
O
(E)-13 R = Ph
O
"
"
Ph
Ph
CH3
CH3
15
O
O
Ph2HC
CH3
Ph2HC
CH3
16
Scheme 3. Preparation of Z and E allylic alcohols 9 and 13.
10] in 80% relative yield, plus 4-methoxy-pentan-2-one in 10% yield,
and 4-acetoxy-pentan-2-one in 10% yield. A pure sample of (R,R,R)-
10 was obtained by gas chromatography and the enantiomeric
excess was determined by 1H NMR in the presence of chiral shift
reagent Eu(hfc)3 to be 82.7%, thus the diastereoselectivity was
96%. The dicarbonylation of (R)-(E)-9 afforded the desired dica-
rboxymethylation product (2R,3S)-dimethyl 2-((R)-1-hydroxy-
ethyl)-3-methylsuccinate, (R,R,S)-10, in 45% relative yield, plus
4-methoxy-pentan-2-one, 4-acetoxy-pentan-2-one, and 4-carbo-
methoxy-pentan-2-one, and 5%, 20%, and 30%relativeyields, respec-
tively. A pure sample of (R,R,S)-10 was collected by GLC and analyzed
by 1H NMR in the presence of the lanthanide shift reagent Eu(hcf)3 to
establish an ee of 64.7%, representing a diastereoselectivity of 78%.
The relative configurations of stereogenic centers in the carbonylat-
ed products (10) of (R)-(Z)-9 and R-(E)-9 were confirmed by NOE.
NOE has been used previously to assign absolute configurations of
cyclic systems39 and the theory for acyclic systems such as 9 with
restricted rotation has also been presented.40 Shown in Figure 2
are the NOE assignments for the most stable rotamers of the two
products. These assignments are in agreement with all the informa-
tion from 1H–1H NOESY NMR. The assignment of absolute configura-
tion is consistent with the expected initial syn addition of the
elements of the carbomethoxy-Pd(II) moiety shown in Scheme 2.
CO2Me
H
OH
H
CO2Me
H
OH
H
CO2Me
CO2Me
(R,R,R)-10
(R,R,S)-10
N.O.E. observed
between C2-H and C4-H
N.O.E. not observed
between C2-H and C4-H
Figure 2. Assignment of relative stereochemistry of stereoisomers of 10 based on
NOE.
Carbonylation of allylic alcohols (R)-(Z)-4-phenyl-but-3-ene-2-
ol [(R)-(Z)-13] and (R)-(E)-4-phenyl-3-buten-2-ol [(R)-(E)-13] were
then evaluated. Propargyl alcohol 12 was prepared in 87% ee with
(R) absolute configuration by the reduction of propagyl ketone 11
again using (S,S)-RuCl[N-(tosyl)-1,2-diphenylethylenediamine)(p-
cymene)] as outlined in Scheme 3. Allylic alcohol (R)-(Z)-13 was
prepared in 87% ee by the reduction of the propagyl alcohol (R)-
4-phenyl-but-3-yne-2-ol (12) using Lindlar’s catalyst. Allylic alco-
hol (R)-(E)-13 was prepared in 75% ee by the reduction of 12 using
LiAlH4.

O. Hamed et al. / Tetrahedron Letters 51 (2010) 3514–3517
3517
Carbomethylation of (R)-(Z)-13 afforded three products that
References and notes
were isolated and purified by flash chromatography. NMR analysis
showed the compounds to be 4-methoxy-4-phenylbutan-2-one, 4-
acetoxy-4-phenyl-butan-2-one, and the desired (2R,3S)-dimethyl
2-((R)-1-hydroxyethyl)-3-phenylsuccinate (R,R,S)-14, in 41% yield.
The ee of (R,R,S)-14 was determined by 1H NMR in the presence of
the lanthanide shift reagent Eu(hcf)3 to be 80.7%, representing a dia-
stereoselectivity of 93%. Dicarbomethoxylation of (R)-(E)-13 also
produced three products, which were isolated and purified by flash
chromatography. 1H NMR analysis showed the compounds to be 4-
methoxy-4-phenylbutan-2-one, 4-acetoxy-4-phenyl-butan-2-one,
and the (2R,3R)-dimethyl 2-((R)-1-hydroxyethyl)-3-phenylsuccinate
(R,R,R)-14 in 17%, 27% and 56% yield, respectively. The diastereo-
meric ratio for (R,R,R)-14 was determined by 1H NMR in the pres-
ence of the lanthanide shift reagent Eu(hcf)3 to be 64.7%, thus the
dicarbomethoxylation proceeded in 86% diastereoselectivity.
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materials containing three contiguous asymmetric centers in good
to excellent (78–98%) diastereoselectivities.
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Acknowledgment is made to the Donors of the American Chem-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.105.