Desymmetrizing hydroformylation with the aid of a planar chiral catalyst-directing group

Article abstract of DOI:10.1021/ja0467364

Desymmetrizing hydroformylation of bisalkenyl- and bisallylcarbinols could be achieved employing a chiral substrate-bound catalyst-directing group (o-DPPF) with excellent levels of diastereotopic alkene face and diastereotopic alkene group discrimination to give bifunctionalized chiral aldehydes in enantiomerically pure form. Copyright

Full text of DOI:10.1021/ja0467364

Published on Web 08/03/2004
Desymmetrizing Hydroformylation with the Aid of a Planar Chiral
Catalyst-Directing Group
Bernhard Breit* and Daniel Breuninger
Institut fu¨r Organische Chemie und Biochemie, Albert-Ludwigs-UniVersita¨t Freiburg, Germany
Received June 3, 2004; E-mail: bernhard.breit@organik.chemie.uni-freiburg.de
Scheme 1. Concept of Desymmetrizing Hydroformylation with the
Aid of o-DPPF as a Planar Chiral Substrate-Bound
Catalyst-Directing Group (CDG*)
Hydroformylation of alkenes belongs to the most important
industrially applied processes that rely on homogeneous catalysis.1
A difficult problem is the control of stereochemistry throughout
the course of this reaction. Despite significant advances employing
asymmetric catalysis with chiral phosphorus ligands, this approach
is limited to a restricted number of substrates.2 An alternative
approach makes use of substrate-bound catalyst-directing groups
(CDG), which allow for diastereoselective hydroformylation of
chiral substrates (Scheme 1, A).3-5 However, if prochiral substrates
were to be employed, the chirality information would have to reside
in the catalyst-directing group. We herein report on a desymme-
trizing hydroformylation of prochiral bisalkenyl-carbinols 1 (n )
0) and bisallylcarbinols 2 (n ) 1) employing a new planar chiral
catalyst-directing group (o-DPPF) (Scheme 1, B).
From previous investigations we know that attachment of the
ortho-diphenylphosphanyl group (o-DPPB) to the alcohol function
of an allylic or homoallylic alcohol substrate allows for diastereo-
and regioselective hydroformylation due to efficient diastereotopic
alkene face discrimination.5 Control experiments established that
the o-DPPB function exhibits the ideal geometry and donor
properties to direct a rhodium catalyst efficiently into an allylic
and homoallylic position of the corresponding substrate. Hence, it
was envisioned that a planar chiral variant of the o-DPPB group
such as the ortho-diphenylphosphanylferrocene carbonyl (o-DPPF)
function may allow efficient stereodiscrimination of prochiral
substrates. As particularly attractive substrates, symmetrical bis-
alkenylcarbinols 1 (n ) 0) and bisallylcarbinols 2 (n ) 1) were
selected since a stereoselective monohydroformylation would set
two stereogenic centers simultaneously to give potentially interesting
chiral building blocks for polyketide synthesis. Stereoselective
hydroformylation of these substrates is particularly challenging since
diastereotopic alkene group discrimination and diastereotopic alkene
face discrimination have to be managed simultaneously.6
Since symmetrical bisalkenylcarbinols of type 1 are rarely found
in the literature, we developed simple access to 1a-e following
the routes depicted in Scheme 2. The bisallylcarbinols 2a-e were
obtained in a similar fashion upon addition of allyl Grignard or
allyl zinc reagent to ethylformiate.7
The subsequent esterification with the ortho-diphenylphospha-
nylferrocene carboxylic acid (o-DPPFA)8 proved difficult, employ-
ing standard esterification protocols presumably due to severe
sterical hindrance. Finally, good results were obtained upon
activation of the carboxylic acid with BOP9 and activation of the
alcohol as the sodium or lithium alcoholate (Table 1).
Scheme 2. Preparation of Bisalkenylcarbinols
mined through X-ray crystal structure analysis of aldehyde syn-
5a.7 Hence, a good diastereotopic alkene face discrimination
concomitant with excellent diastereotopic alkene group discrimina-
tion was achieved. As can be seen from entries 1-5, diastereotopic
face discrimination is somewhat influenced by the steric demand
of the 2-substituent at the alkene, which may be due to increased
1,2-allylic strain.10
In the case of bisallylcarbinol-o-DPPF esters 4, hydroformylation
proceeded at milder conditions (Table 3) to give the anti-aldehydes
6 in good yield, excellent anti/syn-diastereoselectivity and in
enantiomerically pure form. Here again efficient diastereotopic face
discrimination concomitant with excellent diastereotopic group
discrimination was achieved.11
Subjection of bisalkenylcarbinol o-DPPF esters to hydroformy-
lation conditions (Table 2) furnished the syn-aldehydes 5 as the
major product in good to excellent diastereoselectivity and in
enantiomerically pure form. Thus, of the four possible diastereo-
meric monoaldehydes, syn-5 is formed with high selectivity. The
configuration of the major diastereomer was unequivocally deter-
Removal of the substrate-bound catalyst-directing o-DPPF group
was achieved through saponification after protection of the alde-
hydes as the dimethylacetal. The alcohols 7 and 8 were obtained
in good yields, and the o-DPPFA could be recovered. Alternatively,
clean reductive removal of the o-DPPF group is achieved upon
9
10244
J. AM. CHEM. SOC. 2004, 126, 10244-10245
10.1021/ja0467364 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Preparation of Bisalkenyl- and Bisallylcarbinol o-DPPF
Esters 3 and 4
Scheme 3. Removal and Recovery of the Catalyst-Directing
o-DPPF Group
entry
R
n
o-DPPFA
base
product
eea (%)
yield (%)
1
2
3
4
5
6
7
8
9
10
Me
Et
i-Pr
t-Bu
CH2TMS
Me
Et
i-Pr
Ph
CH2OTBS
0
0
0
0
0
1
1
1
1
1
(Sp)-
(Sp)-
(Sp)-
(Sp)-
(Sp)-
(Rp)-
(Rp)-
(Rp)-
(Rp)-
(Rp)-
NaH
NaH
NaH
t-BuLi
t-BuLi
NaH
NaH
NaH
NaH
NaH
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
>99
>99
>99
>99
>99
>99
>99
>99
ndb
68
70
65
75
80
61
85
93
69
83
>99
with excellent levels of stereocontrol. Removal and recovery of
the catalyst-directing o-DPPF group is possible and gives access
to interesting chiral building blocks in enantiomerically pure form.
Furthermore, this stereoselective hydroformylation may be incor-
porated as a key step for synthetically interesting Tandem pro-
cesses.5,12
a Determined by HPLC. b Not determined.
Table 2. Desymmetrizing Hydroformylation of Bisalkenylcarbinol
o-DPPF Esters 3
Acknowledgment. We thank the Fonds of the Chemical
Industry, the Krupp Foundation (Krupp Award for Young Univer-
sity Teachers to B.B.) for financial support, and Dr. M. Keller for
the X-ray structure analysis of syn-5a.
c
T
t
conversion
(%)
yield
drb
syn/anti
ee
(%)
Supporting Information Available: Experimental details (PDF)
and X-ray crystal structure details (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
entry
R
(°C) (h)
product (%)a
1
2
3
4
5
Me
Et
i-Pr
70 48
70 48
70 48
90 72
quant.
quant.
95
61
56
5a
5b
5c
5d
5e
90
80
80
88:12 >99d
93:7
>98:2
>99d
>99e
>99e
>99e
References
t-Bu
82f >99:1
71f >99:1
CH2TMS 60 96
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Table 3. Desymmetrizing Hydroformylation of Bisallylcarbinol
o-DPPF Esters 4
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c
T
(°C)
t
(h)
conversion
(%)
yield
product (%)a anti/syn
drb
ee
entry
R
(%)
1
2
3
4
5
Me
Et
i-Pr
Ph
50 21.5
50 21
60 24
70 24
91
83
81
82
6a
6b
6c
6d
6e
83d 96:4
85d 95:5
>99e
>99e
84d 87:13 >99e
90d 94:6
80 95:5
>99e
>99f
CH2OTBS 50 16
quant.
a Isolated yield after chromatographic workup. b Determined by NMR
of the crude reaction mixture. c Refers to major diastereomer. d Based on
recovered starting material. e Determined by GC or HPLC after DIBAL
reduction to the corresponding 1,4-diols 9 (see Scheme 3). f Determined
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ReV. 1999, 99, 3329. (b) Kohling, P.; Schmidt, A. M.; Eilbracht, P. Org.
Lett. 2003, 5, 3213.
DIBAL reduction. In summary, with the aid of a chiral substrate-
bound catalyst-directing group, desymmetrizing hydroformylation
of bisalkenyl- and bisallylcarbinol derivatives could be achieved
JA0467364
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J. AM. CHEM. SOC. VOL. 126, NO. 33, 2004 10245