Enantioselective hydrogenation of 3-alkylidenelactams: High-throughput screening provides a surprising solution

Article abstract of DOI:10.1021/ja028043y

High-throughput screening of 256 potential catalysts (8 metal precursors × 32 phosphine ligands) has identified [(BDPP)Ir(COD)]BF₄ as a catalyst for the enantioselective hydrogenation of 3-alkylidenelactams. This result is surprising given the

Full text of DOI:10.1021/ja028043y

Published on Web 10/29/2002
Enantioselective Hydrogenation of 3-Alkylidenelactams: High-Throughput
Screening Provides a Surprising Solution
Tai-Yuen Yue* and William A. Nugent*
Bristol-Myers Squibb Company, Process Research and DeVelopment Department, Chambers Works, P.O. Box 269,
Deepwater, New Jersey 08023-0269
Received August 7, 2002
Table 1. Hydrogenation of 3-(p-Fluorobenzylidene)valerolactama
Enantiopure 3-alkylpiperidines are potent pharmacophores with
applications in several areas of medicinal chemistry.1 An attractive
conversion
(%)
ee
(%)
approach to these compounds would be asymmetric hydrogenation
of a 3-alkylidenelactam followed by reduction of the carbonyl
moiety as exemplified by eq 1. Unfortunately, there is little literature
precedent regarding the asymmetric hydrogenation of N-unsubsti-
tuted lactams of this type.2 In contrast, several catalytic systems
have been reported for the asymmetric hydrogenation of acyclic
and endocyclic enamides.3
metal precursor
[(COD)2Ir]BF4
diphosphine
BDPP
100
30
91
85
70
70
69
66
(COD)Ru(MeAll)2 + 2HBrb
(COD)Ru(MeAll)2 + 2HBrb
(COD)Ru(MeAll)2 + BF3 /HBF4
[(COD)2Rh]BF4
BICP
Fc-PPh2-PtBu2
Me-Pennphos
BDPP
98
c
100
100
85
[(COD)2Ir]BF4
DIOP
a Conditions: substrate/catalyst ) 100:1, room temperature, 12 h, 65
psi H2 in solvent ethanol; for details, see the Supporting Information.
b LRuBr2 was generated in situ from (COD)Ru(methallyl)2 and HBr
according to ref 6, run at 40 °C. c [LRuH(COT)]BF4 was generated in situ
from (COD)Ru(methallyl)2, BF3, and HBF4 according to ref 7, run at 40
°C.
Chart 1. Structures of Diphosphine Ligands in Table 1
A potential problem regarding eq 1 is the exocyclic nature of
the CdC bond. The inability of this bond to rotate toward the
carbonyl oxygen is expected to diminish the effectiveness of
chelation of such substrates to the metal atom of a catalyst. Substrate
chelation has long been recognized to be an important element in
achieving highly enantioselective hydrogenations.4
A signficant advance in this area was reported by researchers at
Merck.5 They found that an N-unsubstituted 3-alkylidene-2-
piperidone could be hydrogenated in 57% ee using (BINAP)RuCl2
as catalyst. Moreover, when the piperidone nitrogen was substituted
with a highly functional side chain, the ee could be increased to
93%. The increased selectivity was attributed to “internal chelation”
by the side-chain functionality.5
Encouraged by this report, we sought an improved catalyst for
asymmetric hydrogenation of 3-alkylidene-2-piperidones. Using the
hydrogenation in eq 1 as a model system, we screened a set of 32
chiral phosphines and 8 metal precursors. Ruthenium precursors
were generated in situ using protocols recently reported by Genet
and co-workers.6,7 The 6 most effective combinations of the 256
included in this study are listed in Table 1 (Chart 1). [For a complete
list of phosphines and metal precursors and details of the screening
protocol, see the Supporting Information.]
backbone is known to be highly flexible.11 For a given enantiomer
of BDPP, four possible conformers of a six-membered chelate ring
are possible, two of which are “pseudo-achiral” chair conformations
with the phenyl rings in an approximately achiral array.12 Moreover,
iridium complexes bearing BDPP ligands have proven especially
problematic in this regard. The lower enantioselectivity observed
for imine hydrogenations using Ir(COD)((S,S)-BDPP)+ as compared
with its rhodium analogue (0% ee versus 54% ee) led to the proposal
that achiral chair conformations are prevalent in the iridium
complex.13
The highest enantioselectivity in Table 1 was observed for the
combination of 2,4-bis(diphenylphosphino)pentane (BDPP) and
[(COD)2Ir]BF4 (COD ) 1,5-cyclooctadiene). This result was frankly
surprising. Structural rigidity is often a beneficial feature of
chelating diphosphines, and indeed other successful ligands in Table
1 - BICP,8 PennPhos,9 and the Josiphos type ligand Fc-PPh2-
10
PtBu2 - all share this structural feature. In contrast, the BDPP
The iridium-BDPP catalyst is advantageous from the standpoint
of process chemistry. Iridium is significantly cheaper than rhodium.
* To whom correspondence should be addressed. E-mail: william.nugent@
bms.com.
9
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J. AM. CHEM. SOC. 2002, 124, 13692-13693
10.1021/ja028043y CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Hydrogenation of 3-Alkylidenelactams
Given the protean nature of BDPP ligation, we find its unique
effectiveness as a ligand in these studies to be remarkable. As noted
by Nobel laureate William Knowles in his 1983 review article,4a
“Since achieving 95% ee only involves energy differences of about
2 kcal, which is no more than the barrier encountered in a simple
rotation of ethane, it is unlikely that before the fact one can predict
what kind of ligand structures will be effective.” With Knowles
we look forward to the day when computational techniques will
allow the prediction of the optimal catalyst for novel applications.
Until that day, high-throughput screening15 will remain an invalu-
able tool for catalyst discovery.
with [(S,S)-BDPP]Ir(COD)]BF4 According to Eq 3a
R
R′
n
yield (%)b
ee (%)
p-fluorophenyl
p-trifluoromethylphenyl
p-anisyl
2-furanyl
3-furanyl
n-propyl
isopropyl
p-fluorophenyl
n-propyl
p-fluorophenyl
p-fluorophenyl
H
2
2
2
2
2
2
2
1
1
3
2
97
96
92
91
87
90
95
95
90
81
89
82
75
67
H
H
H
H
H
H
H
H
H
Me
100
98
93c
100
100
98
92
97
Acknowledgment. The authors thank Dr. Mark J. Burk and
the staff of Symyx Technologies for their assistance with the initial
catalyst screen for eq 1. We thank George Emmett for identifying
the mandelic acid salt used to purify 3-(p-fluorobenzyl)piperidine.
Thanks are also due to Douglas McLeod for substrate preparation
and to Yun Ye, Joe Tang, Cathie Xiang, Liya Tang, Chris Wood,
and Brett Preston for developing chiral HPLC and GLC methods.
a Conditions: substrate/catalyst ) 200:1, room temperature, 24 h, 65
psi H2 in solvent CH2Cl2/MeOH (1:1); for details, see the Supporting
Information. b Isolated yield; conversion was quantitative except as noted.
c Conversion was 95%.
Both enantiomers of the BDPP ligand can be prepared inexpensively
on a kilogram scale. The 3-alkylidenelactam substrate is conve-
niently prepared by aldol condensation14 of valerolactam (trifluo-
roacetamide protecting group, lost during aqueous workup) as
shown in eq 2. The stereochemistry of the exocyclic double bond
is exclusively E.
Supporting Information Available: Detailed experimental pro-
cedures and characterization of new compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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i
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