Dynamic kinetic asymmetric allylic alkylations of allenes

Article abstract of DOI:10.1021/ja0543705

The dynamic kinetic asymmetric allylic alkylations of racemic allene acetates has been developed with the DACH-phenyl Trost ligand 2 to give general access to allenes with high enantiomeric excess (84-95%) for both malonate and amine nucleophiles. Further

Full text of DOI:10.1021/ja0543705

Published on Web 09/27/2005
Dynamic Kinetic Asymmetric Allylic Alkylations of Allenes
Barry M. Trost,* Daniel R. Fandrick, and Diana C. Dinh
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 1, 2005; E-mail: bmtrost@stanford.edu
Efficient and atom economic1 methods for construction of chiral
Table 1. Base Effect on the Dynamic Kinetic Asymmetric
Alkylation of Allene 4 with Diethyl Methylmalonatea
allenes are of significance due to the presence of this core structure
in numerous natural and biologically important products,2 as well
as synthetic intermediates for asymmetric synthesis of targets
involving chirality transfer.2,3 Undoubtedly, the potential in this
latter regard has been retarded by the limited accessibility of
enantioenriched allenes. Typically, chiral allenes are derived from
chiral propargylic alcohols.2,4 Only recently has asymmetric
catalysis been employed for the construction of allenes.2,5 Several
limited methods utilize the asymmetric addition of soft nucleophiles
to vinyl-allyl Pd(II) intermediates accessed through both the
oxidative addition of racemic 2,3-alkadienyl phosphates6 and
prochiral vinyl bromides.7 Our group has been active in related
palladium-catalyzed asymmetric allylic alkylations (AAA) through
a dynamic kinetic asymmetric transformation (DYKAT) utilizing
our ligands.8 Therefore, we focused our studies on the use of these
ligands for the dynamic kinetic asymmetric addition of nucleophiles
to allenes (eq 1), which has led to a general access to allenes of
high enantiomeric excess for both carbon- and nitrogen-based
nucleophiles. Further, a most unusual dependence of enantioselec-
tivity on base in the case of amine nucleophiles has been uncovered.
entry
base
ee (%)b
yield (%)c
1
2
3
4
5
LDA
LiHMDS
KHMDS
NaH
85
84
45
75
23
90
84
84
70
46
NR
NR
47
92
85
Cs2CO3
6
c-C6H11MgCl
KHMDS/ZnCl2
BSA/5% KOAc
KHMDS/Et3B
KHMDS/(EtO)3B
7
8d
9
45
48
48
10
a Reaction performed with Pd2dba3CHCl3 (2.5 mol %), (S,S)-2 (7.5 mol
%), allene/malonate/base (1/1.1/1.1) in THF at room temperature. b Deter-
mined by chiral HPLC. c Isolated yield of allene (S)-(+)-10. NR ) no
reaction. BSA) N,O-bis(trimethylsilyl)acetamide. d From ref 9.
Table 2. Dynamic Kinetic Asymmetric Alkylation of Allenes with
Malonatesa
Optimization of the ligand, solvent, palladium precatalyst, and
additive revealed the standard catalyst system as Pd2dba3-CHCl3
(2.5 mol %), ligand 2 (7.5 mol %), and THACl (tetrahexylammo-
nium chloride) (5 mol %) in THF. Asymmetric addition of diethyl
methylmalonate to allene 4 with lithium diisopropylamide (LDA)
afforded allene 10 in 90% yield and 85% ee. THACl as a catalytic
additive provided an incremental but consistent increase in enan-
tioselectivity with THF as the solvent. Unlike previous Pd-catalyzed
asymmetric allylic alkylations using these ligands,11 bases with a
more coordinating and smaller countercation (entries 1 and 2)
provided the highest enantioselectivity (Table 1).12
After establishing the optimized conditions, the scope and
limitation of the dynamic kinetic asymmetric addition of malonates
to allene acetates was explored (Table 2). Increasing the size of
the allene substituent only slightly increased the enantiomeric excess
(entries 1-4). Unsubstituted malonates also afford high enantio-
selectivity (86% ee) by employing a 3-fold excess of the malonate
to suppress bisalkylation (entry 5). Most importantly, these condi-
tions tolerate additional functionality, such as dienes, to provide
chiral precursors suitable for further transformations (entries 6 and
7).
a Absolute configuration determined by comparison to (S)-(+)-10 with
known stereochemistry derived from D-mannitol, analogy, and the Lowe-
Brewster rule.10 b Enantiomeric excess determined by chiral HPLC.
c Isolated yields. d With 3 equiv of malonate employed. Sorbyl ) trans,trans
2,3-hexadienyl.
The dynamic kinetic asymmetric addition of amines to allenes
further demonstrates the profound influence of the base on the
enantioselectivity (Table 3). Chiral (S)-(+)-allenamines 19-21 were
prepared with high enantioselectivities (89-95% ee) by employing
1.1 equiv of the amine and an excess of Cs2CO3 (entries 1-3, 5).
9
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J. AM. CHEM. SOC. 2005, 127, 14186-14187
10.1021/ja0543705 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Dynamic Kinetic Asymmetric Alkylation of Allenes with
Amines
shown to be more active in other types of cycloadditions efficiently
provided the cycloisomers with complete chirality transfer and as
one diastereomer (eq 4).
In conclusion, we have developed highly enantioselective condi-
tions for the dynamic kinetic asymmetric allylic alkylation of
racemic allenes with amines and malonates and demonstrated a
dramatic base effect. Furthermore, these DYKAT products are well
suited for further useful transformations wherein the axial chirality
is faithfully transferred into multiple stereogenic centers as well as
olefin geometry.
a Conditions: A. 1.1 equiv of amine to allene, 3 equiv of Cs2CO3, room
temperature, 1 day. B. 2.2 equiv of amine to allene, room temperature, 1
day. C. 1.1 equiv of indoline to allene, 60 °C, 1 day. b Enantiomeric excess
determined by chiral HPLC. c Absolute configuration determined by
comparison of allene (S)-(+)-23 with known stereochemistry derived from
D-mannitol, analogy, and Lowe-Brewster rule.10 Reversal in stereochemistry
was verified by both chiral HPLC and optical rotation. d Isolated yield.
e Reaction performed at 60 °C for 18 h. f Reaction conducted with Pd2dba3-
CHCl3 (7.5 mol %), (S,S)-2 (22.5 mol %), THACl (15 mol %). g Enantio-
meric excess ((10%) determined by optical rotation compared to material
with known enantiomeric excess.13
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Institute (GM-13598), for their generous support of our programs.
We thank Paul Wender and his group for the generous gift of the
Rh(I) catalyst. D.R.F. thanks Eli Lilly and Company for the Eli
Lilly Graduate Fellowship.
Supporting Information Available: Synthesis of the allene
substrates, experimental details, establishment of the absolute configura-
tions, and characterization data for all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Interestingly, the utilization of the identical (S,S) catalyst system
and a 2-fold excess of the amine resulted in the formation of the
opposite enantiomer (R) with lower enantiomeric excess (28-65%
ee). Indoline did not require a base and provided the DYKAT adduct
with a slight decrease in selectivity (entry 4). The asymmetric
addition of N-benzylmethylamine to allene 4 proceeded with only
partial conversion with 2.5 mol % of palladium dimer. Attributing
this difference in reactivity to product inhibition, tripling the
standard catalyst loading enabled complete conversion to the product
allenamine 23 (entry 5).13
In general, for a Pd-catalyzed AAA involving a DYKAT, one
must establish Curtin-Hammett conditions and promote a selective
nucleophilic addition to one diastereomeric π-allyl Pd(II) intermedi-
ate over the other. The reasonable effect of THACl8 and dba
(dibenzylideneacetone)7b as additives on the enantioselectivity is
due to increasing the rate of such an interconversion. Unlike
previous AAA of allenes with malonate nucleophiles,6,7 the above
conditions afforded high enantioselectivities for allenes, regardless
of the size of the allene substituent ranging from 86% ee for n-butyl
to 91% ee for a tertiary group. Furthermore, the dramatic reversal
in enantioselectivity in the addition of amines to allenes demon-
strates the choice of the base in addition to the chirality of the ligand
determines which diastereomeric π-allyl Pd(II) intermediate is
preferentially attacked and hence the chirality of the product. In
addition to obtaining a Curtin-Hammett situation, conditions must
be optimized to favor a selective nucleophilic attack to one
diastereomeric π-allyl Pd(II) intermediate. This observation may
also explain the base effect on the malonate cases, but its effect
purely on the rate of the interconversion cannot be discredited since
no reversal in asymmetric induction was observed.
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