Iridium-catalyzed enantioselective allylic alkylation with functionalized organozinc bromides

Article abstract of DOI:10.1002/anie.201501851

Iridium-catalyzed enantioselective allylic alkylation of branched racemic carbonates with functionalized alkylzinc bromide reagents is described. Enabled by a chiral Ir/(P,olefin) complex, the method described allows allylic substitution with various primary and secondary alkyl nucleophiles with excellent regio- and enantioselectivities. The developed reaction was showcased in a concise, asymmetric synthesis of (-)-preclamol. An Ir/(P,olefin) complex catalyzes the title reaction and the method provides a variety of allylated products with excellent regio- and stereoselectivities. The utility of the coupling is demonstrated in a catalytic enantioselective synthesis of a preclinical drug (-)-preclamol. Boc=tert-butyloxycarbonyl, cod=1,5-cyclooctadiene.

Full text of DOI:10.1002/anie.201501851

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501851
German Edition: DOI: 10.1002/ange.201501851
Synthetic Methods
Iridium-Catalyzed Enantioselective Allylic Alkylation with
Functionalized Organozinc Bromides**
James Y. Hamilton, David Sarlah, and Erick M. Carreira*
Abstract: Iridium-catalyzed enantioselective allylic alkylation
of branched racemic carbonates with functionalized alkylzinc
bromide reagents is described. Enabled by a chiral Ir/(P,olefin)
complex, the method described allows allylic substitution with
various primary and secondary alkyl nucleophiles with
excellent regio- and enantioselectivities. The developed reac-
tion was showcased in a concise, asymmetric synthesis of
(À)-preclamol.
including functionality such as esters, nitriles, halides, and
acetals with high enantioselectivity (up to > 99% ee) and
complete branched regioselectivity. The synthetic utility of
this method is demonstrated in an asymmetric synthesis of
(À)-preclamol, a promising drug candidate for the treatment
of schizophrenia.
Pioneering studies from the groups of Alexakis, Bꢀckvall,
Feringa, and Hoveyda have led to impressive copper-cata-
lyzed processes for asymmetric alkylations with various
nonstabilized alkyl nucleophiles (pKa > 25),[4] including
Grignard,[5] organolithium,[6] organoaluminum,[7] and organo-
zinc[8] reagents. Asymmetric allylic substitutions catalyzed by
chiral complexes of palladium or iridium represent an
alternative approach. Developments in palladium-catalyzed
processes, the most extensively studied system in this field,
have been hampered by deleterious competing mechanistic
pathways such as b-hydride elimination. Thus, only recently
Maulide and co-workers have disclosed palladium-catalyzed
allylic alkylation using dialkylzinc reagents.[9]
In general, the high reactivity of nonstabilized alkyl
nucleophiles has not only limited their utility in catalytic
processes but also their compatibility with functional groups.
Alkylzinc halides represent a notable exception, and yet they
are a particularly attractive class of nonstabilized alkyl
nucleophiles as a consequence of their superb functional-
group tolerance and the fact that they transfer the sole alkyl
group they bear.[10] Importantly, recent advances by Knochel
and co-workers have allowed ready access to a wide variety of
functionalized organozinc reagents.[11]
T
ransition metal-catalyzed asymmetric allylic substitution
reactions are among the most powerful transformations
currently available for the enantioselective formation of
carbon–carbon bonds.[1] Among these, iridium-catalyzed
allylic substitution reactions have recently enjoyed much
attention, thus resulting in a wide range of reaction partners
which can be employed.[2] Despite these significant advances,
however, nonstabilized alkyl metal reagents are absent
altogether as nucleophiles. The use of nonstabilized alkyl
nucleophiles in iridium-catalyzed reactions would consider-
ably expand the scope of such processes by providing new
routes to previously inaccessible products, especially when
the alkyl reagents incorporate functional groups for further
elaboration.[3] Herein, we disclose the development of an
enantioselective allylic alkylation reaction involving racemic
branched allylic carbonates and functionalized alkylzinc
bromide reagents, and it is catalyzed by a chiral iridium/
(P,olefin) complex (Scheme 1). The method delivers adducts
Chiral iridium complexes have recently emerged as
versatile catalysts for regio- and stereoselective allylic sub-
stitution reactions.[2] In this context, we have developed and
employed a complex formed from iridium(I) and a chiral
phosphoramidite olefin bidentate ligand for a number of
highly enantio- and diastereoselective carbon–carbon bond-
forming transformations.[12] As part of an ongoing effort to
extend the synthetic utility of the allyl iridium intermediates,
we were intrigued by the possible use of functionalized
alkylzinc bromides to gain access to a class of functionalized,
optically pure adducts.[2p] To the best of our knowledge, allylic
substitution with nonstabilized alkyl nucleophiles has not
been documented with iridium catalysis.
In the initial screening studies, we examined the substi-
tution reaction of the 2-naphthyl vinyl carbinol derivative
1 with the bis(homoenolate) reagent 2a, prepared in THF, in
the presence of a complex formed in situ from a phosphor-
amidite olefin ligand (S)-L and [{Ir(cod)Cl}2] (Table 1). By
employing the benzoyl ester of 1 in 1,4-dioxane (entry 1), the
product 3a was obtained in 90% ee, albeit in only 20% yield.
A survey of different derivatives of 1 revealed the corre-
Scheme 1. Iridium-catalyzed enantioselective allylic alkylation with
RZnBr. cod=1,5-cyclooctadiene.
[*] J. Y. Hamilton, Dr. D. Sarlah, Prof. Dr. E. M. Carreira
Eidgençssische Technische Hochschule Zꢀrich, HCI H335
Vladimir-Prelog-Weg 3, 8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] We are grateful to the ETH Zꢀrich and the Swiss National Science
Foundation (200020_152898) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501851.
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Table 1: Reaction development of enantioselective allylic alkylation.[a]
Entry Cat.
[mol%]
R’
Equiv 2a
in THF
Solvent
Yield ee
[%][b] [%][c]
Variation of leaving group
1
2
3
4
4
4
4
4
Bz
TFA
1.5 (0.5m) 1,4-dioxane
1.5 (0.5m) 1,4-dioxane
20
23
46
61
90
93
96
89
CO2Me 1.5 (0.5m) 1,4-dioxane
Boc 1.5 (0.5m) 1,4-dioxane
Variation of organozinc concentration
5
6
4
4
Boc
Boc
1.5 (1.0m) 1,4-dioxane
1.5 (2.0m) 1,4-dioxane
73
79
96
98
Optimization of catalyst loading, organozinc stoichiometry, and solvent
7
8
9
1
1
1
Boc
Boc
Boc
1.5 (2.0m) 1,4-dioxane
1.2 (2.0m) 1,4-dioxane
1.2 (2.0m) PhMe
79
78
85
98
>99
>99
Scheme 2. Substrate scope of enantioselective allylic alkylation. Unless
otherwise noted, all reactions performed on 0.25 mmol scale under the
standard reaction conditions (see Table 1, entry 9). Yield of the isolated
product after purification by chromatography on silica gel. Enantiomer-
ic excess determined by SFC on chiral stationary phase. [a] 24 h
reaction. [b] Obtained as a mixture of two branched regioisomers
(15:1=SN2/SN2’). Ac=acetyl, Bn=benzyl.
[a] Reaction conditions: [{Ir(cod)Cl}2], [Ir]/(S)-L=1:2, 1 (0.125 mmol,
1.0 equiv), 2a (solution in THF), solvent (0.25 mL), 258C, 12 h.
[b] Determined by 1H NMR spectroscopy by using an internal standard
(1,4-dinitrobezene). [c] Determined by supercritical fluid chromatogra-
phy (SFC) on chiral stationary phase. Absolute configuration assigned by
comparison with known compounds. Boc=tert-butoxycarbonyl,
Bz=benzoyl, 2-Np=2-naphthyl, TFA=trifluoroacetyl.
sponding tert-butyl carbonate as optimal, with 3a formed in
61% yield and 89% ee (entries 2–4). The lower yield
observed for the methylcarbonate derivative was traced
back to the formation of the corresponding methyl ether
byproduct (entry 3). Following the identification of the tert-
butyl carbonate as optimal, we then turned our attention to
the evaluation of reaction parameters (see Tables S1–S6 in
the Supporting Information for full details).
Although 2a was prepared as a 0.5m solution in THF
following the protocol of Knochel, we found that increasing
the concentration of 2a to 2.0m by partial evaporation of THF
under reduced pressure was advantageous to the reaction
outcome (Table 1, entries 5 and 6). Thus, the use of 2a (2.0m
in THF) furnished 3a in 79% yield and 98% ee (entry 6). The
use of only 1 mol% [{Ir(cod)Cl}2] and 1.2 equivalents of 2a
led to comparable product yield and greater than 99% ee
(entry 8). With toluene as optimal solvent, the coupled
product was obtained in 85% yield and greater than
99% ee (entry 9). Finally, we note that formation of the
undesired, achiral linear alkylation adduct was not detected
throughout this study.[13]
because of lower conversion, the adduct 3h was produced in
98% ee. Additionally, aromatics with appended protected
amines (3i) and heteroaromatic (3j) allyl carbonates under-
went the asymmetric allylic alkylation successfully. Gratify-
ingly, 1,4-diene 3k and 1,4-enyne 3l furnished adducts in high
yields with greater than 99% ee.[5g] Aliphatic allylic carbo-
nates did not undergo the described allylic alkylation.
As shown in Scheme 3, we then examined a variety of
alkylzinc bromides under the optimal reaction conditions,
using 1a as a standard reaction partner. Alkylzinc reagents of
the protected aldehydes 2m and 2n underwent the reaction
with good yields (62–68%) and greater than 99% enantio-
control. Simple primary (2o) as well as secondary (2p)
alkylzinc bromides could be employed with the latter forming
the adduct with diminished enantioselectivity (80% ee).
Functional groups such as acetoxy (2q), cyano (2r), and
chloro (2s) groups, which may be incompatible with other
main group organometallic reagents, were well tolerated.
Alkylzinc bromides incorporating an alkene (2t) and an arene
(2u) also engaged in allylic alkylation reactions with 58–70%
yield and greater than 99 and 95% ee, respectively.
Having identified optimized reaction conditions for
enantioselective alkylation, we explored the substrate scope
of this reaction with 2a as a standard nucleophile as
summarized in Scheme 2. Unsubstituted (3b) as well as
alkoxy-substituted (3c) phenyl substrates gave the corre-
sponding adducts in 79 and 81% yield, respectively and
greater than 99% ee. Substrates incorporating halogenated
arenes (3d–g) were also compatible with the process.
Although the substrate possessing an electron-withdrawing
ester substituent resulted in a diminished yield (60%)
As a means of highlighting the synthetic utility of the
method, we examined an enantioselective synthesis of (À)-
preclamol,[14] a potent dopaminergic drug candidate with
antipsychotic therapeutic effects for the treatment of schiz-
ophrenia.[15] As illustrated in Scheme 4, exposure of the allylic
carbonate 1c to the alkylzinc bromide reagent 2n under
optimized reaction conditions afforded 4 in 75% yield and
greater than 99% ee. Reaction of 4 with ozone followed by
reductive work up gave the diol 5, which was then subjected to
a three-step sequence[14b] of reactions to deliver (À)-precla-
2
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a gram-scale reaction. Finally, the synthetic utility of this
methodology has been showcased in a concise catalytic
enantioselective synthesis of (À)-preclamol.
Experimental Section
General procedure: [{Ir(cod)Cl}2] (1.7 mg, 2.5 mmol, 1 mol%) and the
phosphoramidite ligand (S)-L (5.1 mg, 10.0 mmol, 4 mol%) were
dissolved in toluene (0.5 mL) and vigorously stirred for 15 min under
an atmosphere of N2. To the resulting dark red solution, allylic
carbonate 1 (0.25 mmol, 1.0 equiv) and alkylzinc bromide 2 (0.15 mL,
0.30 mmol, 1.2 equiv) were sequentially added. The orange reaction
mixture was stirred under N2 at 258C for 12 h. Upon complete
consumption of the starting material, one drop of methanol was
added to the mixture, which was then directly subjected to flash
chromatography to afford the product.
Keywords: alkylation · allylic compounds · enantioselectivity ·
iridium · zinc
Scheme 3. The scope of alkylzinc bromide in enantioselective allylic
alkylation. Unless otherwise noted, all reactions performed on
0.25 mmol scale under the standard conditions (see Table 1, entry 9).
Yield of the isolated product after purification by chromatography on
silica gel. Enantiomeric excess determined by SFC on chiral stationary
phase. [a] Reaction conducted in ethylacetate as solvent. [b] Reaction
conducted with 2 mol% [{Ir(cod)Cl}2] and 8 mol% (S)-L.
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Scheme 4. Enantioselective synthesis of (À)-preclamol. Reagents and
conditions: a) O3, CH2Cl2, À788C, then LAH, 258C, 70%, >99% ee;
b) MsCl, Et3N, 258C; c) propylamine, neat, 258C; d) aqueous HBr,
1208C. LAH=lithium aluminum hydride, MsCl=methanesulfonyl
chloride.
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Received: February 26, 2015
Published online: && &&, &&&&
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Synthetic Methods
J. Y. Hamilton, D. Sarlah,
E. M. Carreira*
&&&& — &&&&
Iridium-Catalyzed Enantioselective Allylic
Alkylation with Functionalized
Organozinc Bromides
An Ir/(P,olefin) complex catalyzes the title
reaction and the method provides a vari-
ety of allylated products with excellent
regio- and stereoselectivities. The utility
of the coupling is demonstrated in a cat-
alytic enantioselective synthesis of a pre-
clinical drug (À)-preclamol. Boc=tert-
butyloxycarbonyl, cod=1,5-cycloocta-
diene.
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