Enantioselective rhodium-catalyzed allylic substitution with a nitrile anion:construction of acyclic quaternary carbon stereogenic centers

Article abstract of DOI:10.1021/jacs.5b02810

A direct and highly enantioselective rhodium-catalyzed allylic alkylation of allyl benzoate with α-substituted benzyl nitrile pronucleophiles is described. This simple protocol provides a new approach toward the synthesis of acyclic quaternary carbon stereogenic centers and provides the first example of the direct asymmetric alkylation of a nitrile anion. The synthetic utility of the nitrile products is amply demonstrated through conversion to various functional groups and the synthesis of a bioactive aryl piperazine in an expeditious four-step sequence.

Full text of DOI:10.1021/jacs.5b02810

Communication
pubs.acs.org/JACS
Enantioselective Rhodium-Catalyzed Allylic Substitution with a
Nitrile Anion: Construction of Acyclic Quaternary Carbon Stereogenic
Centers
Ben W. H. Turnbull and P. Andrew Evans*
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston K7L 3N6, Canada
*
S Supporting Information
Scheme 1. Factors Affecting the Development of the
Enantioselective Rhodium-Catalyzed Allylic Alkylation with
a Nitrile Anion
ABSTRACT: A direct and highly enantioselective rho-
dium-catalyzed allylic alkylation of allyl benzoate with α-
substituted benzyl nitrile pronucleophiles is described.
This simple protocol provides a new approach toward the
synthesis of acyclic quaternary carbon stereogenic centers
and provides the first example of the direct asymmetric
alkylation of a nitrile anion. The synthetic utility of the
nitrile products is amply demonstrated through conversion
to various functional groups and the synthesis of a
bioactive aryl piperazine in an expeditious four-step
sequence.
he enantioselective construction of quaternary carbon
stereogenic centers, particularly in acyclic systems,
T
remains one of the most significant challenges facing modern
1
,2
synthetic chemistry.
Although the catalytic asymmetric
alkylation using classical activating groups, namely ketones,
3,4
aldehydes, esters, and amides
has been described, the
analogous process with a nitrile anion has not been forth-
5
coming. Despite the inherent versatility of these anions, the
fluxional nature of the α-metalated nitrile, due to the
interconversion between the C- and N-metalated forms,
makes the development of the asymmetric process particularly
challenging (Scheme 1A). Consequently, several elegant
methods have been developed centered around the electro-
1
7
18
(
DFT) and X-ray crystallography indicates that lithiated
6
phenylacetonitrile, solvated with a crown ether, stabilizes the N-
metalated resonance structure to provide a prochiral
nucleophile that we envisioned would promote the asymmetric
alkylation by π-facial discrimination. Herein, we now describe
the first direct and highly enantioselective metal-catalyzed
allylic alkylation of the benzyl nitrile pronucleophiles 1 with
allyl benzoate (2) to afford chiral nonracemic quaternary
philic “trapping” of the N-metalated form using silicon to form
1
9
7
axially chiral N-silyl ketene imines (SKIs) that are able to
8a
8b−d
undergo asymmetric acylation and aldol-type
addition
reactions via a dynamic kinetic asymmetric transformation
9
(
DYKAT) (Scheme 1B). Nevertheless, the direct asymmetric
20
carbon-substituted nitriles 3 (Scheme 1C).
alkylation of an α-metalated nitrile would clearly be advanta-
1
0
Table 1 outlines the preliminary studies toward the
development of the enantioselective rhodium-catalyzed allylic
alkylation with α-substituted benzyl nitrile anions. Treatment of
allyl benzoate (2) with the lithium salt of the commercially
available benzyl nitrile 1a, in the presence of the chiral complex
geous. Although the diastereoselective alkylation and
11
enantiospecific acylation of such anions has been reported,
12
the enantioselective variant has so far proven elusive.
In a program directed toward the development of rhodium-
1
3−15
catalyzed allylic substitution reactions,
we recently
derived from RhCl(PPh ) and (R)-BINOL-MeOP at 0 °C for
disclosed the direct and enantioselective allylic alkylation of
prochiral α-alkoxy ketone enolates with allyl benzoate utilizing
the complex derived from Wilkinson’s catalyst and a chiral
3 3
ca. 16 hours furnished the enantioenriched nitrile 3a in
excellent yield and with 46% enantiomeric excess (entry 1).
Given the encouraging efficiency and selectivity, we elected to
examine the effect of temperature on the enantioselectivity,
which we envisioned may impact the fluxionality of the nitrile
16
monodentate phosphite. We envisaged that a similar strategy
could facilitate the asymmetric alkylation of α-substituted
benzyl nitrile anions to construct challenging quaternary carbon
stereogenic centers. Central to this strategy would be the ability
to control the aforementioned equilibrium between the C- and
N-metalated derivatives. Interestingly, density functional theory
Received: March 17, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b02810
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Optimization of the Rhodium-Catalyzed Allylic
Substitution Using the Benzyl Nitrile 1a
Table 2. Scope of the Enantioselective Rhodium-Catalyzed
Allylic Substitution
a
, ,
a b c
rhodium
precatalyst
yield of 3a
ee
(%)
b
c
entry
T (°C)
additive
(%)
1
2
3
4
5
6
7
RhCl(PPh3)3
0
−10
−30
−50
−30
“
−
−
−
−
89
90
88
89
89
92
87
90
46
52
72
70
78
74
84
88
92
“
“
“
“
“
“
“
d
HMPA
d
DMPU
e
e
“
15-crown-5
“
f
8
“
f
g
9
Rh(COD) OTf
−30
15-crown-5
88 (86)
2
a
All reactions were performed on a 0.25 mmol reaction scale using 5
mol % Rh(I), 20 mol % (R)-BINOL-MeOP, 1.3 equiv 1a, and 1.2
b
equiv LiHMDS in THF (0.1 M) for ca. 16 h. GC yields of 3a.
c
Enantiomeric excess was determined by chiral GC on the crude
d
e
reaction mixtures. 9:1 ratio of THF/additive. 1.2 equiv of 15-crown-
5
f
g
. Reaction conducted at 0.05 M in THF. Isolated yield.
anion. Although reducing the temperature from 0 to −30 °C
improved the asymmetric induction, affording 3a in 88% yield
and with 72% enantiomeric excess (entries 2 and 3), further
reduction in the reaction temperature did not provide
additional benefit (entry 4). Nevertheless, it is interesting to
note that temperature did not impact the overall yield of the
reaction, which can presumably be attributed to the high
reactivity of the α-metalated nitrile 1a with the unsubstituted
rhodium-allyl intermediate derived from allyl benzoate (2). In
accord with our hypothesis that the use of deaggregating agents
may affect the equilibrium between C- and N-metalated forms,
HMPA or DMPU led to modest improvement in enantiose-
lectivity (entries 5 and 6), whereas 15-crown-5 provided a
significant improvement in the selectivity, furnishing 3a in 87%
yield and with 84% enantiomeric excess (entry 7). Further
optimization examined the effect of concentration and the
nature of the rhodium(I) precatalyst. Although reducing the
concentration from 0.1 to 0.05 M provided a small improve-
ment in selectivity (entry 8), switching to the cationic
rhodium(I) precatalyst afforded the nitrile 3a in 86% isolated
yield and with 92% enantiomeric excess (entry 9).
Table 2 summarizes the application of the optimized reaction
conditions (Table 1, entry 9) to a number of α-alkyl benzyl
nitriles. Gratifyingly, the reaction is tolerant of a range of
electron-withdrawing and electron-donating aryl substituents,
albeit the strongly electron-donating p-methoxy derivative gave
lower enantioselectivity (entries 1−5). This is in stark contrast
to our previous work with α-alkoxy ketone enolates, wherein
the strongly electron-withdrawing p-trifluoromethyl substituent
gave the lowest enantiomeric excess. Nevertheless, the ability to
introduce different alkyl substituents at the benzylic position
provides significant flexibility with this approach. For instance,
the isopropyl group proceeded with comparable selectivity
a
All reactions were performed on a 0.25 mmol reaction scale using 5
mol % Rh(COD) OTf, 20 mol % (R)-BINOL-MeOP, 1.3 equiv 1, 1.2
equiv LiHMDS, and 1.2 equiv 15-crown-5 in THF (5.0 mL) at −30 °C
for ca. 16 h. Isolated yields. Enantiomeric excess was determined by
2
b
c
chiral GC or HPLC analysis on the purified products and derivatives.
d
7
9% yield and 91% ee on a 10 mmol (1.7 g) scale.
analogous results to the methyl and isopropyl examples (entries
12−15). Finally, the ability to conduct the reaction on gram-
scale, with comparable efficiency and selectivity, highlights the
applicability of this method to large-scale synthesis. Overall, this
work provides the first example of an asymmetric alkylation of a
nitrile anion to prepare acyclic quaternary carbon stereogenic
centers, which should permit the expedient construction of this motif
in target directed synthesis applications.
Scheme 2 illustrates the inherent utility of the nitrile
products, which can be readily converted to a number of
important derivatives in a selective and efficient manner. For
instance, DIBAL-H reduction of the enantioenriched nitrile 3a
furnished the aldehyde 4 in excellent yield and with complete
retention of stereochemistry. Similarly, reduction of the nitrile
to the primary amine 5 was accomplished with lithium
aluminum hydride. Alternatively, the addition of methyllithium
to 3a, followed by hydrolysis of the intermediate imine,
furnished the methyl ketone 6 in good yield. Finally, hydrolysis
of the nitrile to the corresponding amide 7 using hydrogen
peroxide under basic conditions, proceeded in excellent yield
and conservation of enantiomeric excess. Gratifyingly, the
(
entries 6−10), and offered an efficient approach to more
challenging quaternary carbon centers. Alternatively, a benzyl
substituent also provides a competent substrate, albeit with
slightly lower selectivity in this case (entry 11 vs entries 1 and
6). Nevertheless, the substituted phenyl derivatives afforded
B
DOI: 10.1021/jacs.5b02810
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 2. Transformations of Enantioenriched Nitrile 3a
reactions. Furthermore, we demonstrate the synthetic utility of
the nitrile products through functional group interconversion to
a number of important motifs and in the concise and efficient
synthesis of a serotonin antagonist. Hence, given the ubiquity
of the nitrile pharmacophore in medicinal chemistry and their
utility as synthetic intermediates, we envisage that this work will
be of significant interest to the broader community.
23
ASSOCIATED CONTENT
■
*
S
Supporting Information
Experimental procedures, spectral data, and spectra for all
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
jacs.5b02810.
nitrile was converted to an array of useful functionality with
complete retention of stereochemistry, thereby illustrating the
potential utility of this process for synthetic applications.
To further highlight the suitability of this methodology for
target directed synthesis and to establish the absolute
configuration of the products, the serotonin antagonist 10
was prepared (Scheme 3). Interestingly, this agent is a member
of a family of synthetic aryl piperazines that are selective
antagonists of the 5-HT1A receptor and have been touted as
possible treatments for smoking cessation and depression
AUTHOR INFORMATION
■
Corresponding Author
andrew.evans@chem.queensu.ca
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery grant and Queen’s
University for generous financial support. NSERC is also
thanked for supporting a Tier 1 Canada Research Chair
(P.A.E.). We also acknowledge Samuel Oliver for performing
some preliminary studies.
2
1
related disorders. Hence, the enantioenriched nitrile ent-3a
was prepared under the standard reaction conditions from 1-
phenylacetonitrile 1a in 83% yield, albeit using the (S)-BINOL-
MeOP. Treatment of the nitrile ent-3a with phenyl Grignard
followed by acid hydrolysis gave the phenyl ketone, which was
subjected to ozonolysis to afford the aldehyde 8 in 78% overall
yield. Reductive amination of the aldehyde 8 with the
commercially available aryl piperazine 9 gave 10 in 88% yield,
which allowed the absolute configuration of the asymmetric
REFERENCES
■
(
1) For recent reviews on the enantioselective construction of
quaternary carbon stereogenic centers, see: (a) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b) Christoffers, J.;
Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (c) Denissova, I.;
Barriault, L. Tetrahedron 2003, 59, 10105. (d) Trost, B. M.; Jiang, C.
Synthesis 2006, 3, 369. (e) Quasdorf, K. W.; Overman, L. E. Nature
22a
alkylation to be determined. Overall, the four-step sequence
from 1-phenylacetonitrile afforded the serotonin antagonist 10
in 57% yield, thereby providing the most efficient route to this
22
target reported to date.
2
014, 516, 181.
(
2) For a recent review on the enantioselective construction of
Scheme 3. Enantioselective Synthesis of Bioactive Phenyl
Piperazine 10
acyclic quaternary carbon stereogenic centers, see: Das, J. P.; Marek, I.
Chem. Commun. 2011, 47, 4593.
(3) (a) Caine, D. In Comprehensive Organic Synthesis: Carbon-Carbon
σ-Bond Formation; Trost, B. M., Flemming, I., Eds.; Pergamon: New
York, 1991; Vol. 3, pp 1−63. (b) Stoltz, B. M.; Mohr, J. T. In Science of
Synthesis: Stereoselective Synthesis 3; de Vries, J. G., Evans, P. A.,
Molander, G. A., Eds.; Thieme: Stuttgart, Germany, 2011; pp
6
15−674. (c) Macmillan, D. W. C.; Watson, A. J. B. In Science of
Synthesis: Stereoselective Synthesis 3; de Vries, J. G., Evans, P. A.,
Molander, G. A., Eds.; Thieme: Stuttgart, Germany, 2011; pp
6
(
75−745 and pertinent references cited therein.
4) For recent reviews on the transition metal-catalyzed allylic
alkylation of enolates and enolate equivalents, see: (a) Braun, M.;
Meier, T. Synlett 2006, 661. (b) Mohr, J. T.; Stoltz, B. M. Chem.
Asian J. 2007, 2, 1476. (c) Oliver, S.; Evans, P. A. Synthesis 2013, 45,
3
(
179.
5) For examples of the asymmetric addition of nitrile anions to
aldehydes, see: (a) Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron:
Asymmetry 1992, 3, 677. (b) Carlier, P. R.; Lam, W. W.-F.; Wan, N. C.;
Williams, I. D. Angew. Chem., Int. Ed. 1998, 37, 2252. (c) Suto, Y.;
Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett. 2003,
In conclusion, we have developed the direct and highly
enantioselective rhodium-catalyzed allylic alkylation of α-
substituted benzyl nitrile anions with allyl benzoate (2). This
process provides the first example of a direct, enantioselective
alkylation of a nitrile anion, which is driven by the ability to
control the C- versus N-metalated equilibrium with a crown
ether. We anticipate that this finding will be critical for the
further development of asymmetric nitrile anion alkylation
5
(
(
, 3147.
6) (a) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277.
b) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1. (c) Purzycki,
M.; Liu, W.; Hilmersson, G.; Fleming, F. F. Chem. Commun. 2013, 49,
4700.
C
DOI: 10.1021/jacs.5b02810
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Journal of the American Chemical Society
Communication
(
7) For a recent review on the synthesis and alkylation of silyl ketene
imines (SKIs), see: Denmark, S. E.; Wilson, T. W. Angew. Chem., Int.
Ed. 2012, 51, 9980.
(
8) For recent examples of the asymmetric alkylation and
protonation of SKIs, see the following. Alkylation: (a) Mermerian,
A. H.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 949. (b) Denmark, S.
E.; Wilson, T. W.; Burk, M. T.; Heemstra, J. R., Jr. J. Am. Chem. Soc.
2007, 129, 14864. (c) Denmark, S. E.; Wilson, T. W. Nat. Chem. 2010,
2, 937. (d) Notte, G. T.; Baxter Vu, J. M.; Leighton, J. L. Org. Lett.
2011, 13, 816. Protonation: (e) Guin, J.; Varseev, G.; List, B. J. Am.
Chem. Soc. 2013, 135, 2100.
(
(
9) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
10) (a) Reetz, M. T.; Kayser, F.; Harms, K. Tetrahedron Lett. 1994,
3
5, 8769. (b) Gmeiner, P.; Hummel, E.; Haubmann, C. Liebigs Ann.
Chem. 1995, 1987. (c) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward, O.
W. Angew. Chem., Int. Ed. 2007, 46, 7098. (d) Fleming, F. F.; Liu, W.
Eur. J. Org. Chem. 2009, 699.
(
11) (a) Sasaki, M.; Takegawa, T.; Ikemoto, H.; Kawahata, M.;
Yamaguchi, K.; Takeda, K. Chem. Commun. 2012, 48, 2897. (b) Barker,
G.; Alshawish, M. R.; Skilbeck, M. C.; Coldham, I. Angew. Chem., Int.
Ed. 2013, 52, 7700. (c) Sasaki, M.; Takegawa, T.; Sakamoto, K.;
Kotomori, Y.; Otani, Y.; Ohwada, T.; Kawahata, M.; Yamaguchi, K.;
Takeda, K. Angew. Chem., Int. Ed. 2013, 52, 12956.
(
12) For an example providing low enantioselectivity, see: Mi, A. Q.;
Wang, Z. Y.; Jiang, Y. Z. Tetrahedron: Asymmetry 1993, 4, 1957.
13) For recent reviews on transition metal-catalyzed allylic
(
substitution, see: (a) Frost, C. G.; Howarth, J.; Williams, J. M. J.
Tetrahedron: Asymmetry 1992, 3, 1089. (b) Trost, B. M.; Van Vranken,
D. L. Chem. Rev. 1996, 96, 395. (c) Crawley, M. L. In Science of
Synthesis: Stereoselective Synthesis 3; de Vries, J. G., Evans, P. A.,
Molander, G. A., Eds.; Thieme: Stuttgart, Germany, 2011; pp 403−
4
(
11.
14) Evans, P. A.; Leahy, D. K. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005;
Ch. 10, pp 191−214.
(
15) For mechanistic studies, see: Evans, P. A.; Nelson, J. D. J. Am.
Chem. Soc. 1998, 120, 5581.
16) Evans, P. A.; Clizbe, E. A.; Lawler, M. J.; Oliver, S. Chem. Sci.
012, 3, 1835.
(
2
(
(
17) Carlier, P. R.; Madura, J. D. J. Org. Chem. 2002, 67, 3832.
18) Langlotz, I.; Marsch, M.; Harms, K.; Boche, G. Z. Kristallogr.−
New Cryst. Struct. 1999, 214, 509.
(
19) Although the dynamic kinetic resolution of a racemic C-
metalated and/or a mixture of keteniminate enantiomers cannot be
completely ruled out, the X-ray crystal data of the anion of
phenylacetonitrile in conjunction with DFT studies support the
existence of the N-metalated prochiral species.
(
20) For examples of the enantioselective transition metal-catalyzed
allylic substitution reaction with activated nitriles, see: (a) Sawamura,
M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (b) Trost, B.
M.; Miller, J. R.; Hoffman, C. M., Jr. J. Am. Chem. Soc. 2011, 133, 8165.
(
c) Maji, T.; Tunge, J. A. Org. Lett. 2014, 16, 5072.
(
21) Rasmussen, K.; Calligaro, D. O.; Czachura, J. F.; Dreshfield-
Ahmad, L. J.; Evans, D. C.; Hemrick-Leucke, S. K.; Kallman, M. J.;
Kendrick, W. T.; Leander, J. D.; Nelson, D. L.; Overshiner, C. D.;
Wainscott, D. B.; Wolff, M. C.; Wong, D. T.; Branchek, T. A.;
Zgombick, J. M.; Xu, Y.-c. J. Pharmacol. Exp. Ther. 2000, 294, 688.
(
22) For previous syntheses, see: (a) Denmark, S. E.; Fu, J. Org. Lett.
2
002, 4, 1951. (b) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.;
Larouche-Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int.
Ed. 2011, 50, 3760.
(
23) (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597. (b) Fleming, F.
F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem.
010, 53, 7902.
2
D
DOI: 10.1021/jacs.5b02810
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX