Regioselective and Stereospecific Rhodium-Catalyzed Allylic Cyanomethylation with an Acetonitrile Equivalent: Construction of Acyclic β-Quaternary Stereogenic Nitriles

Article abstract of DOI:10.1021/jacs.0c02316

A highly regioselective and stereospecific rhodium-catalyzed cyanomethylation of tertiary allylic carbonates for the construction of acyclic β-quaternary stereogenic nitriles is described. This protocol represents the first example of a metal-catalyzed al

Full text of DOI:10.1021/jacs.0c02316

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Communication
Regioselective and Stereospecific Rhodium-Catalyzed
Allylic Cyanomethylation with an Acetonitrile Equivalent:
Construction of Acyclic #-Quaternary Stereogenic Nitriles
Mai-Jan Tom, and P. Andrew Evans
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02316 • Publication Date (Web): 02 Jun 2020
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Regioselective and Stereospecific Rhodium-Catalyzed Allylic
Cyanomethylation with an Acetonitrile Equivalent: Construction of
Acyclic -Quaternary Stereogenic Nitriles
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Mai-Jan Toma and P. Andrew Evans*,a,b
a Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston ON, K7L 3N6, Canada
b Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, P. R. of China
Supporting Information
Scheme 1. Background for the Development of the
Rhodium-Catalyzed Allylic Cyanomethylation
ABSTRACT: A highly regioselective and stereospecific
rhodium-catalyzed cyanomethylation of tertiary allylic
carbonates for the construction of acyclic -quaternary
stereogenic nitriles is described. This protocol represents
the first example of a metal-catalyzed allylic substitution
reaction using a triorganosilyl-stabilized acetonitrile
anion, which permits access to several carbonyl
derivatives that are challenging to prepare using
conventional pronucleophiles. The synthetic utility of the
stereospecific cyanomethylation is further exemplified
through the construction of the intermediate utilized in the
total synthesis of both (+)-epilaurene and (+)–α-
cuparenone.
A. Alkylation of Stabilized Benzyl Nitriles – �-Quaternary Carbon Centers
cat. Rh(COD)2OTf
(R)-BINOL-POMe
R
O
P
R
CN
OMe
LiHMDS, 15-Crown-5
OBz
Ar
up to 95% ee
O
Ar
CN
THF, - 30 ºC
(R)-BINOL-POMe
B. Development of the Traceless Activation of Acetonitrile – Background
i. Impact of pKa – Alkylnitriles vs. Benzyl Nitriles
CH3
H3C
CN
pKa 32.7
H3C CN
Ph
CN
Ph
CN
pKa 31.3
pKa 23.0
pKa 21.9
increasing acidity of �-protons
Alkyl nitriles represent versatile motifs that are
omnipresent in an array of important bioactive natural
products and pharmaceuticals, in addition to being
versatile synthetic intermediates.1,2 Consequently, the
ability to readily employ alkyl nitriles as pronucleophiles
in asymmetric transition-metal catalysis is highly
desirable, albeit challenging because of the fluxional
nature of the anion (C- vs. N-metalated).3,4 For instance,
the Lewis basic nature of nitrile anions can render the
transition-metal unreactive by binding the nitrogen and
carbon atoms, in addition to forming stable dinuclear
complexes.4,5 Furthermore, the alkylation of primary
nitriles often results in bis-alkylation products, because of
the similar acidity of the -protons in the substrate and
product. Nevertheless, we recently reported the first
enantioselective rhodium-catalyzed allylic alkylation of
-substituted benzyl nitriles for the construction of
challenging acyclic -quaternary nitrile stereocenters
(Scheme 1A).6 We envisaged the ability to employ a
simple alkyl nitrile, such as acetonitrile, would provide a
complementary approach, given that it would access the
ii. Dichotomy of the (Triorganosilyl)acetonitrile Anions – Soft vs. Hard
B
F
H2C CN
• Hard Nucleophile
R3Si
CN
R3Si
CN
• Soft Nucleophile
1
C. Regioselective and Stereospecific Allylic Cyanomethylation – This Work
Me
cat. Rh(I)
RhLn
R3Si
then F
CN
Me
R
Me
R
CN
Ligand
R
OLg
enyl (σ+π)
• Cyanomethylation
• Traceless Activation
• �-Quaternary Stereocenter
i).10,11 As a result, several synthetic equivalents has been
developed that circumvent the limitations of the
acetonitrile anion and thereby facilitate selective
cyanomethylations,12,13
in
which
the
(trimethylsilyl)acetonitrile (TMSAN) has emerged as a
particularly versatile synthon for conventional
electrophiles.14 A key and striking feature with this
pronucleophile is the ability to generate either the silyl
stabilized anion or the unstabilized carbanion via the
direct deprotonation or cleavage of the carbon-silicon
bond, respectively (Scheme 1B, ii).16-17a Notably, the
trimethylsilyl stabilized acetonitrile carbanion undergoes
conjugate addition in the absence of copper, which further
supports the soft nature of the nucleophile.17
Surprisingly, the application of either of these anions in
metal-catalyzed cross-coupling reactions has been
corresponding
acyclic
-quaternary
stereogenic
nitriles.7,8 Nevertheless, the direct transition metal-
catalyzed cyanomethylation reaction has been
underdeveloped,9 which can presumably be ascribed to
the aforementioned challenges and the fact that it
constitutes a hard unstabilized carbanion (Scheme 1B,
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limited.18,19
We envisioned using the stabilized
Table 2. Scope of the Regioselective Rhodium-Catalyzed
Allylic Cyanomethylation Reactiona,b,c
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2
3
4
5
6
7
8
acetonitrile carbanion in a rhodium-catalyzed allylic
substitution with tertiary allylic carbonates would provide
a novel quaternary allylic cyanomethylation product
bearing two synthetic handles. Moreover, given the
versatility of nitriles, this transformation would provide a
unified strategy to access several related carbonyl
derivatives that have proven challenging for conventional
pronucleophiles.20,21 Herein, we now describe the first
highly regioselective and stereospecific rhodium-
catalyzed cyanomethylation of tertiary allylic carbonates
through the traceless activation of an acetonitrile
carbanion for the construction of acyclic -quaternary
stereogenic nitriles (Scheme 1C).
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Table 1. Optimization of the Regioselective and
Stereospecific
Rhodium-Catalyzed
Allylic
Cyanomethylation using Tertiary Carbonate 2aa
3a:4a Yield
ent
ry
(b/l) of 3a
1, R3 =
Me3
b
base
(%)c
1d
2d
3d
4d
5
nBuLi
sBuLi
LDA
a
“
“
“
b
c
d
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
≥19:1
32
11
30
35
40
10
“
“
LiHMDS
“
“
Et3
iPr3
tBuMe
6
“
90
7
LiHMDS
≥19:1
(88)e
2
a All reactions were performed on a 0.25 mmol reaction scale using
10 mol % Rh(COD)2OTf, 30 mol % P(OPh)3, 2.0 equiv 1, and 1.9
equiv of base in THF (2.5 mL) at 0 °C to room temperature for ca.
16 hours. b Regioselectivity was determined by 500 MHz 1H NMR
analysis of the crude reaction mixtures. c GC yields of 3a. d No
TBAF. e Isolated yield of 3a.
Table 1 outlines the optimization of the regioselective
rhodium-catalyzed allylic cyanomethylation.
In
accordance with our hypothesis, we examined the
traceless activation of an acetonitrile equivalent that
provides a stabilized nucleophile to match the reactivity
of the soft enyl organorhodium intermediate.22 Treatment
of tertiary allylic carbonate 2a with the lithium anion of
commercially available TMSAN (1a), in the presence of
triphenyl phosphite modified Rh(COD)2OTf, furnished
the branched regioisomer 3a in 32% yield with excellent
regioselectivity (Table 1, entry 1). In light of the
relatively poor efficiency, we elected to explore the
impact of base on the reaction. To this end, a series of
bases were examined, in which sec-butyllithium was
significantly less efficient (entry 2), and the reactions
with lithium diisopropylamine (LDA) and lithium
a All reactions were performed on a 0.5 mmol reaction scale using
10 mol % Rh(COD)2OTf, 30 mol % P(OPh)3, 2.0 equiv 1d and 1.9
equiv of LiHMDS in THF (5.0 mL) at 0 °C to room temperature
b
for ca. 16 hours. Regioselectivity was determined by 500 MHz
1H NMR analysis of the crude reaction mixtures. c Isolated yields.
d Employing (R)-2f (94% ee) provides (S)-3f (94% ee) in 100% cee.
e From TMS-protected alkyne. f Isolated yield over two steps.
g
From TBS-protected alcohol. h One-pot protocol from the tertiary
allylic alcohol.
bis(trimethylsilyl)amide
comparable efficiency to that with n-butyllithium (entry
(LiHMDS)
provided
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Journal of the American Chemical Society
this process (entries 24-27), which are applicable to
1 vs entries 3 and 4). Interestingly, there is no evidence
of polyalkylation at the α-position of the -quaternary
nitrile 3a, which suggested that the stability of the
pronucleophile was the reason for the reduced efficiency.
Consequently, we envisioned that replacing the
trimethylsilyl group, which is prone to desilylation by
alkoxides generated from the leaving group,16 with more
sterically hindered silyl groups may improve the
efficiency of this process. In accord with this reasoning,
the bulkier silyl groups would be retained and thereby
require the in situ addition of fluoride, albeit the isolation
of the -silyl nitriles may also be desired in some cases.23
Interestingly, the (triethylsilyl)acetonitrile (1b) is slightly
1
2
3
4
5
6
7
8
medicinal chemistry. Hence, a key and striking feature
with this transformation is the high selectivity favoring
the branched nitrile products in all cases, in which there
1
was no detectable linear regioisomer (by 500 MHz H
NMR analysis of the crude reaction mixtures). Overall,
this transformation provides a direct, efficient and
selective route to access an array of β-quaternary
substituted nitriles.
9
To further highlight the synthetic utility of this
transformation, we elected to examine the stereospecific
rhodium-catalyzed cyanomethylation using a chiral
nonracemic tertiary carbonate.26 Treatment of the
enantiomerically enriched tertiary allylic carbonate (S)-
2q under the optimal reaction conditions, using a
decreased catalyst loading, furnished the chiral β-
substituted nitrile (S)-3q in 84% yield in a highly
regioselective and stereospecific manner (100% cee)
(Scheme 2A).27 Gratifyingly, the stereospecific nature of
this transformation is demonstrated with an alkyl
substituted allylic carbonate (R)-2f, which also proceeds
with 100% cee, thus demonstrating that this is generally
applicable to a range of substrates (vide supra).
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more
efficient
(entry
5),
whereas
the
(triisopropylsilyl)acetonitrile (1c) is inferior (entry 6).
Gratifyingly, the (tert-butylsilyl)acetonitrile (1d)
provided the optimal pronucleophile for this process,
which afforded the -quaternary nitrile 3a in 88% isolated
yield in a highly regioselective manner.24,25 Hence, the
silyl group plays a critical role in the generation, stability
and reactivity of the α-cyano carbanion in this type of
alkylation reaction.
Table 2 summarizes the application of the optimized
reaction conditions (Table 1, entry 7) to a variety of
acyclic tertiary carbonates 2a-aa. The reaction is highly
selective for carbonates containing an aromatic
substituent at both the β- and γ-positions, albeit less
efficient with β-substitution (Table 2, entries 1 and 2).
Interestingly, the reaction also tolerates various tertiary
carbonates containing alkyl substitution patterns,
including linear alkyl chains (entry 3), in addition to β-
and γ-branched alkyl carbonates to provide moderate to
excellent yield (entries 4 and 5). More importantly, the
reaction affords the corresponding -quaternary nitriles
for substrates with trisubstituted and terminal olefins
(entries 6 and 7), in addition to providing terminal
alkynes, derived from the TMS-protected internal alkyne,
with excellent selectivity (entry 8). Notably, the reaction
is chemoselective as exemplified by the primary alkyl
chloride, ester and nitrile-containing tertiary carbonates,
which are challenging for more conventional carbanions
(entries 9-11). Moreover, the reaction can be performed
in the presence of benzyl protected γ- and β-alcohol
containing carbonates (entries 12-14), while also
providing the free alcohol after in situ deprotection of the
OTBS ether in good yield (entry 15). Furthermore, the
scope of the tertiary allylic carbonates can be readily
expanded to aryl and heteroaryl tertiary carbonates
(entries 16-27). In this case, a range of electron-rich and
electron-deficient aryl carbonates provide the
corresponding β-quaternary nitriles in excellent yield and
with high regioselectivity (entries 16-23). The reaction
can also be conducted using a one-pot procedure from the
tertiary allylic alcohol to furnish the desired product after
in situ generation of the allylic carbonate (entry 16).
Similarly, several tertiary heteroaromatic allylic
carbonates provide excellent efficiency and selectivity in
Scheme 2. Synthetic Utility of the Rhodium-Catalyzed
Allylic Cyanomethylation.
Scheme 2B illustrates the synthetic utility of the nitrile
products through the conversion of (S)-3q into an array of
important functional groups, which also permits the
stereochemical course of the alkylation to be established.
Specifically, the methyl ketone 5, which is of known
absolute configuration, was readily obtained through the
addition of methylmagnesium bromide and subsequent
hydrolysis of the imine.28 Hence, the reaction proceeds
through a double inversion process to provide overall
retention of configuration, which confirms the anion of
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(3) Fleming, F. F.; Shook, B. C. Nitrile Anion Cyclizations.
Tetrahedron 2002, 58, 1.
(tert-butylsilyl)acetonitrile (1d) behaves as a soft
1
2
3
4
5
6
7
8
nucleophile in this transformation. Furthermore, the level
of stereospecificity is remarkable, given our previous
(4) For examples of nitriles coordinating to transition-metals, see:
(a) Purzycki, M.; Liu, W.; Hilmersson, G.; Fleming, F. F. Metalated
Nitriles: N- and C-coordination preferences of Li, Mg, and Cu Cations.
Chem. Commun. 2013, 49, 4700. (b) Nelin, C. J.; Bagnus, P. S.;
Philpott, M. R. The Nature of the Bonding of CN to Metals and Organic
Molecules. J. Chem. Phys. 1987, 87, 2170.
(5) For examples of nitriles coordinating to rhodium, see: (a)
Sawamura, M.; Sudoh, M.; Ito, Y. An Enantioselective Two-
Component Catalyst System: Rh–Pd-Catalyzed Allylic Alkylation of
Activated Nitriles. J. Am. Chem. Soc. 1996, 118, 3309. (b) Evans, P.
A.; Kennedy, L. J. Regioselective Rhodium-Catalyzed Allylic
Alkylation/Ring-Closing Metathesis Approach to Carbocycles.
Tetrahedron Lett. 2001, 42, 7015.
efforts with cyanohydrin pronucleophiles.29
The
hydrolysis of the nitrile (S)-3q under basic reaction
conditions with hydrogen peroxide affords the
corresponding amide 6 in excellent yield and with
retention of stereochemistry. Additionally, the reduction
of the nitrile (S)-3q with DIBAL-H provides the aldehyde
7, to further demonstrate the utility of the nitrile products.
Notably, the preparation of the β-quaternary aldehyde 7
provides a key intermediate in the syntheses of the natural
products (+)-laurene (8) and (+)-α-cuparenone (9).30
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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(6) Turnbull, B. W. H.; Evans, P. A. Enantioselective Rhodium-
Catalyzed Allylic Substitution with a Nitrile Anion: Construction of
Acyclic Quaternary Carbon Stereogenic Centers. J. Am. Chem. Soc.
2015, 137, 6156.
In conclusion, we have developed
a
highly
regioselective and stereospecific rhodium-catalyzed
allylic cyanomethylation of both aryl and alkyl chiral
tertiary allylic carbonates with a novel acetonitrile
synthetic equivalent. This transformation demonstrates
the first regioselective alkylation of tertiary allylic
carbonates with a triorganosilyl-stabilized nitrile anion
and affords an efficient one-pot access to acyclic -
quaternary nitriles. Additionally, the synthetic utility of
the nitrile products is exemplified in functional group
transformations, one of which permits formal syntheses
of (+)-epilaurene and (+)-α-cuparenone. Hence, given
the utility of this transformation to prepare important -
quaternary nitriles, ketones, aldehydes and amides, we
anticipate that it will provide a useful method for the
construction of challenging natural products and
pharmaceuticals.
(7) For a review on the construction of β-stereocenters using -allyl
chemistry, see: Oliver, S.; Evans, P. A. Transition-Metal-Catalyzed
Allylic Substitution Reactions: Stereoselective Construction of α- and
β-Substituted Carbonyl Compounds. Synthesis 2013, 45, 3179.
(8) For recent reviews for the construction of acyclic quaternary
carbon stereogenic centers, see: (a) Das, J. P.; Marek, I.
Enantioselective Synthesis of All-Carbon Quaternary Stereogenic
Centers in Acyclic Systems. Chem. Commun. 2011, 47, 4593. (b) Feng,
J.; Holmes, M.; Krische, M. J. Acyclic Quaternary Carbon
Stereocenters via Enantioselective Transition Metal Catalysis. Chem.
Rev. 2017, 117, 12564.
(9) For select examples of transition metal-catalyzed
cyanomethylations using acetonitrile, see: (a) Bunescu, A.; Wang, Q.;
Zhu, J. Copper-Catalyzed Cyanomethylation of Allylic Alcohols with
Concomitant 1,2-Aryl Migration: Efficient Synthesis of Functionalized
Ketones Containing an α-Quaternary Center. Angew. Chem., Int. Ed.
2015, 54, 3132. (b) Liu, Y.; Yang, K.; Ge, H. Palladium-Catalyzed
Ligand-Promoted Site-Selective Cyanomethylation of Unactivated
C(sp3)–H bonds with Acetonitrile. Chem. Sci. 2016, 7, 2804.
(10) (a) For the pKa of butyronitrile, see: Judka, M.; Wojtasiewicz,
A.; Danikiewicz, W.; Makosza, M. Halogens in -Position Enhance the
Acidity of Alkyl Aryl Sulfones and Alkane Nitriles. Tetrahedron 2007,
63, 8902. (b) For the pKa of acetonitrile, -methylbenzyl cyanide and
benzyl cyanide, see: Bordwell, F. G. Equilibrium Acidities in Dimethyl
Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456.
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures, spectral data and NMR spectra for
all compounds. The Supporting Information is available free
of charge on the ACS publication website at DOI:
(11) For a more detailed discussion on the mechanism for the
rhodium-catalyzed allylic substitution with a hard and soft nucleophile,
see: (a) 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. (b) Turnbull, B. W. H.; Evans, P.
A. Asymmetric Rhodium-Catalyzed Allylic Substitution Reactions:
Discovery, Development and Applications to Target-Directed
Synthesis. J. Org. Chem. 2018, 83, 11463.
AUTHOR INFORMATION
Corresponding Author.
*Andrew.Evans@chem.queensu.ca
ACKNOWLEDGMENT
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery Grant for
financial support. NSERC is also thanked for supporting a
Tier 1 Canada Research Chair (PAE). We also thank
Queen’s University for an R. S. McLaughlin Fellowship
(MJT) and the Government of Ontario for an Ontario
Graduate Scholarship (MJT).
(12) For approaches using a decarboxylative strategy to provide the
cyanomethyl moiety, see: (a) Hyodo, K.; Kondo, M.; Funahashi, Y.;
Nakamura,
S.
Catalytic
Enantioselective
Decarboxylative
Cyanoalkylation of Imines by Using Palladium Pincer Complexes with
C2-Symmetric Chiral Bis(imidazoline)s. Chem. Eur. J. 2013, 19, 4128.
(b) Diosdado, S.; López, R.; Palomo, C. Ureidopeptide-Based Brønsted
Bases: Design, Synthesis and Application to the Catalytic
Enantioselective
Synthesis
of
β-Amino
Nitriles
from
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A Simple Preparation of Trimethylsilylacetonitrile and a Novel Ring-
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1
2
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(25) Attempts to utilize acetonitrile (2 equiv) with a variety of other
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Carbonyl
Compounds
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5
6
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8
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M.; Aggarwal, V. K. Full Chirality Transfer in the Conversion of
Secondary Alcohols into Tertiary Boronic Esters and Alcohols using
Lithiation-Borylation Reactions. Angew. Chem., Int. Ed. 2010, 49,
5142.
K.;
De
Kimpe,
N.
Synthesis
of
1-Arylmethyl-2-(2-
9
cyanoethyl)aziridines and their Rearrangement into Novel 2-
(Aminomethyl)cyclopropanecarbonitriles. J. Org. Chem. 2007, 72,
7329.
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(16) For an example of the formation of TMSAN anion via cleavage
of the carbon-silicon bond using a fluoride source, see: Palomo, C.;
Aizpurua, J. M.; López, M. C.; Lecea, B. Fluoride-ion Mediated
Reaction Between Trimethylsilylacetonitrile and Carbonyl
Compounds. A New Synthesis of -Trimethylsilyloxy Nitriles. J.
Chem. Soc., Perkin Trans. I, 1989, 1692.
(17) For select examples of TMSAN undergoing a 1,4-addition in
the absence of copper, see: (a) Tomioka, K.; Koga, K. Conjugate
Addition Reaction of Trimethylsilylacetonitrile with α,β-Unsaturated
Carbonyl Compounds. Synthetic Studies Toward Sesbanimide.
Tetrahedron Lett. 1984, 25, 1599. (b) Paquette, L. A.; Friedrich, D.;
Pinard, E.; Williams, J. P.; St. Laurent, D.; Roden, B. A. Total
Synthesis of the Tetracyclic Diquinane Lycopodium Alkaloids
Magellanine and Magellaninone. J. Am. Chem. Soc. 1993, 115, 4377.
(c) Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. Synthesis of (+)-
Complanadine A, an Inducer of Neurotrophic Factor Excretion. J. Am.
Chem. Soc. 2010, 132, 5924.
(18) TMSAN has been used for an enantioselective copper-catalyzed
cyanomethylation of acetophenone to furnish the corresponding -
hydroxy nitrile in 48% yield and 49% ee, see: Suto, Y.; Kumagai, N.;
Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 3147.
(19) The palladium-catalyzed α-arylation of TMSAN (1a) using zinc
fluoride has been reported, see: Wu, L.; Hartwig, J. F. Mild Palladium-
Catalyzed Selective Monoarylation of Nitriles. J. Am. Chem. Soc. 2005,
127, 15824.
(20) For select examples of the preparation of β-ternary ketones,
see: (a) Evans, P. A.; Leahy, D. K. Regioselective and Enantiospecific
Rhodium-Catalyzed Allylic Alkylation Reactions Using Copper(I)
Enolates: Synthesis of (–)-Sugiresinol Dimethyl Ether. J. Am. Chem.
Soc. 2003, 125, 8974. (b) Graening, T.; Hartwig, J. F. Iridium-
Catalyzed Regio- and Enantioselective Allylation of Ketone Enolates.
J. Am. Chem. Soc. 2005, 127, 17192. (c) Weix, D. J.; Hartwig, J. F.
Regioselective and Enantioselective Iridium-Catalyzed Allylation of
Enamines. J. Am. Chem. Soc. 2007, 129, 7720. (d) Chen, M.; Hartwig,
J. F. Iridium-Catalyzed Enantioselective Allylic Substitution of
Unstabilized Enolates Derived from α,β-Unsaturated Ketones. Angew.
Chem., Int. Ed. 2014, 53, 8691. (e) Chen, M.; Hartwig, J. F. Iridium-
Catalyzed Regio- and Enantioselective Allylic Substitution of Silyl
Dienolates Derived from Dioxinones. Angew. Chem., Int. Ed. 2014, 53,
12172. (f) Chen, M.; Hartwig, J. F. Iridium-Catalyzed Enantioselective
Allylic Substitution of Enol Silanes from Vinylogous Esters and
Amides. J. Am. Chem. Soc. 2015, 137, 13972.
(27) The term conservation of enantiomeric excess (cee) = (ee of
product ÷ ee of starting material) × 100. For details, please see: Evans,
P. A.; Robinson, J. E.; Nelson, J. D. Enantiospecific Synthesis of
Allylamines via the Regioselective Rhodium-Catalyzed Allylic
Amination Reaction. J. Am. Chem. Soc. 1999, 121, 6761.
(28) Jung, B.; Hoveyda, A. H. Site- and Enantioselective Formation
of Allene-Bearing Tertiary or Quaternary Carbon Stereogenic Centers
through NHC–Cu-Catalyzed Allylic Substitution. J. Am. Chem. Soc.
2012, 134, 1490.
(29) For the stereospecific rhodium-catalyzed allylic substitution
employing acyl anion equivalents, see: (a) Evans, P. A.; Oliver, S.;
Chae, J. Rhodium-Catalyzed Allylic Substitution with an Acyl Anion
Equivalent: Stereospecific Construction of Acyclic Quaternary Carbon
Stereogenic Centers. J. Am. Chem. Soc. 2012, 134, 19314. (b) Evans,
P. A.; Oliver, S. Regio- and Enantiospecific Rhodium-Catalyzed
Allylic Substitution with an Acyl Anion Equivalent. Org. Lett. 2013,
15, 5626. (c) Turnbull, B. W. H.; Oliver, S.; Evans, P. A. Stereospecific
Rhodium-Catalyzed Allylic Substitution with Alkenyl Cyanohydrin
Pronucleophiles: Construction of Acyclic Quaternary Substituted α,-
Unsaturated Ketones. J. Am. Chem. Soc. 2015, 137, 15374.
(30) For the synthesis of (+)-epilaurene (8), see: (a) Fadel, A.; Canet,
J.-L.; Salaün, J. Asymmetric Construction of Quaternary Carbons from
Chiral Malonates: Total Syntheses of (+)-Epilaurene and (–)-
Isolaurene. Tetrahedron: Asymmetry 1993, 4, 27. For the synthesis of
(+)-α-cuparenone (9), see: (b) Kametani, T.; Kawamura, K.; Tsubuki,
M.; Honda, T. Synthetic Approach to (–)-Cuparenone by Rhodium-
Catalyzed Cyclization. Chem. Pharm. Bull. 1985, 33, 4821. (c) Kumar,
R.; Halder, J.; Nanda, S. Asymmetric Total Synthesis of (R)-α-
Cuparenone, (S)-Cuparene and Formal Synthesis of (R)-β-Cuparenone
through Meinwald Rearrangement and Ring Closing Metathesis
(RCM) Reaction. Tetrahedron 2017, 73, 809.
(21) For select examples for the preparation of β-ternary amides,
esters and aldehydes, see: (a) Sempere, Y.; Carreira, E. M. Trimethyl
Orthoacetate and Ethylene Glycol Mono-Vinyl Ether as Enolate
Surrogates in Enantioselective Iridium-Catalyzed Allylation. Angew.
Chem., Int. Ed. 2018, 57, 7654. (b) Sempere, Y.; Alfke, J. L.; Rössler,
S. L.; Carreira, E. M. Morpholine Ketene Aminal as Amide Enolate
Surrogate in Iridium-Catalyzed Asymmetric Allylic Alkylation.
Angew. Chem., Int. Ed. 2019, 58, 9537.
(22) Evans, P. A.; Nelson, J. D. Conservation of Absolute
Configuration in the Acyclic Rhodium-Catalyzed Allylic Alkylation
Reaction: Evidence of an Enyl (σ + π) Organorhodium Intermediate. J.
Am. Chem. Soc. 1998, 120, 5581.
(23) The crude -silyl nitrile is obtained as a 1.5:1 mixture of
diastereoisomers prior to it cleavage with TBAF.
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Regioselective and Stereospecific Rhodium-Catalyzed Allylic Cyanomethylation with an Acetonitrile Equivalent: Construction of
Acyclic β-Quaternary Stereogenic Nitriles
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cat. Rh(COD)2OTf
P(OPh)3
Me
R
Me
R
CN
CN
OLg
tBuMe2Si
LiHMDS, THF, 0 °C
then TBAF
up to 92% yield
27 examples
R = alkyl, aryl,
heteroaryl
rs ≥19:1
100% cee
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Me
Me
O
Me
Me
Me
Me
Me
(+)-Epilaurene
5 steps from Nitrile
(+)–�-Cuparenone
5 steps from Nitrile
Mai-Jan Tom and P. Andrew Evans*
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