Dynamic Kinetic Resolution of Alkenyl Cyanohydrins Derived from α,β-Unsaturated Aldehydes: Stereoselective Synthesis of E-Tetrasubstituted Olefins

Article abstract of DOI:10.1021/jacs.9b04384

A novel dynamic kinetic resolution (DKR) of tetrasubstituted alkenyl cyanohydrins prepared from the corresponding α,β-unsaturated aldehydes is described. The deprotonation of a geometrical mixture of tetrasubstituted alkenyl cyanohydrins with sodium diiso

Full text of DOI:10.1021/jacs.9b04384

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Communication
Dynamic Kinetic Resolution of Alkenyl Cyanohydrins
Derived from #,#-Unsaturated Aldehydes:
Stereoselective Synthesis of E-Tetrasubstituted Olefins
Jadab Majhi, Ben W. H. Turnbull, Ho Ryu, Jiyong Park, Mu-Hyun Baik, and P. Andrew Evans
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04384 • Publication Date (Web): 10 Jun 2019
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Dynamic Kinetic Resolution of Alkenyl Cyanohydrins Derived from
-Unsaturated Aldehydes: Stereoselective Synthesis of E-
Tetrasubstituted Olefins
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Jadab Majhi,† Ben W. H. Turnbull,† Ho Ryu,‡,§ Jiyong Park,§,‡ Mu-Hyun Baik,*,§,‡
and P. Andrew Evans*,†
† Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada
‡ Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
§ Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea
Supporting Information
which affords the E-tetrasubstituted olefins 4E with
ABSTRACT: A novel dynamic kinetic resolution
exquisite selectivity, thereby providing a convenient and
(DKR) of tetrasubstituted alkenyl cyanohydrins prepared
stereoselective method for preparing this challenging
class of olefins (Scheme 1C).
from the corresponding -unsaturated aldehydes is
described. The deprotonation of a geometrical mixture of
tetrasubstituted alkenyl cyanohydrins with sodium
diisopropylamide (NaDA) enables the equilibration of the
E- and Z-olefins and the selective functionalization of
Scheme 1. Inspiration and Challenges for the Development of
a Dynamic Kinetic Resolution of Tetrasubstituted Olefins
A. Mechanistic Basis for the DKR of Chiral Racemic Mixtures: Classic Strategy
former to selectively afford the E-adduct. Theoretical
studies indicate that the nature of the alkali metal cation
Chiral Cat.
SMR
PR
is a critical component to lowering the barrier for
interconversion between the two geometrical isomers,
which provides the mechanistic basis for the DKR
reaction. In addition, we demonstrate that the DKR
reaction can be combined with a transition-metal-
catalyzed allylic substitution to generate a stereodefined
E-tetrasubstituted olefin and quaternary center in a single
cross-coupling reaction.
kR (fast)
100%
krac
Chiral Cat.
SMS
PS
kS (slow)
B. Outline for the Proposed DKR of Tetrasubstituted Olefins: Unique Approach
Olefination Dynamic Kinetic Resolution
R2
R2
O
R2
O
O
X3P
R1
O
R1
H
R1
E
The exponential growth in the field of asymmetric
synthesis over the last few decades has resulted in the
development of an array of methods for the preparation
of chiral nonracemic molecules.1 Among the particularly
attractive strategies to accomplish this goal are dynamic
kinetic asymmetric transformations (DYKATs), which
facilitate the construction of enantiomerically enriched
products via the selective functionalization of a racemate
(Scheme 1A).2 In this context, the process generally
relies on the formation of two diastereomeric complexes,
which undergo differential reaction governed by the
R3
R3
R3
 Separation
 Efficiency
 Equilibration
 Selectivity
Drawbacks
Challenges
E/Z Mixture
C. Development of a Novel DKR of Tetrasubstituted Olefins: This Work
R2 OTBS
R1
CN
R3
R1 OTBS
CN
R2 OTBS
R2
2E
E+
CN OTBS
B–
R2
R1
CN
R3
R1
E
kiso
with 2E
R3
3
R3
R1 OTBS
1
4E
(E/Z = 1:1)
R2
CN
Curtin-Hammett principle to furnish
a
single
up to E/Z 19:1
R3
stereoisomer. Nevertheless, despite the widespread
utility of dynamic kinetic resolutions (DKR) in the field
of asymmetric synthesis, the extension of this strategy to
other stereochemical motifs, namely olefins, has not been
forthcoming (cf. Scheme 1B). Herein, we describe the
first example of a dynamic kinetic resolution of a mixture
of tetrasubstituted alkenyl cyanohydrins 1 (E/Z = 1:1),
2Z
Requirements for the Proposed Olefin DKR Reaction:
• Full Deprotonation (E/Z) • Low Barrier (kiso) • E-Selective Alkylation
The alkene moiety is among the most ubiquitous
functional groups present in a variety of organic
frameworks. In this regard, tetrasubstituted alkenes
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feature prominently in many natural products,3
Page 2 of 7
tolerant of a variety of alkyl (Table 1A, entries 1 and 2),
allylic (entries 3–5) and propargylic halides (entry 6),
furnishing the products in good yields and with excellent
selectivity for the E-isomer. Interestingly, the reaction is
also amenable to alkylation with a variety of more
functionalized electrophiles, namely, MOM-Cl, BOM-Cl
(entries 7 and 8) and carbonyl-based electrophiles such as
ethyl chloroformate and dimethylcarbamoyl chloride
(entries 9 and 10). A key and striking feature with this
approach is the ability to provide utility to isomeric olefin
mixtures prepared via classical olefination strategies and
thereby avoiding tedious chromatography separations.20
pharmaceuticals4 and materials5 and as important
synthetic intermediates,6 in which the olefin geometry
often plays a critical role in the biological function and/or
the chemical reactivity of a specific compound.7
Consequently, the stereocontrolled construction of these
types of olefins remains an important goal for modern
synthetic methodology development. Nevertheless, the
preparation of geometrically defined tetrasubstituted
olefins represents a formidable challenge because of the
congested nature of the carbon–carbon double bond,
which presents problems associated with controlling both
regio- and stereochemistry.8-10 Although a wide variety
of classical synthetic strategies to construct olefins have
been developed,8 namely the Wittig and Horner-
Wadsworth-Emmons (HWE) carbonyl olefination
reactions, the Julia-Lythgoe and Peterson eliminations
and cross-metathesis,11 many of these methods are
optimal for di- and trisubstituted olefins. Hence, the
application of the aforementioned methods to the
preparation of acyclic tetrasubstituted alkenes is often
limited in the context of selectivity,12 which has led to the
development of several novel approaches.8-11,13
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In an attempt to garner the breadth of alkene
substitution, various substituents on the olefin were
examined. For instance, the reaction is tolerant to a range
of electron-withdrawing and electron-donating aryl
substituents with benzyl bromide as an electrophile
(Table 1B, entries 11–14), in which only the iodo-
substituted aryl group afforded slightly reduced
selectivity (entry 15).21 Furthermore, the reaction is
applicable to polyaromatic systems and a number of
heteroaromatic alkenyl substituted cyanohydrins (entries
16–20). Perhaps the most remarkable feature with this
process is the ability to employ a range of alkyl groups at
the α- and β-position relative to the cyanohydrin (Table
1C).22 For example, linear alkyl substituents such as ethyl
and n-hexyl are well tolerated at both the α - and β -
positions, in addition to more sterically demanding
substituents such as isobutyl, isopropyl and cyclohexyl
groups proceed exquisite selectivity (entries 21–30).
Hence, the DKR reaction of tetrasubstituted alkenyl
cyanohydrins has a useful scope, providing a convenient
approach to E-tetrasubstituted olefins for applications in
target directed synthesis.
We envisioned an alternative strategy, which permits
the formal conversion mixtures of -unsaturated
aldehydes to the corresponding E-tetrasubstituted -
unsaturated carbonyl derivatives using a simple C-C bond
forming reaction (Scheme 1B).14,15 To this end, the
process is initiated by the deprotonation of a geometrical
mixture of an alkenyl cyanohydrins 1 (E/Z = 1:1),
prepared in one-step from the corresponding -
unsaturated aldehydes, to generate anions 2E and 2Z in a
uniform ratio (Scheme. 1C). The isomerization between
these two geometrical isomers is possible via
intermediate 3 in order to relieve A1,3-strain between the
cyanohydrin and/or the larger of the two substituents
(R1/R2).16 Hence, the rate of equilibration (kiso) was
expected to be heavily influenced by the steric and
electronic nature of these substituents (R1/R2).
Furthermore, the stereoelectronic nature of the carbanion
is a critical component that should impact the rate of
attack of the specific anions 2E and 2Z with an
electrophile. Hence, if the rate of reaction for 2E is faster
than 2Z, itwould permit a dynamic kinetic resolution
(DKR).
The construction of tetrasubstituted olefins and
enantioenriched quaternary-substituted stereocenters are
amongst the most challenging functional groups to
prepare in selective manner. To this end, we combined
the DKR with a metal-catalyzed allylic substitution to
install these functionalities in a single operation.
Consequently, the stereospecific rhodium-catalyzed
allylic alkylation of the linalool-derived allylic carbonate
5 (98% ee) with the tetrasubstituted alkenyl cyanohydrin
1b furnished after in situ deprotection, the
enantioenriched α,β-unsaturated ketone 6 (99% cee)23 in
76% yield24 and with excellent geometrical selectivity
(Table 1D). This process highlights the utility of the
DKR reaction to prepare acyclic tetrasubstituted α , β -
unsaturated ketones in combination with a metal-
catalyzed cross-coupling reaction, which we envision
may be applicable to related transformations.
In accord with the proposed hypothesis, the tert-
butyldimethylsilyl protected cyanohydrin of α , β -
dimethylcinnamaldehyde 1a (R1 = Ph, R2, R3 =Me; E/Z =
1:1) was selected to demonstrate proof-of-principle
(Table 1). After careful optimization of the reaction
conditions (see the SI. S27), we established an efficient
protocol using sodium diisopropylamide as the base,
which is critical for achieving good selectivity.17,18 Table
1 summarizes the application of the optimized reaction
conditions to a number of electrophiles and substituted
alkenyl cyanohydrins.19 Gratifyingly, the reaction is
To gain insight into the underlying mechanism of this
novel transformation we constructed a computational
model using density functional theory (DFT) and
extensively explored the putative reaction mechanism by
identifying all plausible intermediates. Special attention
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was given to how the alkali metal cations could interact
with the intermediate anions 2aE and 2aZ, as we
envisioned that they presumably reduce the rate of
alkylation of one of the two isomers and thereby shift the
equilibrium in a way to facilitate the dynamic kinetic
resolution. The
1
2
3
4
5
6
7
8
Table 1. Electrophile and Nucleophile Scope of the Stereoselective Alkylation of Tetrasubstituted Olefinsa,b,c
R2
R1
R2
OTBS
CN
NC OTBS
R1 OTBS
R1 OTBS
NC OTBS
i) NaDA
ii) RX, THF
2E
R1
R
R2
R
+
R1
R2
CN
R3
R2
CN
with
, 1.5 h
R3
THF, 40 °C, 30 min
R3
R3
R3
2Z
2E
1
, (E/Z = 1:1)
4 (E)
4 (Z)
minor
major
9
A.
Electrophile Scope
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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1
2
3
4
5
NC OTBS
( )5
NC OTBS
NC OTBS
NC OTBS
NC OTBS
4aa
4ab
4ac
4ad
4ae
80%, E/Z 19:1
81%, E/Z 19:1
78%, E/Z 19:1
76%, E/Z 19:1
77%, E/Z 19:1
1a
1a
, E/Z = 1:1
1a
1a
, E/Z = 1:1
1a
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
6
7
8
9
10
NC OTBS
NC OTBS
NC OTBS
NC OTBS
NC OTBS
O
O
OMe
OBn
OEt
NMe2
4af
4ah
4ai
4aj
4ak
72%, E/Z 19:1
65%, E/Z 19:1
66%, E/Z 19:1
72%, E/Z 19:1
75%, E/Z 19:1
1a
1a
1a
1a
1a
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
B.
Aryl and Heteroaryl Scope
11
12
13
14
F
15
NC OTBS
NC OTBS
NC OTBS
NC OTBS
NC OTBS
Ph
Ph
Ph
Ph
Ph
MeO
Me
I
4a
4b
4c
4d
4e
62%, E/Z 17:1
81%, E/Z 19:1
74%, E/Z 19:1
76%, E/Z 19:1
80%, E/Z 19:1
1a
, E/Z = 1:1
1b
, E/Z = 1:1
1c
, E/Z = 1:1
1d
, E/Z = 1:1
1e
, E/Z = 1:1
16
17
18
19
20
NC OTBS
NC OTBS
NC OTBS
NC OTBS
NC OTBS
Ph
Ph
Ph
S
Ph
O
Ph
S
N
4h
65%, E/Z 19:1
4f
4g
4i
4j
78%, E/Z 19:1
1f
76%, E/Z 19:1
1g
68%, E/Z 19:1
1i
79%, E/Z 19:1
1j
1h
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
, E/Z = 1:1
C.
,Alkyl Substituent Scope
4( )
21
22
23
24
25
NC OTBS
NC OTBS
NC OTBS
NC OTBS
NC OTBS
Ph
Ph
90%, E/Z 19:1
1l
Ph
Ph
Ph
d
d
4k
4l
91%, E/Z 19:1
4m
86%, E/Z 19:1
4o
4n
84%, E/Z 19:1
84%, E/Z 19:1
1k
, E/Z = 1:1
, E/Z = 1:1
1m
, E/Z = 3:1
1o
1n
, E/Z = 2.1:1
, E/Z = 2.4:1
26
27
28
29
30
NC OTBS
NC OTBS
NC OTBS
Ph
NC OTBS
NC OTBS
Ph
Ph
( )4
Ph
Ph
4p
4q
82%, E/Z 19:1
80%, E/Z 19:1
4r
69%, E/Z 19:1
4t
66%, E/Z 19:1
4s
70%, E/Z 19:1
1p
1q
, E/Z = 1.6:1
, E/Z = 1:1
1r
, E/Z = 1:5
1t
, E/Z = 1.2:1
1s
, E/Z = 2:1
D.
Stereospecific Allylic Substitution
i) NaDA, THF, 40 °C
O
OTBS
CN
E
ii) [Rh(COD)Cl]2, P(OPh)3
iii)
MeO2CO
MeO
MeO
6
, E/Z 19:1
5
1b
, (E/Z = 1:1)
(98% ee)
(99%
)
cee
iv) TBAF, 40 °C
76%
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a All reactions were performed on a 0.5 mmol scale using 1.2 eqiuv. of NaDA in THF (10 mL) at ‒40 °C for 30 min.
b Isolated yield. c E/Z ratios were determined by 500 MHz 1H NMR on crude reaction mixture. d Reactions were run at
‒20 °C instead of ‒40 °C
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indicate that without the sodium cation, which delocalizes
mechanistic model suggested by the calculations is
the negative charge across the molecule as indicated in
summarized in Fig. 1 and further details are provided in
Fig. 1A, the isomerization becomes much more
challenging with an increased barrier for isomerization
(~6 kcal/mol higher). While lithium and potassium are
the supporting information. The initial deprotonation
leads to the anionic species 2aE and 2aZ, which form ion
pairs with the alkali metal cations. Interestingly, we
capable of behaving in an analogous manner, their size
discovered that the two stereoisomers adopt very different
9
and polarizabilities are not as ideal as in the case of
ion pair structures. There are two functional groups that
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sodium, thereby leading to higher isomerization barriers.
can stabilize the negative charge and bind the cation,
namely, the cyano group and the aromatic moiety. In 2aZ
both of these elements are working in concert to
The energy profiles for the reaction are detailed in Fig.
1B and they illustrate the inner workings of the dynamic
accommodate the negative charge (Fig. 1A), whereas in
kinetic resolution. The main reaction trajectory involves
2aE the charge primarily resides on the cyano group
the generation of the sodiated adduct (2aE), either by
stabilized by the sodium cation in the lowest energy
direct deprotonation of 1aE or by deprotonation of 1aZ
followed by isomerization from 2aZ to 2aE. Intermediate
2aE may undergo methylation to produce 4aa and we
were able to locate the transition state TS(2aE–4aa) at –
structure. Hence, our calculations indicate that the
conversion of 2aZ to 2aE should be rapid, even at low
temperatures, with a barrier of only 11.6 kcal/mol. This
rapid conversion is critical to
7.0 kcal/mol to give a barrier of 10.2 kcal/mol for the
A.
2aZ 2aE
to
methylation of 2aE. To produce the undesired product
4aaZ, intermediate 2aZ must undergo methylation and
our calculations suggest a transition state TS(2aZ–4aaZ)
at –3.7 kcal/mol, which corresponds to a barrier of 12.6
kcal/mol, which is nearly 2.5 kcal/mol higher in energy
than the aforementioned barrier for the formation of 4aa
(from 2aE). Alternatively, the energy barrier for the
transition state of the isomerization (TS(2aZ–2aE)) was
located at –4.8 kcal/mol, which is 1 kcal/mol lower in
energy than that of the methylation of 2aZ. Thus,
intermediate 2aZ is much more likely to undergo
isomerization to 2aE as opposed to direct methylation.25
Analysis of the model concluded that the suggested
mechanism implies 4aa/4aaZ ratio of approximately
94:6, which is in good agreement with the experimental
observations. This computational analysis forms a solid
foundation for the mechanism of the dynamic kinetic
resolution seen in the prototype experiment.
Isomerization of
Computed
ratio
Isomerization
2E 2Z
:
~6:1
Na
N
G‡ = 11.65
kiso(Z–E)
TBSO
Na
N
Na
N
C
C
C
OTBS
kiso(E–Z)
OTBS
G‡ = 12.48
2aZ
(–16.40)
TS(2aZ–2aE)
2aE
(–17.23)
(–4.75)
B.
Complete energy profile for DKR of tetrasubstituted olefins
Deprotonation
G
Na
N
(kcal/mol)
N
N
TBSO C
Na
N
C
H
H
Methylation
OTBS
20.00
C
TBSO
I
C
TS(1aZ–2aZ)
TS(1aE–2aE)
TBSO
I
H3
Na
H3
C
Na
N
C
TS(1aZ–2aZ)
N
TS(1aE–2aE)
(7.94)
10.00
0.00
TS(2aZ–4aaZ)
TS(2aE–4aa)
(7.74)
1aE
(0.00)
E
Z
TS(2aZ–4aaZ)
(–3.75)
TS(2aE–4aa)
1aZ
Z to E
TS(2Z–2E)
(–7.02)
(–0.99)
(–4.75)
OTBS
CN
–10.00
–20.00
–60.00
–70.00
In conclusion, we have developed a direct and highly
stereoselective synthesis of E-tetrasubstituted olefins via
a novel DKR of alkenyl cyanohydrins. This is a
remarkable development, given that it represents the first
OTBS
CN
1aE
2aZ
2aE
(–16.40)
(–17.23)
TBSO Na
4aaZ
(–66.95)
Na
N
OTBS
CN
C
OTBS
2aZ
C
N
OTBS
example of
a
dynamic kinetic resolution of
CN
1aZ
2aE
tetrasubstituted olefins and thereby circumvents the
challenge of stereoselectively assembling carbon-carbon
double bonds. The new approach is practical and displays
a usreful substrate scope, which is in itself quite
significant given the relatively close ground state energies
of the E/Z isomers. Our understanding of the mechanism
is derived from computer simulations that provide a
precise model for the exquisite selectivity. Overall, given
the significant challenges posed by the construction of
tetrasubstituted alkenes, we envision that the DKR of
olefins in this manner will provide a powerful alternative
to classical methods of preparing tetrasubstituted alkenes
in target-directed synthetic applications.
4aa
(–68.23)
Isomerization
Deprotonation
Deprotonation
Methylation
Methylation
Figure 1. Computed Energy Profile of DKR. A.
Isomerization of sodiated E/Z-carbanions of
tetrasubstituted alkenyl cyanohydrins. B. Computed
reaction energy profile for the DKR of tetrasubstituted
alkenyl cyanohydrins. Energies are given in kcal/mol.
the dynamic kinetic resolution, as it permits the formation
of the intermediate 2aE from 1aZ via 2aZ, in addition to
the direct deprotonation of 1aE. The calculations also
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(9) For reviews on transition metal-catalyzed stereoselective
ASSOCIATED CONTENT
synthesis of highly substituted olefins, see: (a) Negishi, E.-I.; Huang,
Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008,
41, 1474. (b) Polák, P.; Vá ň ová, H.; Dvo ř ák, D.; Tobrman, T.
Tetrahedron Lett. 2016, 57, 3684.
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Supporting Information.
The Supporting Information is available free of charge on
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the
ACS
publication
website
at
(10) For
a review on the stereoselective construction of
http://pubs.acs.org.
Computational details,
tetrasubstituted olefins using ynolate, see: Shindo, M.; Matsumoto, K.
Top. Curr. Chem. 2012, 327, 1.
(11) For recent reviews on olefin metathesis, see: (a)
Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746. (b)
Paek, S.-M. Molecules 2012, 17, 3348. (c) Mukherjee, N.; Planer, S.;
Grela, K. Org. Chem. Front. 2018, 5, 494.
(12) (a) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; John Wiley & Sons, Inc.: New York, 2001. (b)
Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH:
Weinheim, 2004.
(13) For recent examples of the stereoselective construction of
tetrasubstituted olefins, see: (a) Ragno, D.; Bortolini, O.; Fantin, G.;
Fogagnolo, M.; Giovannini, P. P.; Massi, A. J. Org. Chem. 2015, 80,
1937. (b) Saini, V.; O’Dair, M.; Sigman, M. S. J. Am. Chem. Soc. 2015,
137, 608. (c) Dai, J.; Wang, M.; Chai, G.; Fu, C.; Ma, S. J. Am. Chem.
Soc. 2016, 138, 2532. (d) Li, Y.; Mgck-Lichtenfeld, C.; Studer, A.
Angew.Chem. Int. Ed. 2016, 55, 14435. (e) Domański, S.; Chaładaj,
W. ACS Catal. 2016, 6, 3452. (f). Lim, N.-K.; Weiss, P.; Li, B. X.;
McCulley, C. H.; Hare, S. R.; Bensema, B. L.; Palazzo, T. A.; Tantillo,
D. J.; Zhang, H.-M.; Gosselin, F. Org. Lett. 2017, 19, 6212. (g)
Naveen, K.; Nikson, S. A.; Perumala, P. T. Adv. Synth. Catal. 2017,
359, 2407. (h) Li, B. X.; Le, D. N.; Mack, K. A.; McClory, A.; Lim,
N.-K.; Cravillion, T.; Savage, S.; Han, C.; Collum, D. B.; Zhang, H.
M.; Gosselin, F. J. Am. Chem. Soc. 2017, 139, 10777. (i) Mack, K. A.;
McClory, A.; Zhang, H.; Gosselin, F.; Collum, D. B. J. Am. Chem. Soc.
2017, 139, 12182. (j) Liao, F-M., Cao, Z-Y.; Yu, J-S.; Zhou, J.
Angew.Chem. Int.Ed. 2017, 56, 2459. (k) Ikemoto, H.; Tanaka, R.;
Sakata, K.; Kanai, M.; Yoshino, T.; Matsunaga, S. Angew.Chem. Int.
Ed. 2017, 56, 7156. (l) Shimkin, K. W.; Montgomery, J. J. Am. Chem.
Soc. 2018, 140, 7074.
1
experimental procedures, spectral data, H and 13C NMR
spectra for all compounds including pertinent NOEs.
AUTHOR INFORMATION
Corresponding Author
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*mbaik2805@kaist.ac.kr
*Andrew.Evans@chem.queensu.ca
ACKNOWLEDGMENT
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery Grant and
Queen’s University for financial support. NSERC is also
thanked for supporting a Tier 1 Canada Research Chair
(PAE). We also acknowledge financial support from the
Institute for Basic Science (H.R., J.Y.P. and M.H.B.; Grant
N°: IBS-R10-D1) in Korea.
REFERENCES
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A.; Padilla-Parra, S.; Fry, E. E.; Stuart, D. I. Nature 2016, 535, 169.
(5) For reviews on molecular switches and applications to materials
using tetrasubstituted olefins, see: (a) Feringa, B. L.; van Delden, R.
A.; Koumura, N.; Geerstema, E. M. Chem. Rev. 2000, 100, 1789. (b)
Vicario, J.; Walko, M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc.
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Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 12412. (d)
Tietze, L. F.; Waldecker, B.; Ganapathy, D.; Eichhorst, C.; Lenzer, T.
K. O.; Reichmann, S. O.; Stalke, D. Angew. Chem., Int. Ed. 2015, 54,
10317.
(14) For an example of the challenges in equilibrating E- and Z-
trisubstituted olefins, see: Cuvigny, T.; Herve du Penhoat, C.; Julia,
M. Tetrahedron Lett. 1980, 21, 1331.
(15) For reviews on the selective isomerization of alkenes, see: (a)
Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475. (b) Liu, R. S.
H.; Liu, J. J. Nat. Prod. 2011, 74, 512. (c) Metternich, J. B.; Gilmour,
R. Synlett 2016, 27, 2541. (d) Pearson, C. M.; Snaddon, T. N. ACS
Cent. Sci. 2017, 3, 922 and pertinent references cited therein. (e) For
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(16) For the challeneges with the equilibration of tri- and
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Turnbull, B. W. H.; Oliver, S.; Evans, P. A. J. Am. Chem. Soc. 2015,
137, 15374.
(17) NaDA was prepared via an adaptation of a procedure used for
KDA, see: Raucher, S.; Koolpe, G. A. J. Org. Chem. 1978, 43, 3794.
(18) For an extensive investigation into different metal amide bases
and counter-ions, which delineate the importance of using NaDA, see
the Supporting Information.
(6) (a) Morikawa, K.; Park, J.; Andersson, P. G.; Hashiyama, T.;
Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463. (b) Brandes, B.
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(19) The reaction was quenched with different proton sources (see
SI), albeit the results indicate that 1a is not equilibrated to a
geometrically pure isomer. This result is consistent with the DFT
calculations.
(20) Mandera, L. N.; Williams, C. M. Tetrahedron 2016, 72, 1133.
(21) An 2,6-difluoroarene example affords the product in
comparable yield, albeit with significantly lower selectivity (E/Z = 6:1),
which illustrates the necessity for the aryl group to be planar to
facilitate the equilibration (cf. Supporting Information).
(7) Harper, M. J. K.; Walpole, A. L. Nature 1966, 212, 87.
(8) For a general review on the synthesis of tetrasubstituted olefins,
see: Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
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(22) Trialkyl substituted alkenyl cyanohydrins 1 (R1/R2/R3 = alkyl)
afford the benzylation product 4 with poor E/Z selectivity, which
corroborates the importance of having an aryl substituent for the cation-
pi interaction (cf. SI).
(23) The term conservation of enantiomeric excess (cee) = (ee of
product/ee of starting material) × 100. See: Evans, P. A.; Robinson, J.
E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761.
(24) The overall yield of the stereospecific reaction was 76%;
however, the regioselectivity was modest (b/l = 4:1), albeit the olefin
ratio of the tetrasubstituted olefin was E/Z ≥19:1 for both isomers (see
SI)
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(25) We developed a numerical model of the reaction kinetics using
the computed reaction energy profile (Fig. S8, see Supporting
Information).
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Dynamic Kinetic Resolution of Alkenyl Cyanohydrins Derived from -Unsaturated Aldehydes: Stereoselective Synthesis of E-
Tetrasubstituted Olefins
R2
NC OTBS
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R1
E
R2
OTBS
CN
ii. E+
R3
R1
up to 91% yield
up to 19:1
30 Examples
E-Product
R3
(major)
R2
OTBS
CN
2E
i. NaDA, THF
R1
9
R3
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R1
R1 OTBS
CN
NC OTBS
(E/Z = 1:1)
R2
E
R2
ii. E+
R3
R3
slow reaction
Z-Product
(minor)
2Z
Jadab Majhi,† Ben W. H. Turnbull,† Ho Ryu,‡,§ Jiyong Park,§,‡ Mu-Hyun Baik,*,§,‡ and P. Andrew Evans*,†
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