Enantioselective Construction of Quaternary Stereogenic Centers by the Addition of an Acyl Anion Equivalent to 1,3-Dienes

Article abstract of DOI:10.1021/acs.orglett.0c00412

We report the enantioselective formation of quaternary stereogenic centers by the intermolecular addition of malononitrile, an acyl anion equivalent, and related pronucleophiles to several 1,3-disubstituted acyclic 1,3-dienes in the presence of a Pd-PHOX catalyst. Products are obtained in up to 88% yield and 99:1 er and in most cases are formed as a single regioisomer. The products' malononitrile unit undergoes oxidative functionalization to afford β,γ-unsaturated carbonyls bearing internal olefins and α-quaternary stereogenic centers.

Full text of DOI:10.1021/acs.orglett.0c00412

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Letter
Enantioselective Construction of Quaternary Stereogenic Centers by
the Addition of an Acyl Anion Equivalent to 1,3-Dienes
Nathan J. Adamson, Sangjune Park, Pengfei Zhou, Andrew L. Nguyen, and Steven J. Malcolmson*
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ABSTRACT: We report the enantioselective formation of quaternary
stereogenic centers by the intermolecular addition of malononitrile, an
acyl anion equivalent, and related pronucleophiles to several 1,3-
disubstituted acyclic 1,3-dienes in the presence of a Pd−PHOX catalyst.
Products are obtained in up to 88% yield and 99:1 er and in most cases
are formed as a single regioisomer. The products’ malononitrile unit
undergoes oxidative functionalization to afford β,γ-unsaturated carbonyls bearing internal olefins and α-quaternary stereogenic
centers.
he development of new catalysts and methods that enable
the enantioselective formation of quaternary carbon
type nucleophiles leads to products that are composed of γ,δ-
unsaturated carbonyls. Moreover, in each of these approaches,
as in the allylic substitution illustrated in Scheme 1, the
products bear only a terminal olefin adjacent to the quaternary
center.4d,e Elaboration of this alkene to a more substituted
analogue thus requires additional chemical steps,11 and the
most direct routeolefin cross-metathesiswould most likely
be encumbered by the sterics of the quaternary center.12
We speculated that the regioselective hydroalkylation of 1,3-
disubstituted acyclic dienes with malononitrile as an acyl anion
equivalent13 would enable the synthesis of α-vinyl carbonyl
products bearing a quaternary stereogenic center and internal
alkenes (Scheme 1D).14 However, addition reactions involving
dienes with this substitution pattern are uncommon,15 and to
the best of our knowledge, enantioselective nucleophilic
additions are unknown.16−18 Herein, we illustrate that
malononitrile and similarly activated C-pronucleophiles couple
regio- and enantioselectively with several dienes under the
aegis of Pd−PHOX catalysis.19
We began by attempting the addition of malononitrile to
diene (E)-1a, bearing a phenyl substituent at the 1,1-
disubstituted olefin and a phenethyl group at the diene’s
terminus (Table 1). With PHOX-based catalyst Pd-1, 150 mol
% of the diene, and 200 mol % Et3N, the desired 4,3-addition
product 2a is obtained as the major isomer in 87% yield and
98.5:1.5 er (entry 1). Notably, the reaction affords a small
quantity of product regioisomer 3a.20 In contrast to our
previous findings in hydrofunctionalizations of terminal and
1,4-disubstituted dienes,19,21 where the Pd−PHOX-catalyzed
processes at times deliver product regioisomers arising from
T
stereogenic centers1 is a critical endeavor in chemical synthesis
as several natural products and other biologically active
compounds contain such a motif.2 Yet despite this need, the
ability to prepare quaternary stereogenic centers enantiose-
lectively within acyclic molecules is limited.3 Particularly
challenging in this regard is the synthesis of β,γ-unsaturated
carbonyls, also called α-vinyl carbonyls; only a limited number
of reports exist.4
One tactic in generating this functionality is allylic
substitution.4a,c The Stoltz group has shown that a masked
acyl cyanide (MAC) reagent, one type of acyl anion equivalent,
combines with allylic carbonates in an enantioselective Ir−
phosphoramidite-catalyzed process (Scheme 1A).4c Function-
alization under acidic conditions gives rise to α-vinyl carboxylic
acids and their derivatives.
An atom economic strategy for quaternary stereogenic
center synthesis that has emerged recently is intermolecular
hydrofunctionalization of unsaturated hydrocarbons by the
addition of enol-type nucleophiles. This approach was first
demonstrated by Trost and co-workers for cyclic quaternary
stereogenic center formation in the Pd−bis(phosphine)-
catalyzed addition of 3-aryl-2-oxindoles to alkoxyallenes
(Scheme 1B).5 In 2017, the Dong group developed a dual
catalytic diastereodivergent method for coupling aldehydes to
allylic electrophiles generated from alkynes, allowing for acyclic
quaternary centers to be gained.6−8 In both of these
transformations, the quaternary centers formed are derived
from the nucleophilic component.
In contrast, the laboratories of Breit9 and Kang10
independently accomplished the synthesis of quaternary
stereogenic centers arising from the unsaturated hydrocarbon
partner by the addition of enols/enolates to 1,1-disubstituted
allenes (Scheme 1C). The authors showed four examples each.
In these established hydrofunctionalizations, the use of enol-
Received: January 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00412
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Scheme 1. Catalytic Enantioselective Synthesis of Quaternary Stereogenic Centers by Allylic Substitution with an Acyl Anion
Equivalent and Hydroalkylation Processes
Reducing the quantity of Et3N had little effect on the
malononitrile coupling to 1a (entry 3). In contrast, employing
the diene as the limiting reagent diminished both the regio-
and enantioselectivity (entry 4). As shown in entry 5, having
only a slight excess of the diene and 100 mol % Et3N gave an
identical result to the conditions in entry 1.
Table 1. Reaction Optimization for Malononitrile Additions
to 1,3-Disubstituted Dienes
a
We next explored the scope of dienes amenable to
malononitrile addition (Scheme 2). Although having no
impact in the reaction of 1a, adding only 110 mol % of
diene and 100 mol % Et3N in reactions of these other dienes
diminishes the product yields.22 Therefore, we employed the
conditions in Table 1, entry 1, for expanding the substrate
scope. While maintaining a phenyl substituent on the 1,1-
disubstituted olefin, we examined various alkyl groups at R1,
with reactions leading to malononitriles 2b−g in ≥98.5:1.5 er
within 3 h. Linear, α-branched, and β-branched alkyl groups
are well tolerated with malononitriles 2b−d obtained in 70−
88% yield. Under the mild reaction conditions, potentially
labile groups such as a primary chloride (2e, 80% yield) and an
allylic silyl ethers (2f, 81% yield) remain intact. A nitrogen
heterocycle also does not interfere with the catalysis (2g, 88%
yield). A pinacol boronic ester at R1 in the diene allows for
coupling to form alkenyl boron 2h (44% yield and 99:1 er)
with Pd-2 as catalyst.23
Varying the aryl group identity while maintaining a
phenethyl group at R1 (dienes 1i−n) results in a number of
interesting findings related to arene electronics. With an
electron-rich diene, such as anisole 1i, only the desired
regioisomer is formed (87% yield, 98.5:1.5 er after 3 h). A
longer reaction time, however, results in markedly diminished
enantioselectivity, suggesting reversibility of the product-
forming step. Instead, transformations involving electron-
poor dienes (e.g., 1j−k) show a much slower erosion of er
over time.22 Simultaneously, regioselectivity is more modest
with 1j−n (4:1−16:1 2:3).24 Yields and enantioselectivities
remain excellent.
(E)-1a
Et3N
yield of 2a
b
c
d
entry
Pd
(mol %)
(mol %)
2a:3a
(%)
er of 2a
1
2
3
Pd-1
Pd-2
Pd-3
Pd-4
Pd-5
150
150
150
100
110
200
200
100
100
100
19:1
>20:1
18:1
13:1
19:1
87
80
84
86
87
98.5:1.5
98.5:1.5
98.5:1.5
97.5:2.5
98.5:1.5
e
4
5
a
Reactions run under N2 with 0.2 mmol malononitrile (0.8 M).
Determined by 400 MHz H NMR spectroscopy of the unpurified
mixture. Isolated yield of 2a after purification. Determined by
HPLC analysis of purified 2a. 150 mol % malononitrile (0.3 mmol).
b
1
c
d
e
hydrometalation of the two different olefins of the diene (4,3-
and 1,4-addition products), the 2a/3a mixture occurs only by
reaction of the 1,1-disubstituted alkene of 1a. Subsequent
attack upon the two terminal carbons of the resulting
unsymmetrical Pd−π-allyl intermediate generates the observed
4,3- and 4,1-addition products. The recovered diene 1a is still
>98% the E-isomer.
With Pd-2 (entry 2), which differs from Pd-1 by the aryl
CF3 group substitution pattern on the phosphine, 3a cannot be
detected; however, although enantioselectivity remains un-
changed, the yield of 2a is lower. This proved to be a general
trend as yields from malononitrile additions to dienes 1 were
lower in most cases by 5−10% with Pd-2. In some instances,
enantioselectivities were also lower.22
The positions of the aryl and alkyl groups within diene 1
may be switched to generate products comprised of alkyl-
substituted quaternary centers. While still highly enantiose-
lective at 4 °C (2o−2q formed in 93.5:6.5 to 94.5:5.5 er), the
transformations are lower yielding than those with an aryl
B
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a−d
Scheme 2. Diene Scope for Malononitrile Addition Leading to the Formation of Quaternary Stereogenic Centers
a
Reactions under N2 with 0.2 mmol of malononitrile (0.8 M). Dienes are 100% E-isomer unless otherwise noted; see the Supporting Information
b
c
for details. Ratio of 2/3 determined by 400 MHz 1H NMR spectroscopy of the unpurified mixture and is >20:1 unless otherwise noted. Isolated
yield of 2 plus 3 after purification. Er determined by HPLC analysis of purified 2 unless otherwise noted. E/Z mixture of diene 1 was used. Er
determined after oxidative methanolysis of the malononitrile. Pd-2 used. Reactions run in CH2Cl2 for 20 h at 4 °C.
d
e
f
g
h
group at the branched position. Although the yields can be
slightly improved at room temperature with dienes 1o−1q, the
enantioselectivity suffers (e.g., 2o is obtained in 53% yield and
92:8 er after 5 h at 22 °C). As product 2r indicates (79.5:20.5
er), the R2 alkyl group must be α-branched in order to attain
high enantioselectivity.25
The capacity of the malononitrile group in the products (2)
to undergo oxidative functionalization, thereby allowing its
progenitor to function as an acyl anion equivalent, enables the
synthesis of a variety of desirable carbonyl derivatives (Scheme
3).13 With water, methanol, or pyrrolidine nucleophiles,
carboxylic acid 4a, ester 4b, or amide 4c are obtained in
good yields under mild conditions. The resulting β,γ-
unsaturated carbonyls, with their α-quaternary stereogenic
centers, are thus easily furnished from 1,3-dienes by a two-step
protocol.
We additionally investigated the coupling of substituted
malononitriles and other activated pronucleophiles to diene
(E)-1a (Scheme 4). With sterically unhindered pronucleo-
philes, couplings are efficient: for example, 2-(methyl)- and 2-
(cinnamyl)malononitrile lead to products 2s and 2t, containing
vicinal quaternary centers,26,27 in 78% and 64% yield,
respectively. The MAC reagent4c,28 delivers 2u in 42% yield.
An α-cyanoacetate nucleophile undergoes addition to (E)-1a
to furnish 2v in 82% yield (1:1 dr, 98.5:1.5 er), accompanied
by a small quantity of regioisomer 3v.
Scheme 3. Oxidative Functionalization of Malononitrile-
Containing Products
The initial stereochemical composition of diene 1a has a
large impact on reaction efficiency (eq 1). Compared to
reaction of (E)-1a with malononitrile (Table 1, entry 1), the Z-
isomer affords only 28% yield of 2a. At the same time, a higher
percentage of the product mixture is composed of the minor
regioisomer (3a) when beginning with (Z)-1a (8:1 2a:3a
versus 19:1 from (E)-1a), yet the identity of the major
enantiomer of 2a is the same in both cases. The recovered
diene has not undergone any isomerization to the E-isomer.
Collectively these data indicate that (1) diene hydrometalation
with Pd-1 is irreversible; (2) reactions of (E)- and (Z)-1a
intersect the same Pd−π-allyl intermediate on the major
a
b
With 10 equiv of H2O and no molecular sieves. With MeOH as the
c
cosolvent. With 2.0 equiv of pyrrolidine.
C
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Scheme 4. Reactions of (E)-1a with Additional
Pronucleophiles
Scheme 5. Proposed Regio- and Stereochemical Model for
Malononitrile Additions
a−d
a
Reactions under N2 with 0.2 mmol of pronucleophile (0.8 M).
b
1
Regioselectivity determined by 400 MHz H NMR spectroscopy of
the unpurified mixture and is >20:1 2/3 unless otherwise noted.
c
d
Isolated yield of 2 after purification. Er determined by HPLC
formed, thus illustrating that stereochemical equilibration of
several allyl intermediates to I, wherein allylic strain is
minimized, is faster than nucleophilic attack. This equilibration
also explains the lower enantioselectivity observed in forming
product 2r bearing an isobutyl group, more similar in size to
the π-allyl’s geminal methyl substituent, compared to those
compounds with α-branched alkyl groups (see Scheme 2, 2o−
2q). Pd(0) complex II with the metal coordinated to a
disubstituted alkenea likely driving force for the regiose-
lectivityis then formed en route to product 2.
analysis of purified 2 except for 2v, which was determined after
hydrolytic decarboxylation of the methyl ester; see the Supporting
e
1
Information. Reaction in CH2Cl2; dr determined by 400 MHz H
NMR spectroscopy of the unpurified mixture.
Complex I may equilibrate with π-allyl complex III via single
bond rotation within an η1-coordinated intermediate. Nucle-
ophile attack upon III then affords Pd(0) species IV, having
the metal coordinated to a more sterically hindered
trisubstituted alkene, before forming product 3.20 As the
diene’s arene becomes more electron-poor, the transition state
leading from III to IV may become more accessible due to
increased olefin backbonding to Pd, overcoming the steric
penalty (see Scheme 2). Finally, the identity of the catalyst,
Pd-1 or Pd-2, has little effect on product regioselectivity in
most cases, regardless of electronics. However, regioselectivity
is higher with Pd-1 when the diene’s aryl group is larger (e.g.,
1l or 1m, Scheme 2), likely because of increased steric
interactions within complex III.22
We have demonstrated for the first time that 1,3-
disubstituted acyclic dienes may take part in highly efficient,
enantio- and regioselective couplings with nucleophiles under
mild conditions. Malononitrile, an acyl anion equivalent, and
related pronucleophiles add regio- and enantioselectively
across the 1,1-disubstituted olefin of 1,3-disubstituted dienes
with a Pd−PHOX-based catalyst to deliver products bearing
quaternary carbon stereogenic centers. These malononitrile
adducts are easily converted to β,γ-unsaturated carbonyls
comprised of α-stereogenic centers, thereby providing a
modular two-step route to this challenging functionality.
reaction pathway; and (3) the hydrometalation and/or
isomerizations needed to convert (Z)-1a to this Pd−π-allyl
are slower, resulting in lower yields and greater quantities of 3a
generated along the way.
Malononitrile addition to a 1:1 E/Z mixture of 1a was also
examined (eq 2) and demonstrates that the Z-diene does not
impede the catalytic efficiency of Pd-1 (cf. Table 1, entry 1).
The recovered diene’s 6:1 Z/E ratio (57% recovery) means
that (Z)-1a essentially does not undergo reaction in this
competition experiment. Therefore, either Pd-1 must coor-
dinate (E)-1a exclusively or (E)-1a must displace the Z-isomer
from the metal prior to Pd−π-allyl formation.
ASSOCIATED CONTENT
* Supporting Information
■
The regio- and stereochemical course of the reactions could
be rationalized as proceeding through Pd−π-allyl complex I
(Scheme 5). Regardless of whether (E)- or (Z)-1a is
employed, the same major enantiomer of the product is
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00412.
D
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C−H Functionalization of Methanol: Iridium-Catalyzed Diene
Hydrohydroxymethylation. J. Am. Chem. Soc. 2016, 138, 14210−
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Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid
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1,1-disubstituted olefins, see:. (d) Han, J.; Zhou, W.; Zhang, P.-C.;
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Experimental procedures, analytical data for new
compounds, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Steven J. Malcolmson − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States;
orcid.org/0000-0003-3229-0949;
Email: steven.malcolmson@duke.edu
Authors
Nathan J. Adamson − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States
Sangjune Park − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States
Pengfei Zhou − Department of Chemistry, Duke University,
Durham, North Carolina 27708, United States; orcid.org/
0000-0003-0077-8739
(6) Cruz, F. A.; Dong, V. M. Stereodivergent Coupling of Aldehydes
and Alkynes via Synergistic Catalysis Using Rh and Jacobsen’s Amine.
J. Am. Chem. Soc. 2017, 139, 1029−1032.
Andrew L. Nguyen − Department of Chemistry, Duke
University, Durham, North Carolina 27708, United States
(7) For additional examples of nucleophile-derived quaternary
centers in hydroalkylation, see: (a) Zhou, H.; Wei, Z.; Zhang, J.; Yang,
H.; Xia, C.; Jiang, G. From Palladium to Brønsted Acid Catalysis:
Highly Enantioselective Regiodivergent Addition of Alkoxyallenes to
Pyrazolones. Angew. Chem., Int. Ed. 2017, 56, 1077−1081. (b) Zhou,
H.; Wang, Y.; Zhang, L.; Cai, M.; Luo, S. Enantioselective Terminal
Addition to Allenes by Dual Chiral Primary Amine/Palladium
Catalysis. J. Am. Chem. Soc. 2017, 139, 3631−3634.
(8) For a discussion of dual catalyst strategy applied to allylic
substitution, see: Krautwald, S.; Carreira, E. M. Stereodivergence in
Asymmetric Catalysis. J. Am. Chem. Soc. 2017, 139, 5627−5639.
(9) Beck, T. M.; Breit, B. Regio- and Enantioselective Rhodium-
Catalyzed Addition of 1,3-Diketones to Allenes: Construction of
Asymmetric Tertiary and Quaternary All Carbon Centers. Angew.
Chem., Int. Ed. 2017, 56, 1903−1907.
(10) Bora, P. P.; Sun, G.-J.; Zheng, W.-F.; Kang, Q. Rh/Lewis Acid
Catalyzed Regio-, Diastereo-, and Enantioselective Addition of 2-Acyl
Imidazoles with Allenes. Chin. J. Chem. 2018, 36, 20−24.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00412
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation
(CHE-1800012) and Duke University is gratefully acknowl-
edged. N.J.A. thanks the Duke Chemistry Department for a
Burroughs-Wellcome fellowship.
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Parsutkar, M. M.; Jing, S. M.; Mehta, M. M.; Gallucci, J. C.;
RajanBabu, T. V. Cationic Co(I)-Intermediates for Hydrofunction-
alization Reactions: Regio- and Enantioselective Cobalt-Catalyzed
1,2-Hydroboration of 1,3-Dienes. J. Am. Chem. Soc. 2019, 141, 7365−
7375.
(17) One other reported attempt at enantioselective hydrovinylation
of this type of diene resulted in racemic product; see: Smith, C. R.;
Zhang, A.; Mans, D. J.; RajanBabu, T. V. (R)-3-Methyl-3-phenyl-1-
pentene via Catalytic Asymmetric Hydrovinylation. Org. Synth. 2008,
85, 248−266.
(18) For enantioselective hydrofunctionalizations of 2-substituted
butadienes that result in tetrasubstituted stereogenic centers,
including quaternary centers, see: (a) Reference 4. (b) Yang, X.-
H.; Davison, R. T.; Dong, V. M. Catalytic Hydrothiolation: Regio-
and Enantioselective Coupling of Thiols and Dienes. J. Am. Chem. Soc.
2018, 140, 10443−10446. (c) Yang, X.-H.; Davison, R. T.; Nie, S.-Z.;
Cruz, F. A.; McGinnis, T. M.; Dong, V. M. Catalytic Hydrothiolation:
Counterion-Controlled Regioselectivity. J. Am. Chem. Soc. 2019, 141,
3006−3013.
(19) (a) Adamson, N. J.; Wilbur, K. C. E.; Malcolmson, S. J.
Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of
Acyclic 1,3-Dienes with Activated Pronucleophiles. J. Am. Chem.
Soc. 2018, 140, 2761−2764. (b) Park, S.; Adamson, N. J.;
Malcolmson, S. J. Brønsted Acid and Pd−PHOX Dual-Catalysed
Enantioselective Addition of Activated C-Pronucleophiles to Internal
Dienes. Chem. Sci. 2019, 10, 5176−5182.
(20) We have not proven the identity of the major enantiomer of 3.
(21) (a) Adamson, N. J.; Hull, E.; Malcolmson, S. J. Enantioselective
Intermolecular Addition of Aliphatic Amines to Acyclic Dienes with a
Pd−PHOX Catalyst. J. Am. Chem. Soc. 2017, 139, 7180−7183.
(b) Park, S.; Malcolmson, S. J. Development and Mechanistic
Investigations of Enantioselective Pd-Catalyzed Intermolecular
Hydroaminations of Internal Dienes. ACS Catal. 2018, 8, 8468−8476.
(22) For additional details, see the Supporting Information.
(23) Pd-1 leads to a lower yield in this instance.
(24) Although the yields provided are for the regiomeric mixture, in
most cases, isomers 2 and 3 could be separated. The er for isomer 3
was equally high; see the Supporting Information.
(25) 1,3-Dialkyl-substituted 1,3-dienes are unreactive, and 1,3-diaryl
dienes proved too unstable for study.
(26) For related examples in allylic substitution, see: Hethcox, J. C.;
Shockley, S. E.; Stoltz, B. M. Enantioselective Synthesis of Vicinal All-
Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation.
Angew. Chem., Int. Ed. 2018, 57, 8664−8667.
(27) For an allylic substitution example to prepare a quaternary
center vicinal to a fluorine-containing tetrasubstituted stereogenic
center, see: Butcher, T. W.; Hartwig, J. F. Enantioselective Synthesis
of Tertiary Allylic Fluorides by Iridium-Catalyzed Allylic Fluoroalky-
lation. Angew. Chem., Int. Ed. 2018, 57, 13125−13129.
(28) For the synthesis of this reagent, see: (a) Nemoto, H.; Li, X.;
Ma, R.; Suzuki, I.; Shibuya, M. A Three-Step Preparation of MAC
Reagents from Malononitrile. Tetrahedron Lett. 2003, 44, 73−75 For
an additional example in enantioselective synthesis, see:. (b) Yang, K.
̈
S.; Nibbs, A. E.; Turkmen, Y. E.; Rawal, V. H. Squaramide-Catalyzed
Enantioselective Michael Addition of Masked Acyl Cyanides to
Substituted Enones. J. Am. Chem. Soc. 2013, 135, 16050−16053.
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