Convergent Catalytic Asymmetric Synthesis of Esters of Chiral Dialkyl Carbinols

Article abstract of DOI:10.1021/jacs.0c01324

Because chiral dialkyl carbinols, as well as their derived esters, are significant as intermediates and end points in fields such as organic, pharmaceutical, and biological chemistry, the development of efficient approaches to their asymmetric synthesis is an important endeavor. In this report, we describe a method for the direct catalytic enantioselective synthesis of such esters, beginning with an alkyl halide (derived from an aldehyde and an acyl bromide), an olefin, and a hydrosilane, catalyzed by nickel, an earth-abundant metal. The method is versatile, tolerating substituents that vary in size and that bear a range of functional groups. We further describe a four-component variant of this process, wherein the alkyl halide is generated in situ, thus obviating the need to isolate either an alkyl electrophile or an alkylmetal, while still effecting an alkyl-alkyl coupling. Finally, we apply our convergent method to the efficient catalytic enantioselective synthesis of three esters that are bioactive themselves or that have been utilized in the synthesis of bioactive compounds.

Full text of DOI:10.1021/jacs.0c01324

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Convergent Catalytic Asymmetric Synthesis of Esters of Chiral
Dialkyl Carbinols
Ze-Peng Yang and Gregory C. Fu*
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ABSTRACT: Because chiral dialkyl carbinols, as well as their derived esters,
are significant as intermediates and end points in fields such as organic,
pharmaceutical, and biological chemistry, the development of efficient
approaches to their asymmetric synthesis is an important endeavor. In this
report, we describe a method for the direct catalytic enantioselective
synthesis of such esters, beginning with an alkyl halide (derived from an
aldehyde and an acyl bromide), an olefin, and a hydrosilane, catalyzed by
nickel, an earth-abundant metal. The method is versatile, tolerating
substituents that vary in size and that bear a range of functional groups.
We further describe a four-component variant of this process, wherein the
alkyl halide is generated in situ, thus obviating the need to isolate either an
alkyl electrophile or an alkylmetal, while still effecting an alkyl−alkyl
coupling. Finally, we apply our convergent method to the efficient catalytic enantioselective synthesis of three esters that are
bioactive themselves or that have been utilized in the synthesis of bioactive compounds.
We have begun to explore whether the metal-catalyzed
enantioconvergent coupling of racemic alkyl electrophiles with
olefins can be applied to interesting new families of
electrophiles to generate useful new classes of products. For
example, we envisioned that it might be possible to accomplish
a direct catalytic asymmetric synthesis of esters derived from
enantioenriched dialkyl carbinols (top of Figure 1C).8 In this
report, we describe the achievement of this objective as well as
the development of a variant wherein the same products are
generated in a four-component coupling of readily available
reaction partners (aldehyde, acyl bromide, olefin, and hydro-
silane; bottom of Figure 1C).9
INTRODUCTION
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Esters of enantioenriched dialkyl carbinols, as well as the
dialkyl carbinols themselves, are frequently encountered in
organic chemistry, pharmaceutical science, biochemistry, and
related fields (e.g., Figure 1A). With regard to catalytic
asymmetric approaches to the generation of such esters, the
dynamic kinetic resolution of racemic alcohols is one attractive
strategy, although the scope of suitable partners is somewhat
limited.1 Another straightforward retrosynthesis involves the
acylation of an enantioenriched alcohol, which might in turn
be synthesized via the reduction of a ketone or via the addition
of an organometallic nucleophile to an aldehyde. However, the
asymmetric reduction of dialkyl ketones that bear two alkyl
groups of similar size typically proceeds with poor
enantioselectivity,2 and studies of the asymmetric addition of
alkylmetals to aliphatic aldehydes have largely focused on
relatively simple nucleophiles.3 Consequently, alternative
approaches to the catalytic asymmetric synthesis of enantioen-
riched dialkyl carbinols and/or their ester derivatives have
been pursued.4
The metal-catalyzed enantioconvergent coupling of racemic
alkyl electrophiles with alkyl nucleophiles has begun to emerge
as a powerful strategy in asymmetric synthesis (top of Figure
1B).5 Recently, it has been established that, in certain
instances, an olefin (in combination with a hydrosilane) can
be used in place of an alkyl nucleophile as the coupling partner
(bottom of Figure 1B), thereby obviating the need to
synthesize a discrete alkylmetal reagent,6,7 which can afford
significant practical advantages.
RESULTS AND DISCUSSION
■
In an initial study, we examined the coupling of racemic 1-
bromopropyl benzoate with vinyl cyclohexane (Figure 2A),
and we determined that NiBr2·diglyme and chiral bis-
(oxazoline) ligand L* can accomplish the desired enantio-
convergent reductive coupling in good yield and ee (78% yield,
92% ee; entry 1). In the absence of NiBr2·diglyme or of ligand
L*, essentially no carbon−carbon bond formation is observed
(entries 2 and 3). An array of other ligands are less effective
Received: February 3, 2020
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© XXXX American Chemical Society
A

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Figure 1. (A) Examples of bioactive compounds that include a chiral
dialkyl carbinol, free or acylated. (B) Approaches to metal-catalyzed
enantioconvergent alkyl−alkyl couplings of racemic electrophiles. (C)
This study.
than ligand L* (entries 4−8), whereas the use of i-Pr2O in
place of MTBE leads to a similar outcome (entry 9). If the
coupling is conducted with less catalyst, less olefin, less
hydrosilane/base, or for less time, then a lower yield and/or ee
are obtained (entries 10−13). The presence of a small amount
of water (0.1 equiv) has virtually no effect on the coupling
(entry 14), and a reaction run under air in a closed vial
proceeds relatively smoothly (entry 15). Under these
conditions, the corresponding alkyl chloride (entry 16) and a
1,1-disubstituted olefin (methylenecyclohexane) are not
suitable coupling partners.
Figure 2. Catalytic asymmetric synthesis of an ester of a chiral dialkyl
carbinol. (A) Effect of reaction parameters. (B) Comparison with the
corresponding Negishi and Suzuki reactions.
It is interesting to note that, if the olefin/hydrosilane are
replaced with an alkylmetal reagent (an alkylzinc or an
alkylborane), carbon−carbon bond formation proceeds with
poor yield and enantioselectivity (Figure 2B). Thus, in
addition to the practical advantage of not having to generate
a stoichiometric quantity of an alkylmetal reagent, the use of an
olefin/hydrosilane may enable couplings that are not readily
achieved via the traditional nucleophile−electrophile approach.
The scope of this method for the catalytic enantioconver-
gent synthesis of acylated dialkyl carbinols is fairly broad with
respect to the various substituents (Figure 3). For example, the
alkyl substituent α to bromine can vary in size from methyl to
neopentyl to isopropyl, and consistently good yields and ee’s
are observed (entries 1−8). A variety of functional groups,
including an ether and an unactivated primary alkyl chloride
and bromide, are compatible with the method (entries 9−12).
In the case of an electrophile that bears a nearby stereocenter,
the stereochemistry of the catalyst, rather than that of the
substrate, predominantly controls the stereochemistry of the
product (entries 13−14). On a gram-scale (1.21 g of product),
the coupling illustrated in entry 6 proceeds in similar yield and
ee as for a reaction conducted on a 0.8 mmol scale.
With regard to the acyl substituent of the electrophile, not
only an aryl group (Figure 3, entries 1−14) but also an alkyl
group (entries 15−17) can be present. For these electrophiles,
less (EtO)3SiH and K3PO4·H2O may be used (2.0 equiv), and
a small enhancement in yield is observed when the coupling is
conducted in i-Pr2O. However, in the case of a t-butyl
substituent, a modest yield (but good enantioselectivity) is
observed under either conditions (entry 17).
The scope of the enantioconvergent coupling is broad with
respect to the olefin, leading to an array of products with ∼90%
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Figure 3. Catalytic asymmetric synthesis of esters of chiral dialkyl carbinols: Scope. All data are the average of two experiments. Unless otherwise
noted, couplings were conducted on a 0.8 mmol scale. aIn place of the standard conditions, 2.0 equiv of (EtO)3SiH and 2.0 equiv of K3PO4·H2O
were used with i-Pr2O as the solvent. bIn place of the standard conditions, a balloonful of propylene was used. cIn place of the standard conditions,
d
5.0 equiv of 1-butene (bp 21 °C) was used. In place of the standard conditions, 2.0 equiv of the olefin was used.
ee. For example, the substituent can range in size from methyl
to neopentyl (Figure 3, entries 18−24; for Cy, see entries 1−
14), and a variety of functional groups can be present,
including an acetal, carbonate, boronate ester, and imide
(entries 25−34). Additive studies establish that an aldehyde,
aniline, aryl bromide, aryl chloride, aryl tosylate, aryl triflate,
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Figure 4. Catalytic asymmetric four-component couplings. (A) Initial examples. (B) Preparation of intermediates used in the synthesis of paleic
acid and (R)-dodecanolide. (C) One-step syntheses of (S)-heptadecan-7-yl propionate, a component of a sex pheromone for the lichen moth. All
data are the average of two experiments.
benzofuran, benzothiophene, epoxide, ketone, N-methylindole,
thioether, and unactivated secondary alkyl bromide are fully
compatible with the reaction conditions (see the Supporting
Information). Consistent with the data provided in entry 11 of
Figure 2A, the use of 2.0, rather than 3.0, equivalents of the
olefin generally leads to a modest loss in yield, but little change
in enantioselectivity (Figure 3, entries 22, 26, 30, 31, and 34;
drop in yield: 1−17%).
illustrated in Figure 4A, the four-component reactions proceed
in good yield, leading to the formation of a C−H, a C−C, and
a C−O bond, as well as the creation of a stereocenter with
good enantioselectivity.
This nickel-catalyzed four-component coupling provides
efficient access to enantioenriched compounds that have
been applied by others in the synthesis of natural products
(Figure 4B). Thus, benzoate ester 40, an intermediate in the
synthesis of paleic acid, an antimicrobial agent that is effective
against Mannheimia and Pasteurella, can be generated from
commercially available compounds in two steps and 90% ee via
These three-component reactions can also be conducted as
four-component reactions (aldehyde, acyl bromide, olefin, and
hydrosilane) by preparing the alkyl bromide in situ. As
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Notes
our catalytic asymmetric coupling, whereas it had previously
been synthesized in five steps.10
The authors declare no competing financial interest.
Enantioenriched ester 41 (Figure 4B), generated earlier in
eight steps via a lipase-catalyzed kinetic resolution of a racemic
alcohol, has served as an intermediate in a synthesis of (R)-4-
dodecanolide, which is part of a defensive secretion of rove
beetle Bledius mandibullaris.11 Using our catalytic enantiose-
lective four-component coupling, we can produce ester 41 in
one step and 90% ee from commercially available building
blocks.
Finally, we applied our method to the catalytic asymmetric
synthesis of (S)-heptadecan-7-yl propionate (Figure 4C; 42),
which is a component of a sex pheromone for lichen moths.12
Ester 42 has previously been synthesized in four steps via a
Jacobsen kinetic resolution of a racemic epoxide; using our
method, we produced ester 42 in one step by two different
disconnections from commercially available compounds.
ACKNOWLEDGMENTS
■
Support was provided by the National Institutes of Health
(National Institute of General Medical Sciences; grant R01-
GM062871), the Shanghai Institute of Organic Chemistry
(fellowship to Z.-P.Y.), and the Dow Next-Generation
Educator Fund (grant to Caltech). We thank Dr. Caiyou
Chen, Dr. Haohua Huo, Dr. Paul H. Oyala, Dr. David G.
VanderVelde, Dr. Scott C. Virgil, and Dr. Zhaobin Wang for
assistance and for helpful discussions.
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CONCLUSIONS
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c01324.
Procedures, characterization data, and additional refer-
ences (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Gregory C. Fu − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0002-
0927-680X; Email: gcfu@caltech.edu
Author
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Coupling of Secondary and Tertiary Electrophiles with Olefins.
Nature 2018, 563, 379−383. (b) He, S.-J.; Wang, J.-W.; Li, Y.; Xu, Z.-
Y.; Wang, X.-X.; Lu, X.; Fu, Y. Nickel-Catalyzed Enantioconvergent
Reductive Hydroalkylation of Olefins with α-Heteroatom Phosphorus
or Sulfur Alkyl Electrophiles. J. Am. Chem. Soc. 2020, 142, 214−221.
(c) For a related process, see: Zhou, F.; Zhang, Y.; Xu, X.; Zhu, S.
Ze-Peng Yang − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0003-
0248-1963
Complete contact information is available at:
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