Stereospecific Palladium-Catalyzed Acylation of Enantioenriched Alkylcarbastannatranes: A General Alternative to Asymmetric Enolate Reactions

Article abstract of DOI:10.1002/anie.201609930

We report the development of a Pd-catalyzed process for the cross coupling of unactivated primary, secondary, and tertiary alkylcarbastannatrane nucleophiles with acyl electrophiles. Reactions involving optically active alkylcarbastannatranes occur with exceptional stereofidelity and with net retention of absolute configuration. Because the stereochemistry of the resulting products is entirely reagent-controlled, this process may be viewed as a general, alternative approach to the preparation of products typically accessed via asymmetric enolate methodologies. Additionally, we report a new method for the preparation of optically active alkylcarbastannatranes, which should facilitate their future use in stereospecific reactions.

Full text of DOI:10.1002/anie.201609930

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609930
German Edition: DOI: 10.1002/ange.201609930
Asymmetric Catalysis
Stereospecific Palladium-Catalyzed Acylation of Enantioenriched
Alkylcarbastannatranes: A General Alternative to Asymmetric
Enolate Reactions
Chao-Yuan Wang, Glenn Ralph, Joseph Derosa, and Mark R. Biscoe*
Abstract: We report the development of a Pd-catalyzed
process for the cross coupling of unactivated primary, secon-
dary, and tertiary alkylcarbastannatrane nucleophiles with acyl
electrophiles. Reactions involving optically active alkylcarba-
stannatranes occur with exceptional stereofidelity and with net
retention of absolute configuration. Because the stereochem-
istry of the resulting products is entirely reagent-controlled, this
process may be viewed as a general, alternative approach to the
preparation of products typically accessed via asymmetric
enolate methodologies. Additionally, we report a new method
for the preparation of optically active alkylcarbastannatranes,
which should facilitate their future use in stereospecific
reactions.
must be efficiently controlled. In principle, a stereospecific
coupling reaction between a stable, optically active organo-
metallic nucleophile and an acyl electrophile (Scheme 1b)
would circumvent these constraints. Because such cross-
coupling reactions would feature completely reagent-con-
trolled enantiospecificity, the transfer of stereochemical
information should be both general and predictable.
Over the past few decades, transition-metal-catalyzed
cross-coupling reactions have emerged as invaluable tools for
the construction of organic molecules.[3] Although classical
studies of cross-coupling reactions have largely focused on the
2
2
À
formation of C(sp ) C(sp ) bonds, and thus the construction
of planar molecular topologies, recent studies have suggested
that three-dimensional molecular structure may be manipu-
lated through the strategic use of C(sp3) nucleophiles and
electrophiles.[4,5] Thus, alternative retrosynthetic disconnec-
tions can be envisioned during a planned synthesis, and new
Catalyst- and auxiliary-controlled asymmetric enolate reac-
tions have an extensive history of application in the con-
struction of complex organic molecules (Scheme 1a).[1] How-
À
approaches to C C bond construction may be pursued using
C(sp3) coupling partners.[6] In Stille cross-coupling reactions,
alkyl groups typically serve as inert ligands for tin, the
presence of which enables selective transfer of more labile
alkynyl, alkenyl, and aryl groups (Scheme 2). Achieving facile
Scheme 1. Retrosynthetic approaches to the asymmetric construction
of a-substituted carbonyl compounds.
Scheme 2. Relative transmetallation rates for tin substituents in Pd-
catalyzed Stille cross-coupling reactions.
ever, the development of a general approach to employ
enolates and enolate equivalents in asymmetric reactions has
been hindered by multiple complicating factors. First, a cata-
lyst or auxiliary must broadly control facial attack on the
enolate independent of the enolate carbon skeleton or the
functional groups present. Second, reaction conditions must
not be conducive to racemization of the newly formed
stereogenic center (this is particularly challenging in arylation
reactions).[2] Third, when ketones possess two enolizable
carbon atoms, the chemoselectivity of the enolization process
transfer of secondary and tertiary alkyl groups from tin to
palladium is the greatest challenge to the development of
stereospecific alkyl variants of the Stille cross-coupling
reaction. Building upon the pioneering work of Jurkschat[7]
and Vedejs,[8] we recently showed that secondary alkylcarba-
stannatranes (1) can be employed in stereospecific Pd-
catalyzed cross-coupling reactions with aryl electrophiles
(Scheme 3).[6e,9] The carbastannatrane backbone selectively
activates its apical substituent, which facilitates the trans-
metallation of alkyl groups that are otherwise unactivated
(i.e., without a C(sp2) a-carbon, heteroatomic a-substituent,
[*] C.-Y. Wang, G. Ralph, J. Derosa, Prof. Dr. M. R. Biscoe
Department of Chemistry, The City College of New York (CCNY)
160 Convent Avenue, New York, NY 10031 (USA)
E-mail: mbiscoe@ccny.cuny.edu
C.-Y. Wang, G. Ralph, Prof. Dr. M. R. Biscoe
The Graduate Center of the City University of New York (CUNY)
365 Fifth Avenue, New York, NY 10016 (USA)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609930.
Scheme 3. Use of enantioenriched alkylcarbastannatranes in stereospe-
cific Pd-catalyzed arylation reactions.
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or coordinating b-carbonyl group).[10] This initial work
suggested that alkylcarbastannatrane reagents have tremen-
dous potential for broad application as isolable sources of
stereodefined alkyl nucleophiles in transition metal-catalyzed
reactions. Herein, we demonstrate that carbastannatranes
facilitate the transmetallation of unactivated primary, secon-
dary, and tertiary alkyl units in Pd-catalyzed coupling
reactions with acyl electrophiles. Using an array of isolable,
optically active, secondary alkylcarbastannatranes, we have
developed a stereospecific process to access enantioenriched
a-substituted ketones from acyl electrophiles. This process
represents the first stereospecific cross-coupling reactions of
unactivated alkyltin nucleophiles and acyl electrophiles,[11,12]
and constitutes a synthetic alternative to asymmetric enolate
methodologies.[13]
In our initial exploratory studies, we used the Pd-
catalyzed coupling of benzoyl chloride and isopropylcarba-
stannatrane (2) as a model system. We found that the desired
cross-coupling product (3) could be generated in good yield
using 2 mol% Pd(PPh3)4 alongside two equivalents of CuCl in
acetonitrile at 608C (Table 1). No evidence of isomerization
Scheme 4. Pd-catalyzed cross-coupling reactions of alkylcarbastanna-
tranes and acyl chlorides. [a] Pd(dba)2 (5 mol%), JackiePhos
(10 mol%).
Table 1: Optimization of the Pd-catalyzed cross-coupling reaction of
benzoyl chloride and 2.
Chloro-substituted arenes were also well tolerated under
these reaction conditions, which should enable cross-coupling
products such as 11 and 12 to be further modified using
existing cross-coupling technologies. In regards to the nucle-
ophilic component, use of unactivated primary and unacti-
vated secondary alkylcarbastannatranes was tolerated under
the standard reaction conditions. No isomerization of the
secondary alkyl nucleophiles was observed in these reactions.
In contrast, when t-butyl carbastannatrane was employed
under the standard conditions, significant isomerization of t-
butyl to i-butyl was observed. Use of bulky biarylphosphine
ligand JackiePhos[16] completely suppressed isomerization and
enabled isolation of t-butyl aryl ketones 15 and 17 in decent
yields. This constitutes the first example of t-butyl transfer
from an alkylstannane in a cross-coupling reaction, and again
underscores the remarkable ability of the carbastannatrane
backbone to activate alkyl groups that are typically inert
towards transmetallation.
When we initially disclosed the use of optically active
alkylcarbastannatrane reagents (1) in stereospecific arylation
reactions, enantioenrichment of 1 was achieved only via
asymmetric lithiation/stannylation or via preparative HPLC
separation of racemates. This limitation impeded our ability
to employ derivatives of 1 extensively in stereospecific
reactions. To address this deficiency, we have developed
a method to prepare highly enantioenriched alkylcarbastan-
natranes via the SN2 reaction of lithium carbastannatrane[17]
and enantioenriched secondary alkyl mesylates (Scheme 5).
This process should significantly expand the accessibility of
unactivated, enantioenriched alkylcarbastannatranes for
potential use in stereospecific reactions.
Entry
Variations from above
Yield [%][a]
1
2
3
4
5
6
7
8
9
none
80
90
0
52
15
40
12
38
50
0.1 mmol scale instead of 0.02 mmol
i-Pr4Sn instead of carbastannatrane 2
RT instead of 608C
2 equiv KF added
CuBr instead of CuCl
CuCN instead of CuCl
0.5 equiv CuCl
Toluene instead of CH3CN
[a] Yields and selectivities determined by GC analysis.
of the secondary alkyl component from b-hydride elimina-
tion/reinsertion sequences was observed in this reaction.
When i-Pr4Sn was used in place of carbastannatrane 2, no
product was formed. This highlights the unique ability of the
carbastannatrane backbone to selectively labilize bulky,
unactivated alkyl groups that are typically inert towards
transmetallation. The use of CuCl as a co-transmetallating
agent is essential to the success of this reaction.[14]
Using the optimized conditions of Table 1, we investigated
the scope of acyl chlorides tolerated in this cross-coupling
reaction using achiral and racemic alkylcarbastannatranes
(Scheme 4). We found that acyl chlorides bearing heteroaryl
groups could be efficiently employed as electrophiles. Inclu-
sion of an ortho-methyl substituent on benzoyl chloride had
little impact on the reaction. Acyl chlorides bearing alkyl
groups underwent coupling (products 9 and 10) without
evidence of alkyl isomerization via decarbonylation/b-hy-
dride elimination/reinsertion/re-carbonylation sequences.[15]
When
unactivated,
enantioenriched,
secondary
alkylcarbastannatranes 18 and 19 were employed in cross-
coupling reactions with acyl chlorides, the corresponding
2
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these cross-coupling reactions. 20 and 21 both underwent
cross-coupling reactions with exceptionally high stereofidel-
ity. Therefore, electronic perturbations of the nucleophile
(i.e., inclusion of a C(sp2) a-carbon or strongly coordinating
b-carbonyl group) do not appear to influence stereospecificity
in this process. Retrosynthetically, products 22–29 constitute
formal asymmetric alkylation reactions of enolates, whereas
30 and 31 constitute formal asymmetric arylation reactions of
enolates. It is noteworthy that the mild conditions employed
in this process are not conducive to racemization of the
enantioenriched product, even with an a-aryl substituent
present.
The combined results of Schemes 4 and 6 suggest that the
nucleophilic scope of this reaction is quite broad. Primary,
secondary, and tertiary alkylcarbastannatranes may be suc-
cessfully employed in acylation reactions. Activated and
unactivated secondary alkylcarbastannatranes all undergo
highly efficient stereospecific cross-coupling reactions using
identical conditions. Oxygen-containing nucleophiles could
also be readily employed. Unfortunately, carbastannatranes
bearing nitrogen-containing groups (e.g., piperidine and
pyrrolidine derivatives) were largely unsuccessful in these
reactions. This appears to be the major limitation of the
present system.
Scheme 5. Preparation of enantioenriched carbastannatranes from
optically active alkyl mesylates.
products were obtained with near perfect enantiospecificity
(% es)[18] for most substrates (Scheme 6). This constitutes the
first demonstration of a stereospecific, metal-catalyzed acy-
lation reaction using a stable, unactivated, enantioenriched
nucleophile. Consistent with our previously reported aryla-
tion reactions,[6e] this process proceeds with net retention of
absolute configuration (see Supporting Information for
details). In seminal studies conducted by Falck and others,
stereospecific couplings of enantioenriched alkytin nucleo-
philes and acid chlorides were limited to use of specific classes
of activated alkyltin nucleophiles.[12] To evaluate stereoelec-
tronic influences of the nucleophile on stereospecificity in the
present system, we also studied the use of electronically
activated enantioenriched carbastannatranes (20 and 21) in
Because thioesters are more stable and more easily
handled than their corresponding acid chlorides, we explored
the possibility of using thioesters as acyl electrophiles in
stereospecific cross-coupling reactions.[13,19] Using the stan-
dard conditions with 5 mol% Pd(PPh3)4, we successfully
effected the cross-coupling reaction of (S)-19 and thioester 32
in high yield and with high stereofidelity (Scheme 7). Since
non-racemic thioesters can be readily prepared from enan-
tioenriched a-chiral carboxylic acids, we felt that such
thioesters might be effective substrates for diastereospecific
reactions, forming optically active a,a’-disubstituted ketones
with complete reagent control of stereochemistry. Using the
thioester of (S)-Naproxen (33), we successfully generated syn-
34 and anti-34 from stereospecific reactions with (R)-18 and
(S)-18, respectively. The products of these reactions com-
Scheme 7. Stereospecific coupling reactions of enantioenriched alkyl-
carba-stannatranes and thioesters. [a] Pd(dba)2 (5 mol%), JackiePhos
(10 mol%).
Scheme 6. Stereospecific Pd-catalyzed couplings of enantioenriched
alkylcarbastannatranes and acyl chlorides.
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[5] Reviews articles for stereospecific cross-coupling reactions:
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pletely retained the stereochemistry of their original coupling
partners.
In summary, we have developed a general Pd-catalyzed
process for the stereospecific cross coupling of enantioen-
riched alkylcarbastannatranes and acyl electrophiles. These
reactions occur with outstanding stereofidelity and with
retention of absolute configuration. Because the stereochem-
istry of the resulting products is entirely reagent controlled,
this method offers an alternate, general strategy for the
preparation of compounds typically generated via asymmetric
reactions of enolates or enolate equivalents. We have addi-
tionally shown that the carbastannatrane backbone facilitates
the transfer of t-butyl groups in Pd-catalyzed cross-coupling
reactions. This represents the first example of the selective
transfer of an unactivated tertiary alkyl group from tin, and
suggests the potential for stereospecific quaternary center
formation from enantioenriched tertiary alkylcarbastanna-
tranes.
Acknowledgements
We
thank
the
National
Institutes
of
Health
(1SC1GM110010), the Alfred P. Sloan Foundation, and
PSC-CUNY for financial support. We gratefully acknowledge
the National Science Foundation for an instrumentation grant
(CHE-0840498).
Conflict of interest
The authors declare no conflict of interest.
Keywords: carbastannatrane · cross coupling · enolate ·
palladium catalysis · stereospecific catalysis
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Manuscript received: October 10, 2016
Final Article published: && &&, &&&&
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Communications
Asymmetric Catalysis
C.-Y. Wang, G. Ralph, J. Derosa,
M. R. Biscoe*
&&&& — &&&&
Stereospecific Palladium-Catalyzed
Acylation of Enantioenriched
Alkylcarbastannatranes: A General
Alternative to Asymmetric Enolate
Reactions
Finding new ways: A Pd-catalyzed pro-
cess for the cross-coupling of unactivated
primary, secondary, and tertiary alkyl-
carbastannatrane nucleophiles with acyl
electrophiles was developed. This reac-
tion provides as a general, alternative
approach to the preparation of products
typically accessed via asymmetric enolate
methodologies.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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