Preparation of Enantioenriched Alkylcarbastannatranes via Nucleophilic Inversion of Alkyl Mesylates for Use in Stereospecific Cross-Coupling Reactions

Article abstract of DOI:10.1021/acs.organomet.9b00467

We report the preparation of enantioenriched secondary alkylcarbastannatranes via a stereoinvertive S_N2 reaction of enantioenriched alkyl mesylates and carbastannatranyl anion equivalents. Using this process, enantioenriched secondary alcohols may be converted into highly enantioenriched alkylcarbastannatranes, which are useful in stereospecific cross-coupling reactions.

Full text of DOI:10.1021/acs.organomet.9b00467

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Preparation of Enantioenriched Alkylcarbastannatranes via
Nucleophilic Inversion of Alkyl Mesylates for Use in Stereospecific
Cross-Coupling Reactions
†
,‡
,†,‡
Glenn Ralph and Mark R. Biscoe*
†Department of Chemistry, The City College of New York (CCNY), 160 Convent Avenue, New York, New York 10031, United
States
‡
Ph.D. Program in Chemistry, The Graduate Center of The City University of New York (CUNY), 365 Fifth Avenue, New York,
New York 10016, United States
*
S Supporting Information
ABSTRACT: We report the preparation of enantioenriched
secondary alkylcarbastannatranes via a stereoinvertive SN2
reaction of enantioenriched alkyl mesylates and carbastanna-
tranyl anion equivalents. Using this process, enantioenriched
secondary alcohols may be converted into highly enantioen-
riched alkylcarbastannatranes, which are useful in stereo-
specific cross-coupling reactions.
he use of configurationally stable enantioenriched
organometallic nucleophiles in stereospecific transforma-
Subsequently, we extended this chemistry to stereospecific
acylation reactions, as well as stereospecific fluorination
reactions.
T
9
,10
tions constitutes a powerful approach to the preparation of
1
,2
complex, nonracemic molecules. Accordingly, enantioen-
riched organoboron and organotin compounds have been
extensively used in metal-catalyzed cross-coupling reactions.
These transformations rely on stereospecific mechanisms that
effectively translate chiral information from the starting
materials to final products. Thus, it is vital that such precursors
can be prepared with high enantiopurity in a straightforward
manner.
The lack of an efficient route to prepare enantioenriched
carbastannatrane nucleophiles has been a major bottleneck to
their broader synthetic application. Because unactivated
secondary alkylstannanes typically exhibit low reactivity,
there has previously been limited value in devising synthetic
strategies to prepare enantioenriched variants. As a result, our
laboratory has relied heavily on stereospecific lithiation/
1
1
3
stannylation processes and chiral preparatory HPLC
separation of racemates to obtain enantioenriched alkylcarbas-
tannatrane nucleophiles. We set out to address this limitation
by developing a more general approach to the preparation of
enantioenriched alkylcarbastannatranes. Herein, we report a
study of carbastannatranyl anion equivalents in stereoinvertive
SN2 reactions with enantioenriched alkyl mesylates. We have
found that carbastannatranyllithium (2) readily undergoes
substitution reactions with secondary alkyl mesylates. This
strategy enables the preparation of highly enantiopure
secondary alkylcarbastannatranes from commercially available
single-enantiomer alcohols. With access to more diverse
alkylcarbastannatrane nucleophiles, the scope of stereospecific
Stille cross-coupling reactions is significantly broadened.
Building upon the pioneering work of Jurkschat and
4
Vedejs, in 2013, our laboratory developed a Stille cross-
coupling reaction of enantioenriched secondary alkylcarbas-
5
−7
tannatrane nucleophiles and aryl electrophiles (Figure 1).
Figure 1. Stereospecific Stille cross-coupling reaction using
enantioenriched secondary alkylcarbastannatranes.
This method afforded arylation products in high yields and
with high enantiospecificity. The unique reactivity of
alkylcarbastannatranes is attributed to the selective labilization
of its apical alkyl substituent as a consequence of the dative
Special Issue: Asymmetric Synthesis Enabled by Organometallic
Complexes
4
N−Sn interaction in the “atrane” tin backbone. This approach
enabled the first example of a stereospecific cross-coupling
Received: July 10, 2019
8
reaction using an unactivated secondary organotin species.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00467
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
In 2015, Wang and Uchiyama reported the highly efficient
nucleophiles proved superior to the use of 2 in hexane or ether,
the ability of attenuated nucleophiles such as 5 and 7 to
undergo stereoinvertive substitution with high enantiospeci-
ficity suggests that alkyl mesylates bearing functional groups
not compatible with tin lithium reagents will be still viable
electrophiles in this process.
Using the conditions developed in Table 1, a series of
secondary alkylcarbastannatrane nucleophiles was prepared
from their corresponding mesylates (Table 2). Yields of ca.
lithiation of trialkyltin chlorides using in situ generated
1
2
naphthalide radical anions. Using this method, clean
substitution of methyl and primary allylic/benzylic halides
was observed, which enabled preparation of the corresponding
organostannanes in excellent yield. We hypothesized that
carbastannatranyllithium (2) could be produced under similar
reductive conditions and might be employed in S 2 reactions
N
with enantioenriched secondary alkyl electrophiles to afford
enantioenriched secondary alkylcarbastannatranes via stereo-
inversion. To circumvent potential racemization via a back-
ground radical pathway, we opted to investigate the use of
secondary alkyl sulfonates, which have a lower propensity to
form alkyl radicals than do alkyl halides. We quickly found that
sec-butyl mesylate underwent efficient substitution with
tributylstannyllithium prepared by the method of Wang and
Uchiyama. However, an analogous approach using carbastan-
natranyl chloride failed to generate the corresponding
secondary alkylcarbastannatrane. Ensuing studies revealed
that carbastannatranyllithium (2) could be generated through
sonication of the reaction mixture at 45 °C (see the Supporting
Information).
Table 2. Preparation of Enantioenriched Secondary
Alkylcarbastannatranes from Their Corresponding
Mesylates
Having developed effective conditions for the in situ
generation of tin lithium species 2, we investigated the
1
3
enantiospecificity of the substitution reaction using enan-
tioenriched alkyl mesylate 5 (Table 1). The reaction of 2 with
Table 1. Optimization of Enantiospecificity in the Reaction
of Carbastannatranyl Anion Equivalents and Alkyl Mesylate
5
5
0% were typically obtained alongside high levels of
enantioenrichment, with separable elimination products
accounting for the remaining mass balance. These unactivated
enantioenriched secondary alkylcarbastannatranes (8) are
completely tolerant of air and water. They are also inert to
neutral, basic, and reductive reaction conditions, which enables
synthetic modifications to be performed following installation
of the carbastannatrane unit. For instance, desilylation of 12
was readily achieved by treatment with TBAF. Previously, we
have demonstrated that diborylation of olefins and LiAlH4
reduction of esters do not affect the integrity of the
a
1
b
Calibrated H NMR yields. Determined by chiral HPLC.
10,15,16
carbastannatrane unit.
The majority of the enantioen-
riched alkylcarbastannatranes prepared using this method
contain a methyl group on the stereogenic carbon center.
Unfortunately, analytical chiral HPLC conditions could not be
found to separate enantiomers of carbastannatrane 13, in
which an ethyl group replaces the methyl group. Though the
enantiopurity of 13 could not be determined, we feel that the
enantiospecificity would likely be very high from the
enantioenriched alkyl mesylate, as was observed when other
mesylates were employed alongside our standard conditions.
Previously, we had only reported two examples of stereo-
specific arylation reactions using unactivated secondary
alkylcarbastannatranes (prepared using preparatory chiral
3
predissolved in THF resulted in eroded enantiopurity in the
substitution product. However, we found that excellent
enantiospecificity could be achieved when TMEDA was
added to 2 or when ether or hexane was employed as the
solvent. Access to carbastannatranyllithium (2) not only was
found to be useful in forming tin−carbon bonds directly but
could also be used as a precursor to other metalated tin
1
4
nucleophiles. Using 5 as a model substrate for analysis, we
examined the reactivity of carbastannatranyl anion equivalents
5
−7 in this substitution reaction. Reactions involving 5 and 7
showed excellent enantiospecificity. Though none of these
B
DOI: 10.1021/acs.organomet.9b00467
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
5
HPLC). Now having broader access to enantioenriched
was well tolerated in these reactions. The free alcohol formed
from desilylation of (S)-12 underwent arylation with high yield
and excellent enantiospecificity. Use of (rac)-13 as a
nucleophile resulted in the formation of arylation product
alkylcarbastannatranes nucleophiles, we conducted an inves-
tigation of their use in stereospecific Stille reactions. The cross-
coupling products in Table 3 were all generated with high
1
4h in high yield. Thus, transmetalation of a secondary
Table 3. Stereospecific Stille Cross-Coupling Reactions
Using Enantioenriched Secondary Alkylcarbastannatranes
alkylcarbastannatrane still occurs efficiently from the bulkier,
non-methyl-containing alkylcarbastannatrane nucleophile. Fi-
nally, when (S)-11 was employed in a coupling reaction with
the thioester of (S)-naproxen, acylation product 14j was
obtained with completely reagent controlled diastereoselectiv-
ity.
a
In summary, we have developed a reliable synthetic method
to access enantioenriched secondary alkylcarbastannatranes
from their corresponding alkyl mesylates. Treatment of
enantioenriched alkyl mesylates with stannatranyllithium (2)
results in the formation of highly enantioenriched secondary
alkylcarbastannatranes via a stereoinvertive S 2 pathway.
N
Other carbastannatranyl anion equivalents (e.g., 5 and 7)
were also shown to undergo substitution reactions with high
enantiospecificity. We subsequently demonstrated that these
enantioenriched alkylcarbastannatrane nucleophiles readily
undergo cross-coupling reactions with aryl bromides, with
highly general preference for retention of stereochemistry. We
expect that this method to access enantioenriched alkylcarbas-
tannatranes will facilitate the future development of new
stereospecific transformations of alkylcarbastannatrane com-
pounds.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00467.
Synthetic procedures, spectral data ( H and 13C NMR),
1
and HPLC data (PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail for M.R.B.: mbiscoe@ccny.cuny.edu.
■
*
ORCID
Mark R. Biscoe: 0000-0003-1257-6288
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the City College of New York, the National
Institutes of Health (R01GM131079), and the National
Science Foundation (CHE-1665189) for support of this work.
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DOI: 10.1021/acs.organomet.9b00467
Organometallics XXXX, XXX, XXX−XXX