α-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters

Article abstract of DOI:10.1021/jacs.7b05457

The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (-)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid-base side-reactions under the reaction conditions for homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen's readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon-carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity.

Full text of DOI:10.1021/jacs.7b05457

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α‑Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the
Stereoselective Iterative Homologation of Boronic Esters
Giorgia Casoni,‡ Murat Kucukdisli,‡ James M. Fordham,‡ Matthew Burns, Eddie L. Myers,*
and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, BS8 1TS, United Kingdom
S
* Supporting Information
ABSTRACT: The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable
synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl
triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic
esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (−)-enantiomer of the
scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated
during homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels
of enantiopurity and are prone to undergo deleterious acid−base side-reactions under the reaction conditions for homologation,
leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl
triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with
either enantiomer of Andersen’s readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl
benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive
functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into
lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly
stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of
sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to
steric hindrance, allows sterically encumbered carbon−carbon bonds to be forged. We have also shown that these building blocks
can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography,
to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity.
range of highly enantiomerically pure (>99:1) bench-stable
carbenoid building blocks exists; the carbenoid carbon atom
should bear (a) a group that can be rapidly and stereospecifi-
cally transformed into a reactive metal group, (b) a suitable
leaving group, and (c) an arrangement of substituents (or
protected forms thereof) that can be translated into one
displayed by the desired product. (2) The process has the
ability to stereospecifically metalate (Li or Mg) the carbenoid
under reaction conditions that maintain high chemical and
configurational stability. (3) In the presence of a boronic ester,
which should be the limiting reactant, the metal carbenoid can
undergo irreversible stereospecific metal−boron exchange to
form a boronate complex in quantitative yield. (4) The
boronate complex undergoes invertive 1,2-metalate rearrange-
ment with high stereochemical fidelity, but only at higher
1. INTRODUCTION
The development of stereoselective carbon−carbon bond-
forming reactions that are insensitive to both the configuration
of existing stereogenic centers and the presence of distal
functional groups holds great promise as the driver that will
usher in an era of molecule-making machines.1 Transformations
that allow molecules to be grown one-, two-, or three carbon
atoms at a time, in an iterative fashion, are especially attractive
owing to their suitability for automation.2 The reagent-
controlled stereoselective homologation of boronic esters, a
transformation that employs chiral nonracemic carbenoid
precursors as building blocks, is one such reaction (Figure
1A). Inspired by the work of Matteson,3 Hoppe,4 Beak,5 and
Hoffmann,6 our research group (Figure 1B)7 and the research
group of Blakemore (Figure 1C)8 have developed a series of
building blocks and methods that has ripened this trans-
formation for automation. An ideal process has emerged and
satisfies the following conditions: (1) Ready access to a wide
Received: May 26, 2017
© XXXX American Chemical Society
A
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Figure 1. (A) Iterative homologation of boronic esters for the synthesis of stereochemically well-defined substituted carbon chains. (B) α-Stannyl
benzoates for iterative homologation of boronic esters. (C) α-Sulfinyl chlorides for the iterative homologation of boronic esters. (D) α-Sulfinyl
carbamates for the homologation of boronic esters. (E) This work: α-sulfinyl benzoates.
temperatures in a regime where excess metal-stabilized
carbenoid is no longer chemically stable, thus avoiding
overhomologation. (5) The process has the ability to rapidly
and efficiently isolate the homologated boronic ester for further
transformations (including homologation), or byproducts are
suitably benign to allow further homologations to be carried
out in one pot.
toxicity and that the more benign organomagnesium reagents
could be used for their transformation into carbenoids. Moving
away from chloride as the leaving group, thus hoping to avoid
the side-reactions prevalent in Blakemore’s homologation
protocol, we spent considerable effort investigating α-sulfinyl
benzoates (Figure 1E).11 We found that their conversion into
lithium or magnesium carbenoids through sulfoxide−metal
exchange in single homologations of simple boronic esters led
to the one-carbon-extended boronic esters in good yields and
stereospecificity, as was later independently confirmed in a
single example reported by O’Brien (Figure 1D).12 However,
their use as the sole carbenoid precursor in sequential one-pot
homologations gave levels of efficiency that paled in
comparison to that of the α-stannyl derivatives. Recently,
with the aim of preparing more elaborately substituted
hydrocarbon chains and a changing viewpoint that a
molecule-making machine need not make sole use of one
particular carbenoid, we decided to revisit the α-sulfinyl
benzoates. Herein, we disclose much improved methods for
their synthesis and reveal significant value in their use in
assembly line iterative homologation of boronic esters.
In 2014, we reported on α-stannyl ethyl benzoate 3 (Figure
1B) as a bench-stable carbenoid precursor for the iterative
homologation of contiguously methyl-substituted hydrocarbon
chains.7g This precursor, which could be obtained in very high
levels of enantiopurity (>99.9:0.01) through recrystallization,
allowed assembly line synthesis to be performed with
exceptionally high levels of efficiency, where any diastereomer
of a 10-carbon-long chain (e.g., 4, Figure 1B) could be grown
one carbon atom at a time in high yield as a single enantiomer,
without intervening column chromatography. However, despite
the utility, a number of unfavorable attributes continue to
concern us: (a) both enantiomers of sparteine are required but
the (−)-enantiomer has become more difficult to access than
the (+)-enantiomer;9 (b) only the methyl-substituted pre-
cursors are crystalline, thus making it difficult to obtain other
derivatives in highly enantioenriched form; (c) toxic Me3SnCl
is required for their synthesis, and the precursors themselves
(and byproducts produced during consumption) are perceived
to be toxic,10 thus hampering uptake by the scientific
community.
2. RESULTS AND DISCUSSION
2.1. Synthesis of α-Sulfinyl Benzoates by Sulfinyla-
tion. Initially we focused on the preparation of α-sulfinyl
benzoates by employing conditions reported for the corre-
sponding carbamates. O’Brien discovered that treatment of
racemic lithiated carbamate 8 with enantiomerically pure
Andersen’s menthol-derived sulfinate 9 gave a mixture of the
syn and anti α-sulfinyl carbamates 10, but with only moderate
levels of enantiospecificity (Figure 2A).12 The erosion of
In the early stages of the development of our assembly line
protocol, we were drawn to the α-chloro sulfoxides (e.g., anti-6,
Figure 1C) employed by Blakemore,8 owing to the favorable
attributes conferred by the sulfinyl moiety with respect to
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forms of a range of enantiopure α-sulfinyl benzoates bearing
substituents of varying steric demand (14b−e) and presenting
useful functional handles, alkene 14f and ketal 14g (Figure 2B).
The relative and absolute configuration of α-sulfinyl benzoates
was determined by comparing chiral HPLC traces of products
obtained from the sulfinylation of magnesiated benzoates by
using (a) a racemic magnesiated benzoate/racemic sulfinylation
reagent (mixture of all four stereoisomeric products); (b) a
racemic magnesiated benzoate/enantiopure sulfinylation re-
agent (mixture of two isomers, epimeric at the carbon center);
(c) an enantioenriched magnesiated benzoate/racemic sulfiny-
lation reagent (mixture of two isomers, epimeric at the sulfur
center; see the Supporting Information).
Through retentive sulfoxide−lithium exchange, the syn and
anti diastereomers depicted in Figure 2 are precursors to the S-
and R-configured lithium carbenoids, respectively. However,
should the anti diastereomer be unavailable owing to difficulties
in obtaining it in pure form, the R-configured lithium carbenoid
could alternatively be formed through sulfoxide−lithium
exchange of the enantiomer of the syn-diastereomer, which
can be accessed using the other enantiomer of Andersen’s
menthol-based sulfinate, the enantiomeric reagents being
commercially available with equal readiness. Additionally, we
investigated a number of epimerization experiments under both
kinetic and thermodynamic control and found that the
Knochel−Hauser base (TMPMgCl·LiCl)14 together with
indene as a proton source could affect kinetic epimerization
of a 1:1 mixture of syn- and anti-14b to give a mixture enriched
with the syn-isomer (dr 86:14; see the Supporting Informa-
tion).
Figure 2. Synthesis of α-sulfinyl carbamates (A) and benzoates (B)
through the sulfinylation of α-lithiated and -magnesiated precursors
with Andersen’s menthol-derived sulfinate. Diastereomers were not
a
separable by column chromatography, and yields were determined
1
based on H NMR analysis. A portion of the mixture was purified by
reverse-phase HPLC to obtain analytically pure syn and anti-14d.
2.2. Homologation of Boronic Esters with α-Sulfinyl
Benzoates. With a selection of enantiopure α-sulfinyl
benzoates 14a−g in hand, we tested their effectiveness as
precursors to metal carbenoids, through sulfoxide−metal
exchange, for the homologation of boronic esters. Optimization
of the sulfoxide−metal exchange/borylation sequence was
carried out using enantioenriched α-sulfinyl benzoate anti-14b
and boronic ester 15. Because Blakemore and co-workers
showed that the use of Li carbenoids, which were generated
from α-chloro sulfoxides, gave significantly improved results in
the homologation of boronic esters compared to the
corresponding Mg carbenoids,8g we initially investigated the
use of organolithium reagents to trigger the exchange (Figure
3). Treatment of a solution of anti-14b in tetrahydrofuran
(THF) at −78 °C with n-BuLi, allowing the resulting mixture
stereospecificity was surprising because it was well documented
that organometals react with these sulfinate reagents with high-
fidelity inversion of configuration at the sulfur atom.13 The
origin of the offending minor enantiomer for each diastereomer
was attributed to the degenerate sulfinyl-transfer reaction of
enantiomeric lithiated carbamate and early formed α-sulfinyl
carbamate product, effectively leading to products derived from
a double-inversion pathway. O’Brien overcame this problem by
generating the lithiated carbamate in enantioenriched form
(using chiral nonracemic sparteine or 1,2-diaminocyclohexane
derivative 12), thus allowing one diastereomer to be isolated
with high levels of stereoselectivity. We confirmed that this
enantioeroding side-reaction was also operating in the
sulfinylation of benzoate 13, the chromatographically separable
anti and syn α-sulfinyl products 14a being isolated in 87:13 and
88:12 er, respectively. Interestingly, increasing the number of
equivalents of sulfinate 9 did not lead to a significant increase in
er value of product, going against what would be predicted by
the participation of competing sulfinylating species. We were
hesitant about adopting O’Brien’s solution to the problem, as it
would make us reliant on having ready access to sparteine or
diamine 12. We wondered whether the nucleophilicity of the α-
magnesiated benzoate would be sufficiently tempered to allow
only sulfinyl transfer with Andersen’s reagent 9 and not the
degenerate sulfinyl transfer with product. We were pleased to
discover that upon transmetalation of the initially formed
lithiated benzoate to the magnesiated benzoate (addition of
MgBr2·OEt2) and then treatment with sulfinate 9, the syn and
anti diastereomers 14a were isolated with near-perfect levels of
enantiopurity. These highly enabling reaction conditions
subsequently allowed the preparation of both diastereomeric
Figure 3. Optimization of reaction conditions for the homologation of
boronic esters by using lithium carbenoids derived from α-sulfinyl
benzoates. Reactions performed on a 0.1 mmol scale; conversion
measured by GCMS of the crude reaction mixture; TBME = tert-butyl
methyl ether; CPME = cyclopentyl methyl ether.
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to evolve for only 1 min before addition of the boronic ester,
and warming the ternary mixture to room temperature12 did
not lead to the desired homologation reaction. Presumably, the
initially generated lithium carbenoid is unstable in the presence
of the relatively acidic alkyl−aryl sulfoxide byproduct; in
contrast, the same carbenoid generated through tin−lithium
exchange of the corresponding α-stannyl benzoate is stable for
hours at −78 °C.7g Using Barbier-type conditionsthe
addition of n-BuLi to a solution of anti-14b and boronic ester
15 in THF at −78 °Cdelivered the one-carbon-homologated
boronic ester 16 in 54% yield. Here, the sulfoxide−lithium
exchange is sufficiently faster than reaction of n-BuLi with the
boronic ester; also, the reaction of the lithium carbenoid with
the boronic ester, thus forming the desired boronate complex,
is faster than apparent side-reactions of the carbenoid. The use
of t-BuLi under the same conditions gave the boronic ester 16
in slightly higher yield (59% yield), presumably owing to the
absence of α-hydrogen atoms in the alkyl−aryl sulfoxide
byproduct. Further exploration of reaction conditions revealed
that the use of solvents other than THF (Et2O, TBME, CPME,
PhMe) resulted in low conversion of the boronic ester starting
material. Using t-BuLi (2.0 equiv) and anti-14b (1.05 equiv),
with the boronic ester starting material 15 being the limiting
species, proved to be optimal; these reaction conditions
resulted in complete conversion of 15 (16/15 > 99:1, as
determined by GCMS analysis) and isolation of the
homologated boronic ester 16 in good yield and enantiopurity
(78% yield, 99:1 er; Figure 3, entry 8). The extra equivalent of
t-BuLi is needed as a sacrificial base to neutralize deleterious
internal proton sources, specifically, the ortho-positioned sp2
C−H bonds in the alkyl−aryl sulfoxide byproduct (MeOD-
trapping experiments confirmed the operation of this process;
see the Supporting Information)15 and adventitious H2O;16 the
low yield of isolated byproduct might also point to t-BuLi-
mediated fragmentation of the byproduct to the sulfenic acid
and isobutene.
Figure 4. Optimal reaction conditions for the homologation of
boronic esters by using magnesium carbenoids derived from α-sulfinyl
benzoates.
the homologation of boronic ester 15 under the optimal
homologation conditions.
With optimal conditions for homologating with both lithium
and magnesium carbenoid intermediates established (Figure 3,
entry 8; Figure 4), we explored the substrate scope of the
homologation reactions (Figure 5). Therefore, a range of
boronic esters (17) were homologated with a range of
substituted α-sulfinyl benzoates 14a−g as precursors to lithium
carbenoids (conditions A: sulfinyl benzoate, 1.05 equiv; t-BuLi,
2.0 equiv; Barbier-type conditions) and as precursors to
magnesium carbenoids (conditions B: sulfinyl benzoate, 1.3
With the aim of identifying reaction conditions that are
milder and more tolerant of sensitive functional groups, we also
investigated the homologation of boronic ester 15 by using the
in situ generated magnesium carbenoids, which are more
chemically and configurationally stable than the corresponding
lithium carbenoids.8g,12,17 Initial experiments revealed that
using i-PrMgCl to trigger the putative sulfoxide−magnesium
exchange of α-sulfinyl benzoate, anti-14b, at −78 °C, followed
by addition of the boronic ester 15, gave an inseparable mixture
of the desired one-carbon-homologated boronic product
together with the two-carbon-homologated boronic ester.
Presumably, the in situ formed magnesium carbenoid is stable
at the temperature where the intermediate boronate undergoes
1,2-metalate rearrangement, thus allowing the desired one-
carbon-homologated boronic ester to react with another
equivalent of carbenoid; in contrast, lithium carbenoids
decompose at ca. −40 °C to benign byproducts.7g Interestingly,
the use of the turbo Grignard reagent, i-PrMgCl·LiCl,18 led to
much improved results; the boronic ester starting material 15
was completely converted into the desired one-carbon-
homologated boronic ester 16, with none of the higher
homologues detected (76% yield, >99:1 er; Figure 4). The
same result was obtained by using the more convenient
Barbier-like conditions (addition of the turbo Grignard to a
mixture of the α-sulfinyl benzoates and the boronic ester).
Moreover we did not observe any differences in the reactivity of
the syn and anti diastereomers of α-sulfinyl benzoate 14b for
Figure 5. Homologation of boronic esters with lithium or magnesium
carbenoids derived from α-sulfinyl benzoates, as prepared through the
sulfinylation of α-magnesiated benzoates. Conditions A: 14 (1.05
equiv), 17, and t-BuLi (2.0 equiv) in THF. Conditions B: 14 (1.3
equiv), 17, and i-PrMgCl·LiCl (1.2 equiv) in DCM. Conditions C:
addition of 14 (1.3 equiv) to t-BuLi (2.0 equiv) and PMDTA
(N,N,N′,N″,N″-pentamethyldiethylenetriamine. 2.0 equiv); then add-
ing 17. Reactions performed on a 0.2 mmol scale. Yields are based on
isolated product. The er values were determined by chiral HPLC
analysis of the corresponding alcohols.
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equiv; i-PrMgCl·LiCl, 1.2 equiv; Barbier-type conditions). In
general, the use of α-sulfinyl benzoates bearing nonbranched
substituents (14a−c, 14f, 14g) gave good yields of the
homologated boronic ester with excellent levels of enantiospe-
cificity for both sets of reaction conditions (Figure 5). The
yields were always 10−20% higher when using lithium
carbenoids. However, α-sulfinyl benzoates bearing branched
substituents could provide serviceable quantities of the
homologated boronic ester only when using the lithium
carbenoids (14d). In agreement with the results of Blakemor-
e,8f,g the insertion of magnesium carbenoids into the C−B bond
of boronic esters is much more sensitive to steric hindrance
than that of the corresponding lithium carbenoids, and thus
magnesium carbenoids do not possess the level of reactivity
required for inserting methine units bearing branched
substituents. However, although Blakemore’s isopropyl-sub-
stituted α-chloro lithium carbenoid, the precursor of which
could be prepared in only 70:30 er, did not effect the desired
homologation to any detectable level,8f the corresponding
benzoate, as described here, allowed the same homologation to
be effected in 54% yield and with very high levels of
enantiospecificity (95% es, Figure 5). The superior perform-
ance of the α-sulfinyl benzoates is due to the greater steric
hindrance in the vicinity of the carbenoid carbon atom, a
characteristic that increases the stability of the carbenoid
precursor with respect to α-deprotonation.8b For Blakemore,
this side-reaction could be partially suppressed by using the
deuterium isotopomer of the carbenoids, thus taking advantage
of a primary kinetic isotope effect.8b−d When using tert-butyl-
substituted benzoate 14e, none of the desired homologated
boronic ester was detected using either set of conditions; the
isolation of the neopentyl benzoate (protodesulfinylation of the
carbenoid precursor) suggests that internal quenching of the
lithium carbenoid was the dominant process, formation of the
desired boronate complex being too slow owing to steric
hindrance.
However, moderate conversion of the starting boronic ester
(18e/17a, 80:20) and moderate levels of enantiospecificity
(77% es) were observed by using an inverse-addition protocol:
addition of the carbenoid precursor to a Et2O solution of t-BuLi
in the presence of the tridentate ligand N,N,N′,N″,N″-
pentamethyldiethylenetriamine (PMDTA), followed by addi-
tion of the boronic ester (Figure 5, conditions C). These results
suggest that for sterically hindered α-sulfinyl benzoates,
sulfoxide−lithium exchange is significantly slower than what
is typically expected, where even in the presence of a large
excess of organolithium reagent (inverse addition) internal
quenching of the desired lithium carbenoid through an acid−
base reaction with a carbenoid precursor is a competing
process. The boronic ester component was also varied
(products 18h−o). Boronic esters bearing either a tert-butyl
ester group or an azido group could be homologated only with
in situ formed magnesium carbenoids (products 18h and 18i);
evidently, for lithium carbenoids, these functional groups react
with the organolithium species faster than the formation of the
requisite boronate complex. Again, the magnesium carbenoids
were superior for the homologation of vinyl and aryl boronic
esters (products 18j and 18k). However, lithium carbenoids
were superior for the homologation of more sterically hindered
pinacol boronic esters (products 18m and 18l). We wondered
whether the use of a less sterically hindered diol ligand on the
boron center, specifically a neopentylglycol boronic ester,7d,h,j
could lead to improved yields for the homologation of sterically
hindered organoborons with magnesium carbenoids. Indeed for
the homologation of cyclohexyl neopentylglycol boronic ester
with the magnesium carbenoid, product 18n, which was
obtained through oxidation of the initially formed product
18o, was obtained in 10% higher yield (48%) compared to the
process with the pinacol boronic ester (36%). Interestingly, for
the corresponding homologations with lithium carbenoids, the
neopentylglycol boronic ester gave significantly lower yields
(59% versus 36%).
2.3. Synthesis of α-Sulfinyl Benzoates by Alkylation.
One of the potential advantages of using sulfoxides in place of
stannanes for the homologation of boronic esters is the
extremely rapid sulfoxide−metal exchange reaction in the
presence of organometals; this transformation is typically so fast
that trace amounts of water are trapped by the metal carbenoid
rather than by the initially added organolithium reagent.15 This
rapid exchange process means that the carbenoids can be
generated in the presence of the boronic ester (Barbier-type
conditions) and, if the ensuing trapping of the boronic ester
with carbenoid to form the boronate is sufficiently rapid, that
functional groups that would normally be reactive toward
organometals would be left unscathed. However, the method
described above for preparing α-sulfinyl benzoates (the
sulfinylation of metal carbenoids) nullifies this particular utility
because it is not amenable for preparing α-sulfinyl benzoates
containing such sensitive functional groups. Therefore, we also
decided to explore the synthesis of these precursors through the
alkylation of α-sulfinyl benzoate 19, which can be deprotonated
at the α-position by using relatively weak bases, such as lithium
diisopropylamide (LDA). Enantiomerically pure α-sulfinyl
benzoate 19 could be prepared using the sulfinylation of
magnesiated methyl benzoate or through the SN2 displacement
reaction of known enantioenriched α-chloro sulfoxide.19 The
alkylation of benzoate 19 proved to be highly dependent on the
electrophile and required extensive optimization. For the
methylation of benzoate 19 by using methyl iodide as the
electrophile, the overall yield and diastereoselectivity were
dependent on the base used, whether using in situ (Barbier-
type conditions) or ex situ conditions (MeI added after
deprotonation), and on scale (Figure 6). The use of lithium
hexamethyldisilazane (LiHMDS) under in situ conditions gave
substantial quantities of the dialkylated product; however, by
using ex situ conditions, this undesired process could be
suppressed to give a mixture of the syn and anti products (83%
overall yield), favoring the latter (1:3). The use of NaHMDS
Figure 6. Optimization of reaction conditions for the methylation of
a
α-sulfinyl benzoate 19. Reactions performed on a 0.1 mmol scale. In
situ: sulfoxide and MeI premixed prior to the addition of the base; ex
situ: sulfoxide treated with the base at −78 °C; then, after 10 min, MeI
1
is added. dr values determined by H NMR analysis of the crude
b
c
reaction mixture. Reaction performed on a 7.7 mmol scale. Yields of
isolated product.
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under in situ conditions on a moderately large scale (7.7 mmol)
proved superior, allowing both diastereomers to be isolated in
excellent overall yield and in roughly equal amounts.
Unfortunately, the conditions optimized for MeI (NaHMDS
under in situ conditions) were unsuitable for both less reactive
more hindered electrophiles and highly reactive electrophiles,
decomposition of the in situ formed carbanion or the desired
product being apparent. Therefore, further optimization was
necessary for preparing other classes of substituted α-sulfinyl
benzoates (Figure 7). For example, the introduction of an ethyl
at the carbenoid carbon atom would be obtainable from ent-19,
which would in turn be obtainable by using the alternative
enantiomer of Andersen’s sulfinate. The use of tetramethylsi-
lane (TMS)-protected propargylic bromide as the electrophile
proved challenging owing to a facile E2 elimination reaction of
the desired product: the use of LiHMDS gave a mixture of the
enynyl sulfoxide and starting material. We reasoned that the use
of the Knochel−Hauser base, which would lead to the less
reactive magnesiated carbanion, might engender more stable
conditions for the desired product. Indeed, these reaction
conditions allowed isolation of propargylic-substituted α-
sulfinyl benzoate 14j in moderate yield, this time favoring the
syn product (anti-14j/syn-14j, 1:2). These conditions were also
suitable for introducing a trifluoropropyl group, a trans-
formation that was effected using the triflate electrophile. The
diastereoselectivity of these alkylation reactions was difficult to
predict, but with these sets of results in hand, some general
trends can be noted: the use of lithium bases favors the anti
diastereomer; the use of sodium bases shows low levels of
diastereoselectivity; magnesium bases favor the syn diaster-
eomer. Presumably both the ability of the counterion to activate
or precomplex the incoming electrophile and its effect on the
aggregation state of the carbanion and on the propensity of the
product to undergo deprotonation under the reaction
conditions contribute in varying degrees to dictate the
diastereoselectivity.20
2.4. Homologation of Boronic Esters with Functional-
Group-Rich α-Sulfinyl Benzoates. With a set of highly
enantioenriched, more functional-group-rich α-sulfinyl ben-
zoates in hand (Figure 7), we tested them as homologating
reagents for our standard boronic ester, p-methoxyphenethyl
pinacol boronic ester (17a), using the conditions established
for generating lithium (t-BuLi) and magnesium (i-PrMgCl·
LiCl) carbenoids (Figure 8). In general, the use of the milder
conditions, thus generating the more functional-group-tolerant
magnesium carbenoids, was superior in most cases in terms of
both yield and levels of enantiospecificity. Unsurprisingly,
attempts at generating the lithium carbenoids for the α-sulfinyl
benzoates bearing p-bromobenzyl, azidopropyl, trifluoropropyl,
and ethyl ester-terminated pentyl substituents, were met with
low yields or no detectable amounts of the desired
homologated boronic ester. However, the in situ generation
of magnesium carbenoids proved highly enabling, the desired
products being isolated in moderate to good yields and with
very high levels of enantiospecificity.
2.5. Synthesis of Fully Substituted α-Sulfinyl Ben-
zoates. We then turned our attention to investigating fully
substituted α-sulfinyl benzoates for the homologation of
boronic esters to give enantiopure α-tertiary boronic esters.
At the outset, it was unclear whether we would be able to
prepare the reagents with high levels of diastereoselectivity,
anticipating that diastereomeric mixtures would be difficult to
separate. However, the alkylation of methyl-substituted α-
sulfinyl benzoate 14b with LDA and benzyl bromide, the
electrophile being present during addition of the base, gave
disubstituted α-sulfinyl benzoate 20a with high levels of
diastereoselectivity (>95:5) in favor of the diastereomer
displaying the newly introduced substituent anti to the oxygen
atom of the sulfinyl group, albeit with low yield (10%). The
origin of the diastereoselectivity presumably arises from favored
approach of the electrophile from the less-hindered re face of
the carbanion center presented by the more thermodynamically
stable conformer, that is, the one that places the large OTIB
Figure 7. Optimal reaction conditions for the alkylation of α-sulfinyl
a
benzoate 19 with a range of electrophiles. Prepared from ( )-19.
c
bPrepared from ent-19. In the presence of HMPA.
substituent, using either EtBr or EtI in conjunction with a
variety of bases, failed to give the desired product in useful
levels of conversion. However, treatment of a solution of α-
sulfinyl benzoate 19 and EtOTf (1.1 equiv) in THF at −78 °C
with NaHMDS (1.05 equiv) gave the desired product in 58%
yield as a separable mixture of syn and anti diastereomers (anti-
14c/syn-14c, ca. 1:2). This protocol with highly reactive triflate
electrophiles also proved suitable for introducing a butyl
substituent (anti-14m/syn-14m, ca. 1:1; 78% yield) and an
ester-terminated pentyl substituent (anti-14n/syn-14n, ca. 1:1;
56% yield). For semiactivated alkyl halides, we found that the
use of LDA in the presence of hexamethylphosphoramide
(HMPA) was necessary for the desired level of reactivity. Using
these conditions, the chloropropyl- and azidopropyl-substituted
α-sulfinyl benzoates, 14k and 14l, respectively, could be
obtained in serviceable yields with very high levels of
enantiopurity, the anti diastereomer being the major product.
For more activated electrophiles, namely, benzyl bromides
(benzyl bromide and p-bromobenzyl bromide), the use of
LiHMDS under in situ conditions proved optimal; undesired
dialkylation, which was observed for MeI as the electrophile
under these conditions (Figure 6, entry 1), was not apparent.
The benzyl- and p-bromobenzyl-substituted α-sulfinyl ben-
zoates were isolated in good yield, 63% and 40%, respectively,
the anti diastereomer being the major product in each case. The
product bearing the substituent with the opposite configuration
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Figure 8. Homologation of boronic esters with lithium or magnesium
carbenoids derived from α-sulfinyl benzoates, as prepared through the
alkylation of α-sulfinyl benzoate 19 or ent-19. Conditions A: 14 (1.05
equiv) and t-BuLi (2.0 equiv) in THF. Conditions B: 14 (1.3 equiv)
and i-PrMgCl·LiCl (1.2 equiv) in DCM. Reactions performed on a 0.2
mmol scale. Yields are based on isolated product. The er values were
determined through chiral HPLC analysis of the corresponding
alcohols. aBoronic ester oxidized to the corresponding alcohol prior to
Figure 9. (A) Synthesis of disubstituted α-sulfinyl benzoates through
alkylation of monosubstituted derivatives. (B) Proposed model
rationalizing diastereoselectivity. (C) Sequential alkylation of α-sulfinyl
a
benzoate 19. Reaction conditions: benzoate 14 (1.0 equiv), R2X (1.5
b
b
equiv), LDA (1.8 equiv), THF, −78 °C; then 0 °C. Determined by
isolation. Magnesium carbenoid formed prior to the addition of the
boronic ester. TIB = triisopropylbenzoate.
1H NMR analysis. cBenzoate 19 (1.0 equiv), CH3I (1.1 equiv),
NaHMDS (1.1 equiv), −78 °C to rt; extractive workup; PhCH2I (1.5
equiv), LDA (1.8 equiv), THF, −78 °C then 0 °C.
group gauche to the small substituent (the lone pair) of the
vicinal sulfur center (Figure 9).21 Additionally, re face attack of
this conformer would proceed through a pathway where the
dihedral angle that defines the relative position of the existing
substituent (the R group) and the vicinally related p-Tol group
will increase as the reacting center transforms from sp2 to sp3; si
face attack would involve this dihedral angle getting smaller,
thus causing increased strain. The lower diastereoselectivity for
alkylation of the unsubstituted α-sulfinyl benzoate 19 (Figures
6 and 7) could be explained by the absence of this strain in the
corresponding si face attack; in some cases, poor stereocontrol
may be due to deprotonation of the highly acidic α-proton. The
yield could be increased to 77% by using the more reactive
iodide, the diastereoselectivity remaining high. The use of
either diastereomer of starting material 14b in pure form (or
mixtures of syn and anti diastereomers) gave the same
diastereomer of product, supportive of there being a common
intermediate with a highly trigonal carbanion center.22 The use
of allyl iodide as the electrophile gave the desired product 20b
in equally high yield and level of diastereoselectivity. However,
the introduction of an ethyl substituent, a transformation that
could only be effected by using EtOTf as the electrophile, gave
the desired dialkylated α-sulfinyl benzoate 20c with low levels
of diastereoselectivity (60:40), the constituents being insepa-
rable. The origin of the low diastereoselectivity might be due to
the small size of the electrophile and that the triflyl moiety
presents oxygen atoms that, through coordination to the
lithium ion, could guide the electrophile to the si face of the
major conformer.20 The order of incorporation of substituents
was important for obtaining high yields and levels of
diastereoselectivity. The methylation of allyl- and phenethyl-
substituted α-sulfinyl benzoates, thus employing the smaller
and less reactive MeI as the second electrophile, gave the
corresponding products, 20d and 20e, respectively, in lower
yield and, crucially, with lower levels of diastereoselectivity
(80:20 and 92:8); the constituents were inseparable by column
chromatography. Disubstituted α-sulfinyl benzoate could also
be prepared from methylene derivative 19 in a single process
without intervening chromatographic purification. Thus, treat-
ment of α-sulfinyl benzoate 19 with NaHMDS/MeI and the
performance of an extractive workup, followed by treatment of
a solution of the crude product with LDA/BnI, gave the desired
product 20a in 64% yield with a very high level of
diastereoselectivity (>95:5; Figure 9).
2.6. Synthesis of Enantioenriched Tertiary Boronic
Esters. With diastereo- and enantiopure disubstituted α-
sulfinyl benzoates 20a and 20b in hand, we tested them as
reagents for homologating our standard boronic esters to give
α-tertiary boronic esters. The use of our standard conditions for
the in situ generation of lithium and magnesium carbenoids did
not lead to detectable levels of desired product. Clearly,
sulfoxide−metal exchange for these sterically hindered
disubstituted α-sulfinyl benzoates is too slow, thus allowing
boronic ester to be unproductively consumed by the organo-
lithium or organomagnesium reagent. However, generation of
the lithium carbenoids through an inverse-addition protocol,
that is, addition of the disubstituted α-sulfinyl benzoate to a
solution of t-BuLi in Et2O in the presence of PMDTA at −78
°C, followed by addition of the boronic ester, gave the desired
products 21a and 21b in good yield and with very high levels of
enantiospecificity (Figure 10). It is instructive at this point to
hark back to when the same protocol was used for the
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center, and thus lower rates for the formation of the
intermediate boronate complex, the conditions deviated
markedly in levels of efficiency for the second iteration:
although the use of lithium carbenoids gives very high levels of
conversion (98%; Figure 11, entry 1), the use of magnesium
carbenoids, which are more sensitive to steric hindrance,
showed low levels of conversion (26%; Figure 11, entry 2). The
low levels of conversion were countered by the detection of
significant amounts of protodesulfinylated starting material.
The sequence using the magnesium carbenoids was aborted at
this stage. The third iteration of the lithium-carbenoid
homologation process was carried out using methyl-substituted
α-sulfinyl benzoate 14b; however, only moderate levels of
conversion were observed (60%, Figure 11, entry 1), thus
marking the territory where steric hindrance begins to impact
on the efficiency of homologation using lithium carbenoids.
The target alcohol was isolated in 29% yield, based on a four-
step process from phenethyl pinacol boronic ester (15), thus
representing an average of 65% yield per iteration. At this point,
we decided to reoptimize the lithium-carbenoid conditions for
our target molecule. Ultimately, we found that when the third
iteration was carried out using 1.5 equiv of α-sulfinyl benzoate
14b and 3.0 equiv of t-BuLi, the level of conversion of the
boronic ester for the problematic third iteration could be
increased from 65% to 85%; the target alcohol 22 was then
isolated in 41% overall yield (based on 4 steps; average of 75%
yield per iteration; Figure 11, entry 3).
As an alternative, we considered using the methyl-substituted
α-stannyl benzoate 3 as the carbenoid precursor for the third
iteration. Upon generation of the lithium carbenoid ex situ
(benzoate 3, 1.35 equiv; n-BuLi, 1.30 equiv), followed by
addition of the vicinal diallyl-substituted boronic ester 23, the
level of conversion for that step was increased to 99% and the
overall yield for the process, based on isolated alcohol 22, was
increased to 52% (average of 80% yield per iteration; Figure
12A). The very high levels of conversion observed for the use
of the α-stannyl benzoate highlights once again the relevance of
the acidity of monosubstituted α-sulfinyl benzoates in the
efficiency of forming sterically hindered boronate complexes:
when boronate complex formation is slow for a Barbier-type
process involving dropwise addition of t-BuLi, the lithium
carbenoid is competitively consumed in an acid−base reaction
with its precursor α-sulfinyl benzoate.
Figure 10. Homologation of boronic esters with disubstituted α-
sulfinyl benzoates. Conditions C: addition of benzoate 20 (1.3 equiv)
to a solution of t-BuLi (2.0−2.3 equiv) and PMDTA (2.0−2.3 equiv)
in Et2O, then boronic ester (1.0 equiv). aThe boronic ester was
oxidized to the corresponding alcohol prior to isolation.
homologation of boronic esters with tert-butyl-substituted α-
sulfinyl benzoate 14e, steric hindrance also precluding the use
of our standard conditions; in that case, the desired product
(18e, Figure 5) was obtained in low yield and with poor levels
of enantiospecificity. The low-fidelity transfer of chirality was
ascribed to competing in situ deprotonation/reprotonation of
the α-sulfinyl benzoate. The very high levels of enantiospeci-
ficity observed for homologating with disubstituted α-sulfinyl
benzoates lends further credence to the operation of an
enantioeroding deprotonation/reprotonation process when
employing sterically hindered monosubstituted α-sulfinyl
benzoates.
2.7. Iterative Homologation of Boronic Esters Using
α-Sulfinyl Benzoates. Having demonstrated that functional-
group-rich α-sulfinyl benzoates can be used to homologate
boronic esters, we wanted to investigate their use in iterative
homologation processes. We targeted the contiguously
substituted phenylpentanol 22, which would be obtained
through three consecutive iterations of our homologation
protocol on phenethyl pinacol boronic ester (15) by using allyl-
substituted α-sulfinyl benzoate ent-14f (iterations 1 and 2) and
methyl-substituted α-sulfinyl benzoate 14b (iteration 3);
oxidation of the resulting C−B bond would give the alcohol.
We investigated a three-pot process (a filtration through a silica
pad between each iteration) by using the in situ generation of
both lithium and magnesium carbenoids (Figure 11). In
accordance with the results above, analysis of the crude reaction
mixtures obtained from the first homologation showed
excellent levels of conversion for both sets of conditions.
However, with increased steric hindrance around the boron
To investigate further the effect of steric hindrance on
iterative homologation of boronic esters, we decided to prepare
alcohol 26, which would involve a similar protocol to what is
described above, except that a Matteson homologation is
incorporated between the above second and third iterations.
Owing to the alleviation of steric hindrance through the
insertion of the extra methylene group (effected by the in situ
generation of Matteson’s reagent,3 LiCH2Cl), the final iteration,
where methyl-substituted α-sulfinyl benzoate 14b is used as the
precursor to the corresponding lithium carbenoid, proceeds
with high levels of conversion of the intermediate boronic ester
(desired secondary boronic ester/underhomologated primary
boronic ester; 91:9). Ultimately, target alcohol 26 was isolated
in 37% yield, based on a five-step process from boronic ester
15, thus representing an average of 82% yield per iteration
(Figure 12C). During this investigation, we considered using
the magnesium carbenoid derived from the unsubstituted α-
sulfinyl benzoate 19 as an alternative to the Matteson reagent,3
LiCH2Cl, which, owing to its instability, can sometimes
preclude high yields in homologation reactions. In a test
Figure 11. Iterative homologation of boronic esters by using α-sulfinyl
benzoates. Conditions A: boronic ester (1.00 equiv), sulfoxide (1.05
equiv), and t-BuLi (2.0 equiv) in THF (Barbier conditions).
Conditions B: boronic ester (1.00 equiv), sulfoxide (1.3 equiv), and
i-PrMgCl·LiCl (1.2 equiv) in DCM (Barbier conditions). Conditions
A′: boronic ester (1.00 equiv), sulfoxide (1.5 equiv), and t-BuLi (3.0
equiv) in THF (Barbier conditions). The first two homologations were
performed on a 1.00 mmol scale and the third on a 0.33 mmol scale.
The oxidation step was performed using NaBO3·4H2O. Reaction
conversion measured by GCMS analysis of the crude mixtures. Yields
reported are those of alcohol isolated by column chromatography
(over the 4 steps). Diastereomeric ratios were determined by 13C
NMR analysis.
H
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05457.
■
S
Full experimental data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*Eddie.Myers@bristol.ac.uk
*V.Aggarwal@bristol.ac.uk
ORCID
Eddie L. Myers: 0000-0001-7742-4934
Varinder K. Aggarwal: 0000-0003-0344-6430
Author Contributions
‡G. Casoni, M. Kucukdisli, and J. Fordham contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC (EP/I038071/1) and University of
Bristol for financial support. J.F. and M.B. thank the Bristol
Chemical Synthesis Centre for Doctoral Training, funded by
the EPSRC (EP/G036764/1 and EP/L015366/1), Novartis,
and the University of Bristol for Ph.D. studentships. M.K. is a
recipient of a Deutsche Forschungsgemeinschaft (DFG)
fellowship. We also thank Siying Zhong for providing neopentyl
2,4,6-triisopropylbenzoate and Nisar Ahmed for technical
assistance.
Figure 12. (A) Iterative homologation by using a combination of α-
sulfinyl benzoates and α-stannyl benzoates. (B) Investigation of α-
sulfinyl benzoate 19 as an alternative reagent for Matteson-type
homologation. (C) Iterative homologation by using α-sulfinyl
benzoates with an intervening Matteson insertion of a methylene
group. Conditions for 22: (S)-3 (1.35 equiv) and n-BuLi (1.30 equiv)
in Et2O; then boronic ester 23 (1.00 equiv). Conditions for 24:
sulfoxide (2.00 equiv), boronic ester 15 (1.00 equiv), and i-PrMgCl·
LiCl (2.00 equiv) in DCM (Barbier conditions). Conditions for 26:
boronic ester 23 (1.00 equiv), bromochloromethane (3.00 equiv), and
n-BuLi (2.50 equiv) in Et2O; syn-14b (1.10 equiv) and t-BuLi (2.00
equiv) in THF (Barbier conditions). The oxidation step was
performed using NaBO3·4H2O (10 equiv) in THF/H2O (3:2).
Diastereomeric ratios were determined by 13C NMR analysis.
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