Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: Methodology and applications

Article abstract of DOI:10.1002/anie.201008067

Pin it down: A range of substrates that bear versatile functional groups with quaternary stereogenic centers have been prepared with very high enantioselectivity from tertiary boronic esters (see scheme; Cb=N,N-diisopropylcarbamoyl, pin=pinacolato). The preparation of allylboronic esters bearing contiguous quaternary and tertiary stereogenic centers, and applications to natural product synthesis are also reported.

Full text of DOI:10.1002/anie.201008067

Communications
DOI: 10.1002/anie.201008067
Quaternary Centers
Enantioselective Construction of Quaternary Stereogenic Centers from
Tertiary Boronic Esters: Methodology and Applications**
Ravindra P. Sonawane, Vishal Jheengut, Constantinos Rabalakos, Robin Larouche-Gauthier,
Helen K. Scott, and Varinder K. Aggarwal*
The creation of quaternary stereogenic centers with high
enantioselectivity is challenging, in part, because of the high
steric repulsion between the substituents on the carbon center
that is generated during construction. Nevertheless, signifi-
cant progress has been made towards this goal in recent years,
even in conformationally flexible acyclic systems.[1] However,
whilst in many cases high e.r. values have been achieved, the
selectivities are invariably substrate-dependent.
We have approached this problem from a different
perspective and considered the possibility of employing
stereospecific homologations of tertiary boronic esters 1.
Such boronic esters can be easily prepared from the
corresponding secondary alcohols with very high e.r. values
by using the methodology developed by our group,[2] or
alternatively, by borylation of allylic carbonates/Michael
acceptors reported by Hoveyda and co-workers
(Scheme 1).[3] However, whilst the homologation reaction
steric demand often results in lower selectivity or alternative
reaction pathways being followed.[7] Herein we describe our
success in creating quaternary stereogenic centers with very
high e.r. values and with a range of versatile functional
groups; the subsequent application of the methodology in
synthesis is also presented.
We began our studies using the tertiary boronic ester 2a
which was subjected to standard Matteson homologation
conditions[6] using chloromethyl lithium[6b] at low temper-
ature. However, whilst the homologated alcohol product was
obtained after oxidation in reasonable yield, almost 20% of
the oxidation product 4, seemingly derived from the starting
material 2a, was also isolated even when a large excess
(4.0 equiv) of LiCH2Cl was employed (Scheme 2).
Analysis of the reaction by 11B NMR spectroscopy prior
to oxidation revealed that in addition to the signal of desired
boronic ester 5 at d = 32 ppm, a new peak at d = 49 ppm was
observed, which is indicative of the presence of borinic ester
6.[8] This ester must have formed from the unexpected
migration of the oxygen substituent[9] instead of the normally
favored carbon migration, presumably as a consequence of
the very hindered nature of the boronic ester. We reasoned
that using a bulkier and less polar leaving group (smaller
dipole moment) would favor the conformation required for
C migration and therefore explored LiCH2Br as an alterna-
tive reagent.[10] Making this simple modification resulted in an
improved yield of the desired homologated product (83%
yield) with only about 5% of the product derived from
O migration (Scheme 2).
Scheme 1. Synthesis of chiral tertiary boronic esters. Cb=N,N-diiso-
propylcarbamoyl, Bpin=pinacolboryl, NHC=N-heterocyclic carbene.
may seemingly appear to be a straight forward extension of
the literature it should be noted that hindered tertiary
boranes (e.g., thexyl) have often been employed as non-
migrating groups in homologations of boranes,[4] and exam-
ples of related transformations of tertiary boronic esters are
rare.[5,6] Furthermore, extending methodology from second-
ary to tertiary substrates is rarely straightforward as the extra
This reagent was applied to a series of tertiary boronic
esters and the results are summarized in Table 1. The reaction
worked well with dialkylaryl boronic esters bearing electron-
[*] Dr. R. P. Sonawane, Dr. V. Jheengut, Dr. C. Rabalakos,
Dr. R. Larouche-Gauthier, H. K. Scott, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
Fax: (+44)117-925-1295
E-mail: v.aggarwal@bristol.ac.uk
[**] We thank the EPSRC and the European Research Council (ERC) in
the context of the European Community’s Seventh Framework
Programme (FP7/2007-2013, ERC grant no. 246785) for financial
support. V.K.A. thanks the Royal Society for a Wolfson Research
Merit Award and EPSRC for a Senior Research Fellowship. R. L-G. is
grateful to the FQRNT for a postdoctoral fellowship. We thank
Frontier Scientific for generous donation of boronic acids and
boronic esters.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008067.
Scheme 2. 11B NMR investigation and optimization of the C- versus
O migration in the homologation of boronic ester 2a.
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Table 1: Homologation of chiral tertiary boronic esters with LiCH2Br.[a]
Boronic ester
Product
Entry
R1
R2
e.r.
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
2a
2b
2c
2d
2e[d]
2 f
H
pCl
pMeO
H
H
Et
Et
Et
allyl
iPr
Ph
>99:1
>99:1
>99:1
>99:1
>99:1
98:2
3a
3b
3c
3d
3e
3 f
83
88
62
82
37
41
>99:1
>99:1
99:1
>99:1
>99:1
98:2
pMeO
Scheme 3. 11B NMR investigation and optimization of vinylation of
boronic ester 2a.
[a] 2.5 equiv of CH2Br2 and 2.2 equiv of nBuLi were used. [b] Yield of
isolated product. [c] Determined by either HPLC or GC analysis using a
chiral stationary phase (for details refer to the Supporting Information).
[d] Neopentyl glycol boronic ester was used (the pinacol boronic ester
gave 30% yield).
converted into the vinylated product with very high e.r. values
(Table 2). In the case of the highly hindered substrates 2e and
2 f, the more reactive vinyllithium was found to be consid-
erably superior to vinylmagnesium bromide, thereby furnish-
ing the adducts in good yields. As before complete chirality
transfer accompanied these reactions.
To enhance the methodology further we turned our
attention to exploring alternative homologations of tertiary
boronic esters for the construction of chiral quaternary
centers a to a carbonyl group.[1] Thus, treatment of the
boronic ester 2a with LiCHCl2[5] furnished the chiral aldehyde
12 directly after oxidative workup (Scheme 4). In a manner
analogous to the Zweifel olefination, we tested the reaction of
ethoxy vinyllithium with boronic ester 2a, and after a brief
acid hydrolysis obtained the corresponding ketone 13 in good
yield with an excellent e.r. value. This example represents a
novel, direct conversion of a boronic ester into a ketone.
Attempts to introduce an adjacent stereogenic center by
reaction with a primary or secondary stereodefined lithiated
carbamate were unsuccessful. No ate complex was formed
rich and electron-deficient aromatic rings (entries 1–3), and
with substrates bearing an allyl substituent (entry 4). How-
ever, the tertiary boronic ester 2e bearing an especially
hindered iPr substituent was more challenging and gave a
37% yield of the homologated product, but only when the less
hindered neopentyl glycol boronic ester was used in place of
the pinacol ester (entry 5). Evidently, severe steric hindrance
of the boronic ester slows down the addition of bromo-
methyllithium to the boronic ester and competing decom-
position pathways of the organolithium occur instead. The
diarylalkyl boronic ester 2 f was able to undergo the
homologation reaction to afford the alcohol 3 f, bearing a
congested bis(aryl)-substituted quaternary sterogenic center,
in 41% yield. In all cases complete chirality transfer occurred
leading to quaternary centers with very high e.r. values.
Having established an efficient protocol for the prepara-
tion of quaternary centers bearing an a-primary alcohol
functionality, we focused on the introduction of a vinyl group.
Quaternary centers bearing a vinyl group represent an
important structural motif due, not only to their preponder-
ance in a number of natural products but also to their
considerable versatility in synthesis. Our investigation started
by subjecting the tertiary boronic ester 2a to standard Zweifel
olefination conditions[11] (1 equiv of vinylmagnesium bromide
and subsequent addition of iodine and sodium methoxide),
which afforded product 11a, but in only 26% yield
(Scheme 3). By monitoring the reaction using 11B NMR
spectroscopy, we were surprised to observe a 30:70 mixture
of the borane ate-complex 8 (d = À13 ppm) and starting
boronic ester 2a. Interestingly, the expected boronic ester ate-
complex 7 was not observed under these reaction condi-
tions.[8,12] Nonetheless, the relatively high yield of 11a after
isolation, considering the low conversion into an ate-complex
observed, implies preferential migration of the tertiary
substituent over the two vinyl groups in the zwitterionic
species 9.[13] When 4 equivalents of vinylmagnesium bromide
were used, we observed complete conversion into 8 and we
were able to isolate alkene 11a in 66% yield.
Table 2: Zweifel-type olefination of chiral tertiary boronic esters.[a]
Boronic ester
Product
Entry
R1
R2
e.r.
Yield [%][b] e.r.[c]
1
2
3
4
5
6
2a
2b
2c
2d
2e[d]
2 f
H
pCl
pMeO Et
H
H
Et
Et
>99:1 11a
>99:1 11b
>99:1 11c
66
79
62
79
>99:1
>99:1
>99:1
>99:1
>99:1
98:2
allyl >99:1 11d
iPr
>99:1 11e[e,f] 58
98:2 11 f[e,g] 92
pMeO Ph
[a] 4 equiv of vinylmagnesium bromide were added at RT with subse-
quent addition of 4 equiv of I2 and 8 equiv of NaOMe at À788C. [b] Yield
of isolated product. [c] Determined by either HPLC or GC analysis using a
chiral stationary column (for details refer to the Supporting Information).
[d] Neopentyl glycol boronic ester was used (the pinacol boronic ester
gave only decomposition). [e] 4 equiv of vinyllithium was added at
À788C with subsequent addition of I2 (4 equiv) and NaOMe (8 equiv) at
À788C. [f] The yield with vinylmagnesium bromide was 52%. [g] No
reaction was observed with vinylmagnesium bromide.
The modified protocol was then applied to the same
representative series of tertiary boronic esters and they were
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Communications
Scheme 4. Functional group transformation of boronic ester 2a.
Scheme 6. Synthesis of (+)-(S)-sporochnol (19). TMEDA=N,N,N’,N’-
tetramethylethylene-diamine.
presumably because of the high steric hindrance of both the
electrophilic tertiary boronic ester and the nucleophilic
lithiated carbamate. However, the less hindered 1-chloro-
allyllithium[14] was able to react with the tertiary boronic ester
2a and gave the homologated allylic boronic esters 14a/15a
with surprisingly high diastereoselectivity (24:1) and com-
plete stereospecificity (Scheme 5).[15] 1-Chloro-methallyl-
lithium also reacted efficiently with high diastereoselectivity.
The structure of the major diastereoisomer 14b was deter-
mined by X-ray analysis.[16] When one equivalent of 1-chloro-
allyllithium was reacted with an excess of the boronic ester 2a
(4 equiv), 14a/15a were obtained in 60% yield and again with
a high d.r. value (12:1). This result indicates that 1-chloro-
allyllithium undergoes rapid racemization during the reaction
(dynamic kinetic resolution) and that the high diastereose-
lectivity observed is because one enantiomer of 1-chloro-
allyllithium reacts with the chiral tertiary boronic ester
significantly more rapidly than the other enantiomer
(Scheme 5). The homologation of the tertiary boronic ester
2a with 1-chloro-allyllithium reagents represents a powerful
method for the synthesis of chiral allylboronic esters bearing
two contiguous stereocenters with high diastereocontrol. We
are currently investigating the factors responsible for the
unusually high diastereoselectivity observed.
syntheses reported,[17] the shortest is attributed to Hoveyda
and co-workers, and involves a copper-catalyzed allylic
substitution that furnished the target concisely, albeit with
low enantioselectivity.[17a] Our synthesis is presented in
Scheme 6. The key steps involve lithiation/borylation of the
chiral carbamate 16 which gave the chiral tertiary boronic
ester 17, and subsequent vinylation using our newly estab-
lished methodology to afford 18 efficiently and with essen-
tially complete chirality transfer. Deprotection of the phenol
then completed the synthesis. Our route represents a signifi-
cant improvement in terms of the number of steps and
selectivity to those reported to date.
(S)-1,2-Diphenyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-
2-methyl-1-butanone (25) belongs to a family of arylpiper-
azines that are potential pharmaceutical agents for the
treatment of depression and related disorders.[18] Denmark
et al. have previously reported an efficient synthesis of this
pharmaceutical that utilized enantioselective allylation of
aldehydes as a key step for the construction of the quaternary
stereocenter.[20] Our synthesis of the serotonin antagonist is
shown in Scheme 7. Lithiation/borylation of the carbamate
20, and then homologation with dichloromethyllithium gave
the aldehyde 21 directly. Addition of PhMgBr and subsequent
oxidation afforded the ketone 23 in 70% yield over three
steps. Oxidative cleavage of the olefin in 23 with ozone and
subsequent reductive amination using the commercially
available piperazine gave the target pharmaceutical 25 in a
highly efficient manner and with complete enantioselectivity.
To illustrate its utility, the methodology of homologation
and vinylation of chiral tertiary boronic esters has been
applied to the synthesis of the natural product (+)-sporoch-
nol[17] and the serotonin antagonist (S)-1,2-diphenyl-4-[4-(2-
methoxyphenyl)-1-piperazinyl]-2-methyl-1-butanone.[18]
(+)-Sporochnol (19) is a monoterpene-substituted phenol
that is known to be a chemical defense compound and to
exhibit feeding deterrence activity towards reef fish.[19] Of the
Scheme 5. Homologation of boronic ester 2a with chloro allyllithium
reagents. LDA=lithium diisopropylamide.
Scheme 7. Synthesis of (S)-1,2-diphenyl-4-[4-(2-methoxyphenyl)-1-piper-
azinyl]-2-methyl-1-butanone. PCC=pyridinium chlorochromate.
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[10] According to HSAB theory, it is also possible that the soft
nucleophile (carbon) favors reaction with the soft leaving group
(Br) whereas the hard nucleophile (oxygen) favors the hard
leaving group (Cl). We thank one of the referees for this
suggestion.
[11] a) G. Zweifel, H. Arzoumanian, C. C. Whitney, J. Am. Chem.
Soc. 1967, 89, 3652 – 3653; b) G. Zweifel, N. L. Polston, C. C.
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In conclusion, we report the preparation of a broad range
of substrates bearing versatile functional groups with quater-
nary stereogenic centers and very high enantioselectivities
using the lithiation/borylation reaction and subsequent one-
carbon homologation or vinylation.[21] Especially noteworthy
is the generation of contiguous quaternary and tertiary
stereogenic centers with high d.r. values and essentially
perfect enantioselectivity.
[12] It is possible that the severe steric hindrance between substitu-
ents on the boron atom in 7, together with the Mg salts present,
promote ring-opening of the pinacol ester to give an intermedi-
ate borinic ester. This electrophilic species can then be attacked
by vinylmagnesium bromide again, ultimately leading to borane
ate-complex 8.
[13] This result is rather surprising since Zweifel found that thexyl
and alkenyl groups migrate at similar rates when a bis(alkenyl)
thexylborane was treated with I2 and NaOH; see Ref. [11b].
[14] a) H. C. Brown, M. V. Rangaishenvi, S. Jayaraman, Organo-
metallics 1992, 11, 1948 – 1954; b) H. C. Brown, S. Jayaraman, J.
Org. Chem. 1993, 58, 6791 – 6794.
[15] Reaction of racemic 2a with racemic 1-chloro-allyllithium gave
the same 24:1 ratio of diastereoisomers. This ratio reflects the
relative rates of reaction of the two diastereomeric pairs (e.g.,
R + R vs. R + S) without the intervention of kinetic resolution.
[16] CCDC 800577 contains the supplementary crystallographic data
for allyl boronic ester 14b. This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
[17] For the shortest (3 steps) asymmetric synthesis of (R)-sporoch-
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Inokoishi, N. Sasakura, K. Nakano, Y. Ichikawa, H. Kotsuki,
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Received: December 21, 2010
Published online: March 4, 2011
Keywords: borates · chirality · natural products · olefination ·
.
stereogenic centers
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