Synthesis of highly enantioenriched C-TERTIARY amines from boronic esters: Application to the synthesis of igmesine

Article abstract of DOI:10.1002/anie.201006037

Better than all the rest: Tertiary boronic esters, readily available using the lithiation-borylation reaction, have been converted into tertiary alkylamines in very high ee. The work has been applied to a short, modular, and fully stereocontrolled synthesis of the pharmaceutical igmesine and chiral 2,2-disubstituted piperidines.

Full text of DOI:10.1002/anie.201006037

Communications
DOI: 10.1002/anie.201006037
Enantioselective Synthesis
Synthesis of Highly Enantioenriched C-Tertiary Amines From Boronic
Esters: Application to the Synthesis of Igmesine**
Viktor Bagutski, Tim G. Elford, and Varinder K. Aggarwal*
Tertiary alkylamines are common motifs in many natural
products and pharmaceuticals but access to them in enantio-
merically enriched form can sometimes present a major
challenge. A standard route to these compounds involves the
addition of nucleophiles, for example, organometallic
reagents[1] or cyanide[2] to ketimines, but other indirect
methods have also been reported.[3] Whilst many of these
methods have been successful in delivering high levels of
stereocontrol, the level of selectivity is highly substrate-
dependent.
after some modification of the reaction conditions[9] this
protocol was ultimately successful. Thus, a broad range of
tertiary boronic esters were first converted into the corre-
sponding trifluoroborates 3 and then treated with SiCl4 and an
alkyl azide (Table 1). Using this protocol with benzyl azide
Table 1: Amination of tertiary potassium trifluoroborates with alkyl
azides.[a]
We recently reported a conceptually new method for the
synthesis of tertiary alcohols that routinely delivered more
than 98% ee over a broad range of substrates (Scheme 1).[4] In
Entry
3[b]
R
R1
4
R2
5
Yield [%]
(ee [%])[c]
1
2
3
4
5
6
7
8
a
a
a
b
c
d
e
f
H
H
H
H
4-Cl
2-F
H
Et
Et
Et
cHex
iPr
cHex
4-ClC6H4
3-MeOC6H4
a
b
c
a
a
a
a
a
Bn
aa
ab
ac
ba
ca
da
ea
fa
94 (99)
73 (99)
89 (99)
78 (99)
76 (99)
47 (99)
74 (99)
69 (99)
PMB
cPrCH2
Bn
Bn
Bn
Scheme 1. Synthesis of highly enantioenriched tertiary boronic esters
and tertiary alcohols. Cb=C(O)NiPr2.
Bn
Bn
H
[a] Bn=benzyl, DCE=1,2-dichloroethane, PMB=para-methoxybenzyl.
[b] The ee’s of all trifluoroborates 3a–f were 99%. [c] Yields of isolated
product are given; ee-values of amines 5 were determined by chiral HPLC
following derivatization as their trifluoroacetamides (see Supporting
Information for details).
this process, lithiation of secondary carbamates 1 followed by
treatment with boronic esters and subsequent addition of
MgBr2/MeOH gave the tertiary boronic esters 2, which were
finally oxidized to tertiary alcohols in high ee. We reasoned
that isolation of the intermediate tertiary boronic esters and
subsequent amination could provide a new route to C-tertiary
alkylamines in high ee. Whilst amination of primary and even
secondary boronic esters had been reported,[5–7] the much
more challenging tertiary boronic esters had not. We there-
fore embarked on this study and now report that C-tertiary
alkylamines can indeed be obtained in more than 98% ee
using this methodology.
4a, the tertiary trifluoroborate 3a was converted into the
tertiary benzylamine 5aa in 94% yield and 99% ee (entry 1).
The methodology could be extended to other substituted
benzylic and alkyl azides (entries 2, 3). In terms of the scope
of the tertiary trifluoroborate, hindered alkyl groups (iPr,
cHex; entries 4–6) and even diarylalkyl trifluoroborates
(entries 7, 8) could all be employed, leading to C-tertiary
alkyl amines with very high ee. The latter two examples are
noteworthy as the diarylalkyl boron intermediates are
especially prone to homolysis and radical recombination but
no erosion in ee was observed.
Some limitations of the methodology however, were
uncovered. For example, the homoallylic trifluoroborate salt
6 only gave the tertiary amine 7 in 14% yield together with
ketone 8 in 75% yield (Scheme 2, see Supporting Information
for a mechanistic discussion on the origin of 8).
Of the reported amination transformations, Mattesonꢀs
direct conversion of a potassium trifluoroborate salt into an
amine[7] turned out to be the most efficient and reliable,[8] and
[*] Dr. V. Bagutski, Dr. T. G. Elford, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS81TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
[**] We thank EPSRC for support of this work. V.K.A. thanks the Royal
Society for a Wolfson Research Merit Award and EPSRC for a Senior
Research Fellowship. Dr. Jake Stymiest is thanked for preliminary
studies, and Frontier Scientific for generous donation of boronic
acids and boronic esters.
The para-methoxy analogue of the trifluoroborate 3 f was
also ineffective. Since both the meta-methoxy substrate 3 f
and the para-methoxybenzylic secondary trifluoroborate
salt[10] worked well, it showed that this limitation was specific
to the tertiary, electron-rich diaryl trifluoroborate salt.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006037.
1080
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1080 –1083

across a spectrum of challenging disease areas including
depression,[14] cancer,[15] and diarrhoea.[16] The activity of this
pharmaceutical resides in the (+)-enantiomer but the abso-
lute configuration had not been established, thus providing
further impetus for the need for its stereocontrolled syn-
thesis.[13] However, such a target posed some potential
difficulties because it would involve a homoallylic trifluor-
oborate salt—a motif that was found to be somewhat
problematic in the amination step. Nevertheless, we reasoned
that the additional substitution might retard the unwanted
[3+2] cycloaddition and give a higher yield of the desired
amination product. We therefore embarked on the synthesis,
although with some trepidation. Starting from the commer-
cially available secondary alcohol 12, following carbamate
formation 13 the key lithiation–borylation reaction under the
optimized conditions[4a] furnished the tertiary boronic ester 14
in 92% yield and with perfect enantioselectivity (Scheme 5).
Scheme 2. Unexpected formation of methylketone side-product 8
during attempted amination of homoallylic trifluoroborate 6.
In a representative example we have shown that the
C-tertiary secondary alkylamines can be selectively debenzy-
lated to give the C-tertiary primary alkylamines by catalytic
hydrogenolysis (Scheme 3).[11]
Scheme 3. Representative example for the selective deprotection of
C-tertiary benzylamines.
In order to broaden the scope of the methodology we have
considered its application towards cyclic substrates partic-
ularly since certain 2,2-disubstituted piperidines (e.g. 11) have
emerged as promising neurokinin 1 (NK1) antagonists that
possesses unique antidepressant, anxiolytic, and antiemetic
properties.[12] We were therefore keen to explore the potential
of our methodology to target this important class of com-
pounds (Scheme 4). The key steps involved lithiation of
Scheme 5. Synthesis of (+)-igmesine. Reagents and conditions:
a) iPr2NCOCl (1.05 equiv), NEt3 (1.1 equiv), CH2Cl2, reflux, 24 h, 92%;
b) sec-butyllithium (1.1 equiv), À788C, 20 min; then cinnamyl boronic
acid pinacol ester (1.2 equiv), À788C, 1 h; then 1m MgBr2 in MeOH
(1.2 equiv), À788C, 10 min, then RT, 16 h; then 1m aq KH2PO4, 92%;
c) 4.5m aq KHF2 (2.5 equiv), MeOH, RT, 30 min, evaporation; then
50% aq MeOH, 10 min and evaporation (5ꢀ), 98%; d) SiCl4,
(2 equiv), DCE, RT, 1 h; cPrCH2N3 (2 equiv), 808C, 30 min; then 2m aq
NaOH, RT, 1 h, 56%; e) 37% aq CH2O, NaHB(OAc)3, DCE, RT, 16 h,
99%.[18]
Subsequent conversion to the trifluoroborate salt 15 followed
by amination with cyclopropyl azide (4c) gave the C-tertiary
secondary amine 16 in 56% yield, again without erosion of
enantioselectivity. This showed that the limitation in scope
highlighted above applied to the parent homoallylic substrate
6 but not necessarily to other substituted homoallylic groups.
Finally, methylation gave (+)-igmesine (17) in an overall yield
of 46% and a total of just five synthetic steps starting from
commercially available alcohol 12. The modular nature, high
levels of stereocontrol, and brevity are noteworthy features of
Scheme 4. Synthesis of (+)-piperidine 11. Reagents and conditions:
a) pinacol, MgSO4, Et2O, RT, 97%; b) nBu4NBr, NaN3, H2O/EtOAc,
808C, 16 h, 96%; c) sec-butyllithium (1.1 equiv), À788C, 20 min; then
N3(CH2)4BPin (1.2 equiv), À788C, 1 h; then 1m MgBr2 in MeOH
(1.2 equiv), À788C, 10 min, then RT, 16 h; then 1m aq KH2PO4, 74%;
d) 4.5m aq KHF2 (2.5 equiv), MeOH, RT, 30 min, evaporation; then
60% aq MeOH, 10 min and evaporation (9ꢀ), 95%; e) SiCl4,
(1.5 equiv), DCE, RT, 1 h; 808C, 1 h; then 2m aq NaOH, RT, 1 h, 53%.
23
carbamate 1a followed by borylation with the required
boronic ester which gave the tertiary boronic ester 10 in
74% yield and 99% ee. Subsequent conversion to the
trifluoroborate salt followed by treatment with SiCl4
(second key step) gave piperidine 11 in 53% yield and 99%
ee.
Finally, we considered the application of this methodology
to a stereocontrolled synthesis of the pharmaceutical igme-
sine (17),[13] a compound which shows significant activity
the synthesis. Finally, as the optical rotation of 17·HCl ([a]D
+ 45.7) matched the optical rotation of the active enantiomer
([a]D + 49.7),[17] our stereoselective synthesis enables us to
25
establish the absolute configuration of (+)-igmesine as being
R.
In summary, we have shown that tertiary boronic esters,
readily available in high ee using the lithiation–borylation
reaction, can be converted into tertiary alkylamines including
2,2-disubstituted piperidines with very high ee. Such com-
Angew. Chem. Int. Ed. 2011, 50, 1080 –1083
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www.angewandte.org
1081

Communications
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Experimental Section
General procedure for the aminations of tertiary potassium trifluor-
oborates with alkylazides. SiCl4 (189 mg, 1.10–2.00 mmol) was added
to a stirred suspension of trifluoroborate salt 3a–f (1.00 mmol) in
anhydrous 1,2-dichloroethane (2 mL) under
a
slightly positive
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pressure of argon, and the reaction mixture was stirred at ambient
temperature for 0.5–2 h. Then, the respective azide 4a–c (1.20–
2.00 mmol) was added, the mixture was heated to 708C and stirred at
this temperature for 1 h. After cooling, the reaction mixture was
diluted with THF (2 mL) and quenched with 2m aq. NaOH (5 mL).
After stirring for an additional 1 h, the reaction vessel was discon-
nected from argon line and the reaction mixture was extracted with
diethyl ether (3 ꢁ 10 mL). Combined extracts were washed with brine
(10 mL) and dried over anhydrous K2CO3. Crude product obtained
after solvents removal was purified by flash chromatography and/or
subsequent kugelrohr distillation.
Received: September 27, 2010
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considerably higher yield (74%). Furthermore, any trifluorobo-
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Published online: December 29, 2010
Keywords: azides · boronic esters · C-tertiary amines ·
.
quaternary stereocenters · trifluoroborates
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