Kinetic Resolution of Secondary Allyl Boronates and Their Application in the Synthesis of Homoallylic Amines

Article abstract of DOI:10.1002/chem.201804395

Highly enantioenriched, chromatographically-stable secondary allyl boronates featuring a 1,1,2,2-tetraethyl-1,2-ethanediol fragment (Epin) were obtained by kinetic resolution of their racemic mixtures. The Epin group at boron considerably improved stability of allyl boronates allowing them to be readily isolated by chromatography on silica. The resolved reagents were applied in stereoselective synthesis of homoallylic amines with an internal double bond employing unprotected imines formed in situ from aldehydes and ammonia. The reactions proceeded with an excellent transfer of chirality.

Full text of DOI:10.1002/chem.201804395

A Journal of
Accepted Article
Title: Kinetic resolution of secondary allylboronates and their
application in the synthesis of homoallylic amines
Authors: Laura Villar, Nikolai V. Orlov, Nikolay S. Kondratyev, Uxue
Uria, Jose Luis Vicario, and Andrei V. Malkov
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To be cited as: Chem. Eur. J. 10.1002/chem.201804395
Link to VoR: http://dx.doi.org/10.1002/chem.201804395
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10.1002/chem.201804395
Chemistry - A European Journal
COMMUNICATION
Kinetic resolution of secondary allylboronates and their
application in the synthesis of homoallylic amines
Laura Villar,[b] Nikolai V. Orlov,[a] Nikolay S. Kondratyev,[a] Uxue Uria,[b] Jose L. Vicario,*[b] and
Andrei V. Malkov*[a]
Abstract: Highly enantioenriched, chromatographically-stable
secondary allylboronates featuring 1,1,2,2-tetraethyl-1,2-ethanediol
fragment (Epin) were obtained by kinetic resolution of their racemic
mixtures. The Epin group at boron considerably improved stability of
allyl boronates allowing them to be readily isolated by
chromatography on silica. The resolved reagents were applied in
stereoselective synthesis of homoallylic amines with an internal
double bond employing unprotected imines formed in situ from
aldehydes and ammonia. The reactions proceeded with an excellent
transfer of chirality.
Herein, we present an alternative practical approach to highly
enantioenriched, bench-stable boronates with 1,1,2,2-
tetraethyl-1,2-ethanediol (Epin) fragment at boron through kinetic
resolution of their readily available racemates.
4
Previous work
a) linear achiral allyl boron reagents
NHR2
chiral
catalyst
NR2
R1
+
BX2
*
R1
1
3 up to 99% ee
2
Chiral amines are powerful pharmacophore groups due to their
favourable physico-chemical properties. Homochiral amines and
their derivatives belong to the class of strategic building blocks for
pharmaceutical, agrochemical and fine chemical development.[1]
In this context, chiral homoallylic amines that feature two
conveniently placed functional groups, amine and a double bond,
occupy an important niche. Allylation of imines can be performed
with high enantioselectivity leading to enantioenriched chiral
homoallylic amines,[2] where allyl boronates emerged as highly
versatile nucleophilic reagents. However, the vast majority of the
existing methods are focused on the use of primary achiral
reagents 1 that in the presence of a chiral catalyst produce
terminal alkenes (Scheme 1a, 1 + 2 ® 3).[3] Synthesis of
homologues E-5 and Z-6 is less straightforward. The shortest
approach requires the use of chiral reagents 4, which competently
relay their chirality onto the products (Scheme 1b). However, the
geometry of the resulting alkenes relies on the interplay of steric
and electronic factors in the TS A and B[4,5] leading to the E and
Z isomers of the opposite enantiomeric series, thus making
control of the geometry a very important factor. The existing
synthetic approaches[6] to homochiral boronates 4 can be divided
into three main groups: use of chiral auxiliary on boron,[7] use of
stoichiometric chiral reagents,[8] and catalytic asymmetric
synthesis.[9] It is worth noting that in many instances, boron
reagents of type 4, due to their limited stability, have to be used
in situ, without isolation.
b) branched homochiral allyl boronates
R2
R2
R1
HN
N
NR2
R3
BX2
R1
*
R3
H
R1
(S,E)-5
2
A TS leading to E
+
+
H
BX2
* R3
(R)-4
R2
HN
R1
BX2
N
R2
R1
(R,Z)-6
up to 97% ee, Z-isomer (Roush 2017)
*
R3
R3
B TS leading to Z
up to 96% ee, E- or Z-isomer (Aggarwal 2014)
up to 97% ee, Z-isomer (Morken 2006)
This work
c) branched racemic allyl boronates
NH
kinetic
resolution
NH2
*
B(Epin)
* R3
B(Epin)
* R3
R1
2
R1
chiral
Brønsted
acid
R3
(±)-4
(S)-4
ee 94-99%
(S,Z)-7 major
chromatographically
stable
Scheme 1. Asymmetric synthesis of homoallylic amines (Epin = 1,1,2,2-
tetraethyl-1,2-ethanediol).
Importantly, the Epin fragment developed by us[10a] plays a
dual role: (i) it improves the hydrolytic stability of the boronates,
thus allowing easy purification by chromatography on silica, and
(ii) the increased steric radius of this fragment favors TS B with
the a-alkyl substituent placed in the pseudo-axial position, which
enables stereoselective formation of Z-homoallylic amines 6,7,
which cannot be obtained by direct asymmetric methods
(Schemes 1b and 1c). All this, coupled with ready access to
simple racemic secondary boronates, makes the resolution
method a viable alternative to the asymmetric synthesis of these
reagents.
[a]
[b]
Dr. N. V. Orlov; Mr. N. S. Kondratyev; Prof. Dr. A. V. Malkov
Department of Chemistry
Loughborough University
Loughborough LE11 3TU, UK
E-mail: a.malkov@lboro.ac.uk
Dr. L. Villar, Dr. U. Uria, Prof. Dr. J. L. Vicario
Department of Organic Chemistry II
University of the Basque Country (UPV/EHU)
P.O.Box 644, 48080 Bilbao, Spain
E-mail: joseluis.vicario@ehu.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201804395
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COMMUNICATION
Earlier,[10a] we reported on the asymmetric allylation of
a 1- or 2-step sequence by known methods.[13] The additional
steric bias brought by the substituents affected the reactivity of
these boronates compared to the parent 4a, therefore the catalyst
loading of 5 mol% had to be employed. In all cases, the kinetic
resolution proceeded efficiently to furnish highly enantioenriched
boronates 4b-4e (Scheme 2). It is worth mentioning the
respectable enantiopurity of the alcohols (R)-10 formed during the
resolution of the boronates: (R)-10ab – 84% ee), (R)-10ac – 70%
ee, (R)-10ae – 84% ee.[14]
With the set of enantioenriched boronates in hand, we
embarked on their application in the synthesis of chiral amines. In
contrast to the well-understood asymmetric allylation of
aldehydes, proceeding via highly organised chair-like transition
state, the related allylation of imines is more multifaceted and
hence more challenging.[2b] Substitution on the imine nitrogen
provides an excellent opportunity to tune electrophilicity of the
C=N bond, however that also brings additional elements of
complexity. These, among others, include E/Z isomerism about
the C=N bond and a possible imine-enamine tautomerism in the
case of enolisable imines. Furthermore, the steric constraints
imposed by the R2 substituent on the nitrogen in 2 and forcing it
into a pseudo-axial position in the cyclic transition state (see TS
A and B, Scheme 1b) often lead to different stereochemical
outcome to what would be normally observed with aldehydes.[15]
Taking into consideration that the steric arrangement of the
transition state of NH imines should resemble that of aldehydes,
they would represent an ideal choice. However, due to their poor
stability, the NH aldimines are usually synthesized and used in
situ. In this work, two approaches were explored (Scheme 3).
aldehydes with racemic boronates
4 catalyzed by chiral
phosphoric acid TRIP (9) that proceeded under the conditions of
kinetic resolution furnishing stereoselectively Z-alcohols 10
(Scheme 2). The original method was aiming at the allylation
products 10 using excess boronates (±)-4, while the fate of the
unreacted boronates was ignored, partly because they generally
tend to decompose under the standard basic work up
conditions.[10b] However, the Epin-derived boronates turned out to
remain intact and could be readily separated from 10 by
chromatography on silica.[11] Therefore, we reasoned that the
method could be recast into obtaining highly enantioenriched
boronates 4 by resolving their racemic mixtures. The initial trials
produced encouraging results. With a 2:1 ratio of boronate (±)-4a
to benzaldehyde 8a using 5 mol% of (R)-TRIP at -40ºC,
allylboronate (S)-4a was obtained in 45% yield (or 91% with
respect to the maximum expected amount) and in 97% ee; the
alcohol (Z)-10aa formed in the same process was isolated in 47%
yield and 75% ee (Z/E 5:1). In the absence of a direct procedure,
the enantiopurity of the isolated boronate was established by
reacting it with benzaldehyde and measuring ee of the resulting
alcohols (S)-10aa.[7b] We were able to further boost the
enantiomeric purity of the boronate to 99% ee by slightly
increasing the amount of benzaldehyde to 1.05 equiv.[12] These
conditions were set as optimal. Furthermore, for the resolution of
4a, the catalysts loading can be reduced to 1 mol% without
affecting the efficiency of the reaction (89% yield, 99% ee).
Ar
B(Epin)
R3
B(Epin)
R3
R4
R4
O
a) allylation of N-trimethylsilylimine
O
O
P
(±)-4a-4e
2.0 equiv
(S)-4a-4e
1) THF, MeOH
–78oC to RT
SiMe3
Ac
OH
BX2
N
HN
Ph
+
+
+
Me
Ph
11a
Ar
*
*
OH
O
2) Ac2O, THF, RT
Me
Ar = 1,3,5-(iPr)3-C6H2
9 (R)-TRIP (1-5 mol%)
4’a (X2 = pin)
4a (X2 = Epin)
6aa
Ph
Ph
R4 R3
1.05 equiv
b) aminoallylation of aldehydes
O
Toluene, -40oC, 22-48 h
8a
(R,Z)-10aa-10ae
NH2
B(Epin)
4M NH3/EtOH
0 oC
+
Ph
*
Ph
8a
Me
*
B(Epin)
Me
B(Epin)
Me
(S)-4a
89%, ee 99%
B(Epin)
Ph
7aa
4a
(S)-4b
Scheme 3. Optimization of crotylation of imines with 4.
(S)-4c
62%, ee 94%
70%, ee 98%
First, the N-trimethylsilylimine 11a was assessed (Scheme
3a). The TMS protection is removed during the reaction to expose
the NH group.[4a,4b,16] In preliminary trials that were conducted
using racemic 4’a and 4a, the Bpin boronate 4’a afforded Z-6aa
in 70% and 5:1 dr. The selectivity towards Z isomer improved to
10:1 when 4a was employed (82% yield). With the
enantioenriched (S)-4a (98% ee), a complete transfer of chirality
was observed, in agreement with previous reports on the
reactions of homochiral secondary allylboronates.[4a,4b,4d]
However, synthesis of pure N-TMS imines requires purification by
distillation, which narrows the substrate scope.[16] Alternatively,
they can be made and used in situ at low temperature, which adds
complexity to the synthetic protocol.
B(Epin)
B(Epin)
(S)-4e
62%, ee 96%
(S)-4d
54%, ee 99%
Scheme 2. Kinetic resolution of racemic secondary allylboronates. The yields
of boronates 4 are given with respect to the maximum expected amount in the
resolution protocol.
Next, we examined kinetic resolution of a range of secondary
boronates 4b-4e, where 4b and 4c are higher homologues of 4a,
whereas substrates 4d and 4e feature E and Z internal double
bond, respectively. All the substrates were readily synthesized in
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10.1002/chem.201804395
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Therefore, our attention turned to the aminoallylation of
aldehydes in a solution of ammonia in ethanol (Scheme 3b, 4a ®
7aa). The racemic variant of the method was reported by
Kobayashi,[17] who employed primary pinacol-derived allyl- and
crotylboronates. It is noteworthy that primary boronates decorated
with a chiral auxiliary in the diol moiety failed to induce practical
enantioselectivity.[17a] Later, two examples of the use of chiral
boron reagents was reported by Morken.[4b] In our initial trial, imine
2a was formed by stirring benzaldehyde in 4M ammonia in
ethanol (1 mL, ca. 8 equiv) for 0.5 h at –10°C, followed by addition
of racemic boronate 4a (1.2 equiv). After 18 h, the amine 7aa was
isolated in 83% yield (Z/E 8:1). A similar result was obtained at
0ºC (yield 78%, Z/E 8:1). Other solvents, such as MeOH, iPrOH
tBuOH and THF proved inferior. The conditions shown in Scheme
3b were taken as optimal for investigating the reaction scope
using resolved (S)-4a (Table 1).
Allylation of 2a with (S)-4a gave (S)-7aa in 97% ee and with
the Z/E ratio (8:1), analogous to the racemic reaction (entry 1). A
higher Z-selectivity was observed at -40ºC (24:1), though at the
expense of lower product yield, even after 4 days (entry 2). With
aromatic aldehydes 8b-8g (entries 3-9), the reaction followed the
same trend irrespective of the nature of substituents with a highly
efficient chirality transfer. Note a slight improvement in the Z/E
ratio for 7da at –10ºC (cf. entries 5 and 6). For a more sterically
hindered ortho-substituted aldehyde 8h, the reaction had to be
carried out at RT, which also affected the enantioselectivity of the
process (entry 10). A slight erosion of enantioselectivity was also
observed for cinnamaldehyde 8i and aliphatic aldehydes 8j-8l,
though enantiopurity of the products still remained high (entries
11-14). No product was formed with 2-furylaldehyde 8m, which
was probably due to a very slow formation of the respective imine
under the reaction conditions (entry 15).
Next, other resolved allylboronates 4b-4e were examined in
the aminoallylation reaction (Scheme 4). Boronates (S)-4b and
(S)-4c with an extended alkyl chain exhibited somewhat slower
reaction rates, possibly due to the increased steric size of the
substituent at the chiral center. However, this had a positive
influence on the Z/E ratio (up to 27:1 for 7ac). Boronates (S)-4d
and (S)-4e with E and Z internal double bond produced,
respectively, anti-7ad and syn-7ae, which suggests that the
reaction proceeded through the chair-like transition states
resembling those for the aldehydes. Enantiopurity of the products
closely matches the enantiopurity of the starting boronates
reflecting an efficient transfer of chirality in the process.
Table 1. Scope in the allylation of imines with enantioenriched (S)-4a.[a]
O
NH
0oC, 0.5 h
NH2
B(Epin)
Me
R1
8
R1
R1
4M NH3/EtOH
2
Me
(S)-4a
1.2 equiv
0oC, 18 h
(S,Z)-7
8, R1
7
Yield [%]
76
7, Z/E
8:1
7, ee [%]
97
1
8a, Ph
8a, Ph
7aa
7aa
7ba
7ca
7da
7da
7ea
7fa
7ga
7ha
7ia
2[b]
3
29
24:1
10:1
8:1
n.d.
99
8b, 4-MeC6H4
8c, 4-BrC6H4
8d, 4-ClC6H4
8d, 4-ClC6H4
8e, 4-FC6H4
72
O
NH
0oC, 0.5 h
4
65
98
NH2
B(Epin)
R3
R1
8
R1
R1
R4
5
75
9:1
99
4M NH3/EtOH
2
R4 R3
(S)-4b-4e
6[c]
7[d]
8
57
10:1
7:1
99
0oC, 18 h
(S,Z)-7
1.2 equiv
53
99
NH2
NH2
NH2
8f, 4-MeOC6H4
8g, 3-MeOC6H4
8h, 2-MeOC6H4
8i, PhCH=CH
8j, PhCH2CH2
8k, n-C7H15
63
9:1
98
Ph
Ph
Ph
9
78
9:1
98
nPr
nPr
nPr
10[e]
11
12
13
14[e]
15[e]
61
10:1
10:1
8:1
85
(S)-7ab
(S)-7ib
(R)-7jb
59%, ee 95%
Z/E 15:1
55%, ee 94%
Z/E 10:1
62%, ee 92%
Z/E 10:1
72
94
7ja
59
93[f]
96[f]
91
NH2
NH2
Ph
NH2
Ph
Ph
7ka
7la
76
8:1
Bn
Me nPr
8l, c-C6H11
34
8:1
(S)-7ac
62%, ee 97%
Z/E 27:1
(S)-7ad
71%, ee 99%
Z/E 11:1
(S)-7ae
53%, ee 95%
8m, 2-Furyl
7ma
<10
n.d.
n.d.
[a] The reactions were carried out at 0.1-0.2 mmol scale at 0ºC unless
stated otherwise; yields of the isolated compounds are given; the Z/E
ratios were determined by 1H or 19F NMR of a crude reaction mixture; ee
of the products was determined by chiral HPLC analysis; n.d. – not
determined. [b] At -40oC, reaction time 96 h. [c] At -10oC. [d] The absolute
configuration was confirmed by X-ray analysis of the corresponding
acetamide (see Supporting Information for details). [e] At RT. [f] The
product was (R)-configured due to the change in the preference of the
substituents in the Cahn-Ingold-Prelog system.
Scheme 4. Allylation of imines with enantioenriched boronates (S)-4b-4e.
In conclusion, we have developed an expedient practical
method for obtaining highly enantioenriched secondary
allylboronates (up to 99% ee) by kinetic resolution of their racemic
mixtures employing chiral phosphoric acid TRIP. The use of the
new Epin fragment at boron enhanced stability of the allyl
boronates towards silica thus simplifying their purification and
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10.1002/chem.201804395
Chemistry - A European Journal
COMMUNICATION
[8]
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handling. The resolved boronates were employed for the efficient
stereoselective synthesis of chiral homoallylic amines with Z-
configured internal double bond by reacting with imines formed in
situ from aldehydes and ethanolic ammonia. The salient features
of the process are (i) excellent chirality transfer and (ii) high
stereoselectivity benefiting from the increased steric radius of the
Epin fragment. The work is currently underway in our laboratories
on other synthetic applications of the resolved enantioenriched
allylboronates.
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Acknowledgements
We thank the Leverhulme Trust for the Research grant RGP-
2015-351. Spanish MINECO (FEDER-CTQ2017-83633-P and
FPI-BES-2012-051856 fellowship to L. V.) and Basque
Government (IT908-16), are also gratefully acknowledged. We
thank Prof. Dr. V. K. Aggarwal and J. Bateman (University of
Bristol) for their kind advice and assistance in synthesizing 4d.
[10] a) C. A. Incerti-Pradillos, M. A. Kabeshov, A. V. Malkov, Angew. Chem.
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The resolved boronates have not been isolated.
Keywords: asymmetric synthesis • allylation • amines • kinetic
[11] This contrasts sharply with the boronates decorated with the pinacol
‘helmet‘ which usually needs to be purified on silica within 10 min to
prevent degradation. In fact, Epin-derived allyl boronates did not show
any degradation or erosion of enantiomeric purity even after being left on
silica overnight.
resolution • stereoselectivity
[1]
[2]
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[12] Racemic allyl boronates 4a and 4b may contain small quantity of the
linear isomer (ca. 2-5%). Excess of benzaldehyde during the kinetic
resolution allows to remove the latter as it reacts much faster compared
to the branched isomer.
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[13] Substrate were synthesized following literature protocols. For 4a-4b, see
ref 10a or a) J. W. Clary, T. J. Rettenmaier, R. Snelling, W. Bryks, J.
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10.1002/chem.201804395
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Laura Villar, Nikolai V. Orlov, Nikolay S.
Kondratyev, Uxue Uria, Jose L. Vicario,*
and Andrei V. Malkov*
NH
R1
NH2
*
kinetic
resolution
B(Epin)
B(Epin)
R1
R3
*
(±)
R3
*
in situ
R3
chiral
Brønsted acid
Page No. – Page No.
up to 99% ee
Z/E up to 27:1
ee 94-99%
Kinetic resolution of secondary
allylboronates and their application in
the synthesis of homoallylic amines
Epin = 1,1,2,2-
tetraethyl-1,2-ethanediol
5 examples
18 examples
Size matters: increased hydrolytic stability of allylboronates with Epin fragment
enabled facile kinetic resolution of their racemic mixture followed by stereoselective
allylation of unprotected imines
This article is protected by copyright. All rights reserved.