Highly stereoselective synthesis of z-homoallylic alcohols by kinetic resolution of racemic secondary allyl boronates

Article abstract of DOI:10.1002/anie.201300709

α to Z: Racemic α-chiral allyl boronates, which are readily synthesized from the respective primary allyl halides, undergo a highly efficient kinetic resolution in a face- and Z-selective allylation of aldehydes catalyzed by the chiral Bronsted acid (R)-TRIP (see scheme; Epin=tetraethylethylene glycol). Copyright

Full text of DOI:10.1002/anie.201300709

Angewandte
Chemie
DOI: 10.1002/anie.201300709
Asymmetric Allylation
Highly Stereoselective Synthesis of Z-Homoallylic Alcohols by Kinetic
Resolution of Racemic Secondary Allyl Boronates**
Celia A. Incerti–Pradillos, Mikhail A. Kabeshov, and Andrei V. Malkov*
Asymmetric allylation of aldehydes with stoichiometric
amounts of chiral allylboron reagents 1 has evolved into an
efficient and well-established practical method for the syn-
thesis of enantiomerically enriched homoallylic alcohols
(Scheme 1).[1] Chiral auxiliary based reagents were super-
Scheme 1. Allylation with primary allylboron reagents.
Scheme 2. Allylation with chiral secondary allyl boronates.
seded by asymmetric catalytic methods that relied on the
efficient transfer of chirality from the catalyst.[2] The reaction
proceeds through a closed transition state and results in the
products of g-allylation with excellent diastereocontrol:
E alkenes give anti diastereoisomer 3 and Z alkenes give
rise to syn isomer 4, whereas the products of a-allylation 5/6
are not normally observed.[3] Secondary allylboron reagents
have to be employed for the synthesis of linear isomers 5/6.[4]
Homochiral secondary allyl boronates 7 (Scheme 2) are
known to competently relay their chirality into the products
without the need for an external chiral controller.[5–7] How-
ever, the two competing cyclic transition states, where the
group R1 occupies either the axial (A) or equatorial (B)
position, give rise to a mixture of Z/E isomers (5 and 6), which
belong to the opposite enantiomeric series and thus lower the
effective enantioselectivity of the process. Geometrical selec-
tivity strongly depends on the nature of the group R1 and is
usually high for a-heteroatom-substituted derivatives,[7]
whereas simple alkyl substituents give rise to synthetically
inadequate E/Z ratios. Attempts to control the geometrical
selectivity typically involve varying the nature of the catalysts
and tuning the steric and electronic properties of the chiral
boronate fragment, which frequently requires a laborious
synthetic input.[5,6] However, these efforts brought only
a partial solution to the problem—providing facile access to
(E)-homoallylic alcohols 6[5a,6a–d]—whereas a general catalytic
approach to Z isomers 5, where R1 is a simple alkyl group,
remains underdeveloped.
Herein we introduce a novel, conceptually different
method that involves an efficient kinetic resolution of chiral
racemic allyl boronates 7 in a face- and Z-selective allylation
of aldehydes 2 catalyzed by chiral Brønsted acids (Scheme 2).
Chiral Brønsted acid catalysts provided excellent enan-
tiofacial selectivity in the reaction of achiral primary allyl
boronates with aldehydes, as revealed by Hall and co-
workers[2b–d] as well as Jain and Antilla.[2g] Therefore, it was
reasonable to assume that the combination of chiral Brønsted
acid catalysts with racemic secondary allyl boronate 7 should
also favor the formation of 5 and 6 in the same enantiomeric
series. In this case, the main challenge for the efficient kinetic
resolution to operate would be to enforce a preference for the
transition state with either an equatorial (leading to (E)-6) or
axial (leading to (Z)-5) position of the R1 group. Since
E isomers can be readily obtained by a number of existing
methods,[3,5c,6a–d] we focused our attention on Z isomers, for
which there are currently only a few examples, in which chiral
auxiliaries or the chiral pool are employed.[6e,f,8]
[*] C. A. Incerti–Pradillos, Dr. M. A. Kabeshov, Prof. Dr. A. V. Malkov
Department of Chemistry, Loughborough University
Loughborough LE11 3TU (UK)
E-mail: a.malkov@lboro.ac.uk
[**] We thank the Leverhulme Trust for the Research grant F00 261AD
and LU for a studentship to C.A.I.-P. We also thank Prof. T. Kanger
(Tallinn University of Technology) for access to the computational
resources as part of a collaboration within COST-ORCA action
CM0905.
Reports by Hoffmann and Weidmann[9] as well as
Pietruszka and Schone[6e] demonstrated that the E/Z ratio
of the homoallylic alcohols in the noncatalyzed allylation of
aldehydes with secondary alkylallyl boronates depends on the
steric size of the boronate fragment. Larger groups, such as
pinacolate or benzpinacolate, favor the formation of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300709.
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Z isomer, whereas smaller groups, such as dimethoxy, tend to
lead to formation of the E alkene preferentially. Therefore,
for preliminary investigations we opted for racemic pinacol
boronate 7a (Table 1).
AcOH resulted in the best overall performance. The role of
the acid additive is not clear at the moment, but it is assumed
to suppress formation of catalytically inactive aggregates of
TRIP in the nonpolar medium. At À788C, the enantioselec-
tivity reached a respectable level of 96 and 98% ee for 5aa
and 6aa, respectively, with the Z/E ratio also improving to 4:1
(entry 8); however, the latter still remained insufficient from
a synthetic viewpoint, and indicates that kinetic resolution
was not operating competently.
Table 1: Optimization of the reaction conditions.[a]
Next we focused on the structure of the boronate frag-
ment. To avoid random experimental screening of various
boronate scaffolds we turned instead to in silico analysis
(Figure 1).
Entry
Add. (mol%)
T [8C]
t [h]
5/6[b]
ee [%] (5/6)[c]
1
2
3
4
5
6
7
8
–
–
RT
18
72
18
18
18
18
18
72
67:33
66:34
75:25
72:28
75:25
65:35
75:25
80:20
60:91
91:97
91:97
80:79
85:88
85:87
89:91
96:98
À30
À30
À30
À30
À30
À30
À78
HCl[d]
TFA (2.5)
AcOH (2.5)
TFA (1)
AcOH (1)
AcOH (1)
[a] The reactions were carried out with 0.2 mmol of 2 and 0.5 mmol
(2.5 equiv) of 7a in toluene (2 mL) at the temperature specified. Full
conversion of 2a was observed in all cases. [b] Determined from
1H NMR spectroscopy of a crude reaction mixture. [c] Determined by
HPLC on a chiral stationary phase (see Supporting Information for
details). The products were of R configuration. [d] Trace quantities of HCl
in TRIP.
Figure 1. Computational analysis of transition-state structures with
different boronate fragments.
Reaction of benzaldehyde (2a) with 2.5 equivalents of
(Æ)-7a at RT in the presence of (R)-TRIP (5 mol%)
produced a 2:1 mixture of 5aa and 6aa (entry 1). Importantly,
both isomers were of the same enantiomeric series, thus
indicating that the stereoselectivity in the allylation of 2a
catalyzed by (R)-TRIP relies on the enantiofacial discrim-
ination of the carbonyl group aided by kinetic preference for
the axially oriented a-methyl substituent of boronate 7a in
the chairlike transition state. Note that kinetic resolution[10]
alone, without face selectivity, would yield a mixture of 5aa
and 6aa as opposite enantiomers. Lowering the reaction
temperature to À308C improved the enantioselectivity with-
out changing the Z/E ratio, but the reaction became slow
(entry 2). A brief screening of solvents confirmed toluene as
the optimal choice, with CH2Cl2 and THF, in particular,
producing inferior results in terms of enantioselectivity, thus
mirroring the observations of Jain and Antilla.[2g]
It was noticed that when TRIP (synthesized in-house)
contained traces of HCl after the isolation,[11] the reactivity
markedly increased (entry 3). This prompted us to investigate
the influence of various acid additives on the stereoselectivity
of the process. At 2.5 mol% loading, both trifluoroacetic acid
(TFA) and acetic acid (AcOH) resulted in good acceleration,
however at the expense of enantioselectivity (entries 4 and 5).
When the additive loading was reduced to 1 mol%, the
enantioselectivity improved with no detriment to the geo-
metrical selectivity or the reaction rate (entries 6 and 7).
DFT level calculations[12] were carried out to elucidate the
influence of the steric size of the cyclic boronate moiety on
the E/Z ratio of the resulting homoallylic alcohols. A pinacol
group (i) was compared to tetraethylethylene glycol (ii) and
2,2-dimethylpropan-1,3-diol (iii). Protonation of the allyl
boronate fragment by a Brønsted acid can occur at either of
the two boronate oxygen atoms. A recent mechanistic
investigation by Goodman and co-workers[13] into the asym-
metric addition of primary allyl boronates to aldehydes
catalyzed by a chiral phosphoric acid revealed the preference
for a double coordination mode involving the pseudoaxial
oxygen atom (TS1, TS2) over interaction with the pseudo-
equatorial oxygen atom (TS3, TS4). To make sure that this
mechanism also extends to the secondary allyl boronates, all
four transition states TS1–TS4, which correspond to the
formation of the E and Z isomers through both modes of
activation, were analyzed.
First, the computations revealed that the two-point
activation mode described by Goodman and co-workers is
favored for all three boronates. Secondly, a clear trend
emerged that indicated that the larger the steric size of the
boronate (ii > i > iii), the more pronounced the preference for
the formation of the Z isomer. Importantly, the calculation
predicted that the tetraethylethylene glycol derivative (Epin,
2
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Table 3: Scope of the kinetic resolution of racemic secondary allyl
boronates 7’.[a]
ii) should afford a highly enhanced Z/E ratio of almost 100:1,
whereas 2,2-dimethylpropan-1,3-diol (iii), in contrast, should
favor the E isomer.
To test the theoretical conclusions, boronates 7, 7’, and 7’’
were synthesized by using a single-step protocol recently
developed by Singaram and co-workers.[14] With the set of
racemic allyl boronates in hand, their kinetic resolution was
investigated in the model reaction with benzaldehyde (2a;
Table 2). In excellent agreement with the computational data,
7’, R1
2, R2
5
Yield [%]
5, ee [%][b,c]
1
2
3
4
5
6
7
8
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’a, Me
7’b, nPr
7’b, nPr
7’b, nPr
2a, Ph
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
96
84
81
70
80
81
97
=
2b, PhCH CH
2c, PhCH2CH2
2d, 4-MeOC6H4
2e, 4-FC6H4
2 f, 4-ClC6H4
2g, 2-naphthyl
2h, 2-MeC6H4
2i, 2-thienyl
2j, 4-CF3C6H4
2k, c-C6H11
97
Table 2: Optimization of boronate 7.[a]
91[d]
98
85
99
98
91
99
96
88
94
78
75[e]
78
9
10
11
12
13
14
5aj
80
72
5ak
5ba
5bb
5bc
2a, Ph
2b, PhCH CH
2c, PhCH2CH2
90
97[f]
80[f]
93
=
87[d,g]
7, R1
Add.
t [h]
5/6
5/6
ee [%]
[a] The reactions were carried out on a 0.2 mmol scale in toluene (2 mL).
[b] Determined by HPLC on a chiral stationary phase (see Supporting
Information for details). The absolute configuration has not been
rigorously established, but is assumed to be R in analogy to 5aa. [c] In all
cases, unless stated otherwise, the Z/E ratio was >25:1 (determined
from 1H NMR spectroscopic analysis of a crude reaction mixture).
[d] The product was S-configured as a result of the change in the
preference of the substituents in the Cahn–Ingold–Prelog system.
[e] Reaction time 42 h. [f] Reaction time 60 h. [g] Z/E ratio 13:1.
calcd[b]
exp[c]
(5/6)[d]
1
2
3
4
5
6
7a, Me
7’a, Me
7’a, Me
7’’a, Me
7b, nPr
7’b, nPr
AcOH
AcOH
BzOH
BzOH
BzOH
BzOH
72[e]
48
2:1
100:1
80:20
96:4
97:3
40:60
67:33
98:2
96:98
98 (5)
97 (5)
41:40
60:72
94 (5)
18
72[f]
18
1:8
–
–
18
[a] The reactions were carried out on a 0.2 mmol scale in toluene (2 mL).
Full conversion of 2a was observed in all cases. [b] Predicted by quantum
1
chemical calculations. [c] Determined from H NMR spectroscopic
cantly, all but one of the resulting homoallylic alcohols were
obtained with an impressive Z selectivity of > 25:1.
analysis of a crude reaction mixture. [d] Determined by HPLC on a chiral
stationary phase (see Supporting Information for details). [e] The
reaction was carried out at À788C. [f] 4.0 equiv of 7’’a were used.
Bz=benzoyl.
In conclusion, we have developed a highly efficient
protocol for the kinetic resolution of chiral racemic secondary
allyl boronates in the allylation of aldehydes catalyzed by the
chiral phosphoric acid (R)-TRIP. The success of this reso-
lution method depends on the contribution of the two major
tetraethyl analogue 7’a exhibited far superior Z selectivity
than the parent pinacol boronate 7a (see entries 1 and 2).
Importantly, the homoallylic alcohol 5aa was obtained in
98% ee. At this point it was also found that the reaction rate
can be further enhanced by employing benzoic acid as an
additive (entry 3). With the least sterically biased boronate
7’’a, the Z/E ratio of the products swung in favor of the E
isomer, as predicted computationally, and was accompanied
by a significant drop in enantioselectivity (entry 4). The
superior selectivity shown by the tetraethylethylene glycol
group further extends to the propyl homologues 7b and 7’b,
the latter producing virtually geometrically pure 5ba with
high enantioselectivity (see entries 5 and 6).
À
factors: 1) the enantiofacial selectivity in the C C bond
formation and 2) kinetic preference towards the axially
oriented a-alkyl substituent of the boronate in the transition
state. Quantum chemical calculations identified the tetra-
ethylethylene glycol boronate scaffold (B(Epin)) as optimal
to favor the Z-selective reaction pathway. A wide range of Z-
homoallylic alcohols were obtained with high geometrical and
enantiomeric purity. Further investigation to expand the
reaction scope and to elucidate the mechanism of the enantio-
and stereodifferentiation are in progress.
After establishing the optimal conditions and fine-tuning
the structure of the boronate unit, we next examined the
reaction scope. Boronates 7’a and 7’b were employed in the
allylation of a range of recipient aldehydes (Table 3). The
reaction proved to be very efficient in every instance, with the
enantioselectivity varying in the range 85–99% ee, essentially
irrespective of the nature of aldehyde 2 and the boronate 7,
with the more sterically demanding boronate 7’b (entries 12–
14) mirroring the trend shown by 7’a (entries 1–11). Signifi-
Experimental Section
General procedure for the kinetic resolution of racemic allyl
boronates in the allylation of aldehydes: A reaction tube was fitted
with a stirring bar, and then the vessel evacuated, backfilled with N2,
and then charged successively with a solution of (R)-TRIP (12.6 mg,
0.0168 mmol, 5 mol%) in dry toluene (0.5 mL) and a 0.5m stock
solution of benzoic acid in toluene (6.7 mL, 0.0034 mmol, 1 mol%).
The solution was cooled to À428C. Aldehyde (0.34 mmol, 1 equiv)
dissolved in dry toluene (0.5 mL) was added, followed by the
dropwise addition of
a
solution of allyl boronate (0.84 mmol,
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2.5 equiv) in dry toluene (0.5 mL). After the reaction was complete,
as evidenced by TLC, a saturated solution of NaHCO3 (5 mL) was
added, the mixture stirred for 1 h, and then the organic phase
extracted with ethyl acetate (3 ꢀ 15 mL). The organic layers were
combined and dried over Na2SO4 before removing the solvent under
vacuum. Flash chromatography on silica gel with a gradient eluent
system (100% hexane to 95:5, hexane/ethyl acetate) afforded the
target homoallylic alcohol. Note: the aldehyde should be fully
consumed before stopping the reaction, otherwise a background
reaction occurring during work-up may result in reduced enantio- and
stereoselectivity.
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Received: January 27, 2013
Published online: && &&, &&&&
Keywords: allylation · asymmetric synthesis · organocatalysis ·
.
stereoselectivity · steric effects
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[14] J. W. Clary, T. J. Rettenmaier, R. Snelling, W. Bryks, J. Banwell,
W. T. Wipke, B. Singaram, J. Org. Chem. 2011, 76, 9602 – 9610;
for details, see the Supporting Information.
[3] For asymmetric a-crotylation methods, see a) J. Nokami, M.
Ohga, H. Nakamoto, T. Matsubara, I. Hussain, K. Kataoka, J.
Am. Chem. Soc. 2001, 123, 9168 – 9169; b) J. Nokami, K.
Nomiyama, S. Matsuda, N. Imai, K. Kataoka, Angew. Chem.
2003, 115, 1311 – 1314; Angew. Chem. Int. Ed. 2003, 42, 1273 –
1276; c) T.-P. Loh, C.-L. K. Lee, K.-T. Tan, Org. Lett. 2002, 4,
2985 – 2987; d) A. V. Malkov, M. A. Kabeshov, M. Barłꢁg, P.
ˇ
´
Kocovsky, Chem. Eur. J. 2009, 15, 1570 – 1573; e) A. V. Malkov,
ˇ
ˇ
´
O. Kysilka, M. Edgar, A. Kadlcꢂkovꢃ, M. Kotora, P. Kocovsky,
Chem. Eur. J. 2011, 17, 7162 – 7166.
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Allylation
C. A. Incerti–Pradillos, M. A. Kabeshov,
A. V. Malkov*
&&&& — &&&&
Highly Stereoselective Synthesis of Z-
Homoallylic Alcohols by Kinetic
Resolution of Racemic Secondary Allyl
Boronates
a to Z: Racemic a-chiral allyl boronates,
which are readily synthesized from the
respective primary allyl halides, undergo
a highly efficient kinetic resolution in
a face- and Z-selective allylation of alde-
hydes catalyzed by the chiral Brønsted
acid (R)-TRIP (see scheme; Epin=tetra-
ethylethylene glycol).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!