Highly selective allylborations of aldehydes using α,α- disubstituted allylic pinacol boronic esters

Article abstract of DOI:10.1002/anie.201402995

α,α-Disubstituted allylic pinacol boronic esters undergo highly selective allylborations of aldehydes to give tetrasubstituted homoallylic alcohols with exceptional levels of anti-Z-selectivity (>20:1). The scope of the reaction includes both acyclic and

Full text of DOI:10.1002/anie.201402995

Angewandte
Chemie
DOI: 10.1002/anie.201402995
Allylboration
Highly Selective Allylborations of Aldehydes Using a,a-Disubstituted
Allylic Pinacol Boronic Esters**
Matthew J. Hesse, Stꢀphanie Essafi, Charlotte G. Watson, Jeremy N. Harvey, David Hirst,
Christine L. Willis, and Varinder K. Aggarwal*
Abstract: a,a-Disubstituted allylic pinacol boronic esters
undergo highly selective allylborations of aldehydes to give
tetrasubstituted homoallylic alcohols with exceptional levels of
anti-Z-selectivity (> 20:1). The scope of the reaction includes
both acyclic and cyclic allylic boronic esters which lead to
acyclic and exocyclic tetrasubstituted homoallylic alcohols.
The use of b-borylated allylic boronic esters gave fully
substituted alkenes bearing a boronic ester which underwent
further cross-coupling enabling a highly modular and stereo-
selective approach to the synthesis of diaryl tetrasubstituted
alkenes. Computational analysis revealed the origin of the
remarkable selectivity observed.
T
he asymmetric allylboration of aldehydes is one of the most
reliable C C bond forming reactions in synthesis,[1,2] simulta-
neously controlling both double bond geometry and syn/anti
stereochemistry[3] of the product, as a consequence of the
closed, chair-like transition state (TS) involved.[4] Whilst such
reactions have been extensively applied to the synthesis of
homoallylic alcohols bearing mono-, di- and trisubstituted[5]
alkenes, there are essentially no examples of its application to
the synthesis of homoallylic alcohols bearing tetrasubstituted
alkenes.[6] Indeed, of all the olefin classes, the stereocontrolled
synthesis of tetrasubstituted alkenes is the most challeng-
ing.[7,8]
ꢀ
Scheme 1. Allylboration of a-substituted allylic pinacol boronic esters.
pin=pinacol ester, neo=neopentyl ester, dIpc=diisopinocampheyl.
In designing a method to control stereochemistry in
allylborations, the critical issue is to control which substituent
occupies the axial/equatorial position in the chair TS.
Examples from the literature highlighted the challenge we
faced: reaction of an a,a-disubstituted allylic boronic ester
bearing two very different substituents (Cy/Me) gave a 1:1
E/Z mixture of homoallylic alcohols albeit in high yield and
high enantiomeric ratio (e.r.) (Scheme 1a).[9] Similar results
were observed by Roush but subtle effects were clearly in
operation since one diastereoisomer gave a 1:1 ratio of E/Z
isomers but the other diastereoisomer gave the E isomer
exclusively (Scheme 1b).[2a]
Our own work on allylboration had shown that allylic
pinacol boronic esters bearing a b-methyl group led to
moderate Z selectivity for the trisubstituted alkene, presum-
ably because the large pinacol group and the b-Me group only
left a small pocket in which to accommodate the equatorial
substituent (Scheme 1c).[10] We were keen to evaluate how
the combination of a b-Me group and an a,a-disubstituted
allylic boronic ester would fare when tested in the formation
of homoallylic alcohols bearing tetrasubstituted alkenes. Here
we show that such combinations lead to extraordinarily high
levels of Z-selectivity for these most challenging of substrates
(Scheme 1d).
We started our investigations by the preparation of a-
methyl, a-phenyl allylic boronic ester 1a using our lithiation–
borylation methodology[11] between benzylic carbamate 2a
and propenyl pinacol boronic ester. Reaction of 1a with
benzaldehyde at low temperature gave the product homo-
allylic alcohol 3aa in essentially quantitative yield, with
[*] Dr. M. J. Hesse, Dr. S. Essafi, C. G. Watson, Prof. Dr. J. N. Harvey,
Prof. Dr. C. L. Willis, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Homepage: http://www.bris.ac.uk/chemistry/research/organic/
aggarwal-group
Dr. D. Hirst
GlaxoSmithKline
Gunnels Wood Road, Stevenage, Herts, SG1 2NY (UK)
[**] We thank EPSRC and the European Research Council (FP7/2007-
2013, ERC grant no. 246785) for financial support. M.J.H. thanks the
EPSRC-funded Bristol Synthesis Centre for Doctoral Training (BSC
CDT) and GSK for funding.
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Table 1: Lithiation–borylation–allylboration of secondary benzylic carbamates.
Entry
R1
R2
R3
Yield [%][a]
1a–e
R
Yield [%][a]
d.r. (3:4)[b]
e.r.[b]
1
2
3
Me
–
–
Me
–
–
H
–
–
85
–
–
Ph 3aa
Cy 3ab
Me 3ac
99
99
98
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
4
5
6
Me
–
–
Me
–
–
Me
–
–
87 (85)[c]
–
–
Ph 3ba
Cy 3bb
Me 3bc
99 (99)[c]
99
98
>99:1
>99:1
99:1
>99:1
99:1
>99:1
7
Me
Me
OTBS
84
Ph 3c
91
>99:1
>99:1
8
9
Et
Me
H
Me
Me
90
90
Ph 3d
Ph 3e
99
98
98:2
99:1
Me
14:86
>99:1
[a] Yield of isolated products. [b] Determined by chiral supercritical fluid chromatography (SFC) of the crude reaction mixture. CbO=N,N-diisopropyl
carbamate. [c] Reaction conducted on 4 mmol scale.
surprisingly high selectivity (> 99:1 d.r. and > 99:1 e.r.;
Table 2: Allylboration of endocyclic allylic boronic esters.
Table 1, entry 1). By using nuclear Overhauser effect (nOe)
correlations, we determined that the product was the Z-
isomer. We were intrigued by the remarkable selectivity
observed and turned to investigating its scope and limitations.
Thus, a variety of substituted vinylic pinacol boronic esters
were submitted to the lithiation–borylation reaction with
different carbamates thereby providing a range of a,a-
disubstituted allylic boronic esters 1a–e, which were tested
with a range of aldehydes (Table 1).
Entry
5
Li/B
Allylboration product 7
yield [%][a]
99%[a]
1
2
88
80
>99:1 d.r.[b]
In all cases, the same high selectivity was observed
provided the allylic boronic esters contained a b-substituent.
Thus, if R3 was H, Me, or CH2OTBS[12] high selectivity was
always observed (Table 1, entries 1–7). The reaction in entry 4
was conducted on gram scale with similar yields and identical
selectivities. Replacing the small Me group at R1 for a larger
Et group again led to the same high selectivity (entry 8).
Aliphatic aldehydes, including acetaldehyde, worked just as
well as aromatic aldehydes (entries 2, 3 and 5, 6). However,
boronate 1e, which lacked a b-alkyl substituent, gave an 86:14
mixture of diastereoisomers (albeit with excellent e.r. for both
isomers) but now in favor of the E-isomer 4e (entry 9).
The synthesis of tetrasubstituted exocyclic alkenes[13] can
be even more challenging than acyclic ones and we were
therefore keen to determine whether this methodology could
be applied here too. Thus, using an array of commercially
available cycloalkenyl boronic esters,[14] 5a–d, the requisite
allylic boronates 6 were synthesized in high yield and high
enantioselectivity using our lithiation–borylation methodol-
ogy once again (Table 2). Treatment with benzaldehyde
99:1 e.r.[b]
99%[a]
>99:1 d.r.[b]
99:1 e.r.[b]
99%[a]
3
4
88
82
>99:1 d.r.[b]
99:1 e.r.[b]
81%[a]
95:5 d.r.[b]
99:1 e.r.[b]
[a] Yield of isolated products. [b] Determined by chiral SFC analysis of the
crude reaction mixture.
furnished the homoallylic alcohols 7 with essentially perfect
diastereoselectivity and enantioselectivity as before
(entries 1–3). We were pleased to observe that this method-
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ology was even capable of effecting dearomatization of
a furan ring, again with similarly high selectivity (entry 4).[6b]
The synthetic utility of the methodology would be further
enhanced if variation at the R2 position was possible. One of
the most useful groups is a boronic acid as this would be
potentially capable of undergoing Suzuki–Miyaura cross-
coupling. We therefore prepared bisboronate 8[15] and
employed it in the lithiation–borylation reaction, furnishing
the 1,2-bisborylated product 9 (Scheme 2). Subsequent reac-
Figure 1. Calculated allylboration transition states.
free energy of activation at ꢀ788C lies between 16 and
18 kcalmolꢀ1, consistent with a process taking place in hours
between ꢀ788C and room temperature. In the case of b-
methyl substituted allylic boronic ester Ia, the transition state
in which the phenyl occupies the equatorial position (TS-IaSi)
lies 2.3 kcalmolꢀ1 higher in free energy than the correspond-
ing axial TS (TS-IaRe), in agreement with a very high Z-
selectivity.
Scheme 2. Access to diaryl-substituted homoallylic alcohols through
Suzuki coupling of boracycle 10. a) sBuLi, Et2O, ꢀ788C, 15 min, then
8, 1 h, followed by MgBr2/MeOH, D, 16 h. 79% yield. b) PhCHO, THF,
ꢀ788C!RT, 16 h. c) NaOH, RT, 1 h, 95% yield. d) [Pd{P(tBu3)}2]
(5 mol%), dioxane/H2O (10:1), 4-MePhI, K2CO3, 808C, 16 h, 81%
yield.
Inspection of the two TS structures suggests a key role for
ꢀ
steric interactions, associated with the short B O (1.5–1.6 ꢀ)
ꢀ
tion with PhCHO followed by basic work-up gave the
boracyclic hemiester 10 in 95% yield and perfect selectivity.
This reaction initially gave a mixture of the pinacol boronic
ester and the hemiester[16] but addition of NaOH in the work-
up fully converted the mixture into the hemiester. Suzuki–
Miyaura cross-coupling[17] with tolyl iodide gave the tetrasub-
stituted alkene 11 in > 99:1 d.r. and 98:2 e.r. Clearly, this
chemistry is quite modular as variation in carbamate,
aldehyde and aryl halide should allow access to a wide
range of tetrasubstituted alkenes.
In order to investigate whether the high selectivity
observed in the allylboration reaction was a consequence of
having an a-phenyl substituent, a,a-dialkyl substituted sub-
strate 12, bearing two sterically very different substituents,
was tested. It was prepared using our lithiation–borylation
methodology of secondary allylic carbamates[18] with iPrBpin.
Treatment of 12 with benzaldehyde in THF at ꢀ788C led to
homoallylic alcohol 13 in excellent yield, but with only 4:1 Z-
selectivity. Interestingly, reaction of the desmethyl analogue,
14, led to a 1.4:1 E-selectivity in 15, showing the impact of the
b-methyl substituent on stereocontrol (Scheme 3).
and B C (1.7–1.8 ꢀ) bonds. The substituent in the more
hindered pseudoequatorial position (Ph in TS-IaSi vs. Me in
TS-IaRe, see Figure 1) is found to lie close to both a pinacol
methyl and the b-substituent. NBO steric analysis confirms
this,[19] with the sum of pairwise steric exchange energies
between electron pairs lying within the allylic moiety being
smaller by 3 kcalmolꢀ1 for TS-IaRe compared to TS-IaSi. In
the case of b-unsubstituted allylic boronic ester Ib, the TS in
which the phenyl occupies the equatorial position (TS-IbSi) is
found to be slightly lower in free energy than the correspond-
ing axial TS (DDG° = 0.4 kcalmolꢀ1), in agreement with
a moderate E-selectivity.
Inspection of TS-IbSi revealed that the equatorial phenyl
group is able to adopt a face-on orientation with respect to the
proximal pinacol methyl group, allowing a stabilizing CH–p
interaction. The methyl group lies directly above the phenyl
ring, with the nearest proton only 2.8 ꢀ from the center of the
ring.[20] In TS-IaSi, this type of CH–p interaction is precluded
as the aryl ring cannot adopt the required orientation due to
a steric clash with the b-methyl group. This is illustrated by the
difference in dihedral angles, f (in green) between TS-IaSi
and TS-IbSi, with the former having a much larger angle (698
vs 458) due to the rotation of the phenyl ring to avoid clashing
with the b-methyl group. For reaction of 12, calculations
predict a lower selectivity (see Supporting Information),
apparently because in the less favored TS, the isopropyl group
is able to orient itself so as to minimize steric clashes.
DFT calculations for the model systems Ia and Ib,
analogous to 1a and 1e, by using the dispersion-corrected
B3LYP-D3 functional provided insight into the origin of the
unusually high selectivity observed (Figure 1). The calculated
The remarkable selectivities observed in the allylbora-
tions of aldehydes of these a-phenyl, a-methyl substrates
encouraged us to explore other transformations. Using
functionalized allylic boronic ester 1c, it was found that the
allylboration of an imine according to the Brown–Ramachan-
Scheme 3. Allylborations of a-dialkyl allylic boronic esters.
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Scheme 4. Further transformations of 1c.
dran protocol[21] proceeded with excellent stereocontrol to
yield, following acetylation, the product homoallylic amide 16
as a single isomer (Scheme 4). Protodeboronation with TBAF
(tetrabutylammonium fluoride),[12a] whilst furnishing a small
amount of the a-product, gave the g-product 17 with
essentially complete diastereocontrol and was chemoselective
over desilylation of the tert-butyl dimethylsilyl (TBS)-ether.
Using nOe analysis, we were surprised to observe that the
product alkene was the E-isomer. Basic peroxide oxidation
gave the tertiary allylic alcohol 18 in quantative yield and as
a single isomer.
In summary, we have developed a methodology for the
synthesis of tetrasubstituted homoallylic alcohols with excep-
tional levels of diastereo- and enantioselectivity through the
allylboration of aldehydes. Both acyclic and the difficult to
access exocyclic alkenes can be synthesized in a highly
stereocontrolled manner. Furthermore, through the use of b-
boryl-a,a-disubstituted allylic boronic esters, tetrasubstituted
homoallylic alcohols bearing a boronic ester were obtained
which enabled a highly modular and stereoselective approach
to the synthesis of diaryl tetrasubstituted alkenes. Computa-
tional analysis revealed that the surprisingly high levels of
stereocontrol originated from the combined steric effects of
the b-substituent and pinacol group which leave only a small
pocket for an equatorial a-substituent in the closed, six-
membered transition state.
Received: March 4, 2014
Published online: && &&, &&&&
Keywords: alkenes · allylation · asymmetric synthesis ·
.
ꢀ
C C coupling · synthetic methods
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
ꢀ
Allylboration
Asymmetric C C coupling: a,a-Disubsti-
tuted allylic pinacol boronic esters
undergo highly selective allylborations of
aldehydes to give tetrasubstituted
homoallylic alcohols with exceptional
levels of anti-Z-selectivity (see scheme).
The scope of the reaction includes both
acyclic and cyclic allylic boronic esters. b-
Borylated allylic boronic esters gave fully
substituted vinyl boronates suitable for
further cross-coupling.
M. J. Hesse, S. Essafi, C. G. Watson,
J. N. Harvey, D. Hirst, C. L. Willis,
V. K. Aggarwal*
&&&& — &&&&
Highly Selective Allylborations of
Aldehydes Using a,a-Disubstituted Allylic
Pinacol Boronic Esters
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!