Enantioselective synthesis of allylboronates and allylic alcohols by copper-catalyzed 1,6-boration

Article abstract of DOI:10.1002/anie.201310380

Chiral secondary allylboronates are obtained in high enantioselectivities and 1,6:1,4 ratios by the copper-catalyzed 1,6-boration of electron-deficient dienes with bis(pinacolato)diboron (B₂(pin)₂). The reactions proceed efficiently using catalyst loadings as low as 0.0049 mol %. The allylboronates may be oxidized to the allylic alcohols, and can be used in stereoselective aldehyde allylborations. This process was applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was performed using only a 0.02 mol % catalyst loading. 1,6-Borations of electron-deficient dienes with bis(pinacolato)diboron using copper catalyst loadings as low as 0.0049 mol % provided chiral allylboronates that, after oxidation, result in allylic alcohols in high enantioselectivities and 1,6:1,4 ratios. The allylboronates can also be used in stereoselective allylations of aldehydes. This process was applied to a concise synthesis of atorvastatin.

Full text of DOI:10.1002/anie.201310380

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Communications
DOI: 10.1002/anie.201310380
Asymmetric Catalysis
Enantioselective Synthesis of Allylboronates and Allylic Alcohols by
Copper-Catalyzed 1,6-Boration**
Yunfei Luo, Iain D. Roy, Amaꢀl G. E. Madec, and Hon Wai Lam*
Abstract: Chiral secondary allylboronates are obtained in high
enantioselectivities and 1,6:1,4 ratios by the copper-catalyzed
1,6-boration of electron-deficient dienes with bis(pinacolato)-
diboron (B2(pin)2). The reactions proceed efficiently using
catalyst loadings as low as 0.0049 mol%. The allylboronates
may be oxidized to the allylic alcohols, and can be used in
stereoselective aldehyde allylborations. This process was
applied to a concise synthesis of atorvastatin, in which the
key 1,6-boration was performed using only a 0.02 mol%
catalyst loading.
established using chiral catalysts based upon copper,[6–8] other
metals,[9] or by using organocatalysts,[10] the enantioselective
1,6-boration of electron-deficient dienes is not well-devel-
oped. Progress has been made in related processes, such as
enantioselective copper-catalyzed monoboration[4h] and plat-
inum-catalyzed 1,4-diboration of 1,3-dienes.[11] Kobayashi and
co-workers also recently reported four examples of enantio-
selective CuII-catalyzed 1,6-borations of a,b,g,d-unsaturated
cyclic ketones with 33–89% ee, using a 5 mol% catalyst
loading.[2j] However, these substrates were disubstituted at
the b-position, and acyclic a,b,g,d-unsaturated carbonyls
lacking an additional group at the b-carbon underwent
exclusive 1,4-boration.
Herein, we describe highly enantioselective copper-cata-
lyzed 1,6-borations of acyclic a,b,g,d-unsaturated esters and
ketones. High selectivities for 1,6-boration over 1,4-boration
are achieved without a “blocking” substituent at the b-carbon.
Furthermore, the chiral copper complex employed exhibits
high stability, allowing the reactions to proceed effectively at
catalyst loadings as low as 0.0049 mol%. Application of this
method to the synthesis of the cholesterol-lowering drug
atorvastatin is also described.
E
nantioselective transition-metal-catalyzed reactions have
transformed the way in which enantiomerically enriched
chiral compounds can be prepared. However, the majority of
industrial-scale catalytic asymmetric processes developed to
date employ precious second- or third-row transition metals
that are costly and limited in availability.[1] Moreover, the
chiral ligands employed in these reactions are often expen-
sive. Therefore, new enantioselective reactions that are
catalyzed by earth-abundant metals, and that proceed effi-
ciently at very low catalyst loadings to minimize the quantity
of chiral ligand employed, are in high demand.
Given the ability of electron-deficient dienes to serve as
effective substrates for various catalytic asymmetric 1,6-
addition reactions,[2,3] we became interested in the enantio-
selective 1,6-boration of a,b,g,d-unsaturated carbonyl com-
pounds as a potential method to prepare functionalized chiral
allylboronates[4] and allylic secondary alcohols,[5] which are
versatile building blocks for synthesis. Although enantiose-
lective 1,4-borations of electron-deficient alkenes are well-
This study began with a search for an effective method for
the enantioselective copper-catalyzed 1,6-addition of bis(pi-
nacoloto)diboron (1, 1.2 equiv) to benzyl sorbate (2a)
(Scheme 1; see the Supporting Information for full details).
The best results were obtained using [CuF(PPh3)3·2MeOH]
and the Josiphos ligand L1[6c,d,8c,f] in THF at room temper-
ature, in the presence of iPrOH (2.0 equiv) as a protic
additive.[6c,8f] The 1,6-boration of 2a proceeded smoothly on
a 0.50 mmol scale using only 0.20 mol% of the copper
complex [CuF(PPh3)3·2MeOH/L1] (Scheme 1). After the
reaction was complete, filtration of the mixture through
a short plug of silica using EtOAc as the eluent and removal of
the solvent provided the E-allylboronate 3a, accompanied by
HOB(pin). Oxidation of this mixture with NaBO3·4H2O[12]
then gave the allylic alcohol 4a in 91% yield of isolated
product over the two steps and in 95% ee.[13] Alternatively,
pure allylboronate 3a was isolated in 80% yield and 96% ee
by using 5% Et2O/hexane in the filtration of the 1,6-boration
reaction mixture.[14] A range of other a,b,g,d-unsaturated
benzyl esters also underwent enantioselective 1,6-boration–
oxidation to provide allylic alcohols 4a–4 f in 70–92% yield,
high regioselectivities (> 19:1 ratio of 1,6:1,4-addition) and
high enantioselectivities (95–96% ee). Along with benzyl
sorbate (2a), substrates containing other linear alkyl groups
at the d-position were effective (4b and 4c). The process is
compatible with nitrogen-containing substituents (4d and
4h), an alkyl chloride (4e), and silyl ethers (4 f and 4g).
Substrates containing ethyl esters (4g and 4h) or tert-butyl
[*] Dr. Y. Luo, I. D. Roy, A. G. E. Madec, Prof. H. W. Lam
EaStCHEM, School of Chemistry, University of Edinburgh
Joseph Black Building, The King’s Buildings
West Mains Road, Edinburgh EH9 3JJ (UK)
Dr. Y. Luo, A. G. E. Madec, Prof. H. W. Lam
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: hon.lam@nottingham.ac.uk
Homepage: http://www.nottingham.ac.uk/~pczhl
[**] We thank the ERC (Starting Grant No. 258580), the EPSRC
(Leadership Fellowship to H.W.L.), Pfizer, AstraZeneca, and the
University of Edinburgh for support. We thank Xiaoming Yang of
Shanghai Chiral Chemistry Co., Ltd. for providing starting materials
and NMR data for atorvastatin (13). We are grateful to Dr. Gary S.
Nichol (University of Edinburgh) for X-ray crystallography, and the
EPSRC National Mass Spectrometry Facility for high-resolution
mass spectra. We thank Dr. Ai-Lan Lee at Heriot-Watt University for
the use of a polarimeter.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310380.
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followed by immediate treatment of the resulting allylboro-
nate 3i with KF and l-(+)-tartaric acid according to
procedure of Lennox and Lloyd-Jones[15] (Scheme 2).[16]
Scheme 2. Conversion of 2i into the allyltrifluoroborate 6.
Next, larger scale 1,6-borations were conducted to assess
whether the catalyst loading could be decreased.[17]
A
40.4 mmol scale 1,6-boration of 2a with 1.06 equiv of B2(pin)2
(1), 0.0049 mol% of CuF(PPh3)3·2MeOH and 0.0074 mol%
of L1 was complete in 30 h, providing 3a as an 11:1 mixture of
1,6:1,4-boration isomers (Scheme 3). Oxidation of 3a then
gave 4a in 80% yield and 95% ee over the two steps. Notably,
in this experiment, only 1.9 mg of the chiral ligand L1 was
required to prepare 7.10 g of 4a.[17]
Scheme 1. Scope of enantioselective 1,6-boration–oxidation. Reactions
were conducted with 0.50 mmol of 2. Cited yields are of isolated
material. Enantiomeric excesses were determined by HPLC analysis on
a chiral stationary phase. [a] Pure allylboronate 3a (R1 =Me, R2 =OBn)
was isolated in 80% yield and 96% ee without performing the
oxidation. [b] Enantiomeric excess determined on the corresponding
benzoate ester. [c] Oxidation was performed using 5.0 equiv of
NaBO3·4H2O. [d] Isolated as a 12:1 inseparable mixture of 4j and the
E-conjugated enone. [e] Isolated as a 15:1 inseparable mixture of 4l
and the E-conjugated enone.
esters (4i) were also tolerated. However, a substrate contain-
ing a phenyl group at the d-position provided a complex
mixture of unidentified products. The process is not limited to
esters as the activating group; a,b,g,d-unsaturated aryl and
alkyl ketones were also effective (4j–4m).
The selectivity for 1,6-boration over 1,4-boration is
sensitive to steric effects, as shown by the boration–oxidation
of 2n, which contains a d-cyclopropyl group. This reaction
gave the 1,4-adduct 5a as the major product in 49% yield and
77% ee, while the 1,6-adduct 4n was isolated in 25% yield
and 87% ee [Eq. (1)]. Increasing the size of the d-substituent
further led to exclusive 1,4-boration, as shown by the
cyclohexyl-substituted substrate 2o, which gave the b-hydrox-
yester 5b only, in 89% yield and 87% ee [Eq. (2)].
Scheme 3. Larger scale 1,6-boration-oxidation of 2a.
Along with oxidation to allylic alcohols, the allylboronates
resulting from 1,6-boration can be employed in stereoselec-
tive carbonyl allylborations. For example, treatment of 3a
with benzaldehyde in the presence of BF3·OEt2 provided
homoallylic alcohol 7 in 77% yield as a 23:1 inseparable
mixture of E/Z isomers, and in 93% ee for the E-isomer
[Eq. (3)].[18]
The sense of enantioinduction in these reactions was
determined by X-ray crystallography of potassium allyltri-
fluoroborate 6, which was obtained by 1,6-boration of 2i
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Recrystallization of 11 from iPrOH/hexane led to selective
crystallization of the racemate, which enabled isolation of an
enantioenriched sample of 11 (> 99% ee) in 34% yield over
the four steps from 8 after concentration of the mother liquor.
Deprotection of the acetal of 11 with HCl was followed by
basic hydrolysis of the ester with NaOH to give the sodium
salt 12 of atorvastatin (13) in 89% yield, which was converted
into atorvastatin (13) itself in 94% yield by acidification.
In conclusion, we have reported highly enantioselective
copper-catalyzed 1,6-borations of a,b,g,d-unsaturated carbon-
yl compounds with bis(pinacoloto)diboron (1). For the first
time, high selectivities for 1,6-boration over 1,4-boration are
achieved without a “blocking” substituent at the b-carbon.
The reactions proceed at ambient temperature and are
promoted by a CuI-Josiphos complex at catalyst loadings as
low as 0.0049 mol% to provide chiral allylboronates on the
way to chiral secondary allylic alcohols. Application of this
process on a 40.4 mmol scale has been demonstrated. The
allylboronates may also be employed in highly stereoselective
allylborations of aldehydes. Finally, the utility of this method
was demonstrated by a concise synthesis of atorvastatin (13),
the well-known cholesterol-lowering drug. Efforts to under-
stand the origin of the selectivity for 1,6-boration over 1,4-
boration, which is currently unclear, along with the develop-
ment of other catalytic enantioselective 1,6-additions, are
topics for future study in our laboratory.
As a further demonstration of its utility, the enantiose-
lective 1,6-boration was applied in a concise synthesis of
atorvastatin (13), a well-known inhibitor of 3-hydroxy-3-
methylglutaryl coenzyme A reductase and the active ingre-
dient in Lipitor, currently the best-selling pharmaceutical in
history.[19–21] The synthesis began with the preparation of
diene 8.[22] Enantioselective 1,6-boration–oxidation of geo-
metrically pure 8 (obtained in 39% overall yield from
commercial starting materials) on a 0.40 mol scale gave the
allylic alcohol 9 in 87% yield and 95% ee (Scheme 4, top).
However, multiple recrystallizations were required to obtain
8 in geometrically pure form, and for reasons of practicality as
well as overall yield, it was preferable to use a 16:1 E:Z
mixture of 8 (obtained in 60% overall yield from commercial
starting materials) in the synthesis of atorvastatin (Scheme 4,
bottom).[22]
Enantioselective 1,6-boration of this 16:1 E:Z mixture of
8 on a 7.40 mmol scale proceeded smoothly using only
0.02 mol% of the CuI-Josiphos complex, and oxidation of
the resulting allylboronate with NaBO3·4H2O provided the
allylic alcohol 9 in 84% ee (Scheme 4, bottom). The lower
enantioselectivity of this reaction is due to the presence (ca.
6%) of the minor 2E,4Z-isomer of diene 8.[23] Without
purification, 9 was isomerized to the conjugated ester 10 with
catalytic DBU in MeCN at room temperature. The crude a,b-
unsaturated ester 10 was then reacted with benzaldehyde and
KOtBu according to the method of Evans and Gauchet-
Prunet,[24] which gave the benzylidene acetal-protected syn-
1,3-diol 11 with high diastereoselectivity (> 19:1 d.r.).[21c]
Received: November 29, 2013
Revised: February 3, 2014
Published online: March 12, 2014
Keywords: 1,6-addition · asymmetric catalysis · boron · copper ·
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enantioselectivity
Scheme 4. Enantioselective synthesis of atorvastatin (13).
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Kawato, S. Chaudhary, N. Kumagai, M. Shibasaki, Chem. Eur.
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[22] See the Supporting Information for details of the synthesis of 8.
[23] The 2E,4Z-a,b,g,d-unsaturated ester 14 underwent 1,6-boration–
oxidation to give ent-4g in only 42% ee, with the opposite
absolute configuration to that depicted in Scheme 1.
[24] D. A. Evans, J. A. Gauchet-Prunet, J. Org. Chem. 1993, 58,
2446 – 2453.
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