'Transmitted' remote double diastereoselection effects on the asymmetric reduction of β-boronate oxime ethers

Article abstract of DOI:10.1016/S0040-4039(00)00179-9

Remote asymmetric induction in the reduction of a homochiral β-boronate oxime ether to the corresponding amine failed to provide asymmetric induction with a chiral reducing agents, but use of a chiral reducing agent produced extreme double diastereoselection effects which show that remote asymmetry can be 'transmitted' by suitable choice of a 'partner' molecule. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00179-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2457–2461
‘Transmitted’ remote double diastereoselection effects on the
asymmetric reduction of β-boronate oxime ethers
Helen E. Sailes,a John P. Watts b and Andrew Whiting a,∗
aDepartment of Chemistry, Faraday Building, U.M.I.S.T., PO Box 88, Manchester M60 1QD, UK
bKnoll Pharmaceuticals, Research and Development, Pennyfoot Street, Nottingham NG1 1GF, UK
Received 11 November 1999; revised 20 January 2000; accepted 25 January 2000
Abstract
Remote asymmetric induction in the reduction of a homochiral β-boronate oxime ether to the corresponding
amine failed to provide asymmetric induction with achiral reducing agents, but use of a chiral reducing agent
produced extreme double diastereoselection effects which show that remote asymmetry can be ‘transmitted’ by
suitable choice of a ‘partner’ molecule. © 2000 Published by Elsevier Science Ltd. All rights reserved.
Establishing correct relationships between remote asymmetric centres, i.e. over a distance of more
than three atoms, in conformationally flexible, acyclic systems is a challenging task in organic synthesis.
Recently there has been some notable success in tackling this problem,1 particularly in the remote
asymmetric reduction of carbonyl groups.2–4 However, the application of remote asymmetric induction
to C_N double bond reduction is unprecedented in the literature.
Following our success in the directed 1,6-asymmetric reduction of a ketone via homochiral boronate
ester 1a to provide alcohol 3a in 89% e.e., via active complex 2a,3,4 we have been seeking to adopt an
analogous methodology for stereoselective C_N double bond reduction. For example, the asymmetric
reduction of an imine or oxime ether of type 1b or 1c, respectively, may take place via complexes 2b or
2c to provide amino alcohol 3b. Herein we report preliminary results in this area.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00179-9
tetl 16459

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(1)
Extremely hydrolytically sensitive imines of type 1b can be generated in situ from ketone 1a upon
treatment with an amine, for example benzylamine or p-methoxybenzylamine, in the presence of
molecular sieves. Subsequent reduction with a wide range of borane-derived reducing agents (followed
by oxidative boronate cleavage, acetylation and oxidative removal of the p-methoxybenzyl moiety)
results universally in poor asymmetric induction (<15% e.e.) for the formation of 3c (after acetylation).
The corresponding homochiral β-boronate oxime ether 1c and its enantiomer 1d were stable and readily
prepared from acetophenone as shown in Scheme 1, via a deprotonation of oxime 45 and alkylation
with iodide 5,6,7 to provide oxime 6 as a single E-stereoisomer. Transesterification via diethanolamine
derivative 7 with the appropriate homochiral diols 83 and 9,4 yielded the desired β-boronate oxime ethers
1d and 1c, respectively.
Scheme 1.
Both homochiral β-boronate oxime ethers 1c and 1d were successfully reduced with
borane–dimethylsulfide complex and borane–tetrahydrofuran complex. Unfortunately, no asymmetric
induction was obtained (Table 1, entries 1–3). In view of the E-oxime stereochemistry, it is likely
that the formation of a boron–nitrogen chelate 2c is precluded for substrates 1c and 1d. However,
application of Itsuno’s oxazaborolidine 10a (prepared in situ from homochiral α,α-diphenyl-β-amino
alcohols and borane8) produced interesting results. (S)-Valine-derived oxazaborolidine 10a was applied
to borane-mediated reductions of achiral β-boronate oxime ether 6 and homochiral systems 1c and 1d

2459
(Table 1), followed by quenching with acetic anhydride, oxidative cleavage of the boronate function and
final acetylation, to produce the N- and O-acetyl derivative 3c and/or 3d.*,§
Table 1
Reductions of β-oxime boronate esters 6, 1c and 1d (see Eq. (1))
Reduction of 6 resulted in formation of the (S)-diacetyl derivative 3c in good yield (after oxidative
boronate cleavage and acetylation) and excellent enantioselectivity (e.e. 98%) (Table 1, entry 4), which
constitutes an efficient and novel route to enantio-enriched γ-phenyl-γ-amino alcohols (precursors to
*
Racemic 1-acetoxy-3-acetylamino-3-phenylpropane 3c: HPLC [SFC, Chiralpak AS, 35°C, 3000 psi, λ=215 nm, 2 ml min−1
,
86% CO2: 14% (IPA+0.2% Et2NH) elution] tR(min) 5.06 (49.7%), 8.01 (50.3%); νmax (KBr)/cm−1 ∼3300, 1732, 1642, 1548,
1244; δ (1H, CDCl3) 2.00 (3H, s, CH3C:ON), 2.01 (3H, s, CH3C:OO), 2.08–2.20 (2H, m, CH2CHN), 4.01–4.11 (2H, m, CH2O),
5.08–5.17 (1H, m, CH2CHN), 5.76 (1H, br, NH), 7.27–7.34 (5H, m, ArH) (addition of D2O caused peak at δ 5.76 to disappear,
and that at δ 5.08–5.17 to collapse to a t, J 7.2, δ 5.12); δ (13C, CDCl3) 20.9 (CH3C:ON), 23.4 (CH3C:OO), 34.7 (CH2CHN),
50.7 (CH2CHN), 61.4 (CH2O), 126.5, 127.7, 128.8, 141.1 (aromatic C), 169.2 (CH3C:ON), 171.0 (CH3C:OO); m/z (CI, NH3)
236 (M+H)+, 471 (2M+H)+ [found (HRMS): m/z 235.1216. C13H17NO3 requires M+ 235.1208].
§
Enantiopure (S)-3-amino-3-phenylpropan-1-ol was donated by Chirotech 1-acetoxy-(3S)-acetylamino-3-phenylpropane:
[α]D23 −72.4 (c 0.468, MeOH); HPLC [SFC, Chiralpak AS, 35°C, 3000 psi, λ=215 nm, 2 ml min−1, 86% CO2: 14% (IPA+0.2%
Et2NH) elution] tR (min) 5.04 (0.9%), 7.97 (99.1%).

2460
β-amino acids9). Reduction of the (4R,5R)-β-boronate oxime ether 1d under the same conditions gave a
comparable enantiomeric excess (e.e. 95%) to that obtained for 6 (Table 1, entry 5). In contrast however,
the reduction of (4S,5S)-β-boronate oxime ether 1c afforded (R)-diacetyl derivative 3c (after oxidative
boronate cleavage and acetylation) but with only 8% e.e. (Table 1, entry 6) and the opposite sense of
absolute asymmetric induction. This result shows that the homochiral boronate functionality in 1c and 1d
is capable of influencing the C_N double bond reduction by interaction with a suitable partner reducing
agent, despite (a) its remoteness, and (b) the disadvantageous E-oxime ether geometry.
These results therefore raised the question of whether other achiral reducing agents could also
constructively interact with the remote auxiliary and effect efficient asymmetric induction at the C_N
bond. A range of other achiral borane–nitrogen reducing systems were examined, two of which are shown
in entries 7 and 8 (Table 1). Use of the achiral oxazaborolidine-based system 10b results in a very slow
reduction and low (13%) asymmetric induction (Table 1, entry 7) and this is improved to 28% e.e. by use
of triethylamine–borane complex, which is again a slow reaction.
At this moment, it is not clear exactly how 10a or 10b and triethylamine–borane interacts with the
boronate esters of 1d and 1c. It is clear however, that 10a destructively transmits the boronate ester
information through to the oxime of 1c, resulting in low and reversed asymmetric induction compared
to the boronate ester of 1d. It is also clear that other achiral borane–nitrogen complexes are capable of
transmitting the remote asymmetry to the C_N bond. Possible intermediates involved in the reduction
process are structures A and B. Remote asymmetric induction is inherently poor in structure A due
to the chelation of the boronate ester to the methoxy group, instead of the oxime nitrogen, making
the boronate ester too remote. However, triethylamine–borane is seemingly sufficiently hindered that
a degree of selectivity does occur for Si-face attack. In order to more effectively transmit the asymmetry
of the boronate ester to the oxime double bond, another molecule must be involved in the transition state,
which seemingly occurs with oxazborolidines 10, i.e. as shown by an intermediate of type B. Further
investigations on the exact nature of such transmitted remote asymmetric interactions are underway,
together with the application of such methods for the synthesis of β-amino acids.
Acknowledgements
We thank the E.P.S.R.C. (award no. 96311892) and Knoll Pharmaceuticals for a grant to H.E.S., Elaine
K. Brigham (Knoll Pharmaceuticals) for chiral HPLC and Dr. R. McCague (Chirotech Ltd, Cambridge)
for a sample of (S)-3-amino-3-phenylpropan-1-ol.
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