A practical procedure for the multigram synthesis of the SuperQuat chiral auxiliaries

Article abstract of DOI:10.1055/s-1998-1700

An efficient and simple synthesis of oxazolidin-2-one SuperQuat chiral auxiliaries is described which provides rapid access to multigram quantities of the auxiliaries.

Full text of DOI:10.1055/s-1998-1700

May 1998
SYNLETT
519
A Practical Procedure for the Multigram Synthesis of the SuperQuat Chiral Auxiliaries
*
†
Steven D. Bull, Stephen G. Davies , Simon Jones, Mario E. C. Polywka, R. Shyam Prasad and Hitesh J. Sanganee
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford. OX1 3QY. UK
†Oxford Asymmetry Ltd., 151 Milton Park, Abingdon, Oxon. OX14 4SD. UK
Received 4 February 1998
Abstract: An efficient and simple synthesis of oxazolidin-2-one
SuperQuat chiral auxiliaries is described which provides rapid access to
multigram quantities of the auxiliaries.
suppress the endocyclic cleavage pathway and also convey a high
degree of crystallinity to both the auxiliaries themselves and the
acylated derivatives, enabling simple purification of intermediates and
products by recrystallisation (Scheme 3).
The versatile oxazolidin-2-one based methodology developed by Evans
et al has been widely used in asymmetric synthesis for the preparation
1
of highly functionalised homochiral molecules. This methodology
generally involves coupling the auxiliary to an acyl fragment which is
then chemically derivatised to afford ideally a single diastereoisomer
with one or more new stereocentres. Subsequent cleavage and
purification of the transformed acyl fragment affords the desired
homochiral product and the chiral auxiliary which may be recycled as
required (Scheme 1).
Scheme 3
Work carried out within these laboratories has clearly demonstrated that
the repertoire of chemistry which ensured the popularity of Evans’
5
auxiliary is equally accessible using the SuperQuat methodology and
we now report on a new synthesis of these auxiliaries which enables
their preparation on a multigram scale. The original preparation of
SuperQuat auxiliaries involved the addition of methylmagnesium
bromide to an α-amino acid methyl ester 3 to afford amino alcohol 4,
4
followed by direct treatment with carbonyl diimidazole. An alternative
procedure was developed based on conversion of alcohol 4 to
trichloroacetamide derivative 5 followed by base promoted cyclisation
4
to the desired auxiliary 1 (Scheme 4).
Scheme 1
The range of chemistry to which these acylated auxiliaries has been
2
subjected is highly impressive, but there are problems associated with
its use. The major problem concerns its recyclability due to the tendency
of the oxazolidinone ring of large branched acylated auxiliaries to
undergo endocyclic ring opening under the alkaline cleavage conditions
3
(
Scheme 2).
Scheme 4
While these methods were amenable to small scale synthesis, attempts
at scale-up were either low yielding, or resulted in partial racemisation
of the target auxiliary. In order to address these problems we proposed a
new synthetic protocol involving addition of MeMgBr to the N-Boc
methyl esters of α-amino acids to afford N-Boc-protected amino
alcohols. The presence of the Boc protecting group was central to our
synthetic strategy since initial deprotonation of the acidic carbamate
proton results in the formation of an anion which disfavours any further
deprotonation/racemisation of the stereogenic centre by excess Grignard
Scheme 2
This deviation from the desired exocyclic cleavage pathway results in
loss of product, difficulty in purification, and loss of recyclability.
Although these endocyclic cleavage problems may be overcome using
6
reagent. Subsequent base catalysed cyclisation of the resulting amino
alcohols would afford the desired auxiliary invoking a strategy whereby
the N-Boc protecting group acts as a sacrificial carbonyl equivalent.
3
the more nucleophilic reagent LiOOH, the use of large volumes of
peroxide on a large scale is clearly undesirable.
Treatment of BOC-(L)-valine methyl ester 6 in THF with 4 equivalents
of methylmagnesium bromide gave the desired tertiary alcohol 7 in
good yield without the need for purification. The crude alcohol 7 was
treated with potassium t-butoxide in THF to give an alkoxide species
which cyclised smoothly in situ to afford SuperQuat 8 which was easily
We have recently reported on the development of a new family of
oxazolidinone based auxiliaries, the ‘SuperQuats’, which successfully
address these problems. The salient features of these auxiliaries are the
presence of the geminal dimethyl groups at C-5 which completely
4

5
20
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SYNLETT
isolated in high yield by simple recrystallisation of the crude product
7
mixture (Scheme 5).
Scheme 5
The versatility of this methodology was demonstrated by preparing a
known range of SuperQuats 9-11 derived from (L)-phenylglycine, (L)-
phenylalanine, and (L)-alanine respectively in good yields (Figure 1).
The stereochemical integrity of each auxiliary was confirmed by chiral
8
gas chromatography and found to be homochiral (≥98% e.e.) by direct
comparison with authentic racemic samples.
Scheme 6
ketone 12, thus ensuring that racemic ketone 12 is never exposed to
Grignard reagent.
In conclusion, we have developed an improved synthesis of SuperQuat
family of chiral auxiliaries which is rapid and affords good yields of the
desired product. The method is amenable to scale up and has been used
routinely for the synthesis of 100g batches of the auxiliaries.
Figure 1
Acknowledgements
We are grateful to Oxford Asymmetry Ltd (S. D. B.) for funding.
While addition of Grignard reagent to the Boc methyl esters of the
various α-amino acids always afforded the desired tertiary alcohol in
high yield, a small quantity of ketone impurity (<5%) was always
observed in the 1H NMR spectra of the crude reaction mixture.
Purification of the crude reaction mixture obtained from addition of
MeMgBr to N-Boc-Valine-methyl ester, and examination of the optical
rotation of ketone 12 revealed that the stereogenic centre had been
totally racemised. This observation led us to propose that the following
mechanism was operating during Grignard addition.
References and Notes
1
2
.
.
Evans, D. A. Aldrichimica Acta, 1982, 15, 23.
Ager, D. J.; Prakash, I; Scaad, D. R. Aldrichimica Acta, 1997, 30,
3
.
3
.
Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.,
987, 28, 6141.
Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry, 1995, 6,
71.
1
4.
5.
6
Initial addition of the first equivalent of methylmagnesium bromide to
N-Boc-ester 6 deprotonates the acidic urethane NH proton resulting in
the generation of an anion α to the stereogenic centre. The second
equivalent of MeMgBr attacks the ester functionality of 13 to afford
ketone 14 which is then free to react via one of two possible pathways.
The major reaction pathway involves nucleophilic addition of a third
equivalent of MeMgBr to the ketone to afford the desired homochiral
alkoxide 15. The minor reaction pathway involves the Grignard reagent
acting as a base which irreversibly deprotonates ketone 14 at the
stereogenic centre to afford enolate 16 (Scheme 6).
Sanganee, H. J. D. Phil thesis, Oxford, 1997.
6
.
A similar racemisation process has been reported during addition
of phenyl lithium to the benzyl carbamates of α-amino acids;
Buckley III, T. F.; Rapoport H. J. Am. Chem. Soc. 1981, 103,
6
157; Delair, P.; Einhorn, C.; Einhorn, J.; Luche, J. L. J. Org.
Chem., 1994, 59, 4680.
7
.
Typical procedure for the preparation of the SuperQuat
auxiliaries:
(
S)-N-(t-Butylcarboxy)-3-amino-2,4-dimethylpentan-2-ol 7
It follows from examination of the enantiomeric excess of the resulting
homochiral SuperQuat auxiliary 7 that this enolisation process is
irreversible since any transenolisation processes would result in excess
Grignard reagent reacting with racemic ketone 12 thus compromising
the stereochemical integrity of both the alcohol 7 and the final
SuperQuat auxiliary product 8. Upon quenching the reaction mixture
magnesium enolate 16 is reprotonated to afford the observed racemic
BOC-(L)-Valine methyl ester 6 (16.0g, 0.069mol) was dissolved
in freshly distilled THF (400mL) and cooled to 0°C. Methyl
magnesium bromide (92mL, 0.276mol, 3.0M solution in ether)
was added dropwise under nitrogen (Care! Initial addition results
in evolution of methane) over 30 minutes and the reaction left to
stir at room temperature for 36 hours. The reaction was cooled to
0°C and methanol (200mL) added cautiously, followed by water

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521
+
(
50mL). A fine white precipitate formed which was filtered
[α]23 = +21.3 (c 0.8, CHCl ); (Found MH 158.1187. C H15NO2
D
3
8
+
through Celite and washed with ethyl acetate (2x100mL). The
combined filtrates were evaporated, redissolved in ether (100mL),
filtered through Celite and evaporated again to provide the
dimethyl alcohol 7 as an oil (13.84g, 87%); [α] D= -6.0 (c 1.0,
CHCl ); (Found: MH 232.1913. C12H25NO requires MH+
2
(
1
(
CH C), 0.89 (6H, m, CH(CH ) ); δ (50MHz; CDCl ) 157.2
(
(
(
1
(
requires MH 158.1181); υ
(KBr) 1732 (C=O); δH (500MHz;
CDCl ) 6.30 (1H, s (br), NH), 3.19 (1H, d, J 8.7, CHNH), 1.80-
max
3
1.87 (1H, m, CH CH), 1.48 (3H, s, CH C), 1.39 (3H, s, CH C),
3
3
3
2
3
1.00 (3H, d, J 6.6, CH CH), 0.92 (3H, d, J 6.6, CH )CH); δ
3 3 C
+
3
3
(50MHz; CDCl ) 155.9 (C=O), 83.9 (OC(CH ) ), 68.5 (CHNH),
3 3 3
32.1913);.υmax (Film)/cm-1 3446 (OH), 1694 (C=O); δH
28.4 (CH CH), 28.3 (CH C), 21.1 (CH C), 20.9 (CH CH) 19.8
3
3
3
3
200MHz, CDCl ) 4.88 (1H, d (br), J 10.4, NHCH), 3.35 (1H, dd,J
+
+
+
3
(CH CH); m/z (CI ) 315 (M H , 20%), 271 (5), 158 (MH , 70),
3
2
0.4, J 2.4, NHCH), 2.07-2.17 (1H, m, CH(CH ) ), 2.04 (1H, s
3 2
br), OH), 1.42 (9H, s, 3xCH ), 1.23 (3H, s, CH C), 1.19 (3H, s,
3 3
128 (5), 114 (100).
(RS)-N-(t-butylcarboxy)-3-amino-4-methylpentan-2-one 12
3
3 2
C
3
Ketone 13 was separated from the crude reaction for the
C=O), 78.9 (OC(CH ) ), 73.6 (COH), 61.7 (CHNH), 28.8
3 3
preparation of the valine dimethyl alcohol 7 by column
CH CH), 28.2 (3xCH ), 28.1 (CH C), 26.9 (CH C), 22.2
3 3 3 3
chromatography (1:5 ether / petrol) (341mg, 1.59mmol, 2%) as
colourless needles; m.p. 71-74°C; [α]23D= +0.4 (c 1.0, CHCl3);
+
+
CH CH), 16.8 (CH CH); m/z (CI ) 232 (MH , 10%), 176 (42),
3 3
58 (76), 132 (100), 114 (68).
S)-4-i-Propyl-5,5-dimethyloxazolidin-2-one 8
(
Found: C, 61.05; H, 9.80; N, 6.1. C11H21NO requires C, 61.4;
3
H, 9.8; N, 6.5%); υmax (KBr)/cm-1 3292 (NH), 1736 (C=O), 1678
N-CO); δH (200MHz; CDCl ) 5.13 (1H, m, NH), 4.31 (1H, m,
Potassium t-butoxide (7.18g, 0.064mol) was added in one portion
to a stirred solution of (S)-N-(t-Butylcarboxy)-3-amino-2,4-
dimethyl pentan-2-ol 7 (12.39g, 0.054 mmol) in freshly distilled
(
3
CHNH), 2.22 (3H, s, CH CO), 1.60 (1H, s, CH CH), 1.46 (9H, s,
3
3
3
xCH ), 1.03 (3H, d, J 6.8, CH CH), 0.80 (3H, d, J 6.8, CH )CH);
3 3 3
δC (50MHz, CDCl3) 207.8 (CH CO), 156.2 (C=O), 79.7
THF (250mL) at 0°C. After 30 minutes, saturated NH Cl solution
4
3
(
100mL) and ethyl acetate (100mL) were added and the layers
separated. The aqueous layer was extracted with ethyl acetate
2x100mL), washed with brine (50mL) and dried over MgSO4.
(
(
OC(CH ) ), 64.6 (CHNH), 29.9 (CH CO), 28.3 (3xCH ), 27.9
3 3 3 3
CH CH), 19.8 (CH CH), 16.4 (CH CH); m/z (CI ) 160 (35%,
+
3
+
3
3
(
MH -C H ).
4
8
The solvent was evaporated to give a crude oil, which was
recrystallised from petroleum ether (40-60) / diethyl ether (6.06g,
7
8.
Gas chromatographic analysis was carried out over a Chirasil
valine stationary phase.
1%) to give the desired SuperQuat 8 as needles; m.p. 88-89°C;