Enantioselective synthesis of α,β-diamino ester derivatives: memory of chirality in imino-aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2008.11.050

A simple strategy for the synthesis of chiral α,β-diamino ester derivatives in good yields and ee (up to 92%) utilizing the 'memory of chirality' concept is reported. This methodology has been extended for the enantioselective synthesis of substituted azi

Full text of DOI:10.1016/j.tetlet.2008.11.050

Tetrahedron Letters 50 (2009) 476–479
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Tetrahedron Letters
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Enantioselective synthesis of a,b-diamino ester derivatives:
memory of chirality in imino-aldol reactions
*
Manas K. Ghorai , Koena Ghosh, A. K. Yadav
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple strategy for the synthesis of chiral
a,b-diamino ester derivatives in good yields and ee (up to
Received 6 September 2008
Revised 6 November 2008
Accepted 13 November 2008
Available online 19 November 2008
92%) utilizing the ‘memory of chirality’ concept is reported. This methodology has been extended for
the enantioselective synthesis of substituted aziridines with excellent ee (92%).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Memory of chirality
Enolate
Imino-aldol
a,b-Diamino esters
Aziridine
Optically active
a
,b-diamino acid derivatives are an important
we have developed a simple strategy for the enantioselective
synthesis of ,b-diamino esters and report herein our preliminary
results. Our strategy provides direct access to non-racemic ,b-di-
class of compounds found as key structural frameworks in a num-
a
ber of antibiotics and other natural products.1 Several synthetic
a
routes to
a
,b-diamino acids and their derivatives are known in
amino esters with consecutive quaternary and tertiary stereogenic
centers in high enantiopurity. We have designed a new substrate
N-benzyl-N-tert-butoxycarbonylamino acid ester 1a to study
asymmetric induction by the MOC concept in imino-aldol reac-
tions. We anticipated that the enolate A from 1a with a chiral
CꢀN axis would be non-racemic and be able to preserve the stereo-
chemical information of starting material 1a to produce non-race-
mic products (Fig. 1).3c
The substrate 1a with high enantiopurity (>99% ee) is readily
accessible from the (S)-phenylalanine ethyl ester through N-benz-
ylation with benzaldehyde and sodium borohydride followed by
Boc protection with di-tert-butyldicarbonate in the presence of
the literature,1a,2 which include direct catalytic asymmetric Man-
nich reactions,2a–c opening of aziridine rings,2d–f imino-aldol reac-
tions,2g and catalytic asymmetric aza-Henry reactions.2h We
anticipated that non-racemic
easily be made from -amino acid derivatives via a simple inter-
a,b-diamino acid derivatives could
a
molecular imino-aldol reaction by using the ‘memory of chirality’
(MOC) concept. The MOC concept describes a protocol in which
the reactive intermediate is chiral and scalemic with the stereo-
chemical memory of the starting substrate even though the origi-
nal stereocenter is destroyed during the reaction.3c It was first
introduced and established by Fuji and Kawabata for the enantio-
selective
a
-alkylation of enolates.3a–g They utilized this concept
triethyl amine (Scheme 1). Toward the synthesis of chiral a,b-di-
for the asymmetric synthesis of various substituted nitrogen het-
erocycles and cyclic amino acids with tetrasubstituted stereocen-
ters and made a seminal contribution to the field.4 The MOC
concept has added a new dimension3–8 to asymmetric synthesis
amino esters initially the ester enolate A (M = K) was generated
from (S)-1a by the treatment of KHMDS at ꢀ78 °C and was reacted
with N-tosylphenylaldimine at the same temperature to afford the
involving the
a-C substitution reaction of a-amino esters or
ketones3 and different polycyclization processes.6 For the wider
applicability of this novel concept in asymmetric organic synthesis,
further exploration with important organic reactions is necessary.
In continuation of our research activities in enolate chemistry
exploring the scope of the MOC concept in imino-aldol reactions,
OM
O
O
EtO
X
N
Ph
Boc
OMe
Boc
Ph
Boc
OEt
Ph
t
R
CO2 Bu
N
N
1a
1b
A (R , X = CH2Ph)
* Corresponding author. Tel.: +91 512 2597518; fax: +91 512 2597436.
E-mail address: mkghorai@iitk.ac.in (M. K. Ghorai).
Figure 1. Amino acid ester derivatives and chiral enolate.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.050

M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 476–479
477
1. PhCHO/Et3N
MeOH
(Boc)2O/Et3N
CH2Cl2/r.t.
CO2Et
Ph
CO2Et
CO2Et
Ph
Ph
Boc
Ph
Ph
12 h
N
2. NaBH4/r.t.
Yield: 90%
NH2.HCl
HN
Yield 75%
1a
Scheme 1. Synthesis of N-benzyl-N-tert-butoxycarbonylamino acid ester 1a.
Table 1
corresponding non-racemic
a,b-diamino ester derivative 2a as an
Effect of bases and solvents on imino-aldol reaction
inseparable mixture of diastereomers (Scheme 2). It is worth not-
ing that the corresponding b-lactam could not be formed probably
because the negative charge developing on nitrogen was highly
delocalized over the sulfonyl group. The 1H NMR spectrum of 2a
contained broad signals probably because of its existence as atrop-
isomers due to restricted rotation along CꢀN bond although the
13C NMR, DEPT NMR, and mass spectral analyses clearly showed
the formation of this product. It was assumed that upon lowering
the temperature, one of the atropisomers might be frozen to pro-
vide a clean 1H NMR spectrum. The 1H NMR spectrum was found
to be better on decreasing the temperature; however, a clean spec-
trum was not obtained even at ꢀ55 °C (in CDCl3). On the other
hand, a high temperature 1H NMR study also failed to give a
well-resolved spectrum at 60 °C (in DMSO). Other NMR studies,
for example, 1H–1H and 1H–13C correlations at low temperature,
could not provide further information about the structure of 2a.
At this stage, we anticipated that the 1H NMR spectrum could be
simplified if the N-Boc group is deprotected. The Boc group of 2a
was deprotected using 1:2 trifluoroacetic acid and dichlorometh-
ane to give 3a in moderate yield with poor ee. As per our expecta-
tions, we got a clean 1H NMR spectrum of compound 3a.
To find out the optimum reaction conditions for better yield and
ee, the reaction of 1a with N-tosylphenylaldimine was studied in
different solvents with a number of bases. All these results are
summarized in Table 1. The best result was obtained with LDA as
the base in THF (ee up to 92% for the major diastereomer, entry
1). When toluene served as the solvent, 2a was formed only in
trace amounts (entry 2). Although 2a was produced in moderate
yield using KHMDS as the base, the enantioselectivity was found
to be very poor (Table 1, entries 3–6). Other bases, for example,
LHMDS or NaHMDS did not work; however, LTMP gave a clean
reaction with high yield (80%) and selectivity (ee 80% for the major
diastereomer of 3a) (Table 1, entry 8). Based on the above results,
we switched over to LDA as the base and carried out the same reac-
tion. When the reaction was quenched after 2 h, 2a was obtained in
62% yield but a further improvement in yield and ee was observed
when the reaction was continued for 10 h. To generalize this ap-
proach, several N-activated imines were reacted under optimized
Entry
Base
Solvent
Time
(h)
Yield
Yield
eeb,c
(%)
2aa (%)
3aa (%)
1
2
3
4
5
6
7
8
LDA
LDA
THF
Toluene
THF
THF:toluene 4:1
THF:toluene 1:4
Toluene
THF
10.0
10.0
6.0
2.0
2.5
2.5
14.0
2.0
84
Trace
55
71
70
56
Trace
80
88
—
92
—
4
16
26
28
—
KHMDS
KHMDS
KHMDS
KHMDS
LHMDS
LTMP
89
94
92
87
—
THF
80
80
a
Combined yield of both the diastereomers after purification.
HPLC separation was done using Chiral AD-H column (95:5 hexane/isopropanol
b
as mobile phase and 1.0 mL/min flow rate).
c
ee was determined from HPLC analysis of 3a.
conditions9 to give non-racemic
a,b-diamino acid derivatives 2a–f
(based on optical rotation) in good yields (Scheme 2).
The stereomers of imino-aldol products 2 could not be sepa-
rated at this stage. The diastereoselectivity as well as the enanti-
oselectivity of
2 could only be determined from its Boc
deprotected derivative 3. To get clear 1H NMR spectra and to deter-
mine ee/de, the Boc group was removed from the addition prod-
ucts 2a–f by the treatment of TFA in dichloromethane to produce
3a–f in high yields10 (Scheme 3, Table 2). 3a–f were fully charac-
terized by 1H NMR, 13C NMR, DEPT NMR, and HRMS analyses.
Moderate diastereoselectivity and moderate to high enantio-
selectivity (for major diastereomer 74–92% and for minor
diastereomer 62–88%) were obtained in all the cases (Table 2,
entries 1–6). In most of the cases, diastereomers (3a, 3d–f) could
be separated after Boc deprotection through flash column chroma-
tography. The relative configuration of the major diastereomers of
*
*
imino-aldol adducts 2 was determined to be (2R , 3S ) based on
X-ray crystallographic analysis of their derivatives 3 (Fig. 2).11 To
provide convincing evidence in support of the MOC effect in
imino-aldol reactions, (S)-methyl-2-[bis(tert-butoxycarbonyl)
amino]-3-phenylpropanoate 1b was reacted with N-tosylphenyl-
aldimine under identical reaction conditions where the corre-
sponding addition product 4 was formed as a racemate because
the enolate generated from the diBoc ester does not possess any
chiral CꢀN axis (Scheme 4).
O
O
*
i) Base
THF, -78 °C
This strategy has been extended further for the synthesis of
substituted aziridines. To transform 3a into the corresponding
substituted aziridine 7a, the ester moiety of 3a was reduced with
*
*
Ph
OEt
Ph
OEt
NH
N
SO2Ar1
N
ii)
N
Ar
THF, -78 °C, 10 h
Boc
Bn
Boc
SO2Ar1
Bn Ar
(ee > 99%)
1
2
Base: LDA, KHMDS, LTMP
O
*
O
*
a: Ar = Ph, Ar1 = 4-MeC6H4
b: Ar = Ph, Ar1 = Ph
c: Ar = 3-BrC6H4, Ar1 = 4-MeC6H4
*
Yield: 84%
Yield: 62%
Yield: 68%
*
Ph
OEt
NH
Ph
OEt
TFA / CH2Cl2
N
NH NH
0 °C to r.t., 2 h
yield upto 88%
Boc
Bn
SO2Ar1
SO2Ar1
Bn Ar
Ar
(ee upto 92%)
2a-f
3a-f
d: Ar = 2-ClC6H4, Ar1 = 4-MeC6H4
e: Ar = 2-furyl, Ar1 = 4-MeC6H4
f: Ar = Ph, Ar1 = 4-NO2C6H4
Yield: 74%
Yield: 74%
Yield: 80%
a: Ar = Ph, Ar1 = 4-MeC6H4; b: Ar = Ph, Ar1 = Ph; c: Ar = 3-
BrC6H4, Ar1 = 4-MeC6H4; d: Ar = 2-ClC6H4, Ar1 = 4-MeC6H4;
e: Ar = 2-furyl, Ar1 = 4-MeC6H4; f: Ar = Ph, Ar1 = 4-NO2C6H4
Scheme 2. Synthesis of
a
,b-diamino acid derivatives 2a–f.
Scheme 3. Boc deprotection of compounds 2a–f.

478
M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 476–479
Table 2
Asymmetric imino-aldol adducts 3a–f generated from Boc deprotection of 2a–f
Entry Product (3)a
Yield
drc (%) ee major
diastereomer diastereomer
ee minor
(3)b (%)
H
(%)
(%)
NHTs
CO2Et
Ph
Ph
HN
CO2Et
Ph
Ph
Bn
1
2
3
88
70
87
83:17 92
80
NH
NHTs
3a
Figure 2. Crystal structure of 3a.
CO2Et
Ph
Ph
Bn
71:29 80
80
62
Ph
NH
NHSO2Ph
NHTs
*
*
LiBH4 / THF
MsCl / Et3N
CH2Cl2
OH
NH
3b
Ph
Bn
3a
Ph
*
*
0 °C to r.t.
4 h
N
NH
Ar SO2Ar1
NHTs
0 °C to r.t.,
Bn
5 h
EtO2C
Ph
Br
Ar = Ph
7a
6a
Ar1 = SO2(4-C6H4)
Yield 75%; ee 92%
Yield 65%; ee 92%
71:29 84
NH
Bn
3c
Scheme 5. Synthesis of non-racemic aziridine 7a.
N,N-diprotected amino acid esters with N-activated imines utiliz-
ing the MOC concept. We believe that this strategy will contribute
significantly toward the enantioselective synthesis of a,b-diamino
acid derivatives and aziridines as well. The determination of the
absolute configuration of compounds 2 and 3 followed by mecha-
nistic study, further modulation of the reaction conditions to get a
single diastereomer, and the use of nonactivated imines which
would lead to nonracemic b-lactams in a single step are under
active study in our laboratory.
O
OEt
Ph
4
80
79:21 74
—
NH
Bn
TsHN
Cl
3dd
NHTs
EtO2C
Ph
O
5
6
87
84
67:33 80
88
NH
Bn
Acknowledgments
3e
O
M.K.G. is grateful to IIT-Kanpur and DST, India. K.G. thanks CSIR,
India and A.K.Y. thanks DST, India for a research fellowship.
OEt
NH
Ns
Ph
Supplementary data
83:17 88
—
NH
Bn
Ph
3fd
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.050.
a
b
c
Corresponding imino-aldol adducts (3a–f) obtained after 10 h.
Overall yield of both the diastereomers after purification.
dr based on crude 1H NMR analysis.
Minor isomer could not be separated in chiral HPLC columns (chiralpak AD-H,
OD-H).
References and notes
d
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lithium borohydride in THF at room temperature followed by cycli-
zation in the presence of mesyl chloride and triethyl amine to give
7a in good yield and high enantioselectivity (ee 92%) (Scheme 5).12
In summary, we have developed a straightforward route to opti-
cally active a,b-diamino acid derivatives and chiral aziridine with
contiguous quaternary and tertiary stereocenters with moderate
to high enantiopurity by a base-promoted imino-aldol reaction of
O
O
O
i) LDA
THF, 78 °C
TFA / CH2Cl2
0 °C to r.t., 2 h
*
Ph
OMe
Ph
H2N
OMe
Ph
Boc
OMe
ii)
Ph
N
Ts
N
NHTs
NHTs
Boc
N
THF, 78 °C, 10 h
Boc
Boc
Ph
Ph
5 (racemic)
1b (ee >99%)
4 (racemic)
Scheme 4. Synthesis of racemic a,b-diamino ester derivative 5.

M. K. Ghorai et al. / Tetrahedron Letters 50 (2009) 476–479
479
3. (a) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694–9696; (b)
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10. (a) Combined yields of two diastereomers of 3a–f obtained as a mixture from
the corresponding crude reaction mixture after passing through a small silica
gel column.
(b) General method for Boc deprotection of imino-aldol products 2a–f: To a
stirring solution of substrates 2a–f (0.10 mmol) in dry dichloromethane (1 mL)
was added trifluoroacetic acid (0.5 mL) at 0 °C. The reaction mixture was
stirred at room temperature for 2 h. It was neutralized with aq saturated
NaHCO3 solution and the aqueous layer was extracted with CH2Cl2 (3 ꢂ 5 mL).
The combined organic extract was washed with brine and dried over
anhydrous Na2SO4 and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica gel to
provide 3a–f.
Characterization data for 3a: The general procedure described above was
followed to afford 3a as a white solid in 88% overall yield (combined yield of
both the diastereomers). It was obtained as a mixture of diastereomers in
83:17 ratio (based on 1H NMR analysis of crude reaction mixture), where the
diastereomers were separated through flash column chromatography (eluent:
EtOAc/petroleum ether 10/90).
For the major diastereomer of 3a: IR mmax (KBr, cmꢀ1): 3344, 2925, 2854, 2354,
1732, 1600, 1454, 1263, 1161, 1091, 1019; 1H NMR (400 MHz, CDCl3): d (ppm)
1.03 (t, J = 7.2 Hz, 3H), 2.20 (s, 3H), 3.04 (d, J = 14.7 Hz, 1H), 3.33 (d, J = 14.8 Hz,
1H), 3.51 (d, J = 12.4 Hz, 1H), 3.66 (d, J = 12.4 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H),
4.83 (d, J = 6.6 Hz, 1H), 6.2 (br s, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.97–7.06 (m, 4H),
7.08–7.23 (m, 11H), 7.31 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): d
(ppm) 13.7, 21.2, 38.7, 46.9, 61.6, 61.7, 68.8, 126.8, 127.0, 127.6, 127.7, 128.26,
128.28, 128.3, 128.4, 128.9, 129.8, 130.4, 135.9, 136.3, 137.9, 139.5, 142.5,
173.1; HRMS (ESI) m/z Calcd for C32H34N2O4S (M++H): 543.2329, found:
543.2311; Rf 0.45 (ethyl acetate/petroleum ether: 20/80); mp: 158–160 °C;
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5883–5887.
9. (a) General experimental procedure for the imino-aldol reaction of N-benzyl-N-
tert-butoxycarbonylamino acid ester 1a with various imines: To a solution of
diisopropylamine (0.12 mL, 0.848 mmol) in 2 mL dry THF was added n-BuLi
(1.6 M in hexane) (0.53 mL, 0.848 mmol) at 0 °C and stirred for 20 min. It was
cooled to ꢀ78 °C and a solution of N-benzyl-N-tert-butoxycarbonyl amino acid
ester 1a (0.848 mmol) in 1.0 mL dry THF was added to it and allowed to stir for
1 h. N-Sulfonylimine (0.385 mmol) dissolved in 1.0 mL dry THF was slowly
added into the reaction mixture and stirring was continued at the same
temperature for 10 h. After completion of the reaction (monitored with TLC), it
was quenched with a saturated aqueous ammonium chloride solution and
extracted with 5 mL of ethyl acetate in two portions. The combined organic
extract was dried over anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was purified on a silica gel column by
flash column chromatography using ethyl acetate in petroleum ether as the
eluent to afford the pure products 2a-f.
Optical rotation: ½a D25
ꢁ
+10.25 (c 0.335, CHCl3) for a 92% ee sample; Optical
purity was determined by chiral HPLC analysis (Chiralpak AD-H column) using
95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 72.6 min (major), TR 2:
97.3 min (minor).
For the minor diastereomer of 3a: IR mmax (KBr, cmꢀ1): 3347, 3296, 2959, 2924,
2853, 1730, 1661, 1600, 1454, 1264, 1161, 1090, 1019; 1H NMR (500 MHz,
CDCl3): d (ppm) 1.08 (t, J = 7.1 Hz, 3H), 2.25 (s, 3H), 3.02 (d, J = 15.2 Hz, 1H),
3.34 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 11.8 Hz, 1H), 3.81 (d, J = 11.8 Hz, 1H), 3.98
(q, J = 7.1 Hz, 2H), 4.22 (d, J = 6.6 Hz, 1H), 4.73 (d, J = 7.7 Hz, 1H), 6.10 (d,
J = 7.7 Hz, 1H), 6.85–6.88 (m, 2H), 6.98–7.09 (m, 4H), 7.22–7.33 (m, 11H), 7.70
(d, J = 8.3 Hz, 2H); HRMS (ESI) m/z Calcd for C32H34N2O4S (M++H): 543.2329,
found: 543.2315; Rf 0.44 (ethyl acetate/petroleum ether: 20/80); optical
rotation ½a 2D5
ꢀ10.77 (c 0.65, CHCl3) for a 80% ee sample; optical purity was
ꢁ
determined by chiral HPLC analysis (Chiralpak AD-H column) using 95/5
hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 35.1 min (major), TR 2:
43.2 min (minor).
11. The crystals were obtained as a racemate hence the absolute configuration
could not be assigned. After crystallization of 3a, the mother liquor contained
the pure enantiomer which could not be crystallized. CCDC No. of 3a: 693721.
12. Synthesis of [(2-benzyl, N-benzylaziridin-2-yl)-phenylmethyl]-4-methylbenzene
sulfonamide (7a): To a solution of alcohol 6a (30 mg, 0.059 mmol) (single
diastereomer) in dry CH2Cl2 (0.5 mL) were added mesyl chloride (2 mmol) and
triethylamine (2.5 mmol). The reaction mixture was stirred at room
temperature for 5 h. It was poured into water and the aqueous layer was
extracted with CH2Cl2 (2 ꢂ 10 mL). The combined organic extract was washed
with brine and dried over anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography over silica gel (eluent: EtOAc/petroleum ether 10/90) to
provide 7a as a white solid in 65% yield. IR
2923, 2854, 1600, 1495, 1454, 1426, 1324, 1286, 1163, 1089, 1062, 1044, 1030;
1H NMR (400 MHz, CDCl3):
(ppm) 2.21 (s, 3H), 2.27 (s, 2H), 2.47 (d,
m
max (KBr, cmꢀ1): 3286, 3060, 3029,
d
J = 14.9 Hz, 1H), 2.67 (d, J = 14.9 Hz, 1H), 3.46 (d, J = 13.4 Hz, 1H), 3.85 (d, J =
13.4 Hz, 1H), 4.23 (d, J = 7.6 Hz, 1H), 5.52 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 7.8 Hz,
2H), 6.87–7.04 (m, 6H), 7.18–7.34 (m, 11H); 13C NMR (100 MHz, CDCl3): d
(ppm) 21.3, 29.7, 34.0, 35.7, 44.1, 56.5, 126.7, 126.8, 127.3, 127.4, 127.9, 128.1,
128.4, 128.5, 128.6, 129.0, 129.2, 137.2, 139.2, 139.3, 142.3, 142.4; HRMS (ESI)
m/z: Calcd for C30H31N2O2S (M++H): 483.2106, found: 483.2106; Rf 0.33 (ethyl
Characterization data for compound 2a: white solid; yield 84%; eluent: EtOAc/
petroleum ether 10/90; Rf 0.45 (ethyl acetate/petroleum ether: 20/80); ½a D25
ꢁ
+10.76 (c 0.415, CHCl3); IR mmax (KBr, cmꢀ1): 3334, 2978, 2927, 1738, 1696,
1389, 1160, 1090; 13C NMR for the mixture of stereoisomers (100 MHz, CDCl3):
d 13.4, 21.0, 21.3, 27.9, 29.6, 37.1, 40.6, 49.5, 61.2, 61.4, 61.9, 71.0, 80.9, 81.1,
81.5, 125.5, 125.8, 126.2, 127.0, 127.2, 127.80, 127.86, 128.0, 128.1, 128.5,
128.7, 128.8, 129.4, 129.9, 130.8, 131.2, 134.6, 135.7, 136.8, 138.1, 139.6, 139.9,
141.9, 142.3, 156.1, 157.1, 169.5; HRMS (ESI) m/z Calcd for C37H43N2O6S
(M++H): 643.2841, found: 643.2834.
acetate/petroleum ether: 15/85); mp: 140–142 °C; optical rotation: ½ ꢁ
a 2D5
+31.80 (c 0.22, CHCl3) for a 92% ee sample; optical purity was determined by
chiral HPLC analysis (Chiralpak AD-H column); 95/5 hexane/isopropanol, flow
rate = 1.0 mL/min. TR 1: 28.3 min (major), TR 2: 35.3 min (minor). (eluent:
EtOAc/petroleum ether 10/90).
(b) The reaction is highly dependent on temperature, solvent, bases, and most
importantly on time, and the corresponding de/ee of the product may change
with slight changes in any of these conditions.