Memory of chirality trapping of low inversion barrier 1,4-benzodiazepin-2- one enolates

Article abstract of DOI:10.1016/j.tetasy.2005.08.017

We have previously demonstrated that chiral, enantiopure 3-substituted 1,4-benzodiazepin-2-ones undergo retentive deprotonation/trapping at -78°C, if the N1-substituent is sufficiently large (e.g., i-Pr). Stereocontrol in this reaction is attributed to the formation of an enantiopure, conformationally chiral enolate; at -78°C a large N1 substituent (e.g., i-Pr) is needed to impart a sufficient barrier to enolate racemization. Herein, we report strategies to achieve high enantiomeric excess in deprotonation/alkylation of low inversion barrier 1,4-benzodiazepin-2-ones featuring small N1 substituents.

Full text of DOI:10.1016/j.tetasy.2005.08.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2998–3002
Memory of chirality trapping of low inversion barrier
1,4-benzodiazepin-2-one enolates
Paul R. Carlier,* Polo C.-H. Lam, Joseph C. DeGuzman and Hongwu Zhao
Department of Chemistry, Virginia Tech, Blacksburg, VA 24060, USA
Received 25 July 2005; accepted 11 August 2005
Abstract—We have previously demonstrated that chiral, enantiopure 3-substituted 1,4-benzodiazepin-2-ones undergo retentive
deprotonation/trapping at ꢀ78 ꢀC, if the N1-substituent is sufficiently large (e.g., i-Pr). Stereocontrol in this reaction is attributed
to the formation of an enantiopure, conformationally chiral enolate; at ꢀ78 ꢀC a large N1 substituent (e.g., i-Pr) is needed to impart
a sufficient barrier to enolate racemization. Herein, we report strategies to achieve high enantiomeric excess in deprotonation/
alkylation of low inversion barrier 1,4-benzodiazepin-2-ones featuring small N1 substituents.
ꢁ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The racemic outcome realized with (S)-1a was proposed
to be a consequence of the smaller N1 substituent and
rapid racemization of the enolate at ꢀ78 ꢀC. However,
the possibility that 1a forms an achiral enolate could
not be ruled out. Herein, we report successful techniques
for the enantioselective deprotonation/trapping of 1,4-
benzodiazepin-2-ones that bear sterically small substitu-
ents at N1, such as 1a. These results suggest the interme-
diacy of conformationally chiral enolate intermediates
and open the way to the synthesis of enantiopure quater-
nary 1,4-benzodiazepin-2-ones bearing diverse N1
substitution.
1,4-Benzodiazepin-2-ones, for example, 1a and 2a, are
considered privileged scaffolds, because they have sup-
ported the development of drug candidates for a wide
array of biomolecular targets.1 To further expand the
structural diversity within this scaffold, we developed
an enantioselective route to analogs that feature a qua-
ternary stereogenic center at C3 (e.g., 2b in Scheme 1);2
note that prior to our work these compounds were lar-
gely unknown.3 Whereas deprotonation/alkylation of
(S)-1a gives racemic 1b, identical treatment of (S)-2a
gives (R)-2b in 97% ee. Stereocontrol in the second case
was attributed to Ômemory of chiralityÕ,4 whereby the
original central chirality of 2a is memorized in a chiral
conformation of the derived enolate intermediate.2
2. Results and discussion
To test the hypothesis that the enolate derived from (S)-
1a is conformationally chiral but rapidly racemizing, we
sought to generate it under conditions where it could be
instantaneously quenched. Thus, we performed an H–D
exchange of N-methyl 1,4-benzodiazepin-2-ones (S)-1a
and 3a–5a (Scheme 2).
Ph
N
Ph
N
1. 1.2 equiv. LDA,
6 equiv. HMPA
THF, -78 ˚C
15 min; 1.2 equiv
n-BuLi, 15 min
Cl
Cl
N
3
N
3
Bn
H3C
H3C
O
R1
O
R1
2. 10 equiv.
BnBr, 30 min
3. NH4Cl (aq.)
The required ÔtertiaryÕ 1,4-benzodiazepin-2-one starting
materials (S)-1a and 3a–7a were prepared in 100% ee
from the corresponding (S)-N-Boc amino acids, accord-
ing to our variation2 of Shea and co-workers protocol.5,6
H–D exchange of 1a and 3a–5a proved slow in basic
CD3OD, but after 6–13 days deuterium incorporation
exceeded 94% (1H NMR). As was hoped, analysis by
chiral stationary phase HPLC indicated retention and
%ee %yield
R1
Me
i-Pr
0
72
74
(S)-1a
(S)-2a
( )-1b
(R)-2b 97
Scheme 1. Enantioselective synthesis of quaternary 1,4-benzodiazepin-
2-ones.
*
Corresponding author. E-mail: pcarlier@vt.edu
0957-4166/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.017

P. R. Carlier et al. / Tetrahedron: Asymmetry 16 (2005) 2998–3002
2999
improvement in ee was observed which depended on
the amount of electrophile added (Table 1, entries 2
and 3). Although 80% ee could be attained in the pres-
ence of 100 equiv of BnBr (Table 1, entry 3) it was clear
that further improvement would require an acceleration
of the alkylation rate constant. Benzyl iodide proved to
be incompatible with the in situ protocol, most likely
due to the rapid reaction with KHMDS. However, fol-
lowing a 10 s deprotonation time, the desired product
(R)-6b was obtained in 88 ee (Table 1, entry 4).
Ph
N
Ph
Cl
Cl
1.7 equiv.
KO-t-Bu
CD3OD
N
N
D
R2
R2
N
O
Me
O
Me
6 - 13 days
25 ˚C
%ee
97
(S)-3c 97
%D
R2
Me
Bn
98
100
99
(S)-1a
(S)-3a
(S)-4a
(S)-5a
(S)-1c
(S)-4c
(S)-5c
95
98
CH2CHMe2
CH2CH2SMe
94
Scheme 2. Enantioselective H–D exchange of N-Me 1,4-benzodiaze-
pin-2-ones 1a and 3a–5a.
The data in Table 1 indicate that the enolate derived
from (S)-6a racemizes within minutes, even at
ꢀ100 ꢀC. To determine the approximate racemization
half-life of this species, we performed deprotonation/
quenching experiments. After considerable experimenta-
tion, we found superior results with the N-Bn analog
(S)-7a: Following deprotonation for a time t, a protic
quench was applied. Following the approach of Kawa-
bata et al.4b the recovered starting material was analyzed
by a chiral stationary phase HPLC, and ln(%eet) was
plotted versus time t (Fig. 1).
95–98% ee in each case. This successful outcome can be
rationalized in terms of a thermodynamically unfavor-
able deprotonation to a conformationally chiral enolate
and instantaneous deuteration of this otherwise rapidly
racemizing intermediate.
Encouraged by this success, we then attempted the enan-
tioselective deprotonation/alkylation of N-PMB analog
(S)-6a; realization of this goal would greatly expand
the scope of our protocol, since facile removal of the
PMB group would allow subsequent diverse functional-
ization at N1 (Table 1).
Note that the 61% benzylation yield obtained after a
10 s deprotonation of (S)-6a (Table 1, entry 4) suggests
that the deprotonation of 7a should be substantially
complete at the first time point (30 s) in Figure 1. Simi-
larly, the low ee (8%) obtained after 480 s indicates
>90% deprotonation within 8 min. Therefore the recov-
ered starting material 7 at all time points can be assumed
to arise predominantly from protonation of an enolate
intermediate. The plot of ln(%ee/100) versus t appeared
roughly linear over three half-lives; the slope corre-
sponds to ꢀkrac and indicates an estimated racemization
t1/2 of 2.3 min at ꢀ100 ꢀC. This value is consistent with
the dependence of alkylation %ee on the deprotonation
time (Table 1, entries 1 and 2). The dependence of alkyl-
ation %ee on the electrophile concentration (Table 1,
entries 2and 3) and reactivity ( Table 1, entries 2and
4) also shows competition between the racemization
and alkylation. Application of the Eyring equation7 to
the estimated krac for the enolate derived from 7a indi-
cates a barrier to inversion (DGzrac) of 12.0 kcal/mol at
As we anticipated a low inversion barrier for the enolate
derived from 6a, we began our synthetic investigations
at ꢀ100 ꢀC (Et2O/CO2). Concurrent with these investi-
gations, we examined a range of deprotonation proto-
cols. Whereas, LiHMDS was ineffective for the
deprotonation of 6a, KHMDS proved an excellent base
and offered a much simplified alternative to our pub-
lished LDA/n-BuLi protocol.2 After a 5 min deprotona-
tion time (t1) at ꢀ100 ꢀC, the addition of BnBr
essentially gave racemic 6b (Table 1, entry 1). This
unsatisfactory outcome led us to develop an in situ pro-
tocol (t1 = 0) that involves deprotonation in the pres-
ence of the electrophile. The use of KHMDS proved
essential here, since LDA apparently undergoes a com-
petitive reaction with the electrophile. An immediate
Table 1. Sequential versus in situ enantioselective deprotonation/trapping of N-PMB 1,4-benzodiazepin-2-one (S)-6a at ꢀ100 ꢀC
Ph
Ph
1. 2.4 equiv
KHMDS
6 equiv HMPA
THF, -100 ˚C,
t1
Cl
Cl
N
N
E
H3C
H3C
N
N
O
PMB
O
PMB
(R)-6b, d
Product
2. E-X, t2
(S)-6a
Entry
E–X (equiv)
BnBr (10)
t1
t2 (min)
eea
Yield (%)
1
5 min
120
6b
6b
6b
6b
6d
3
75
80
88
65
100
78
46
61
38
0)
2BnBr (2 0 min
5
3
4
5
BnBr (100)
BnI (20)
C3H5Br (100)
0 min
10 s
0
1
1
1
a All reactions run at [6a] = 1.2mM; enantiomeric excess determined by HPLC. Retention is assumed based on H–D exchange results in Scheme 2
and benzylation of the enolate derived from (S)-2a.

3000
P. R. Carlier et al. / Tetrahedron: Asymmetry 16 (2005) 2998–3002
which is a significant improvement from the 65% ee
attained with allyl bromide at ꢀ100 ꢀC (Table 2, entry
2). Substituted benzyl iodides also react in excellent
enantiomeric excess (Table 2, entries 3 and 4). Finally,
ethyl iodide reacts very slowly with the enolate at
ꢀ109 ꢀC. After 60 min, reaction time, only 8% of the
desired product 6g was obtained, while the 46% ee
observed evidences substantial enolate racemization
during the slow alkylation reaction.
We assigned the temperature of this protocol as
ꢀ109 ꢀC based on individual temperature measurements
and the known freezing point of THF. However, local-
ized supercooling in the THF/N2 cooling slush may be
partly responsible for these high enantioselectivities.
3. Conclusion
In conclusion, we have demonstrated enantioselec-
tive deprotonation/trapping sequences for 3-substituted
1,4-benzodiazepin-2-ones 1a–7a. The observed depen-
dencies of reaction %ee on temperature and the size of
the N1 substituent add further support to our proposal
that these transformations rely upon memory of chiral-
ity. Even when the barrier to inversion of the enolate is
in the order of 12kcal/mol (e.g., 1a and 6a), high enanti-
oselectivities can be attained by room temperature base-
catalyzed H–D exchange, or by sequential deprotona-
tion/trapping at ꢀ109 ꢀC. Finally, since the PMB pro-
tecting group of 6b,d–f can be easily removed under
mildly acidic conditions, this methodology could be
used to prepare enantiopure quaternary benzodiaze-
pines with diverse N1-functionalization.
Figure 1. Estimation of the racemization half-life of the enolate
derived from 7a.
173 K, similar to the 11.5 kcal/mol previously calculated
for the N-Me analog.2 In contrast the enolate derived
from N-i-Pr analog 2a was calculated to have an inver-
sion barrier of 17.5 kcal/mol (195 K).2
In the hope that slightly lowering the reaction tempera-
ture would result in a significantly improved enantio-
selection, we investigated deprotonation/alkylation
reactions at ꢀ109 ꢀC (THF/N2 cooling bath). Indeed,
at this temperature we found that excellent enantioselec-
tion could be obtained using a sequential protocol
(20 min deprotonation time) and allylic and benzylic
iodides (Table 2). Whereas, the highest %ee attained
for benzylation at ꢀ100 ꢀC was 88%, at ꢀ109 ꢀC, prod-
uct 6b was obtained in 97 ee (Table 2, entry 1).8 Reac-
tion with allyl iodide occurs in 89% ee at ꢀ109 ꢀC,
Acknowledgments
We thank the National Science Foundation (CHE-
0213525), the Jeffress Memorial Trust, and the
Virginia Tech Department of Chemistry for financial
support.
Table 2. Sequential enantioselective deprotonation/trapping of (S)-6a at ꢀ109 ꢀC (THF/N2)
Ph
Ph
1. 2.4 equiv
KHMDS
12 equiv HMPA
THF, -109 ˚C,
20 min.
Cl
Cl
N
N
E
H3C
H3C
N
N
O
PMB
(S)-6a
O
PMB
2. 20 equiv. E-X, t.
3. NH4Cl (aq.)
(R)-6b, d-g
Entry
E–X (equiv)
t (min)
Product
eea (%)
Yield (%)
1
2
3
4
5
BnI
C3H5I
2-PhC6H5CH2I
4-MeC6H5CH2I
EtI
10
5
30
10
60
6b
6d
6e
6f
97
89
97
93
46
93
88
81
92
8
6g
a All reactions run at [6a] = 1.2mM; % enantiomeric excess determined by HPLC. Retention is assumed based on H–D exchange results in Scheme 2
and benzylation of the enolate derived from (S)-2a.

P. R. Carlier et al. / Tetrahedron: Asymmetry 16 (2005) 2998–3002
3001
NH); 13C NMR (CDCl3) d 17.07, 58.86, 122.72, 128.45,
128.74, 129.03, 129.77, 130.50, 130.57, 131.82, 137.17,
138.74, 167.91, 172.86; HRMS (FAB) calcd for
C16H14N2OCl [M+H]+: 285.0795. Found: 285.0779
(ꢀ5.5 ppm, ꢀ1.6 mmu). HPLC tR(R): 11.1 min; tR(S):
14.1 min [Chiralpak AD (0.46 cm · 25 cm, Daicel Chemical
Ind., Ltd.) hexane/i-PrOH, 90/10, 1.0 mL/min] 100% ee.
N1-Alkylation reaction: the above material (200 mg,
0.70 mmol, 1.0 equiv) was dissolved in dry THF (10 mL),
cooled to 0 ꢀC and added to NaH (29 mg, 0.73 mmol,
1.05 equiv, 60% in mineral oil). After stirring for 20 min at
0 ꢀC for 20 min, PMB–Br (2.11 mmol, 3.0 equiv) was added
dropwise. After 10 min at 0 ꢀC, TLC indicated complete
reaction. The reaction was quenched at 0 ꢀC with 10 mL of
saturated aqueous NH4Cl solution and extracted with
CH2Cl2 (5 · 20 mL). The combined extracts were dried over
Na2SO4, filtered, concentrated, and purified by flash
chromatography to afford (S)-6a as a white solid (217 mg,
References
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R.
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Biophys. 1999, 368, 394–400.
25
0.535 mmol, 76% yield), mp 160.9–161.5 ꢀC; ½aꢁD = +129
2. Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P. C.-H. J.
Am. Chem. Soc. 2003, 125, 11482–11483.
3. The only previously published route to such compounds
involves lipase-catalyzed acylation of prochiral 3,3-
3
(c 0.985, CHCl3), 1H NMR (CDCl3) d 1.77 (d, JHH
=
3
6.5 Hz, 3H), 3.70 (s, 3H), 3.8 (q, JHH = 6.4 Hz, 1H), 4.58
(d, JHH = 15.1 Hz, 1H), 5.68 (d, JHH = 15.2Hz, 1H),
6.62(d, JHH = 8.7 Hz, 2H), 6.90 (d, JHH = 8.7 Hz, 2H),
7.13 (d, JHH = 2.3 Hz, 1H), 7.29–7.36 (m, 5H), 7.40 (dd,
2
2
3
3
bis(hydroxymethyl)-1,4-benzodiazepin-2-ones:
A.; Lesac, A.; Majer, Z.; Hollosi, M.; Sunjic, V. Helv.
Chim. Acta 1998, 81, 1567–1582.
Avdagic,
4
3JHH = 8.8 Hz, 4JHH = 2.4 Hz, 1H), 7.44 (t, 3JHH = 7.2Hz,
1H); 13C NMR (CDCl3) d 17.46, 49.58, 55.26, 59.02,
114.11, 124.25, 128.33, 128.67, 129.00, 129.44, 129.55,
129.87, 130.55, 131.21, 132.74, 138.15, 140.37, 158.97,
167.27, 170.42; HRMS (FAB) calcd for C24H22N2O2Cl
[M+H]+: 405.1370. Found: 405.1364 (ꢀ1.4 ppm,
ꢀ0.6 mmu). HPLC tR(R): 12.9 min; tR(S): 18.5 min [Chir-
alpak AD (0.46 cm · 25 cm, Daicel Chemical Ind., Ltd.)
hexane/i-PrOH, 90/10, 1.0 mL/min] 100% ee.
4. (a) Fuji, K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373–376;
(b) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew.
Chem., Int. Ed. 2000, 39, 2155–2157; (c) Kawabata, T.;
Fuji, K. In Topics in Stereochemistry; Denmark, S. E., Ed.;
John Wiley and Sons: New York, 2003; Vol. 23, pp 175–
205; (d) Zhao, H.; Hsu, D.; Carlier, P. R. Synthesis 2005, 1–
16.
5. Hart, B. R.; Rush, D. J.; Shea, K. J. J. Am. Chem. Soc.
2000, 122, 460–465.
7. Activation free energy is calculated as DGà =
ꢀRT[ln(krac) + ln(h/2kT)]: Eyring, H. Chem. Rev. 1935,
17, 65–77.
6. Synthesis of (S)-(+)-6a from L-Boc-Ala-OH. Coupling
reaction: 2-amino-5-chlorobenzophenone (1.35 g, 5.81
mmol, 1.0 equiv) and L-Boc-Ala-OH (1.00 g, 5.82mmol,
1.0 equiv) were combined in CH2Cl2 (20 mL) and DCC
(1.20 g, 5.81 mmol, 1.0 equiv) was added at 0 ꢀC. After
stirring overnight, the urea by-product was filtered off and
the filtrate was concentrated in vacuo. Flash chromatogra-
phy yielded a white solid (1.57 g, 3.89 mmol, 75% yield), mp
8. Synthesis of (R)-(+)-6b: to a stirred solution of (S)-6a
(20.0 mg, 0.0494 mmol, 1.0 equiv) and HMPA (103 lL,
0.593 mmol, 12.0 equiv) in anhydrous THF (4.0 mL) at
ꢀ109 ꢀC (THF/N2 slush) was added KHMDS (237 lL,
0.119 mmol, 2.4 equiv, 0.5 M in toluene). The resulting
solution was stirred for a further 20 min before the benzyl
iodide (216 mg, 0.99 mmol, 20 equiv) was added dropwise
via syringe. The reaction was stirred at ꢀ109 ꢀC until the
starting benzodiazepine was consumed (TLC). The reaction
was quenched at ꢀ109 ꢀC with saturated NH4Cl (10 mL)
and extracted with CH2Cl2 (4 · 20 mL). The combined
organic extracts were dried over Na2SO4, filtered, concen-
trated, and purified by flash chromatography to afford (R)-
6b as a colorless oil (22.8 mg, 0.0461 mmol, 93% yield),
25
152.5–153.9 ꢀC; ½aꢁD = ꢀ49.5 (c 1.00, CHCl3), 1H NMR
3
(CDCl3) d 1.42(s, 9H), 1.48 (d, JHH = 7.3 Hz, 3H), 4.33
(br s, 1H), 5.09 (br s, 1H), 7.49–7.54 (m, 4H), 7.62(tt,
3JHH = 7.5 Hz, JHH = 1.2Hz, 1H), 7.69 (dd, JHH
=
4
3
4
3
7.1 Hz, JHH = 1.4 Hz, 2H), 8.63 (d, JHH = 9.4 Hz, 1H),
11.16 (br s, 1H, NH); 13C NMR (CDCl3) d 18.62, 28.34,
51.72, 80.46, 123.04, 125.04, 127.62, 128.59, 130.00, 132.69,
133.00, 133.94, 137.89, 138.62, 172.15, 198.03 (17C, found:
16); HRMS (FAB) calcd for C21H24N2O4Cl [M+H]+:
403.1425. Found: 403.1410 (ꢀ3.6 ppm, ꢀ1.5 mmu). HPLC
tR(R): 16.6 min; tR(S): 20.0 min [Chiralpak AD (0.46 cm ·
25 cm, Daicel Chemical Ind., Ltd.), hexane/i-PrOH, 90/10,
1.0 mL/min] 100% ee.
25
1
½aꢁD = +11.5 (c 1.17, CHCl3), H NMR (CDCl3) indicated
a 60:40 mixture of axial-Me and equatorial-Me conformers
d 0.89 (s, 3H · 0.6 ax-Me), 1.85 (s, 3H · 0.4 eq-Me), 2.62 (d,
2
2JHH = 13.6 Hz, 1H · 0.4 eq-Me), 2.68 (d, JHH = 13.6 Hz,
1H · 0.4 eq-Me), 3.36 (d, 2JHH = 14.0 Hz, 1H · 0.6 ax-Me),
3.79 (s, 3H), 3.84 (d, 2JHH = 14.0 Hz, 1H · 0.6 ax-Me), 4.89
Cyclization reaction: the above material (1.45 g, 6.25 mmol,
1.0 equiv) was dissolved in CH2Cl2 (20 mL) and trifluoro-
acetic acid (6 mL) added with stirring at 0 ꢀC. After 1 h, the
reaction mixture was concentrated in vacuo and dissolved
in methanol (20 mL). This solution was stirred with 10%
NaHCO3/10% Na2CO3 (20 mL, both w/v) overnight,
diluted with water (20 mL) and extracted with CH2Cl2
(6 · 50 mL). Flash chromatography yielded a white solid
(1.10 g, 3.88 mmol, 62% yield), mp 204.9–205.5 ꢀC;
2
2
(d, JHH = 16.4 Hz, 1H · 0.6 ax-Me), 4.93 (d, JHH
=
17.2Hz, 1H · 0.4 eq-Me, overlapping with peak at 4.89),
5.56 (d, JHH = 15.2Hz, 1H · 0.4 eq-Me), 5.59 (d, JHH
2
2
=
15.6 Hz, 1H · 0.6 ax-Me, overlapping with peak at 5.56),
6.77 (d, 3JHH = 8.4 Hz, 2H), 6.94–7.64 (m, 15H); 13C NMR
(CDCl3) was consistent with an approximate 60:40 mixture
of axial-Me and equatorial-Me conformers (46 resonances
found for a possible 2 · 25 unique carbons): d 17.61, 28.52,
37.81, 47.70, 51.62, 52.03, 55.31 (2 overlapping peaks),
66.07, 68.16, 114.15, 114.19, 123.37, 123.89, 126.31, 126.76,
127.57, 128.27, 128.42, 128.58, 128.93, 128.96, 129.09,
129.16, 129.36, 129.54, 129.66, 129.94, 130.36, 130.42,
131.33, 131.61, 132.25, 133.56, 133.64, 136.73, 138.46,
25
½aꢁD = +124 (c = 0.925, CHCl3), 1H NMR (CDCl3) d
3
3
1.76 (d, JH3H = 6.7 Hz, 3H), 3.75 (q, JHH = 6.4 Hz, 1H),
7.16 (dd, JHH = 8.7 Hz,4JHH = 2.7 Hz, 1H), 7.29 (d,
3
4JHH = 2.1 Hz, 1H), 7.37 (t, JHH = 7.7 Hz, 2H), 7.42–
3
7.47 (m, 2H), 7.51 (d, JHH = 8.1 Hz, 2H), 9.50 (br s, 1H,

3002
P. R. Carlier et al. / Tetrahedron: Asymmetry 16 (2005) 2998–3002
139.87, 139.96, 140.91, 140.93, 158.92, 158.96, 165.32,
165.86, 172.12, 172.80; HRMS (FAB) calcd for
C31H28N2O2Cl[M+H]+: 495.1839. Found: 495.1852
(+2.6 ppm, +1.3 mmu). HPLC tR(S): 11.1 min; tR(R):
16.5 min [Chiralpak AD (0.46 cm · 25 cm, Daicel Chemical
Ind., Ltd.) hexane/i-PrOH, 90/10, 1.0 mL/min] 97% ee.