Diastereoselective lithiation and substitution of (S)-N-benzylprolinol and rac-N-benzylpiperidine-2-methanol via the carbamate esters: Kinetic resolution by means of (-)-sparteine-mediated deprotonation

Article abstract of DOI:10.1055/s-1999-3612

The (S)-N-benzylprolinol carbamate (S)-8 is deprotonated by sec- butyllithium with the removal of the pro-R-H and the intermediate lithium compound 10 is trapped by several electrophiles. Complete ul-diastereotopos- differentation is achieved irrespective

Full text of DOI:10.1055/s-1999-3612

PAPER
1915
Diastereoselective Lithiation and Substitution of (S)-N-Benzylprolinol and rac-
N-Benzylpiperidine-2-methanol via the Carbamate Esters: Kinetic Resolution
by Means of (–)-Sparteine-Mediated Deprotonation
B. Weber,a J. Schwerdtfeger,a R. Fröhlicha, A. Göhrt,b D. Hoppe*a
aInstitut für Organische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
Fax +49(251)8339772
bBayer AG, D-51368 Leverkusen, Germany
Received 7 June 1999
Abstract: The (S)-N-benzylprolinol carbamate (S)-8 is deprotonat-
ed by sec-butyllithium with the removal of the pro-R-H and the in-
termediate lithium compound 10 is trapped by several electrophiles.
Complete ul-diastereotopos-differentation is achieved irrespective
of the supporting additive [TMEDA, (-)-sparteine, or ether]. For
the homologous piperidine derivative rac-9, the substrate-directed
diastereoselectivity is less pronounced (~6:1). Thus, an efficient ki-
netic resolution is observed by means of sec-butyllithium/(-)-
sparteine, leading to the preferential consumption of the (+)-(R)-9
with abstraction of the pro-S-H, followed by its substitution by elec-
trophiles. Enantioenriched (-)-(S)-9 remains unchanged.
Key words: b-amino alcohols, b-amino-a-oxy carbanions, diaste-
reoselective deprotonation, (-)-sparteine, kinetic resolution, carb-
anions, lithiation, Mosher esters
Introduction
As we have recently reported, carbamate esters of 2-(N,N-
dibenzylamino)alkan-1-ols 1 are deprotonated in the a-
position by means of sec-butyllithium/tertiary diamine re-
agents (Scheme 1).1-4
The selection between the diastereotopic protons pro-R-
H1 and pro-S-H1 is greatly influenced by the nature of the
complexing diamine. The achiral additive N,N,N’,N’-tet-
Scheme 1
ramethylethylenediamine (TMEDA, conditions A) usual-
ly supports the substrate-directed removal of the ul-
proton5 [pro-R-H in (S)-1, pro-S-H in (R)-1] to form pref-
poled version of the usual route consisting in the addition
of nucleophiles to N-protected a-amino aldehydes
(Scheme 2).9
erentially 2·TMEDA [or ent-2·TMEDA from (R)-1]. The
base sec-butyllithium/(-)-sparteine (conditions B), due to
its high preference for pro-S-protons in alkyl carbamates,
reacts with (S)-1 in a mismatched situation6 slowly lead-
ing to the lithium intermediate epi-2·3.7 Trapping of the
mixtures by electrophiles ElX gives rise to the main prod-
ucts 4 or epi-4, respectively, in a substitution reaction with
complete retention of the configuration.3a Consequently,
with substrates (R)-1 under (-)-sparteine conditions B,
the matched pair6 results in a very rapid deprotonation
and, therefore, could be utilized for the kinetic resolution
of a racemic amino alcohol.8 The accumulated experimen-
tal evidence led to the conclusion, that the dibenzylamino
group does not support the deprotonation step by com-
plexation of the lithium cation.2-4 The method provides a
flexible solution for generating synthetic equivalents for
the synthons B, epi-B, and their enantiomers. It is an um-
Scheme 2
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1916
B. Weber et al.
PAPER
In this work, we investigated the carbamates (S)-81 and Compound (S)-8 was allowed to react with 2.0 equiva-
rac-9, derived from the cyclic amino alcohols (S)-N-ben- lents of sec-butyllithium (approx. 1.3 M in cyclohexane/
zylprolinol [(S)-5] and rac-N-benzylpiperidine-2-meth- hexane, 92:8) in diethyl ether in the presence of TMEDA
anol (rac-6), which, surprisingly, exhibit a different stere- (2.0 equiv) at -78°C for 3 hours (conditions A) and the re-
ochemical reactivity pattern, deviating from that of the action mixture was quenched with methyl chloroformate.
open-chain counterparts 1.
Workup afforded the methyl ester 14a, arising from the
substitution of the pro-R-H, via the lithiated diastereomer
10 as a single diastereomer (Table 1, Entry 1). The same
result was obtained (Entry 3) when (-)-sparteine (3) was
used as the additive (conditions B), and - even in a higher
yield (Entry 4) - in the absence of any diamine ligand
(conditions C). Unlike the N,N-dibenzylaminoalkyl car-
Results and Discussion
Deprotonation and Substitution
The carbamates (S)-8 and rac-9 were prepared from the bamates 1, for efficient deprotonation of (S)-8, no biden-
corresponding N-benzylamino alcohols (S)-510 or rac-610 tate diamine is required. The same turned out to be true for
and the oxazolidinecarbonyl chloride 7 by the sodium hy- the next homologue rac-9 (Entry 14). For a possible ex-
dride method (Scheme 3).11
planation see below.
The reaction of (S)-8 via 10 with methyl iodide, chlorotri-
methylsilane, chlorotributyltin, and acetone also yielded
the expected compounds 14 with high diastereoselectivity
(for spectroscopic data, see Table 3). As we had already
observed in related cases,12 no stereospecifity with respect
to the former carbanionic center was achieved in the reac-
tion with allyl bromide (Table 1, Entry 11). In all other
cases, deprotonation and substitution - as found for all sp3-
carbamoyloxy-substituted carbanions - proceeded with
complete stereoretention. The expected configuration
[2S,2(1R)] for the methylation product 14b was confirmed
by transformation into the known amino alcohol 20b11,13
(Scheme 4). The stereostructure of the acetone addition
product 14g was established by an X-ray crystal structure
analysis (Figure 1).14
Reagents and conditions: a) i. MeSO3H/MeOH, reflux; ii
Ba(OH)2∑8H2O/MeOH, reflux; b) Pd black, MeOH/HCO2H (95:5).
Scheme 4
Figure 1 X-ray structure of 14g14
2-Methylpropanal as a prochiral electrophile led to the
diastereomers 14i and 14i’ (dr = 27:73) arising from
Scheme 3
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Kinetic Resolution by Means of (–)-Sparteine-Mediated Deprotonation
1917
Table 1 Yields and Diastereomeric Ratios in the Reaction of (S)-8 and rac-9 with Various Electrophiles
Entry
Substrate ElX
Product
Diamine
Yield (%)a,b
mp (°C)
(solvent)
Ratio
(dr)
[a]2D0 c,d,e
1
2
3
4
5
6
7
8
(S)-8
(S)-8
ClCO2CH3
14a
14a
14a
14a
14b
14b
14b
14c
TMEDA
TMEDA
(–)-sparteine
–
TMEDA
(–)-sparteine
–
TMEDA
TMEDA
TMEDA
TMEDA
59a
40b
66a
84a
71b
56b
73a
33b
71b
33b
49a
33a
23b
62b
80a
oil
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
60:40
–19.6c
–19.2c
–18.9c
–19.3c
–51.0d
–51.4d
–51.8d
–54.8e
–69.6c
– 7.4c
–47.6c
–54.1c
– 8.1c
– 1.3c
CO2/CH2N2
ClCO2CH3
ClCO2OMe
MeI
MeI
MeI
Me3SiCl
Bu3SnCl
Me2CO
52 (E/P)
(S)-8
(S)-8
(S)-8
(S)-8
45 (E/P)
oil
102 (E/P)
oil
oil
64 (E/P)
oil
9
10
11
14e
14g
(CH2=CH)CH2Br
14ff +
15fg
12
13
14
15
16
(S)-8
rac-9
rac-9
rac-9
rac-9
Me2CHCHO
ClCO2Me
ClCO2Me
MeI
14ig +
TMEDA
TMEDA
–
27:73
85:15
92:8
14i’f
rac-16ag +
rac-17ah
rac-16ag +
rac-17ah
rac-16b +
rac-17b
rac-16b +
rac-17b
rac-16c
rac-16d +
rac-17d
rac-16d +
rac-17d
rac-16h +
rac-17h
rac-16h +
rac-17h
oil
h
–
49a
86a
50a
i
TMEDA
–
–
84:16
94:6
MeI
17
18
rac-9
rac-9
Me3SiCl
Me3SnCl
TMEDA
TMEDA
66a
72k
95-97 (E/P)
oili
>95:<5j
79:21
19
20
21
rac-9
rac-9
rac-9
Me3SnCl
Me3COCl
Me3COCl
–
34k
84a
52a
87:13
85:15
95:5
TMEDA
oili
–
a Flash chromatography on silica gel.
b Flash chromatography on aluminium oxide.
c c = 1.0 in CHCl3.
d c = 0.5 in CHCl3.
e c = 1.5 in CHCl3.
f More polar diastereomer on Al2O3.
g Less polar diastereomer on Al2O3.
h Mixture of rac-17 and educt rac-9, which is not separable by flash chromatography.
i Diastereomeric mixture of rac-16 and rac-17, which is not separable by flash chromatography.
j No evidence was found for the other diastereomer by TLC or 1H and 13C NMR spectra.
k Purified by flash chromatography with Et2O/pentane (1:5) and 3% Et3N on silica gel.
diminished facial selectivity at the carbonyl group (Table The deprotonation of the piperidine derivative rac-9 un-
1, Entry 12). We assume the following relative configura- der conditions A (TMEDA) and trapping with different
tions for 14i and 14i’ by comparison of their polarities on electrophiles occurred with lower diastereotopic selectiv-
silica gel and their OH-proton shifts in CDCl3 in analogy ity affording rac-16 and rac-17 in a ratio of roughly 6:1
to former results (Scheme 5).3a
(Table 1). When applying conditions C (no additive), the
diastereomeric ratio increased to 95:5 (e.g., see Entries 20
and 21), but the yields are lower due to a slower deproto-
nation. Both facts are the reasons for a successful kinetic
resolution of rac-9 (see below).
Why the lithiation of the N,N-dibenzylaminoalkyl car-
bamates 1 requires the presence of a bidentate external
ligand whereas for the cyclic carbamates 8 and 9 a weak
donor solvent such as diethyl ether is sufficient? In the cy-
clic N-benzyl compounds 8 and 9, a more rigid conforma-
tion and a less shielded lone pair at the nitrogen atom are
Scheme 5
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1918
B. Weber et al.
PAPER
given. This led us to the speculation that tricyclic chelate When comparing the diastereomeric chelate complexes u-
complexes such as 10A and 12A, containing one molecule 10A and l-11A one expects the first one, bearing anti-
of diethyl ether (Figure 2), are the energetically most pre- fused five-membered rings connected at the azalithiocy-
ferred arrangements in the systems. Four membered-ring clobutane ring and arising from an ul-deprotonation, to be
lithium structures15 are numerous.16 We encountered sev- the more stable one. In the syn-fused tricycle 11A severe
eral cases, where donor-ligands being attached to stereo- steric interactions between the two five-membered rings
genic centers cause extremely high and reliable are expected to occur. Similar arguments may count for
diastereoselectivities.4,17,18 Obviously, all important fea- the preferential formation of 12A in the annulated 6,4,5-
tures, stabilizing the particular transition states of diaste- tricyclic intermediates, although to a lesser extent, since a
reomeric deprotonation reactions, are also reflected in the decreased diastereotopic selection is observed in the ex-
ground state energies of bi- or tricyclic chelate complexes. periment (Table 1, e.g. Entries 14 and 16). In addition, it
must be concluded that the (-)-sparteine complex 11·3
[L2 = (-)-sparteine] is largely disfavoured in competition
with 10A.
Kinetic Resolution
Fortunately, sec-BuLi/(-)-sparteine reacts more rapidly
than sec-BuLi/Et2O with rac-9, when applying deprotona-
tion conditions B (varying ratios of substrate/base/ligand;
see Scheme 6, Table 2). Methoxycarbonylation or trime-
thylsilylation of the lithium intermediates furnishes the
optically active products (+)-ent-16a and (+)-ent-16c,
which were produced besides some recovered, partially
enantiomerically enriched starting material consisting in
excess of (-)-(S)-9.
The best results were achieved when 0.6–0.7 equivalents
of sec-BuLi and 0.8 equivalent of (-)-sparteine (3) (based
on rac-9) were applied: The methyl carboxylate ent-16a
and the silane ent-16c were produced with high diastereo-
selectivity (dr >96:4) and in high enantiomeric excess (up
to er = 97:3, 94% ee). The relative and absolute configu-
ration of (+)-ent-16c [2R,2(1S)], was confirmed by an X-
ray crystal structure analysis19 employing anomalous dis-
persion (Figure 3), the enantiopole parameter of 0.00(3)
for (+)-ent-16c accounts for a high reliability.
Since the stereochemistry is determined on the deprotona-
tion step, it is certain that the silane (+)-ent-16c and the
ester (+)-ent-16a have the equal topicity, which is
[2R,2(1R)] for the latter one due to a change in the CIP pri-
orities. The same stereochemical reaction course was
found for a carbolithiation reaction applying a related N-
cinnamyl derivative (rac-9, CH2CH=CHPh for Bn).20
Thus (+)-(R)-9 is consumed preferentially by abstraction
of the pro-S-H and (-)-(S)-9 remains behind. This is also
Figure 2 Chelate complex structures of 10–13
Table 2 Kinetic Resolution of (S)-9 and (R)-9
Entry
Product
ElX
(–)-Sparteine
(equiv)
s-BuLi
(equiv)
Yield
(product)
Ratio
(dr)
[a] (% ee ent-16) a,b
1
2
3
4
ent-16a + ent-17a
ent-16a + ent-17a
ent-16a + ent-17a
ent-16c
ClCO2Me
ClCO2Me
ClCO2Me
Me3SiCl
0.60
0.80
0.80
0.80
0.55
0.65
0.60
0.70
39 (56)
38 (53)
41 (43)
40 (40)
98:2
96:4
>98:<2
>98:<2
+ 9.8
+ 9.4 (86)c
+10.4 (94)
+22.1
ac = 1.0 in CH2Cl2.
bDetermined by Mosher ester method (see Scheme 7).
c80% ee for enantioenriched educt (S)-9, determined by Mosher ester method (see Scheme 8).
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Kinetic Resolution by Means of (–)-Sparteine-Mediated Deprotonation
1919
Scheme 6
Figure 3 X-ray structure of (+)-ent-16c19
Reagents and conditions: a) LiEt3BH/THF, 0°C. b) (R)-(-)-a-Meth-
oxy-a-trifluoromethylphenylacetyl chloride/pyridine/CH2Cl2
Scheme 7
predicted from the considerations (see Scheme 3) since
only in (R)-9 both the substrate- and the reagent-directed
preferences match.
The recovered starting material (S)-9 and the silane ent-
16c were deprotected to the alcohols (S)-6 and ent-24c by
the standard method (Scheme 8). The enantioenriched
(S)-6 was converted to the Mosher ester22 23 and its
epimer;23 their diastereomeric ratio was determined by 1H
NMR spectroscopy (Table 2, Entry 2).
The enantiomeric ratios in ent-16a, ent-16c, and (S)-9
could not be determined directly by applying optically ac-
tive NMR shift reagents. The enantioenriched ester ent-
16a was partially reduced with LiEt3BH21 to the mono
protected diol ent-21, which was converted to the Mosher
ester22 22 and its epimer23 (Scheme 7); their diastereomer-
ic ratio was analyzed by 1H NMR spectroscopy (Table 2,
Entries 2 and 3).
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1920
B. Weber et al.
PAPER
Table 3a Selected Data of C-1’-Substituted Carbamatesa
Product IR (KBr/
film)
1H NMR (300 MHz, CDCl3), d, J (Hz)
n (cm-1)
2-(1-H)
2-H
NCH2Ph
14a
14b
1755,
1700
5.29 (d, 3J2,2-1 2.85-2.95 (m)
= 3.3)
3.28, 4.16/4.17
1.64–1.71 (m, 4-H2), 1.84–2.02 (m, 3-H2), 2.10–2.23 (m, 5-Ha),
2.99–3.11 (m, 5-Hb), 3.75 (s, CO2CH3)
(2 d, 2JBn = 13.0)
1700,
1680
5.14 (dq, 3J2,2-1 2.55-2.66 (m)
= 3.4, 3J2-1,2-2
3.17, 4.22/4.23
1.30 [2-(2-H3)], 1.55–1.97b (m, 3-H2, 4-H2), 2.03–2.18 (5-Ha),
2.83–2.92 (5-Hb), 3.75 (s, CO2CH3)
(2 d, 2JBn = 12.8)
= 6.5)
14c
14e
1690
5.26 (d, 3J2,2-1 2.55 (dt, 3J2,3
2.92, 4.32 (2 d, 2JBn 0.13 [Si(CH3)3], 1.44–1.70b (m, 4-H2), 1.84–2.05 (m, 3-H2,
= 2.1)
= 8.3)
= 12.6)
5-Ha), 2.79–2.88 (m, 5-Hb)
1685,
1675
5.12/5.16 (d,
2.65-2.73 (m)
3.01/3.04, 4.21/
0.85–2.12b [m, 3-H2, 4-H2, 5-Ha, Sn(C4H9)3], 2.84–2.94 (m,
5-Hb)
3J2,2-1 = 2.0)
4.25 (2 d, 2JBn
=
12.9)
14f
15f
1695,
1640
5.22 (dd, 3J2,2-1 2.86 (dt, 3J2,3
= 3.3, 3J2-1,2-2 = –c)
= 7.7)
3.11, 4.23/4.24 (2 1.30–1.98b (m, 3-H2, 4-H2), 2.04-2.13, 2.61–2.72 (m, 5-Ha,
d, 2JBn = 13.0)
5-Hb), 2.37–2.50 [m, 2-(2-H2)], 5.05, 5.10 [2 ddt, 2J2-4,2-4 = 2.0,
3J2-3,2-4 = 10.2, 4J2-2,2-4 = 1.1, 1.8, 2-(4-H2)], 5.84 [ddt, 2-(3-H)]
1690,
1640
5.00-5.16b (m) 2.87-3.00b (m) 3.36, 4.15 (2 d, 2JBn 1.35–1.91b (m, 3-H2, 4-H2), 2.04–2.41 (m, 5-Ha, 5-Hb), 2.73
= 13.4)
[dddt, 2J2-2a,2-2b = 14.8, 3J2-1,2-2 = 3.0, 3J2-2,2-3 = 6.0, 4J2-2,2-4 = 1.7,
2-(2-H)], 2.87–3.00b [m, 2-(2-Hb)], 5.00–5.16b [m, 2-(4-H2)]
14g
3180,
1685
4.74 (d, 3J2,2-1 3.26-3.38 (m)
= 9.8)
3.50, 3.90/3.91
1.17–2.00b [m, 3-H2, 4-H2, 2-(3-H3), 2-(2-CH3)], 2.62, 2.92
(2 dt, 2J5a,5b = 12.0, 3J4,5 = 5.9, 7.6)
(2 d, 2JBn = 12.7)
14i’
3400,
1690,
1680
4.85 (dd, 3J2,2-1 2.77-2.98 (m)
= 7.0, 3J2-1,2-2
= 8.8)
3.29-3.50, 4.10-
4.30 (2 m)
0.95, 1.04 [2 d, 3J2-3,2-4 = 6.8, 3J2-3,2-3-CH3 = 7.0, 2-(4-H3), 2-
(3-CH3)], 1.68–1.93 [m, 3-H2, 4-H2, 2-(3-H)], 1.93–2.17, 2.38–
2.48 (2 m, 5-Ha, 5-Hb); 3.11 (br s, OH), 3.78 (dd, 3J2-2,2-3 = 2.9,
2-(3-H)]
14i
3240,
1685,
1680
4.85 (dd, 3J2,2-1 3.57 (dt, 3J2,3
3.28/3.29, 4.30/
4.34 (2 d, 2JBn
= 12.6)
0.86/0.87, 1.08/1.09 [2 d, 3J2-3,2-4 = 3J2-3,2-3-CH3 = 6.6, 2-(4-H3),
2-(3-CH3)], 1.31–2.30 [m, 3-H2, 4-H2, 2-(3-H)], 2.82-2.92,
3.42–3.54 (2 m, 5-Ha, 5-Hb), 3.73 [dd, 3J2-2,2-3 = 1.2, 2-(3-H)],
6.88–7.28b (m, OH)
= 1.2, 3J2-1,2-2
= = 8.9)
2.2)
rac-16a 1750,
5.63 (bs)
2.74-2.93b (m) 3.18/3.20, 4.17/
1.25–1.85b (m, 3-H2, 4-H2, 5-H2), 1.93–2.05 (m, 6-Ha); 2.74–
1690
4.19 (2 d, 2JBn
=
2.93b (m, 6-Hb), 3.76 (s, CO2CH3)
13.2)
c
rac-17ad
–
5.52 (d, 3J2,2-1
= 4.5)
3.32/3.37, 4.18
3.77 (s, CO2CH3)
(2 d, 2JBn = 13.1)
rac-16b 1680
5.25-5.36 (m) 2.25-2.43 (m)
3.15, 4.27 (2 d, 2JBn 1.24–1.86b [m, 3-H2, 4-H2, 5-H2, 2-(2-H3)], 1.90–2.06 (m,
= 13.4)
6-Ha), 2.82 (d, 2J6a,6b = 11.4, 6-Hb)
c
rac-17bd
–
5.45-5.55 (m)
rac-16c 1680
5.36 (d, 3J2,2-1 2.60-2.80b (m) 3.25-3.40, 4.14
= 6.7)
0.11 [s, Si(CH3)3], 1.15–1.88b (m, 3-H2, 4-H2, 5-H2), 2.01–2.16
(m, 6-Ha), 2.60–2.80b (m, 6-Hb)
(m and d, 2JBn
= 13.1)
rac-16d 1680
5.15 (d, 3J2,2-1 2.65-2.80b (m) 3.38, 4.16 (2 d, 2JBn 0.16 [s, Sn(CH3)3], 1.00–1.75 (m, 3-H2, 4-H2, 5-H2), 1.75–1.90
= 5.2)
= 13.0)
(m, 6-Ha), 2.65–2.80b (m, 6-Hb)
c
rac-17dd
–
5.36 (d, 3J2,2-1
3.21/4.05 (2 d, 2JBn
= 5.5)
= 13.4)
rac-16h 1690,
6.05 (d, 3J2,2-1 2.81-2.97b (m) 3.31/3.34, 4.09 (2 1.10–1.85b (m, 3-H2, 4-H2, 5-H2), 1.23 [s, C(CH3)3], 2.07–2.22
= 4.3)
1680
d, 2JBn = 13.1)
(m, 6-Ha), 2.81–2.97b (m, 6-Hb)
c
rac-17he
–
6.03 (d, 3J2,2-1
= 9.1)
aNMR data of the Cby group and the aromatic rings are omitted. NMR data carrying the symbol * are interchangeable.
bAs part of a multiplet; cNot recorded.
d Recorded from the mixture of diastereomers; e Recorded from the mixture with the starting material rac-7.
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Kinetic Resolution by Means of (–)-Sparteine-Mediated Deprotonation
1921
Table 3b Selected Data of C-1’-Substituted Carbamates
Product
13C NMR (75 MHz, CDCl3), d
2-(C-1)
72.6/72.7
70.2
C-2
NCH2Ph
58.8
14a
14b
14c
14e
14f
64.6
67.6
65.8*
68.3
66.3
22.9 (C-4), 26.6 (C-3), 52.0 (CO2CH3), 53.8 (C-5), 170.5 (CO2CH3)
17.3 [2-(C-2)], 22.6 (C-4), 26.9 (C-3), 54.4 (C-5)
59.3
66.0*
70.4
57.9
–2.18 [Si(CH3)3], 22.0 (C-4), 29.1 (C-3), 53.7 (C-5)
58.6
10.4, 13.7, 28.1, 29.2 [Sn(C4H9)3], 22.2 (C-4); 27.6 (C-3), 54.2 (C-5)
72.1
58.9
22.5 (C-4), 25.9 (C-3), 37.0 [2-(C-2)], 54.2 (C-5), 117.0 [2-(C-4)], 134.6
[2-(C-3)]
15f
74.5
64.8
59.4
23.8 (C-4), 26.0 (C-3), 33.4 [2-(C-2)], 54.3 (C-5), 116.6 [2-(C-4)], 135.7
[2-(C-3)]
14g
76.0
72.4
66.2
68.6
60.4
61.0
22.6 [2-(C-3), 2-(2-CH3)] 26.2 (C-4), 27.9 (C-3), 51.3 (C-5), 72.7 [2-(C-2)]
14i’
15.1, 20.1 [2-(C-4), 2-(3-CH3)], 22.4 (C-4), 27.5 (C-3), 29.8 [2-(C-3)], 52.8
(C-5), 68.6 [2-(C-2)]
14i
74.7
66.4
61.3
18.8, 19.5 [2-(C-4), 2-(3-CH3)], 23.9 (C-4), 28.6 (C-3), 30.8 [2-(C-3)], 54.6
(C-5), 66.4 [2-(C-2)]
rac-16a
72.4/72.6
62.5
62.8
64.8
58.3
57.9
57.9
24.0, 24.6, 26.8 (C-3, C-4, C-5), 52.0 (CO2CH3), 52.2 (C-6), 170.4 (CO2CH3)
51.9 (CO2CH3), 51.0 (C-6)
rac-17ad 73.3
rac-16b
71.0/71.2
16.6 [2-(C-2)], 24.0, 24.2, 25.9 (C-3, C-4, C-5), 52.0 (C-6)
rac-16c
rac-16d
67.7
74.2
62.2
64.3
57.9
58.7
–1.9 [Si(CH3)3], 22.2, 22.7, 24.9 (C-3, C-4, C-5), 49.0 (C-6)
–7.9 [Sn(CH3)3], 23.3, 24.8, 26.7 (C-3, C-4, C-5), 50.0 (C-6)
rac-16h
72.4/72.6
60.7
58.1
23.7, 24.0, 24.8 (C-3, C-4, C-5), 26.9 [C(CH3)3], 43.6 [C(CH3)3], 51.9 (C-6),
211.5 (C=O)
aNMR data of the Cby group and the aromatic rings are omitted. NMR data carrying the symbol * are interchangeable.
bAs part of a multiplet.
cNot recorded.
d Recorded from the mixture of diastereomers.
e Recorded from the mixture with the starting material rac-7.
Conclusions
As we have demonstrated, the carbamates of 2-pyrrolidi-
nyl- and 2-piperidinylmethanols react with alkyllithium
bases with strong selection between the diastereotopic
protons adjacent to the carbamate group. As a result, in the
presence of a chiral ligand, such as (-)-sparteine, efficient
kinetic resolution is achievable, which is coupled with a
highly diastereoselective electrophilic substitution.
All experiments involving organometallic reagents were carried out
under argon in dried glasswares. All solvents were purified by dis-
tillation and dried, if necessary, prior to use. 1H and 13C NMR spec-
tra were recorded on a Bruker WM300 or U600 spectrometer.
Optical rotations were recorded on a Perkin-Elmer polarimeter 241.
Mps were obtained on Gallenkamp melting point apparatus MFB-
595 and are uncorrected. Products were purified by flash column
Reagents and conditions: a) i. MeSO3H/MeOH, reflux; ii.
Ba(OH)2∑8H2O/ MeOH, reflux. b) (S)-(-)-a-Methoxy-a-trifluorome-
thylphenylacetic acid/ DCC/DMAP/CH2Cl2
Scheme 8
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1922
B. Weber et al.
PAPER
chromatography on silica gel (40–63 mm) or aluminium oxide
1H NMR (CDCl3, 300 MHz): d = 1.30–1.65 (m, 4 H, 3-H2, 5-H2),
1.41, 1.56 (2 s, 12 H, Cby-CH3), 1.65–1.82 (m, 2 H, 4-H2), 2.02
(ddd, 1 H, 2J6a,6b = 11.9 Hz, 3J5a,6a, 3J5b,6a = 3.3, 9.5 Hz, 6-Ha), 2.48–
2.62 (m, 1 H, 2-H), 2.76 (ddd, 1 H, 3J5a,6b = 3J5b,6b = 3.9 Hz, 6-Hb),
(activity = 0).
rac-N-Benzylpiperidine-2-methanol (rac-6)10
2
3.27, 4.10 (2 d, 2 H, JBn = 13.4 Hz, NCH2Ph), 3.73 (s, 2 H, Cby-
rac-Piperidine-2-methanol (4.61 g, 40 mmol) was dissolved in tolu-
ene (40 mL) and K2CO3 (5.53 g, 40 mmol) was added. The suspen-
sion was heated under reflux for 30 min and BnBr (4.75 mL, 6.84 g,
42 mmol) was added dropwise. After refluxing for 16 h the inorgan-
ic salts were filtered off and washed with Et2O (30 mL). The sol-
vents were evaporated in vacuo and the residue was purified by
flash chromatography (silica gel, Et2O/pentane 1:1, 3 vol% Et3N) to
afford the pure alcohol rac-6 (6.63 g, 81%); Rf 0.15 (Et2O/pentane,
1:2, silica gel); colorless oil.
CH2), 4.29 [d, 2 H, 2J2-1a,2-1b = 5.0 Hz, 2-(1-H2)], 7.10–7.35 (m, 5 H,
C6H5).
13C NMR (CDCl3, 75 MHz): d = 23.4, 25.3, 29.5 (C-3, C-4, C-5),
24.1/25.3, 25.3/26.6 (4 C, Cby-CH3), 51.7 (C-6), 58.8 (2 C,
NCH2Ph), 59.7/60.5 [NC(CH3)2CH2], 60.5 (C-2), 66.7 [2-(C-1)],
76.1/76.4 (Cby-CH2), 94.9/96.0 [OC(CH3)2N], 126.7, 128.1, 128.7,
139.5 (6 C, C6H5), 152.1/152.8 (NC=O).
Anal. Calcd. for C21H32N2O3 (360.50): C, 69.97; H, 8.95; Found C,
69.57; H, 9.14.
IR (film): n = 3430 cm-1 (OH).
1H NMR (CDCl3, 300 MHz): d = 1.25–1.80 (m, 6 H, 3-H2, 4-H2, 5-
H2), 2.15 (ddd, 1 H, 2J6a,6b = 12.4 Hz, 3J5a,6a, 3J5b,6a = 3.1, 10.3 Hz, 6-
Deprotonation of Carbamates (S)-8 and rac-9 with s-BuLi/Di-
amine and Preparation of Substituted Products; General Pro-
cedures
Method A: Carbamate ( S)-8 or rac-9 (1.00 mmol) and TMEDA
(232 mg, 2.00 mmol) were dissolved in anhyd Et2O (15 mL) under
argon in a dry ice/acetone bath and a 1.3 M solution of s-BuLi in cy-
clohexane/hexane (1.5 mL, 2.00 mmol) was added to the solution
dropwise.
3
Ha), 2.45 (dddd, 1H, J2,2-1a = 3J2,2-1b = 4.3 Hz, 3J2,3a, 3J2,3b = 4.3, 8.1
Hz, 2-H), 2.58 (br s, 1 H, OH), 2.87 (ddd, 1 H, 3J5a,6b = 3J5b,6b = 3.8,
2
5.2 Hz, 6 Hb), 3.32, 4.06 (2 d, 2 H, JBn = 13.4 Hz, NCH2Ph), 3.52
2
[dd, 1 H, J2-1a,2-1b = 11.0 Hz, 2-(1-Ha)], 3.85 [dd, 1 H, 2-(1-Hb)],
7.15–7.35 (m, 5 H, C6H5).
13C NMR (CDCl3, 75 MHz): d = 23.4, 24.1, 27.3 (C-3, C-4, C-5),
50.9 (C-6), 57.7 (2C, NCH2Ph), 60.5 (C-2), 62.3 [2-(C-1)], 126.9,
128.3,128.8, 139.1 (6 C, C6H5).
After stirring for 3 h [(S)-8] or 6 h (rac-9), the electrophile (3.00
mmol) was slowly introduced via a syringe.
Anal. Calcd. for C13H19NO (205.3): C, 76.06; H, 9.33; Found C,
75.87; H, 9.52.
Method B: In Method B, TMEDA was replaced by (-)-sparteine
(469 mg, 2.00 mmol) for the deprotonation of carbamate (S)-8.
Carbamates (S)-8 and rac-9; General Procedure11
Method C: In Method C, no diamine was used as complex ligand in
A solution of the monobenzylated alcohol (S)-5 or rac-6 (15 mmol)
in anhyd THF (12 mL) was added dropwise to a suspension of NaH
(880 mg, 22 mmol, 60% in mineral oil) in THF (12 mL). The mix-
ture was refluxed for 30 min, before 2,2,4,4-tetramethyloxazoli-
dine-3-carbonyl chloride11a (CbyCl, 7, 3.23 g, 17 mmol) in THF
(8 mL) was added. After heating under reflux for 2 h and cooling to
r.t., H2O (15 mL) and Et2O (30 mL) were added carefully to the
mixture. The organic layer was separated and the aqueous layer was
extracted with Et2O (3 × 20 mL) and the combined extracts were
dried (MgSO4). The solvents were evaporated in vacuo and the
crude products were purified by flash chromatography (silica gel,
Et2O/pentane, 1:6 to 1:3) to yield pure carbamate (S)-8 (4.26 g,
82%) or rac-9 (5.02 g, 93%).
the deprotonation step of carbamate ( S)-8 or rac-9.
Carboxylation
After stirring at -78°C for 3 h, a stream of dry CO2 was introduced
into the solution of the deprotonated carbamate (S)-8 via a syringe
for 30 min. After warming to r.t. and hydrolysis with H2O (10 mL),
2 N HCl was added until pH 5. The organic layer was separated and
the aqueous solution was extracted with Et2O (3 × 10 mL). The
combined extracts were dried (MgSO4) and the solvents were evap-
orated in vacuo. The crude product was dissolved in Et2O (10 mL)
and treated with ethereal CH2N2 solution until the color of the solu-
tion remain yellow. After stirring for 1 h, silica gel (50 mg) was
added and the mixture was stirred for 15 min in order to destroy the
excess of CH2N2.
(S)-8
Subsequent flash chromatographic purification (Et2O/pentane, 1:4,
Al2O3) yielded the methyl ester 14a.
Rf 0.37 (Et2O/pentane, 1:1, silica gel); yellow oil; [a]D20 -60.2
(c = 2, CHCl3).
Other Electrophiles
IR (film): n = 1705, 1690 (NC=O), 1095, 1070 cm-1 (COC).
After stirring at -78°C for 3 h [(S)-8] or 6 h (rac-9), the electrophile
was slowly introduced with a syringe. The mixture was allowed to
warm up to r. t. for 12 h and H2O (10 mL) was added. The Et2O lay-
er was separated and the aqueous phase was extracted with Et2O
(3 × 10 mL).
1H NMR (CDCl3, 300 MHz): d = 1.38/1.40, 1.43/1.44, 1.54/1.56,
1.58 (4 s, 12 H, Cby-CH3), 1.65–2.26 (m, 5 H, 3-H2, 4-H2, 5-Ha),
2.70–2.85 (m, 1 H, 2-H), 2.85–2.98 (m, 1 H, 5-Hb), 3.34, 4.10 (2 d,
2H, 2JBn = 13.0 Hz, NCH2Ph), 3.74 (s, 2 H, Cby-CH2), 3.97 [dd, 1
2
3
H, J2-1a,2-1b = 10.8 Hz, J2,2-1a = 1.7 Hz, 2-(1-Ha)], 4.27 [dd, 1 H,
3J2,2-1b = 3.9 Hz, 2-(1-Hb)], 7.18–7.36 (m, 5 H, C6H5).
The combined Et2O extracts were dried (MgSO4) and evaporated in
vacuo. The residue was purified by flash chromatography (Et2O/
pentane, 1:1 to 1:8) to afford the substituted carbamates 14, 16, and
17. For yields and physical data of substituted carbamates 14, 16,
and 17, see Tables 1 and 3.
13C NMR (CDCl3, 75 MHz): d = 22.8, 28.9 (C-3, C-4), 24.2, 25.3,
26.6 (4 C, Cby-CH3); 54.2 (C-5); 59.2 (2 C, NCH2Ph), 59.7/60.5
[NC(CH3)2CH2], 62.5 (C-2), 66.5 [2-(C-1)], 75.1/75.4 (Cby-CH2),
94.8/95.8 [OC(CH3)2N], 126.7, 128.0, 128.6, 139.6 (6 C, C6H5),
152.0/152.7 (NC=O).
Kinetic Resolution of (S)-9 and (R)-9; General Procedure
Carbamate rac-9 (1.00 mmol) and (-)-sparteine (amounts, see Ta-
ble 2) were dissolved in anhyd Et2O (15 mL) under argon and a
1.3 M solution of s-BuLi in cyclohexane/hexane (amounts, see Ta-
ble 2) was added to the solution dropwise at -78°C. Stirring was
continued for 6 h at this temperature and, finally, the electrophile
(3.00 mmol) was slowly introduced via a syringe. Work up was ac-
complished in the same manner as described above.
Anal. Calcd. for C20H30N2O3 (346.5): C, 69.33; H, 8.72; Found C,
69.33; H, 8.77.
rac-9
Rf 0.38 (Et2O/pentane, 1:2, silica gel); pale yellow oil.
IR (film): n = 1690, 1680 (NC=O), 1090, 1060 cm-1 (COC).
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Kinetic Resolution by Means of (–)-Sparteine-Mediated Deprotonation
1923
2
3
3
Decarbamoylation of 14b, ent-16c, and (S)-9; Preparation of
19b, ent-24c, and (S)-6; General Procedure11
2.95 (ddd, 1 H, J6a,6b = 12.5, J5a,6b, J5b,6b = 3.2, 6.8, 6-Hb), 3.57/
3.59, 4.11 (2 d, 2 H, 2JBn = 13.1, NCH2Ph), 3.72 (s, 2 H, Cby-CH2),
3.65–3.80 [m, 1 H, 2-(2-Ha)], 3.87 [dd, 1 H, 2J2a,2b = 11.4, 2-(2-Hb)],
The substituted carbamate 14b (Table 1, Entry 5), ent-16c (Table 2,
Entry 4) or (S)-9 (Table 2, Entry 2) (1.00 mmol) and MeSO3H (324
mL, 480 mg, 5.00 mmol) were dissolved in MeOH (10 mL) and the
solution was refluxed for 5 h. After the addition of Ba(OH)2◊8H2O
(3.15 g, 10 mmol), the mixture was refluxed for further 4 h. The
salts were filtered off and washed with MeOH (30 mL). The solvent
was evaporated in vacuo and the residue was purified by flash chro-
matography to give the pure alcohol 19b, ent-24c or (S)-6.
5.26 [ddd, 1 H, J2,2-1, J2-1,2-2a, 3J2-1,2-2b = 5.5, 5.5, 6.9, 2-(1-H)],
7.15–7.35 (m, 5 H, C6H5).
3
3
13C NMR (CDCl3, 75 MHz): d = 21.2, 22.0, 23.0 (C-3, C-4, C-5),
24.0/24.2, 25.0/25.2, 25.4/25.6 26.6/26.8 (4,C, Cby-CH3), 49.2 (C-
6), 57.9 (2,C, NCH2Ph), 59.8/60.9 [NC(CH3)2CH2], 62.1 (C-2);
65.0 [2-(C-2)], 72.5 [2-(C-1)], 76.1/76.4 (Cby-CH2), 94.9/96.1
[OC(CH3)2N], 127.2, 128.5, 128.8, 138.7 (6 C, C6H5) 151.8/152.5
(NC=O).
[1R,1(1S)]-1-(N-Benzylpyrrolidin-2-yl)ethanol (19b)
135 mg (66%); yellow oil; Rf 0.56 (Et2O/pentane, 1:1, Al2O3);
[a]D20 -85.0 (c = 0.7, CHCl3).
Anal. Calcd for C22H34N2O4 (390.5): C, 67.66; H, 8.78; Found C,
67.46; H, 8.52.
IR (film): n = 3450 cm-1 (OH).
1H NMR (CDCl3, 300 MHz): d = 1.15 [d, J2-1,2-2 = 6.4, 2-(2-H3)],
ent-[2R,2(2R)]-21
Yield: 71 mg (72%); [a]D20 +9.8 (c = 1.0, CH2Cl2; from ent-16a, Ta-
3
1.53–1.93 (m, 3-H2, 4-H2), 2.20–2.29 (m, 5-Ha), 2.45–2.51 (m, 5-
Hb); 2.93–2.99 (m, 2-H), 3.10 (br s, OH), 3.28, 4.04 (2 d,
2JBn = 13.0, N-CH2Ph), 3.95 [dq, 3J2,2-1 = 2.6, 2-(1-H)], 7.187.36 (m,
5 H, C6H5).
ble 2, Entry 2).
20
Yield: 84 mg (88%); [a]D +10.8 (c = 1.3, CH2Cl2; from ent-16a;
Table 2, Entry 3).
13C NMR (CDCl3, 75 MHz): d = 18.5 [2-(C-2)], 23.2, 23.3 (C-3, C-
4), 54.6 (C-5), 58.3 (2 C, NCH2Ph), 64.3 (C-2); 68.8 [2-(C-1)],
127.0, 128.3, 128.7, 139.4 (6 C, C6H5).
MS (CI, isobutane): m/z Calcd for C13H19NO (205.30); Found M+ +
1 = 206.
Mosher Ester 22 and its Epimer from rac-21 or ent-2122a
To a solution of rac-21 or ent-21 (Table 2, Entries 2 and 3) (38 mg,
0.10 mmol) in CH2Cl2 (0.3 mL) and pyridine (0.2 mL) was added
(R) (-)-a-methoxy-a-trifluoromethylphenylacetyl chloride (21 mL,
28 mg, 0.11 mmol). The suspension was stirred for 24 h at r.t. The
salts were filtered off and washed with CH2Cl2 (5 mL). After evap-
oration of the solvents, the residue was purified by flash chromatog-
raphy (Et2O/pentane, 1:5, silica gel) to give 22 and its epimer as a
diastereomeric mixture, which could not be separated by flash chro-
matography.
1-(N-Benzylpiperidin-2-yl)-1-(trimethylsilyl)methanol (ent-24c)
Yield: 136 mg (50%); colorless oil; Rf 0.78 (Et2O/pentane, 4:1, 3%
Et3N, silica gel); [a]D20 + 49.1 (c = 1, CH2Cl2).
IR (film): n = 3430 cm-1 (OH).
1H NMR (CDCl3, 300 MHz): d = 0.09 [s, 9 H, Si(CH3)3], 1.15–1.85
In the 1H NMR spectrum (600 MHz, CDCl3, TMS) the 2-(2-Ha)pro-
tons of 22 (d = 4.43) and of its epimer (d = 4.47) could be detected
separately.
2
3
(m, 6 H, 3-H2, 4-H2, 5-H2), 2.00 (ddd, 1 H, J6a,6b = 11.6, J5a,6a
,
3J5b,6a = 2.9, 11.4, 6-Ha), 2.31 (ddd, 1 H, J2,2-1 = 3.1, J2,3a
,
3
3
3J2,3b = 3.6, 10.6, 2-H), 2.81 (br s, 1 H, OH), 2.89 (ddd, 1 H,
3J5a,6b = 3J5b,6b = 3.3, 6 Hb), 3.04, 4.23 (2 d, 2 H, JBn = 13.4,
2
From rac-[2R*,2(2R*)]-21; yield: 51 mg (84%); dr = 50:50.
NCH2Ph), 3.85 [d, 1 H, 2-(1-H)], 7.05–7.25 (m, 5 H, C6H5).
From ent-[2R,2(2R)]-21 (Table 2, Entry 2); yield: 49 mg (82%); dr
13C NMR (CDCl3, 75 MHz): d = -1.9 [Si(CH3)3], 24.4, 25.5, 27.6
(C-3, C-4, C-5), 53.1 (C-6), 57.6 (2C, NCH2Ph), 63.8, 64.1[C-2, 2-
(C-1)], 126.9, 128.3, 128.9, 139.1 (6 C, C6H5).
= 93:7 or 86% ee.
From ent-[2R,2(2R)]-21 (Table 2, Entry 3); yield: 51 mg (84%); dr
= 97:3 or 94% ee.
Anal. Calcd for C16H27NOSi (277.5): C, 69.26; H, 9.81; Found C,
68.89; H, 10.05.
Mosher Ester 23 and its Epimer from rac-6 or (S)-622b
To a solution of rac-6 or (S)-6 (Table 2, Entry 2) (20 mg, 0.10
mmol), dicyclohexyl carbodiimide (DCC, 25 mg, 0.12 mmol), and
(S)-(-)-a-methoxy-a-trifluoromethylphenylacetic acid (23 mg,
0.10 mmol) in CH2Cl2 (1.0 mL) was added 4-(dimethylamino)pyri-
dine (0.6 mg, 5 mmol). The suspension was stirred for 24 h at r.t. The
salts were filtered off and washed with CH2Cl2 (5 mL). After evap-
oration of the solvents the residue was purified by flash chromato-
graphy (Et2O/pentane, 1:5, silica gel) to give 23 and its epimer as a
diastereomeric mixture, which could not be separated by flash chro-
matography.
(S)-6
Yield: 207 mg (82%); [a]D20 -35.0 (c = 1, CH2Cl2).
Reduction of rac-16a and ent-16a with LiEt3BH; 2-(N-Benzylpi-
peridin-2-yl)-2-(2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbo-
nyloxy)ethanol21
LiEt3BH (1.00 mL, 1 M in THF) was added to the substituted car-
bamate rac-16a (Table 1, Entry 13) or ent-16a (Table 2, Entries 2
and 3) (0.25 mmol) in anhyd THF (4 mL) at 0°C and the stirring was
continued for 90 min. After hydrolysis with H2O (5 mL) at this tem-
perature Et2O (10 mL) was added and the two layers were separated.
The aqueous phase was extracted with Et2O (3 × 10 mL) and the
combined organic phases were dried (MgSO4). The solvent was
evaporated in vacuo and the crude product was purified by flash
chromatography (Et2O/pentane, 1:4, 1% Et3N, silica gel) to yield
the pure alcohol as a pale yellow oil.
In the 1H NMR spectrum (600 MHz, D8-toluene) the 2-(1-Ha) pro-
tons of 23 (d = 3.37) and of its epimer (d = 3.40) could be detected
separately.
From rac-6; yield: 25 mg (60%); dr = 50:50.
From (S)-6 (Table 2, Entry 2); yield: 29 mg (70%); dr = 90:10 or
80% ee.
rac-[2R*,2(2R*)]-21
Debenzylation of 19b; Preparation of [1R,1(1S)]-1-(Pyrrolidin-
2-yl)ethanol (20b)13
A suspension of PdCl2 (163 mg, 0.90 mmol, 40 mol%) in MeOH
(20 mL) was reduced with H2 for 30 min at r.t. The solvent was de-
canted and the residue was washed with MeOH (2 × 5 mL). The
freshly prepared Pd was suspended in MeOH/HCOOH (10 mL,
Yield: 83 mg (83%); colorless oil; Rf 0.11 (Et2O/pentane, 1:2, silica
gel).
IR (film): n = 3460 (OH), 1660 cm-1 (NC=O).
1H NMR (CDCl3, 300 MHz): d = 1.25–1.92 (m, 18 H, 3-H2, 4-H2,
5-H2, Cby-CH3), 2.28–2.42 (m, 1 H, 6-Ha), 2.74–2.88 (m, 1 H, 2-H),
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York

1924
B. Weber et al.
PAPER
95:5) and a solution of 19b (471 mg, 2.30 mmol) in MeOH/HCO2H
(5 mL, 95:5) was added dropwise. After stirring for 12 h at r.t., the
solid materials were filtered off and washed with MeOH (2 × 5
mL). The solvents were removed in vacuo. Purification of the resi-
due by flash chromatography (EtOAc/pentane, 2:1, silica gel) af-
forded the amino alcohol 20b (180 mg, 68%) as air-sensitive
crystals; mp 86°C (Et2O/pentane); [a]D20 -36.4 (c = 1, MeOH).
(No. 19), l = 1.54178 Å, T = 293 K, w/2q scans, 4792
reflections collected ( h,+k,+l), [(sinq)/l] = 0.61 Å-1, 4444
independent and 4194 observed reflections [I ≥ 2 s(I)], 270
refined parameters, R = 0.047, wR2 = 0.120, max. residual
electron density 0.28 (–0.21) e Å-3, Flack parameter 0.1(2),
hydrogens calculated and refined as riding atoms.
(15) Lambert, C.; Schleyer, P. v. R., Houben Weyl, Thieme:
Stuttgart 1993, 4th Ed., E 19d, 1.
(16) (a) Sato, D.; Kawasaki, H.; Shimada, I.; Arata, Y.; Okamura,
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Acknowledgement
Generous support by the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and the Bayer AG is gratefully
acknowledged.
(c) Edwards, A. J.; Hockey, S.; Mair, F. S.; Raithby, P. R.;
Snaith, R.; Simpkins, N. S. J. Org. Chem. 1993, 58, 6942; and
references cited therein.
(d) Armstrong, D. R.; Davidson, M. G.; Davies, R. P.;
Mitchell, H. J.; Oakley, R. M.; Raithby, P. R.; Snaith, R.;
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therein.
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deprotonation is observed at all [1,3a].
(18) Helmke, H.; Hoppe, D. Synlett 1995, 978.
(19) X-ray crystal structure analysis of ent-16c: formula
C24H40N2O3SI, M = 432.67, colourless crystal, 0.6 x 0.1 x 0.1
mm, a = 7.909(1), b = 9.918(1), c = 31.840(2) Å,
V = 2497.6(4) Å3, rcalc = 1.151 g cm-3, F(000) = 944 e,
m = 10.27 cm-1, empirical absorption correction via j scan
data (0.981 £ C £ 0.999), Z = 4, orthorhombic, space group
P212121 (No. 19), l = 1.54178 Å, T = 223 K, w/2q scans, 5175
reflections collected ( h,+k,+l), [(sinq)/l] = 0.62 Å-1, 4776
independent and 3926 observed reflections [I ≥ 2 s(I)], 278
refined parameters, R = 0.044, wR2 = 0.116, max. residual
electron density 0.19 (–0.26) e Å-3, Flack parameter 0.00(3),
hydrogens calculated and refined as riding atoms. Data sets
were collected with Enraf Nonius CAD4 diffractometers.
Programs used: data reduction MolEN, structure solution
SHELXS-97, structure refinement SHELXL-97, graphics
SCHAKAL-92.Crystallographic data (excluding structure
factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-124693 (14g) and
124694 (ent-16c). Copies of the data can be obtained free of
charge on application to The Director, CCDC, 12 Union Road,
CambridgeCB2 1EZ, UK [fax +44(1223)336033, e-mail:
deposit@ccdc.cam.ac.uk].
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102, 1457; Angew. Chem., Int. Ed. Engl. 1990, 29, 1422.
(b) Hintze, F.; Hoppe, D. Synthesis 1992, 1216.
(12) van Bebber, J.; Ahrens, H.; Fröhlich, R.; Hoppe, D. Chem.
Eur. J. 1999, 5, 1905.
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(23) Only the major diastereomer is shown.
(14) X-ray crystal structure analysis of 14g: formula C23H36N2O4,
M = 404.54, colourless crystal, 0.4 x 0.4 x 0.3 mm,
a = 10.041(5), b = 11.594(6), c = 20.064(8) Å,
V = 2335.8(19) Å3, rcalc = 1.150 g cm-3, F(000) = 880 e,
m = 6.26 cm-1, empirical absorption correction via j scan data
(0.928 £ T £ 0.958), Z = 4, orthorhombic, space group P212121
Article Identifier:
1437-210X,E;1999,0,11,1915,1924,ftx,en;P03599SS.pdf
Synthesis 1999, No. 11, 1915–1924 ISSN 0039-7881 © Thieme Stuttgart · New York