Comprehensive experimental and theoretical studies of configurationally labile epimeric diamine complexes of α-lithiated benzyl carbamates

Article abstract of DOI:10.1055/s-2008-1067242

Different primary benzyl-type carbamates were deprotonated by sec-butyllithium in the presence of a tert-leucinol-derived bis(oxazoline) ligand. The resulting configurationally labile epimeric complexes equilibrated and one diastereomer was strongly favor

Full text of DOI:10.1055/s-2008-1067242

PAPER
2905
Comprehensive Experimental and Theoretical Studies of Configurationally
Labile Epimeric Diamine Complexes of a-Lithiated Benzyl Carbamates
Studies of
D
iamine
e
Complexe
i
s
of
a
-
k
LithiatedBen
o
zyl Carbamates Lange, Robert Huenerbein, Birgit Wibbeling, Roland Fröhlich, Stefan Grimme,* Dieter Hoppe*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8336531; E-mail: dhoppe@uni-muenster.de; E-mail: grimmes@uni-muenster.de
Received 16 April 2008; revised 29 May 2008
O
TMEDA•Li
O
Abstract: Different primary benzyl-type carbamates were deproto-
nated by sec-butyllithium in the presence of a tert-leucinol-derived
bis(oxazoline) ligand. The resulting configurationally labile
epimeric complexes equilibrated and one diastereomer was strongly
favored in the equilibria. After dynamic thermodynamic resolution,
the complexes could be trapped with different classes of electro-
philes to yield highly enantioenriched secondary benzyl carb-
amates. The stereochemical course of the substitution reactions was
elucidated. High-level quantum chemical investigations were per-
formed and allowed a prediction of both the favored complex and
the enantiomeric excess that could be expected within the reactions.
Li
TMEDA•Li
O
tBu
N
Li•12
∗
N
OtBu
O
Ar
Ar
(R)-1
2
(R)-3
TMEDA•Li
O
TMEDA•Li
O
TMEDA•Li
O
S
N
O
NiPr2
O
O
NiPr2
(S)-5
(S)-6
(S)-4
Key words: asymmetric synthesis, carbanions, lithium, bis(oxazo-
line) ligands, quantum chemical calculations
R1 R1
O
O
N
N
N
N
N
N
One of the most important and most challenging features
within the field of asymmetric synthesis via chiral carban-
ions is the configurational stability of the metalated car-
banionic species.1,2 Several research groups have
investigated different classes of such metalated carban-
ions concerning their configurational stability and the
possibility to use them as valuable precursors for the syn-
thesis of highly enantioenriched compounds.3,4
R2
bis(oxazoline) 9
R2
(−)-sparteine (7)
(−)-α-isosparteine (8)
9a R1 = Me, R2 = iPr
9b R1 = Me, R2 = tBu
9c R1 = Et, R2 = iPr
9d R1 = Et, R2 = tBu
N
N
TMEDA
Figure 1 Configurationally stable diamine complexes of a-hetero-
substituted, a-lithiated mesomerically stabilized carbanions and di-
amine ligands used
Configurationally stability is a rare feature, especially if
mesomeric stabilization of the carbanion is possible.
Nevertheless, if the carbanionic center is a tertiary one,
synthetically useful configurational stability, despite pos-
sible mesomeric stabilization of the carbanion, can be
found [Figure 1, (R)-1,5 2,5 (R)-3,6 (S)-4,3b (S)-5,3c,d,7 (S)-
68]. The complexing abilities of the moieties connected to
the carbanionic center, usually by heteroatoms, are impor-
tant and may even influence the enantiodetermining step
of an asymmetric substitution reaction in the very end.9,10
Only a few configurationally stable benzyllithium deriva-
tives are known [Figure 1, (R)-1,5 2,5 (R)-3,6 (S)-5,3c,d,7
(S)-68]. More often these compounds exhibit distinct con-
figurational lability. An increasing planarization of the
carbanionic center as a result of the stabilization of the an-
ion by resonance11–14 is usually accompanied by a higher
tendency for the formation of solvent-separated ion
pairs.15 Both factors probably facilitate the migration of
the lithium cation from one enantiotopic face to the other
by complex intra- and intermolecular processes, thus lead-
ing to epimerization. Short-lived benzyl anions have been
trapped in situ with high enantiomeric excess by deproto-
nation/reprotonation of optically active phenyl alkanes14b
as well as in the Haller–Bauer cleavage of tertiary benzyl
phenyl ketones.14a,16 Chiral a-oxybenzyl anions are
trapped as short-lived intermediates in the Brook17 and the
reverse Brook rearrangements.18,19 Nevertheless, highly
enantioenriched substitution products were obtained us-
ing configurationally labile benzyllithium compounds
(Figure 2): Nakai and co-workers presented the asymmet-
ric substitution of bis(oxazoline) containing lithium com-
plexes like 13/14.20–22 Toru and co-workers successfully
worked on different aryl benzyl sulfides 16–18.9
Deprotonating primary benzyl carbamate 1923 yields a-
lithiated benzyl carbamate 15, which seemed to be config-
urationally stable within the timescale set by the Hoff-
mann test.24 We recently reported our initial studies on the
bis(oxazoline) complexes 15·9d (Table 1, entry 1) and
proved that the epimeric complexes equilibrate and that
the RC-configured complex (RC)-15·9d is energetically
strongly favored within the equilibrium.25 In addition we
showed that the equilibrium position and the enantiomeric
excess can be predicted by calculating DDE and DDH
(0 K),26 using high level quantum chemical methods
SYNTHESIS 2008, No. 18, pp 2905–2918
x
x.
x
x
.
2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1067242; Art ID: T06008SS
© Georg Thieme Verlag Stuttgart · New York

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H. Lange et al.
PAPER
(SCS-MP2/TZVPP//B97-D/TZVP).27 For other recent at-
tempts to compute stereoselectivity, see, for example, ref.
28. We now wish to demonstrate the general applicability
of the experimental and computational methods devel-
oped.25,29
9d•Li
O
7•Li
O
diamine•Li
O
∗
∗
∗
NiPr2
OtBu
S
NiPr2
S
N
12•9d
7•Li
10
11•diamine
Substitution reactions employing parent carbamate 19:
First, we were interested in further substitution products
employing the parent system 19 and its diamine com-
plexes 15·9d. Employing different classes of electro-
philes, we were especially interested in the stereochemical
pathways of the substitution reactions, since all electro-
philes employed so far reacted with inversion of configu-
ration.25 Employing standard conditions as outlined in
Table 1, we synthesized various substitution products.
The results are summarized in Table 1.
O
9c•Li
Li•9c
∗
∗
∗
O
O
NiPr2
O
n
15•7
13
14a n = 1
14b n = 2
9a/b•Li
N
9a•Li
N
9a•Li
∗
∗
∗
S
S
S
Like methylation,25 allylation worked fine, took place
with inversion of configuration, and afforded a-allylated
compound (–)-(S)-20c in 75% yield (Table 1, entry 3).
The enantiomeric excess decreased to 62% ee most prob-
ably due to a radical pathway. The S-configuration was
proven after decarbamoylation to (S)-34 (Table 3).30
18
17
16
Figure 2 Some configurationally labile diamine complexes of
a-hetero-substituted benzyllithium derivatives
smoothly so that ester (–)-(R)-20d was isolated in high
yield (95%) and with high enantiomeric excess of 91%.
The absolute configuration of (–)-(R)-20d was deter-
We then used different acid chlorides as electrophiles
(Table 1, entries 4–6). Methyl chloroformate reacted
Table 1 Substitution Reactions with Benzyl Carbamate 19 in the Presence of Chiral Bis(oxazoline) 9da
O
El
O
9d•Li
O
∗
NiPr2
O
NiPr2
O
NiPr2
a
b
O
19
(RC)-15•9d
20a–j
Entry ElX
Diamine Product Yield (%)
eeb (%)
98c
30c
62
[a]D20 (c, solvent)
–19.7 (1.1, CHCl3)
+8.5 (1.0, CHCl3)c
–2.3 (0.12, CHCl3)
–93.3 (1.00, MeOH)
–155.1 (0.97, CHCl3)
–134.6 (0.40, CHCl3)
–8.4 (0.98, CHCl3)
+196.2 (0.50, CHCl3)
–
Config
Inversion /retention
inversion
1
2
Bu3SnCl
Me3SiCl
9d
8d
20a
20b
20c
20d
20e
20f
20g
20h
20i
98
S
67
Rd
S
inversiond
inversion
3
H2C=CHCH2Br
MeOC(O)Cl
t-BuC(O)Cl
4-BrC6H4C(O)Cl
Me2CO
9d
9d
9d
9d
9d
9d
9d
9d
75
4
95
91
R
R
R
S
inversion
5
87
63
inversion
6
24
96
inversion
7
28
54
retention
8
Ph2CO
81
94
R
Sf
Rf
inversion
9
t-BuCHO
70 (dr 1.1:1)e
80 (dr 1.3:1)g
32f
97f
retention
10
4-BrC6H4CHO
20j
–
inversion
a Reagents and conditions: (a) bis(oxazoline) 9d, s-BuLi, toluene, –78 °C, 2.5 h; electrophile (ElX), –78 °C, 2 h. Products: 20a: El = SnBu3;
20b: El = SiMe3; 20c: El = CH2CH=CH2; 20d: El = CO2Me; 20e: El = C(O)t-Bu; 20f: El = 4-BrC6H4CO; 20g: El = C(OH)Me2; 20h:
El = C(OH)Ph2; 20i: El = CH(OH)t-Bu; 20j: El = 4-BrC6H4CH(OH).
b Determined by HPLC on chiral phase; see the experimental section for details.
c Determined by GC on chiral phase; see the experimental section for details.
d Here the SC-configured complex is favored in the equilibrium of epimeric complexes. Invertive silylation affords the R-configured silane 20b
in this case.
e Yield of mixture of diastereomers. Diastereomeric ratio determined by 1H NMR; (1S,2S)-isomer favored.
f Determined after the diastereomeric mixture of alcohols was oxidized by PDC into (S)-20e and (R)-20f, respectively; see the experimental
section for details.
g Yield of mixture of diastereomers. Diastereomeric ratio determined by 1H NMR; (1R,2R)-isomer favored.
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

PAPER
Studies of Diamine Complexes of a-Lithiated Benzyl Carbamates
2907
Trapping the lithiated species with pivaldehyde, we found
reaction with retention of configuration; the two possible
diastereomeric alcohols 20i were obtained in the form of
an inseparable ~1:1 mixture (Table 1, entry 9). Oxidation
of these alcohols by means of pyridinium dichromate35
yielded ketone 20e with the S-configured enantiomer en-
riched. Therefore, the favored configuration of the ben-
zylic carbon in the starting alcohol must have been S-
configured, corresponding to predominant reaction with
retention of configuration (Scheme 1). The enantioenrich-
ment of only 32% ee determined at the stage of the ketone
(S)-20e revealed that the aliphatic aldehyde did not react
with particular stereoselectivity with equilibrated lithium
complexes 15·9d. When 4-bromobenzaldehyde was used
as the electrophile, a 1.3:1-mixture of the diastereomeric
alcohols 20j was obtained (Table 1, entry 10). Corey’s py-
ridinium dichromate oxidation35 delivered the well known
ketone (–)-(R)-20f with an enantiomeric excess of 97%.
These two facts indicate that the reaction of the aromatic
aldehyde took place with high stereospecificity and with
inversion of configuration (Scheme 1).
Figure 3 X-ray crystal structure of (–)-(R)-20f32
mined by comparing its optical rotation with that reported
in the literature ([a]D20 –93.3 (c 1.00, MeOH), ref.25
[a]D20 –107.6 (c 0.99, MeOH), 95% ee). Therefore, reac-
tion with inversion of configuration must be concluded.
The same stereochemical course is assumed when piv-
aloyl chloride is reacted with the equilibrated lithiated
complexes 15·9d (Table 1, entry 5);31 ketone (–)-(R)-20e
was obtained in 87% yield. The enantiomeric ratio of
81.5:17.5 is comparably low, indicating a nonhomoge-
neously stereochemical course for this particular electro-
phile. However, aromatic acid chlorides react with
defined stereochemistry as shown by employing 4-bro-
mobenzoyl chloride as trapping reagent (Table 1, entry 6).
Albeit in moderate yield (24%), the desired (–)-(R)-20f is
formed with 96% ee. Since we obtained single crystals of
(–)-(R)-20f suitable for X-ray crystal structure analysis
with anomalous dispersion, we determined the stereogen-
ic carbon atom in ketone 20f to be R-configured
(Figure 3). Again, the acid chloride reacted with inversion
of configuration.31
Discussion of the stereochemistry observed: The observed
stereochemical course of the different substitution reac-
tions and the stereodivergence observed may be under-
stood by having a closer look at the reacting benzylic
center, the reacting electrophile, and the leaving group.
The benzylic carbanionic center of the different complex-
es is not perfectly tetrahedral, but slightly flattened; this
can be concluded from our quantum chemical investiga-
tions (vide infra, ref. 25). For example, the sum of angles
Li–Cbenzylic–O, Li–Cbenzylic–Cipso, and O–Cbenzylic–Cipso in
complex 15·9d amounts to 314.8° (the ideal values for sp3
hybridization are 328.4°, for sp2 hybridization 300.0°).36
This causes enhanced electron density at the rear face and
enables the electrophile to attack from the rear face, there-
by avoiding hindrance by the lithium cation. This fact cor-
responds to an antarafacial reaction, i.e. a reaction with
inversion of configuration. This reaction pathway should
be preferred by every electrophile exhibiting an energeti-
cally low LUMO in addition to lacking a good complex-
ing group for the lithium cation; these features are found,
for example, in silyl and stannyl chlorides and in acid
chlorides. Both methyl iodide and allyl bromide also fit
this interpretation as invertive reactions are found.3c,d,7,25
According to our investigations, aromatic aldehydes and
ketones as well as carbon dioxide belong to this group.
However, aliphatic aldehydes and ketones are known to
posses an energetically higher LUMO and to have better
complexing abilities, thereby enhancing the complexation
of the lithium cation by the carbonyl oxygen atom, and,
thus, they prefer the suprafacial reaction pathway.3c,d,7a
Nevertheless, the fact that the enantiomeric ratios of the
corresponding substitution products are comparably low
indicates that these electrophiles still react antarafacially
to a significant degree. Although regarded as being un-
likely, it cannot be excluded that kinetic resolution takes
place in the substitution step [both epimeric complexes
(RC)-15·9d and (SC)-15·9d remain in solution], in particu-
When employing ketones as carbonyl electrophiles, the
stereochemical course of the substitution reactions highly
depends on the nature of the ketone (Table 1, entries 7, 8).
In contrast to the electrophiles used so far, acetone, as rep-
resentative for aliphatic ketones, reacted predominantly
with retention of configuration (28% yield, 54% ee,
Table 1, entry 7). The S configuration of (–)-20g was
proven by reacting known ester (+)-(S)-20d33 with excess
methylmagnesium chloride as outlined in Scheme 1. Aro-
matic ketones react highly stereospecifically with inver-
sion of configuration as trapping of the equilibrated
lithiated complexes 15·9d with benzophenone shows
(Table 1, entry 8). The desired alcohol (+)-(R)-20h was
obtained in good yield (81%) with a very good enantio-
meric ratio of 97:3 in favor of the R-configured enantio-
mer. Determination of the absolute configuration was
achieved once more by decarbamoylation of the product,
which led to the corresponding known diol (+)-(R)-21
(Table 3).34
The same divergence in stereochemistry was found when
different aldehydes were used (Table 1, entries 9, 10).
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2908
H. Lange et al.
PAPER
tBu
O
tBu
OH
tBu
OH
OH
PDC
OCb
OCb
OCb
OCb
+
tBu
O
(1S,2R)-20i
(1S,2S)-20i
(S)-20e
(S)-20g
Me2CO
retention
O
OCb
tBu Cl
MeMgCl
O
tBu
H
retention
(R)-20e
(S)-20d
inversion
Ph
Ph
OH
O
O
O
9d•Li
O
MeO Cl
NiPr2
Ph2CO
O
OCb
OCb
inversion
inversion
(RC)-15•9d
(R)-20d
(R)-20h
O
O
Cl
inversion
CO2
inversion
H
Br
CH2N2
inversion
Br
p-BrC6H4
O
p-BrC6H4
OH
p-BrC6H4
OH
HO
O
PDC
OCb
OCb
OCb
OCb
+
(1R,2S)-20j
(R)-20f
(1R,2R)-20j
(R)-22
Scheme 1 Addition of aldehydes, ketones, and acid chlorides and stereochemical correlations; for reagents and conditions, see the experi-
mental section. For the synthesis of acid (R)-22 and its subsequent transformation into ester (R)-20d and for information on the stereochemical
pathway of the substitution reaction, see ref. 25.
R4
R4
O
lar if it is a slow reaction and the minor diastereomer is re-
acting faster.
NiPr2
a
OH
O
Further extension of the methodology: We then tested fur-
ther benzylic substrates. We were especially interested in
sterically more demanding and electronically differing
benzyl carbamates like 23,25 24, and 25.23a All these were
synthesized in greater than 90% yield from the corres-
ponding benzyl alcohols using sodium hydride as the base
R3
R1
R3
R1
R2
R2
23
R3 = H
R
R
R
4 = H
R1–R2
R1–R2
=
=
93%
98%, >98% ee
4 = Me
3 = H
(+)-(S)-26a
4 = H
4 = H
1 = Et
1 = H
R
R
3 = H
3 = OMe
24
25
R
R
2 = H
2 = H
R
R
R
R
98%
98%
and
N,N-diisopropylcarbamoyl
chloride
(CbCl)
(Scheme 2). Relying on the results obtained for the silyla-
tion and stannylation of 1-naphthylmethyl carbamate 2325
for which we have already determined the RC-configured
complex to be energetically favored within an equilibrium
of epimers, we tried methylation [(+)-(S)-26a], allylation
[(+)-(S)-26b], and carboxylation [(–)-(R)-26c]. We ob-
tained the desired substitution products in good yields and
high enantiomeric excesses (Table 2, entries 1–3). The ab-
solute configuration of the methylated product (+)-(S)-
26a (77%, 93% ee) was determined by comparing its op-
tical rotation {[a]D20 +34.4 (c 1.05, CHCl3), 93% ee} with
the value obtained from a sample of 26a, which was pre-
pared by carbamoylating a commercially available sam-
ple of the corresponding enantioenriched tertiary alcohol
{[a]D20 +34.9 (c 1.0, CHCl3), 98% ee} (Scheme 2). The S
configuration of allylation product (+)-26b (80%,
78% ee) was elucidated after decarbamoylation and com-
parison of the optical rotation of the corresponding tertia-
ry alcohol (–)-35 with literature values (Table 3, entry 3).30
Carboxylation of 23 to give (R)-26c is also assumed to pro-
ceed with inversion of configuration (65%, 90% ee).25
Scheme 2 Synthesis of the primary benzyl-type carbamates 23–25,
26a. Reagents and conditions: (a) NaH, CbCl, THF, r.t., 2 d.
2-Ethylbenzyl carbamate (24) was substituted via the
same mechanism (Table 2, entries 4–7). Stereochemical
aspects were clarified by a silylation experiment (Table 2,
entry 5; Scheme 3). Liquid silane (–)-(S)-27b was formed
in 97% yield with an enantiomeric excess of >98% ee. Re-
moval of the carbamoyl group to give (–)-28 and forming
new monocarbamate (–)-29 as a single diastereomer (dr
1
>98%, determined by H NMR of the crude product) by
using enantiomerically pure (S)-1-phenylethyl isocyanate
yielded single crystals of 29 suitable for X-ray crystal
structure analysis under anomalous dispersion (Scheme 3,
Figure 4) from which we determined the absolute config-
uration to be S,S. Therefore silylated benzyl carbamate
(–)-27b must also be S-configured, indicating an energet-
ically favored RC-configured complex (RC)-32·9d within
the equilibrium, since silylation is expected to occur with
inversion of configuration. The same stereochemical
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

PAPER
Studies of Diamine Complexes of a-Lithiated Benzyl Carbamates
2909
Me3Si
Me3Si
O
Me3Si
a
b
OCb
O
N
H
OH
(−)-(S,S)-29
41%, dr >98:2
(−)-(S)-27a
> 98% ee
(−)-(S)-28
86%, 98% ee
Scheme 3 Synthesis of monocarbamate (–)-(S,S)-29. Reagents and
conditions: (a) DIBAL-H, THF, reflux, 2 d (TLC control); (b) (S)-1-
phenylethyl isocyanate, cat. DMAP, DMF, r.t., 1 d.
course was assumed for the stannylation [(–)-(S)-27a],
methylation [(–)-(S)-27c], and carboxylation [(–)-(R)-
27d] in analogy to the results obtained so far. The enanti-
omeric excesses obtained were above 90% ee with the ex-
ception of carboxylation (70% ee). We do not want to
exclude downstream racemization of a higher enantio-
merically enriched product at the moment.
Figure 4 X-ray crystal structure of (–)-(S,S)-2937
tioenriched up to 78%. As there was no sterical hindrance
compared to the parent system 19, the low enantiomeric
excesses must be explained by complex electronic effects
induced by the 4-methoxy group. This assumption is un-
derlined by the results obtained during the theoretical
treatment of the complex 33·9d (cf. Table 4), in which we
found a significantly lower energy difference than for the
parent system 15·9d.
As a last substrate, we investigated 4-methoxy-substituted
benzyl carbamate 25 (Table 2, entries 8–10). Using
bis(oxazoline) 9d to bring in chiral information, silylation
and stannylation yielded the desired substitution products
in 80% and 64% yield, respectively (Table 2, entries 8,
10). Whereas stannane (–)-(S)-30a exhibited a satisfying
enantiomeric excess of 92%, silane (–)-(S)-30b was enan-
Cleavage of substituted benzyl carbamates: Removal of
the diisopropylcarbamoyl protecting group was achieved
by refluxing the benzyl carbamates in the presence of a
Table 2 Substitution Reactions with Benzyl Carbamates 23–25 in the Presence of Chiral Bis(oxazoline) 9da
El
9d•Li
O
O
NiPr2
23, 31, 26 R1 , R2
=
R
3 = H
3 = H
a
b
OCb
OCb
R3
R1
R3
R1
R3
R1
R2 = H
R2 = H
R
1 = Et
R
R2
R2
R2
24, 32, 27
25, 33, 30 R1 = H
R3 = OMe
23, 24, 25
(RC)-31, 32, 33•9d
26a–c, 27a–d, 30a,b
Entry Substrate Diamine
ElX
MeI
Product Yield (%) eeb (%) [a]D20 (c, solvent)
Config Inversion /retention
1
23
23
23
24
24
24
24
25
25
25
9d
9d
9d
9d
9d
9d
9d
9d
7d
26a
77
80
65
92
97
36
70
64
96
80
93
78
90
92
>98
92
78
92
40
78
+34.4 (1.04, CHCl3)
+21.5 (1.08, CHCl3)
–142.2 (0.61, CHCl3)
–46.1 (1.01, CHCl3)
–38.9 (0.96, CHCl3)
–2.3 (1.04, CHCl3)
–101.0 (0.96, CHCl3)
–17.8 (1.03, CHCl3)
+14.2 (1.00, CHCl3)d
–26.9 (1.02, CHCl3)
S
inversion
inversion
inversion
inversion
inversion
inversion
inversion
inversion
inversion
inversion
2
H2C=CHCH2Br 26b
S
3c
4
CO2
26c
27a
27b
27c
27d
30a
30b
30b
R
S
Bu3SnCl
Me3SiCl
MeI
5
S
6
S
7c
8
CO2
R
S
Bu3SnCl
Me3SiCl
Me3SiCl
9
Rd
S
10
9d
a Reagents and conditions: (a) bis(oxazoline) 9d, s-BuLi, toluene, –78 °C, 2.5 h; electrophile (ElX), –78 °C, 2 h. Products: 26a/27c: El = Me;
26b: El = CH2CH=CH2; 26c/27d: El = CO2Me; 27a/30a: El = SnBu3; 27b/30b: El = SiMe3.
b Determined by HPLC on chiral phase; see the experimental section for details.
c The initially formed crude acid was converted into the methyl ester with diazomethane before yield and enantiomeric excess were determined.
d Here the SC-configured complex is favored in the equilibrium of epimeric complexes. Invertive silylation affords the R-configured silane 20b
in this case.
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2910
H. Lange et al.
PAPER
Table 3 Deprotection of Selected Benzyl Carbamatesa
El
El
a
OCb
OH
R3
R1
R3
R1
R2
20c
20h
26b
27b
R2
R2 = H
R
34
21
R3 = H El = CH2CH=CH2
R
1 = H
R1 = H
2 = H R3 = H El = Ph2C(OH)
R
3 = H El = CH2CH=CH2
3 = H El = SiMe3
R1–R2
=
35
28
R
1 = Et
R
R2 = H
20
Entry
Substrate (ee)
(S)-20c (62%)
(R)-20h (94%)
(S)-26b (78%)
(S)-27b (>98%)
Yield (%) eeb or op
[a]D
Product
(S)-3430
(R)-2134
(S)-3530
(S)-28
1
2
3
4
75
69
81
86
60% ee
>84% op
74% op
98% ee
–32.9 (1.08, benzene)
+179.7 (1.01, EtOH)
–72.8 (1.04, benzene)
–95.9 (0.64, CHCl3)
a Reagents and conditions: DIBAL-H, THF, reflux, 12 h.
b Determined by HPLC on chiral phase; see the experimental section.
Table 4 Experimental and Calculated Results for Different Diamine-Containing Lithium Complexes
Complex
Experimental
Config
SCS-MP2/TZVPP//B97-D/TZVP
era
DDGa
Config
erb
DDEc
(kcal mol–1)
(kcal mol–1)
–1.15
1.21
15·8
SC
RC
RC
SC
RC
SC
RC
RC
35:65
98:2
–0.26
1.51
SC
RC
RC
SC
RC
SC
RC
RC
5:95
15·9d
32·9d
33·7
96:4
99:1
1.78
>>99:1
15:87
63:37
40:60
>>99:1
>>99:1
2.56
30:70
93:7
–0.32
0.97
–0.72
0.20
33·9d
11·7
42:58
98:2
–0.13
1.51
–0.15
2.92
11·9d
12·9d
99:1
1.78
3.28
a Experimentally derived.
b Predicted quantum chemically.
c DE(SC) – DE(RC).
tenfold excess of diisobutylaluminum hydride (DIBAL- vent effects are also negligible as we have already shown
H) in tetrahydrofuran (Table 3).38 The stereogenic center (see ref. 25 for a detailed description of the theoretical
is usually not touched under these conditions.
procedure). For all the calculated complexes the most sta-
ble epimer was found correctly by the theoretical treat-
ment in comparison to experimental findings. Concerning
quantitative aspects we can state that again we can esti-
mate the amount of enantioenrichment that can be expect-
ed when using a special substrate–ligand system, provided
that the electrophile reacts stereospecifically with the
complexes. Experimentally detectable small changes
within the position of the equilibrium that emanate most
probably from electronic effects brought in by the choice
of substrate are reproduced by the calculations (Table 4,
complex 33·9d). The ratio of the analogous (–)-sparteine
Quantum chemical calculations: In addition, we again
were able to determine the energy differences in the equi-
libriums of the different epimeric complexes quantum
chemically as outlined in Table 4.27,39,40 Within the dy-
namic thermodynamic resolution taking place, DDG can
be determined experimentally from the enantiomeric ra-
tios of the trapping products 26, 27, and 30.26 The values
are comparable to the quantum chemically derived DDE
values as temperature and entropy effects are negligibly
small due to structural similarities of the complexes.25,26
Zero-point vibrational energy contributions as well as sol-
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

PAPER
Studies of Diamine Complexes of a-Lithiated Benzyl Carbamates
2911
with a Nonius KappaCCD diffractometer. Programs used: data col-
lection COLLECT (Nonius B.V., 1998), absorption correction
SORTAV,44 Denzo,45 structure solution SHELXS-97,46 structure
refinement SHELXL-97,47 graphics SCHAKAL.48 All given CCDC
data contain the supplementary crystallographic data for this pa-
per.49 Known compounds have not been fully re-characterized.
complexes 33·7 was computed with high accuracy. Simu-
lation of the epimeric complexes obtained when employ-
ing tricyclic, C2-symmetric diamine (–)-a-isosparteine (8)
worked satisfying as well (Table 4, complex 15·8). Al-
though the SC-configured complex (SC)-15·8 is quantum
chemically more favored than determined experimentally,
the results are still within estimated error bars of our com-
putations of about 0.5–1 kcal·mol–1.
Benzyl Carbamates 23, 24, 26a; General Procedure A (GPA)
NaH (60% in mineral oil, 920 mg, 23 mmol, 1.15 equiv) was sus-
pended in anhyd THF (30 mL). The mixture was cooled to 0 °C and
the corresponding benzyl alcohol (20 mmol, 1.0 equiv) dissolved in
anhyd THF (5 mL), was slowly added. When the evolution of H2
ceased, a soln of CbCl (3.76 g, 23 mmol, 1.15 equiv) in anhyd THF
(10 mL) was added in such a way that the temperature did not rise.
The mixture was allowed to warm to r.t. and stirred at this tem-
perature for 2 d. The reaction flask was then immersed in an ice bath
and H2O (25 mL) and 2 M HCl (3 mL) were added to obtain a clear
yellowish soln. TBME (50 mL) was added, the phases were sepa-
rated, and the aqueous phase was extracted with TBME (3 × 20
mL). The combined organic layers were washed successively with
sat. NaHCO3 and brine. The soln was dried (anhyd MgSO4), filtered
through glass wool, and the solvent was removed to give the crude
product, which was subjected to column chromatography (Et2O–
pentane) to obtain the pure benzyl carbamates.
We have already investigated epimeric lithium complexes
of S-benzyl thiocarbamates and shown the utility of
bis(oxazoline) 9d containing complexes in enantioselec-
tive synthesis.29 As shown in Table 4 (complexes 11·7,
11·9d, 12·9d) these systems can also be described very ac-
curately by quantum chemical means.
Altogether, the synthetic methodology developed pro-
vides an easy access to different highly enantioenriched
user-defined secondary benzyl alcohols. These com-
pounds can be used as chiral precursors in further trans-
formations.3c,d,41 The broad applicability of the quantum
chemical methodology developed25 is proven.
Asymmetric Lithiation and Substitution of 19 and 23–25;
General Procedure B (GPB)
All solvents were dried and purified prior to use. Toluene was dis-
tilled over Na/benzophenone. Me3SiCl was distilled from powdered
CaH2 and stored under argon. s-BuLi was filtered through Celite be-
fore use and its concentration was determined by titration against
Ph2CHCO2H.42 A soln of CH2N2 in Et2O was obtained as described
in literature,43 stored under argon in the refrigerator and used with-
out determination of its concentration. Bis(oxazoline) ligand 9d was
prepared according to ref. 22. All reactions were performed under
argon atmosphere in flame-dried glassware using septum and sy-
ringe techniques. Flash column chromatography (FCC) was per-
formed on Merck 60 silica gel, 0.040–0.063 mm, using an argon
pressure of 1.2–1.4 bar, and monitored by TLC on Merck 60 F254
silica gel. Gas chromatography was performed on Agilent 6890
plus, Agilent, Böblingen. HP-5 was used as an achiral column (HP-
5: 30 m long, 0.32 mm diameter, 0.25 mm thick stationary phase, N2
as the mobile phase, 106 kPa pressure, 290 °C injection tempera-
ture, 300 °C detector temperature, program: 50 °C start tempera-
ture, 10 °C min–1 heating rate, 300 °C final temperature for 15 min)
and Supelco b-DEX 120 was used as chiral stationary phase (Supel-
co b-DEX 120, 30 m long, 0.32 mm diameter, 0.25 mm thick station-
ary phase, N2 as the mobile phase, 14.5 kPa pressure, 240 °C
injection temperature, 260 °C detector temperature). Melting points
were measured on an SMP3 melting point apparatus purchased
from Stuart Scientific, UK (uncorrected values). The optical rota-
tions were measured in a 10-cm cuvette on a polarimeter 341 pur-
Benzyl-type carbamate 19, 23–25 (71 mg/86 mg/79 mg/80 mg,
0.30 mmol, 1.00 equiv) was dissolved in toluene (3 mL), ligand 9d
(0.36 mmol, 1.20 equiv) was added and the reaction flask was
cooled to –78 °C. To this mixture, 1.2–1.3 M s-BuLi in hexane–cy-
clohexane (92:8) (0.36 mmol, 1.20 equiv) was injected in a drop-
wise manner. The mixture was stirred at –78 °C for 2.5 h and then
the appropriate electrophile (0.36–1.50 mmol, 1.2–5.0 equiv) was
injected and the mixture was stirred for 2 h. The reaction was
quenched with MeOH (0.5 mL) followed by H2O (1 mL) and 2 M
HCl (0.5 mL). The layers were separated and the aqueous layer was
extracted with TBME (3 × 10 mL). The combined organic layers
were washed with sat. NaHCO3, dried (MgSO4), filtered through
glass wool, and concentrated under reduced pressure to obtain the
crude product. This was subjected to column chromatography
(Et2O–pentane) to obtain the pure products.
2-Ethylbenzyl N,N-Diisopropylcarbamate (24)
According to GPA, reaction of 2-ethylbenzyl alcohol (2.72 g,
20.00 mmol) with CbCl (3.76 g, 23.00 mmol) afforded 24 as color-
less liquid; yield: 5.17 g (98%); Rf = 0.86 (Et2O–pentane, 1:1);
tR = 14.1 min.
IR (film): 3065, 2969, 2934, 2876, 1694, 1435, 1368, 1310, 1289,
1217, 1188, 1100, 1052, 1049, 757, 618, 597 cm–1.
1
chased from Perkin-Elmer. Unless otherwise stated, H and 13C
3
1H NMR (300 MHz, CDCl3): d = 1.21 [d, J(H3C)2CH,(H3C)2CH
=
NMR data were recorded on Bruker ARX 300 and AMX 400 spec-
trometers; spectra were obtained from solns in CDCl3 (dC = 77.0)
and were calibrated relative to residual content of CHCl3
(dH = 7.24) or TMS (dH = 0.0). Diastereotopic methylene protons
with different chemical shifts are abbreviated as HA and HB. IR:
Nicolet 5DCX, Bruker IFS 28 or Varian 3100 Excalibur Series
spectrophotometer with Specac Golden Gate Single Reflection
ATR. Elemental analyses were performed at the Microanalytical
Section of the Organisch-Chemisches Institut, WWU Münster, on a
Vario El III, purchased from Elementar Analysen Systeme, Hanau
(Germany). MS data were obtained on Finnigan MAT 8230 (EI);
Micromass Quattro LCZ (ESI), Micromass MAT 8200 (GC-TOF/
HRMS). HPLC: Waters 600E Multisolvent Delivery System and
996 PDA detector. Crystallographic data: Data sets were collected
3
6.8 Hz, 12 H, (H3C)2CH], 1.24 (t, JCH3CH2,CH3CH2 = 7.2 Hz, 3 H,
CH3CH2), 2.73 (q, 2 H, CH3CH2), 3.94 [ps s, 2 H, (H3C)2CH], 5.18
(s, 2 H, Hbenzylic), 7.15–7.40 (m, 4 H, Haryl).
13C NMR (75 MHz, CDCl3): d = 15.1 (CH3CH2), 20.8 [(H3C)2CH],
25.2 (CH3CH2), 45.9 [(H3C)2CH], 64.1 (Cbenzylic), 125.8 (C3), 127.0
(C2), 128.4 (C4), 129.2 (C5), 134.3 (C6), 142.6 (C1), 155.4
(NC=O).
MS (EI, 70 eV): m/z (%) = 248 [M – CH3]+ (1), 204 (10), 153 (1),
146 (8), 128 [Cb]+ (4), 119 [(H5C2)C6H4CH2]+ (100), 104 (14), 91
[C7H7]+ (53), 77 [C6H5]+ (19), 58 (13), 43 [C3H7]+ (32).
Anal. Calcd for C16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found: C,
72.74; H, 9.39; N, 5.25.
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

2912
H. Lange et al.
PAPER
1-(1-Naphthyl)ethyl N,N-Diisopropylcarbamate [(S)-26a]
Via carbamoylation: According to GPA, a downscaled reaction of
(S)-1-(1-naphthyl)ethanol (>99% ee) (172 mg, 1.00 mmol) with
NaH (60% in mineral oil, 46 mg, 1.15 mmol) and CbCl (188 mg,
1.15 mmol) gave (S)-26a as a colorless oil; yield: 292 mg (98%);
Rf = 0.49 (Et2O–pentane, 1:4); tR = 17.30 min.
(H2CCHCH2), 126.5 (C2), 127.5 (C4), 128.2 (C3), 133.8
(H2CCHCH2), 141.1 (C1), 154.9 (NC=O).
MS (ESI): m/z = 298.1778 [M + Na]+.
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C,
74.11; H, 9.22; N, 4.78.
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (2000:1),
0.3 mL·min–1, l = 210 nm]: tR = 18.6 (–), 21.9 min (+); 98% ee.
[a]D20 +34.9 (c 1.0, CHCl3).
(–)-(R)-Methyl 2-(Diisopropylcarbamoyloxy)-2-phenylacetate
[(R)-20d]
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then methyl chloroformate (85 mg, 0.90 mmol)
was added; yield: 84 mg (95%); Rf = 0.13 (Et2O–pentane, 1:8);
tR = 16.3 min (HP-5).
IR (film): 3050, 2970, 2933, 2874, 1692, 1598, 1537, 1511, 1433,
1368, 1189, 1157, 1131, 1090, 1073, 1047, 799, 777, 735 cm–1.
3
1H NMR (300 MHz, CDCl3): d = 1.21 [d, J(H3C)2CH,(H3C)2CH
=
7.3 Hz, 12 H, (H3C)2CH], 1.71 (d, 3JHbenzylic,H3C = 6.7 Hz, 3 H, H3C),
3.94 [ps s, 2 H, (H3C)2CH], 6.64 (q, 1 H, Hbenzylic), 7.35–7.54 (m, 3
H, H3, H2, H7), 7.59 (dd, JH5,H6 = 8.1 Hz, JH6,H7 = 6.7 Hz, 1 H,
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (1000:1),
0.2 mL·min–1, l = 210 nm]: tR = 25.1 (+), 35.3 min (–); 91% ee.
[a]D20 –93.3 (c 1.00, MeOH).
3
3
4
H6), 7.77 (m, 1 H, H4), 7.85 (dd, JH5,H7 = 1.4 Hz, 1 H, H5), 8.13
(dd, 3JH7,H8 = 8.5 Hz, 4JH6,H8 = 0.9 Hz, 1 H, H8).
(–)-(R)-3,3-Dimethyl-2-oxo-1-phenylbutyl N,N-Diisopropyl-
carbamate [(R)-20e]
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then pivaloyl chloride (182 mg, 1.50 mmol) was
added; 20e was obtained as a colorless solid; yield: 83 mg (87%);
mp 79 °C (Et2O); Rf = 0.37 (Et2O–pentane, 1:3); tR = 14.5 min.
13C NMR (75 MHz, CDCl3): d = 20.9 [(H3C)2HC], 22.3 (CH3), 45.9
[(H3C)2HC], 69.6 (C9), 122.9 (C8), 123.4 (C2), 125.3 (C3), 125.5
(C6), 126.0 (C7), 128.0 (C4), 128.7 (C5), 130.4 (C8a), 133.8 (C4a),
138.7 (C1), 154.9 (NC=O).
MS (ESI): m/z = 322.3 [M + Na]+.
Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C,
76.03; H, 8.63; N, 4.82.
HPLC [CHIRA-GROM 2 (2·250 mm), hexane–i-PrOH (1000:1),
0.2 mL·min–1, l = 210 nm]: tR = 11.6 (+), 12.8 min (–); 63% ee.
[a]D20 –155.1 (c 0.97, CHCl3).
Via asymmetric substitution: According to GPB, a mixture of
carbamate 23 (86 mg, 0.30 mmol) and 9d (116 mg, 0.36 mmol) was
treated with s-BuLi (0.26 mL, 0.36 mmol) and then MeI (51 mg,
0.36 mmol) was added; yield: 69 mg (77%); 93% ee.
IR (KBr): 3065, 2975, 2928, 1714, 1684, 1586, 1499, 1478, 1441,
1386, 1368, 1304, 1243, 1208, 1189, 1134, 1091, 1055, 969, 906,
867, 812, 768, 723, 701 cm–1.
[a]D20 +34.4 (c 1.04, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.09 [s, 9 H, (H3C)3C], 1.13 [d,
3J(H3C)2CH,(H3C)2CH = 7.0 Hz, 12 H, (H3C)2CH], 3.72 [ps s, 1 H,
(H3C)2CH], 4.07 [ps s, 1 H, (H3C)2CH], 6.35 (s, 1 H, Hbenzylic), 7.30–
7.45 (m, 5 H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = 21.0 [(H3C)2CH], 27.2 [(H3C)3C],
43.7 [(H3C)3C], 46.0 [(H3C)2CH], 76.7 (Cbenzylic), 128.8 (C2), 128.9
(C4), 129.3 (C3), 134.5 (C1), 154.7 (NC=O), 210.4 (C=O).
(+)-(R)-Phenyl(trimethylsilyl)methyl N,N-Diisopropyl-
carbamate [(R)-20b]
According to GPB, a mixture of carbamate 19 (118 mg, 0.50 mmol)
and 8 (141 mg, 0.60 mmol) was treated with s-BuLi (0.44 mL,
0.60 mmol). The mixture was stirred at –78 °C for 3 h and then
Me3SiCl (65 mg, 0.60 mmol) was added; yield: 103 mg (67%);
Rf = 0.38 (Et2O–pentane, 1:8); tR = 14.1 min (HP-5).
GC [chiral phase; temperature program 94/1/1/ 95/999]: tR = 938 (–),
MS (ESI): m/z = 320.2220 [M + H]+, 342.2042 [M + Na]+.
958 min (+); 30% ee.
[a]D20 +8.5 (c 1.0, CH2Cl2).
Anal. Calcd for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C,
71.44; H, 9.29; N, 4.24.
(–)-(S)-1-Phenylbut-3-enyl N,N-Diisopropylcarbamate [(S)-
20c]
According to GPB, a mixture of carbamate 19 (118 mg, 0.50 mmol)
and 9d (193 mg, 0.60 mmol) was treated with s-BuLi (0.49 mL,
0.60 mmol) and then allyl bromide (91 mg, 0.6 mmol) was added;
20c was obtained as a colorless oil; yield: 102 mg (75%); Rf = 0.65
(Et2O–pentane, 1:1); tR = 14.4 min.
(+)-(S)-3,3-Dimethyl-2-oxo-1-phenylbutyl N,N-Diisopropyl-
carbamate [(S)-20e]
Via Corey’s PDC oxidation: Epimeric alcohols 20i (51 mg,
0.16 mmol) were dissolved CH2Cl2 (2 mL). PDC (67 mg,
0.18 mmol) was added and the mixture was stirred at r.t. for 20 h.
The solids were filtered off and the solvents removed in vacuo to
give a crude product that was purified by column chromatography
(Et2O–pentane, 1:6); yield: 21 mg (41%); 32% ee.
HPLC [CHIRA GROM 1 (2·250 mm), hexane–i-PrOH (1000:1),
0.3 mL·min–1, l = 210 nm]: tR = 13.5 (+), 14.9 min (–); 62% ee.
[a]D20 +79.7 (c 0.38, CHCl3).
[a]D20 –2.3 (c 0.12, CHCl3).
(–)-(R)-2-(4-Bromophenyl)-2-oxo-1-phenylethyl N,N-Diisopro-
pylcarbamate [(R)-20f]
IR (ATR): 3078, 3066, 3034, 2999, 2970, 2934, 2876, 1691, 1643,
1495, 1476, 1434, 1368, 1336, 1302, 1290, 1215, 1190, 1157, 1133,
1051, 980, 914, 767, 634 cm–1.
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then 4-bromobenzoyl chloride (329 mg,
1.50 mmol) was added; 20f was obtained as a colorless solid; yield:
30 mg (24%); mp 131 °C (Et2O); Rf = 0.34 (Et2O–pentane, 1:2);
tR = 21.4 min.
1H
NMR
(300 MHz,
CDCl3):
d = 1.08
[br
d,
3J(H3C)2CH,(H3C)2CH = 6.4 Hz, 12 H, (H3C)2CH], 2.42–2.66 (m, 2 H,
H2CCHCH2), 3.80 [ps s, 2 H, (H3C)2CH], 4.90–5.06 (m, 2 H,
H2CCHCH2), 5.55–5.75 (m, 2 H, Hbenzylic, H2CCHCH2), 7.07–7.24
(m, 5 H, Hphenyl).
HPLC [CHIRA-GROM 2 (2·250 mm), n-hexane–i-PrOH (1000:1),
0.3 mL·min–1, l = 210 nm]: tR = 58.0 (–), 79.1 min (+); 96% ee.
[a]D20 –134.6 (c 0.40, CHCl3).
13C NMR (75 MHz, CDCl3): d = 20.6 [(H3C)2CH], 41.3
(H2CCHCH2), 45.5 [(H3C)2CH], 75.6 (Cbenzylic), 117.6
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

PAPER
Studies of Diamine Complexes of a-Lithiated Benzyl Carbamates
2913
IR (KBr): 3069, 3002, 2968, 2933, 2861, 1698, 1686, 1588, 1475,
1456, 1436, 1397, 1367, 1297, 1256, 1227, 1211, 1187, 1131, 1090,
1068, 1010, 971, 954, 907, 856, 826, 769, 728, 695 cm–1.
3
6.73 (s, 1 H, Hbenzylic), 7.00–7.38 (m, 13 H, Hphenyl), 7.56–7.66 (m, 2
H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = 20.5 [(H3C)2CH], 46.3
[(H3C)2CH], 79.3 (Cbenzylic), 80.8 [(H5C6)2C(OH)], 126.2, 126.4,
126.9, 127.0, 127.4, 127.6, 127.7, 128.2, 128.4, 136.5, 143.0, 145.2
(Cphenyl), 153.9 (NC=O).
1H NMR (400 MHz, CDCl3): d = 1.21 [d, J(H3C)2CH,(H3C)2CH
=
6.7 Hz, 12 H, (H3C)2CH], 3.90 [ps s, 1 H, (H3C)2CH], 4.02 [ps s, 1
H, (H3C)2CH], 6.25 (s, 1 H, Hbenzylic), 6.75–6.85 (m, 5 H, Hphenyl),
7.05–7.21 (m, 4 H, Haryl).
13C NMR (100 MHz, CDCl3): d = 20.6 [(H3C)2CH], 46.4
[(H3C)2CH], 78.7 (Cbenzylic), 121.2, 122.8, 127.5, 127.9, 129.2,
130.1, 136.3, 136.8 (Cphenyl, Caryl), 154.9 (NC=O), 191.8 (C=O).
MS (ESI): m/z = 440.2194 [M + H]+.
Anal. Calcd for C27H31NO3: C, 77.67; H, 7.48; N, 3.35. Found: C,
77.52; H, 7.68; N, 3.35.
MS (ESI): m/z = 420.1001 [M + H]+, 442.0841 [M + Na]+.
(–)-2-Hydroxy-3,3-dimethyl-1-phenylbutyl N,N-Diisopropyl-
carbamate [(1S,2R)-20i, (1S,2S)-20i]
Anal. Calcd for C21H24BrNO3: C, 60.29; H, 5.78; N, 3.35. Found: C,
60.09; H, 5.67; N, 3.24.
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then pivaldehyde (78 mg, 0.90 mmol) was added;
(1S,2R)-20i/(1S,2S)-20i was obtained as a colorless liquid; yield:
67 mg (70%); Rf = 0.49 (Et2O–pentane, 1:1); tR = 15.6 min (1S,2R),
15.7 min (1S,2S) (HP 5). 32% ee was determined by conversion
into (S)-20e.
Via Corey’s PDC oxidation: Epimeric alcohols 20j (168 mg,
0.40 mmol) were dissolved CH2Cl2 (2 mL). PDC (168 mg,
0.45 mmol) was added and the mixture was stirred at r.t. for 12 h.
The solids were filtered off and the solvent removed in vacuo to
give a crude product that was purified by column chromatography
(Et2O–pentane, 1:6); yield: 56 mg (33%); 97% ee.
[a]D20 +2.0 (c 0.67, CHCl3).
[a]D20 –134.6 (c 0.40, CHCl3).
IR (film): 3486, 3082, 3064, 3032, 2969, 2872, 2713, 1684, 1586,
1486, 1479, 1436, 1368, 1320, 1300, 1217, 1157, 1135, 1100, 1048,
984, 905, 848, 767, 734, 700, 604 cm–1.
(–)-(S)-2-Hydroxy-2-methyl-1-phenylpropyl N,N-Diisopropyl-
carbamate [(S)-20g]
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then acetone (87 mg, 1.50 mmol) was added; 20g
was obtained as a colorless oil; yield: 25 mg (28%); Rf = 0.32
(Et2O–pentane, 1:2); tR = 14.0 min.
1H NMR (300 MHz, CDCl3): d = 0.93 [s, 9 H, (H3C)3C (1S,2S)],
0.96 [s, 9 H, (H3C)3C (1S,2R)], 1.15–1.27 [m, 24 H, (H3C)2CH
3
(1S,2R), (1S,2S)], 1.55 [d, JCH(OH),OH = 5.0 Hz 1 H, OH (1S,2S)],
3
2.16 [d, JCH(OH),OH = 7.2 Hz, 1 H, OH (1S,2R)], 3.49 [dd,
3JHbenzylic,CH(OH) = 3.0 Hz,
1 H, CH(OH) (1S,2S)], 3.71 [dd,
3JHbenzylic,CH(OH) = 5.0 Hz, 1 H, CH(OH) (1S,2R)], 3.91 [ps s, 4 H,
(H3C)2CH (1S,2R), (1S,2S)], 5.85 [d, 1 H, Hbenzylic (1S,2S)], 6.00 [d,
1 H, Hbenzylic (1S,2R)], 7.18–7.43 [m, 10 H, Hphenyl (1S,2R), (1S,2S)].
HPLC [CHIRA-GROM 2 (2·250 mm), hexane–i-PrOH (400:1), 0.3
mL·min–1, l = 210 nm]: tR = 25.3 (–), 33.2 min (+); 54% ee.
[a]D20 –8.4 (c 0.98, CHCl3).
13C NMR (75 MHz, CDCl3): d = 20.6 [(H3C)2CH (1S,2R), (1S,2S)],
26.4 [(H3C)3C (1S,2R*)], 26.5 [(H3C)3C (1S,2S*)], 45.9 [(CH(OH)
(1S,2R*)], 46.1 [(CH(OH) (1S,2S*)], 46.0 [(H3C)2CH (1S,2R),
(1S,2S)], 74.8 [Cbenzylic (1S,2R*)], 76.7 [Cbenzylic (1S,2S*)], 80.3
[(H3C)3C (1S,2S*)], 82.0 [(H3C)3C (1S,2R*)], 126.8 [C2 (1S,2R*)],
127.7 [C2 (1S,2S*)], 128.1 [C4 (1S,2R*)], 128.3 [C4 (1S,2S*)],
128.4 [C3 (1S,2R*)], 128.5 [C3 (1S,2S*)], 138.7 [C1 (1S,2R*)],
140.7 [C1 (1S,2S*)], 153.7 [NC=O (1S,2R*)], 154.0 [NC=O
(1S,2S*)].
IR (ATR): 3461, 3088, 3065, 3033, 2972, 2935, 2876, 1682, 1495,
1436, 1369, 1323, 1300, 1213, 1157, 1135, 1054, 962, 905, 866,
818, 768, 735, 701, 650 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.13 (s, 3 H, H3C), 1.15 (s, 3 H,
H3C), 1.17 [br d, 3J(H3C)2CH,(H3C)2CH = 6.1 Hz, 12 H, (H3C)2CH], 2.11
(br s, 1 H, OH), 3.90 [sept, 2 H, (H3C)2CH], 5.56 (s, 1 H, Hbenzylic),
7.16–7.35 (m, 5 H, Hphenyl).
13C NMR (75 MHz, CDCl3): d = 20.7 [(H3C)2CH], 25.3 (H3C), 26.7
(H3C), 45.9 [(H3C)2CH], 72.7 [(H3C)2C(OH)], 82.8 (Cbenzylic), 127.8
(C2), 127.9 (C4), 128.0 (C3), 138.0 (C1), 155.0 (NC=O).
MS (ESI): m/z = 344.2213 [M + Na]+.
Anal. Calcd for C27H31NO3: C, 70.99; H, 9.72; N, 4.36. Found: C,
70.87; H, 9.81; N, 4.28.
MS (ESI): m/z = 316.1881 [M + Na]+.
Anal. Calcd for C17H27NO3: C, 69.59; H, 9.28; N, 4.77. Found: C,
69.34; H, 9.39; N, 4.60.
(+)-2-(4-Bromophenyl)-2-hydroxy-1-phenylethyl N,N-Diiso-
propylcarbamate [(1R,2S)-20j, (1R,2R)-20j]
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then 4-bromobenzaldehyde (275 mg, 1.50 mmol)
was added; (1R,2S)-20j/(1R,2R)-20j was obtained as a colorless
solid; yield: 168 mg (80%); mp 84 °C (Et2O); Rf = 0.31 (Et2O–pen-
tane, 1:1); tR = 21.5 min (1R,2S), 21.6 min (1R,2R) (HP 5). 97% ee
was determined by conversion into (R)-20f.
(+)-(R)-2-Hydroxy-1,2,2-triphenylethyl N,N-Diisopropyl-
carbamate [(R)-20h]
According to GPB, a mixture of carbamate 19 (71 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then benzophenone (82 mg, 0.45 mmol) was
added; 20h was obtained as a colorless solid; yield: 100 mg (81%);
mp 104 °C (Et2O); Rf = 0.56 (Et2O–pentane, 1:1); tR = 23.6 min.
[a]D20 +19.2 (c 0.87, CHCl3).
HPLC [Chiralcel OD-H (4.6·250 mm), hexane–i-PrOH (200:1), 1.0
mL·min–1, l = 210 nm]: tR = 14.1 (–), 15.4 min (+); 94% ee.
[a]D20 +196.2 (c 0.50, CHCl3).
IR (KBr): 3408, 3065, 3001, 2974, 2932, 1659, 1590, 1480, 1445,
1398, 1384, 1368, 1299, 1213, 1197, 1158, 1137, 1074, 1010, 980,
957, 899, 858, 822, 767, 719, 701, 614 cm–1.
IR (ATR): 3446, 3090, 3059, 3034, 2971, 2935, 2875, 1668, 1495,
1442, 1369, 1230, 1299, 1214, 1156, 1134, 1048, 1035, 999, 828,
761, 729, 697, 674, 625 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87 [ps s, 3 H, (H3C)(H3C)CH],
1.05 [ps s, 3 H, (H3C)(H3C)CH], 1.14 [ps s, 6 H, (H3C)2CH], 2.63
(s, 1 H, OH), 3.74 [ps s, 1 H, (H3C)2CH], 3.86 [ps s, 1 H, (H3C)2CH],
1H NMR (400 MHz, CDCl3): d = 1.08–1.28 [m, 24 H, (H3C)2CH
(1R,2S), (1R,2R)], 3.68 [ps s, 1 H, OH (1R,2S)], 3.75 [ps s, 1 H, OH
(1R,2R)], 3.82–3.96 [m, 4 H, (H3C)2CH (1R,2S), (1R,2R)], 4.89 [d,
3JHbenzylic,CH(OH) = 7.4 Hz,
1 H, CH(OH) (1R,2R)], 4.95 [d,
3JH1,H8 = 3.9 Hz, 1 H, CH(OH) (1R,2S)], 5.79 [d, 1 H, Hbenzylic
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

2914
H. Lange et al.
PAPER
(1R,2R)], 6.25 [d, 1 H, Hbenzylic (1R,2S)], 6.87–7.45 [m, 9 H, Hphenyl
,
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (1000:1),
0.3 mL·min–1, l = 210 nm]: tR = 38.2 (+), 43.5 min (–); 90% ee.
Haryl (1R,2S), (1R,2R)].
13C NMR (100 MHz, CDCl3): d = 20.7 [(H3C)2CH (1R,2S),
(1R,2R)], 46.0 [(H3C)2CH (1R,2S), (1R,2R)], 65.8 [(CH(OH)
(1R,2S*)], 77.3 [(CH(OH) (1R,2R*)], 80.1 [Cbenzylic (1R,2R*)], 81.2
[Cbenzylic (1R,2S*)], 121.6, 127.1, 127.4, 127.5, 128.0, 128.1, 128.2,
128.9, 129.0, 129.1, 130.7, 130.9, 131.1, 136.8, 136.9, 138.5, 139.0
[Cphenyl, Caryl (1R,2S), (1R,2R)], 155.0 [NC=O (1R,2R*)], 155.5
[NC=O (1R,2S*)].
[a]D20 –142.2 (c 0.61, CHCl3).
IR (ATR): 3069, 2978, 2970, 2935, 1753, 1688, 1513, 1434, 1371,
1332, 1300, 1222, 1209, 1160, 1138, 1064, 1042, 1007, 930, 906,
868, 806, 786, 764, 736, 641, 621, 572 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 [ps s, 6 H, (H3C)2CH], 1.27
3
[br d, J(H3C)2CH,(H3C)2CH = 7.4 Hz, 6 H, (H3C)2CH], 3.69 (s, 3 H,
H3CO), 3.95 [ps s, 2 H, (H3C)2CH], 6.73 (s, 1 H, Hbenzylic), 7.42–7.60
MS (ESI): m/z = 422.0979 [M + H]+, 444.0961 [M + Na]+.
(m, 3 H, H2, H3, H7), 7.63 (ps dd, JH5,H6 = 3JH6,H7 = 7.1 Hz,
3
Anal. Calcd for C21H26BrNO3: C, 60.00; H, 6.23; N, 3.33. Found: C,
59.92; H, 6.47; N, 3.23.
4JH6,H8 = 1.1 Hz, 1 H, H6), 7.83–7.89 (m, 2 H, H5, H6), 8.26 (dd,
3JH7,H8 = 8.5 Hz, 1 H, H8).
13C NMR (75 MHz, CDCl3): d = 20.9 [(H3C)2CH], 46.2
[(H3C)2CH], 52.4 (H3CO), 72.7 (Cbenzylic), 124.1, 125.2, 125.9,
126.7, 127.3, 128.7, 129.7, 131.0, 131.2, 134.0 (Cnaphthyl), 154.4
(NC=O), 170.7 (C12).
(+)-(S)-1-(1-Naphthyl)but-3-enyl N,N-Diisopropylcarbamate
[(S)-26b]
According to GPB, a mixture of carbamate 23 (143 mg, 0.50 mmol)
and 9d (193 mg, 0.60 mmol) was treated with s-BuLi (0.49 mL,
0.60 mmol) and then allyl bromide (301 mg, 2.50 mmol) was add-
ed; 26b was obtained as a colorless liquid; yield: 130 mg (80%);
Rf = 0.64 (Et2O–pentane, 1:1); tR = 17.5 min (HP 5).
MS (ESI): m/z = 366.1682 [M + Na]+.
Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C,
69.87; H, 7.37; N, 3.95.
HPLC [CHIRA GROM 1 (2·250 mm), hexane–i-PrOH (1000:1),
0.3 mL·min–1, l = 210 nm]: tR = 13.7 (–), 16.5 min (+); 78% ee.
[a]D20 +21.5 (c 1.08, CHCl3).
(–)-(S)-(2-Ethylphenyl)(tributylstannyl)methyl N,N-Diisopro-
pylcarbamate [(S)-27a]
According to GPB, a mixture of carbamate 24 (79 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) before Bu3SnCl (117 mg, 0.36 mmol) was added; 27a
was obtained as a colorless liquid; yield: 153 mg (92%); Rf = 0.56
(Et2O–pentane, 1:12); tR = 20.6 min (HP 5).
IR (ATR): 3075, 3051, 2998, 2970, 2934, 2875, 1686, 1643, 1598,
1511, 1475, 1431, 1375, 1339, 1309, 1294, 1215, 1189, 1157, 1132,
1046, 974, 914, 775, 734 cm–1.
1H
3J(H3C)2CH,(H3C)2CH = 6.5 Hz, 12 H, (H3C)2CH], 2.45–2.55 [m, 2 H,
H2CCHCH2], 3.98 [ps s, H, (H3C)2CH], 5.04 [ddd,
3JH2CCHCH2,HcisHtransCCHCH2
10.1 Hz, JHcisHtransC=CH,HcisHtransC=CH
2.1 Hz, 4JH2C=CHCH2,HcisHtransC=CH = 1.1 Hz, 1 H, HcisHtransC=CHCH2),
NMR
(400 MHz,
CDCl3):
d = 1.24
[br
d,
HPLC [EC250/4 Nucleosil 100-5 Chiral-2 (4·250 mm), hexane–i-
PrOH–TFA (1000:1:0.5), 0.3 mL·min–1, l = 210 nm]: tR = 20.1 (+),
23.4 min (–); 92% ee.
[a]D20 –46.1 (c 1.01, CHCl3).
2
2
=
=
5.10
(ddd,
3JH2C=CH,HcisHtransC=CH = 17.1 Hz,
4JH2C=CHCH2,HcisHtransC=CH = 2.1 Hz, 1 H, HcisHtransC=CHCH2), 5.69
IR (ATR): 3063, 2959, 2930, 2871, 2853, 1681, 1602, 1493, 1463,
1433, 1377, 1331, 1310, 1216, 1157, 1135, 1048, 951, 936, 865,
771, 755 cm–1.
3
(m, 1 H, H13), 6.62 (t, JH2C=CHCH2,Hbenzylic = 6.3 Hz, 1 H, Hbenzylic),
7.43–7.50 (m, 7 H, Hnaphthyl).
1H NMR (300 MHz, CDCl3): d = 0.81 (t, 3JH3CCHH,(H3C)CH2 = 6.9 Hz,
3 H, H3CCH2), 0.83 [t, 3J(H3C)CH2CH2CH2,(H3C)CH2CH2CH2 = 7.3 Hz, 9 H,
(H3C)CH2CH2CH2], 1.13–1.48 [m, 18 H, (H3C)CH2CH2CH2], 1.24
13C NMR (100 MHz, CDCl3): d = 21.2 [(H3C)2CH], 40.8
(H2C=CHCH2), 46.0 [(H3C)2CH], 72.5 (Cbenzylic), 117.5 (H2C=CH),
134.1 (H2C=CH) 123.4, 123.6, 125.2, 125.5, 126.1, 128.0, 128.8,
130.4, 133.8, 137.1 (Cnaphthyl), 154.7 (NC=O).
3
[d, J(H3C)2CH,(H3C)2CH = 6.6 Hz, 12 H, (H3C)2CH], 2.61 (dq,
2JH3CCHH,(H3C)CHH = 14.5 Hz, 1 H, H3CCHH], 2.65 (dq, 1 H,
H3CCHH), 3.98 [sept, 2 H, (H3C)2CH], 5.90 (s, 1 H, Hbenzylic), 6.99–
7.32 (m, 4 H, Haryl).
MS (ESI): m/z = 348.1933 [M + Na]+.
Anal. Calcd for C21H27NO2: C, 77.50; H, 8.36; N, 4.30. Found: C,
77.31; H, 8.49; N, 4.20.
13C NMR (75 MHz, CDCl3): d = 10.5 [(H3C)CH2CH2CH2], 13.6
[(H3C)CH2CH2CH2], 14.3 (H3CCH2), 20.9 [(H3C)2CH], 25.5
(H3CCH2), 27.4 [(H3C)CH2CH2CH2], 28.8 [(H3C)CH2CH2CH2],
45.9 [(H3C)2CH], 71.2 (Cbenzylic), 124.7 (C5), 124.9 (C6), 125.9
(C4), 127.7 (C3), 137.1 (C2), 144.0 (C1), 155.6 (NC=O).
MS (EI, 70 eV): m/z (%) = 552 [M]+ (1), 496 [M – Bu]+ (49), 440
[M – 2 Bu]+ (4), 378 (2), 322 (2), 263 (12) [M – SnBu3]+, 175 (16),
119 (100) [M – SnBu3 – OCb]+.
(–)-(R)-Methyl 2-(Diisopropylcarbamoyloxy)-2-(1-naphthyl)-
acetate [(R)-26c]; Typical Procedure
As described in GPB, the lithiated species was synthesized by
deprotonating 23 (143 mg, 0.50 mmol) in the presence of 9d
(193 mg, 0.60 mmol) and equilibrated. As electrophile, dried and
pre-cooled gaseous CO2 was bubbled through the mixture over a pe-
riod of 10–15 min. The mixture was stirred at –78 °C for an addi-
tional 1 h, then the reaction was carefully quenched with MeOH
(0.5 mL) and H2O (1 mL). Workup was performed as described in
GPB. The crude acid was directly dissolved in Et2O and a soln of
CH2N2 in Et2O was added at r.t. until a yellowish color of the mix-
ture remained. The soln was stirred for 1 h. In order to destroy the
remaining CH2N2, silica gel (ca. 1 g) was added and the suspension
was stirred for 1 h. The solvent was removed under reduced pres-
sure and, thereby, the crude product adsorbed on the silica gel. This
was directly submitted to column chromatography (Et2O–pentane,
1:4) to yield 26c as a colorless crystalline solid; yield: 111 mg
(65%); mp 93 °C (Et2O); Rf = 0.55 (Et2O–pentane, 1:1);
tR = 18.2 min (HP 5).
Anal. Calcd for C28H51NO2Sn: C, 60.88; H, 9.31; N, 2.54. Found:
C, 61.00; H, 9.34; N, 2.44.
(–)-(S)-(2-Ethylphenyl)(trimethylsilyl)methyl N,N-Diisopropyl-
carbamate [(S)-27b]
According to GPB, a mixture of carbamate 24 (79 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then Me3SiCl (39 mg, 0.36 mmol) was added; 27b
was obtained as a colorless liquid; yield: 96 mg (97%); Rf = 0.45
(Et2O–pentane, 1:6); tR = 14.2 min (HP 5).
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (4000:1),
0.3 mL·min–1, l = 210 nm]: tR = 6.5 (+), 7.0 min (–); >98% ee.
[a]D20 –38.9 (c 0.96, CHCl3).
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

PAPER
Studies of Diamine Complexes of a-Lithiated Benzyl Carbamates
2915
IR (film): 3064, 2967, 2936, 2877, 1693, 1475, 1428, 1377, 1368,
1334, 1311, 1294 1260, 1188, 1157, 1135, 1045, 940, 877, 865,
840, 765, 617, 601 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 9 H, (H3C)3Si], 1.16–1.36
1H NMR (400 MHz, CDCl3): d = 1.14–1.34 [br m, 15 H, H3CCH2,
(H3C)2CH], 2.80–2.86 (m, 2 H, H3CCH2), 3.69 (s, 3 H, H3CO), 3.94
[br s, 2 H, (H3C)2CH], 6.23 (s, 1 H, Hbenzylic), 7.17–7.29 (m, 2 H, H5,
3
4
H3), 7.31 (ps dt, JH3,H4 = 3JH4,H5 = 7.9 Hz, JH4,H6 = 1.3 Hz, 1 H,
H4), 7.43 (dd, 3JH5,H6 = 7.7 Hz, 1 H, H6).
[br
m,
15
H,
(H3C)2CH,
H3CCH2],
2.53
(dq,
H,
2JH3CCHH,H3CCHH = 14.8 Hz, 3JH3CCHH,(H3C)CHH = 7.4 Hz,
1
13C NMR (100 MHz, CDCl3): d = 15.5 (H3CCH2), 21.0
[(H3C)2CH], 25.5 (H3CCH2), 46.8 [(H3C)2CH], 52.2 (H3CO), 71.1
(Cbenzylic), 126.2 (C5), 128.2 (C6), 129.0 (C4), 129.9 (C3), 132.6
(C2), 142.8 (C1), 154.5 (NC=O), 170.8 (C=O).
3
H3CCHH), 2.75 (dq, JH3CCHH,(H3C)CHH = 7.4 Hz, 1 H, H3CCHH),
3.92 [ps s, 2 H, (H3C)2CH], 5.89 (s, 1 H, Hbenzylic), 7.02–7.22 (m, 4
H, Haryl).
13C NMR (75 MHz, CDCl3): d = –3.2 [(H3C)3Si), 14.5 (H3CCH2),
21.1 [(H3C)2CH], 25.4 (H3CCH2), 45.8 [(H3C)2CH], 65.7 (Cbenzylic),
125.5 (C3), 125.9 (C5), 126.3 (C6), 128.0 (C4), 138.7 (C1), 139.6
(C2), 155.8 (NC=O).
MS (EI, 70 eV): m/z (%) = 321 [M – CH3]+ (5), 278 (8), 216 (48),
172 (54), 144 [OCb]+ (6), 130 (16), 119 [(H5C2)C6H4CH2]+ (9), 73
[(H3C)3Si]+ (100), 43 [H7C3]+ (32).
MS (EI, 70 eV): m/z (%) = 262 [M – COOCH3]+ (1), 177 [M –
OCb]+ (65), 149 (25), 145 (30), 133 (31), 131 (38), 128 [Cb]+ (4),
119 [(H5C2)C6H4CH2]+ (18), 117 (84), 115 (66), 105 [(H5C2)C6H4]+
(23), 103 (41), 91 [C7H7]+ (53), 84 (28), 77 [C6H5]+ (47), 70 (81), 63
(31), 58 (26), 51 [C4H3]+ (48), 42 [C2H2O]+ (100).
Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36. Found: C,
67.31; H, 8.52; N, 4.19.
Anal. Calcd for C19H33NO2Si: C, 68.01; H, 9.91; N, 4.17. Found: C,
67.87; H, 9.98; N, 4.06.
(–)-(S)-(4-Methoxyphenyl)(tributylstannyl)methyl N,N-Diiso-
propylcarbamate [(S)-30a]
According to GPB, a mixture of carbamate 25 (80 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then Bu3SnCl (117 mg, 0.36 mmol) was added;
30a was obtained as a colorless liquid; yield: 106 mg (64%);
Rf = 0.24 (Et2O–pentane, 1:12); tR = 23.3 min (HP 5).
(–)-(S)-1-(2-Ethylphenyl)ethyl N,N-Diisopropylcarbamate [(S)-
27c]
According to GPB, a mixture of carbamate 24 (263 mg, 1.00 mmol)
and 9d (387 mg, 1.20 mmol) was treated with s-BuLi (0.88 mL,
1.20 mmol) and then MeI (284 mg, 1.20 mmol) was added; 27c was
obtained as a colorless liquid; yield: 101 mg (36%); Rf = 0.50
(Et2O–pentane, 1:3); tR = 14.5 min (HP 5).
HPLC [EC250/4 Nucleosil 100-5 Chiral-2 (4·250 mm), hexane–i-
PrOH–TFA (500:1:0.5), 0.3 mL·min–1, l = 210 nm]: tR = 40.1 (+),
49.7 min (–); 92% ee.
[a]D20 –17.8 (c 1.03, CHCl3).
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (1000:1),
0.3 mL·min–1, l = 210 nm]: tR = 5.8 (+), 6.4 min (–); 92% ee.
[a]D20 –2.3 (c 1.04, CHCl3).
IR (ATR): 3060, 2998, 2956, 2926, 2872, 2853, 1673, 1609, 1509,
1460, 1438, 1377, 1346, 1312, 1298, 1245, 1213, 1157, 1135, 1048,
827, 772, 745, 659 cm–1.
IR (film): 3064, 2969, 2934, 1692, 1475, 1428, 1368, 1293, 1216,
1190, 1133, 1100, 1068, 1047, 906 (m), 757, 624, 600 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.83 [t, 3JH3C(CH2)3,H3CCH2 = 7.1 Hz,
9 H, H3C(CH2)3], 1.13–1.47 (m, 18 H, H3CCH2CH2CH2), 1.22 [d,
3J(H3C)2CH,(H3C)2CH = 7.1 Hz, 12 H, (H3C)2CH], 3.77 (s, 3 H, H3CO),
3.94 [ps s, 2 H, (H3C)2CH], 5.72 (s, 1 H, Hbenzylic), 6.81 (dd,
1H NMR (300 MHz, CDCl3): d = 1.02–120 [br m, 15 H, H3CCH2,
3
(H3C)2CH], 1.39 (d, JH3C,Hbenzylic = 6.8 Hz, 3 H, H3C), 2.61 (dq,
2JH3CCHH,H3CCHH = 14.8 Hz, 3JH3CCHH,(H3C)CHH = 7.5 Hz,
1
H,
3
H3CCHH), 2.65 (dq, JH3CCHH,(H3C)CHH = 7.5 Hz, 1 H, H3CCHH),
3.79 [ps s, 2 H, (H3C)2CH], 5.99 (q, 1 H, Hbenzylic), 7.00–7.34 (m, 4
H, Haryl).
3JH2,H3 = 8.8 Hz, 4JH3,H3¢ = 1.9 Hz,
2
H, H3), 7.04 (dd,
4JH2,H2¢ = 2.1 Hz, 2 H, H2).
13C NMR (75 MHz, CDCl3): d = 10.1 (H3CCH2CH2CH2), 13.7
(H3CCH2CH2CH2), 21.1 [(H3C)2CH], 27.5 (H3CCH2CH2CH2), 29.0
(H3CCH2CH2CH2), 45.9 [(H3C)2CH], 55.3 (H3CO), 73.1 (Cbenzylic),
113.8 (C3), 125.3 (C2), 136.1 (C1), 155.7 (NC=O), 157.1 (C4).
13C NMR (75 MHz, CDCl3): d = 15.4 (H3CCH2), 21.0 [(H3C)2CH],
22.8 (H3C), 25.4 (H3CCH2), 45.8 [(H3C)2CH], 68.9 (Cbenzylic), 125.7
(C5), 126.0 (C6), 127.5 (C4), 128.5 (C3), 139.0 (C2), 140.6 (C1),
155.0 (NC=O).
MS (ESI): m/z = 578.2623 [M + Na]+.
MS (EI, 70 eV): m/z (%) = 277 [M]+ (1), 218 (8), 146 (3), 133
[(H5C2)C6H4CH(CH3)]+
(100), 128 [OCb]+
(4), 117
Anal. Calcd for C27H49NO3Sn: C, 58.49; H, 8.91; N, 2.53. Found:
C, 58.65; H, 9.02; N, 2.37.
[(H5C2)C6H4CH2]+ (100), 105 [(H5C2)C6H4]+ (14), 91 [C7H7]+ (53),
77 [C6H5]+ (19), 43 [C3H7]+ (32).
(–)-(S)-(4-Methoxyphenyl)(trimethylsilyl)methyl N,N-Diisopro-
pylcarbamate [(S)-30b]
According to GPB, a mixture of carbamate 25 (80 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.26 mL,
0.36 mmol) and then Me3SiCl (39 mg, 0.36 mmol) was added; 30b
was obtained as a colorless liquid; yield: 85 mg (80%); Rf = 0.43
(Et2O–pentane, 1:4); tR = 15.5 min (HP 5).
Anal. Calcd for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found: C,
73.58; H, 9.74; N, 4.92.
(–)-(R)-Methyl 2-(Diisopropylcarbamoyloxy)-2-(2-ethylphe-
nyl)acetate [(R)-27d]
According to GPB, a mixture of carbamate 24 (79 mg, 0.30 mmol)
and 9d (116 mg, 0.36 mmol) was treated with s-BuLi (0.27 mL,
0.36 mmol) to generate the lithiated species. After 2.5 h the reaction
was continued according to the synthesis of 26c; 27d was obtained
as a highly viscous, colorless oil; yield: 67 mg (70%); Rf = 0.88
(Et2O–pentane, 1:1); tR = 15.9 min (HP 5).
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (4000:1),
0.3 mL·min–1, l = 210 nm]: tR = 11.8 (+), 17.1 min (–); 78% ee.
[a]D20 –26.9 (c 1.02, CHCl3).
IR (film): 3059, 2966, 2935, 2835, 1692, 1612, 1510, 1368, 1314,
1279, 1248, 1217, 1174, 1157, 1046, 877, 842, 767 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 9 H, (H3C)3Si], 1.22 [br s,
12 H, (H3C)2CH], 3.75 (s, 3 H, H3CO), 3.94 [ps s, 2 H, (H3C)2CH],
5.52 (s, 1 H, Hbenzylic), 6.81 (dd, 3JH2,H3 = 8.7 Hz, 4JH3,H3¢ = 1.3 Hz, 2
H, H3), 7.07 (dd, 4JH2,H2¢ = 1.3 Hz, 2 H, H2).
HPLC [CHIRA-GROM 1 (2·250 mm), hexane–i-PrOH (1000:1),
0.2 mL·min–1, l = 210 nm]: tR = 20.2 (+), 25.4 min (–); 78% ee.
[a]D20 –101.0 (c 0.96, CHCl3).
IR (film): 3064, 2970, 2936, 2877, 1758, 1692, 1493, 1436, 1369,
1297, 1263, 1213, 1188, 1159, 1134, 1075, 1046, 1017, 926, 906,
793, 757, 734, 627 cm–1
.
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

2916
H. Lange et al.
PAPER
13C NMR (75 MHz, CDCl3): d = –3.5 [(H3C)3Si], 21.2 [(H3C)2CH],
45.7 [(H3C)2CH], 55.1 (H3CO), 71.5 (Cbenzylic), 113.6 (C3), 126.7
(C2), 133.1 (C1), 155.6 (NC=O), 157.85 (C4).
MS (EI, 70 eV): m/z (%) = 322 [(M – CH3)]+ (6), 216 (28), 194 (14),
179 (49), 172 (28), 165 [CH3OC6H4CH2OCO]+ (20), 158 (13), 144
[OCb]+ (6), 135 (10), 130 (12), 121 [CH3OC6H4CH2]+ (19), 73
[(CH3)3Si]+ (100), 43 [C3H7]+ (23).
stereomer (S,S)-29 as single product; yield: 44 mg (41%); mp
109 °C (Et2O); Rf = 0.44 (Et2O–pentane, 1:1); tR = 19.3 min (HP 5).
[a]D20 –78.5 (c 0.28, CHCl3).
IR (ATR): 3232, 3126, 3085, 3032, 2969, 2936, 2903, 2875, 1705,
1679, 1485, 1451, 1378, 1360, 1324, 1280, 1247, 1223, 1177, 1093,
1047, 1028, 1006, 1000, 882, 868, 833, 758, 700, 638, 609, 588
cm–1.
Anal. Calcd for C18H31NO3Si: C, 64.05; H, 9.26; N, 4.15. Found: C,
63.88; H, 9.39; N, 4.00.
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 9 H, (H3C)3Si], 1.27 (t,
3JH3CCH2,H3CCH2 = 7.5 Hz,
3
H,
H3CCH2),
1.44
(d,
3JH3C,Hbenzylic = 7.4 Hz, 3 H, H3C), 2.51–2.58 (m, 1 H, H3CCHH),
2.69–2.73 (m, 1 H, H3CCHH), 4.80 (dq, 3JHbenzylic,NH = 7.3 Hz, 1 H,
(+)-(R)-1-(4-Methoxyphenyl)-1-(trimethylsilyl)methyl N,N-Di-
isopropylcarbamate [(R)-30b]
According to GPB, a mixture of carbamate 25 (265 mg, 1.00 mmol)
and 7 (282 mg, 1.20 mmol) was treated with s-BuLi (0.96 mL,
1.20 mmol) and then Me3SiCl (130 mg, 1.20 mmol) was added;
yield: 324 mg (96%); 40% ee.
Hbenzylic), 4.96 (ps s, 1 H, NH), 5.82 (s, 1 H, Hbenzylic), 7.00–7.40 (m,
9 H, Haryl, Hphenyl).
13C NMR (75 MHz, CDCl3): d = –3.4 [(H3C)3Si], 14.7 (H3CCH2),
25.7 (H3C), 27.1 (H3CCH2), 50.8 (Cbenzylic), 68.2 (Cbenzylic), 125.6,
125.9, 126.1, 127.2, 128.0, 128.6 (C3, C4, C5, C6, C2¢, C3¢), 134.6
(C2), 138.1 (C1¢), 141.0 (C1), 156.0 (NC=O).
[a]D20 +14.2 (c 1.00, CHCl3).
MS (ESI): m/z = 378.1875 [M + Na]+.
(–)-(S)-(2-Ethylphenyl)(trimethylsilyl)methanol [(S)-28]; Typi-
cal Procedure
Anal. Calcd for C21H29NO2Si: C, 69.90; H, 7.41; N, 4.29. Found: C,
69.64; H, 7.50; N, 4.26.
To a soln of carbamate (–)-(S)-27b (168 mg, 0.50 mmol) in THF (5
mL) was added 1 M DIBAL-H in n-hexane (5.00 mL, 5.00 mmol).
The mixture was refluxed for 16 h (TLC). The mixture was then
cooled to r.t. and diluted with Et2O (10 mL). 2 M HCl was added
until the two-phase system became clear. The phases were separat-
ed and the aqueous phase was extracted with Et2O (3 × 10 mL). The
combined organic layers were washed with sat. NaHCO3 and dried
(MgSO4). The solvents were removed in vacuo and the crude prod-
uct was purified by column chromatography (silica gel, Et2O–pen-
tane, 1:4) to give the pure product as a colorless liquid; yield: 90 mg
(86%); Rf = 0.61 (Et2O–pentane, 1:1); tR = 10.2 min (HP 5).
(–)-(S)-1-Phenylbut-3-en-1-ol [(S)-34]
According to the synthesis of (S)-28, benzyl carbamate (S)-20c
(80 mg, 0.29 mmol) was decarbamoylated using 1 M DIBAL-H in
n-hexane (2.90 mL, 2.90 mmol) in refluxing THF; (S)-34 was ob-
tained as a colorless liquid; yield: 32 mg (75%); Rf = 0.45 (Et2O–
pentane, 1:1); tR = 9.0 min (HP 5).
[a]D20 –32.9 (c 1.08, benzene).
(+)-(R)-1,1,2-Triphenylethane-1,2-diol [(R)-21]
HPLC [Chiralcel OD-H (4.6·250 mm), hexane–i-PrOH (200:1),
1.0 mL·min–1, l = 210 nm]: tR = 33.6 (+), 38.9 min (–); 98% ee.
[a]D20 –95.9 (c 0.64, CHCl3).
According to the synthesis of (S)-28, benzyl carbamate (R)-20h
(63 mg, 0.15 mmol) was decarbamoylated using 1 M DIBAL-H in
n-hexane (2.25 mL, 2.25 mmol) in refluxing THF; (R)-21 was ob-
tained as a colorless solid; yield: 30 mg (69%); mp 128 °C (Et2O);
Rf = 0.63 (Et2O–pentane, 1:1); tR = 6.7 min (HP 5).
IR (ATR): 3419, 3066, 3022, 2962, 2930, 2875, 1669, 1601, 1483,
1452, 1407, 1377, 1290, 1247, 1212, 1140, 1055, 990, 946, 859,
838, 753, 695, 651, 611 cm–1.
[a]D20 +179.7 (c 1.01, EtOH).
1H NMR (300 MHz, CDCl3): d = 0.03 [s, 9 H, (H3C)3Si], 1.21 (t,
(–)-(S)-1-(1-Naphthyl)but-3-en-1-ol [(S)-35]
3JH3CCH2,H3CCH2 = 7.7 Hz, 3 H, H3CCH2), 1.54 (ps s, 1 H, OH), 2.47
According to the synthesis of (S)-28, 1-naphthylmethyl carbamate
(S)-26b (98 mg, 0.30 mmol) was decarbamoylated using 1 M
DIBAL-H in n-hexane (3.00 mL, 3.00 mmol) in refluxing THF; (S)-
35 was obtained as a colorless liquid; yield: 101 mg (81%);
Rf = 0.70 (Et2O–pentane, 1:1); tR = 11.1 min (HP 5).
2
(dq, JH3CCHH,H3CCHH = 14.9 Hz, 1 H, H3CCHH), 2.60 (dq, 1 H,
H3CCHH), 4.83 (s, 1 H, Hbenzylic), 7.09–7.25 (m, 3 H, H3, H4, H5),
7.39 (br d, 3JH5,H6 = 7.4 Hz, 1 H, H6).
13C NMR (75 MHz, CDCl3): d = –3.7 [(H3C)3Si], 14.8 (H3CCH2),
25.3 (H3CCH2), 65.9 (Cbenzylic), 126.0 (br s, C4, C5, C6), 128.0 (C3),
139.3 (C2), 141.8 (C1).
[a]D20 –72.8 (c 1.04, benzene).
Computational details: For all calculations the Turbomole 5.9 suite
of programs39a was used. The structures of the complexes were op-
timized at DFT level employing the B97-D functional27a including
an empirical dispersion correction (DFT-D) using a Gaussian AO
basis set of triple-zeta quality with polarization functions on all at-
oms (TZVP)27b and numerical quadrature multiple grid (‘grid m4’
option in Turbomole).39b The resolution of the identity (RI)
approximation39c was applied for all DFT-calculations. Single point
energies were computed with SCS-MP227c using the TZVPP basis
set27b and also employing the RI-approximation.39d
MS (EI, 70 eV): m/z (%) = 208 [M]+ (15), 179 [M – Et]+ (72), 117
[C9H9]+ (93), 95 (13), 73 [(H3C)3Si]+ (100).
Anal. Calcd for C12H20OSi: C, 69.10; H, 9.67. Found: C, 68.99; H,
9.89.
(–)-(S,S)-[(2-Ethylphenyl)(trimethylsilyl)methyl] N-1-Phenyl-
ethylcarbamate [(S,S)-29]
A catalytic amount of DMAP was added to a soln of alcohol (–)-(S)-
28 (63 mg, 0.30 mmol, 98% ee) in DMF (5 mL). The mixture was
stirred at r.t. until it became clear. Then, (–)-(S)-1-phenylethyl iso-
cyanate (66 mg, 0.45 mmol) was added and the resulting mixture
was stirred at 60 °C until no starting material was detected (TLC).
Et2O (5 mL) and H2O (2 mL) were added prior to the addition of 2
M HCl (2 mL). The phases were separated and the aqueous phase
was extracted with Et2O (3 × 10 mL). The combined organic layers
were washed with sat. NaHCO3 and dried (MgSO4). The solvents
were removed in vacuo. Purification by column chromatography
(silica gel, Et2O–pentane, 1:6) yielded the colorless crystalline dia-
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 424), the Fonds der Chemischen Industrie (stipend for H.L.),
and the International NRW Graduate School of Chemistry, Mün-
ster, Germany (stipends for H.L. and R.H.). Excellent experimental
support by Mrs. Cornelia Weitkamp is gratefully acknowledged.
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

PAPER
Studies of Diamine Complexes of a-Lithiated Benzyl Carbamates
2917
connected to one particular enantiotopic face. For the
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Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York

2918
H. Lange et al.
PAPER
(31) For examples for the addition of carboxylic acid chlorides to
mesomerically stabilized a-lithiated carbamates under
inversion of configuration, see: (a) Ref. 3c and 3d.
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r
calcd = 1.0981 g cm–3, m = 10.52 cm–1, empirical absorption
correction (0.779 £ T £ 0.949), Z = 4, monoclinic, space
group C2 (No. 5), l = 1.54178 Å, T = 223 K, w and f scans,
5904 reflections collected ( h, k, l), [(sinq)/l] = 0.59 Å–1,
2448 independent (Rint = 0.048) and 1962 observed
reflections [I £ 2 s(I)], 254 refined parameters, R = 0.052,
Rw2 = 0.122, Flack parameter 0.02 (6), max. residual
electron density 0.17 (–0.23) e Å–3, hydrogen atoms
calculated and refined as riding atoms, CCDC 684785.
(38) Tomooka, K.; Shimizu, H.; Nakai, T. J. Organomet. Chem.
2001, 624, 364; and references cited therein.
(32) X-ray crystal structure analysis for (R)-20f: formula
C21H24BrNO3, M = 418.32, colorless crystals
0.30 × 0.30 × 0.15 mm, a = 5.774(1), b = 17.816(1),
c = 19.291(1) Å, V = 1984.5(4) Å3, rcalcd = 1.400 g cm–3,
m = 29.81 cm–1, empirical absorption correction (0.468 £ T £
0.663), Z = 4, orthorhombic, space group P212121 (No. 19),
l = 1.54178 Å, T = 223 K, w and f scans, 9441 reflections
collected ( h, k, l), [(sinq)/l] = 0.60 Å–1, 3384
independent (Rint = 0.034) and 3338 observed reflections [I
£ 2 s(I)], 239 refined parameters, R = 0.028, Rw2 = 0.074,
Flack parameter –0.021(15), max. residual electron density
0.28 (–0.24) e Å–3, hydrogen atoms calculated and refined as
riding atoms, CCDC 684786.
(39) TURBOMOLE V5.9: (a) Ahlrichs, R. et al.; University of
Karlsruhe: Germany, 2006, see: http://www.turbomole.com.
‘grid m4’: (b) Treutler, O.; Ahlrichs, R. J. Chem. Phys.
1995, 102, 346.
RI-approximation: (c) Eichkorn, K.; Treutler, O.; Öhm, H.;
Häser, M.; Ahlrichs, R. Chem. Phys. Lett. 1995, 242, 652.
(d) Eichkorn, K.; Weigend, F.; Treutler, O.; Ahlrichs, R.
Theor. Chem. Acc. 1997, 97, 119.
RI-MP2: (e) Sierka, M.; Hogekamp, A.; Ahlrichs, R. J.
Chem. Phys. 2003, 118, 9136. (f) Weigend, F.; Häser, M.
Theor. Chem. Acc. 1997, 97, 331. (g) Weigend, F.; Häser,
M.; Patzelt, H.; Ahlrichs, R. Chem. Phys. Lett. 1998, 294,
143.
(33) Ester (+)-(S)-20d was prepared by asymmetric lithiation of
benzyl carbamate 19 in the presence of chiral diamine (–)-
sparteine (7) in n-hexane at –78 °C (4 M soln). Trapping of
the equilibrated and crystallized intermediate epimeric
complex (SC)-15·7 with CO2 at –78 °C after 4 h and
subsequent esterification of the resulting carboxylic acid
(S)-22 with diazomethane yielded 78% of (+)-(S)-20d with
97% ee (HPLC) {[a]D20 +107.2 (c 0.92, MeOH)}. Compare:
(a) ref. 1a. (b) Retzow, S. Diploma Thesis; University of
Kiel: Germany, 1990.
(40) Tables containing the atom coordinates of the different
complexes can be obtained from the author upon request.
(41) Lange, H.; Fröhlich, R.; Hoppe, D. Tetrahedron 2008, 64,
9123.
(42) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41,
1879.
(43) de Boer, T. J.; Backer, H. J. Org. Synth. Coll. Vol. IV; John
Wiley & Sons: London, 1963, 250.
(34) Yang, W. K.; Cho, B. T. Tetrahedron: Asymmetry 2000, 11,
2947.
(44) (a) Blessing, R. H. Acta Crystallogr., Sect. A 1995, 51, 33.
(b) Blessing, R. H. J. Appl. Cryst. 1997, 30, 421.
(45) Otwinowski, Z.; Borek, D.; Majewski, W.; Minor, W. Acta
Crystallogr., Sect. A 2003, 59, 228.
(46) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467.
(47) SHELXL-97: Sheldrick, G. M. Acta Crystallogr., Sect. A
2008, 64, 112.
(35) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(36) All the bis(oxazoline) 9d containing complexes calculated
show values for this sum of angles between 314° [(RC)-
33·9d] and 316° [(RC)-32·9d] for the favored RC-configured
epimers and values around 312° to 313° for the unfavored
SC-configured epimers.
(48) SCHAKAL: Keller, E. University of Freiburg, Germany,
(37) X-ray crystal structure analysis for (S,S)-29: formula
C21H29NO2Si, M = 355.54, colorless crystals
1997
(49) These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data request/cif.
0.25 × 0.06 × 0.05 mm, a = 22.666(1), b = 7.897(1),
c = 12.669(1) Å, b = 108.45(1)°, V = 2151.1(3) Å3,
Synthesis 2008, No. 18, 2905–2918 © Thieme Stuttgart · New York