Enantioselective, (-)-sparteine-mediated deprotonation of geranyl and neryl N,N-diisopropylcarbamate: Configurational stability of the intermediate lithium compounds

Article abstract of DOI:10.1016/j.tet.2005.01.100

(E)/(Z)-Isomeric allylic carbamate esters were deprotonated by n-butyllithium/(-)-sparteine in toluene. Trapping experiments with chlorotrimethylsilane afforded the α-substitution products, with (R)-configuration, revealing that the pro-S proton is removed predominantly to form the corresponding (S)-lithium·(-)-sparteine derivatives; k _S/k_R>15:1 and >7:1, respectively. A slow (S)→(R)-epimerization occurs at -78°C (T_1/2>60 min). The allylic double bond is stable to (Z)-(E) isomerization under these conditions.

Full text of DOI:10.1016/j.tet.2005.01.100

Tetrahedron 61 (2005) 3281–3287
Enantioselective, (K)-sparteine-mediated deprotonation of
geranyl and neryl N,N-diisopropylcarbamate: configurational
stability of the intermediate lithium compounds
†
*
¨
Wenbin Zeng, Roland Frohlich and Dieter Hoppe
¨ ¨
Organisch-Chemisches Institut der Universitat, Corrensstrasse 40, D-48149 Munster, Germany
Received 1 November 2004; revised 1 December 2004; accepted 21 January 2005
Abstract—(E)/(Z)-Isomeric allylic carbamate esters were deprotonated by n-butyllithium/(K)-sparteine in toluene. Trapping experiments
with chlorotrimethylsilane afforded the a-substitution products, with (R)-configuration, revealing that the pro-S proton is removed
predominantly to form the corresponding (S)-lithium$(K)-sparteine derivatives; kS/kRO15:1 and O7:1, respectively. A slow (S)/(R)-
epimerization occurs at K78 8C (T1/2O60 min). The allylic double bond is stable to (Z)–(E) isomerization under these conditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
presence of cyclohexane, a selective crystallization of
complex (S)-3 takes place. As a consequence of the
dynamic thermodynamic resolution8 nearly all of the
material is converted into (S)-3.4 It can be transformed
stereospecifically via metal exchange with complete
stereoinversion to the corresponding tris(isopropoxy)-
titanium intermediate. On the other hand, the trisubstituted
cyclic allyllithium derivative (S)-4 undergoes epimerization
only very slowly (T1/2O10 h at K78 8C), rendering (S)-4
and related lithium intermediates synthetically very useful.9
Chiral carbanionic species play an important role in modern
stereoselective synthesis.1 In particular, the (K)-sparteine-
mediated deprotonation of suitable substrates provides an
efficient, rapid access to enantioenriched lithium inter-
mediates.2 As we found several years ago, O-alkyl-,3 O-2-
alkenyl-,4 O-benzyl-,5 and O-2-alkynyl6 carbamates react
with n-butyl- or s-butyllithium/(K)-sparteine (1) with
preferential abstraction of the pro-S-proton (Fig. 1). The
method was extended by Beak et al. to several
N-carbamates7 and benzylic compounds.2b The lithium
complexes (S)-2, formed from alkyl carbamates at K78 8C
with selectivities (S)/(R) between 50 to 100:1, are con-
figurationally stable below K70 8C and react with all
electrophiles with complete retention of the configuration.3
However, the epimeric ion pairs (S) and (R)-3 of the
lithiated crotyl carbamate turned out to be configurationally
unstable even in pentane solution at K78 8C. In the
Although the mechanism of the epimerization is not known
yet, it became clear that a high degree of substitution at the
allylic moiety and, usually, a secondary carbanionic center
support high configurational stability. Further information
on the configurational behaviour of the lithiated 2-alkenyl
carbamates is required. Unfortunately, the system is not
suitable for NMR investigation at low temperature, although
these (K)-sparteine complexes are monomeric even in the
Figure 1.
Keywords: (K)-Sparteine; Allyllithium; Asymmetric deprotonation; Stereoselectivity.
* Corresponding author. Tel.: C49 251 8333211; fax: C49 251 83 36531; e-mail: dhoppe@uni-muenster.de
† X-ray structure analysis.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.100

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W. Zeng et al. / Tetrahedron 61 (2005) 3281–3287
solid (for a representative X-ray structure analysis see
Ref. 10), line broadenings and splittings of the N,N-
diisopropylcarbamoyl group, due to slow rotation and
diastereotopicity, hamper NMR investigation severely.11
For question (1) we used an in situ experiment13 by
deprotonating either (E)- or (Z)-6 in toluene at K78 8C with
n-butyllithium/(K)-sparteine (1) (each 1.5 equiv) in the
presence of excess chlorotrimethylsilane (entry 1 and 6,
Table 1). The silylation of the carbanionic intermediates (S)/
(R)-7 or 8 is highly a-selective and proceeds with strict
inversion of the configuration11a,14 producing the a-silyl-
alkenyl carbamates (S)/(R)-9 and (S)/(R)-10, respectively.
The ratios of enantiomers were determined by 1H NMR shift
experiments in the presence of (C)-Eu(hfc)3. The R/S-ratio
expresses the minimum of kinetically controlled enantio-
topic differentiation in the deprotonation step. In principle,
errors might arise by a renewed deprotonation of silanes 9 or
10. These could be excluded by control experiments: Firstly,
n-butyllithium/1 is not able to deprotonate 9 and 10 under
the reaction condition. Secondly, the lithium compounds,
derived from silanes 9 and 10, undergo only very slow
epimerization. Enantiomeric ratios up to 93.5:6.5 (87% ee)
for (S)-9, starting from (E)-6, and up to 87.5:12.5 (75% ee)
for (S)-10 from (Z)-6 could be obtained. Using pentane as a
solvent under the same conditions (entry 1 and 6, Table 2)
these selectivities are diminished: 72% ee from (E)-6 and
61% ee from (Z)-6.
We have now studied the E/Z-isomers geranyl- and neryl
N,N-diisopropylcarbamate [(E)- and (Z)-6], which both
were prepared by our standard procedure from the pure
alcohols (E)- and (Z)-5 (Scheme 1), by applying lithiation
and trapping experiments. The results are presented herein.
Scheme 1.
2. Results and discussion
The following questions were addressed (Scheme 2):
For finding an answer to question (2), the reaction mixture
was allowed defined times for deprotonation before the
trapping agent Me3SiCl was added. Whereas the yields
increased (due to a higher degree of deprotonation), the er
decreased, giving evidence for configurational lability of the
lithium compounds in toluene at K78 8C. After 30 min, the
er of (R)/(S)-9 was 84.5:15.5 (69% ee, Table 1, entry 4), and
after 240 min (entry 5), the ratio 55.5:44.5 (11% ee)
presumably closely reflects the thermodynamically deter-
mined ratio of the epimers (S)- and (R)-7. Applying a lower
(1) What is the direction and magnitude of enantiotopos-
differentiating deprotonation of (E)- and (Z)-6 in the
presence of (K)-sparteine?
(2) How rapidly do the intermediate diastereomer pairs (R)-
and (S)-7, (R)- and (S)-8 epimerize under the reaction
conditions?
(3) Is there an interconversion of 7 and 8 occurring by E–Z
isomerization of the allylic double bond as we have
observed for an a-silyl-substituted derivative?12
Scheme 2. Reagents: (a) 1, n-BuLi, K78 8C. (b) ClSiMe3; MeOH.

W. Zeng et al. / Tetrahedron 61 (2005) 3281–3287
Table 1. Enantioselective deprotonation and silylation of (E)- and (Z)-6 in toluene
3283
Entry
Starting
material
Conditions
Time
(min)
Product(s)
Yield
(%)
Ratio
(R)/(S)
% ee
1
2
3
4
5
6
7
8
(E)-6
(E)-6
(E)-6
(E)-6
(E)-6
(E)-6
(Z)-6
(Z)-6
(Z)-6
(Z)-6
(Z)-6
(Z)-6
(Z)-6
In situa, K78 8C
In situa, K78 8C
K78 8C
(360)b
(90)b
15
9
9
9
9
9
9
10
10
10
10
10
10
10
76
37
47
59
85
30
43
75
84
87
87
88
31
88.5:11.5
93.5:6.5
77
87
73
69
11
75
75
69
44
12
4
86.5:13.5
84.5:15.5
55.5:44.5
87.5:12.5
87.5:12.5
84.5:15.5
72.0:28.0
56.0:44.0
52.0:48.0
50.5:49.5
90.5:9.5
K78 8C
K78 8C
30
240
In situa, K95 8C
In situa, K78 8C
K78 8C
(90)b
(180)b
15
9
K78 8C
K78 8C
120
240
10
11
12
13
K78 8C
K78 8C
360
480
1
81
In situa, K95 8C
(90)b
a Deprotonation was carried out in the presence of Me3SiCl.
b The reaction time is not identical with the standing time of 7 or 8.
Table 2. Enantioselective deprotonation and silylation of (E)- and (Z)-6 in pentane at K78 8C
Entry
Starting material
Conditions
Product(s)
Yield (%)
Ratio (R)/(S)
% ee
1
2
3
4
5
6
7
8
9
10
(E)-6
(E)-6
(E)-6
(E)-6
(E)-6
(Z)-6
(Z)-6
(Z)-6
(Z)-6
(Z)-6
In situa, (90)b
5 min
15 min
9
9
9
9
49
52
59
54
61
44
66
70
79
81
86.0:14.0
87.0:13.0
94.5:5.5
79.5:20.5
78.0:22.0
80.5:19.5
80.0:20.0
75.0:25.0
68.0:32.0
63.0:37.0
72
74
89c
59
56
61
60
50
36
26
30 min
60 min
9
In situa, (90)b
5 min
15 min
10
10
10
10
10
60 min
120 min
a n-Butyllithium was added to a solution of 6 and 1.
b Reaction time does not represent the standing time of the lithium compound.
c A crystallization was observed which disappeared after 30 min.
temperature K95 8C (entry 6), both rates of deprotonation
and epimerization are diminished.
isomerization in the lithium compounds 7 and 8, we
carefully investigated the reaction mixture by GC. In no
case, more than 2% of the opposite silane 9 or 10,
respectively, was found. So, at K78 8C, the 2,3-double
bond is perfectly stable against isomerization. This also
turned out for the corresponding lithium–TMEDA com-
plexes in toluene, pentane, and ether. Usually, substituted
allyllithium compounds undergo facile isomerization of the
2,3-double bond.16,17 Here again, the five-membered
chelate complex, accomplishing a strong contact of the
lithium cation with the a-carbon atom, causes an improved
configurational stability both of the stereogenic a-carbon
atom and the adjacent double bond.
The situation is similar for the experiments with (Z)-6
(entries 7–13), but the level of kinetically controlled
stereoselection (entry 7) of 87.5:12.5 (75% ee) is somewhat
lower. A kinetic resolution during the silylation step could
be excluded by the following experiment: neryl carbamate
(Z)-6 was deprotonated in toluene by sec-butyllithium at
K78 8C in the absence of any diamine, and later, (K)-
sparteine (1.5 equiv) was added before the chlorosilane was
introduced. The enantiomeric ratio (R/S) of silane 10 was
51:49 (59% yield). This result demonstrates that only a very
slow interconversion of the epimers 8 and epi-8 takes place.
2.1. Determination of the absolute configuration
A surprising result applying (E)-6 was obtained, when the
same series of experiments were carried out in n-pentane
(Table 2). The er of (S)-9 (94.5:5.5, 89% ee) after 15 min
reaction time (entry 3) exceeded the kinetically controlled
ratio (entry 1), 86:14 (72% ee); but it dropped again after
prolonged reaction times (entry 4 and 5). After 15 min, a
precipitate was observed in the reaction mixture, which
subsequently dissolved again. We have no sound expla-
nation for the phenomenon. Certainly, a dynamic thermo-
dynamic resolution of the diastereomers occurred,8 but the
nature of the precipitating associate remains unknown.15
All attempts to convert the optically active silanes (C)-9 or
(K)-10 into crystalline derivates, suitable for X-ray analysis
with anomalous dispersion, failed. Finally, the neryl
carbamate (Z)-6 was transformed with n-butyllithium/1
and chloromethyldiphenylsilane to (K)-11 (Scheme 3),
followed by DIBAL-H-mediated decarbamoylation,18 and,
subsequently, the a-silyl alcohol (C)-12 was added to
phenyl isocyanate to furnish the crystalline N-phenyl-
urethane (K)-13. The X-ray structure analysis with
anomalous dispersion of (K)-13 (Fig. 2) clearly shows the
(R)-configuration of the major enantiomer.19
Concerning the question (3) of double bond (Z)–(E)

3284
W. Zeng et al. / Tetrahedron 61 (2005) 3281–3287
Scheme 3. Reagents: (a) ClSiPh2Me, 1, n-BuLi (in situ procedure); 70%. (b) DIBAL-H in hexane (8 equiv), THF, 6 h, rt, 78%. (c) PhN]C]O, toluene,
pyridine, 70 8C, 4d, 77%.
4. Experimental
4.1. General
All organometallic reactions were performed under argon at
K78 8C with exclusion of air and moisture. Toluene was
distilled from sodium benzophenone ketyl before use and
THF was dried by refluxing over potassium/benzophenone.
Pentane was dried over CaH2 by refluxing overnight,
˚
distilled, and stored over 4 A molecular sieves under an
argon atmosphere; (K)-sparteine and TMEDA were dried
over CaH2 prior to use. LC separations were carried out at
0.5–1.5 bar on silica gel 40–63 mm (Merck, Darmstadt) with
petroleum ether (PE)/Et2O. Melting point: Gallenkamp
melting point apparatus MFB-595; value uncorrected.
Optical rotations: Perkin-Elmer 341 polarimeter. IR:
Nicolet 5 DXC. Infrared spectra were recorded on a Fourier
transform spectrometer and data were reported in wave
numbers (cmK1). NMR: Bruker ARX 300, AM 360, or
AMX 400. All NMR spectra were recorded using CDCl3 as
the solvent with reference to residual CHCl3 (1H at
7.24 ppm and 13C at 77.0 ppm). The 1H NMR shift
experiments were performed by addition of (C)-Eu(hfc)3
to a solution of enantioenriched product (20 mg) in CDCl3
(0.7 mL). Elemental analyses: Elementar Analysensysteme
Vario EL III. All new compounds gave satisfactory
elemental analyses (C, H G0.3%).
Figure 2. X-ray crystal structure analysis of (K)-13.19
Since all reported silylations of lithiated allyl carbamates14,2c
are known to proceed with inversion of the configuration,
the major epimer of lithium compounds 8 is likely to have
the (S) configuration.
The similar reaction sequence applied to (E)-6 did not lead
to crystalline urethanes. However, (S)-1D-geraniol [(C)-
15] (Scheme 4) is a known compound.20,21 Hence, (E)-6b
was deprotonated by means of n-butyllithium/(K)-sparteine
(Scheme 4), and addition of MeOD yielded the a-deuterated
carbamate (K)-14, followed by reductive cleavage with
DIBAL-H reduction to form (S)-1D-geraniol (C)-15.18 The
specific rotation of the sample ([a]2D0ZC0.97, cZ1.75 in
cyclopentane) matches well with the reported data C0.44
(cZ1.23)21 and C1.38 (cZ1.70).20 Since all known
protonation reactions of lithiated carbamates proceed with
retention, it is very likely that the major intermediate of 7
has the (S)-configuration.
4.1.1. (Z)-3,7-Dimethylocta-2,6-dienyl N,N-diisopropyl-
carbamate (Z)-6. A solution of nerol (12.6 g, 81.7 mmol) in
THF (100 mL) was added to a suspension of NaH (3.9 g,
60% in mineral oil) in THF (40 mL) under an argon
atmosphere. After refluxing for 2.5 h, CbCl (15.5 g,
1.17 equiv) in THF (40 mL) was added dropwise and the
mixture was refluxed for 17 h. Cooled with ice (50 g),
diluted with diethyl ether (60 mL), quenched with 2 N HCl
(15 mL), the reaction mixture was extracted with diethyl
ether. The combined organic layers were washed by
saturated NaHCO3 and brine, dried over MgSO4. Evapor-
ation of the solvents gave the crude product which was
purified by distillation under reduced pressure to yield (Z)-6
(17.5 g, 76%) as colourless oil. bp 112 8C (0.2 torr). IR
(film) n 2973, 2933, 2882, 1703 cmK1. 1H NMR (400 MHz,
Scheme 4. Reagents: (a) n-BuLi, 1; MeOD at K78 8C, 92%. (b) DIBAL-H
in hexane (8 equiv), THF, 8 h, rt, 78%.
3
0
0
CDCl3) d 1.20 (d, 12H, Cb-CH3, J2 ,1 Z6.8 Hz), 1.60, 1.67,
1.76 (each s, 9H, 3-CH3, 7-CH3, 8-H3), 2.04–2.12 (m, 4H,
4-H2, 5-H2), 3.68–3.91 (m, 2H, Cb-CH), 4.58 (d, 2H, 1-H,
JZ6.8 Hz), 5.08–5.14 (m, 1H, 6-H), 5.38 (t, 1H, 2-H, JZ
6.8 Hz). 13C NMR (100 MHz, CDCl3) d 21.4, 18.0, 26.0,
23.8, 27.1, 32.6, 46.1, 61.6, 120.8, 124.1, 132.3, 141.2,
156.2. ESI-MS (m/e) 304.4 [MCCNa]. C17H31NO2 calcd.
C 72.55 H 11.10 N 4.98; found C 72.55 H 11.42 N 4.83.
3. Conclusion
The kinetically controlled deprotonation of geranyl and
neryl carbamate (E)- and (Z)-6 by n-butyllithium/(K)-
sparteine removes preferentially the pro-S proton, leading to
the lithium intermediates (S)-7 and (S)-8, respectively.
These epimerize only slowly and have been employed in
synthetically useful enantioselective homoaldol reactions.22
4.1.2. (E)-3,7-Dimethylocta-2,6-dienyl N,N-diisopropyl-
carbamate (E)-6. The carbamate (E)-6 (18.8 g, 76%) was

W. Zeng et al. / Tetrahedron 61 (2005) 3281–3287
3285
obtained from geraniol (12.9 g, 83.8 mmol) and CbCl
(17.5 g, 1.27 equiv) according to the procedure for (Z)-6.
Colourless oil; bp 100 8C (0.1 torr). IR (film) n 2950, 2910,
1.66, 1.68 (each s, 9H, 3-CH3, 7-CH3, 8-H3), 2.00–2.05 (m,
4H, 4-H2, 5-H2), 3.69–3.91 (m, 2H, Cb-CH), 5.06–5.10 (m,
1H, 1-H), 5.14–5.18 (m, 1H, 6-H), 5.35 (d, 1H, 2-H, JZ
10.2 Hz). 13C NMR (75 MHz, CDCl3) d K3.6, 16.9, 17.6,
21.2, 25.7, 27.1, 39.9, 45.6, 67.4, 122.7, 126.3, 131.3, 135.7,
156.3. EI-MS (m/e) 353.2 [MC], 338.2 [MCKMe], 216.1
[MCKCb], 128.1 [CbC], 73.0 [SiMeC3 ]. C20H39NO2Si
calcd. C 67.93 H 11.12 N 3.96; found C 68.21 H 11.14 N
4.24.
1
1685 cmK1. H NMR (300 MHz, CDCl3) d 1.20 (d, 12 H,
3
0
0
Cb-CH3, J2 ,1 Z6.9 Hz), 1.60, 1.67, 1.70 (each s, 9H,
3-CH3, 7-CH3, 8-H3), 2.05–2.13 (m, 4H, 4-H2, 5-H2), 3.70–
3.91 (m, 2H, Cb-CH), 4.60 (d, 2H, 1-H, JZ6.9 Hz), 5.07–
5.13 (m, 1H, 6-H), 5.38 (t, 1H, 2-H, JZ6.9 Hz). 13C NMR
(75 MHz, CDCl3) d 16.5, 19.9, 24.5, 25.2, 38.4, 44.6, 60.3,
118.5, 122.8, 130.4, 139.6, 154.8. ESI-MS (m/e) 304.3
[MCCNa]. C17H31NO2 calcd. C 72.55 H 11.10 N 4.98;
found C 72.60 H 11.14 N 4.86.
4.3.2. (1R,2Z)-3,7-Dimethyl-1-(trimethylsilyl)-octa-2,6-
dienyl N,N-diisopropylcarbamate (10). As described
under Section 4.3, the solution of (Z)-6 (281 mg,
1.0 mmol), TMSCl (162 mg, 1.5 mmol), and (K)-sparteine
(351 mg, 1.5 mmol) was treated with n-BuLi (0.94 mL,
1.5 mmol, 1.6 M solution in hexane) at K78 8C. The
reaction mixture was stirred for 180 min at K78 8C, and
then quenched with MeOH. The described work-up
procedure and a subsequent purification of the crude
product by flash chromatography on silica gel (PE/E 15:1)
furnished 10 (153 mg, 43%); colourless oil; [a]2D0ZK15.0
(c 0.85 in MeOH); shift experiment: erZ87.5:12.5 (75%
ee), 23.5 mol % (C)-Eu(hfc)3. Rf (PE/Et2O, 8:1)Z0.66. IR
(film) n 2968, 2933, 2871, 1708. 1H NMR (400 MHz,
4.2. General procedure for the lithiation and silylation of
(E)- or (Z)-6
n-Butyllithium (1.5 equiv) was added dropwise with
vigorous stirring to a solution of allyl carbamate 6
(1.0 mmol) and diamine (1.5 equiv) in toluene (5 mL) at
K78 8C under an argon atmosphere. After this had been
stirred for a given time (Tables 1 and 2) at the same
temperature, the electrophile (1.5 equiv) was added. The
mixture was stirred for a given time (see Tables 1 and 2) at
K78 8C, after which it was quenched with MeOH (1 mL) at
the same temperature, and saturated NH4Cl solution
(10 mL) was added. The aqueous layer was extracted with
diethyl ether (3!15 mL). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuum. The residues were purified by
silica gel flash column chromatography.
CDCl3) d 0.00 (s, 9H, Si–CH3), 1.21 (d, 12H, Cb-CH3,
3
0
0
J2 ,1 Z6.8 Hz), 1.61, 1.68, 1.74 (each s, 9H, 3-CH3, 7-CH3,
8-H3), 2.10–2.20 (m, 4H, 4-H2, 5-H2), 3.68–3.89 (m, 2H,
Cb-CH), 5.15–5.20 (m, 2H, 6-H, 1-H), 5.36 (d, 1H, 2-H, JZ
11.2 Hz). 13C NMR (100 MHz, CDCl3) d K3.4, 17.5, 21.1,
23.4, 25.5, 26.7, 32.4, 45.2, 66.8, 124.4, 122.2, 131.2, 137.3,
156.0. ESI-MS (m/e) 376.4 [MCCNa], 729.7 [2MCCNa].
C20H39NO2Si calcd. C 67.93 H 11.12 N 3.96; found C 67.78
H 11.23 N 3.75.
4.3. General procedure for the in situ lithiation and
silylation of (E)- or (Z)-6
To a pre-dried one-necked round bottomed flask under
argon atmosphere, was added allyl carbamate 6 (1.0 mmol),
(K)-sparteine (1.5 equiv), toluene (5 mL), and the chloro-
silane (1.5 equiv). After the reaction mixture was cooled to
K78 8C, 1.6 M n-BuLi (1.5 equiv) was added slowly while
stirring. Stirring was continued for a given time (Tables 1
and 2), the reaction was quenched with methanol (1 mL) at
K78 8C. Saturated NH4Cl solution was added to the
reaction mixture. The aqueous layer was extracted with
diethyl ether (3!15 mL). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, and
then concentrated in vacuum; the crude product was purified
by silica gel flash column chromatography.
4.3.3. (1R,2Z)-3,7-Dimethyl-1-(methyldiphenylsilyl)-
octa-2,6-dienyl N,N-diisopropylcarbamate (11). As
described under Section 4.3, the solution of (Z)-6
(562 mg, 2.0 mmol), chloromethyldiphenylsilane (1.420 g,
2.0 equiv), and (K)-sparteine (701 mg, 1.5 mmol) was
treated with n-BuLi (1.87 mL, 3.0 mmol, 1.6 M solution
in hexane) at K78 8C. The reaction mixture was stirred for
210 min at K78 8C, and then quenched with MeOH. The
described work-up procedure and a subsequent purification
of the crude product by flash chromatography on silica gel
(PE/E 15:1) furnished 11 (920 mg, 70%); colourless oil;
[a]2D0ZK10.7 (c 1.04 in MeOH). Rf (PE/Et2O, 8:1)Z0.57.
Determination of the enantiomeric excess failed by using
(C)-Eu(hfc)3 or (C)-Pr(hfc)3 in CDCl3. IR (film) n 2973,
1
2934, 2874, 1690. H NMR (300 MHz, CDCl3) d 0.63 (s,
4.3.1. (1R,2E)-3,7-Dimethyl-1-(trimethylsilyl)-octa-2,6-
dienyl N,N-diisopropylcarbamate (9). As described
under Section 4.3, the solution of (E)-6 (281 mg,
1.0 mmol), TMSCl (162 mg, 1.5 equiv), and (K)-sparteine
(351 mg, 1.5 mmol) was treated with n-BuLi (0.94 mL,
1.5 mmol, 1.6 M solution in hexane) at K78 8C. The
reaction mixture was stirring for 90 min at K78 8C then
quenched with MeOH. The described work-up procedure
and a subsequent purification of the crude product by flash
chromatography on silica gel (PE/E 20:1) furnished 9
(130 mg, 37%); colourless oil; [a]2D0ZC16.9 (c 0.90 in
MeOH); shift experiment: erZ93.5:6.5 (87% ee), 17.9 mol
% (C)-Eu(hfc)3. Rf (PE/Et2O, 8:1)Z0.47. IR (film) n 2967,
3
0
0
3H, Si–CH3), 1.21 (d, 12H, Cb-CH3, J2 ,1 Z6.9 Hz), 1.51,
1.63, 1.68 (each s, 9H, 3-CH3, 7-CH3, 8-H3), 2.00–2.05 (m,
4H, 4-H2, 5-H2), 3.70–3.90 (m, 2H, Cb-CH), 5.00–5.05 (m,
1H, 6-H), 5.30 (d, 1H, 1-H, JZ10.8 Hz), 5.98 (d, 1H, 2-H,
JZ10.8 Hz), 7.18–7.40 (m, 10H, Ph). 13C NMR (75 MHz,
CDCl3) d K4.9, 17.7, 21.0, 23.4, 25.5, 26.3, 32.4, 45.7,
65.9, 121.9, 124.6, 127.6, 127.9, 129.3, 129.9, 131.1, 134.0,
134.3, 155.4. ESI-MS (m/e) 537.7 [MCCNaCK], 500.6
[MCCNa]. C30H43NO2Si calcd. C 75.42 H 9.07 N 2.93;
found C 75.24 H 9.12 N 2.91.
4.3.4. (1R,2Z)-3,7-Dimethyl-1-(methyldiphenylsilyl)-
octa-2,6-dien-1-ol (12). DIBAL-H (1.0 M in hexane,
12.0 mL) was added dropwise to a solution of the carbamate
1
2931, 2883,1692. H NMR (300 MHz, CDCl3) d 0.01 (s,
0
3
0
9H, Si–CH3), 1.20 (d, 12H, Cb-CH3, J2 ,1 Z6.9 Hz), 1.59,

3286
W. Zeng et al. / Tetrahedron 61 (2005) 3281–3287
(R)-11 (826 mg, 1.89 mmol) in anhydrous THF (14 mL) at
0 8C. The reaction mixtures were stirred for 6 h at room
temperature. After it had been again cooled to 0 8C, MeOH
(20 mL) was added, followed by saturated solution of
NH4Cl (30 mL). The aqueous phase was extracted with
Et2O (3!30 mL). The combined organic layers were
washed with saturated NaHCO3 and brine, dried over
anhydrous MgSO4. Purification of the crude product by
flash chromatography on silica gel (PE/E, 4:1) yielded
alcohol (R)-12 (515 mg, 78%) as a colourless liquid.
[a]2D0ZC31.5 (c 1.08 in MeOH). Rf (PE/Et2O, 2:1)
Z0.43. Attempts to determine the ee failed by using (C)-
Eu(hfc)3 or (C)-Pr(hfc)3 in CDCl3. IR (film) n 3384, 2965,
in MeOH). Rf (PE/Et2O, 8:1)Z0.47. IR (film) n 2967, 2930,
2882, 1695. H NMR (300 MHz, CDCl3) d 1.20 (d, 12 H,
1
3
0
0
Cb-CH3, J2 ,1 Z6.9 Hz), 1.60, 1.67, 1.69 (each s, 9H,
3-CH3, 7-CH3, 8-H3), 2.03–2.10 (m, 4H, 4-H2, 5-H2), 3.70–
3.92 (m, 2H, Cb-CH), 4.57 (d, 1H, 1-H, JZ6.9 Hz), 5.05–
5.09 (m, 1H, 6-H), 5.36 (d, 1H, 2-H, JZ6.9 Hz). 13C NMR
(75 MHz, CDCl3) d 16.8, 21.4, 26.0, 26.7, 29.4, 39.9, 45.6,
61.8, 120.0, 124.3, 132.0, 141.1, 156.3. EI-MS (m/e) 282.3
[MC], 213.2 [MCKC5H9], 128.1 [CbC], 94.1 [C7H1C0], 86.1
[C4H9NOC], 69.1 [C5H9C]. C17H30DNO2 calcd. C 72.29 H
11.42 N 4.96; found C 72.66 H 11.29 N 4.84.
4.3.7. (1S,2E)-1-Deuterio-3,7-dimethyl-octa-2,6-dien-1-
ol (15). As described for (R)-12, DIBAL-H (1.0 M in
hexane, 5.4 mL) was added dropwise to a solution of the
carbamate (S)-14 (190 mg, 0.67 mmol) in anhydrous THF
(4 mL) at 0 8C. The reaction mixture was stirred for 8 h at
room temperature. After it had been cooled to 0 8C,
methanol (2 mL) was added, followed by saturated solution
of NH4Cl. The usual work-up was done and a subsequent
purification of the crude product by flash chromatography
on silica gel (PE/E 5:1) furnished 15 (81 mg, 78%) as a
colourless liquid. Deuterium content was O99% (mass
spectral analysis); [a]2D0ZC0.97 (c 1.75 in cyclopentane).
Other spectral data correspond to Refs. 20, 21.
1
2929, 2833, 1602. H NMR (300 MHz, CDCl3) d 0.52 (s,
3H, Si–CH3), 1.56, 1.69, 1.73 (each s, 9H, 3-CH3, 7-CH3,
8-H3), 1.96–2.04 (m, 4H, 4-H2, 5-H2), 4.66 (d, 1H, 1-H, JZ
10.8 Hz), 5.00–5.06 (m, 1H, 6-H), 5.37 (d, 1H, 2-H, JZ
10.8 Hz), 7.25–7.40 (m, 10H, Ph). 13C NMR (75 MHz,
CDCl3) d K6.4, 15.2, 17.6, 23.4, 25.6, 49.5, 66.8, 124.0,
125.3, 127.3, 127.7, 128.8, 129.7, 131.9, 134.0. EI-MS (m/e)
350.3 [MC], 335.2 [MCKCH3], 268.2 [MCKC6H10],
197.1 [SiPh2MeC], 121.1 [SiPhMeC], 69.1 [C5HC9 ].
C23H30OSi calcd. C 78.80 H 8.63; found C 78.78 H 8.75.
4.3.5. (1R,2Z)-3,7-Dimethyl-1-(methyldiphenylsilyl)-
octa-2,6-dienyl N-phenylcarbamate (13). Under argon, a
solution of methyldiphenylsilyl alcohol (R)-12 (158 mg,
0.45 mmol), phenyl isocyanate (126 mg, 1.06 mmol,
2.35 equiv) and pyridine (21 mg, 0.60 equiv) in toluene
(1 mL) was stirred for 4 days at 70 8C. The solution was
poured into a mixture of Et2O (10 mL) and 2 N aq HCl
(3 mL). The aqueous phase was extracted with Et2O (3!
15 mL). The combined organic layers were washed with
saturated NaHCO3 and brine, dried over anhydrous Na2SO4,
and then concentrated in vacuum. Flash chromatography
(PE/Et2O, 5:1) of the crude product gave (R)-13 (163 mg,
77%) as a white solid. mp 105–106 8C (PE/Et2O).
[a]2D0ZK21.3 (c 1.20 in MeOH). Rf (PE/Et2O, 8:1)Z0.27.
Acknowledgements
Generous support by the Deutsche Forschungsgemeinschaft
(SFB 424), the Fonds der Chemischen Industrie, and the
NRW International Graduate School of Chemistry at
University of Mu¨nster (fellowship for W. Zeng) are
gratefully acknowledged.
1
IR (KBr) n 3352, 2962, 2926, 2852, 1695, 1604, 1535. H
References and notes
NMR (300 MHz, CDCl3) d 0.82 (s, 3H, Si–CH3), 1.75, 1.82,
1.87 (each s, 9H, 3-CH3, 7-CH3, 8-H3), 2.20–2.25 (m, 4H,
4-H2, 5-H2), 4.95–4.99 (m, 1H, 6-H), 5.19 (d, 1H, 1-H, JZ
10.8 Hz), 5.87 (d, 1H, 2-H, JZ10.8 Hz), 6.36 (s, 1H, N–H),
7.34–7.49 (m, 15H, Ph). 13C NMR (75 MHz, CDCl3) d
K5.8, 17.6, 22.6, 23.5, 26.4 (C-5), 39.8, 66.0, 118.8, 121.0,
123.2, 124.3, 127.8, 129.6, 131.4, 133.8, 134.4, 135.0,
138.1, 153.6. ESI-MS (m/e) 469.3 [MC], 400.2
[MCKC5H9], 256.1 [MCKCH3–SiPh2Me], 197.1 [SiPh2-
MeC], 136.1 [OCNHPhC], 69.1 [C5HC9 ]. C27H37NO2Si
calcd. C 76.71 H 7.51 N 2.98; found C 76.51 H 7.50 N 2.85.
1. Reviews: several authors in Organolithiums in Enantio-
selective Synthesis, Hodgson, D. M., Ed.; Topics in Organo-
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2376–2410. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
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Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365–390.
4.3.6. (1S,2E)-1-Deuterio-3,7-dimethylocta-2,6-dienyl
N,N-diisopropylcarbamate (14). As described under
Section 4.1.1, the solution of (E)-6 (281 mg, 1.0 mmol)
and (K)-sparteine (351 mg, 1.5 mmol) was treated with
n-BuLi (0.94 mL, 1.5 mmol, 1.6 M solution in hexane) at
K78 8C. The reaction mixture was stirring for 30 min at
K78 8C. MeOD (0.06 mL, 50 mg) was added to the solution
and the mixture was stirred for 1 h. The usual work-up was
done and a subsequent purification of the crude product by
flash chromatography on silica gel (PE/E 10:1) furnished 15
(260 mg, 92%); deuterium content was O99% (mass
spectral analysis); colourless liquid. [a]2D0ZK0.45 (c 1.34
3. (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. 1990, 102,
1457–1459. (b) Hoppe, D.; Hintze, F.; Tebben, P. Angew.
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(b) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl. 1989,
28, 69–71. (c) Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis
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5. For the more efficient deprotonation of enantioenriched
¨
precursors see: (a) Hoppe, D.; Carstens, A.; Kramer, T.
Angew. Chem. 1990, 102, 1455–1456. (b) Hoppe, D.; Carstens,
¨
A.; Kramer, T. Angew. Chem., Int. Ed. Engl. 1990, 29,

W. Zeng et al. / Tetrahedron 61 (2005) 3281–3287
3287
1424–1425. (c) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50,
6097–6108.
17. Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc.
1991, 113, 5893–5895.
¨
6. (a) Schultz-Fademrecht, C.; Wibbeling, B.; Frohlich, R.;
Hoppe, D. Org. Lett. 2001, 3, 1221–1224. (b) Dreller, S.;
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2001, 624, 364–366.
19. X-ray crystal structure analysis: formula C30H35NO2Si, MZ
7. (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113,
9708–9709. (b) Weisenburger, G. A.; Beak, P. J. Am. Chem.
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469.68, colourless crystal 0.55!0.15!0.10 mm, aZ
3
˚
˚
21.870(1), cZ15.137(1) A, VZ6270.0(6) A , rcalc
Z
1.120 g cmK3, mZ9.29 cmK1, empirical absorption correction
(0.629%T%0.913), ZZ9, trigonal, space group P32 (No.
˚
145), lZ1.54178 A, TZ223 K, u and f scans, 30,818
K1
˚
reflections collected (Gh, Gk, Gl), [(sin q)/l]Z0.60 A
,
10,055 independent (RintZ0.041) and 6304 observed reflec-
tions [IR2s(I)], 941 refined parameters, RZ0.051, wR2Z
0.126, Flack parameter K0.04(3), max. residual electron
density 0.27 (K0.30) e AK3, hydrogens calculated and refined
˚
as riding atoms. Data set was collected with a Nonius
KappaCCD diffractometer. Programs used: data collection
COLLECT (Nonius B. V., 1998), data reduction Denzo-SMN
(Otwinowski, Z.; Minor, W. Meth. Enzymol., 1997, 276, 307–
326), absorption correction data SORTAV (Blessing, R. H.
Acta Crystallogr. 1995, A51, 33–37; Blessing, R. H. J. Appl.
Crystallogr. 1997, 30, 421–426), structure solution SHELXS-
97 (Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473),
structure refinement SHELXL-97 (Sheldrick, G. M. Universi-
¨
9. (a) Ozlu¨gedik, M.; Kristensen, J.; Wibbeling, B.; Frohlich, R.;
¨
¨
Hoppe, D. Eur. J. Org. Chem. 2002, 414–427. (b) Ozlu¨gedik,
¨
M.; Kristensen, J.; Reuber, J.; Frohlich, R.; Hoppe, D.
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10. (a) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D.
Angew. Chem. 1995, 107, 2328–2330. (b) Hoppe, I.; Marsch,
M.; Harms, K.; Boche, G.; Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2158–2160.
¨
¨
tat Gottingen, 1997), graphics SCHAKAL (Keller, E. 1997).
Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication CCDC-252331. Copies of the data can be
obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: int.
code C44(1223)336-033, e-mail: deposit@ccdc.cam.ac.uk].
20. Nishizawa, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
2821–2824.
¨
11. (a) Behrens, K.; Frohlich, R.; Meyer, O.; Hoppe, D. Eur.
J. Org. Chem. 1998, 2397–2403. (b) Heinl, T.; Retzow, S.;
Hoppe, D.; Fraenkel, G.; Chow, A. Chem. Eur. J. 1999, 5,
3464–3470.
12. (a) van Hu¨lsen, E.; Hoppe, D. Tetrahedron Lett. 1985, 26,
411–414. (b) Rehders, F.; Hoppe, D. Synthesis 1992, 865–870.
13. Under the reaction conditions, n-BuLi and s-BuLi react only
slowly with Me3SiCl.9a
14. Deiters, A.; Hoppe, D. J. Org. Chem. 2001, 66, 2842–2849.
15. One possibility is, that a complex from (S)-7 and starting
material (E)-6 crystallizes, which redissolves when (E)-6 is
being consumed to a larger extent.
21. Inoue, S.; Takaya, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori, R.
J. Am. Chem. Soc. 1990, 112, 4897–4905.
¨
¨
22. Zeng, W. Dissertation, Universitat Munster, 2004.
16. Schlosser, M.; Desponds, O.; Lehmann, R.; Moret, E.;
Rauchschwalbe, G. Tetrahedron 1993, 49, 10175–10203.