Asymmetric γ-deprotonation and substitution reactions of (Z)-1,3-diphenyl-1-propenyl N,N-diisopropylcarbamate

Article abstract of DOI:10.1002/ejoc.200500145

(Z)-1,3-Diphenyl-1-propenyl N,N-diisopropylcarbamate (6d) is deprotonated by n-butyllithium/(-)-sparteine (5) with a high degree of enantiotopic differentiation in the γ-position to form the enantiomerically enriched allyllithium derivative 7d. Despite of

Full text of DOI:10.1002/ejoc.200500145

FULL PAPER
Asymmetric γ-Deprotonation and Substitution Reactions of (Z)-1,3-Diphenyl-
1-propenyl N,N-Diisopropylcarbamate
Jenny Reuber,[a] Roland Fröhlich,[a][‡] and Dieter Hoppe*[a]
Keywords: Asymmetric synthesis / Carbanions / Allylic compounds / Homoaldol addition / (–)-Sparteine
(Z)-1,3-Diphenyl-1-propenyl N,N-diisopropylcarbamate (6d)
is deprotonated by n-butyllithium/(–)-sparteine (5) with a
high degree of enantiotopic differentiation in the γ-position
to form the enantiomerically enriched allyllithium derivative
7d. Despite of its high mesomeric stabilization it shows a high
degree of configurational stability. Trapping with carbonyl
electrophiles proceeds exclusively in a syn-SEЈ substitution
as shown by direct assignments and stereochemical corre-
lations. Thus, the involvement of a η3 complex is suggested.
After transfer to the analogous allyltitanates 16 enantiomer-
ically and diastereomerically pure homoaldol products 17 are
furnished. Evidence for a competing retro-homoaldol reac-
tion is reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
hydes with a high degree of chirality transfer to give anti-
configured 4-hydroxy-1-alkenyl carbamates 3 which are
enol esters of γ-hydroxy carbonyl compounds.[2] The enan-
tiomeric ratio of 3 usually reflects the enantiomeric purity
of intermediates 2. Other electrophiles such as trialkylsilyl-
and trialkyltin halides prefer anti-SEЈ substitution to form
preferentially products 4. Lithium compound 1 (R1, R2 =
alkyl, L2 = TMEDA) could be produced by deprotonation
of the enantioenriched precursors and are configurationally
stable in diethyl ether or pentane below –70 °C.[3] Configu-
rational stability was also found for appropriate α,γ-disub-
stituted (–)-sparteine complexes (L2 = 5) furnished from ra-
cemic precursors through kinetic resolution during depro-
tonation.[4]
Introduction
Nonracemic, chiral lithio-2-alkenyl N,N-diisopropylcarb-
amates 1 proved to be valuable intermediates in enantiose-
lective homoaldol reactions (Scheme 1).[1]
Previously, a surprising and efficient approach to highly
enantioenriched 1,3-disubstituted (–)-sparteine complexes
was found through γ-deprotonation of achiral 1-alkenyl
carbamates 6a–c (Scheme 2).[5,6]
Scheme 1.
Their synthetic utility largely depends on the configura-
tional stability of the lithium intermediates 1. After trans-
metallation to titanium compounds 2, these add to alde-
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-
versität Münster,
Corrensstrasse 40, 48149 Münster, Germany
Fax: +49-251-8336531
E-mail: dhoppe@uni-muenster.de
[‡] To whom correspondence regarding X-ray analysis should be
addressed.
Scheme 2.
Eur. J. Org. Chem. 2005, 3017–3025
DOI: 10.1002/ejoc.200500145
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J. Reuber, R. Fröhlich, D. Hoppe
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In most cases, diastereomeric ratios of the carbanionic methyl chloroformate with formation of ester (+)-15
intermediates 7a–c:8a–c of greater than 95:5 were produced, (96% op) also produced highly enantioenriched products
as determined by trapping experiments.[5,6] The question if when the reaction was carried out at –90 °C (Scheme 5).
the 1,3-diphenyl-substituted 7d has considerable configura- Lower enantiomeric excesses (89% ee and 69% ee, respec-
tional stability, due to its high mesomeric stabilization, is tively) were recorded at the usual reaction temperature of
now addressed. This issue was questionable since the (–)-α- –78 °C, presumably due to subsequent partial enolization at
isosparteine complex 9 (Figure 1) and the appropriate (–)- the stage of the carbonyl compounds. For assignment of the
sparteine complex, of which an X-ray structure analysis absolute configurations see below.
could be obtained, is configurationally labile even at
–78 °C.[7]
Figure 1.
Results and Discussion
1,3-Diphenylallyl carbamate was obtained by heating
1,3-diphenyl-1-propanone (10) with N,N-diisopropylcarb-
Scheme 5.
amoyl chloride (CbCl) in pyridine (Scheme 3).[8]
Homoaldol Reactions
The exchange of the lithium cation in compound 7 with
[10]
ClTi(NEt2)3
to covalently bound intermediate 16 pro-
ceeds with inversion of the configuration (Scheme 6). Re-
markably, acetone now forms the opposite enantiomer
(–)-13. Since in the titanation method one inversion step is
involved, it is concluded that both intermediates 7d and 16
undergo a syn-SEЈ-reaction with acetone. An X-ray struc-
ture analysis of the p-bromobenzaldehyde adduct 17e re-
veals (Figure 2), besides the 3,4-anti- and the (1Z)-configu-
ration, the absolute configuration (R) at C-3; this is in ac-
cordance with (S)-7 as the lithium precursor (Scheme 6).
The enantiomeric excesses of compounds (–)-13 and (–)-
17, obtained after lithium-titanium exchange (Method A,
Table 1), vary between 73 and 92% ee. This is surprising,
since usually the enantiomeric purity of the titanium inter-
mediate determines the enantiomeric excesses of the prod-
ucts and leads therefore to equally high enantiomeric ex-
cesses with different carbonyl electrophiles. In a second set
of experiments, Ti(OiPr)4 (3.0 equiv.) was added (Method
B) together with the carbonyl compound and the optical
purities rose up to 99%. We assumed that a retro-homoal-
dol reaction, which might not be completely stereospecific,
Scheme 3.
Deprotonation with n-butyllithium/(–)-sparteine (5) in
toluene at –78 °C furnished immediately a deeply red solu-
tion of the carbanion, which was quenched below –70 °C
after 30 min with CH3CO2D/MeOD to give a mixture of
the γ- and α-deuterated precursors 11 and 12 with 97%
yield in a ratio 1:2, indicating complete and rapid deproton-
ation (Scheme 4).[9]
Scheme 4.
No substantial reaction of 7d and 8d occurred with chlo- comes into operation,[11] due to the high stabilization of the
ro(trimethyl)silane or chloro(tributyl)tin, indicating a low carbanionic part. The involvement of a partial retro-cleav-
reactivity of the intermediate carbanionic species.
Trapping the lithium species by acetone yielded the the acetone adduct (–)-13 by the following experiments:
homoaldol product (+)-13 with high yield and Ն 95% ee Compound (–)-13 was converted by n-butyllithium/(–)-
age was confirmed for the lithium alcoholate, derived from
(Scheme 5). Acylations with excess 2,2-dimethylpropanoyl sparteine (5) into its alcoholate and stirred with excess 2,2-
chloride to form the ketone (+)–14 (99% op) and with dimethylpropanal for 1 h at –90 °C affording 17d with
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γ-Deprotonation and Substitution of (Z)-1,3-Diphenyl-1-propenyl N,N-Diisopropylcarbamate
FULL PAPER
Table 1. Yields and enantiomeric purities of homoaldol products
(–)-17 and (–)-13.
R1
R2 17
Method A[a]
Method B[b]
Yield
Yield
ee/op
ee
(%)
(%)
(CH3)2CHCH2
(CH3)2CH
c-propyl
(CH3)3C
p-Br-C6H4
CH3
H
H
H
H
H
a
b
c
d
e
–
83
–
75
59
88
–
68
81
64
92
77
48
91%
99%
Ն 95%
91%
Ն 95%
Ն 95%
89% ee
–
92% ee
89% op
73% op
CH3 13
[a] Method A: i. n-butyllithium/(–)-5, toluene, –78 °C, 30 min; ii.
ClTi(NEt2)3, –78 °C, 30 min; iii. RCHO; iv. H+. [b] Method B: i. n-
butyllithium/(–)-5, toluene, –90 °C, 20 min; ii. ClTi(NEt2)3, –90 °C,
15 min; iii. RCHO/Ti(OiPr)4; iv. H+.
Scheme 6.
Scheme 7.
Stereochemical Correlations
Scheme 8 summarizes the stereochemical relationships
which could be established by either direct assignments or
chemical correlations.
All carbonyl additions of aldehydes, ketones and acid
chlorides onto lithium intermediate (S)-7 proceed as highly
γ-selective syn-SEЈ processes. This fact implies the involve-
ment of a η3-ion pair 7B, since in all reactions, where an
allylic η3-intermediate is likely to contribute, similar stereo-
chemical characteristics had been recorded by Hoppe et
al.[6,12] and Beak et al.[13,14] It seems that η3-allyllithium
compounds (e.g. 7B) have a higher Lewis acidity than the
η1-isomers (e.g. 7A) and thus, the lithium cation “lures” all
Figure 2. X-ray structure of 17e.
3% yield and 38% op (Scheme 7). A similar experiment in incoming carbonyl electrophiles by complexation to enter
the presence of 5 equiv. of 2,2-dimethylpropanoyl chloride, from the face accommodating it. It is concluded on the base
which was carried out at –78 °C, furnished the ketone (–)- of the experimental results, that the lithium carbanion pair
14 with 21% yield and 49% op. Although the reasons are 7 is highly diastereomerically enriched and possesses a con-
unknown, the addition of Ti(OiPr)4 (3.0 equiv.) suppresses siderable configurational stability at and below –78 °C. We
the formation of 17d under these conditions. Excess here exclude a mobile equilibrium between diastereomeric
Ti(OiPr)4 might retard the retro-homoaldol reaction by for- carbanion pairs and a kinetic resolution[15] in the substitu-
mation of the less reactive titanium alkoxide of 13.
tion step as the origin of high enantioenrichment, since all
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Scheme 8.
accomplished with UV light and KMnO4 or vanilline solution.
Column chromatography was carried out at 1.5 bar on silica gel
40–63 μm (Merck, Darmstadt). Only distilled solvents were used as
eluents. 1H NMR and 13C NMR spectra were recorded at room
applied electrophiles lead to substitution products of nearly
identical enantiomeric excesses.
After lithium–titanium exchange under stereoinversion,
the addition of aldehydes and ketones leads, via a Zimmer-
man–Traxler transition state, to the opposite enantiomers
ent-17 or ent-13 (Scheme 8).
1
temp. with a Bruker AM 300 (300 MHz and 75.5 MHz for H and
13C NMR, respectively) or with a Bruker AM 400 (400 MHz and
100 MHz for 1H and 13C NMR, respectively). CDCl3 or C6D6 were
1
used as solvents; chemical shifts are reported in ppm (δ); H shifts
are related to TMS and 13C shifts to δC = 77.0 ppm; multiplicities
are indicated by s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), mc (centric multiplet) and bs (broad singlet); ψ refers
to pseudo signals; * refers to signals which are interchangeable;
brackets refer to signals which arise from frozen rotations of the
amide bond. The numbering of the compounds can differ from
the IUPAC name. Mass spectroscopy and elemental analysis were
performed at the Institute of Organic Chemistry, University of
Conclusions
In summary, the methodology outlined above permits
the simple generation of enantiomerically pure (1,3-di-
phenylallyl)lithium carbanion pairs. The absolute configu-
ration of intermediate 7 as well as the substitution mecha-
nism to carbonyl electrophiles was determined. After trans-
fer to the analogous allyl titanate 16, enantiomerically and Münster. IR absorption spectra were recorded using a Perkin–El-
mer 298. The optical rotations were measured using a Perkin–El-
mer polarimeter 241. Melting points are not corrected.
diastereomerically pure homoaldol products are accessible
in the reaction with aldehydes.
(Z)-1,3-Diphenyl-1-propenyl N,N-Diisopropylcarbamate (6d): N,N-
Diisopropylcarbamoyl chloride (CbCl) (3.0 equiv., 60.00 mmol,
9.880 g) was dissolved in anhydrous, refluxing pyridine (5.0 mL).
Afterwards, 1,3-diphenyl-1-propanone (10) (20.00 mmol, 4.260 g),
dissolved in pyridine (1.0 mL), was added over a period of 10 min.
The solution was refluxed for 5 days. The cooled solution was
poured to a mixture of 2 n HCl (100 mL) and 30 g ice. The two-
phase mixture was filtered through Celite. After warming to room
temp. and separation of the phases, the aqueous solution was ex-
tracted with diethyl ether (3×50 mL). The organic layers were com-
Experimental Section
General Remarks: All organometallic reactions were performed un-
der anhydrous conditions under argon in dried glassware. Solutions
were transferred by means of syringes. Toluene was dried with Na
before use. Electrophiles were distilled prior to use. (–)-Sparteine
was kept under argon in a refrigerator after the original bottles had
been opened. Analytical thin-layer chromatography was performed
on Merck silica gel plates (Silica gel 60 F254). Visualization was
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γ-Deprotonation and Substitution of (Z)-1,3-Diphenyl-1-propenyl N,N-Diisopropylcarbamate
FULL PAPER
bined and dried with MgSO4. After evaporation of the solvent in
vacuo, the residue was purified by flash chromatography on silica
gel (pentane/Et2O, 12:1) to afford 5.400 g (16.00 mmol, 80%) 6d as
a colourless solid. Rf = 0.27 (pentane/Et2O, 4:1). M.p. 75 °C (pen-
tane/Et2O). 1H NMR (300 MHz, CDCl3): δ = 1.31 (mc, 12 H, OCb-
CH3), 3.50 [d, 3JH,H = 7.2 Hz, 2 H, CH2], 4.05 (mc, 2 H, OCb-CH),
13C NMR (75 MHz, CDCl3): δ = 20.5 [21.6] (OCb-CH3), 27.4/28.6
[C(OH)(CH3)2], 46.6 (OCb-CH), 53.9 [CHCHC(OH)], 72.8 (Cq-
OH), 117.2 [CHCHC(OH)], 124.9/126.7/128.1/128.2/128.3/129.1
(aryl-CH), 136.1/140.9 (aryl-Cq), 147.7 (Cq), 152.9 (OCON) ppm.
IR (KBr): ν = 3441, 1697 cm–1. ESI-MS: (m/z) = 396.2 [M + H]+,
˜
418.4 [M + Na]+, 434.3 [M + K]+. C25H33NO3 (395.53): calcd.
5.90 (t, 3JH,H = 7.2 Hz, 1 H, CH), 7.15–7.55 (m, 5 H, aryl-H) ppm. C 75.91, H 8.41, N 3.54; found C 75.70, H 8.38, N 3.53. [α]2D0 = +55
13C NMR (75 MHz, CDCl3): δ = 20.5 [21.7] (OCb-CH3), 32.5 (c = 0.59 in CHCl3, Ն 95 % ee). Shift experiment (300 MHz):
(CH2), 46.3 [46.6] (OCb-CH), 116.5 (CH), 124.6/126.2/127.8/128.2/ 10 mol-% Eu(hfc)3 in CDCl3, δ (CH) = 6.79 ppm (major enantio-
128.4/128.6 (CH-aryl), 136.1/140.2 (Cq-aryl), 146.9 (Cq), 152.8
mer appears at lower field). Compound rac-13 [yield 80%, m.p.
84 °C (pentane/Et2O)] was obtained as a colourless powder in the
same way by using 1.4 equiv. rac-trans-N,N,NЈ,NЈ-tetramethylcyclo-
hexane-1,2-diamine/n-butyllithium for the deprotonation.
(OCON) ppm. IR (KBr): ν = 1708 cm–1. ESI-MS: (m/z) = 338.2
˜
[M + H]+, 360.1 [M + Na]+. C22H27NO2 (337.46): calcd. C 78.30,
H 8.06, N 4.15; found C 78.21, H 7.97, N 4.05.
General Procedure for the Deprotonation and Substitution of Enol
Carbamate 6d at –78 °C (GP1): A solution of (–)-sparteine (5)
(1.2 equiv.) in toluene (1.5 mL) was cooled to –78 °C and n-butyl-
lithium (1.2 equiv., 1.6 m in hexane) was added. After the mixture
was stirred for 10 min, a solution of (Z)-1,3-diphenyl-1-propenyl
N,N-diisopropylcarbamate (6d) (1.0 equiv., 0.30–0.50 mmol) in tol-
uene (1.1 mL) was slowly added over 10 min. After a deprotonation
(1Z,3S)-5,5-Dimethyl-4-oxo-1,3-diphenyl-1-hexenyl N,N-Diisopro-
pylcarbamate (14). GP1: According to GP1 (–)-sparteine (5) (1.2
equiv., 0.36 mmol, 84 mg) was dissolved in toluene (1.5 mL) and
cooled to –78 °C before 1.6 m n-butyllithium (1.2 equiv., 0.36 mmol,
0.23 mL) was added, followed by a solution of 6d (1.0 equiv.,
0.30 mmol, 101 mg) in toluene (1.1 mL) after 10 min. The reaction
mixture was stirred for 30 min and then pivaloyl chloride
time of 10–30 min, the electrophile (3.0 equiv.) was added over (3.0 equiv., 0.90 mmol, 153 mg) was added and stirring was contin-
10 min and the resulting mixture was stirred at –78 °C for 2.0–
2.5 hours. The pale yellow reaction mixture was quenched by ad-
dition of acetic acid (0.05 mL) and methanol (0.3 mL) at –78 °C.
After warming to room temp., the organic phase was diluted with
diethyl ether and dried with MgSO4. The solvent was removed with
a rotary evaporator. The resultant crude mixture was applied to
silica gel purification and eluted with solvent mixtures of pentane
and diethyl ether.
ued for 2.5 hours. After quenching at –78 °C and work up, the resi-
due was purified by flash chromatography (pentane/Et2O, 6:1 Ǟ
4:1) to give 103 mg (0.24 mmol, 81%) (3S)-14 as colourless oil. RF
1
= 0.47 (pentane/Et2O, 2:1). H NMR (400 MHz, CDCl3): δ = 1.15
(s, 9 H, tBu), 1.30 [1.41] (mc, 12 H, OCb-CH3), 3.86 [4.27] (sept,
3
3JH,H = 6.7 Hz, 2 H, OCb-CH), 5.28 (d, JH,H = 10.0 Hz, 1 H,
3
CHCHC=O), 6.24 (d, JH,H = 10.0 Hz, 1 H, CHCHC=O), 7.20–
7.40 (m, 10 H, aryl-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
20.5 [21.6] (OCb-CH3), 26.5 (tBu-CH3), 45.3 (tBu-Cq), 46.3 [46.9]
(OCb-CH), 49.4 (CHCHC=O), 117.4 (CHCHC=O), 124.6/126.7/
127.8/127.9/128.5 (aryl-CH), 128.8/135.7 (aryl-Cq), 146.1 (Cq),
General Procedure for the Deprotonation and Substitution of Enol
Carbamate 6d at –90 °C (GP2): To a stirred solution of (–)-sparte-
ine (5) (1.01 equiv., 0.51 mmol, 120 mg) in toluene (1.5 mL) was
added n-butyllithium (1.6 m in hexane, 1.01 equiv., 0.51 mmol,
0.32 mL) at –90 °C. After 10 min, a solution of 6d (1.0 equiv.,
0.50 mmol, 169 mg) in toluene (1.1 mL) was added dropwise over
10 min, and the clear deep red solution was stirred for additional
10 min. A solution of the electrophile (3.0 equiv.) in toluene
(0.5 mL) was added dropwise over 10 min. Then the reaction mix-
ture was stirred for 1 hour at –90 °C and was quenched with acetic
acid (0.05 mL) and methanol (0.3 mL). After warming to room
temp. and dilution of the organic phase with diethyl ether, it was
dried with MgSO4, and the solvent was removed in vacuo. The
crude product was purified by column chromatography with sol-
vent mixtures of pentane and diethyl ether.
151.8 (OCON), 213.2 (COtBu) ppm. IR (KBr): ν = 1709 cm–1.
˜
ESI-MS (m/z) = 422.1 [M + H]+, 439.2 [M + NH4]+, 444.2 [M +
Na]+, 860.5 [2M + NH4]+. C27H35NO3 (421.57): calcd. C 76.92, H
8.37, N 3.32; found C 76.91, H 8.46, N 3.27. [α]2D0 = +56 (c = 0.75
in CHCl3; 89% op, determined by conversion of 17d to 14, see be-
low). Compound rac-14 (yield 93%) was obtained in the same way
by using 1.4 equiv. rac-trans-N,N,NЈ,NЈ-tetramethylcyclohexane-
1,2-diamine/n-butyllithium for the deprotonation.
(3S)-14 (GP2): According to GP2 (–)-sparteine (5) (1.01 equiv.,
0.51 mmol, 120 mg) and 1.6 m n-butyllithium (1.01 equiv.,
0.51 mmol, 0.32 mL) was used for the deprotonation of 6d
(1.0 equiv., 0.50 mmol, 169 mg) at –90 °C. After a deprotonation
time of 10 min, a solution of pivaloyl chloride (3.0 equiv.,
1.50 mmol, 182 mg) in toluene (0.5 mL) was added dropwise over
10 min. Then the reaction mixture was stirred for 1 hour at –90 °C
and was quenched and worked up as described. Purification by
column chromatography (pentane/Et2O, 8:1 Ǟ 6:1) furnished
171 mg (3S)-14 (0.41 mmol, 81%). [α]2D0 = +63 (c = 0.79 in CHCl3;
99% op, determined by conversion of 17d to 14, see below).
(1Z,3S)-4-Hydroxy-4-methyl-1,3-diphenyl-1-pentenyl N,N-Diisopro-
pylcarbamate (13): To a solution of (–)-sparteine (5) (1.2 equiv.,
0.36 mmol, 84 mg) in toluene (1.5 mL) at –78 °C was added drop-
wise n-butyllithium (1.2 equiv., 0.36 mmol, 0.23 mL, 1.6 m in hex-
ane) ) whilst stirring according to GP1. The reaction mixture was
stirred for 10 min and then 6d (1.0 equiv., 0.30 mmol, 101 mg) in
toluene (1.1 mL) was added slowly over 10 min. The reaction mix-
ture was stirred for 30 min at –78 °C and then, acetone (3.0 equiv.,
0.90 mmol, 55 mg), dissolved in toluene (0.5 mL), was added. Fi-
nally, the reaction mixture was stirred for 2 hours at –78 °C and
quenched as described by GP1. The residue was purified by silica
gel flash column chromatography (pentane/Et2O, 2:1 Ǟ 1:1) to af-
ford 105 mg (0.27 mmol, 88%) (3S)-13 as a colourless resinous oil.
(1Z,3S)-3-Methoxycarbonyl-1,3-diphenyl-1-propenyl N,N-Diisopro-
pylcarbamate (15). GP1: According to GP1 (–)-sparteine (5)
(1.2 equiv., 0.60 mmol, 141 mg) was dissolved in toluene (2.0 mL)
and cooled to –78 °C before 1.6 m n-butyllithium (1.2 equiv.,
0.60 mmol, 0.38 mL) was added, followed by a solution of 6d
(1.0 equiv., 0.50 mmol, 169 mg) in toluene (1.1 mL) after 10 min.
RF = 0.22 (pentane/Et2O, 1:1). 1H NMR (300 MHz, CDCl3): δ = The reaction mixture was stirred for 30 min and then methyl chlo-
1.22–1.29 (m, 12 H, OCb-CH3), 1.33/1.35 [s, 6 H, C(OH)(CH3)2], roformate (3.0 equiv, 1.50 mmol, 142 mg) was added. Stirring was
2.35 (s, 1 H, OH), 3.72 [d, JH,H = 10.5 Hz, 1 H, CHCHC(OH)], continued for 2.0 hours. After quenching at –78 °C and work up,
3
3
3
3.92 [4.07] (sept, JH,H = 6.4 Hz, 2 H, OCb-CH), 6.31 [d, JH,H
=
the residue was purified by flash chromatography (pentane/Et2O,
10.5 Hz, 1 H, CHCHC(OH)], 7.18–7.45 (m, 10 H, aryl-H) ppm. 4:1) to give 60 mg (0.15 mmol, 30%) (3S)-15 as a colourless oil. RF
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J. Reuber, R. Fröhlich, D. Hoppe
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= 0.28 (pentane/Et2O, 2:1). 1H NMR (300 MHz, CDCl3): δ = 1.18–
stirred for 0.5–1.0 hour at –90 °C before it was quenched with a
1.33 (m, 12 H, OCb-CH3), 3.70 (s, 3 H, OCH3), 3.86 [4.09] (mc, 2 mixture of acetic acid (0.05 mL) and methanol (0.3 mL) at –90 °C.
3
H, OCb-CH), 4.68 (d, JH,H = 9.3 Hz, 1 H, CHCHC=O), 6.25 (d,
The solution was poured into an ice cooled mixture of diethyl ether
(15 mL) and 2 n aq. HCl (20 mL). The aqueous layer was extracted
3JH,H = 9.3 Hz, 1 H, CHCHC=O), 7.21–7.46 (m, 10 H, aryl-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 20.4 [21.5] (OCb-CH3), 46.5 with diethyl ether (3×10 mL). The combined organic extracts were
(OCb-CH), 48.8 (CHCHC=O), 52.3 (OCH3), 114.9 (CHCHC=O),
124.9/127.2/127.7/127.8/128.3/128.8 (aryl-CH), 135.6/138.3 (aryl-
dried with anhydrous MgSO4 and concentrated in vacuo. The resi-
due was purified by silica gel flash column chromatography.
Cq), 148. (Cq), 152.0 (OCON), 172.4 (COOMe). IR (film): ν =
˜
(3R)-13: According to GP3 (–)-sparteine (5) (1.2 equiv., 0.36 mmol,
84 mg) was dissolved in toluene (1.5 mL) and cooled to –78 °C be-
fore 1.6 m n-butyllithium (1.2 equiv., 0.36 mmol, 0.23 mL) and sub-
sequently 6d (1.0 equiv., 0.30 mmol, 101 mg) was added. The reac-
tion mixture was stirred for 30 min after which ClTi(NEt2)3
(1.5 equiv., 0.45 mmol, 135 mg) was added. The solution was
stirred for 30 min at –78 °C and then acetone (4.0 equiv.,
0.90 mmol, 55 mg), dissolved in toluene (0.5 mL), was added. The
1735 cm–1. ESI-MS: (m/z) = 396.2 [M + H]+, 413.2 [M + NH4]+,
808.3 [2M + NH4]+. C24H29NO4 (395.49): calcd. C 72.89, H 7.39,
N 3.54; found C 72.61, H 7.31, N 3.54. [α]2D0 = +22 (c = 0.57 in
CHCl3; 69% op, determined by conversion to 13, see below). rac-
15 (yield 49%) was obtained in the same way by using 1.4 equiv.
rac-trans-N,N,NЈ,NЈ-tetramethylcyclohexane-1,2-diamine/n-butyl-
lithium for the deprotonation.
(3S)-15 (GP2): To a stirred solution of (–)-sparteine (5) (1.01 equiv., reaction was quenched after 4 h. Flash chromatography yielded
0.51 mmol, 120 mg) in toluene (1.5 mL) was added 1.6 m n-butyl-
lithium (1.01 equiv., 0.51 mmol, 0.32 mL) at –90 °C according to
GP2. After 10 min, 6d (1.0 equiv., 0.50 mmol, 169 mg) was added
dropwise over 10 min and the clear deep red solution was stirred
for 10 min. A solution of 3.0 equiv., 1.50 mmol, 142 mg) methyl
chloroformate in toluene (0.5 mL) was added dropwise over
10 min. The mixture became pale yellow within 50 min and was
quenched with a mixture of acetic acid (0.05 mL) and methanol
(0.3 mL) at –90 °C. After warming to room temp. and dilution of
the organic phase with diethyl ether it was dried with MgSO4 and
the solvent was removed in vacuo. Purification by column
chromatography (pentane/diethyl ether, 9:1 Ǟ 4:1) furnished
130 mg (3S)-15 (0.33 mmol, 72%) as a colourless oil. [α]2D0 = +31
(c = 0.79 in CHCl3; 96% op; determined by conversion to 13, see
below).
104 mg (0.26 mmol, 88%) (3R)-13 as a colourless oil. [α]2D0 = –42
(c = 1.32 in CHCl3, 73% op).
(1Z,3R,4R)-4-Hydroxy-6-methyl-1,3-diphenyl-1-heptenyl N,N-Diiso-
propylcarbamate (17a). Method B. GP4: Compound 6d (1.0 equiv.,
0.30 mmol, 101 mg) was lithiated with (–)-sparteine (5) (1.2 equiv.,
0.36 mmol, 84 mg) and 1.6 m n-butyllithium (1.2 equiv., 0.36 mmol,
0.23 mL) at –90 °C as described by GP4. After titanation with a
solution of ClTi(NEt2)3 (1.5 equiv., 0.45 mmol, 135 mg) in toluene
(1 mL), the intermediate was trapped with a mixture of 3-methylbu-
tanal (3.0 equiv., 0.90 mmol, 78 mg) and Ti(OiPr)4 (3.0 equiv.,
0.90 mmol, 256 mg) in toluene (2.0 mL). The solution was then
stirred for additional 30 min at –90 °C before the reaction was
stopped at –90 °C. After work up and chromatography of the crude
product (pentane/Et2O, 4:1 Ǟ 2:1), 87 mg (0.21 mmol, 68 %)
(1Z,3R,4R)-17a were obtained as a colourless solid. RF = 0.38
(pentane/Et2O, 1:1). m.p. 141 °C (pentane/Et2O). 1H NMR
Homoaldol Reaction of 6d. Method A. General Procedure 3 (GP3):
A solution of (–)-sparteine (5) (1.2–1.4 equiv., 0.33–0.60 mmol) in
toluene (1.5 mL) was cooled to –78 °C and 1.6 m n-butyllithium
(1.2–1.4 equiv., 1.6 m in hexane, 0.33–0.60 mmol) was added drop-
3
(300 MHz, CDCl3): δ = 0.75/0.77 [d, JH,H = 6.8 Hz, 6 H,
CH2CH(CH3)], 1.02–1.11 [m, 2 H, CH2CH(CH3)], 1.18–1.30 (m,
12 H, OCb-CH3), 1.75–1.82 [m, 1 H, CH2CH(CH3)], 2.83 (d,
wise. After 10 min, 6d (1.0 equiv., 0.30–0.50 mmol) in toluene 3JH,OH = 5.1 Hz, 1 H, OH), 3.50 (dd, JH,H = 10.5/7.5 Hz, 1 H,
3
(1.1 mL) was added dropwise within 10 min under vigorous stir-
ring. The deep red solution was stirred at this temperature for
20 min and then a solution of ClTi(NEt2)3 (1.5 equiv., 0.45–
0.75 mmol) in toluene (0.5 mL) was added dropwise over 10 min.
The dark reaction mixture was stirred for 30 min at –78 °C and
then the aldehyde (3.0–4.0 equiv., 0.90–2.0 mmol), dissolved in tol-
uene (0.5 mL), was added. Finally, the reaction mixture was stirred
for 2–4 hours at –78 °C before it was quenched with a mixture of
acetic acid (0.05 mL) and methanol (0.3 mL) at –78 °C. The solu-
tion was poured into a ice-cooled mixture of diethyl ether (15 mL)
and 2 n aq. HCl (15 mL). The aqueous layer was extracted with
diethyl ether (3×10 mL). The combined organic extracts was dried
with anhydrous MgSO4 and concentrated in vacuo. The residue
was purified by silica gel flash column chromatography.
CqCHCHPh), 3.84–4.04 (m, 3 H, CHOH/OCb-CH), 6.09 (d, 3JH,H
= 10.5 Hz, 1 H, CqCHCHPh), 7.13–7.38 (m, 10 H, aryl-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.5 [21.6] (OCb-CH3), 21.6/23.8
[CH2CH(CH3)2], 24.5 [CH2CH(CH3)2], 44.9 [CH2CH(CH3)2], 46.6
[46.8] (OCb-CH), 50.2 (CqCHCHPh), 73.1 (CHOH), 118.4
(CqCHCHPh), 125.9/126.6/128.0/128.3/128.4/128.7 (aryl-CH),
135.7/141.8 (aryl-Cq), 147.6 (Cq), 153.4 (OCON) ppm. IR (KBr):
ν = 3479, 1672 cm–1. ESI-MS (m/z) = 424.3 [M + H]+, 446.3 [M +
˜
Na]+, 869.5 [2M + Na]+. C27H37NO3 (423.59) calcd. C 76.56,
H 8.80, N 3.31; found C 76.18, H 8.67, N 3.05. [α]2D0 = –81 (c = 1.07
in CHCl3; 91 % ee). Shift experiment (300 MHz): 8 mol-% Eu-
(hfc)3 in CDCl3, Δδ = 0.15 ppm, [CH, IH (δ = 7.60 ppm): IT (δ =
7.65 ppm) = 4.5:96.5]. Compound rac-17a [yield 80%, m.p. 126 °C
(pentane/Et2O)] was obtained in the same way by using 1.2 equiv.
rac-trans-N,N,NЈ,NЈ-tetramethylcyclohexane-1,2-diamine/n-butyl-
lithium for the deprotonation.
Homoaldol Reaction of 6d. Method B. General Procedure 4 (GP4):
To a cooled (–90 °C) solution of (–)-sparteine (5) (1.2 equiv.,
0.36 mmol) in toluene (1.5 mL) was added dropwise 1.6 m n-butyl-
lithium (1.2 equiv., 0.36 mmol) . After 10 min, 6d (1.0 equiv.,
0.30 mmol) in toluene (1.1 mL) was added dropwise within 10 min
under vigorous stirring. The deep red solution was stirred at –90 °C
for additional 10 min and then a solution of ClTi(NEt2)3
(1.5 equiv., 0.45 mmol) in toluene (0.5 mL) was added dropwise
over 10 min. The dark reaction mixture was stirred for 5 min at
–90 °C. Then, a mixture of the aldehyde (4.0 equiv., 1.2 mmol) and
Ti(OiPr)4 (4.0 equiv., 1.2 mmol), dissolved in toluene (2.0 mL), was
added dropwise over 15 min. Finally, the reaction mixture was
(1Z,3R,4R)-4-Hydroxy-5-methyl-1,3-diphenyl-1-hexenyl N,N-Diiso-
propylcarbamate (17b). Method A. GP3: According to GP3 a solu-
tion of (–)-sparteine (5) (1.2 equiv., 0.36 mmol, 84 mg) in toluene
(1.5 mL) was cooled to –78 °C. 1.6 m n-butyllithium (1.2 equiv.,
0.36 mmol, 0.23 mL) was added followed by a solution of 6d (1.0
equiv., 0.30 mmol, 101 mg) in toluene (1.0 mL) after 10 min and
the solution was stirred for 20 min. A solution of ClTi(NEt2)3
(1.5 equiv., 0.45 mmol, 135 mg) in toluene (0.5 mL) was added and
the reaction mixture was stirred for additional 30 min before 2-
methylpropanal (4.0 equiv., 1.20 mmol, 86 mg) was added. The
3022
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3017–3025

γ-Deprotonation and Substitution of (Z)-1,3-Diphenyl-1-propenyl N,N-Diisopropylcarbamate
FULL PAPER
solution was stirred for additional 2 h and then the reaction was
quenched at –78 °C. After work up and chromatography (pentane/
(hfc)3 in C6D6, δ (CH) = 7.87 ppm (major enantiomer appears at
lower field). Compound rac-17c [yield 74%, m.p. 132 °C (pentane/
Et2O, 1:1) 102 mg (0.25 mmol, 83 %) (1Z,3R,4R)-17b were af- Et2O)] was obtained in the same way by using 1.2 equiv. rac-trans-
forded. RF = 0.47 (pentane/Et2O, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 0.88/0.98 (d, 3JH,H = 6.9 Hz, 6 H, iPr-CH3), 1.28–1.90
N,N,NЈ,NЈ-tetramethylcyclohexane-1,2-diamine/n-butyllithium for
the deprotonation.
3
(m, 13 H, iPr-CH/OCb-CH3), 3.31 (d, JH,OH = 4.5 Hz, 1 H, OH),
(1Z,3R,4S)-4-Hydroxy-5,5-dimethyl-1,3-diphenyl-1-hexenyl N,N-
Diisopropylcarbamate (17d). Method A. GP3: According to GP3 a
solution of (–)-sparteine (5) (1.2 equiv., 0.60 mmol, 145 mg) in tolu-
ene (1.5 mL) was cooled to –78 °C. 1.6 m n-Butyllithium (1.2 equiv.,
0.60 mmol, 0.38 mL) was added, followed by a solution of 6d
(1.0 equiv., 0.50 mmol, 169 mg) in toluene (1.0 mL) after 10 min
and the solution was stirred for 20 min. A solution of ClTi(NEt2)
3
3.77–3.79 (m, 2 H, CHCHPh/CHOH), 4.10 (sept, JH,H = 6.8 Hz,
3
2 H, OCb-CH), 6.19 (d, JH,H = 10.5 Hz, 1 H, CHCHPh), 7.22–
7.47 (m, 10 H, aryl-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.6/
20.4 (iPr-CH3), 20.4 [22.1] (OCb-CH3), 29.7 (iPr-CH), 46.4 [47.1]
(OCb-CH), 47.3 (CHCHPh), 79.1 (CHOH), 119.4 (CHCHPh),
124.9/126.6/127.8/128.1/128.3/128.8 (aryl-CH), 135.5/141.6 (aryl-
Cq), 147.1 (Cq), 153.9 (OCON) ppm. IR (KBr): ν = 3412, 1677
˜
(1.5 equiv., 0.75 mmol, 225 mg) in toluene (1.0 mL) was added
cm–1. ESI-MS: (m/z) = 410.4 [M + H]+, 432.3 [M + Na]+, 448.3 [M
+ K]+. C26H35NO3 (409.56): calcd. C 76.25, H 8.61, N 3.42; found
C 76.08, H 8.56, N 3.41. [α]2D0 = –117 (c = 1.08 in CHCl3; 89% ee).
Shift experiment (300 MHz): 5.3 mol-% Eu(hfc)3 in CDCl3, Δδ =
0.16 ppm, [CH, IH (δ = 6.50 ppm): IT (δ = 6.66 ppm) = 5.5:94.5].
Compound rac-17b [yield 84%, m.p. 126 °C (pentane/Et2O)] was
obtained in the same way by using 1.4 equiv. rac-trans-N,N,NЈ,NЈ-
tetramethylcyclohexane-1,2-diamine/n-butyllithium for the depro-
tonation.
3
and the reaction mixture was stirred for additional 30 min before
2,2-dimethylpropanal (4.0 equiv., 2.00 mmol, 173 mg) was added.
The solution was stirred for additional 2.5 h and then the reaction
was quenched at –78 °C. After work up and chromatography (pen-
tane/Et2O, 4:1 Ǟ 2:1) 158 mg (0.37 mmol, 75%) (1Z,3R,4S)-17d
were afforded. RF = 0.65 (pentane/Et2O, 1:1), m.p. 99 °C (pentane/
1
Et2O). H NMR (300 MHz, CDCl3): δ = 0.87 (s, 9 H, tBu), 1.25–
3
1.38 (m, 12 H, OCb-CH3), 3.06 (d, JH/OH = 6.9 Hz, 1 H, OH),
3.68 (ψt, 3JH,H = 6.9, 3JH/OH = 6.9 Hz 1 H, CHOH), 3.93 (dd, 3JH,H
= 10.5, 6.9 Hz, 1 H, CHCHPh), 4.04 (mc, 2 H, OCb-CH), 6.22
(1Z,3R,4R)-17b (Method B, GP4): Compound 6d (1.0 equiv.,
0.30 mmol, 101 mg) was lithiated with (–)-sparteine (5) (1.2 equiv.,
0.36 mmol, 84 mg) and 1.6 m n-butyllithium (1.2 equiv., 0.36 mmol,
0.23 mL) at –90 °C as described by GP4. After titanation with a
solution of ClTi(NEt2)3 (1.5 equiv., 0.45 mmol, 135 mg) in toluene
(1 mL), the intermediate was trapped with a mixture of 2-methyl-
propanal (4.0 equiv., 1.20 mmol, 86 mg) and Ti(OiPr)4 (4.0 equiv.,
1.20 mmol, 284 mg) in toluene (2.0 mL). The solution was then
stirred for an additional hour at –90 °C before the reaction was
stopped at –90 °C. Work up and chromatography of the crude pro-
duct (pentane/Et2O, 4:1 Ǟ 2:1) yielded 100 mg (0.24 mmol, 81%)
(1Z,3R,4R)-17b. M.p. 132 °C (pentane/Et2O). [α]2D0 = –138 (c = 0.99
in CHCl3; 99% op).
3
(d, JH,H = 10.5 Hz, 1 H, CHCHPh), 7.13–7.41 (m, 10 H, aryl-H)
ppm.13C NMR (75 MHz, CDCl3): δ = 20.4 [21.7] (OCb-CH3), 26.8
(tBu-CH3), 36.4 (tBu-Cq), 45.7 (CHCHPh), 46.3 [46.9] (OCb-CH),
82.1 (CHOH), 119.7 (CHCHPh), 124.8/126.3/ 127.9/128.0/128.3/
128.6 (aryl-CH), 135.9/143.9 (aryl-Cq), 145.7 (Cq), 153.5 (OCON)
ppm. IR (KBr): ν = 3409, 1674 cm–1. ESI-MS: (m/z) = 446.4 [M +
˜
Na]+. C27H37NO3 (423.59): calcd. C 76.56, H 8.80, N 3.31; found
C 76.52, H 8.77, N 3.18. [α]2D0 = –132 (c = 1.02 in CHCl3; 92% ee).
Shift experiment (300 MHz): 10 mol-% Eu(hfc)3 in CDCl3, Δδ =
0.22 ppm, [CH, IH (δ = 6.66 ppm): IT (δ = 6.89 ppm) = 96:4]. Com-
pound rac-17d [yield 77 %, m.p. 141 °C (pentane/Et2O)] was ob-
tained in the same way by using 1.4 equiv. rac-trans-N,N,NЈ,NЈ-
tetramethylcyclohexane-1,2-diamine/n-butyllithium for the depro-
tonation.
(1Z,3R,4R)-4-Cyclopropyl-4-hydroxy-1,3-diphenyl-1-butenyl N,N-
Diisopropylcarbamate (17c). Method B. GP4: Compound 6d
(1.0 equiv., 0.30 mmol, 101 mg) was lithiated with (–)-sparteine (5)
(1.2 equiv., 0.36 mmol, 84 mg) and 1.6 m n-butyllithium (1.2 equiv.,
0.36 mmol, 0.23 mL) at –90 °C as described by GP4. After titan-
ation with a solution of ClTi(NEt2)3 (1.5 equiv., 0.45 mmol,
135 mg) in toluene (1 mL), the intermediate was trapped with a
mixture of cyclopropanecarbaldehyde (3.0 equiv., 0.90 mmol,
63 mg) and Ti(OiPr)4 (3.0 equiv., 0.90 mmol, 256 mg) in toluene
(2.0 mL). The solution was then stirred for an additional hour be-
fore the reaction was stopped at –90 °C. After work up and
chromatography of the crude product (pentane/Et2O, 2:1 Ǟ 1:1)
78 mg (0.19 mmol, 64%) (1Z,3R,4R)-17c were obtained. RF = 0.22
(pentane/Et2O, 1:1), m.p. 81 °C (pentane/Et2O).1H NMR
(300 MHz, CDCl3): δ = 0.04–0.23 (m, 4 H, c-propyl-CH2), 0.60–
0.67 (m, 1 H, c-propyl-CH), 1.09–1.24 (m, 12 H, OCb-CH3), 2.86
(1Z,3R,4S)-17d (Method B, GP4): Compound 6d (1.0 equiv.,
0.30 mmol, 101 mg) was lithiated with (–)-sparteine (5) (1.2 equiv.,
0.36 mmol, 84 mg) and 1.6 m n-butyllithium (1.2 equiv., 0.36 mmol,
0.23 mL) at –90 °C as described by GP4. After titanation with a
solution of ClTi(NEt2)3 (1.5 equiv., 0.45 mmol, 135 mg) in toluene
(1 mL), the intermediate was trapped with a mixture of 2,2-dimeth-
ylpropanal (3.0 equiv., 0.90 mmol, 103 mg) and Ti(OiPr)4
(3.0 equiv., 0.90 mmol, 256 mg) in toluene (2.0 mL). The solution
was then stirred for an additional hour at –90 °C before the reac-
tion was stopped at –90 °C. Work up and chromatography of the
crude product (pentane/Et2O, 6:1 Ǟ 4:1) yielded 117 mg
(0.28 mmol, 92%) (1Z,3R,4S)-17d. [α]2D0 = –130 (c = 0.99 in CHCl3;
91 % ee). Shift experiment (300 MHz): 10 mol-% Eu(hfc)3 in
CDCl3, Δδ = 0.24 ppm, [CH, IH (δ = 6.84 ppm): IT (δ = 7.08 ppm)
= 96.5:4.5].
3
(br. s, 1 H, OH), 3.32 (ψt, JH,H = 10.5/7.2 Hz, 1 H, CHCHPh),
3
3
3.58 (dd, JH,H = 7.2/10.5 Hz, 1 H, CHOH), 3.89 (sept, JH,H
=
3
6.6 Hz, 2 H, OCb-CH), 6.19 (d, JH,H = 10.5 Hz, 1 H, CHCHPh),
7.02–7.28 (m, 10 H, aryl-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
1.0/2.5 (c-propyl-CH2), 15.7 (c-propyl-CH), 20.5 [21.7] (OCb-CH3),
45.6 [46.9] (OCb-CH), 50.7 (CHCHPh), 77.3 (CHOH), 118.2
(CHCHPh), 124.9/126.6/128.2/ 128.4/128.6 (aryl-CH), 135.7/141.5
(1Z,3R,4S)-4-(4-Bromophenyl)-4-hydroxy-1,4-diphenyl-1-butenyl
N,N-Diisopropylcarbamate (17e). Method A. GP3: According to
GP3 a solution of (–)-sparteine (5) (1.2 equiv., 0.60 mmol, 145 mg)
in toluene (1.5 mL) was cooled to –78 °C. 1.6 m n-Butyllithium
(1.2 equiv., 0.60 mmol, 0.38 mL) was added followed by a solution
of 6d (0.50 mmol, 169 mg) in toluene (1.0 mL) after 10 min, and
(aryl-Cq), 147.4 (Cq), 153.6 (OCON) ppm. IR (KBr): ν = 3469,
˜
1673 cm–1. ESI-MS: (m/z) = 408.3 [M + H]+, 430.2 [M + Na]+, the solution was stirred for 20 min. A solution of 1.5 equiv.,
837.5 [2M + Na]+. C26H33NO3 (407.55): calcd. C 76.62, H 8.16,
N 3.44; found C 76.51, H 8.18, N 3.18. [α]2D0 = –88 (c = 0.97 in
CHCl3; Ն 95% ee). Shift experiment (300 MHz): 10 mol-% Eu-
0.75 mmol, 225 mg) ClTi(NEt2)3 in toluene (1.0 mL) was added,
and the reaction mixture was stirred for additional 30 min before
p-bromobenzaldehyde (4.0 equiv., 2.00 mmol, 370 mg) was added.
Eur. J. Org. Chem. 2005, 3017–3025
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3023

J. Reuber, R. Fröhlich, D. Hoppe
FULL PAPER
The solution was stirred for 2 h and afterwards the reaction was
quenched at –78 °C. After work up and chromatography (pentane/
Et2O, 4:1 Ǟ 2:1) 153 mg (0.30 mmol, 59%) (1Z,3R,4S)-17e were
afforded. RF = 0.25 (pentane/Et2O, 2:1). M.p. 125 °C (pentane/
fore the pale yellow reaction mixture was quenched by addition of
acetic acid (0.05 mL) and methanol (0.3 mL) at –78 °C. After
warming to room temp., the organic phase was diluted with diethyl
ether and dried with MgSO4. The solvent was removed on a rotary
Et2O). 1H NMR (300 MHz, CDCl3): δ = 1.32–1.38 (m, 12 H, OCb- evaporator and the resultant crude mixture was applied to flash
3
CH3), 3.66 (ψt, JH/H = 10.5/11.1 Hz, 1 H, CHCHPh), 4.05–4.13
column chromatography (pentane/Et2O, 2:1). The purification fur-
3
(m, 2 H, OCb-CH), 4.57 (bd, JH,OH = 4.8 Hz, 1 H, OH), 4.81 (m, nished 18 mg (0.04 mmol, 21%) (3R)-14 ([α]2D0 = –31, c = 0.32 in
1 H, CHOH), 6.31 (d, 3JH,H = 11.1 Hz, 1 H, CHCHPh), 6.87–7.47 CHCl3; 49% op) and 60 mg (0.15 mmol, 77%) (3R)-13 ([α]2D0
(m, 14 H, aryl-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.9 –48, c = 1.52 in CHCl3; 83% op).
[22.1] (OCb-CH3), 47.1 [47.5] (OCb-CH), 53.4 (CHCHPh), 78.2
=
Retro-Homoaldol Reaction. Conversion of (3R)-13 to (3R,4S)-17d:
(–)-Sparteine (5) (1.5 equiv., 0.23 mmol, 53 mg) in toluene (1.0 mL)
was cooled to –90 °C and n-butyllithium (1.6 m in hexanes,
1.5 equiv., 0.23 mmol, 0.14 mL) was added to the stirred solution.
After 15 min a solution of 1.0 equiv., 0.15 mmol, 60 mg) (3R)-13
([α]2D0 = –48, c = 1.52 in CHCl3; 83% op) in toluene (0.8 mL) was
added slowly within 10 min. 2,2-Dimethylpropanal (5.0 equiv.,
0.75 mmol, 65 mg) in toluene (0.5 mL) was added to the red solu-
tion over 10 min after 2 hours stirring at –78 °C. The reaction mix-
ture was stirred for 1 hour before the pale yellow reaction mixture
was quenched by addition of acetic acid (0.05 mL) and methanol
(0.3 mL) at –78 °C. After warming to room temp. the organic phase
was diluted with diethyl ether and dried with MgSO4. The solvent
was removed on a rotary evaporator and purification of the residue
by flash column chromatography (pentane/Et2O, 2:1) yielded 2 mg
(0.01 mmol, 3%) (3R,4S)-17d. [α]2D0 = –55 (c = 0.10 in CHCl3; 38%
op).
(CHOH), 118.5 (CHCHPh), 121.1/125.4/127.3/128.4/128.6/128.7/
128.9/129.0 (aryl-CH), 131.0/140.3/143.0 (aryl-Cq), 148.2 (Cq),
154.4 (OCON) ppm. IR (KBr): ν = 3352, 1673 cm–1 . ESI-MS:
˜
(m/z) = 544.3 [M + Na]+. C29H32BrNO3 (522.47): calcd. C 66.67,
H 6.17, N 2.68; found C 66.54, H 6.15, N 2.60. [α]2D0 = –55 (c = 1.13
in CHCl3; 89% op). Compound rac-17e [yield 80%, m.p. 122 °C
(pentane/Et2O)] was obtained in the same way by using 1.4 equiv.
rac-trans-N,N,NЈ,NЈ-tetramethylcyclohexane-1,2-diamine/n-butyl-
lithium for the deprotonation.
(1Z,3R,4S)-17e (Method B, GP4): Compound 6d (1.0 equiv.,
0.30 mmol, 101 mg) was lithiated with (–)-sparteine (5) (1.2 equiv.,
0.36 mmol, 84 mg) and 1.6 m n-butyllithium (1.2 equiv., 0.36 mmol,
0.23 mL) at –90 °C as described by GP4. After titanation with a
solution of ClTi(NEt2)3 (1.5 equiv., 0.45 mmol, 135 mg) in toluene
(1 mL), the intermediate was trapped with a mixture of ) p-bro-
mobenzaldehyde (3.0 equiv., 0.90 mmol, 167 mg) and Ti(OiPr)4
(3.0 equiv., 0.90 mmol, 256 mg) in toluene (2 mL). The solution
was then stirred for additional 30 min before the reaction was
stopped at –90 °C. Work up and chromatography of the crude pro-
duct (pentane/Et2O, 2:1) yielded 121 mg (0.23 mmol, 77 %)
(1Z,3R,4S)-17e. [α]2D0 = –59 (c = 0.99 in CHCl3; Ն 95% ee). Shift
experiment (300 MHz): 10 mol-% Eu(hfc)3 in CDCl3, δ (CH) =
6.02 ppm (major enantiomer appears at lower field).
X-ray Crystallographic Study. Structure Analysis for HOP2669:
Formula C29H32BrNO3,
0.35×0.20×0.10 mm,
M
=
522.47, colorless crystal
a
=
10.652(1), 13.493(2),
b
=
c =
37.419(6) Å, V = 5378.1(13) Å3, ρcalcd. = 1.291 g cm–3, 23.08 cm–1,
empirical absorption correction by ψ scan data (0.499 Յ T Յ
0.802), Z = 8, orthorhombic, space group P212121 (No. 19), λ =
1.54178 Å, T = 223 K, ω/2θ scans, 6106 reflections collected (–h,–
k,–l), [(sinθ)/λ] = 0.62Å–1, 6106 independent and 4145 observed
Conversion of (3S)-15 to (3S)-13: To a stirred solution of (3S)-15
(1.0 equiv., 0.15 mmol, 69% op) ([α]2D0 = +22, c = 1.13 in CHCl3;
69% op) in 2.0 mL diethyl ether was added MeMgBr (3.0 m solu-
tion in THF, 3.0 equiv., 0.45 mmol, 0.15 mL) ). The reaction mix-
ture was stirred for 1.5 hours before the reaction was stopped by
the addition of 0.5 mL 2n HCl. The organic layer was diluted with
10 mL diethyl ether and was dried with MgSO4. After removal of
the solvent in vacuo, the residue was purified by column
chromatography which furnished 30 mg (3S)-13 (0.08 mmol, 51%).
[α]2D0 = +40 (c = 1.42 in CHCl3; 68% op).
reflections [I Ն2σ(I)], 653 refined parameters, R = 0.047, wR2
=
0.147, Flack parameter 0.00(3), two almost identical independent
molecules in the asymmetric unit, max. residual electron density
0.34 (–0.51) e·Å–3, hydrogen atoms calculated and refined as riding
atoms. Data set was collected with an Enraf–Nonius CAD4 dif-
fractometer. Programs used: data collection EXPRESS (Nonius
B.V., 1994), data reduction MolEN (K. Fair, Enraf–Nonius B.V.,
1990), structure solution SHELXS-97 (G.M. Sheldrick, Acta
Cryst., Sect. A 1990, 46, 467–473), structure refinement SHELXL-
97 (G. M. Sheldrick, University of Göttingen, 1997), graphics
SCHAKAL (E. Keller, University of Freiburg, 1997).
Conversion of (3R,4S)-17d to (3R)-14: Pyridinium dichromate (2.0
equiv., 0.58 mmol, 218 mg) was suspended in CH2Cl2 (2.5 mL).
Then a solution of (3R,4S)-17d (1.0 equiv., 0.29 mmol, 124 mg)
([α]2D0 = –132, c = 1.02 in CHCl3; 92% op) was added to the stirred
suspension at room temp. The mixture was stirred for additional
5 hours, then poured to 10 mL diethyl ether, and filtered through
celite. The solvent was removed on a rotary evaporator. The result-
ant crude mixture was applied to silica gel purification. Elution
with pentane/Et2O, 6:1 yielded 43 mg (0.10 mmol, 35%) (3R)-14.
[α]2D0 = –57 (c = 2.17 in CHCl3; 92% op).
CCDC-264159 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Acknowledgments
The support provided by the Deutsche Forschungsgemeinschaft,
Sonderforschungsbereich 424, the Graduiertenkolleg “Hochreak-
tive Mehrfachbindungssysteme”, and by the Fonds der Chemischen
Industrie is gratefully acknowledged. J. Reuber thanks Mrs. Corne-
lia Weitkamp and Ms. Verena Hack for their excellent experimental
assistance.
Retro-Homoaldol Reaction; Conversion of (3R)-13 to (3R)-14: To a
stirred solution of (–)-sparteine (5) (1.5 equiv., 0.30 mmol, 69 mg)
in toluene (1.0 mL) was added n-butyllithium (1.6 m in hexanes,
1.5 equiv., 0.30 mmol, 0.19 mL) at –78 °C. After 15 min a solution
of (3R)-13 (1.0 equiv., 0.20 mmol, 78 mg) ([α]2D0 = –49, c = 0.94 in
CHCl3; 85 % op) in toluene (0.8 mL) was added slowly within
10 min. Pivaloyl chloride (5.0 equiv., 1.00 mmol, 121 mg) in toluene
(0.3 mL) was added to the red solution over 10 min after 2 hours
stirring at –78 °C. The reaction mixture was stirred for 1 hour be-
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3024
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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γ-Deprotonation and Substitution of (Z)-1,3-Diphenyl-1-propenyl N,N-Diisopropylcarbamate
FULL PAPER
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Received: March 5, 2005
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Eur. J. Org. Chem. 2005, 3017–3025
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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