Nonracemic, chiral homoenolate reagents derived from (cycloalk-1-enyl)methyl carbamates and evaluation of their configurational stabilities

Article abstract of DOI:10.1002/1099-0690(20022)2002:3<414::aid-ejoc414>3.0.co;2-2

Several (cycloalk-1-enyl)methyl N,N-diisopropylcarbamates 11 were synthesised by three different methods and their asymmetric deprotonation by butyllithium/(-)-sparteine was investigated. The ratios of epimeric ion pairs 18·4/epi-18·4 were determined by (stereospecific) trimethylsilylation, forming the products 19/ent-19. Lithiated 2-unsubstituted (cyclopent-1-enyl) methyl carbamates, such as 11a or 11h, epimerise rapidly at -78 °C and the thermodynamically controlled ratio is opposite to the kinetically achieved ratio. High configurational stability was found for the 2-methylcycloalk-1-enyl derivatives 11d, 11e and 11j. These turned out to be valuable reagents for enantioselective homoaldol reaction; er values of up to 96:4 could be achieved. X-ray crystal structure analyses with anomalous diffraction, obtained from the heavy atom containing products 22, 23b, 27d, and 27e derived from (2-methylcyclopentenyl)methyl and (2-methyl-cyclohexenyl)methyl reagents, established the (1S) configuration of the major lithium compound. Thus, the kinetically controlled deprotonation of the corresponding allyl carbamates removes the (pro-S) proton. Overall, a simple method for the enantioselective synthesis of cyclic homoaldol adducts from achiral precursors is reported.

Full text of DOI:10.1002/1099-0690(20022)2002:3<414::aid-ejoc414>3.0.co;2-2

FULL PAPER
Nonracemic, Chiral Homoenolate Reagents Derived from (Cycloalk-1-
enyl)methyl Carbamates and Evaluation of Their Configurational Stabilities
Mustafa Özlügedik,[a] Jesper Kristensen,[b] Birgit Wibbeling,[a][‡] Roland Fröhlich,[a][‡] and
Dieter Hoppe*[a]
Dedicated to Professor Joachim Thiem on the occasion of his 60th birthday
Keywords: Asymmetric synthesis / Carbanions / Chirality / Lithiation
Several (cycloalk-1-enyl)methyl N,N-diisopropylcarbamates
11 were synthesised by three different methods and their
asymmetric deprotonation by butyllithium/(−)-sparteine was
investigated. The ratios of epimeric ion pairs 18·4/epi-18·4
were determined by (stereospecific) trimethylsilylation, for-
valuable reagents for enantioselective homoaldol reaction; er
values of up to 96:4 could be achieved. X-ray crystal struc-
ture analyses with anomalous diffraction, obtained from the
heavy atom containing products 22, 23b, 27d, and 27e de-
rived from (2-methylcyclopentenyl)methyl and (2-methyl-
ming the products 19/ent-19. Lithiated 2-unsubstituted cyclohexenyl)methyl reagents, established the (1S) config-
(cyclopent-1-enyl)methyl carbamates, such as 11a or 11h, uration of the major lithium compound. Thus, the kinetically
epimerise rapidly at −78 °C and the thermodynamically con- controlled deprotonation of the corresponding allyl carba-
trolled ratio is opposite to the kinetically achieved ratio. High mates removes the (pro-S) proton. Overall, a simple method
configurational stability was found for the 2-methylcycloalk- for the enantioselective synthesis of cyclic homoaldol adducts
1-enyl derivatives 11d, 11e and 11j. These turned out to be
from achiral precursors is reported.
Introduction
Among the nonracemic, chiral homoenolate reagents,[1]
1-hetero-substituted 2-alkenylmetal derivatives of type A
are the most powerful intermediates for performing ste-
reocontrolled homoaldol reactions.[2] Compounds of type A
reliably add aldehydes, through cyclic ZimmermanϪTraxler
transition states[3] B, to form the homoaldol adducts C or
D with essentially complete γ-regio- and anti-diastereoselec-
tivity. Covalently bound ‘‘cations’’ M give rise to complete
transfer of chirality from position 1 in A to position 3 in
the addition products C and D. Depending on whether the
heterosubstituent X takes a pseudoaxial or a pseudoequat-
orial position [(Z)-B or (E)-B],[4] an opposite sense of chir-
ality is induced in the products C and D, with enantiomeric
γ-hydroxy carbonyl compounds E and ent-E, respectively,
being formed after hydrolysis (Scheme 1).
Scheme 1
metallated 2-alkenyl N,N-diisopropylcarbamates as versatile
homoenolate reagents.[9,2] Because of the strongly activating
properties of N,N-diisopropylcarbamoyloxy groups, these
are easily prepared by facile deprotonation, and the cation
is fixed in the α-position by chelation.[10] Exchange of li-
thium by tetra(isopropoxy)titanium enhances the regiose-
lectivity and diastereoselectivity of the aldehyde addition
dramatically.[11,12]
Enantioenriched (α-lithio-2-alkenyl)carbamates, derived
from secondary esters such as 1, are configurationally stable
at Ϫ78 °C and can be obtained by deprotonation of the
optically active precursors[13] or through kinetic resolution
of the racemic carbamates during deprotonation by sec-bu-
(1-Alkoxyallyl)boronates,[5] [(1-methoxymethoxy)but-2-
enyl]tributylstannane[6] and metallated cinnamylamides[7,8]
have been applied in this respect. We have introduced α-
[a]
Organisch-Chemisches Institut der Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
Fax: (internat.) ϩ 49-(0)251/833-9772
E-mail: Hoppe@uni-muenster.de
[b]
Department of Medicinal Chemistry, The Royal Danish School
of Pharmacy,
Universitetsparken, 2100, Copenhagen, Denmark
Fax: (internat.) ϩ 45-35372209
[‡]
X-ray crystal structure
414
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0203Ϫ0414 $ 17.50ϩ.50/0 Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
tyllithium/(Ϫ)-sparteine (4).[14] The lithium ion pairs pro- the corresponding homoenolate reagents of type G might
duced from primary 2-alkenyl carbamates such as 3[15] or be accessible in enantioenriched forms through (Ϫ)-spart-
2[16] with butyllithium/(Ϫ)-sparteine (4) turned out to be eine-induced deprotonation of the achiral allyl carbamates
configurationally unstable in solution even at Ϫ78 °C. F (Scheme 3).
However, the sparteine complex (S)-5·4 crystallised from
the pentane/cyclohexane solution[15] with concomitant dy-
namic kinetic resolution,[17] resulting in up to 92% de in the
Results and Discussion
solid. The metal exchange proceeded with inversion of the
configuration and gave rise to the allyltitanium interme-
Synthesis of the Allyl Carbamates
diate (R)-6, which was stable in solution (Scheme 2). The
homoaldol adducts of aldehydes and ketones were obtained
with Ͼ 90% ee values. These are easily transformed into
optically active γ-lactones 8,[18] and have frequently been
utilised in natural product synthesis.[19]
Carbamates 11a, d؊g, i and j were prepared from the
corresponding allylic alcohols 10 by carbamoylation with
N,N-diisopropylcarbamoyl chloride by use of the pyrid-
ine[22] or the sodium hydride methods[23] (Method A or B).
The known allylic alcohols 10a,[24] 10d,[25] 10e,[26] 10i[27] and
10j[28] were prepared by literature methods (see Scheme 4
and Table 1).
Scheme 4. a) Method A: 1.25 equiv. N,N-diisopropylcarbamoyl
chloride, 10 mol % DMAP, pyridine, 12 h reflux; b) Method B: 1.2
equiv. NaH, 1.4 equiv. N,N-diisopropylcarbamoyl chloride, THF,
16 h reflux
Scheme 2
Table 1. Prepared 1-cycloalk-1-enyl N,N-diisopropylcarbamates 11
From investigations of the carbamates 2[16] and 9[20] it is
known that removal of the (pro-S) protons by butyllithium/
4 is kinetically favoured, as found for the O-alkyl derivat-
ives;[7a,21] however, a rapid epimerisation took place even at
low temperatures.
Entry Substrate Method Product
n
R
H
Yield (%)
75
1
2
3
4
5
6
7
10a
10d
10e
10f
10g
10i
B
B
B
A
A
B
B
11a
11d
11e
11f
11g
11i
0
0
1
2
3
Me 58
Me 90[a]
Me 58
Me 66
Because of the importance of bicyclic γ-lactones J in nat-
ural product chemistry, we undertook a study of whether
Ϫ
Ϫ
Ϫ
Ϫ
68
84
10j
11j
[a]
Based on the ester 14e.
The 2-methyl-substituted alcohols 10f؊g were obtained
in a three-step synthetic sequence starting from the corres-
ponding 2-oxocycloalkanecarboxylic esters, via the enol
phosphates, nucleophilic methylation by lithium dimethyl-
cuprate and DIBALH reduction (Scheme 5).[29] Carba-
mates 11b, 11c and 11h were synthesised directly from the
cycloalkanones 15b, 15c or 15h by nucleophilic addition of
lithiomethyl N,N-diisopropylcarbamate 16[30] and elimina-
Scheme 3
Eur. J. Org. Chem. 2002, 414Ϫ427
415

M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D. Hoppe
FULL PAPER
tion of water from the intermediate tertiary alcohols 17b,
17c or 17h, respectively (Scheme 6).
Scheme 5. a) NaH, THF, ClP(O)(OPh)2, yields: 13f: 86%;[29] 13g:
90%; b) LiCuMe2, Et2O, yields: 14f: 85%;[29] 14g: 86%; c) DI-
BALH, THF, yields: 10f: 94%; 10g: 90%
Scheme 7. a) For individual conditions, yields and ee values see
Table 2; b) yields: rac-11a: 59%; rac-11b: 87%; rac-11c: 88%; rac-
11d: 73%; rac-11e: 85%; rac-11f: 68%; rac-11g: 66%; rac-11h: 69%;
rac-11i: 71%; rac-11j: 56%
Scheme 6. a) Ϫ78 °C, THF, 4 h, yields (n ϭ 1): 17b used without
purification; (n ϭ 2): 17c: 56%, 17h: 64%; b) POCl3 or SOCl2, pyr-
idine, 3Ϫ20 h, yields (n ϭ 1): 11b: 54% over two steps; (n ϭ 2): 11c:
63%, 11h: 55%
With the (cyclopentenyl)methyl carbamate 11a, after a
short deprotonation time at Ϫ78 °C, the enantiomer (ϩ)-
19a was obtained with a low ee (Table 2, Entries 1). Pro-
longed reaction times gave rise to excess (Ϫ)-19a (Entries 2
and 3). When the deprotonation was performed at Ϫ110 °C
Deprotonations and Silylation Reactions
In a series of deprotonation experiments with n-butylli- for 120 min, (ϩ)-19a was isolated with 58% ee and in 21%
thium/(Ϫ)-sparteine (4), the efficiency of the enantiotopic yield. A 71% ee of (ϩ)-19a and a 34% yield were obtained
differentiation in carbamates 11 and the configurational when the deprotonation was carried out in the presence of
stability of the lithioallyl carbamate/4 complexes were in- chlorotrimethylsilane (Entry 5). The value of 71% ee
vestigated (Scheme 7). Silylations of α-substituted lithioallyl roughly reflects a kinetically determined 18a·4/ent-18a·4 ra-
carbamates are known to proceed rapidly, with high α-se- tio of 85.5:14.5. A rapid epimerisation proceeded and after
lectivity[31] and with reliable inversion of the configuration. 120 min (Entry 3) the thermodynamically determined op-
Consequently, we selected chlorotrimethylsilane as the trap- posite 18a·4/ent-18a·4 ratio (38.5:61.5) had essentially been
ping reagent for establishing the ratios of the epimeric ion established. The use of pentane as a solvent or of sec-butyl-
pairs. The ratio of the enantiomers 19/ent-19 roughly re- lithium instead of n-butyllithium changed the situation only
flects the diastereomer ratio in the lithiated intermediates slightly. In summary, the epimeric (Ϫ)-sparteine/lithium
18·4/epi-18·4 (Table 2), although kinetic resolution originat- complexes, derived from 11a have a high degree of config-
ing from different reactivities of the diastereomers may urational lability; the half-times of epimerisation are of the
cause some error. (Time-dependent changes in the ratios are magnitude of few minutes. The equilibrium between the epi-
a strong hint of configurational lability.) When a very high mers (approx. 3:7) in solution is less distinct and dynamic
lability was suspected, 18·4/epi-18·4 were produced ‘‘in situ’’ kinetic resolution by preferential crystallisation has not
by deprotonation of 11 in the presence of chlorotrimethylsi- been achieved so far.
lane. The enantiomeric ratios were determined by 1H NMR
The situation was similar for the (5,5-dimethylcyclopen-
spectroscopy in the presence of chiral shift reagents or by tenyl)methyl derivative 11h (Entries 8 and 9). However, it
GC on a chiral column, by comparison with the corres- was interesting to find that bulky substituents in the α-posi-
ponding racemates rac-19, prepared by deprotonation un- tion, where the lithium cation is attached, do not increase
der ‘‘achiral conditions’’, with N,N,NЈ,NЈ-tetramethylethyl- the configurational stability significantly. The 5,5-ethylene-
enediamine (TMEDA) as the chelating diamine.
dioxy-substituted complexes 18·4/ent-18·4 derived from 11i
416
Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
Table 2. (Ϫ)-Sparteine-mediated lithiation, silylation and stannylation of allyl carbamates 11
Entry Substrate (solvent)[a]
n
R
Time [min], base[b] Product[c]
Yield (%) [recovered. 11 (%)] er 19/ent-19 (ee) [α]2D0[d]
1
2
3
4
5
6
7
11a (pentane)[e]
11a (pentane)
11a (pentane)
11a (pentane)
11a (toluene)
11a (toluene)
11a (toluene)
0
0
0
0
0
0
0
H
H
H
H
H
H
H
10
40
19a/ent-19a 54 [[f]]
67:33 (34)
42:58 (16)
38.5:61.5 (23)
79:21 (58)
85:5:14:5 (71)
38.5:61.5 (23)
39: 61 (22)
ϩ6.8
Ϫ3.4
Ϫ4.9
ϩ12.9
ϩ15.2
Ϫ4.4
19a/ent-19a 71 [[f]]
19a/ent-19a 57 [[f]]
19a/ent-19a 21 [[f]]
19a/ent-19a 34 [43]
19a/ent-19a 67 [[f]]
19a/ent-19a 71 [[f]]
120
120[g][h]
0[i]
[j]
180[h]
Ϫ4.8
[k]
[k]
[k]
[k]
8
9
11h (pentane)
11h (pentane)
40
240
19h/ent-19h 25 [50]
19h/ent-19h 18 [70]
43: 57 (14)
62.5:37.5 (25)
ϩ4.1
Ϫ7.4
[k]
[k]
[k]
[k]
10
11
11i (pentane)
11i (pentane)
10
120
19i/ent-19i
19i/ent-19i
64 [19]
49 [2]
30:70 (40)
34:66 (32)
ϩ6.8
ϩ5.5
12
13
14
11d (toluene)
11d (toluene)
11d (toluene)
0
0
0
Me 10
Me 180
Me 0[i]
19d/ent-19d 44 [[f]]
19d/ent-19d 70 [[f]]
19d/ent-19d 34 [[f]]
94.5:6.5 (89)
85:15 (70)
96.5:3.5 (93)
ϩ7.9
ϩ6.0
ϩ8.0
[f]
[f]
15
16
17
18
11b (toluene)
11b (toluene)
11b (toluene)
11b (toluene)
1
1
1
1
H
H
H
H
30
19b/ent-19b 78 [0]
77:23 (54)
75.5:24.5 (51)
76:24 (52)
rac
[f]
180
19b/ent-19b
0[i]
19b/ent-19b 88 [0]
ϩ4.1
Ϫ
15[h]
19b/ent-19b 45 [[f]]
19
20
11e (toluene)
11e (toluene)
1
1
Me 10
Me 120
19e/ent-19e 20 [62]
19e/ent-19e 88 [0]
92.5:7.5 (85)
92.5:7.5 (85)
Ϫ12.0
Ϫ12.0
[k]
[k]
[k]
21
22
11j (toluene)
11j (toluene)
10
120
19j/ent-19j
19j/ent-19j
45 [45]
69 [0]
88:12 (76)
87.5:12.5 (75)
Ϫ9.3
Ϫ10.1
[k]
23
11c (toluene)
2
H
10[h]
19c/ent-19c 15 [43]
46.5:53.5 (7)
Ϫ1.1
24
25
26
27
11f (toluene)
11f (toluene)
11f (toluene)
11f (toluene)
2
2
2
2
Me 10
19f/ent-19f
19f/ent-19f
19f/ent-19f
19f/ent-19f
30 [54]
48 [25]
78 [0]
3:97 (94)
Ϫ25.2
Ϫ18.4
Me 120
Me 5[h]
Me 10[h]
12.5:87.5 (75)
9.5:90.5 (81)
87:13 (74)
Ϫ20.8
[f]
74 [0]
28
29
30
11g (toluene)
11g (toluene)
11g (toluene)
3
3
3
Me 10
19g/ent-19g 7 [89]
19g/ent-19g 35 [39]
19g/ent-19g 68 [14]
3.5:96.5 (93)
13.5:86.5 (73)
12.5:87.5 (75)
Ϫ13.8
Ϫ10.4
Ϫ11.7
Me 120
Me 10[h]
[a]
[b]
[c]
[d]
In toluene, other solvent stated.
Deprotonation with n-butyllithium at Ϫ78 °C; other bases stated. All products are oils.
c ϭ
[e]
[f]
[g]
[h]
[i]
0.2Ϫ2.0 in CHCl3.
Approx. 0.15  solution. Not determined.
At Ϫ110 °C.
Deprotonation with sec-butyllithium. In situ
[j]
[k]
experiment, see text. The reaction mixture was kept at Ϫ40 °C for 30 min prior to silylation. See Scheme 4.
(Entries 10 and 11) seem to have a higher configurational
Deprotonation of the (cyclohexenyl)methyl carbamate
stability,[31] which might be caused by the presence of an 11b by n-butyllithium/(Ϫ)-sparteine in toluene afforded the
additional complexing intramolecular oxy group in the mo- silane 19b with very similar enantiomeric excesses
lecule. If this is the case, the rate of enantiotopic differenti- (51Ϫ54%), irrespective of the standing time of the interme-
ation in the (Ϫ)-sparteine-induced deprotonation step is diate lithium carbanion (Entries 15 and 16). Even the in situ
low (approx. 70:30).
experiment (Entry 17) gave a 52% ee. From these results, the
The introduction of a γ-methyl group onto the allylic following is concluded: The intermediate lithium carbanion
moiety causes a dramatic increase in the configurational pair 18b·4 is configurationally stable in toluene, but the abil-
stability. With the (2-methylcyclopentyl)methyl carbamate ity of the n-butyllithium/(Ϫ)-sparteine reagent to discrimin-
11d, the original, kinetically achieved, 18d/ent-18d ratio of ate between the enantiotopic protons is only moderate. If
96.5:3.5 (Entry 14) decreased only to 85:15 after 3 h at Ϫ78 n-butyllithium was replaced by sec-butyllithium (Entry 18),
°C (Entry 13). It is obvious from this series of experiments a racemic mixture of silane rac-19b was isolated. A control
that a compromise between achievable yield and ee has to experiment revealed that sec-butyllithium deprotonates 11b
be chosen, since a little epimerisation does already take (toluene, Ϫ78 °C) even in the absence of a complexing di-
place during complete deprotonation. After 10 min, the ee amine.
is 89% but the yield is low (44%) (Entry 12). A better yield
(70%) is offset by a lower ee (70%, Entry 13).
On introduction of a 2-methyl group into the six-mem-
bered ring, almost complete configurational stability of the
Eur. J. Org. Chem. 2002, 414Ϫ427
417

M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D. Hoppe
FULL PAPER
lithium intermediates 18e·4/ent-18e·4 was achieved at Ϫ78
°C. The enantiomeric ratio (92.5:7.5; 85% ee) did not
change after 120 min, but the yield of 19e/ent-19e increased
from 20% after 10 min to 88% after 2 h (Entries 19 and 20).
Even more highly functionalised substrates of this type,
such as the ketal 11j, also exhibit these characteristics (Ent-
ries 21 and 22).
The lithium intermediates derived from the (2-methyl-
cycloheptenyl)methyl (11f) and the (2-methylcyclooctenyl)-
methyl (11g) carbamates (Entries 24Ϫ27 and 28Ϫ30, re-
spectively) also have very high configurational stabilities. It
turned out that the use of sec-butyllithium/4 is advantage-
ous over that of n-butyllithium/4 here, since the depro-
tonation of 11f or 11g proceeds within 10 min at Ϫ78 °C.
The racemates rac-19aϪg were obtained in good yields by
use of sec-butyllithium/TMEDA.
Figure 1. Structure of (R)-(2-methyl-1-cyclohexenyl)(methyldiphen-
ylsilyl)methyl N,N-diisopropylcarbamate [(Ϫ)-22][32]
Further Reactions for Assignment of Absolute
Configurations
was subjected to a crystal structure analysis, which clearly
indicated its (R) configuration (Figure 2).[32]
Unfortunately, none of the trimethylsilanes 19 could be
crystallised to furnish crystals suitable for X-ray analysis
with use of anomalous diffraction methods for assignment
of the absolute configuration. Therefore, a number of reac-
tions offering the potential for formation of crystalline,
heavy atom containing compounds were performed.
Quenching of the lithium intermediates produced from
11e with n-butyllithium/4 with chloromethyldiphenylsilane
yielded the substitution product (Ϫ)-20 as a noncrystalline
solid (Scheme 8). Deprotection with diisobutylaluminium 1 h, Ϫ78 °C, Ϫ78 °C to room temp.; c) attempts to determine the
hydride provided the liquid α-silyl alcohol (Ϫ)-21, which
Scheme 9. a) nBuLi/4, toluene, 2 h, Ϫ78 °C; b) R3SnCl (1.5 equiv.);
ee failed
was converted into the crystalline urethane (Ϫ)-22 by addi-
tion of isopropyl isocyanate. X-ray analysis of (Ϫ)-22 (Fig-
ure 1)[32] established the (R) configuration at the ste-
reogenic centre.
Scheme 8. a) nBuLi/4, toluene, 2 h, Ϫ78 °C; b) Ph2MeSiCl, 76%;
c) DIBALH (10 equiv.), THF, 15 h, room temp., 87%; d) iPrNϭ
CϭO (3 equiv.), DMAP (0.1 equiv.), CH2Cl2, 24 h, 40 °C, 90%
Treatment of the analogously generated solution of 18e·4/
ent-18e·4 with chlorotrimethylstannane gave a mixture of
Figure 2. Structure of (R)-(2-methyl-1-cyclohexenyl)(triphenylstan-
the α-adduct (Ϫ)-23a (13%, 67% ee) and the γ-adduct (ϩ)-
24a (47%, 85% ee) (Scheme 9), while rac-18e-TMEDA af-
forded the α-adduct rac-23a (50%) in excess over rac-24a
(18%). When chlorotriphenylstannane was used as the scav-
nyl)methyl N,N-diisopropylcarbamate [(ϩ)-23b][32]
Addition of tetra(isopropoxy)titanium (3 equiv.) to a
enger, we exclusively isolated the α-adduct rac-23b in 80% toluene solution of rac-18d؊g at Ϫ78 °C resulted in smooth
yield. However, the sparteine complexes 18e·4/ent-18eϪ4 metal exchange, which in each case was apparent in the
gave rise to (ϩ)-23b (34%) besides an inseparable mixture of formation of a single rac-27d؊g diastereomer after homoal-
24b and 11e; we were unable to determine the enantiomeric dol addition with p-bromobenzaldehyde, in yields between
excesses in these triphenylstannanes. Compound (ϩ)-23b 71 and 79% (Scheme 10). When the same conditions were
418
Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
applied to the corresponding sparteine complexes 18d؊g·4/
epi-18d؊g·4, inseparable diastereomeric mixtures resulted.
Obviously, no lithium/titanium exchange had taken place.
However, after use of the more reactive chlorotri(isopro-
poxy)titanium, the optically active homoaldol adducts
27d؊g were formed, although in low yields (21Ϫ35%).
Compounds (ϩ)-27d and (Ϫ)-27e could be subjected to X-
ray analysis with anomalous diffraction (Figure 3 and Fig-
ure 4),[32] establishing (S) configurations at the stereogenic
ring carbon atoms and (R) configurations at the benzylic
position of each of them.
Figure 4. Structure of {1Z,1[2S,2(1R)]}-{2-[(4-bromophenyl)(hy-
droxy)methyl]-2-methylcyclopentylidene}methyl N,N-diisopropyl-
carbamate [(ϩ)-27d][32]
ect precursors. Since the lithium/titanium exchange in
lithiated allyl carbamates has been recognised to proceed
with stereoinversion,[15c] the major lithium complexes 18d·4
and 18e·4 must have the (S) configuration. The same con-
clusion results for 18e·4 from the analysis of the mode of
formation of the silane (Ϫ)-(R)-20 and the stannane (ϩ)-
(R)-23b, since similar silylations and stannylations have
regularly been observed to proceed with stereoinver-
sion.[16,33] Thus, in the kinetically controlled deprotonation
processes of 11d and 11e, the (pro-S) proton is removed
preferentially. The (pro-S) preference of alkyllithium/(Ϫ)-
sparteine has also been found for the primary allyl carba-
mates 2[16] and 9.[20] Therefore, it is quite likely that the
remaining major intermediates 18·4, formed under kinetic
control, and the resulting products 19 and 27 have the pro-
posed analogous absolute configurations. The assumption
is less certain for the derivatives of the 2,2-disubstituted
(cyclopentenyl)methyl carbamates 11h and 11i, since there
are substantial structural differences compared to the
‘‘usual’’ allyl carbamates seen.
Scheme 10. a) Ϫ78 °C, toluene, 1 h; b) Ϫ78 °C, 1 h, warm to
room temp.
Conclusion
2-Alkyl-substituted (cycloalk-1-enyl)methyl carbamates
such as 10d, 10e and 10f are deprotonated by butyllithium/
(Ϫ)-sparteine with efficient enantiotopic differentiation in
favour of the α-(pro-S) proton. The resulting lithium/(Ϫ)-
sparteine complexes exhibit satisfactory configurational
stability at Ϫ78 °C, and can be converted into highly enanti-
oenriched products in stereospecific reactions with elec-
trophiles. The analogous 2-unsubstituted compounds 10a
Figure 3. Structure of {1Z,1[2S,2(1R)]}-{2-[(4-bromophenyl)(hy-
droxy)methyl]-2-methylcyclohexylidene}methyl N,N-diisopropyl-
carbamate [(ϩ)-27e][32]
Because of the highly ordered nature of the and 10c, but not the (cyclohex-1-enyl)methyl derivative 10b,
ZimmermanϪTraxler transition state TS A, the titanium in- epimerise within a few minutes under these conditions. The
termediates (R)-25d and (R)-25e are assumed to be the dir- mechanism of the epimerisation, which requires the formal
Eur. J. Org. Chem. 2002, 414Ϫ427
419

M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D. Hoppe
FULL PAPER
(CH3), 119.1 [119.2] (Cq), 120.0 [120.1] (CH), 125.3 (CH), 129.7
(CH), 150.5 [150.6] (Cq, Ph), 153.4 [153.5] (Cq), 166.9 (Cq). IR
migration of the lithium cation from one face to the other,
is still unknown, although attempts to achieve better insight
have been performed.[34] The semiquantitative relationships
observed in this paper may be explained by an anti-SEЈ sub-
stitution reaction at the γ-position of the ion pairs 17·4 by
‘‘vagabonding’’ lithium cation in the solution; its rate
should be decreased with increasing steric shielding of this
position. Further efforts are necessary to uncover the mech-
anism. From the synthetic point of view, a simple and effici-
ent route to structurally complex homoaldol adducts has
been established, and has been utilised in the stereoselective
synthesis of highly substituted, bicyclic γ-lactones.[35]
(film): ν [cmϪ1] ϭ 1719 ν(CϭO), 1592 ν(CϭC). C22H25O6P
˜
(416.40): calcd. C 63.46, H 6.05; found C 63.62, H 6.30.
Methyl 2-Methyl-1-cycloheptene-1-carboxylate (14f): Methyllithium
(1.6 , 31.6 mL, 50.6 mmol) was added to a suspension of cop-
per(I) iodide (4.81 g, 25.3 mmol) in Et2O (175 mL), cooled to 0 °C.
After the mixture had been cooled to Ϫ40 °C, 13f (8.50 g,
21.1 mmol), dissolved in Et2O (10 mL), was added over 30 min.
The mixture was stirred for 3 h at this temperature and quenched
at room temperature with 2  aq. HCl. The aqueous phase was
extracted with Et2O (4 ϫ 30 mL). The combined organic layers
were dried with MgSO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (PE/
Et2O, 4:1). Yield: 3.02 (85%) colourless oil. RF ϭ 0.65 (PE/Et2O,
4:1). For experimental details see ref.[29]
Experimental Section
Methyl 2-Methyl-1-cyclooctene-1-carboxylate (14g): In the same
manner as described for 14f, 13g (8.79 g, 21.1 mmol) was converted
into 3.29 (86%) of 14g. Colourless oil. RF ϭ 0.63 (PE/Et2O, 4:1).
1H NMR (300 MHz, CDCl3): δ ϭ 1.27Ϫ1.46 (2 m, 8 H), 1.98 (s,
3 H), 2.20Ϫ2.42 (2 m, 4 H), 3.68 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ ϭ 21.3 (CH3), 26.5 (CH2), 26.5 (CH2), 28.3 (CH2), 28.3
(CH2), 30.1 (CH2), 34.9 (CH2), 51.1 (CH3), 127.1 (Cq), 148.6 (Cq),
169.9 (CϭO).
General Remarks: All solvents were dried and distilled prior to use.
Unless otherwise specified, materials were obtained from commer-
cial sources and used without purification. TMEDA and TMSCl
were distilled from calcium hydride and stored under argon. All
air- and moisture-sensitive reactions were performed in oven-dried
glassware under argon. Analytical thin layer chromatography was
performed on Polygram SIL G/UV254 plates (MachereyϪNagel &
Co.), or on Merck silica gel (60 F254) plates. For flash column chro-
matography, silica gel 60, 0.040Ϫ0.063 mm (230Ϫ400 mesh) was
used. Melting points are uncorrected. IR: Nicolet 5 DXC Fourier
transform IR spectrometer. Optical rotations: PerkinϪElmer 241
polarimeter. Elemental analyses: Heraeus CHN-O-rapid elemental
analyser. HRMS: Finnigan MAT 8200 or Micromass Quattro LC-
Z mass spectrometer. NMR: Bruker spectrometer 200 P-FT NMR,
ARX 300, AM360, AMX400 or Varian Associated Unity Plus 600
spectrometer. X-ray: EnrafϪNonius CAD4-diffractometer. The fol-
lowing abbreviations are used in the text: Cq ϭ quaternary C; PE ϭ
petroleum ether.
(2-Methyl-1-cycloheptenyl)methanol (10f): DIBALH (1 , 42.7 mL,
42.7 mmol, 2.5 equiv.) was added to a solution of ester 14f (2.87 g,
17.1 mmol, 2.5 equiv.) in THF (100 mL) at 0 °C and the mixture
was stirred for 2 h at 0 °C. It was allowed to warm up to room
temperature before addition of methanol (10 mL), followed by satd.
aq. NH4Cl (10 mL) and 2  aq. HCl (50 mL). The aqueous layer
was extracted with Et2O (3 ϫ 40 mL). The combined organic layers
were washed with satd. aq. NaHCO3, dried with MgSO4 and con-
centrated under reduced pressure. The remaining residue was puri-
fied by flash column chromatography on silica gel (PE/Et2O, 1:1)
to give 2.25 g (94%) of alcohol 10f. Colourless oil. RF ϭ 0.48 (PE/
Et2O, 1:1). 1H NMR (300 MHz, CDCl3): δ ϭ 1.34Ϫ1.49 (m, 4 H),
1.44 (s, 1 H), 1.61Ϫ1.79 (m, 5 H), 2.16 (mc, 2 H), 2.22 (mc, 2 H),
4.05 (s, 2 H).
Methyl 2-[(Diphenoxyphosphoryl)oxy]-1-cycloheptene-1-carboxylate
(13f): Compound 12f (8.51 g, 50.0 mmol) was added to a suspen-
sion of sodium hydride (60% in mineral oil, 2.20 g, 55.0 mmol, 1.1
equiv.) in THF (50 mL), cooled to Ϫ30 °C, and the mixture was
stirred for 1 h at Ϫ30 °C. Diphenyl chlorophosphate (14.8 g,
55.0 mmol) was then added and the mixture was stirred for 1 h at
Ϫ30 °C. After this had warmed to room temperature, satd. aq.
NH4Cl (40 mL) and water (100 mL) were added. The aqueous
phase was extracted with Et2O (3 ϫ 50 mL). The combined organic
layers were dried with MgSO4 and concentrated in vacuo. The res-
idue was purified by silica gel column (PE/Et2O, 1:1) to afford the
pure product 13f. Yield: 17.3 g (86%) colourless oil. RF ϭ 0.33 (PE/
Et2O, 1:1). 1H NMR (300 MHz, CDCl3): δ ϭ 1.56Ϫ1.80 (2 m, 6
H), 2.41Ϫ2.66 (2 m, 4 H), 3.54 (s, 3 H), 7.14Ϫ7.37 (m, 10 H). 13C
NMR (75 MHz, CDCl3): δ ϭ 24.0 (CH2), 25.9 (CH2), 27.7 (CH2),
31.0 (CH2), 34.3 (CH2), 51.6 (CH3), 120.0 [120.1] (Cq), 122.0 [122.1]
(CH), 125.4 (CH), 129.7 (CH), 150.5 [150.6] (Cq, Ph), 155.9 [156.0]
(2-Methyl-1-cyclooctenyl)methanol (10g): In the same manner as
described for 10f, 14g (3.17 g, 17.4 mmol) was converted into 2.43
(90%) of 10g. RF ϭ 0.46 (PE/Et2O, 1:1). 1H NMR (300 MHz,
CDCl3): δ ϭ 1.34Ϫ1.59 (m, 8 H), 1.72 (s, 3 H), 2.12Ϫ2.30 (2 m, 4
H), 4.20 (s, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ 18.1 (CH3),
26.4 (CH2), 26.8 (CH2), 28.3 (CH2), 29.4 (CH2), 30.0 (CH2), 33.1
(CH2), 62.7 (CH2), 132.5 (Cq), 134.0 (Cq,). IR (film): ν [cmϪ1] ϭ
˜
3334 ν(OH), 1666 ν(CϭC). C10H18O (154.25): calcd. C 77.87, H
11.76; found C 77.32, H 11.71.
(2-Methyl-1-cycloheptenyl)methyl N,N-Diisopropylcarbamate (11f)
(Method A): N,N-Diisopropylcarbamoyl chloride (3.11 g,
19.0 mmol, 1.25 equiv.) in THF (10 mL) was added to a solution
of allylic alcohol 10f (2.15 g, 15.2 mmol), DMAP (186 mg
1.52 mmol) and pyridine (20 mL). The reaction mixture was heated
under reflux for 12 h. After cooling to room temperature, the solu-
tion was poured into 2  aq. HCl (30 mL). The aqueous phase was
extracted with Et2O (3 ϫ 30 mL). The combined organic layers
(Cq), 167.6 (Cq). IR (film): ν [cmϪ1] ϭ 1719 ν(CϭO); 1596 ν(Cϭ
˜
C). C21H23O6P (402.380): calcd. C 62.68, H 5.76; found C 62.49,
H 5.77.
Methyl 2-[(Diphenoxyphosphoryl)oxy]-1-cyclooctene-1-carboxylate
(13g): In the same manner as described for 13f, 12g (9.21 g, were washed with satd. aq. NaHCO3, dried with MgSO4 and con-
50.0 mmol) was converted into 18.8 g (90%) of 13g. Colourless oil. centrated in vacuo. The residue was chromatographed on silica gel
RF ϭ 0.33 (PE/Et2O, 1:1). 1H NMR (300 MHz, CDCl3): δ ϭ (PE/Et2O, 4:1). Yield: 2.36 g (58%) 11f as a colourless oil; 366 mg
1.48Ϫ1.79 (2 m, 8 H), 2.37Ϫ2.60 (2 m, 4 H), 3.56 (s, 3 H), (17%) of 10f was also recovered. RF ϭ 0.47 (PE/Et2O, 4:1). 1H
7.13Ϫ7.38 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ ϭ 25.8 (CH2), NMR (300 MHz, CDCl3): δ ϭ 1.16 (d, J ϭ 6.9 Hz, 12 H),
26.3 (CH2), 27.9 (CH2), 27.9 (CH2), 29.8 (CH2), 31.5 (CH2), 51.5 1.36Ϫ1.74 (2 m, 6 H), 1.75 (s, 3 H), 2.16 (mc, 4 H), 3.87 (br. s, 2
420
Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
H), 4.53 (d, J ϭ 0.5 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ 6.7 Hz, 12 H), 1.60 (m, 4 H), 1.70 (s, 3 H), 1.94Ϫ2.09 (m, 4 H),
20.9 (CH3), 25.8 (CH2), 26.8 (CH2), 31.9 (CH2), 32.4 (CH2), 36.1
3.80Ϫ4.2 (m, 2 H), 4.58 (d, J ϭ 0.5 Hz, 2 H). 13C NMR (75 MHz,
(CH2), 45.7 (CH), 66.3 (CH2), 131.6 (Cq), 139.2 (Cq), 156.2 (CϭO). CDCl3): δ ϭ 18.9, 20.9, 20.9, 27.9, 31.9, 45.6, 64.9, 125.9, 132.1,
IR (film): ν˜ [cmϪ1] ϭ 1693 ν(CϭO). C16H29NO2 (267.41): calcd. C
71.86, H 10.93, N 5.24; found C 71.61, H 11.04, N 5.39.
156.0. C15H27NO2 (253.38): calcd. C 71.10, H 10.74, N 5.53, found
C 70.94, H 10.81, N 5.85.
(2-Methyl-1-cyclooctenyl)methyl N,N-Diisopropylcarbamate (11g)
(1,4-Dioxaspiro[4.4]non-6-en-6-yl)methyl N,N-Diisopropylcarbamate
(Method A): In the same manner as described for 11f, 10g (2.31 g, (11i) (Method B): In the same manner as described for 11a, 10i
15.0 mmol), DMAP (183 mg 1.50 mmol), and N,N-diisopropylcar- (2.05 g, 13.1 mmol) in hexane (20 mL) was deprotonated with so-
bamoyl chloride (3.07 g, 18.8 mmol) in pyridine (20 mL) were dium hydride (60% in mineral oil, 0.63 g, 15.7 mmol, 1.2 equiv.)
heated under reflux for 12 h. After cooling to room temperature, and N,N-diisopropylcarbamoyl chloride (2.78 g, 17.0 mmol, 1.30)
the mixture was worked up. Flash chromatography (PE/Et2O, 4:1)
gave 11g. Yield: 2.80 g (66%) colourless oil; 570 mg (25%) of 10g column chromatography (PE/Et2O, 1:2). Yield 2.51 g (68%) 11i as
were also recovered. RF
0.54 (PE/Et2O, 4:1). 1H NMR a colourless oil. RF ϭ 0.67 (PE/Et2O, 1:2). 1H NMR (300 MHz,
was added. After workup, the residue was purified by silica gel
ϭ
(300 MHz, CDCl3): δ ϭ 1.18 (d, J ϭ 6.7 Hz, 12 H), 1.36Ϫ1.58 (m, CDCl3): δ ϭ 1.19 [1.17] (d, J ϭ 6.8 Hz, 12 H), 2.00Ϫ2.08 (m, 2 H),
8 H), 1.74 (s, 3 H), 2.14Ϫ2.27 (m, 4 H), 3.88 (br. s, 2 H), 4.58 (s, 2 2.29Ϫ2.32 (m, 2 H), 3.78Ϫ3.99 (m, 6 H), 4.64 (dd, J ϭ 3.8, 2.2 Hz,
H). 13C NMR (75 MHz, CDCl3): δ ϭ 18.5 (CH3), 21.0 (CH3), 26.4 2 H), 5.99 (ddd, J ϭ 3.9, 2.5, 1.5 Hz, 1 H). 13C NMR (75 MHz,
(CH2), 26.8 (CH2), 28.3 (CH2), 29.7 (CH2), 29.9 (CH2), 33.3 (CH2), CDCl3): δ ϭ 21.0 (CH3), 28.0 (CH2), 36.0 (CH2), 45.9 (CH), 59.7
45.7 (CH), 65.0 (CH2), 128.7 (Cq), 135.9 (Cq), 156.0 (CϭO). IR
(CH2), 65.2 (CH2), 109.5 (Cq), 133.7 (CH), 139.2 (Cq), 155.4 (Cϭ
(film): ν [cmϪ1] ϭ 1691 ν(CϭO). C16H29NO2 (267.41): calcd. C
O). IR (film): ν [cmϪ1] ϭ 1700 ν(CϭO). C15H24NO4 (283.36):
˜
˜
72.55, H 11.10, N 4.98; found C 72.45, H 11.09, N 5.20.
calcd. C 63.58, H 8.89, N 4.94, found C 63.47, H 8.98, N 5.17.
1-Cyclopentenylmethyl N,N-Diisopropylcarbamate (11a): A solution
(7-Methyl-1,4-dioxaspiro[4.5]dec-7-en-8-yl)methyl N,N-Ddiisoprop-
of allylic alcohol 10a (5.60 g, 57.1 mmol) in THF (10 mL) was ad- ylcarbamate (11j): In the same manner as described for 11a, 10j
ded dropwise to a suspension of sodium hydride (60% in mineral
oil, 2.74 g, 68.6 mmol, 1.2 equiv.) in hexane (75 mL) at 0 °C. The
(3.90 g, 21.2 mmol) in THF (20 mL) was deprotonated with sodium
hydride (60% in mineral oil, 600 mg, 25.2 mmol, 1.2 equiv.) and
reaction mixture was stirred for 1 h at room temperature, after N,N-diisopropylcarbamoyl chloride (4.47 g, 27.5 mmol, 1.3 equiv.)
which N,N-diisopropylcarbamoyl chloride (11.2 g, 73.2 mmol, 1.28
equiv.) was added in small portions over 5 min, and the mixture
was then heated under reflux for 16 h. After cooling to room tem-
perature, the solution was poured into 2  aq. HCl (20 mL). The
was added. The crude product was purified by silica gel column
chromatography (PE/Et2O, 1:1). Yield: 5.56 g (84%) 11d as a col-
ourless oil. RF ϭ 0.46 (PE/Et2O, 1:1). 1H NMR (300 MHz,
CDCl3): δ ϭ 1.14 (d, J ϭ 6.9 Hz, 12 H), 1.64Ϫ1.72 (m, 2 H), 1.67
aqueous phase was extracted with Et2O (3 ϫ 20 mL). The com- (s, 3 H), 2.17Ϫ2.30 (m, 4 H), 3.69Ϫ4.00 (m, 6 H), 4.56 (s, 2 H).
bined organic layers were washed with satd. aq. NaHCO3, dried
with MgSO4 and concentrated in vacuo. Distillation of the crude
13C NMR (75 MHz, CDCl3): δ ϭ 18.8 (CH3), 21.0 (CH3), 26.9
(CH2), 31.2 (CH2), 41.8 (CH2), 45.7 (CH), 63.9 (CH2), 64.3 (CH2),
product yielded 1.72 g (75%) 11a as a colourless oil. b.p. 75Ϫ80 °C 64.3 (CH2), 107.9 (Cq), 125.6 (Cq), 129.6 (Cq), 155.8 (CϭO). IR
1
(0.01 Torr). H NMR (90 MHz, CDCl3): δ ϭ 1.15 (d, J ϭ 7.0 Hz, (film): ν [cmϪ1] ϭ 1690 ν(CϭO). C17H29NO4 (311.42): calcd. C
˜
12 H), 1.60Ϫ2.40 (m, 6 H), 3.81 (sept, J ϭ 7.0 Hz, 2 H), 4.55 (m, 65.57, H 9.39, N 4.50, found C 65.51, H 9.40, N 4.79.
2 H), 5.55 (m, 1 H). 13C NMR (22.5 MHz, CDCl3): δ ϭ 21.0 (CH3),
23.4 (CH2), 32.4 (CH2), 33.1 (CH2), 45.8 (CH), 63.4 (CH2), 126.9
(CH), 140.1 (Cq), 155.3 (CϭO). C13H23NO2 (255.32): calcd. C
69.30, H 10.29; found C 69.25, H 10.25.
(1-Hydroxycycloheptyl)methyl N,N-Diisopropylcarbamate (17c):
sec-Butyllithium (1.3 , 8.5 mL, 11.0 mmol, 1.1 equiv.) was added
dropwise to
a solution of methyl N,N-diisopropylcarbamate
(1.95 g, 10.0 mmol) and TMEDA (1.79 g, 15.0 mmol, 1.5 equiv.) in
(2-Methyl-1-cyclopentenyl)methyl N,N-Diisopropylcarbamate (11d): THF (30 mL), cooled to Ϫ78 °C. Stirring was continued at Ϫ78
In the same manner as described for 11a, 10d (1.40 g, 12.5 mmol) °C for 2 h, after which cycloheptanone (2.24 g, 20.0 mmol, 2.0
in hexane (20 mL) was deprotonated with sodium hydride (60% in equiv.) was added in small portions over 1 h. Finally the reaction
mineral oil, 0.60 g, 15.0 mmol, 1.2 equiv.) and N,N-diisopropylcar- mixture was stirred at Ϫ78 °C for 4 h and 2  aq. HCl (40 mL)
bamoyl chloride (2.46 g, 16.0 mmol, 1.28 equiv.) was added. The was added at room temperature. The aqueous phase was extracted
crude product was purified by silica gel column chromatography
(PE/Et2O, 4:1). Yield: 2.36 g (58%) 11d as a colourless oil. RF
0.54 (PE/Et2O, 4:1). 1H NMR (300 MHz, CDCl3): δ ϭ 1.16 (d, J ϭ
with Et2O (3 ϫ 20 mL). The combined organic layers were washed
with satd. aq. NaHCO3, dried with MgSO4 and concentrated in
vacuo. The residue was purified by silica gel column chromato-
ϭ
6.9 Hz, 12 H), 1.67 (s, 3 H), 1.71Ϫ1.82 (m, 2 H), 2.37Ϫ2.24 (m, 4 graphy (PE/Et2O, 1:1) to afford the pure product (R)-20. Yield:
1
H), 3.87 (br. s, 2 H), 4.60 (s, 2 H). 13C NMR (75 MHz, CDCl3): 1.53 mg (56%) colourless oil. RF ϭ 0.43 (PE/Et2O, 1:1). H NMR
δ ϭ 13.8 (CH3), 21.0 (CH3), 21.6 (CH2), 34.8 (CH2), 38.7 (CH2), (300 MHz, CDCl3): δ ϭ 1.21 (d, J ϭ 6.7 Hz, 12 H), 1.30Ϫ1.72 (m,
45.7 (CH), 61.2 (CH2), 130.7 (Cq), 137.1 (Cq), 156.0 (CϭO). IR 12 H), 2.25 (br. s, 1 H), 3.90 (br. s, 2 H), 3.98.(s, 2 H). 13C NMR
(film): ν˜ [cmϪ1] ϭ 1696 ν(CϭO). C14H25NO2 (239.35): calcd. C (75 MHz, CDCl3): δ ϭ 20.9 (CH3), 22.2 (CH2), 29.8 (CH2), 37.9
(CH2), 45.9 (CH), 72.4 (CH2), 156.0 (CϭO). IR (film): ν [cmϪ1] ϭ
˜
70.25, H 10.53, N 5.85; found C 69.85, H 10.43, N 6.20.
3449 ν(OH), 1683 ν(CϭO). C15H29NO3 (271.40): calcd. C 66.38,
H 10.77, N 5.16, found C 66.26, H 10.59, N 5.49.
(2-Methyl-1-cyclohexenyl)methyl N,N-Diisopropylcarbamate (11e):
In the same manner as described for 11a, 10e (1.93 g, 15 mmol) in
THF (10 mL) was deprotonated with sodium hydride (60% in min- (1-Hydroxycyclohexyl)methyl N,N-Diisopropylcarbamate (17b): In
eral oil, 0.96 g, 24.0 mmol) and N,N-diisopropylcarbamoyl chloride
(3.93 g, 24.0 mmol) was added. Purification of the crude product
by silica gel column chromatography (PE/Et2O, 4:1) gave 11e in
the same manner as described for 17c, methyl N,N-diisopropylcar-
bamate (2.41 g, 15.1 mmol) and TMEDA (3.43 g, 22.7 mmol, 1.16
equiv.) were dissolved in THF (40 mL) and cooled to Ϫ78 °C, after
86% yield (3.51 g) over two steps as a colourless oil. RF ϭ 0.44 which sec-butyllithium (1.25 , 14.8 mL, 18.5 mmol, 1.23 equiv.)
(PE/Et2O, 4:1). 1H NMR (300 MHz, CDCl3): δ ϭ 1.20 (d, J ϭ
was added. Stirring was continued at Ϫ78 °C for 2 h, after which
Eur. J. Org. Chem. 2002, 414Ϫ427
421

M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D. Hoppe
FULL PAPER
cyclohexanone (2.05 g, 19.6 mmol) was added over a period of (CH2), 41.1 (CH2), 45.2 (Cq), 45.8 (CH), 61.3 (CH2), 125.7 (CH),
1.5 h. After workup, the crude product was used without further
purification.
147.1 (Cq), 155.3 (CϭO). IR (film): ν [cmϪ1] ϭ 1699 ν(CϭO).
˜
C15H27NO2 (253.38): calcd. C 71.10, H 10.74, N 5.53, found C
70.91, H 10.96, N 5.75.
1-(Hydroxy-2,2-dimethylcyclopentyl)methyl N,N-Diisopropylcarba-
mate (17h): In the same manner as described for 17c, methyl N,N-
diisopropylcarbamate (2.72 g, 17.1 mmol, 2.1 equiv.) and TMEDA
(2.94 g, 25.7 mmol, 3.0 equiv.) in THF (30 mL), cooled to Ϫ78 °C,
was deprotonated with sec-butyllithium (1.23 , 15.3 mL,
18.8 mmol). Stirring was continued at Ϫ78 °C for 2.5 h, after which
2,2-dimethylcyclopentanone (1.00 g, 8.56 mmol) was added over
1.5 h. The crude product was purified by silica gel column chroma-
tography (PE/Et2O, 5:1). Yield: 1.48 g (64%) of 17h as a colourless
General Procedure for Deprotonation of Allyl Carbamates (GP1):
Butyllithium (1.2 equiv.) was added dropwise with vigorous stirring
to a 0.15  solution of allyl carbamates 11 and diamine (1.2 equiv.)
in toluene or pentane at Ϫ78 °C. After this had been stirred for
0Ϫ180 min (see Table 2) at the same temperature, the electrophile
(1.5 equiv.) was added. The mixture was stirred for 1 h at Ϫ78 °C,
after which it was allowed to warm to room temperature and
poured into an ice-cooled mixture of Et2O (10 mL) and 2  aq.
HCl (10 mL). The aqueous layer was extracted with Et2O (3 ϫ
15 mL). The combined organic layers were dried with MgSO4 and
concentrated in vacuo. The residue was purified by silica gel flash
column chromatography.
1
oil. RF ϭ 0.36 (PE/Et2O, 5:1). H NMR (300 MHz, CDCl3): δ ϭ
0.89 (s, 3 H), 1.01 (s, 3 H), 1.18 (d, J ϭ 6.9 Hz, 12 H), 1.33Ϫ1.97
(m, 6 H), 2.59 (s, 1 H), 3.87 (sept, J ϭ 6.9 Hz, 2 H), 4.09 (d, J ϭ
11.4 Hz, 2 H), 4.19 (d, J ϭ 11.4 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): δ ϭ 19.2 (CH2), 20.9 (CH3), 22.3 (CH3), 24.5 (CH3), 35.9
(CH2), 39.7 (CH2) 44.5 (Cq), 46.1 (CH), 69.1 (CH), 82.8 (Cq), 156.1
In situ Silylation of Carbamates: n-Butyllithium (1.2 equiv.) was
added over 10 min to a solution of 11 and TMSCl (1.5 equiv.) in
toluene (5 mL) at Ϫ78 °C. Stirring was continued for 30 min and
the mixture was quenched with methanol (1 mL) at Ϫ78 °C. After
usual workup, the crude product was purified by silica gel flash
column chromatography.
(CϭO). IR (film): ν [cmϪ1] ϭ 3467 ν(OH), 1683 ν(CϭO).
˜
C15H29NO3 (271.40): calcd. C 66.38, H 10.77, N 5.16, found C
66.14, H 10.93, N 5.40.
1-Cycloheptenylmethyl N,N-Diisopropylcarbamate (11c): Com-
pound 17c (1.31 g, 4.83 mmol) was dissolved in pyridine (12 mL),
cooled to 0 °C and POCl3 (2.5 mL) was added dropwise. The mix-
ture was stirred for 20 h at 0 °C, after which it was poured into
crushed ice (50 g). The aqueous phase was extracted with Et2O (3
ϫ 30 mL). The combined organic layers were washed with satd.
aq. NaHCO3, dried with MgSO4 and concentrated in vacuo. The
residue was purified by silica gel column chromatography (PE/
EtOAc, 10:1) to afford the pure product 11c. Yield: 768 mg (63%),
colourless oil. RF ϭ 0.54 (PE/EtOAc, 10:1) 1H NMR (300 MHz,
CDCl3): δ ϭ 1.16Ϫ1.26 (m, 12 H), 1.43Ϫ2.23 (3 m 10 H), 3.89 (br.
s, 2 H), 4.42 (s, 2 H), 5.83 (t, J ϭ 6.1 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): δ ϭ 21.0 (CH3), 26.7 (CH2), 26.9 (CH2), 28.3 (CH2), 30.4
(CH2), 32.3 (CH2), 45.8 (CH), 70.4 (CH2), 130.2 (CH), 140.0 (Cq),
(1-Cyclopentenyl)(trimethylsilyl)methyl N,N-Diisopropylcarbamate
(19a): As described under GP1, 11a (158 mg, 0.70 mmol) was de-
protonated with n-butyllithium/(Ϫ)-sparteine (10 min) and
quenched with TMSCl. Yield: 112 mg (54%) colourless oil. RF
ϭ
0.67 (PE/Et2O, 4:1). [α]2D0 ϭ ϩ6.8 (c ϭ 1.08, CHCl3). Shift experi-
ment: er 67:33 (34% ee), 9.4 mg ϩ 11 mol % Eu(hfc)3 in CDCl3,
∆δ[Si(CH3)3 at δ ϭ 0.05] ϭ 0.03, signal of major enantiomer ap-
1
pears at lower field. H NMR (300 MHz, CDCl3): δ ϭ 0.05 (s, 9
H), 1.20 (d, J ϭ 6.9 Hz, 12 H), 1.72Ϫ1.92 (m, 2 H), 2.14Ϫ2.40 (m,
4 H), 3.90 (br. s, 2 H), 5.12Ϫ5.20 (m, 1 H), 5.31Ϫ5.37 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ ϭ 0.7 (CH3), 21.1 (CH3), 23.1
(CH2), 32.3 (CH2), 34.0 (CH2), 45.8 (CH), 69.6 (CH), 122.1 (CH),
143.3 (Cq), 155.8 (CϭO). IR (film): ν [cmϪ1] ϭ 1693 ν(CϭO), 1645
˜
155.8 (CϭO). IR (film): ν [cmϪ1] ϭ 1701 ν(CϭO). C15H27NO2
˜
ν(CϭC). C16H31NO2Si (297.51): calcd. C 64.59, H 10.50, N 4.71,
found C 64.60, H 10.49, N 4.91.
(253.38): calcd. C 71.10, H 10.74, N 5.53, found C 70.73, H 10.71,
N 5.86.
(1-Cyclohexenyl)(trimethylsilyl)methyl N,N-Diisopropylcarbamate
(19b): As described under GP1, 11b (145 mg, 0.61 mmol) was de-
protonated with n-butyllithium/(Ϫ)-sparteine (30 min) and
1-Cyclohexenylmethyl N,N-Diisopropylcarbamate (11b): In the same
manner as described for 17c, the crude product 17b was dissolved
in pyridine (30 mL) and cooled to 0 °C, after which SOCl2 (1.65
mL, 22.7 mmol) was added dropwise. The mixture was stirred at 0
°C for 3 h. After workup, the residue was purified by silica gel
column chromatography (PE/Et2O, 9:1) to yield 11b (1.95 g, 54%
over two steps) as a colourless oil. RF ϭ 0.58 (PE/Et2O, 9:1). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.22 (d, J ϭ 6.7 Hz), 1.55Ϫ1.75 (m,
4 H), 1.96Ϫ2.10 (m, 4 H), 3.70Ϫ4.20 (m, 2 H), 4.46 (br. s, 2 H),
5.71 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ 21.1, 22.4, 22.6,
25.1, 26.2, 45.9, 69.0, 124.8, 133.8, 155.6.
quenched with TMSCl. Yield: 167 mg (88%) colourless oil. RF
ϭ
0.63 (PE/Et2O, 9:1). [α]2D0 ϭ ϩ4.1 (c ϭ 0.75, CHCl3). Shift experi-
ment: er 77:23 (54% ee), 50 mol % Eu(hfc)3 in CDCl3. 1H NMR
(300 MHz, CDCl3): δ ϭ 0.09 (s, 9 H), 1.15 (d, J ϭ 6.7 Hz, 12 H),
1.45Ϫ1.70 (m, 4 H), 1.90Ϫ2.10 (m, 4 H), 3.95 (br. s, 2 H), 4.93 (s,
1 H), 5.49 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ2.8, 21.0,
22.4, 22.6, 24.9, 26.9, 45.9, 73.4, 119.9.136.5, 155.6. C17H33NO2Si
(311.53): calcd. C 65.54, H 10.68, N 4.50, found C 65.58, H 10.59,
N 4.76.
(5,5-Dimethyl-1-cyclopentenyl)methyl
(11h): In the same manner as described for 17c, 17h (271 mg,
1.0 mmol) was dissolved in pyridine (2.5 mL), cooled to 0 °C and
N,N-Diisopropylcarbamate
(1-Cycloheptenyl)(trimethylsilyl)methyl N,N-Diisopropylcarbamate
(19c): As described under GP1, 11c (127 mg, 0.50 mmol) was de-
protonated with sec-butyllithium/(Ϫ)-sparteine (10 min) and
SOCl2 (238 mg, 2.0 mmol, 2.0 equiv.) was added dropwise. The quenched with TMSCl. Yield: 15 mg (15%) colourless oil and
mixture was stirred for 3 h at room temperature. After workup, the 33 mg (43%) 11c recovered. RF ϭ 0.63 (PE/Et2O, 4:1). [α]2D0 ϭ Ϫ1.1
residue was purified by silica gel column chromatography (PE/
(c ϭ 0.75, CHCl3). Shift experiment: er 53.5:46.5 (7% ee), 18.0 mg
ϩ 75 mol % Eu(hfc)3 in CDCl3, ∆δ[Si(CH3)3 at δ ϭ 0.04] ϭ 0.03,
Et2O, 4:1) to yield 11h (138 mg, 55%) as a colourless oil together
with 20 mg of an isomer that was not characterised. RF ϭ 0.42 signal of major enantiomer appears at higher field. 1H NMR
(PE/Et2O, 4:1). 1H NMR (300 MHz, CDCl3): δ ϭ 1.04 (s, 6 H), (300 MHz, CDCl3): δ ϭ 0.04 (s, 9 H), 1.20 (d, J ϭ 6.8 Hz, 12 H),
1.19 (d, J ϭ 6.9 Hz, 12 H), 1.71 (t, J ϭ 7.0 Hz, 2 H), 2.19Ϫ2.27
1.30Ϫ2.22 (2 m, 10 H), 3.91 (m, 2 H), 4.91 (s, 1 H), 5.55 (t, J ϭ
(m, 2 H), 3.89 (sept, J ϭ 6.9 Hz, 2 H), 4.58 (mc, 2 H), 5.52 (mc, 1 6.4 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ2.3 (CH3), 21.5
H). 13C NMR (75 MHz, CDCl3): δ ϭ 21.0 (CH3), 26.9 (CH3), 29.3 (CH3), 27.2 (CH2), 27.6 (CH2), 28.8 (CH2), 31.4 (CH2), 33.1 (CH2),
422
Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
46.3 (CH), 75.3 (CH), 125.5 (CH), 143.3 (Cq), 156.0 (CϭO). IR (5,5-Dimethyl-1-cyclopentenyl)(trimethylsilyl)methyl N,N-Diisopro-
(film): ν [cmϪ1] ϭ 1701 ν(CϭO).
pylcarbamate (19h): As described under GP1, 11h (152 mg,
0.60 mmol) was deprotonated with n-butyllithium/(Ϫ)-sparteine
(40 min) and quenched with TMSCl. Yield: 48 mg (25%) colourless
oil and 76 mg (50%) of 11h. RF ϭ 0.65 (PE/Et2O, 4:1). [α]2D0ϭ ϩ4.1
(c ϭ 0.54, CHCl3. Shift experiment: er 57:43 (14% ee), 22.1 mg ϩ
10 mol % Eu(hfc)3 in CDCl3, ∆δ[Si(CH3)3 at δ ϭ 0.05] ϭ 0.03,
signal of major enantiomer appears at higher field. 1H NMR
(300 MHz, CDCl3): δ ϭ 0.05 (s, 9 H), 0.99 (s, 3 H), 1.01 (s, 3 H),
1.18[1.16] (d, J ϭ 6.8 Hz, 12 H), 1.54Ϫ1.72 (m, 2 H), 2.22 (mc, 2
H), 3.87 (sept, J ϭ 6.8 Hz, 2 H), 5.21 (m, 1 H), 5.55 (m, 1 H). 13C
NMR (75 MHz, CDCl3): δ ϭ Ϫ2.4 (CH3), 21.1 (CH3), 26.5 (CH3),
27.5 (CH3), 29.5 (CH2), 40.5 (CH2), 45.8 (CH), 46.3 (Cq), 64.7
˜
(2-Methyl-1-cyclopentenyl)(trimethylsilyl)methyl N,N-Diisopropyl-
carbamate (19d): As described under GP1, 11d (120 mg,
0.50 mmol) was deprotonated with n-butyllithium/(Ϫ)-sparteine
(180 min) and quenched with TMSCl. Yield: 109 mg (70%) colour-
less oil. RF ϭ 0.66 (PE/Et2O, 4:1). [α]2D0 ϭ ϩ4.0 (c ϭ 1.02, CHCl3).
Shift experiment: er 85:15 (70% ee), 4.0 mg ϩ 10 mol % Eu(hfc)3
in CDCl3, ∆δ(3 H at δ ϭ 1.68) ϭ 0.28, signal of major enantiomer
appears at lower field. 1H NMR (300 MHz, CDCl3): δ ϭ Ϫ0.06 (s,
9 H), 1.21 (d, J ϭ 6.7 Hz, 12 H), 1.68 (s, 3 H), 1.75 (mc, 2 H),
2.26Ϫ2.40 (m, 4 H,), 3.91 (br. s, 2 H), 5.41 (m, 1 H). 13C NMR
(75 MHz, CDCl3): δ ϭ Ϫ2.5 (CH3), 14.6 (CH3), 21.1 (CH3), 22.0
(CH2), 34.7 (CH2), 38.6 (CH2), 45.8 (CH), 68.1 (CH), 131.5 (Cq),
133.5 (Cq), 156.1 (CϭO). IR (film): ν˜ [cmϪ1] ϭ 1694 ν(CϭO).
C17H33NO2Si (311.53): calcd. C 65.54, H 10.68, N 4.50, found C
65.41, H 10.76, N 4.70.
(CH), 127.3 (CH), 150.2 (Cq), 155.4 (CϭO). IR (film): ν [cmϪ1] ϭ
˜
1690 ν(CϭO), 1634 ν(CϭC). C18H35NO2Si (325.56): calcd. C
66.41, H 10.84, N 4.30, found C 66.02, H 10.96, N 4.42.
(؉)-(1,4-Dioxaspiro[4.4]non-6-en-6-yl)(trimethylsilyl)methyl N,N-
Diisopropylcarbamate (19i): As described under GP1, 11i (170 mg,
0.60 mmol) was deprotonated with n-butyllithium/(Ϫ)-sparteine
(10 min) and quenched with TMSCl. Yield: 138 mg (64%) colour-
(2-Methyl-1-cyclohexenyl)(trimethylsilyl)methyl N,N-Diisopropyl-
carbamate (19e): As described under GP1, 11e (177 mg, 0.70 mmol)
was deprotonated with n-butyllithium/(Ϫ)-sparteine (120 min) and
less oil and 33 mg (19%) of 11i. RF ϭ 0.61 (PE/EtOAc, 2:1). [α]2D0
ϭ
quenched with TMSCl. Yield: 141 mg (88%) colourless oil. RF
ϭ
ϩ6.8 (c ϭ 1.02, CHCl3). Shift experiment: er 70:30 (40% ee),
16.1 mg ϩ 35 mol % Eu(hfc)3 in CDCl3, ∆δ[Si(CH3)3 at δ ϭ
0.05] ϭ 0.16, signal of major enantiomer appears at higher field.
1H NMR (600 MHz, CDCl3): δ ϭ 0.05 (s, 9 H), 1.18 (d, J ϭ 6.8 Hz,
12 H), 1.94 (ddd, J ϭ 13.5, J ϭ 6.5, J ϭ 5.5 Hz, 1 H), 2.02 (ddd,
J ϭ 13.5, J ϭ 7.1, J ϭ 6.3 Hz, 1 H), 2.30Ϫ2.33 (m, 2 H), 3.78Ϫ4.04
(m, 6 H), 5.21 (dd, J ϭ 1.5, J ϭ 2.9, 1 H), 5.83 (td, J ϭ 2.5, J ϭ
1.5, 1 H). 13C NMR (150 MHz, CDCl3): δ ϭ Ϫ2.7 (CH3), 21.1
(CH3), 28.1 (CH2), 35.7 (CH2), 45.8 (CH), 64.6 (CH2), 64.9 (CH2),
65.3 (CH), 119.5 (Cq), 131.5 (CH), 142.5 (Cq), 155.2 (CϭO). IR
0.74 (PE/Et2O, 9:1). [α]2D0 ϭ Ϫ12.0 (c ϭ 0.54, CHCl3). Shift experi-
ment: er 92.5:7.5 (85% ee), 35 mol % Eu(hfc)3 in CDCl3. 1H NMR
(300 MHz, CDCl3): δ ϭ 0.02 (s, 9 H), 1.15 (d, J ϭ 6.9 Hz, 2 H),
1.42Ϫ155 (m, 4 H), 1.60 (s, 2 H), 1.75Ϫ2.00 (m, 4 H), 3.85 (br. s,2
H), 5.46 (s, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ2.2, 19.7,
21.0, 22.96, 23.02, 26.7, 32.1, 45.7, 70.5, 126.1, 128.7, 155.9.
C18H35NO2Si (325.56): calcd. C 66.41, H 10.84, N 4.30, found C
66.49, H 10.83, N 4.71.
(2-Methyl-1-cycloheptenyl)(trimethylsilyl)methyl N,N-Diisopropyl-
carbamate (19f): As described under GP1, 11f (134 mg, 0.50 mmol)
was deprotonated with sec-butyllithium/(Ϫ)-sparteine (5 min) and
(film): ν [cmϪ1] ϭ 1690 ν(CϭO). C18H33NO4Si (355.54): calcd. C
˜
60.81, H 9.35, N 3.94, found C 60.65, H 9.53, N 4.08.
quenched with TMSCl. Yield: 132 mg (78%) colourless oil. RF
ϭ
(؊)-(7-Methyl-1,4-dioxaspiro[4.5]dec-7-en-8-yl)(trimethyl-
silyl)methyl-N,N-Diisopropylcarbamate (19j): As described under
GP1, 11i (249 mg, 0.80 mmol) was deprotonated with n-butylli-
thium/(Ϫ)-sparteine (10 min) and quenched with TMSCl. Yield:
0.39 (PE/EtOAc, 20:1). [α]2D0 ϭ Ϫ20.8 (c ϭ 0.65, CHCl3). Shift ex-
periment: er 90.5:9.5 (81% ee), 11.4 mg ϩ 80 mol % Eu(hfc)3 in
CDCl3, ∆δ[Si(CH3)3 at δ ϭ 0.02] ϭ 0.07, signal of major enanti-
omer appears at higher field. 1H NMR (400 MHz, CDCl3): δ ϭ
0.02 (s, 9 H), 1.19 (br. s, 12 H), 1.28Ϫ1.82 (m, 6 H), 1.75 (s, 3 H),
2.00Ϫ2.21 (m, 4 H), 3.75 [4.08] (br. s, 2 H), 5.46 (s, 1 H). 13C NMR
(100 MHz, CDCl3): δ ϭ Ϫ2.4 (CH3), 20.7 [21.3] (CH3), 21.4 (CH3),
25.9 (CH2), 27.2 (CH2), 29.9 (CH2), 32.8 (CH2), 36.5 (CH2), 45.2
[46.4] (CH), 71.1 (CH), 133.5, (Cq), 134.2 (Cq), 156.2 (CϭO). IR
(film): ν˜ [cmϪ1] ϭ 1691 ν(CϭO). C19H37NO2Si (339.59): HR-MS:
calcd. 339.25937, found 339.26040.
211 mg (69%) colourless oil. RF ϭ 0.77 (PE/EtOAc, 1:1). [α]2D0
ϭ
Ϫ9.3 (c ϭ 0.53, CHCl3). Shift experiment: er 88:12 (76% ee),
15.9 mg ϩ 5 mol % Eu(hfc)3 in CDCl3, ∆δ(3 H at δ ϭ 1.66) ϭ
1
0.07, signal of major enantiomer appears at lower field. H NMR
(300 MHz, CDCl3): δ ϭ 0.05 (s, 9 H), 1.19 (d, J ϭ 6.9 Hz, 12 H),
1.57Ϫ1.78 (m, 5 H), 2.02Ϫ2.31 (m, 4 H), 3.84Ϫ3.99 (m, 6 H), 5.55
(s, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ2.2 (CH3), 19.5 (CH3),
21.1 (CH3), 25.8 (CH2), 31.4 (CH2), 42.1 (CH2), 45.8 (CH), 64.2
(CH2), 70.0 (CH), 108.1 (Cq), 123.8 (Cq), 128.5 (Cq), 155.8 (CϭO).
(2-Methyl-1-cyclooctenyl)(trimethylsilyl)methyl
N,N-Diisopropyl-
IR (film): ν [cmϪ1] ϭ 1688 ν(CϭO). C20H37NO4Si (383.60): calcd.
˜
carbamate (19g): As described under GP1, 11g (141 mg,
0.50 mmol) was deprotonated with sec-butyllithium/(Ϫ)-sparteine
C 62.62, H 9.72, N 3.65, found C 62.53, H 9.58, N 3.83.
(10 min) and quenched with TMSCl. Yield: 121 mg (68%) colour- (R)-(2-Methyl-1-cyclohexenyl)(methyldiphenylsilyl)methyl N,N-Di-
less oil and 20 mg (14%) of starting compound was recovered.
R
isopropylcarbamate [(R)-20]: As described under GP1, n-butylli-
thium (1.6 , 1.88 mL, 3.0 mmol, 1.2 equiv.) was added to a solu-
F ϭ 0.20 (PE/Et2O, 40:1). [α]2D0 ϭ Ϫ11.2 (c ϭ 0.56, CHCl3). Shift
experiment: er 87.5:12.5 (75% ee), 16.7 mg ϩ 100 mol % Eu(hfc)3 tion of 11e (633 mg, 2.50 mmol) and (Ϫ)-sparteine (703 mg,
in CDCl3, ∆δ[Si(CH3)3 at δ ϭ 0.03] ϭ 0.12, signal of major enanti-
3.0 mmol, 1.2 equiv.) in toluene (18 mL) at Ϫ78 °C and the mixture
was stirred for 2 h at Ϫ78 °C, after which chloromethyldiphenylsil-
omer appears at higher field. 1H NMR (300 MHz, CDCl3): δ ϭ
0.03 (s, 9 H), 1.18 [1.20] (d, J ϭ 6.8 Hz, 12 H), 1.23Ϫ1.62 (m, 8 ane (873 mg, 3.75 mmol) was added. After workup, the residue was
H), 1.70 (s, 3 H), 1.84Ϫ2.40 (m, 4 H), 3.90 (br. s, 2 H), 5.47 (s, 1 purified by silica gel column chromatography (PE/Et2O, 10:1) to
H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ0.3 (CH3), 21.0 (CH3), afford the pure product (R)-20. Yield: 855 mg (76%) colourless oil.
23.0 (CH3), 28.0 (CH2), 28.9 (CH2), 29.4 (CH2), 30.9 (CH2), 33.1
R
F ϭ 0.41 (PE/Et2O, 10:1). [α]2D0 ϭ Ϫ19.1 (c ϭ 0.67, CHCl3), deter-
1
(CH2), 34.8 (CH2), 47.8 (CH), 73.1 (CH), 121.2 (Cq), 133.4 (Cq), mination of the ee value failed. H NMR (400 MHz, CDCl3): δ ϭ
157.8 (CϭO). IR (film): ν [cmϪ1] ϭ 1696 ν(CϭO), 1654 ν(CϭC).
0.64 (s, 3 H), 1.16 (br. s, 12 H), 1.33 (s, 3 H), 1.36Ϫ1.63 (m, 4 H),
˜
C20H39NO2Si (353.61): calcd. C 67.93, H 11.12, N 3.96, found C 1.72Ϫ1.95 (m, 4 H), 3.82 (br. s, 2 H), 6.12 (s, 1 H), 7.25Ϫ7.64 (m,
68.09, H 11.33, N 4.48.
10 H). 13C NMR (100 MHz, CDCl3): δ ϭ Ϫ4.4 (CH3), 19.7 (CH3),
Eur. J. Org. Chem. 2002, 414Ϫ427
423

M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D. Hoppe
FULL PAPER
20.9 (CH3), 22.95 (CH2), 22.97 (CH2), 26.8 (CH2), 32.1 (CH2), 45.8 (R)-23a: Colourless oil. RF ϭ 0.60 (PE/Et2O, 10:1). [α]2D0 ϭ ϩ6.9
(CH), 68.5 (CH), 127.50 (Cq), 127.53 (CH), 127.7 (CH), 127.8 (Cq), (c ϭ 0.82, CHCl3). Shift experiment: er 83.7:16.3 (67% ee), 15.9 mg
129.3 (CH), 129.4 (CH), 135.2 (CH), 135.3 (CH), 135.3 (Cq), 155.5 ϩ 10.1 mol % Eu(hfc)3 in C6D6, ∆δ[Sn(CH3)3 at δ ϭ 0.06] ϭ 0.04,
(CϭO). IR (film): ν˜ [cmϪ1] ϭ 1691 ν(CϭO).
signal of major enantiomer appears at higher field. 1H NMR
(300 MHz, CDCl3): δ ϭ 0.06 (s, 9 H), 1.19[1.18] (d, J ϭ 6.9 Hz, 12
H), 1.45Ϫ1.72 (m, 7 H), 1.74Ϫ2.25 (m, 4 H), 3.88 (br. s, 2 H), 5.41
(s, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ (8.4 (CH3), 19.2 (CH3),
21.0 (CH3), 23.0 (CH2), 23.2 (CH2), 27.3 (CH2), 32.0 (CH2), 45.9
(R)-(2-Methyl-1-cyclohexenyl)(methyldiphenylsilyl)methanol [(R)-
21]: DIBALH in hexane (1 , 18.7 mL, 18.7 mmol, 10 equiv.) was
added to a solution of (R)-21 (842 mg, 1.87 mmol, [α]2D0 ϭ Ϫ19.1)
in THF (10 mL), cooled to 0 °C, and the mixture was stirred for
15 h at room temperature. After this had again been cooled to 0
°C, methanol (2 mL) was added followed by satd. aq. NH4Cl
(10 mL) and 2  aq. HCl (50 mL). The aqueous phase was ex-
tracted with Et2O (3 ϫ 30 mL). The combined organic layers were
washed with satd. aq. NaHCO3, dried with MgSO4 and concen-
trated in vacuo. Flash chromatography (PE/Et2O, 4:1) of the crude
product gave 525 mg (87%) of 11f as a colourless oil. RF ϭ 0.25
(PE/Et2O, 4:1). [α]2D0 ϭ Ϫ11.1 (c ϭ 0.95, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 0.60 (s, 3 H), 1.01Ϫ2.23 (m, 11 H), 5.01
(s, 1 H), 7.27Ϫ7.64 (m, 10 H). IR (film): ν˜ [cmϪ1] ϭ 3445 ν(OH).
˜
(CH), 74.5 (CH), 122.9 (Cq), 130.0 (Cq), 156.1 (CϭO). IR (film): ν
[cmϪ1] ϭ 1674 ν(CϭO). C18H35NO2Sn (416.19): calcd. C 51.95, H
8.48, N 3.37, found C 52.08, H 8.69, N 3.48.
(R)-24a: Amorphous solid. RF ϭ 0.45 (PE/Et2O, 10:1). [α]2D0
ϭ
ϩ15.3 (c ϭ 0.15, CHCl3). Shift experiment: er 92.6:7.4 (85% ee),
20.5 mg ϩ 20.4 mol % Eu(hfc)3 in C6D6, ∆δ[Sn(CH3)3 at δ ϭ
0.06] ϭ 0.05, signal of major enantiomer appears at lower field. 1H
NMR (300 MHz, CDCl3): δ ϭ 0.06 (s, 9 H), 0.99Ϫ1.83 (m, 6 H),
1.22[1.23] (d, J ϭ 6.9 Hz, 12 H), 1.22 (s, 3 H), 1.83 (dm, J ϭ
14.1 Hz, 1 H), 2.86 (dm, J ϭ 14.1 Hz, 1 H), 3.92 (br. s, 2 H), 6.69
(mc, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ9.0 (CH3), 21.0
(CH3), 24.7 (CH3), 25.6 (CH2), 25.6 (CH2), 26.5 (CH2), 35.5 (Cq),
40.2 (CH2), 46.1 (CH), 126.9 (CH), 129.6 (Cq), 153.6 (CϭO). IR
(R)-(2-Methyl-1-cyclohexenyl)(methyldiphenylsilyl)methyl N-Isopro-
pylcarbamate [(R)-22]: A solution of (R)-21 (113 mg, 0.35 mmol,
[α]2D0 ϭ Ϫ11.1), isopropyl isocyanate (98 µL, 1.0 mmol, 2.86 equiv.)
and DMAP (5 mg, 0.04 mmol, 10 mol %) was heated for 24 h at
50 °C. The solution was allowed to cool to room temperature and
was poured into a mixture of Et2O (10 mL) and 2  aq. HCl
(10 mL). The aqueous phase was extracted with Et2O (3 ϫ 10 mL).
The combined organic layers were washed with satd. aq. NaHCO3,
dried with MgSO4 and concentrated in vacuo. Flash chromato-
graphy (PE/Et2O, 4:1) of the crude product gave 129 mg (90%) of
(R)-22 as a colourless solid. RF ϭ 0.20 (PE/Et2O, 4:1). M.p.
102Ϫ103 °C (PE). [α]2D0 ϭ Ϫ19.8 (c ϭ 0.42, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 0.60 (s, 3 H), 1.07 (d, J ϭ 6.4 Hz, 6 H),
1.23Ϫ1.99 (m, 11 H), 3.74 (br. s, 1 H), 4.33 (br. s, 1 H), 6.02 (s, 1
H), 7.20Ϫ7.69 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.75
(CH3), 19.6 (CH), 22.9 (CH2), 22.9 (CH2), 23.1 (CH3), 26.6 (CH2),
32.1 (CH2), 43.2 (CH), 68.7 (CH), 127.6 (CH), 127.7 (CH), 128.2
(Cq), 129.4 (CH), 129.4 (CH), 135.0 (CH), 135.1 (CH), 135.3 (Cq,),
(KBr): ν [cmϪ1] ϭ 1711 ν(CϭO). C18H35NO2Sn (416.19): calcd. C
˜
51.95, H 8.48, N 3.37, found C 52.07, H 8.31, N 3.17.
(R)-(2-Methyl-1-cyclohexenyl)(tributylstannyl)methyl N,N-Diisopro-
pylcarbamate [(R)-23b] and [(1Z,2S)-2-Methyl-2-(tributylstannyl)cy-
clohexylidene]methyl N,N-Diisopropylcarbamate [(S)-24b]: As de-
scribed under GP1, n-butyllithium (1.6 , 2.75 mL, 4.4 mmol) was
added to a solution of 11e (957 mg, 3.78 mmol) and (Ϫ)-sparteine
(1.03 g, 4.4 mmol, 1.16 equiv.) in 5 mL toluene at Ϫ78 °C. After
this had been stirred for 2 h at Ϫ78 °C, chlorotributylstannane
(1.95 g, 6.0 mmol, 1.6 equiv.) in toluene (2 mL) was added. Flash
chromatography (PE/Et2O, 100:1 to 10:1) of the crude product gave
497 mg (24%) of (R)-23b and 1.06 g (52%) of (S)-24b.
(R)-23b: Colourless oil. RF ϭ 0.48 (PE/Et2O, 10:1). [α]2D0 ϭ ϩ14.4
1
(c ϭ 0.48, CHCl3), determination of the ee value failed. H NMR
(400 MHz, CDCl3): δ ϭ 0.80Ϫ0.88 (m, 15 H), 1.17[1.18] (d, J ϭ
6.9 Hz, 12 H), 1.28 (m, 6 H), 1.35Ϫ1.70 (m, 10 H), 1.58 (s, 3 H),
1.76Ϫ2.21 (m, 4 H), 3.78[3.97] (br. s, 2 H), 5.55 (s, 1 H). 13C NMR
(100 MHz, CDCl3): δ ϭ10.5 (CH3), 13.6 (CH3), 19.3 (CH3), 21.1
(CH3), 23.0 (CH2), 23.2 (CH2), 27.5 (CH2), 32.1 (CH2), 27.6 (CH2),
29.1 (CH2), 45.6 (CH), 73.9 (CH), 122.7 (Cq), 130.5 (Cq), 155.9
156.1 (CϭO). IR (KBr): ν [cmϪ1] ϭ 3308 ν[N(H)], 1702/1680
˜
ν[(CϭO)/amide I], 1534 (amide II). C25H33NO2Si (407.62): calcd.
C 73.66, H 8.16, N 3.44, found C 73.56, H 8.44, N 3.29.
X-ray Crystal Structure Analysis of (R)-22: Colourless crystal 0.40
ϫ 0.05 ϫ 0.05 mm, a ϭ 12.216(2), b ϭ 12.497(2), c ϭ 14.168(1) A,
˚
3
(CϭO). IR (film): ν [cmϪ1] ϭ 1675 ν(CϭO). C27H53NO2Sn
˜
˚
α ϭ 83.99(1), β ϭ 87.88(1), γ ϭ 60.95(2)°, V ϭ 1880.2(5) A ,
(542.43): calcd. C 59.78, H 9.85, N 2.58, found C 59.50, H 10.04,
N 2.42.
ρ
calcd. ϭ 1.080 g cmϪ3, µ ϭ 9.61 cmϪ1, empirical absorption correc-
tion by ψ scan data (0.700 Յ T Յ 0.954), Z ϭ 3, triclinic, space
˚
(R)-24b: Colourless oil. RF ϭ 0.51 (PE/Et2O, 10:1). [α]2D0 ϭ ϩ12.0
(c ϭ 0.74, CHCl3). Shift experiment: er 83.4:16.6 (67% ee), 19.5 mg
ϩ 30 mol % Eu(hfc)3 in C6D6, ∆δ(1 H at δ ϭ 2.83) ϭ 0.13, signal
group P1 (no. 1), λ ϭ 1.54178 A, T ϭ 223 K, ω/2θ scans, 7988
reflections collected (Ϯh, Ϯk, ϩl), [(sinθ)/λ] ϭ 0.62 AϪ1, 7988 inde-
˚
pendent and 5734 observed reflections [I Ն 2 σ(I)], 806 refined
parameters, R ϭ 0.045, wR2 ϭ 0.112, max. residual electron density
1
of major enantiomer appears at higher field. H NMR (400 MHz,
0.25 (Ϫ0.24) e AϪ3, Flack parameter Ϫ0.07(3), contains three al-
˚
CDCl3): δ ϭ 0.76Ϫ0.93 (m, 15 H), 1.13Ϫ1.85 (2 m, 33 H), 1.89 (d,
J ϭ 14.0 Hz, 1 H), 2.83 (d, J ϭ 14.0 Hz, 1 H), 3.82 [4.02] (br. s, 2
H), 6.69 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ ϭ 10.2 (CH2),
13.6 (CH3), 20.9 (CH3), 25.2 (CH3), 25.7 (CH2), 25.8 (CH2), 26.5
(CH2), 27.6 (CH2), 29.3 (CH2), 37.5 (Cq), 40.9 (CH2), 46.1 (CH),
most identical molecules in the unit cell, connected by hydrogen
bonds, hydrogen atoms calculated and refined as riding atoms.[32]
(R)-(2-Methyl-1-cyclohexenyl)(trimethylstannyl)methyl N,N-Diiso-
propylcarbamate [(R)-23a)] and [(1Z,2S)-2-Methyl-2-(trimethylstan-
nyl)cyclohexylidene]methyl N,N-Diisopropylcarbamate [(S)-24a]: As
described under GP1, n-butyllithium (1.6 , 1.38 mL, 2.2 mmol)
was added to a solution of 11e (506 mg, 2.0 mmol) and (Ϫ)-spart-
126.7 (CH), 130.0 (Cq), 153.6 (CϭO). IR (film): ν [cmϪ1] ϭ 1707
˜
ν(CϭO), 1653 ν(CϭC). C27H53NO2Sn (542.43): calcd. C 59.78, H
9.85, N 2.58, found C 59.75, H 10.09, N 2.48.
eine (516 mg, 2.2 mmol) in 5 mL toluene at Ϫ78 °C. After this had (R)-(2-Methyl-1-cyclohexenyl)(triphenylstannyl)methyl N,N-Diiso-
been stirred for 2 h at Ϫ78 °C, chlorotrimethylstannane (1 , propylcarbamate [(R)-23c] and [(1Z,2S)-2-Methyl-2-(triphenylstan-
3.0 mL, 3.0 mmol) was added. Flash chromatography (PE/Et2O, nyl)cyclohexylidene]methyl N,N-Diisopropylcarbamate [(S)-24c]: As
100:1 to 10:1) of the crude product gave 107 mg (13%) of (R)-23a,
391 mg (47%) of (S)-24a and 37 mg of an unknown impurity.
described under GP1, n-butyllithium (1.6 , 2.75 mL, 4.4 mmol)
was added to a solution of 11e (957 mg, 3.78 mmol) and (Ϫ)-spart-
424
Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
eine (1.03 g, 4.4 mmol, 1.16 equiv.) in 5 mL toluene at Ϫ78 °C. ν(OH), 1691 ν(CϭO). C21H30BrNO3 (424.37): calcd. C 59.43, H
After this had been stirred for 2 h at Ϫ78 °C, chlorotriphenylstan- 7.13, N 3.30, found C 59.62, H 6.88, N 3.53.
nane (2.75, 6.0 mmol, 1.6 equiv.) in toluene (2 mL) was added.
X-ray Crystal Structure Analysis of 27d: Colourless crystal 0.40 ϫ
Flash chromatography (PE/Et2O, 100:1 to 10:1) of the crude prod-
uct gave 774 mg (34%) of (R)-23b and 928 mg (52%) of an insepar-
able mixture of (S)-24b and 11e.
˚
0.25 ϫ 0.15 mm, a ϭ 13.758(2), b ϭ 20.135(3), c ϭ 7.671(1) A, V ϭ
3
2125.0(5) A , ρcalcd. ϭ 1.326 g cmϪ3, µ ϭ 27.84 cmϪ1, empirical
˚
absorption correction by ψ scan data (0.402 Յ T Յ 0.680), Z ϭ 4,
˚
orthorhombic, space group Pna21 (no. 33), λ ϭ 1.54178 A, T ϭ
(R)-23c: Colourless solid. A first attempt to grow crystals at room
temperature by diffusion of pentane into a solution of (R)-23c gave
racemic material only. After removal of the racemic crystals, the
same sample was stored at Ϫ30 °C for 2 d and then gave crystals
suitable for single-crystal X-ray analysis. RF ϭ 0.46 (PE/Et2O,
10:1). [α]2D0 ϭ ϩ48.9 (c ϭ 0.93, CHCl3), determination of the ee
value failed. 1H NMR (300 MHz, CDCl3): δ ϭ 0.78Ϫ1.34 (2 m, 16
H), 1.57 (s, 3 H), 1.68Ϫ2.37 (2 m, 4 H), 3.75 (br. s, 2 H), 5.87 (s, 1
H), 7.25Ϫ7.35 (m, 9 H), 7.54Ϫ7.61 (m, 6 H). 13C NMR (75 MHz,
CDCl3): δ ϭ 19.5 (CH3), 20.4 [21.1] (CH3), 22.3 (CH2), 22.7 (CH2),
27.8 (CH2), 32.1 (CH2), 45.2 [46.1] (CH), 75.8 (CH), 125.8 (Cq),
128.0 (CH), 128.4 (CH), 129.0 (Cq), 137.3 (CH), 140.6 (Cq), 156.0
(CϭO). IR (KBr): ν˜ [cmϪ1] ϭ 1678 ν(CϭO). C33H41NO2Sn
(602.39): calcd. C 65.80, H 6.86, N 2.33, found C 65.66, H 6.65,
N 2.16.
223 K, ω/2θ scans, 2338 reflections collected (Ϫh, Ϫk, ϩl), [(sinθ)/
λ] ϭ 0.62 AϪ1, 2338 independent and 2197 observed reflections [I
˚
Ն 2 σ(I)], 241 refined parameters, R ϭ 0.035, wR2 ϭ 0.103, max.
residual electron density 0.39 (Ϫ0.57) e AϪ3, Flack parameter
˚
0.02(2), hydrogen atoms calculated and refined as riding atoms.[32]
{(1Z,2S)-2-[(R)-(4-Bromophenyl)(hydroxy)methyl]-2-methylcyclo-
hexylidene}methyl N,N-Diisopropylcarbamate (27e): In the same
manner as described for 27d, n-butyllithium (1.6 , 0.48 mL,
0.77 mmol, 1.1 equiv.) was added dropwise to a solution of 11e
(177 mg, 0.70 mmol) and (Ϫ)-sparteine (180 mg, 0.77 mmol, 1.1
equiv.) in toluene (5 mL) at Ϫ78 °C. The reaction mixture was
stirred for 10 min, after which precooled (Ϫ78 °C) Cl-TiPT in tolu-
ene (1 , 2.1 mL, 2.1 mmol, 3.0 equiv.) was added. The dark mix-
ture was stirred for 2 h at Ϫ78 °C, and p-bromobenzaldehyde
(389 mg, 2.1 mmol, 3 equiv.) in toluene (1 mL) was then added.
After workup, the residue was purified by flash chromatography
(PE/EtOAc, 10:1) to give 107 mg (35%) 27d as a colourless solid.
Crystals suitable for single-crystal X-ray analysis were grown by
diffusion of pentane into a solution of 27e in Et2O. RF ϭ 0.26 (PE/
EtOAc, 10:1). [α]2D0ϭ Ϫ46.3 (c ϭ 0.44, CHCl3). Shift experiment:
er 93.6:6.4 (87% ee), 4.7 mg ϩ 14.9 mol % Eu(hfc)3 in CDCl3, ∆δ(1
H at δ ϭ 5.02) ϭ 0.39, signal of major enantiomer appears at lower
field. M.p. 119Ϫ120 °C (PE/EtOAc). 1H NMR (300 MHz, CDCl3):
δ ϭ 0.82Ϫ1.92 (m, 18 H), 1.08 (s, 3 H), 2.07Ϫ2.33 (m, 2 H), 3.66
[4.17] (br. s, 2 H), 5.02 (s, 1 H), 6.95 (s, 1 H), 7.25 (m, 2 H), 7.44
(m, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ 20.8 (CH3), 21.6 (CH3),
21.9 (CH2), 26.9 (CH2), 29.3 (CH2), 36.9 (CH2), 44.6 (Cq), 45.9
[47.0] (CH), 74.2 (CH), 121.1 (Cq), 124.6 (Cq), 129.6 (CH), 130.5
X-ray Crystal Structure Analysis of (R)-23c: Colourless crystal 0.20
˚
ϫ 0.20 ϫ 0.10 mm, a ϭ 8.085(1), b ϭ 12.026(1), c ϭ 31.722(2) A,
3
V ϭ 3084.3(5) A , ρcalcd. ϭ 1.297 g cmϪ3, µ ϭ 67.92 cmϪ1, empir-
˚
ical absorption correction by ψ scan data (0.344 Յ T Յ 0.550),
Z ϭ 4, orthorhombic, space group P212121 (no. 19), λ ϭ 1.54178
˚
A, T ϭ 223 K, ω/2θ scans, 3559 reflections collected (Ϫh, Ϫk, ϩl),
[(sinθ)/λ] ϭ 0.62 AϪ1, 3559 independent and 3284 observed
˚
reflections [I Ն 2 σ(I)], 339 refined parameters, R ϭ 0.043, wR2 ϭ
Ϫ3
˚
0.116, max. residual electron density 1.52 (Ϫ1.06) e A close to
Sn, Flack parameter 0.007(12), hydrogen atoms calculated and re-
fined as riding atoms.[32]
{(1Z,2S)-2-[(R)-(4-Bromophenyl)(hydroxy)methyl]-2-methylcyclo-
pentylidene}methyl N,N-Diisopropylcarbamate (27d): n-Butylli-
thium (1.6 , 0.48 mL, 0.77 mmol, 1.1 equiv.) was added to a solu-
tion of 11d (120 mg, 0.50 mmol) and (Ϫ)-sparteine (129 mg,
0.55 mmol, 1.1 equiv.) in toluene (5 mL) at Ϫ78 °C. The reaction
mixture was stirred for 10 min, after which a precooled (Ϫ78 °C)
solution of chlorotri(isopropoxy)titanium (Cl-TiPT) (390 mg,
1.5 mmol, 3.0 equiv.) was added. The dark reaction mixture was
stirred for 1 h at Ϫ78 °C, and p-bromobenzaldehyde (278 mg,
1.5 mmol, 3.0 equiv.) in toluene (1 mL) was then added. Finally,
the mixture was stirred for 1 h at Ϫ78 °C and then allowed to warm
to room temperature. The yellow solution was poured into an ice-
cooled mixture of Et2O (10 mL) and 2  aq. HCl (10 mL). The
aqueous layer was extracted with Et2O (3 ϫ 10 mL). The combined
organic layers were dried with MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography (PE/EtOAc,
20:1) to give 61 mg (29%) 27d as a colourless solid. Crystals suitable
(CH), 133.2 (CH), 139.1 (Cq), 152.4 (CϭO). IR (KBr): ν [cmϪ1] ϭ
˜
3453 ν(OH), 1680 ν(CϭO). C22H32BrNO3 (438.40): calcd. C 60.27,
H 7.36, N 3.19, found C 60.25, H 7.55, N 3.11.
X-ray Crystal Structure Analysis of 27e: Colourless crystal 0.50 ϫ
˚
0.30 ϫ 0.10 mm, a ϭ 7.933(1), b ϭ 11.157(1), c ϭ 25.162(1) A, V ϭ
3
2227.1(4) A , ρcalcd. ϭ 1.308 g cmϪ3, µ ϭ 18.66 cmϪ1, empirical
˚
absorption correction by SORTAV (0.456 Յ T Յ 0.835), Z ϭ 4,
˚
orthorhombic, space group P212121 (no. 19), λ ϭ 0.71073 A, T ϭ
293 K, ω and scans, 8818 reflections collected (Ϯh, Ϯk, Ϯl),
[(sinθ)/λ] ϭ 0.67 AϪ1, 4356 independent (Rint ϭ 0.036) and 2989
˚
observed reflections [I Ն 2 σ(I)], 250 refined parameters, R ϭ 0.041,
Ϫ3
wR2 ϭ 0.084, max. residual electron density 0.19 (Ϫ0.39) e A
,
˚
Flack parameter 0.015(10), hydrogen atoms calculated and refined
as riding atoms.[32]
for single-crystal X-ray analysis were grown by diffusion of pentane (؉)-{(1Z,2SR)-2-[(RS)-(4-Bromophenyl)(hydroxy)methyl]-2-methyl-
into a solution of 27d in Et2O. RF ϭ 0.14 (PE/EtOAc, 10:1). [α]2D0
ϭ
cycloheptylidene}methyl N,N-Diisopropylcarbamate (27f): In the
ϩ112.5 (c ϭ 0.20, CHCl3). Shift experiment: er 95.8:4.2 (92% ee), same manner as described for 27d, sec-butyllithium (1.32 ,
4.1 mg ϩ 10.5 mol % Eu(hfc)3 in CDCl3, ∆δ(1 H at δ ϭ 4.96) ϭ 0.64 mL, 0.84 mmol, 1.2 equiv.) was added dropwise to a solution
0.06, signal of major enantiomer appears at lower field. M.p. 116 of 11f (188 mg, 0.70 mmol) and (Ϫ)-sparteine (196 mg, 0.84 mmol,
1
°C (PE/EtOAc). H NMR (300 MHz, CDCl3): δ ϭ 1.14Ϫ1.54 (m, 1.2 equiv.) in toluene (5 mL) at Ϫ78 °C. The mixture was stirred
14 H), 1.38 (s, 3 H), 1.76Ϫ1.94 (m, 2 H), 2.16Ϫ2.38 (m, 2 H), 3.69 for 15 min, after which a precooled (Ϫ78 °C) solution of Cl-TiPT
[4.24] (br. s, 2 H), 4.96 (s, 1 H), 6.95 (t, J ϭ 1.9 Hz, 1 H), 7.26 (m, (657 mg, 2.52 mmol, 3.6 equiv.) in toluene was added. The dark
2 H), 7.44 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ 20.6 (CH3), reaction mixture was stirred for 2 h at Ϫ78 °C, and p-bromobenzal-
22.4 (CH3), 23.5 (CH2), 31.5 (CH2), 36.0 (CH2), 46.4 (CH), 50.4 dehyde (194 mg, 1.05 mmol, 1.5 equiv.) in toluene (1 mL) was then
(Cq), 76.4 (CH), 120.0 (Cq), 129.0 (CH), 129.5 (CH), 130.0 (Cq), added. After workup, the residue was purified by flash chromato-
130.5 (CH), 140.5(Cq), 151.6 (CϭO). IR (KBr): ν [cmϪ1] ϭ 3496 graphy (PE/EtOAc, 20:1) to give 68 mg (22%) 27d as a colourless
˜
Eur. J. Org. Chem. 2002, 414Ϫ427
425

M. Özlügedik, J. Kristensen, B. Wibbeling, R. Fröhlich, D. Hoppe
FULL PAPER
[5d]
solid. RF ϭ 0.08 (PE/EtOAc, 20:1). [α]2D0 ϭ ϩ34.4 (c ϭ 0.22,
CHCl3). Shift experiment: er 74.9:25.1 (50% ee), 6.2 mg ϩ 7.3
mol % Eu(hfc)3 in CDCl3, ∆δ(1 H at δ ϭ 4.64) ϭ 0.09, signal of
major enantiomer appears at lower field. M.p. 166 °C (PE/EtOAc).
1H NMR (300 MHz, CDCl3): δ ϭ 0.98Ϫ1.75 (m, 20 H), 1.37 (s, 3
H), 1.75Ϫ1.88 (m, 1 H), 1.94Ϫ2.07 (m, 1 H), 2.25 (s, 1 H), 3.68
[4.11] (br. s, 2 H), 4.64 (s, 1 H), 6.94 (s, 1 H), 7.20 (mc, 2 H), 7.38
(mc, 2 H). 13C NMR (75 MHz, CDCl3): δ ϭ 20.8 (CH3), 22.3
(CH3), 23.6 (CH2), 29.9 (CH2), 31.8 (CH2), 32.0 (CH2), 35.8 (CH2),
46.5 (CH), 46.5 (Cq), 78.9 (CH), 121.1 (Cq), 128.4 (Cq), 129.8 (CH),
Stürmer, Chem. Ber. 1989, 122, 1783Ϫ1789.
R. W.
Hoffmann, S. Dresely, Angew. Chem. 1986, 98, 186Ϫ189; An-
[5e]
gew. Chem. Int. Ed. Engl. 1986, 25, 189Ϫ190.
R. W.
Hoffmann, S. Dresely, Tetrahedron Lett. 1987, 28, 5303Ϫ5306.
[5f]
R. W. Hoffmann, S. Dresely, Chem. Ber. 1989, 122,
[5g]
903Ϫ909.
R. W. Hoffmann, B. Landmann, Angew. Chem.
1984, 96, 427Ϫ428; Angew. Chem. Int. Ed. Engl. 1984, 23,
[5h]
437Ϫ438.
R. W. Hoffmann, B. Landmann, Chem. Ber.
[5i]
1986, 119, 2013Ϫ2024.
R. W. Hoffmann, S. Dresely, J. W.
[5j]
Lanz, Chem. Ber. 1988, 121, 1501Ϫ1507.
R. W. Hoffmann,
S. Dresely, Synthesis 1988, 103Ϫ106.
[6]
V. J. Jephcote, A. J. Pratt, E. J. Thomas, J. Chem. Soc., Chem.
Commun. 1984, 800Ϫ802.
˜
130.4 (CH), 135.2 (CH), 140.0 (Cq), 152.0 (CϭO). IR (KBr): ν
[cmϪ1] ϭ 3445 ν(OH), 1691 ν(CϭO), 1653 ν(CϭC). C23H34BrNO3
(452.43): calcd. C 61.06, H 7.57, N 3.10, found C 61.88, H 7.73,
N 2.84.
[7] [7a]
G. A. Weisenberg, P. Beak, J. Am. Chem. Soc. 1996, 118,
12218Ϫ12219. [7b] D. J. Pippel, G. A. Weisenburg, S. R. Wilson,
P. Beak, Angew. Chem. 1998, 110, 2600Ϫ2602; Angew. Chem.
Int. Ed. 1998, 37, 2522Ϫ2524. [7c] G. A. Weisenberg, N. C. Faib-
(؉)-{(1Z,2SR)-2-[(RS)-(4-Bromophenyl)(hydroxy)methyl]-2-methyl-
cyclooctylidene}methyl N,N-Diisopropylcarbamate (27g): In the
same manner as described for 27d, sec-butyllithium (1.32 ,
0.64 mL, 0.84 mmol, 1.2 equiv.) was added dropwise to a solution
of 11g (197 mg, 0.70 mmol) and (Ϫ)-sparteine (196 mg, 0.84 mmol,
1.2 equiv.) in toluene (5 mL) at Ϫ78 °C. The reaction mixture was
stirred for 15 min, after which a precooled (Ϫ78 °C) solution of
Cl-TiPT (657 mg, 2.52 mmol, 3.6 equiv.) in toluene was added. The
dark mixture was stirred for 2 h at Ϫ78 °C, and p-bromobenzal-
dehyde (194 mg, 1.05 mmol, 1.5 equiv.) in toluene (1 mL) was then
added. After workup, the residue was purified by flash chromato-
graphy (PE/EtOAc, 20:1) to give 66 mg (21%) 27d as a colourless
solid. RF ϭ 0.12 (PE/EtOAc, 20:1). [α]2D0 ϭ ϩ6.8 (c ϭ 0.19, CHCl3).
Shift experiment: er 68.3:31.7 (37% ee), 6.0 mg ϩ 7.8 mol %
Eu(hfc)3 in CDCl3, ∆δ(1 H at δ ϭ 4.40) ϭ 0.15, signal of major
enantiomer appears at lower field. M.p. 66 °C (PE/EtOAc). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.03Ϫ1.95 (m, 23 H), 1.27 (s, 3 H),
2.08Ϫ2.20 (m, 1), 2.22 (br. s, 1 H), 3.65 [4.08] (br. s, 2 H), 4.40 (s,
1 H), 6.93 (s, 1 H), 7.19 (mc, 2 H), 7.38 (mc, 2 H). 13C NMR
(75 MHz, CDCl3): δ ϭ 19.5 (CH3), 20.8 (CH3), 24.7 (CH2), 25.0
(CH2), 26.3 (CH2), 29.4 (CH2), 31.3 (CH2), 33.9 (CH2), 46.1 (Cq),
46.5 (CH), 79.2 (CH), 121.2 (Cq), 126.9 (Cq), 130.0 (CH), 130.4
isch, D. J. Pippel, P. Beak, J. Am. Chem. Soc. 1999, 121,
[7d]
9522Ϫ9530.
M. C. Whisler, L. Vaillancourt, P. Beak, Org.
Lett. 2000, 2655Ϫ2658.
See also: H. Ahlbrecht, A. Kramer, Chem. Ber. 1996, 129,
1161Ϫ1168.
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R. Hanko, D. Hoppe, Angew. Chem. 1982, 94, 378Ϫ379; An-
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Organometallics in Synthesis (Ed.: M. Schlosser), John Wiley &
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22, 31Ϫ45.
(CH), 136.6 (CH), 139.6 (Cq), 152.3 (CϭO). IR (KBr): ν [cmϪ1] ϭ
3462 ν(OH), 1693, ν(CϭO), 1654 ν(CϭC). C24H36BrNO3 (466.45):
calcd. C 61.80, H 7.78, N 3.00, found C 61.54, H 7.81, N 2.83.
˜
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D. Hoppe, T. Krämer, Angew. Chem. 1986, 98, 171Ϫ173;
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Acknowledgments
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D. Hoppe, O. Zschage, Angew. Chem. 1989, 101, 67Ϫ69;
The work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. M. Ö. thanks the Gradu-
iertenkolleg ‘‘Hochreaktive Mehrfachbindungssysteme’’ for a sti-
pend. Jenny Reuber, Thorsten Kreickmann and Wenzel Strojek
contributed to the result by careful work during their Forschungs-
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[19b]
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J. P. Ferezou, M. Julia, R. Khourzom, Y. Li, A. Pancrazi,
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Eur. J. Org. Chem. 2002, 414Ϫ427

Nonracemic, Chiral Homoenolate Reagents
FULL PAPER
[19f]
[32]
´
´
I. Berque, P. Le Menez, P. Razon, A. Pancrazi, J. Ardisson,
Data sets were collected with an EnrafϪNonius CAD4 and a
NoniusϪKappa CCD diffractometer, the latter equipped with
a Nonius FR591 rotating anode generator. Programs used:
data collection EXPRESS (Nonius B. V., 1994) and COLLECT
(Nonius B. V., 1998), data reduction MolEN (K. Fair,
EnrafϪNonius B. V., 1990) and Denzo-SMN (Z. Otwinowski,
W. Minor, Methods Enzymol. 1997, 276, 307Ϫ326), absorption
correction for CCD data SORTAV (R. H. Blessing, Acta Crys-
tallogr., Sect. A 1995, 51, 33Ϫ37; R. H. Blessing, J. Appl. Crys-
tallogr. 1997, 30, 421Ϫ426), structure solution SHELXS-97 (G.
M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467Ϫ473),
structure refinement SHELXL-97 (G. M. Sheldrick, Univer-
sität Göttingen, 1997), graphics Mopict Vers. 3 (M. Brügge-
mann, University of Münster, 2000). Crystallographic data
(excluding structure factors) for the structures reported in
this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
nos. CCDC-166178 [(R)-22], -166179 [(R)-23c], -166180 (27d),
-166181 (27e). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033, E-mail:
deposit@ccdc.cam.ac.uk].
A. Neuman, T. Prange, J.-D. Brion, Synlett 1998, 1132Ϫ1134.
[19g]
´
I. Berque, P. Le Menez, P. Razon, A. Pancrazi, J. Ardisson,
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A. Deiters, D. Hoppe, Angew. Chem. 1999, 111, 529Ϫ532; An-
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The opposite situation Ϫ extremely rapid epimerisation Ϫ can-
not be completely excluded.
[35]
Manuscript in preparation.
[31]
Received July 13, 2001
[O01349]
Eur. J. Org. Chem. 2002, 414Ϫ427
427