Efficient desymmetrization of meso-cis-1,2-cyclohexanedimethanol with differentiation between diastereotopic and enentiotopic C-H bonds by (-)- sparteine-mediated deprotonation

Article abstract of DOI:10.1002/(SICI)1521-3765(19990604)5:6<1905::AID-CHEM1905>3.0.CO;2-4

The deprotonation of a dicarbamate prepared from cis-1,2- cyclohexanedimethanol by sec-butyllithium/(-)-sparteine proceeds with efficient selection between the enantiotopic branches and their diastereotopic protons with high preference for the pro-S proto

Full text of DOI:10.1002/(SICI)1521-3765(19990604)5:6<1905::AID-CHEM1905>3.0.CO;2-4

FULL PAPER
Efficient Desymmetrization of meso-cis-1,2-Cyclohexanedimethanol with
Differentiation between Diastereotopic and Enantiotopic C H Bonds by
( )-Sparteine-Mediated Deprotonation
Jan van Bebber, Hartmut Ahrens, Roland Fröhlich, and Dieter Hoppe*[a]
Dedicated to Professor Armin de Meijere on the occasion of his 60th birthday
Abstract: The deprotonation of a dicarb-
amate prepared from cis-1,2-cyclohexa-
nedimethanol by sec-butyllithium/( )-
sparteine proceeds with efficient selec-
tion between the enantiotopic branches
and their diastereotopic protons with
high preference for the pro-S proton at
the R branch to afford the intermediate,
configurationally stable lithium com-
pound as a single diastereomer. Trap-
ping of this intermediate by electro-
philes (DOMe, CO2, CH3I, Me3SiCl, or
R3SnCl) takes place with retention of
the configuration to yield highly enan-
tiomerically and diastereomerically en-
riched substitution products, which are
easily converted to diols, to anellated
tetrahydrofurans, or to g-lactones. The
chiral base is also capable of efficient
kinetic resolution of the racemic a-
deuterated starting material, by the
utilization of an extraordinarily high
kinetic H/D isotope effect within the
deprotonation step. The, presumably,
first example of the kinetic resolution
of a racemic stannane by lithiodestan-
nylation, utilizing methyllithium/( )-
sparteine, is reported.
Keywords: desymmetrization ´ iso-
tope effects ´ kinetic resolution ´
stereotopic differentiation
As we have already reported,[7, 8] the chiral base butyllithi-
um/( )-sparteine[9] has a pronounced tendency to discrim-
inate in the rate of abstraction of enantiotopic protons in alkyl
carbamates. The method has also been applied to N-Boc-
pyrrolidines,[10, 11] several benzylic substrates,[12] ferrocenes,[13]
P,P-dimethylarylphosphane derivatives,[14] as well as to the
kinetic resolution of a racemic allyl carbamate[15] and of
several b-stereogenic alkyl carbamates.[16] Moreover, a de-
symmetrization of meso-oxabicycles by alkyllithium/( )-
sparteine-induced ring-opening has been described by Laut-
ens et al.[17] and Hodgson et al.[18]
Introduction
The desymmetrization of meso-substrates[1] is particularly
rewarding in cis-1,2-disubstituted cyclohexanes; it leads to
products 2 or ent-2, in which one of the enantiotopic X groups
has been selectively converted into a Y group. Frequently, cis-
cyclohexane dicarboxylic acids and their derivatives[2] or cis-
cyclohexanedimethanols[3] have been used as substrates
(Scheme 1),[4] and desymmetrization is achieved by means
of enzymes[5] or other chiral reagents.[1d, 6]
The ( )-sparteine-induced deprotonation of alkyl carba-
mates 3 generated from primary alcohols, which bear non-
mesomerically stabilizing groups adjacent to the carbanionic
center in 5, is characterized by a pronounced pro-S selectivity
in the deprotonation step. The intermediates 5 are configura-
tionally stable and the reaction with most electrophiles occurs
with retention of the configuration to produce the adducts 6
(Scheme 2).[19, 20]
This method has been applied to the desymmetrization of
the cis-1,2-(cyclohexane)dimethyl dicarbamate 8, which offers
an interesting stereochemical situation:[21] The R and S
branches are enantiotopic; each bears a pair of diastereotopic
methylene protons (Scheme 3). The desymmetrization of this
substrate is possible by the preferential abstraction of
diastereotopic pro-S protons, R-HS and S-HS (which leads to
the intermediates 9 and 10), over the diastereotopic pro-R
protons R-HR and S-HR in the ( )-sparteine-mediated,
kinetically controlled deprotonation. Additionally, the ratio
Scheme 1. Desymmetrization of cis-1,2-disubstituted cyclohexanes 1.
[a] Prof. Dr. D. Hoppe, J. van Bebber, H. Ahrens, R. Fröhlich[‡]
Organisch-Chemisches Institut der Universität
Corrensstrasse 40, D-48149 Münster (Germany)
Fax: (‡49)251-8339772
‡
[ ] X-ray crystal structure analysis
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D. Hoppe et al.
FULL PAPER
Scheme 2. ( )-Sparteine-induced deprotonation of alkyl carbamates 3 to
give enantiomerically enriched carbamates 6.
Scheme 3. The four possible stereoisomers formed by the deprotonation
of 8.
Scheme 4. Deprotonation of cis-1,2-cyclohexanedimethyl dicarbamate (8)
with sec-BuLi in the presence of ( )-sparteine or TMEDA and the
subsequent reaction with electrophiles. Reaction conditions: a) 1) NaH,
THF, 30 min, room temperature, 2) CbyCl, THF, reflux, 16 h. b) sec-BuLi/4
(2.2 equiv), toluene, 788C, 4 h. c) sec-BuLi/TMEDA (2.2 equiv), toluene,
788C, 4 h.
of proton abstraction between the diastereotopic pro-S
protons R-HS and S-HS is determined by the sense and
strength of the substrate-inherent chiral induction.[22]
pro-S and S-pro-R] by 9:1. Fortunately, the selective decom-
position of the minor diastereomer, rac-10, leads to a
diastereomeric enrichment of up to 99:1.
Results and Discussion
Initially, we carried out the reactions with diethyl ether as
the solvent, before we noticed that under these conditions a
slow ether-mediated nonselective deprotonation takes place
(entry 12).
When 8 was deprotonated by sec-BuLi/( )-sparteine (2.2/
2.3 equiv; toluene), the essentially pure stannane 11c or ester
11d, respectively, was formed (Table 1, entries 4 and 6). We
assume that the minor diastereomer 12 results from the
intermediate 10 ´ 4 (Scheme 4a), which is produced by the
removal of HS in the S branch.[26]
The reactions of rac-9 ´ TMEDA/rac-10 ´ TMEDA and 9 ´ 4/
10 ´ 4 with further electrophiles are collected in Table 1.
Formylation leads to 9:1 mixtures of the diastereomeric
aldehydes rac-11h and rac-12h (entry 20), or to 7:3 mixtures
of 11h and ent-12h (entry 19). This is due to base-catalyzed
epimerization of the major isomer 11h which is formed
initially. This hypothesis is supported by the fact that the ratio
is influenced by the stirring time of 10 with the electrophile
(ꢀ50:50, for 2 h).
The dicarbamate 8 was obtained by treatment of the disodium
bisalkoxide of the diol 1b[23] with 2.2 equivalents of 2,2,4,4-
tetramethyl-1,3-oxazolidine-3-carbonyl chloride (CbyCl)
(Scheme 4).[24]
The deprotonation of 8 with 2.2 equivalents of sec-BuLi/
TMEDA in toluene ( 788C, 4 ± 5 h), proceeded smoothly to
give the major intermediate rac-9 ´ TMEDA, which reacted
with tributyltin chloride to afford the stannanes rac-11c and
rac-12c in 77% yield and a diastereomeric ratio (dr) of 99:1
(Table 1, entry 5). Similarly, if the intermediate mixture was
trapped with carbon dioxide followed by methylation of the
crude acids with diazomethane, the esters rac-11d and rac-
12d were formed (yield: 70%, drˆ 98:2; entry 9). If the same
procedure was used but only 3 h were allowed for the
deprotonation, the yield increased to 85%, while the dr
decreased to 91:9 (Table 1, entry 10). It can be concluded from
these experiments that the kinetically controlled, substrate-
induced deprotonation step favors the unlike-process[25] [R-
1906
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Efficient Desymmetrization
1905±1916
Table 1. Deprotonation and electrophilic substitution of 8.
Entry
Diamine
ElX
Products
11 ‡ 12
Ratio
11:12
ee [%]
(recovered 8)
Yield [%]
1
2
3
4
5
6
7
8
9
10[e]
11
12
13
14
15
16
17
18
19
20
21
22
4
4
H3CCO2D
Me3SnCl
Me3SnCl
Bu3SnCl
Bu3SnCl
11a ‡ 12a
64 (16)[a]
65 (19)
75 ( ± )
43 (25)
77 ( ± )
63 (16)
46 (36)
25 (62)
70 ( ± )
85 ( ± )
40 (28)
18 (72)
70 (8)
51 ( ± )
59 (24)
68 (3)
44 (25)
58 (7)
16 (56)[i]
45 ( ± )[i]
42 (33)
58 (6)
±
98:2
99:1
99:1[c]
99:1[c]
96:4
96:4
96:4
98:2
91:9
88:12
40:60
95:5[g]
99:1[g]
68:32
70:30
74:26
85:15
70:30[i]
90:10[i]
85:15
90:10
> 95[b]
> 95
11b ‡ 12b
TMEDA
4
TMEDA
4
4
4
TMEDA
TMEDA
TMEDA
none[f]
4
TMEDA
4
TMEDA
4
TMEDA
4
TMEDA
4
rac-11b ‡ rac-12b
11c ‡ 12c
±
> 95[c]
rac-11c ‡ rac-12c
11d ‡ 12d
±
> 95
> 95
> 95
±
±
±
±
[d]
CO2
MeOC(O)Cl
11d ‡ 12d
MeOC(O)OMe
11d ‡ 12d
[d]
CO2
CO2
rac-11d ‡ rac-12d
rac-11d ‡ rac-12d
rac-11d ‡ rac-12d
rac-11d ‡ rac-12d
11e ‡ 12e
[d]
MeOC(O)Cl
[d]
CO2
MeI
MeI
> 95
rac-11e ‡ rac-12e
11 f ‡ ent-12 f
rac-11 f ‡ rac-12 f
11g ‡ ent-12g
rac-11g ‡ rac-12g
11h ‡ ent-12h
rac-11h ‡ rac-12h
11i ‡ ent-12i
±
CH2 CH-CH2Br
> 95[h]
ˆ
ˆ
CH2 CH-CH2Br
±
C6H5CH2Br
C6H5CH2Br
HCO2Et
> 95[h]
±
> 95[h]
HCO2Et
PhCO2Et
PhCO2Et
±
> 95[h]
TMEDA
rac-11i ‡ rac-12i
±
[a] Recovered in 80% yield as a mixture of 8 and 11a with [D1] ˆ 81%. [b] Determined after deprotonation and carboxylation to 14. [c] Determined after
lithiodestannylation and conversion into 11d. [d] The crude acid was esterified with diazomethane. [e] Deprotonation time of 3 h. [f] Et2O was used as the
solvent. [g] Determined after conversion into the diol 15e. [h] The ee > 95% was determined in the deprotonation step, as proved by the entries 2, 4, 6 ± 8,
and 13. [i] Reaction of 10 with the electrophile with a reduced reaction time.
Except for methyl iodide, ordinary alkyl halides do not
react with the ion pairs 9 or 10. Surprisingly, low diastereo-
selectivities are observed for the reaction with allyl and benzyl
bromides (entries 15 ± 18) to give 11 f/ent-12 f and 11g/ent-
12g, respectively. It is quite likely that a single electron-
transfer (SET) process,[27] which proceeds through a config-
urationally labile radical pair, is operating. This reaction path
is supported by mesomeric stabilization in the alkyl residue
(here allyl and benzyl). It should be pointed out that the
enantioselectivity is not influenced, since it is determined in
the deprotonation step by the selection between the enantio-
topic methylene groups. Overall, a partial inversion at the R
branch takes place, which is equivalent to the formal
substitution of HR in 8 via the lithium intermediate ent-10
(see Scheme 3).
overrides the preference of the substrate by a factor of at least
3 (Scheme 5a). The latter is expressed by the result of the
following experiment (Scheme 5b): When 11a ([D1] ˆ 93%)
was deprotonated in the presence of the achiral ligand
TMEDA, the esters 13 and 14 were isolated with 79% yield
in a 4:96 ratio, with [D1] ˆ 96% in 14; the major product was
formed from the S-pro-R-H. From these results, the order of
preferences of the ( )-sparteine base for the attack of the four
nonequivalent protons can be concluded to be: R-HS > S-
HS > S-HR ꢁ R-HR. Blocking R-HS by deuteration permits the
access to (deuterated) diastereomers (with 4) or enantiomers
(with TMEDA) of the regularly produced products 11.
Furthermore, the high kinetic isotope effect enables the
kinetic resolution of rac-11a by deprotonation (Scheme 5c).
Lithiodestannylations and kinetic resolution of racemic
stannanes: The reaction of enantiomerically enriched (1-
alkoxyalkyl)trialkylstannanes provided the first route to
nonracemic (1-alkoxyalkyl)lithium derivatives, since it pro-
ceeds with rigid stereoretention.[11, 20a, 20b, 33, 34] The application
of this method to stannylated alkyl carbamates, such as 11b, c,
provides a route to the lithio derivatives in amine-free
solutions.[35] The treatment of the trimethyl- or tributylstan-
nane 11b or 11c, respectively, with n-butyllithium in diethyl
ether at 788C, generates the intermediates 9 ´ OEt2 with
high yields and purities, as estimated from the trapping
experiments (Scheme 6); the products reached diastereomer-
ic ratios of 99:1 and ee values of >95%.
Studies with the deuterated substrates: Kinetic resolution:
The deprotonation of alkyl carbamates[28] and thiocarba-
mates[29] exhibits an extraordinarily high kinetic H/D isotope
effect with a magnitude of 100. We have already used this
feature for the protection of acidic C H bonds.[30, 31] In 11a,
the former R-HS is blocked by D ([D1] > 99%[32]). Deproto-
nation of 11a with sec-butyllithium/4 under the usual con-
ditions resulted in a very low conversion: only 4% of the
carboxylic esters 13 and 14 (ratio 73:27) were obtained. In 13,
which arises from the removal of S-HS, there is still 99% [D1]
present, whereas 14 contains only 76% [D1]. The decreased
[D1]-ratio of 14 is caused by the product 11d, which is formed
from traces of 8 present in 11a. This result clearly shows that
in competition of two possible mismatched situationsÐ4/S-
pro-S-H and 4/S-pro-R-HÐthe preference of the reagent
In principle, chiral alkyllithium complexes should be able to
differentiate between enantiomeric, C-stereogenic stannanes,
although we are not aware of an efficient example.[36] When
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D. Hoppe et al.
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Scheme 7. Kinetic resolution of the tributylstannane 11c to give the
enantiomerically enriched products 11d and ent-11c. Reaction conditions:
a) MeLi/4 (1.7 ± 2.0 equiv), Et2O, 788C, 0.5 ± 2.3 h. b) 1) CO2, 788C,
2) CH2N2, room temperature.
Table 2. Cleavage of rac-11c with kinetic resolution by methyllithium/( )-
sparteine.
Run
equiv
MeLi/4
Time [min]
Yield 11d [%]
(ee [%])
Yield ent-11c [%]
(ee [%])
1
2
3
1.9
2.0
1.7
30
60
140
16 (52)
32 (48)
53 (44)
63 (13)
54 (27)
33 (60)
base-mediated cleavage of the (2-hydroxy)alkyl urethanes
in methanol (method A).[7, 24]
2. One-step hydrolysis with aqueous 5n HCl (method B).[38]
3. Reductive cleavage with metal hydrides (methods C1 and
C2).[38b, 39, 40]
If the dicarbamates 11 are heated together with one
equivalent of methanesulfonic acid in methanol, the amino-
acetal moiety of the oxazolidine group is split off and the
bisurethanes 15 are formed (Scheme 8). Treatment of the
crude products with NaOH or K2CO3 in methanol yields the
Scheme 5. Deprotonation and carboxylation of the deuterated carbamate
11a. Reaction conditions: a) sec-BuLi/4 (2.2 equiv), toluene, 788C, 4 h.
b) sec-BuLi/TMEDA (2.2 equiv), toluene, 788C, 4 h. c) i) CO2, 788C,
ii) CH2N2, room temperature.
Scheme 6. Lithiodestannylation of the stannanes 11b and 11c and electro-
philic substitution of the intermediate 9 ´ OEt2. Reaction conditions:
a) nBuLi (2.2 equiv), Et2O, 788C, 1 h. b) ElX.
rac-11c in diethyl ether was allowed to react with about
two equivalents[37] of methyllithium/( )-sparteine (4) at
788C for 30 ± 140 min with subsequent trapping of the
reaction mixture by carbon dioxide (followed by esterification
of the crude acid), both enantiomerically enriched 11d and
stannane ent-11c were isolated with medium ee values
(Scheme 7, Table 2).
Deprotection and stereochemical correlation: Three methods
have been developed for the removal of the Cby group:
1. Stepwise deprotection by acid-catalyzed deketalization
and cleavage of the 1,3-oxazolidine ring, followed by
Scheme 8. Cleavage of the carbamates 11 by method A. Reaction
conditions: a) MeSO3H (1.0 equiv), MeOH, reflux, 3 h. b) K2CO3
(0.5 equiv), MeOH, reflux, 3 h.
1908
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Efficient Desymmetrization
1905±1916
diols 16. The formation of 1,3-oxazolidine 17[41] as a by-
product illustrates the anchimeric assistance of the b-hydroxy
group in the final deblocking step. Unfortunately, methyl ester
15d undergoes an intramolecular aminolysis to form the
amide 18, which epimerizes at C2 of the acetic acid moiety.
Refluxing the ester 11d in aqueous 5n HCl[38] converted it
to the tetrahydrofuran-carboxylic acid 19 (H for Me in 19,
Scheme 9), which was reesterified by diazomethane. Ruthe-
nium-catalyzed metaperiodate oxidation furnished the crys-
talline lactonic acid ester 20.[42] The quality of the crystal was
intramolecular aminolysis, and deacetylationÐled to the cis-
fused 4-hydroxy-decahydroisoquinolin-3-one 23.
Reductive cleavage[39] of the methylated dicarbamate 11e
with excess lithium alanate in refluxing THF (method C1)
furnished the diol 16e in high yield. Alternatively, a large
excess of diisobutylaluminum hydride (DIBAH) can be used
in THF at room temperature.[40] Ruthenium-mediated oxida-
tion according to Ley et al.[46a, 46c] and Bloch et al.[46b] gave the
stereohomogeneous g-lactone rac-24, which correlates well
with the published data (Scheme 10).[47, 48]
Scheme 10. Methods C1 and C2 and transformations of 11e. a) LiAlH4
(4 equiv), THF, reflux, 5 h. b) DIBAH (16 equiv), THF, room temperature,
17 h. c) NMO/TPAP.
Conclusions
The desymmetrization of the dicarbamate 8 by means of ( )-
sparteine-mediated deprotonation is a powerful route to
enantiomer-enriched cis-1,2-dicarbon-substituted cyclohex-
anes. In contrast to all of the known methods for desymme-
trization of cis-1,2-disubstituted cyclohexanes,[5] a third stereo
center is introduced incidentally with a high diastereoselec-
tivity as a result of the outstanding preference of the ( )-
sparteine reagent for pro-S protons.
Scheme 9. Cleavage by method B and stereochemical correlation of 11d;
products derived from 11d. Reaction conditions: a) (i) Aqueous HCl (5n),
reflux, 3 h, (ii) CH2N2, room temperature. b) NaIO4/RuCl3. c) FeCl3/Ac2O.
d) AgO3SCF3/CH3COCl. e) BnNH2, room temperature, 13 h.
outstanding, so that by application of anomalous X-ray
dispersion the absolute configuration depicted in Figure 1,
which is that expected,[43], is almost certain (Flack Parameter,
calcd: 0 for the R and ‡1 for the S enantiomer; found: 0.5).
Selective opening of the tetrahydrofuran ring following the
Experimental Section
General methods: 1H and 13C NMR spectra were recorded on Bruker
AW200 or WM300 instruments with 200 MHz or 300 MHz and 50 or
75.5 MHz, respectively. Chemical shifts in CDCl3 are reported in ppm
relative to tetramethylsilane (TMS). The doubling of some signals occurs as
a result of the E/Z isomerism of the carbamate group; the minor signal is
given in parentheses. IR spectra were registered on a Perkin ± Elmer 298
spectrometer. Optical rotations were measured with a Perkin ± Elmer 241
polarimeter. Melting points were obtained on a Gallenkamp melting point
apparatus and are uncorrected. Elementary analyses were performed by
the Mikroanalytische Abteilung des Organisch-Chemischen Institutes der
Universität Münster on a Perkin ± Elmer CHNanalyser240. All products
were purified by flash column chromatography on silica gel (Merck, 60 ±
200 mesh). The solvents for extraction and chromatography were distilled
before use. The solvents for the reactions were purified by distillation and
dried, if necessary, prior to use. ( )-Sparteine is commercially available
(Sigma) and was stored under argon. N,N,N',N'-Tetramethylethylenedi-
amine (TMEDA) was dried over CaH2 and distilled before use. sec-
Butyllithium was received as a 1.4m solution in cyclohexane/hexane (92:8),
n-butyllithium as 3.0m or 1.6m solutions in hexane, and methyllithium as a
1.6m solution in hexane. All organolithium compounds were titrated before
use.[49] The determination of the diastereomeric ratios was carried out by
1H NMR spectroscopy (by integration of the methine signal of the newly
generated stereocenter) or with analytical gas chromatography (Hewlett
Packard HP5890II chromatograph with a 25 m HP1 column (for the
dicarbamates) or on a HP6890 chromatograph with a 25 m HP1701 column
(for the diols)). The ee values of the carbamates 11 were determined by
1H NMR spectroscopy in the presence of the chiral shift reagent (‡)-
Eu(hfc)3 or as their alcohols, 16, by GC analyses of the corresponding (S)-1-
phenylethylurethanes.[50]
Figure 1. X-ray crystal structure of the lactone 20.[43]
method employed by Ganem et al.[44] with iron(iii) chloride
and acetic anhydride gave the diacetate 21. Regiodifferentia-
tion was achieved by treatment of 19 with acetyl chloride/
silver triflate, according the method used by Effenberger
et al.,[45] to give the triflate 22. Treatment of 22 with benzyl-
amineÐevidently by the substitution of the triflate moiety,
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D. Hoppe et al.
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cis-1,2-Cyclohexanedimethyl
bis(2,2,4,4-tetramethyl-1,3-oxazolidine-3-
(4C; NC(CH3)2CH2), 25.40 (26.55, 26.89) (4C; NC(CH3)2O), 25.98 (CH2),
26.39 (CH2), 27.90 (CH2), 33.97 (CH), 41.79 (CH), 59.48 (60.56) (2C;
NC(CH3)2CH2), 61.43 (CH2OCby), 73.73 (CHOCby), 76.06 (75.82) (2C;
CH2OC(CH3)2), 95.80 (94.59) (2C; NC(CH3)2O), 152.25 (153.02, 153.12)
carboxylate) (8): A solution of cis-1,2-cyclohexanedimethanol[23] (5.67 g,
39.4 mmol) in anhydrous THF (25 mL) was added dropwise to an ice-
cooled suspension of sodium hydride (3.37 g, 112 mmol, 80% in mineral
oil) in THF (40 mL). The reaction mixture was stirred for 30 min at room
temperature. 2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carbonyl chloride[24]
(CbyCl, 14.7 g, 76.9 mmol) in THF (25 mL) was added and the mixture
was refluxed for 16 h. After the mixture was allowed to cool to room
temperature, HCl (2n, 50 mL) and Et2O (50 mL) were carefully added.
The organic layer was separated and the aqueous solution extracted with
Et2O (3 Â 50 mL). The collected extracts were kept over NaHCO3/Na2SO4.
The solvents were evaporated in vacuo and the crude product was purified
by flash chromatography on silica gel (Et2O/hexanes 1:2) to yield 8 (15.4 g,
ˆ
(2C; NC O); C27H50N2O6Sn (617.39): calcd C 52.53, H 8.16; found C 52.51,
H 8.14.
1
12b: H NMR (300 MHz, CDCl3): d ˆ 0.12 (s, Sn(CH3)3).
rac-11b: The reaction of 8 (504 mg, 1.11 mmol) with sec-BuLi (1.27m,
2.00 mL, 2.54 mmol) in the presence of TMEDA (314 mg, 2.70 mmol) and
trimethyltin chloride (518 mg in 2.60 mL hexane, 2.60 mmol) gave rac-11b.
Yield: 510 mg (75%), drˆ 99:1; m.p. 117 ± 1208C (hexanes).
[1S,1(1R,2S)]-1-[2-(2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carbonyloxyme-
thyl)cyclohexyl]-1-(tributylstannyl)methyl 2,2,4,4-tetramethyl-1,3-oxazoli-
dine-3-carboxylate (11c): To a solution of 8 (450 mg, 0.99 mmol) in toluene
(10 mL) were added sec-BuLi (1.23m, 1.85 mL, 2.27 mmol), 4 (577 mg,
2.46 mmol), and tributyltin chloride (0.80 mL, 968 mg, 2.97 mmol) at
788C to afford 8 (yield: 113 mg (25%)) and, after a second chromato-
graphic purification (Et2O/hexanes 1:4), 11c as a viscous oil. Yield: 318 mg
88%) as a colorless solid. M.p. 119 ± 1218C (hexanes); IR (KBr): nÄ ˆ
1
1685 cm (C O); 1H NMR (200 MHz, CDCl3): d ˆ 1.30 ± 1.70 (m, 8H;
ˆ
CH2), 1.42 (1.35), 1.42 (1.36) (s, 12H; NC(CH3)2CH2), 1.56 (1.51) and 1.56
(1.52) (s, 12H; NC(CH3)2O), 2.00 ± 2.30 (m, 2H; CH), 3.73 (s, 4H,
CH2OC(CH3)2), 3.99 ± 4.21 (m, 4H, CH2OCby); 13C NMR (50 MHz,
CDCl3): d ˆ 23.18 (2C; CH2), 25.32 (24.16) (4C; NC(CH3)2CH2), 26.42
(2C; CH2), 26.57 (4C; NC(CH3)2O), 36.88 (2C; CH), 59.60 (60.67) (2C;
NC(CH3)2CH2), 64.54 (2C; CH2OCby), 76.16 (2C; CH2OC(CH3)2), 95.92
(43%); [a]2D1
ˆ
0.35 (c ˆ 1.14 in CH2Cl2); IR (film): nÄ ˆ 2940, 2910, 2850
ˆ
(C H), 1680, 1665 (C O), 1455, 1440 (d-C H), 1385, 1365 (d-CH3), 1090,
ˆ
(94.73) (2C; NC(CH3)2O), 152.81 (152.11) (2C; NC O); C24H42N2O6
(454.61): calcd C 63.41, H 9.31; found C 63.42, H 9.32.
1
1065 cm (C-O-C); 1H NMR (300 MHz, CDCl3): d ˆ 0.80 ± 0.89 (m, 6H;
SnCH2), 0.89 (t, 3J(H,H) ˆ 7.3 Hz, 9H; Sn(CH2)3CH3), 1.22 ± 1.62 (m, 18H;
SnCH2(CH2)2, CH2), 1.35 (1.40, 1.41) (s, 12H; NC(CH3)2CH2), 1.54 (1.49,
1.50) (s, 12H; NC(CH3)2O), 1.72 ± 1.98 (m, 2H; CH2) 2.08 ± 2.25 (m, 1H;
CH), 2.41 (ddt, 3J(H,H) ˆ 3.3 Hz, 3J(H,H) ˆ 12.6 Hz, 1H; CH), 3.71, 3.72 (s,
4H, CH2OC(CH3)2), 4.19 ± 4.39 (m, 3H, CHOCby, CH2OCby); 13C NMR
(75 MHz, CDCl3): d ˆ 10.31 (3C; SnCH2), 13.58 (3C; Sn(CH2)3CH3), 20.32
(CH2), 25.28 (24.06, 24.27) (4C; NC(CH3)2CH2), 25.34 (26.46, 26.59) (4C;
NC(CH3)2O), 26.13 (CH2), 26.96 (CH2), 27.47 (3C; SnCH2CH2CH2CH3),
27.87 (CH2), 29.05 (3C; Sn(CH2)2CH2CH3), 33.90 (CH), 42.16 (CH), 59.38
(60.52) (2C; NC(CH3)2CH2), 61.40 (CH2OCby), 73.16 (CHOCby), 76.32
(76.06) (2C; CH2OC(CH3)2), 95.84 (94.60) (2C; C(CH3)2), 153.09 (152.42)
Deprotonation of carbamate 8 and preparation of substituted products 11:
General procedure: Carbamate 8 (454 mg, 1.00 mmol) was dissolved in
toluene (10 mL) under argon and ( )-sparteine (501 mg, 2.20 mmol) was
added. The stirred solution was cooled to 788C and sec-BuLi (2.1 mmol,
1.2 ± 1.4m) was introduced by a syringe. The mixture was stirred for 4 h at
788C and the electrophile (2.5 mmol) was then added at this temper-
ature. The reaction mixture was stirred for a further 2 h before HCl (2n,
1 mL) was added at 788C. The mixture was allowed to warm to room
temperature, HCl (2n, 10 mL) and Et2O (10 mL) were added, the layers
were separated, and the aqueous phase was extracted with Et2O (3 Â
10 mL). The combined organic layers were stirred over NaHCO3/Na2SO4,
concentrated in vacuo, and the residue was purified by column chromatog-
raphy on silica gel (Et2O/hexanes 1:4 to 1:1) to give the substituted
carbamates 11.
ˆ
(2C; NC O); C36H68N2O6Sn (743.66): calcd C 58.14, H 9.22, N 3.77; found
C 58.22, H 9.38, N 3.85.
rac-11c : The same reaction with 8 (512 mg, 1.13 mmol), TMEDA (332 mg,
2.86 mmol), sec-BuLi (1.27m, 2.05 mL, 2.60 mmol), and tributyltin chloride
(0.79 mL, 956 mg, 2.94 mmol) gave rac-11c. Yield: 651 mg (77%).
[1R,2S,1(1S)]-1[D1]-cis-1,2-Cyclohexanedimethyl bis(2,2,4,4-tetramethyl-
1,3-oxazolidine-3-carboxylate) (11a): To
a solution of 8 (227 mg,
Methyl [2R,1(1R,2S)]-2-{1-[2-(2,2,4,4-tetramethyl-1,3-oxazolidine-3-car-
bonyloxy-methyl)cyclohexyl]}-2-(2,2,4,4-tetramethyl-1,3-oxazolidine-3-car-
bonyloxy)acetate (11d): Dicarbamate 8 (244 mg, 0.54 mmol) was deproto-
nated with sec-BuLi (1.30m, 0.96 mL, 1.25 mmol) in the presence of 4
(319 mg, 1.36 mmol). Carboxylation was carried out by bubbling a stream
of dry CO2 through the reaction solution for 10 min. After warming the
mixture, treatment with HCl/Et2O, and extraction, the collected organic
layers were dried over Na2SO4. The Et2O was evaporated and the residue
was treated with a solution of CH2N2 in diethyl ether until it remained
yellow. The solution was stirred for 30 min, silica gel (100 mg) was added,
and the mixture was stirred for a further 15 min to destroy the excess
CH2N2. Chromatographic purification (Et2O/hexanes 1:2 then 1:1) yielded
8 (58 mg (24%)) and 11d (175 mg (63%), drˆ 96:4, ee > 95%) as a
0.50 mmol) and ( )-sparteine (4) (290 mg, 1.24 mmol) in toluene (8 mL)
was added sec-BuLi (1.30m, 0.88 mL, 1.14 mmol). After treatment with
CH3CO2D (0.09 mL, 1.55 mmol), the reaction mixture was allowed to
warm to room temperautre for 16 h. Workup and purification on silica gel
(Et2O/hexanes 1:2 then 1:1) afforded 11a (184 mg (81%), [D1] ˆ 80%) as a
colorless solid. M.p. 1178C (hexanes); IR (KBr): nÄ ˆ 2140 ± 2130 (C ± D),
1
1675 cm (C O); 1H NMR (300 MHz, CDCl3): d ˆ 1.31 ± 1.72 (m, 8H;
ˆ
CH2), 1.42 (1.36) (s, 12H; NC(CH3)2CH2), 1.56 (1.52) (s, 12H;
NC(CH3)2O), 2.12 (m, 2H; CH), 3.72 (s, 4H, CH2OC(CH3)2), 4.02 ± 4.19
(m, 3H; CHDOCby, CH2OCby); 13C NMR (75 MHz, CDCl3): d ˆ 23.11
(2C; CH2), 25.26 (24.10) (4C; NC(CH3)2CH2), 25.40 (26.60) (4C;
NC(CH3)2O), 26.31 (2C; CH2), 36.70 (CH), 36.79 (CH), 59.54 (60.61)
(2C; NC(CH3)2CH2), 64.14 (t; CHDOCby), 64.46 (CH2OCby), 76.32
(76.05) (2C; CH2O(CH3)2), 95.87 (94.56) (2C; NC(CH3)2O), 153.79
colorless solid. M.p. 124 ± 1268C (hexanes); [a]2D1 ˆ ‡16.3 (c ˆ 1.00 in
1
CH2Cl2); IR (KBr): nÄ ˆ 1750 (OC O), 1700, 1685 cm (C O); 1H NMR
(300 MHz, CDCl3): d ˆ 1.22 ± 1.99 (m, 8H; CH2), 1.39 (1.41) (s, 12H;
NC(CH3)2CH2), 1.54, 1.55 (1.53) (s, 12H; NC(CH3)2O), 2.06 ± 2.24 (m, 1H;
CH), 2.24 ± 2.40 (m, 1H; CH), 3.71, 3.72(s, 4H; CH2OC(CH3)2), 3.74 (s, 3H;
OCH3), 3.93 ± 4.24 (m, 1H; CH2OCby), 4.33 (t, 2J(H,H) ˆ 3J(H,H) ˆ
10.1 Hz, 1H; CH2OCby), 4.78 (d, 3J(H,H) ˆ 9.8 Hz, 1H; CHOCby);
13C NMR (75 MHz, CDCl3): d ˆ 20.29 (CH2), 24.04 (25.19) (4C;
NC(CH3)2CH2), 24.72 (CH2), 25.46 (CH2), 26.64 (25.68) (4C; NC(CH3)2O),
27.43 (CH2), 34.22 (CH), 41.08 (CH), 51.81 (OCH3), 59.49 (60.61), 59.86
(61.04) (2C; NC(CH3)2CH2), 61.90 (CH2OCby), 74.88 (CHOCby), 76.29
(76.04), 76.39 (2C; CH2OC(CH3)2), 95.85 (94.61), 96.21 (94.94) (2C;
ˆ
ˆ
ˆ
(152.08) (2C; NC O); C24H41DN2O6 (455.61): calcd C 63.27, H 9.51, N
6.15; found C 63.31, H 9.36, N 6.15.
[1S,1(1R,2S)]-1-[2-(2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carbonyloxyme-
thyl)cyclohexyl]-1-(trimethylstannyl)methyl 2,2,4,4-tetramethyl-1,3-oxa-
zolidine-3-carboxylate (11b): Compound
8 (433 mg, 0.95 mmol) was
deprotonated with sec-BuLi (1.19m, 1.85 mL, 2.20 mmol) in the presence
of 4 (563 mg, 2.41 mmol). After 4 h at 788C, trimethyltin chloride
(577 mg in 1.28 mL toluene, 2.90 mmol) was added. After workup and
column chromatography (Et2O/hexanes 1:4 then 1:2) 84 mg (19%) of 8
were recovered and 11b (381 mg (65%), drˆ 98:1, ee > 95%) was isolated
as a colorless solid. M.p. 98 ± 1008C (hexanes); [a]2D1 ˆ ‡2.2 (c ˆ 1.02 in
ˆ
NC(CH3)2O), 151.99 (151.02), 152.77 (151.79) (2C; NC O); C26H44N2O8
1
CH2Cl2); IR (KBr): nÄ ˆ 1680 ± 1650 cm (C O); 1H NMR (300 MHz,
ˆ
(512.64): calcd C 60.92, H 8.65, N 5.46; found C 60.96, H 8.83, N 5.56.
CDCl3): d ˆ 0.09 (s, 2J(H,117Sn) ˆ 51.0 Hz
,
2J(H,119Sn) ˆ 52.2 Hz, 9H;
12d: 1H NMR (300 MHz, CDCl3): d ˆ 5.03 (d, 3J(H,H) ˆ 6.2 Hz, CHO-
Cby).
Sn(CH3)3), 0.85 ± 1.98 (m, 8H; CH2), 1.40, 1.34 (s, 12H; NC(CH3)2CH2),
1.50, 1.53 (s, 12H; NC(CH3)2O), 2.08 ± 2.27 (m, 1H; CH), 2.40 (tt,
3J(H,H) ˆ 3.6 Hz, 3J(H,H) ˆ 12.6 Hz, 1H; CH), 3.70, 3.71 (s, 4H,
CH2OC(CH3)2), 4.06 ± 4.40 (m, 3H, CHOCby, CH2OCby); 13C NMR
(75 MHz, CDCl3): d ˆ 8.53 (3C; Sn(CH3)3), 20.39 (CH2), 25.24 (24.09)
rac-11d : The racemic ester was prepared in 70% yield (160 mg, drˆ 98:2)
from 8 (225 mg, 0.48 mmol), TMEDA (127 mg, 1.09 mmol), sec-BuLi
(0.88 mL, 1.30m, 1.14 mmol), and CO2 as described above.
1910
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1910 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6

Efficient Desymmetrization
1905±1916
The same reaction of 8 (236 mg, 0.52 mmol) with TMEDA (151 mg,
1.30 mmol) and sec-BuLi (1.30m, 0.90 mL, 1.17 mmol), however with the
introduction of CO2 after 3 h at 788C gave rac-11d in 85% yield (217 mg,
drˆ 91:9).
Without a diamine: The deprotonation of 8 (239 mg, 0.53 mmol) with sec-
BuLi (1.30m, 0.95 mL, 1.29 mmol) in Et2O (10 mL), resulted in rac-11d
(49 mg, drˆ 40:60; 18% yield) and starting material 8 (171 mg; 72%).
Methyl chloroformate as the electrophile: According to the general
procedure, 8 (441 mg, 0.97 mmol) was metallated with sec-BuLi (1.80 mL,
1.23m, 2.21 mmol) and 4 (567 mg, 2.42 mmol) in toluene (10 mL). Addition
of methyl chloroformate (0.22 mL, 274 mg, 2.90 mmol), workup, and
purification gave 11d (230 mg; 46%, drˆ 96:4, ee > 95%) and 8 (157 mg;
36%).
(0.24 mL, 336 mg, 2.78 mmol) afforded rac-11 f (311 mg; 68%, drˆ 70:30)
and 8 (14 mg; 3%).
[1S,1(1R,2S)]- and [1R,1(1R,2S)]-1-[2-(2,2,4,4-Tetramethyl-1,3-oxazoli-
dine-3-carbonyl-oxymethyl)cyclohexyl]-2-phenylethyl 2,2,4,4-tetramethyl-
1,3-oxazolidine-3-carboxylate (11g and 12g): Carbamate
8 (420 mg,
0.92 mmol) was deprotonated with sec-BuLi (1.63 mL, 1.30m, 2.12 mmol)
in the presence of 4 (544 mg, 2.32 mmol) and then benzyl bromide
(0.34 mL, 496 mg, 2.90 mmol) was added. After purification (Et2O/hexanes
1:4), 8 (105 mg; 25%) was recovered and a 74:26 mixture of 11g and 12g
(223 mg; 44%) was obtained as a colorless oil. IR (film): nÄ ˆ 3060, 3040
1
ˆ
ˆ
ˆ
ˆ
(C C H), 1680 (C O), 1590, 1480 (C C), 750, 690 cm (C C H);
C31H48N2O6, mixture (544.73): calcd C 68.35, H 8.88, N 5.14; found C
68.13, H 8.81, N 5.07.
11g: 1H NMR (300 MHz, CDCl3): d ˆ 1.03 ± 1.96 (m, 9H; CH, 4CH2), 1.26
(1.31) (s, 12H; NC(CH3)2CH2), 1.41 (1.44) (s, 12H; NC(CH3)2O), 2.18 (m,
1H; CH), 2.75 (dd, 2J(H,H) ˆ 14.1 Hz, 3J(H,H) ˆ 8.4 Hz, 1H; CH2Ph), 3.04
(dd, 3J(H,H) ˆ 4.2 Hz, 1H; CH2Ph), 3.62 (3.53) (s, 4H; CH2OC(CH3)2),
4.19 ± 4.44 (m, 2H; CH2OCby), 5.05 (dd, 3J(H,H) ˆ 8.4 Hz, 1H; CHOCby),
7.08 ± 7.38 (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d ˆ 20.08 (CH2), 24.50
(CH2), 25.19 (23.98) (4C; NC(CH3)2CH2), 25.33 (26.58) (4C; NC(CH3)2O),
25.90 (CH2), 27.12 (CH2), 33.93 (CH), 39.11 (CH2Ph), 43.80 (CH), 59.30
(60.55) (2C, NC(CH3)2CH2), 61.73 (CH2OCby), 75.85 (CHOCby), 76.25
(76.00) (2C; CH2OC(CH3)2), 95.70 (94.48) (2C; NC(CH3)2O), 126.09 (p-
By the use of the same procedure, rac-11d (206 mg; 40%, drˆ 88:12) was
formed by the reaction of 8 (453 mg, 1.00 mmol) with TMEDA (293 mg,
2.52 mmol), sec-BuLi (1.23m, 1.87 mL, 2.30 mmol), and methyl chlorofor-
mate (0.23 mL, 281 mg, 2.97 mmol). Additionally, the starting material 8
(128 mg; 28%) was recovered.
Dimethyl carbonate as the electrophile: To a solution of 8 (452 mg,
0.99 mmol),
4 (583 mg, 2.49 mmol), and sec-BuLi (1.30m, 1.75 mL,
2.28 mmol) in toluene (10 mL) was added dimethyl carbonate (0.25 mL,
267 mg, 2.97 mmol). Workup and purification afforded 11d (125 mg; 25%,
drˆ 96:4, ee > 95%) and 8 (279 mg; 62%).
CH, arom.), 127.95 (o-CH, arom.), 129.43 (m-CH, arom), 137.58 (Cquart
,
[1S,1(1R,2S)]-1-[2-(2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carbonyloxyme-
ˆ
arom.), 151.91 (152.68) (2C; NC O).
thyl)cyclohexyl]ethyl
2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate
12g: 1H NMR (300 MHz, CDCl3): d ˆ 4.00 ± 4.19 (m, 2H; CH2OCby), 5.14
(dd, 3J(H,H) ˆ 5.5 Hz, 3J(H,H) ˆ 7.6 Hz, CHOCby); 13C NMR (75 MHz,
CDCl3): d ˆ 20.28 (CH2), 27.69 (CH2), 35.91 (CH), 38.78 (CH2Ph), 43.39
(CH), 128.04 (o-CH, arom.), 129.36 (m-CH, arom), 137.68 (Cquart, arom.).
(11e): Dicarbamate 8 (2.03 g, 9.48 mmol) was deprotonated with sec-BuLi
(1.03m, 9.20 mL, 9.48 mmol) in the presence of 4 (2.31 g, 9.85 mmol).
Addition of methyl iodide (1.67 g, 11.79 mmol), warming to room temper-
ature for 16 h, workup, and column chromatography (Et2O/hexanes ˆ 1:4),
gave the starting dicarbamate 8 (156 mg (8%)) and well as 11e (1.47 g
rac-11g: The reaction of
8 (391 mg, 0.86 mmol), TMEDA (248 mg,
(70%), ee > 95%) as a colorless oil. [a]2D1 ˆ ‡28.1 (c ˆ 0.79 in CH2Cl2); IR
2.13 mmol), sec-BuLi (1.52 mL, 1.30m, 1.98 mmol), and benzyl bromide
(0.32 mL, 460 mg, 2.69 mmol) gave the racemate in 58% yield (271 mg,
drˆ 85:15); 8 was recovered in 7% yield (27 mg).
1
(film): nÄ ˆ 1660 cm (C O); 1H NMR (300 MHz, CDCl3): d ˆ 1.08 ± 2.36
ˆ
(m, 10H; 2CH, 4CH2), 1.24 (d, 3J(H,H) ˆ 6.2 Hz, 3H; CH3), 1.39 (1.34) (s,
12H; NC(CH3)2CH2), 1.55 (1.50) (s, 12H; NC(CH3)2O), 3.71, 3.72, (s, 4H;
CH2OC(CH3)2), 3.98 ± 4.20 (m, 1H; CH2OCby), 4.29 (t, 2J(H,H) ˆ
3J(H,H) ˆ 11.0 Hz, 1H; CH2OCby), 4.87 (dd, 3J(H,H) ˆ 9.1 Hz,
3J(H,H) ˆ 6.2 Hz, 1H; CHOCby); 13C NMR (75 MHz, CDCl3): d ˆ 19.17
(CH3), 20.52 (CH2), 24.77 (CH2), 25.27 (24.09) (4C; NC(CH3)2CH2), 25.27
(26.59) (4C; NC(CH3)2O), 25.78 (CH2), 27.16 (CH2), 34.47 (CH), 45.05
(CH), 59.44 (60.49) (2C, NC(CH3)2CH2), 62.07 (CH2OCby), 71.74
(CHOCby), 76.33 (76.12) (2C; CH2OC(CH3)2), 94.62 (94.19), 95.87
[2R,1(1R,2S)]- and [2S,1(1R,2S)]-2-{1-[2-(2,2,4,4-Tetramethyl-1,3-oxa-
zolidine-3-carbon-yloxymethyl)cyclohexyl]}-2-(2,2,4,4-tetramethyl-1,3-oxa-
zolidine-3-carbonyloxy)ethanal (11h and 12h): To a solution of 8 (452 mg,
0.99 mmol) and 4 (581 mg, 2.48 mmol) in toluene (10 mL) was added sec-
BuLi (1.80 mL, 1.26m, 2.27 mmol). The mixture was treated with ethyl
2
formate (0.24 mL, 221 mg, 2.98 mmol) and then with H2PO4 /HPO4
buffer (1.0 mL, pH ˆ 7). Workup and purification (silica gel, Et2O/hexanes
1:4 to 1:1) afforded 8 (120 mg, 27%) and a 55:45 mixture of 11h and 12h
(142 mg, 30%) as a viscous oil. IR (film): nÄ ˆ 2960, 2920, 2850 (C H), 1730,
ˆ
(95.47) (2C; NC(CH3)2O), 152.75 (152.05) (2C; NC O); C25H44N2O6
(468.63): calcd C 64.07, H 9.46; found C 64.08, H 9.47.
1
ˆ
1700 ± 1680 (C O), 1460, 1440 (C H), 1405, 1365 (-CH3), 1090, 1060 cm
rac-11e: The reaction of 8 (455 mg, 1.00 mmol) and sec-BuLi (2.00 mL,
1.25m, 2.50 mmol) in the presence of TMEDA (295 mg, 2.54 mmol) and
methyl iodide (0.19 mL, 431 mg, 3.04 mmol) gave rac-11e (238 mg, 51%).
(C-O-C); C25H42N2O7, mixture (482.62): calcd C 62.22, H 8.77, N 5.80; found
C 62.26, H 8.83, N 5.54.
11h: 1H NMR (300 MHz, CDCl3): d ˆ 1.18 ± 2.44 (m, 10H; 2CH, 4CH2),
1.41 (1.36) (s, 12H; NC(CH3)2CH2), 1.55 (1.58) (s, 12H; NC(CH3)2O), 3.72
(3.73, 3.76, 3.78) (s, 4H; CH2OC(CH3)2), 4.15 (m, 2H; CH2OCby), 4.75 (d,
3J(H,H) ˆ 10.2 Hz, 1H; CHOCby), 6.00 (s, 1H; CHO); 13C NMR (75 MHz,
CDCl3): d ˆ 20.25 (CH2), 24.73 (CH2), 25.21 (24.03) (4C; NC(CH3)2CH2),
25.41 (26.59) (4C; NC(CH3)2O), 25.78 (CH2), 27.70 (CH2), 34.20 (CH),
39.49 (CH), 59.51 (60.62), 59.98 (61.23) (2C; NC(CH3)2CH2), 61.70
(CH2OCby), 76.29 (75.99) (2C; CH2OC(CH3)2), 79.39 (CHOCby), 95.87
[1S,1(1R,2S)]- and [1R,1(1R,2S)]-1-[2-(2,2,4,4-Tetramethyl-1,3-oxazoli-
dine-3-carbonyl-oxymethyl)cyclohexyl]-but-3-enyl 2,2,4,4-tetramethyl-1,3-
oxazolidine-3-carboxylate (11 f and 12 f): To a solution of 8 (1.025 g,
2.25 mmol) in toluene (20 mL) were added sec-BuLi (3.00 mL, 1.40m,
4.20 mmol), 4 (1.140 g, 4.27 mmol), and allyl bromide (0.44 mL, 623 mg,
5.15 mmol). After flash chromatography (Et2O/hexanes 1:4), 8 (241 mg;
24%) was recovered and a 68:32 mixture of 11 f and 12 f (651 mg, 59%)
ˆ
ˆ
was obtained as a colorless oil. IR (film): nÄ ˆ 3050 (C C H), 1680 (C O),
ˆ
(94.69), 96.31 (94.89) (2C; NC(CH3)2O), 151.77 (152.62) (2C; NC O),
198.14 (CHO).
1
1
ˆ
1630 cm (C C); H NMR (300 MHz, CDCl3): d ˆ 1.08 ± 2.00 (m, 9H; CH,
4CH2), 1.39 (1.34) (s, 12H; NC(CH3)2CH2), 1.54 (1.49) (s, 12H;
12h: 1H NMR (300 MHz, CDCl3): d ˆ 4.34 (t, 3J(H,H) ˆ 10.5 Hz,
ˆ
NC(CH3)2O), 2.15 ± 2.43 (m, 2H; CH2CH CH2), 2.44 ± 2.63 (m, 1H; CH),
3
2J(H,H) ˆ 10.5 Hz; CH2OCby), 5.07 (d, J(H,H) ˆ 5.2 Hz; CHOCby), 6.02
3.71 (s, 4H; CH2OC(CH3)2), 4.02 ± 4.22 (m, 1H; CH2OCby), 4.32 (t,
(s, CHO); 13C NMR (75 MHz, CDCl3): d ˆ 27.19 (CH2), 36.43 (CH), 39.70
(CH), 62.41 (CH2OCby).
2J(H,H) ˆ 3J(H,H) ˆ 11.1 Hz, 1H; CH2OCby), 4.94 (m, 3J(H,H) ˆ 6.3 Hz,
1H; CHOCby), 5.01 ± 5.13 (m, 2H; CH2CH CH2), 5.81 (ddd, 3J(H,H) ˆ
ˆ
11.1 Hz, 3J(H,H) ˆ 17.5 Hz, 1H; CH2CH CH2); 13C NMR (75 MHz,
ˆ
When the stirring time was reduced to 10 min after addition of the
electrophile, the reaction of 8 (243 mg, 0.53 mmol) with 4 (313 mg,
1.33 mmol), sec-BuLi (1.25m, 0.98 mL, 1.22 mmol), and ethyl formate
(0.13 mL, 120 mg, 1.61 mmol) gave 8 (134 mg; 56%) and 11h (41 mg; 16%,
drˆ 70:30). [a]D21 ˆ ‡17.8 (c ˆ 2.05 in CH2Cl2).
CDCl3): d ˆ 20.14 (CH2), 24.50 (CH2), 25.34 (24.14) (4C; NC(CH3)2CH2),
25.90 (CH2), 26.88 (25.36) (4C; NC(CH3)2O), 27.13 (CH2), 34.89 (CH),
ˆ
37.30 (CH2CH CH2), 42.80 (CH), 59.55 (60.59) (2C; NC(CH3)2CH2), 61.79
(CH2OCby), 74.79 (CHOCby), 76.32 (76.05) (2C; CH2OC(CH3)2), 95.78
ˆ
ˆ
(94.60) (2C; NC(CH3)2O), 117.67 (CH2CH CH2), 133.95 (CH2CH CH2),
rac-11h: Dicarbamate 8 (249 mg, 0.55 mmol) was treated with TMEDA
(160 mg, 1.38 mmol), sec-BuLi (1.00 mL, 1.28m 1.28 mmol), and ethyl
formate (0.14 mL, 129 mg, 1.74 mmol). The mixture was stirred for 1 h, and
ˆ
152.72 (152.21) (2C; NC O); C27H46N2O6, mixture (494.67): calcd C 65.56,
H 9.37, N 5.66; found C 65.47, H 9.36, N 5.75.
2
rac-11 f : The same reaction with 8 (421 mg, 0.93 mmol), TMEDA (275 mg,
2.37 mmol), sec-BuLi (1.70 mL, 1.25m, 2.13 mmol), and allyl bromide
then quenched with the H2PO4 /HPO4 buffer to give rac-11h (120 mg;
45% yield, drˆ 90:10).
Chem. Eur. J. 1999, 5, No. 6
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1911 $ 17.50+.50/0
1911

D. Hoppe et al.
FULL PAPER
[2R,1(1R,2S)]-2-{1-[2-(2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carbonyloxy-
methyl)cyclohexyl]}-2-(2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyl-
oxy)-1-phenylethan-1-one (11i): Dicarbamate 8 (430 mg, 0.94 mmol) was
deprotonated with sec-BuLi (1.25m, 1.73 mL, 2.16 mmol) in the presence of
4 (554 mg, 2.36 mmol). After addition of methyl benzoate (0.33 mL,
360 mg, 2.64 mmol), workup, and column chromatography (Et2O/hexanes
1:4 then 1:1), the dicarbamate 8 (142 mg; 33%) was recovered and 11i
(220 mg; 42%, drˆ 85:15) was obtained as a colorless oil. [a]2D1 ˆ ‡21.5
(61.06) (2C; NC(CH3)2CH2), 61.60 (CHDOCby), 74.88 (CHOCby), 76.29
(76.04), 76.60 (2C; CH2OC(CH3)2), 95.87 (94.59), 96.21 (94.96) (2C;
ˆ
NC(CH3)2O), 151.98 (151.00), 152.72 (151.78) (2C; NC O); C26H45N2O8
(513.65): calcd C 60.80, H 8.83, N 5.45; found C 60.86, H 8.70, N 5.58.
Kinetic resolution of rac-11a (ent-14): The reaction of rac-11a (205 mg,
0.45 mol, [D1] ˆ 97%, derived from the lithiodestannylation and deutera-
tion of 11c) with sec-BuLi (1.31m, 0.69 mL, 0.90 mmol) in the presence of
(
)-sparteine (233 mg, 0.99 mmol), afforded, after carboxylation with CO2,
ˆ
(c ˆ 0.52 in CH2Cl2); IR (film): nÄ ˆ 3060, 3040 (C C H), 1690 ± 1670
11a (130 mg (63%), [D1] ˆ 97%, drˆ 93:17, ee ˆ 36%) and ent-14 (58 mg
1
ˆ
ˆ
ˆ
(C O), 1590, 1570 (C C), 735, 700 cm (C C H); C31H46N2O7 mixture
(558.71): calcd C 66.64, H 8.30, N 5.01; found C 66.82, H 8.12, N 4.92.
(25%), [D1] ˆ 94%, drˆ 88:12, ee > 95%).
Lithiodestannylation of 11b and 11c: Preparation of the substituted
carbamates 11a, 11d, and 11e: General procedure: To a stirred solution of
carbamate 11b or 11c (dr> 98:2, ee > 95%, 0.50 mmol) in Et2O (10 mL)
under argon at 788C was added a solution of n-butyllithium (2.3 mmol,
1.6 ± 3.0m) with a syringe. The mixture was stirred for 1 ± 2 h at 788C, the
electrophile (2.5 mmol) was added, and the reaction mixture stirred for a
further 1 ± 2 h. HCl, (2n, 1 mL) was added at 788C and the mixture was
allowed to warm to room temperature. HCl (2n, 5 mL) and Et2O (5 mL)
were added, the layers were separated, and the aqueous phase was
extracted with Et2O (3 Â 5 mL). The combined extracts were stirred over
NaHCO3/Na2SO4, concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (Et2O/hexanes 1:1) to yield the
substituted carbamates 11.
11i: 1H NMR (300 MHz, CDCl3): d ˆ 1.06 ± 2.53 (m, 10H; 2CH, 4CH2),
1.41 (1.34) (s, 12H; NC(CH3)2CH2), 1.53 (1.50) (s, 12H; NC(CH3)2O), 3.72
(3.69) (s, 4H; CH2OC(CH3)2), 3.93 ± 4.47 (m, 2H; CH2OCby), 5.80 (d,
3J(H,H) ˆ 10.2 Hz, 1H; CHOCby), 7.11 ± 7.27 (m, 3J(H,H) ˆ 7.4 Hz,
4J(H,H) ˆ 1.4 Hz, 2H; m-CH, arom.), 7.43 ± 7.58 (m, 4J(H,H) ˆ 1.4 Hz,
2H; p-CH, arom.), 7.96 ± 8.02 (m, 2H; o-CH, arom.); 13C NMR (75 MHz,
CDCl3): d ˆ 19.98 (CH2), 23.08 (CH2), 24.87 (24.09) (4C; NC(CH3)2CH2),
25.44 (26.62) (4C; NC(CH3)2O), 26.35 (CH2), 27.56 (CH2), 33.87 (CH),
41.48 (CH), 59.51 (60.49) (2C; NC(CH3)2CH2), 61.73 (CH2OCby), 74.84
(CHOCby), 76.29 (76.06) (2C; CH2OC(CH3)2), 94.62 (95.77) (2C;
NC(CH3)2O), 128.39 (o-CH, arom.), 128.79 (m-CH, arom.), 133.21 (p-
ˆ
CH, arom.), 136.95 (Cquart, arom.), 151.94 (152.58) (2C; NC O), 197.23
ˆ
(C O).
Lithiodestannylation of 11b: A mixture of 11b (327 mg, 0.53 mmol) and
nBuLi (0.41 mL, 3.0m, 1.23 mmol) in Et2O (7 mL) was stirred at 788C for
2 h. The mixture was treated with CO2 and esterified to give 11d (252 mg;
93%, drˆ 98:2, ee > 95%). [a]2D1 ˆ ‡17.0 (c ˆ 1.01 in CH2Cl2).
The reaction of 11b (974 mg, 1.58 mmol) with nBuLi (2.00 mL, 1.6m,
3.20 mmol) and methyl iodide (0.21 mL, 427 mg, 3.36 mmol) afforded 11e
(560 mg; 76%). [a]D21 ˆ ‡31.8 (c ˆ 1.07 in CH2Cl2).
Lithiodestannylation of 11c: Carbamate 11c (271 mg, 0.36 mmol) was
allowed to react with nBuLi (0.28 mL, 3.00m, 0.84 mmol) for 2 h. The
mixture was treated with CO2 and esterified. Workup and purification gave
tetrabutyltin (125 mg; 100%) and 11d (171 mg; 93%, drˆ 98:2, ee > 95%).
[a]2D1 ˆ ‡17.2 (c ˆ 1.00 in CH2Cl2).
A solution of 11c (30 mg, 0.50 mmol) in Et2O was treated with nBuLi
(0.50 mL, 3.0m, 1.50 mmol) and the mixture was stirred for 3 h at 788C.
CH3CO2D (0.09 mL, 1.55 mmol) dissolved in Et2O (5 mL) was added and
the reaction mixture was allowed to warm to room temperature and stirred
for 16 h. Column chromatography yielded 11a (222 mg; 98%, [D1] ˆ 97%)
and tetrabutyltin (139 mg; 80%).
12i: 1H NMR (300 MHz, CDCl3): d ˆ 5.97 (d, 3J(H,H) ˆ 3.8 Hz; CHOC-
by); 13C NMR (75 MHz, CDCl3): d ˆ 24.57 (CH2), 26.05 (CH2), 27.93 (CH2),
37.03 (CH), 42.09 (CH), 62.10 (CH2OCby), 77.10 (CHOCby), 199.05
ˆ
(C O).
rac-11i: The reaction of 8 (423 mg, 0.93 mmol) with sec-BuLi (1.25m,
1.71 mL, 2.14 mmol) in the presence of TMEDA (268 mg, 2.30 mmol) and
methyl benzoate (0.32 mL, 354 mg, 2.60 mmol) yielded rac-11i (300 mg;
58%, drˆ 90:10) and 8 (23 mg; 6%).
Methyl {2R,2[1S,2R(1S)]}- and {2S,2[1S,2R(1S)]}-{2[2(1D)]}-2-{1-[2-
(2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyloxymethyl)cyclohexyl]}-2-
(2,2,4,4-tetramethyl-1,3-oxazolidine-3-carbonyloxy)acetate (13 and 14):
The reaction of 11a (125 mg, 0.27 mmol, [D1] ˆ 99%, recovered from
deprotonation reactions of 11a ([D1] ˆ 93%)), with sec-BuLi (1.30m,
0.55 mL, 0.72 mmol), 4 (195 mg, 0.83 mmol), and CO2 yielded 13 (5 mg
(4%), dr of 13 ([D1] ˆ 99%)/14 ([D1] ˆ 76%) ˆ 73:27) as a colorless oil.
11a was recovered in 75% yield (92 mg, [D1] > 99%). 13: 1H NMR
(300 MHz, CDCl3): d ˆ 5.03 (d, 3J(H,H) ˆ 5.7 Hz; CHOCby); 14: 1H NMR
3
(300 MHz, CDCl3): d ˆ 4.81 (d, J(H,H) ˆ 9.8 Hz; CHOCby).
Kinetic resolution of the tributylstannane 11c: Stannane 11c (0.38, 0.41, or
0.87 mmol, respectively) was dissolved in Et2O (7 mL) and treated with
MeLi (1.64m, 0.74 mmol, 0.82 mmol, and 1.47 mmol) and ( )-sparteine
(0.83 mmol, 0.91 mmol, and 1.80 mmol) for 30 min, 60 min, and 140 min,
respectively. The mixture was treated with CO2 and the crude acid was then
esterified. Workup, as described for the preparation of 11d, and column
chromatography (silica gel, Et2O/hexanes 1:3) gave tributylmethyltin,
stannane ent-11c, and ester 11d (dr> 99:1) (Table 3).
Deprotection of the dicarbamates 11: Method A:[7, 24] A solution of a
dicarbamate 11 (1.00 mmol) and methanesulfonic acid (1.00 mmol) in
methanol (10 mL) was refluxed for 3 h. The solvent was removed under
reduced pressure and the residue purified on silica gel (90 g, EtOAc/
cyclohexane 1:2 to pure EtOAc) to yield the bisurethanes 15. The diols 16
were obtained by refluxing 15 (1.00 mmol) with K2CO3 (0.50 mmol) in
methanol (10 mL) for 3 h or by adding K2CO3 or NaOH (0.50 mmol) to the
above reaction mixture and refluxing for a further 3 h. Concentration and
column chromatography (silica gel, Et2O/hexanes 2:1 to pure EtOAc)
afforded the analytically pure diols.
Methyl {2S,2[1S,2R(1S)]}-{2[2(1D)]}-2-{1-[2-(2,2,4,4-tetramethyl-1,3-oxa-
zolidine-3-carbonyloxymethyl)cyclohexyl]}-2-(2,2,4,4-tetramethyl-1,3-oxa-
zolidine-3-carbonyloxy)-acetate (14): Compound 11a (245 mg, 0.54 mmol,
[D1] ˆ 93%), derived from a second deprotonation and deuteration of 11a
([D1] ˆ 80%), was treated with sec-BuLi (1.27m, 0.98 mL, 1.24 mmol) in
the presence of TMEDA (157 mg, 1.35 mmol) and carboxylated with CO2.
After esterification and purification, 14 (218 mg (79%), drˆ 96:4, ee >
95%, [D1] ˆ 96%) was obtained as a colorless solid. M.p. 123 ± 1258C
(hexanes); [a]2D1 ˆ ‡16.9 (c ˆ 1.04 in CH2Cl2); IR (KBr): nÄ ˆ 2960, 2920,
ˆ
ˆ
2860, 2840 (C H), 2160 (C-D), 1740 (OC O), 1685, 1675 (C O), 1405,
1
1
(-CH3), 1095, 1055 cm (C-O-C); H NMR (300 MHz, CDCl3): d ˆ 1.20 ±
1.98 (m, 8H; CH2), 1.40 (1.41) (s, 12H; NC(CH3)2CH2), 1.54, (1.53, 1.55) (s,
12H; NC(CH3)2O), 2.06 ± 2.23 (m, 1H; CH), 2.24 ± 2.41 (m, 1H; CH), 3.72
(s, 4H; CH2OC(CH3)2), 3.74 (s, 3H; OCH3), 4.13 (m, 1H; CHDOCby), 4.81
(d, 3J(H,H) ˆ 9.8 Hz, 1H; CHOCby); 13C NMR (75 MHz, CDCl3): d ˆ
20.32 (CH2), 24.02 (CH2), 23.96 (24.06), 25.17 (25.04, 25.31), (4C;
NC(CH3)2CH2), 25.48 (CH2), 26.66 (24.73, 25.68) (4C; NC(CH3)2O),
27.43 (CH2), 34.14 (CH), 41.08 (CH), 51.83 (OCH3), 59.51 (60.59), 59.88
Table 3. Kinetic resolution of the tributylstannane 11c.
11c [mg]
MeLi [mL] (equiv)
4 [mg] (equiv)
Time [min]
Yield 11d [%]
(ee [%])[a]
Yield ent-11c [%]
(ee [%])[b]
Bu3MeSn
yield [%]
282
308
651
0.45 (1.9)
0.82 (2.0)
0.92 (1.7)
194 (2.2)
214 (2.2)
422 (2.1)
30
60
140
16 (52)
32 (48)
53 (44)
63 (13)
54 (27)
33 (60)
16
45
67
1
21
[a] Determined by H NMR shift experiments with (‡)-Eu(hfc)3 (32 mol%). [b] Determined by comparing the [a] with that of 11c.
365
1912
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1912 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6

Efficient Desymmetrization
1905±1916
cis-1,2-Cyclohexanedimethyl bis[N-(2-hydroxy-1,1-dimethylethyl)carba-
mate] (15a): The reaction of 8 (314 mg, 0.69 mmol) with methanesulfonic
acid (69 mg, 0.72 mmol) for 3 h yielded 15 (231 mg (89%)) as a colorless
solid. M.p. 93 ± 958C (EtOAc); IR (KBr): nÄ ˆ 3470, 3420 (N H), 3355, 3310
This mixture was heated under reflux for 3 h and then purified to give diol
1a (78 mg; 98%) and oxazolidin-2-one 17 (113 mg; 89%).
17: M.p. 54 ± 568C (EtOAc) (ref.:[41a] 56 ± 588C); 1H NMR (300 MHz,
CDCl3): d ˆ 1.35 (s, 6H; CH3), 4.07 (s, 2H; CH2), 6.24 ± 6.39 (br, 1H; NH);
C5H9NO2 (115.13): calcd C 52.16, H 7.88; found C 52.10, H 7.97.
ˆ
(O H), 2980, 2940, 2870 (C H), 1695 (C O), 1550 (N H), 1365 (-CH3),
1105, 1070 cm 1 (C-O); 1H NMR (300 MHz, CDCl3): d ˆ 1.27, 1.28 (s, 12H;
[1S,1(1R,2S)]-1-[2-(Hydroxymethyl)cyclohexyl]ethanol (16e): Refluxing
of 15e (124 mg, 0.32 mmol) with K2CO3 (23 mg, 0.17 mmol) in MeOH
(6 mL) for 17 h gave incomplete conversion. Addition of further K2CO3
(22 mg, 0.16 mmol) and refluxing for a further 3 h gave 17 (53 mg; 73%)
along with 16e (51 mg; 100%, drˆ 99:1) as a colorless oil. [a]2D1 ˆ ‡23.2
(c ˆ 1.37 in MeOH); IR (film): nÄ ˆ 3680 ± 3020 (O H), 2970, 2935, 2870
(C H), 1390 (-CH3), 1100, 1060 cm 1 (C-O); 1H NMR (300 MHz, CDCl3):
C(CH3)2), 1.32 ± 1.64 (m, 8H; CH2), 1.94 ± 2.09 (m, 2H; CH), 3.24 ± 3.51 (br,
3
2H; NH), 3.57 (d, J(H,H) ˆ 11.3 Hz, 2H; C(CH3)2CH2OH), 3.63 (d, 2H;
C(CH3)2CH2OH), 3.92 (dd, 2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ 6.4 Hz, 2H;
CH2OH), 4.12 (dd, 3J(H,H) ˆ 7.6 Hz, 1H; CH2OH), 4.84 ± 5.16 (br, 2H;
OH); 13C NMR (75 MHz, CDCl3): d ˆ 23.42 (2C; CH2), 24.36 (24.20) (4C;
C(CH3)2), 26.82 (2C; CH2), 38.60 (2C; CH), 54.19 (2C; C(CH3)2), 65.34
ˆ
(2C; CH2OH), 69.73 (2C; C(CH3)2CH2OH), 156.23 (2C; NC O);
3
d ˆ 1.14 ± 1.78 (m, 9H; 1CH, 4CH2), 1.24 (d, J(H,H) ˆ 6.2 Hz, 3H; CH3),
C18H34N2O6 (374.48): calcd C 57.73, H 9.15, N 7.48; found C 58.04, H 9.26,
N 7.64.
2.14 ± 2.25 (m, 1H; CH), 2.69 (s, 2H; OH), 3.54 (dd, 2J(H,H) ˆ 10.8 Hz,
3
3J(H,H) ˆ 3.5 Hz, 1H; CH2OH), 3.77 (dq, J(H,H) ˆ 7.9 Hz, 1H; CHOH),
3.93 (dd, 3J(H,H) ˆ 9.3 Hz, 1H; CH2OH); 13C NMR (75 MHz, CDCl3): d ˆ
21.40 (CH3), 22.58 (CH2), 25.44 (CH2), 25.98 (CH2), 29.65 (CH2), 37.44
(CH), 46.40 (CH), 63.25 (CH2OH), 69.25 (CHOH); C9H18O2 (158.13): calcd
C 68.31, H 11.46; found C 68.40, H 11.19.
Methyl [1R,1(1R,2S)]-{2-[N-(2-hydroxy-1,1-dimethylethyl)carbamoyloxy-
methyl]cyclohexyl]}-2-[N-(2-hydroxy-1,1-dimethylethyl)carbamoyloxy]-
acetate (15d): A mixture of 11d (312 mg, 0.61 mmol, drˆ 96:4) and
methanesulfonic acid (44 mg, 0.46 mmol) in methanol was refluxed for 6 h
to afford 15d (248 mg; 94%, dr> 98:2) as a colorless solid. M.p. 94 ± 968C
The one-pot reaction of 11e (1.97 g, 4.2 mmol) with methanesulfonic acid
(148 mg, 1.54 mmol) and then with NaOH (638 mg, 15.95 mmol) in
methanol (20 mL), followed by chromatographic purification (Et2O/
hexanes 2:1, then pure Et2O) yielded 16e (610 mg, 92%, drˆ 95:5) and
17 (208 mg, 21%).
(EtOAc); [a]2D1
ˆ
0.7 (c ˆ 1.02 in CH2Cl2), ‡23.3 (c ˆ 1.01 in MeOH); IR
(KBr): nÄ ˆ 3400 (N H), 3300 (O H), 2985, 2940, 2880 (C H), 1750
1
ˆ
ˆ
(OC O), 1700 (C O), 1545 (N H), 1375 (-CH3), 1060 cm (C O);
1H NMR (300 MHz, CDCl3): d ˆ 1.17 ± 1.54 (m, 6H; CH2), 1.28 (1.27), 1.29
(1.30) (s, 12H; C(CH3)2), 1.67 ± 1.91 (m, 1H; CH), 1.95 ± 2.24 (m, 1H; CH),
3.55 (3.36, 3.40, 3.57) (s, 4H; C(CH3)2CH2OH), 3.76 (s, 3H; OCH3), 3.87
(m, 1H; CH2OH), 4.35 (dd, 2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ 7.1 Hz, 1H;
[1S,1(1R,2S)]- and [1R,1(1R,2S)]-1-[2-(Hydroxymethyl)cyclohexyl]-2-
phenyl-ethan-1-ol (16g): Carbamate 11g (703 mg, 1.29 mmol) was con-
verted into the diol by treatment with methanesulfonic acid (111 mg,
1.16 mmol), K2CO3 (164 mg, 1.19 mmol), and NaOH (105 mg, 2.62 mmol).
Purification (Et2O/hexanes 2:1 to neat Et2O) yielded the two diastereo-
meric diols 16g as colorless solids (140 mg; 46% and 64 mg; 21%); drˆ
70:30).
3
CH2OH), 5.13 (d, J(H,H) ˆ 6.9 Hz, 1H; CHOH), 5.57 (br, 2H, OH) 6.09
(br, 2H, NH); 13C NMR (75 MHz, CDCl3): d ˆ 20.96 (2C; CH2), 23.84
(23.56), 23.96 (25.23) (4C; C(CH3)2), 24.50 (CH2), 25.48 (CH2), 27.83 (CH2),
34.37 (CH), 41.04 (CH), 52.13 (OCH3), 54.29, 54.52 (2C; C(CH3)2), 63.52
(CH2OH), 68.37 (69.05), 69.82 (69.42) (2C; C(CH3)2CH2OH), 74.20
[1S,1(1R,2S)]-16g: M.p. 58 ± 598C (hexanes); [a]D21
MeOH); IR (KBr): nÄ ˆ 3560 ± 3100 (O H), 3090, 3060, 3035 (C C H),
ˆ
12.0 (c ˆ 1.03 in
ˆ
ˆ
(CHOH), 154.87, 156.39 (2C; NC O), 171.52 (OC O); C20H36N2O8
(432.51): calcd C 55.54, H 8.39, N 6.48; found C 55.80, H 8.76, N 6.20.
ˆ
1
ˆ
2930, 2860 (C H), 1610, 1500 (C C), 1110, 1030 (C-O), 745, 695 cm
[1S,1(1R,2S)]-15d: 1H NMR (300 MHz, CDCl3): d ˆ 5.05 (d, 3J(H,H) ˆ
7.6 Hz; CHOH).
1
ˆ
( C H); H NMR (300 MHz, CDCl3): d ˆ 1.03 ± 1.78 (m, 9H; 1CH, 4CH2),
2.21 (m, 1H; CH), 2.67 (dd, 2J(H,H) ˆ 13.6 Hz, 3J(H,H) ˆ 9.2 Hz, 1H;
CH2Ph), 2.93 (dd, 3J(H,H) ˆ 3.6 Hz, 1H, CH2Ph), 3.05 ± 4.02 (br, 2H; OH),
3.45 (dd, 2J(H,H) ˆ 10.8 Hz, 3J(H,H) ˆ 3.3 Hz, 1H; CH2OH), 3.74 (ddd,
3J(H,H) ˆ 6.6 Hz, 1H; CHOH), 3.87 (dd, 3J(H,H) ˆ 9.5 Hz, 1H; CH2OH),
7.08 ± 7.41 (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d ˆ 22.41 (CH2), 25.68
(CH2), 25.91 (CH2), 29.89 (CH2), 37.44 (CH), 41.41 (CH2Ph), 44.18 (CH),
63.05 (CH2OH), 74.71 (CHOH), 126.16 (p-CH, arom.), 128.35 (o-CH,
arom.), 129.30 (m-CH, arom.), 139.21 (Cquart , arom.); C12H22O2 (234.34):
calcd C 76.88, H 9.46; found C 76.35, H 9.52.
[1S,1(1R,2S)]-1-{2[N-(2-Hydroxy-1,1-dimethylethyl)carbamoyloxymethyl]-
cyclohexyl}-ethyl N-(2-hydroxy-1,1-dimethylethyl)carbamate (15e): The
methyl-substituted bisurethane 15e was obtained as a colorless solid in
80% yield (325 mg) by heating 11e (504 mg, 1.07 mmol) with methane-
sulfonic acid (131 mg, 1.36 mmol) for 3 h. M.p. 91 ± 928C (EtOAc); [a]D21
‡26.8 (c ˆ 1.03 in CH2Cl2); IR (KBr): nÄ ˆ 3400 (N H), 3300 (O H), 2970,
ˆ
ˆ
2935, 2870 (C H), 1720, 1700, 1680 (C O), 1545, 1510 (N H), 1390 (-CH3),
1100, 1060 cm
1
(C-O); 1H NMR (300 MHz, CDCl3): d ˆ 1.13 ± 1.56
(m, 6H; CH2), 1.18 (d, 3J(H,H) ˆ 6.2 Hz, 3H; CH3), 1.27 (1.26), 1.29 (s,
12H; C(CH3)2), 1.56 ± 1.86 (m, 3H; CH, CH2), 2.15 ± 2.34 (m, 1H; CH),
3.31 ± 3.81 (m, 4H; C(CH3)2CH2OH), 3.87 (dd, 2J(H,H) ˆ 11.0 Hz,
3J(H,H) ˆ 7.0 Hz, 1H; CH2OH), 3.96 (br, 2H; OH), 4.26 (dd, 3J(H,H) ˆ
[1R,1(1R,2S)]-16g: M.p. 109 ± 1128C (hexanes); [a]2D1 ˆ ‡7.2 (c ˆ 1.03 in
ˆ
MeOH); IR (KBr): nÄ ˆ 3525 ± 3100 (O H), 3085, 3065, 3025 (C C H),
1
ˆ
2930, 2850 (C H), 1610, 1500 (C C), 1110, 1030 (C-O), 735, 695 cm
( C H); 1H NMR (300 MHz, CDCl3): d ˆ 1.02 ± 1.96 (m, 10H; 2CH,
ˆ
3
4CH2), 2.80 (d, 3J(H,H) ˆ 7.0 Hz, 2H; CH2Ph), 3.02 ± 4.12 (br, 2H; OH),
3.48 (dd, 2J(H,H) ˆ 11.1 Hz, 3J(H,H) ˆ 4.0 Hz, 1H; CH2OH), 3.90 (ddd,
3J(H,H) ˆ 1.9 Hz, 1H; CHOH), 3.98 (dd, 3J(H,H) ˆ 9.4 Hz, 1H; CH2OH),
7.07 ± 7.39 (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d ˆ 20.15 (CH2), 21.80
(CH2), 26.62 (CH2), 31.17 (CH2), 41.28 (CH), 41.75 (CH2Ph), 44.62 (CH),
62.48 (CH2OH), 75.58 (CHOH), 126.33 (p-CH, arom.), 128.52 (o-CH,
arom.), 129.30 (m-CH, arom.), 139.07 (Cquart , arom.); C12H22O2 (234.34):
calcd C 76.88, H 9.46; found C 76.07, H 9.48.
7.9 Hz, 1H; CH2OH), 4.72 (dq, J(H,H) ˆ 3.8 Hz, 1H; CHOH), 4.98, 5.36
(s, 2H, NH); 13C NMR (75 MHz, CDCl3): d ˆ 19.38 (CH3), 21.36 (CH2),
24.28 (CH2), 24.36 (24.19, 24.84) (4C; C(CH3)2), 25.61 (CH2), 28.31 (CH2),
33.66 (CH), 44.82 (CH), 54.19 (2C; C(CH3)2), 64.31 (CH2OH), 69.38, 69.86
ˆ
(2C; C(CH3)2CH2OH), 72.08 (CHOH), 156.12, 156.49 (2C; NC O);
C19H36N2O6 (388.51): calcd C 58.74, H 9.34, N 7.21; found C 58.36, H 9.60,
N 6.92.
rac-1-{2-[N-(2-Hydroxy-1,1-dimethylethyl)carbamoyloxymethyl]cyclohex-
yl}-2-phenyl-ethyl N-(2-hydroxy-1,1-dimethylethyl)carbamate (rac-15g):
Carbamate rac-11g (464 mg, 0.85 mmol) was heated with methanesulfonic
acid (148 mg, 1.54 mmol) for 6 h to give rac-15g (241 mg, (61%)) as a
colorless solid. It was converted into the diol rac-16g without further
identification. 1H NMR (300 MHz, CDCl3): d ˆ 1.14 ± 1.52 (m, 4H; CH2),
1.26, 1.27 (s, 12H; C(CH3)2), 1.54 ± 1.86 (m, 5H; 1CH, 2CH2), 2.22 (m, 1H;
CH), 2.76 (dd, 2J(H,H) ˆ 14.1 Hz, 3J(H,H) ˆ 6.7 Hz, 1H; CH2Ph), 3.02 (dd,
rac-16g: Bisurethane rac-15g (241 mg, 0.52 mmol) was cleaved with K2CO3
(168 mg, 1.22 mmol). Column chromatography (Et2O/hexanes 2:1, then
pure EtOAc) afforded 17 (126 mg, 100%) and rac-16g (118 mg; 96%, drˆ
81:19) as a colorless solid.
[2RS,2(1S,2R)]-2-Hydroxy-2-[2-(hydroxymethyl)cyclohexyl]-N-(2-hy-
droxy-1,1-dimethyl-ethyl)acetamide (18): The reaction of 11d (345 mg,
0.67 mmol) with methanesulfonic acid (22 mg, 0.23 mmol) and K2CO3
(43 mg, 0.31 mmol), followed by purification (EtOAc/cyclohexane 2:1,
then neat EtOAc) yielded 18 (112 mg (64%), drˆ 51:49) as a viscous oil.
The two diastereomers were separated by a second purification by column
chromatography (EtOAc/EtOH 10:1).
2
3J(H,H) ˆ 4.5 Hz, 1H; CH2Ph), 2.8 ± 3.2 (br, 2H; NH), 3.55 (d, J(H,H) ˆ
11.3 Hz, 2H; C(CH3)2CH2OH), 3.61 (d, 2H; C(CH3)2CH2OH), 3.88 (dd,
2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ 7.4 Hz, 1H; CH2OH), 4.36 (dd, 3J(H,H) ˆ
3
6.9 Hz, 1H; CH2OH), 4.83 (s, 1H; OH), 4.96 (ddd, J(H,H) ˆ 9.1 Hz, 1H;
CHOH), 5.17 (br, 1H; OH).
[2R,2(1S,2R)]-18: Viscous oil; Rf ˆ 0.18 (EtOAc); IR (film): nÄ ˆ 3500 ±
ˆ
cis-1,2-Cyclohexanedimethanol (1a): To
a
solution of 15a (207 mg,
3200 (O H, N H), 2935, 2860 (C H), 1655 (C O), 1545 (N H), 1125,
1
0.55 mmol) in methanol (5 mL) was added K2CO3 (40 mg, 0.29 mmol).
1030 cm (C O); 1H NMR (300 MHz, CDCl3): d ˆ 1.04 ± 1.38 (m, 4H;
Chem. Eur. J. 1999, 5, No. 6
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1913 $ 17.50+.50/0
1913

D. Hoppe et al.
FULL PAPER
ˆ
CH2), 1.29, 1.31 (s, 6H; C(CH3)2), 1.38 ± 1.86 (m, 4H; CH2), 2.01 (m, 1H;
CH), 2.17 (dq, 3J(H,H) ˆ 3.0 Hz, 3J(H,H) ˆ 5.8 Hz, 3J(H,H) ˆ 12.2 Hz, 1H;
CH), 3.59 (d, 2J(H,H) ˆ 2.6 Hz, 2H; C(CH3)2CH2OH), 3.62 (dd, 2J(H,H) ˆ
11.0 Hz, 3J(H,H) ˆ 2.9 Hz, 1H; CH2OH), 4.00 (t, 3J(H,H) ˆ 11.0 Hz, 1H;
CH2OH), 4.11 (d, 3J(H,H) ˆ 2.4 Hz, 1H, CHOH), 7.11 (s, 1H; NH);
13C NMR (75 MHz, CDCl3): d ˆ 20.36 (CH2), 21.53 (CH2), 24.95, 25.15 (2C;
C(CH3)2), 26.38 (CH2), 31.26 (CH2), 40.67 (CH), 43.25 (CH), 55.69
(C(CH3)2), 62.78 (CH2OH), 70.52 (C(CH3)2CH2OH), 75.04 (CHOH),
(CH2), 25.76 (CH2), 29.76 (CH2), 37.49 (CH), 39.42 (CH2CH CH2), 43.94
ˆ
ˆ
(CH), 63.20 (CH2OH), 72.40 (CHOH), 117.60 ( CH2), 135.38 (CH CH2).
[1R,1(1R,2S)]-16 f: 1H NMR (300 MHz, CDCl3): d ˆ 2.26 ± 2.36 (m, 2H;
CH2CH CH2), 2.46 (ddt, 3J(H,H) ˆ 1.4 Hz, 3J(H,H) ˆ 6.3 Hz, 3J(H,H) ˆ
ˆ
3.6 Hz, 1H; CH), 3.52 (dd, 2J(H,H) ˆ 11.4 Hz, 3J(H,H) ˆ 4.0 Hz, 1H;
CH2OH), 3.72 (ddd, 3J(H,H) ˆ 8.1 Hz, 3J(H,H) ˆ 1.7 Hz, 1H; CHOH), 3.99
(dd, 3J(H,H) ˆ 9.3 Hz, 1H; CH2OH); 13C NMR (75 MHz, CDCl3): d ˆ
ˆ
26.62 (CH2), 31.19 (CH2), 39.85 (CH2CH CH2), 41.54 (CH), 44.76 (CH),
‡
ˆ
174.58 (NC O); HRMS (EI) calcd for C13H25NO4 [M ]: 259.1783; found:
259.1786.
ˆ
62.35 (CH2OH), 73.49 (CHOH), 135.61 (CH CH2).
rac-16 f: rac-11 f (255 mg, 0.51 mmol) was treated with LiAlH4 (83 mg,
2.19 mmol) to give, after chromatography (Et2O/hexanes 1:1), rac-16 f
(63 mg; 67%, drˆ 77:23).
[2S,2(1S,2R)]-18: Viscous oil; Rf ˆ 0.11 (EtOAc); IR (film): nÄ ˆ 3500 ± 3200
1
ˆ
(O H, N H), 2935, 2860 (C H), 1655 (C O), 1545 (N H), 1125, 1030 cm
(C O); 1H NMR (300 MHz, CDCl3): d ˆ 1.08 ± 1.87 (m, 8H; CH2), 1.27,
1.35 (s, 6H; C(CH3)2), 2.03 (dt, 3J(H,H) ˆ 3.6 Hz, 3J(H,H) ˆ 6.9 Hz, 1H;
CH), 2.25 (dq, 3J(H,H) ˆ 8.4 Hz, 3J(H,H) ˆ 11.8 Hz, 1H; CH), 3.43 (d,
2J(H,H) ˆ 11.2 Hz, 2H; C(CH3)2CH2OH), 3.54 (dd, 2J(H,H) ˆ 11.2 Hz,
3J(H,H) ˆ 3.3 Hz, 1H; CH2OH), 3.86 (t, 3J(H,H) ˆ 11.2 Hz, 1H; CH2OH),
3.96 (d, 3J(H,H) ˆ 5.0 Hz, 1H; CHOH), 6.79 (s, 1H; NH); 13C NMR
(75 MHz, CDCl3): d ˆ 21.70 (CH2), 23.79 (C(CH3)2), 25.05 (CH2), 25.10
(C(CH3)2), 26.42 (CH2), 30.43 (CH2), 37.17 (CH), 42.66 (CH), 55.20
(C(CH3)2), 62.41 (CH2OH), 68.91 (C(CH3)2CH2OH), 75.92 (CHOH),
Method C2:[40] rac-16e: Carbamate rac-11e (211 mg, 0.45 mmol) was
dissolved in dry THF (5 mL) and cooled to 08C. Then a solution of
DIBAH in THF (7.40 mL, 7.40 mmol, 1.0m) was added and the reaction
mixture was allowed to warm to room temperature. After stirring for 18 h,
the reaction was quenched with HCl (5n, 20 mL) and rac-16e (69 mg;
97%, drˆ 98:2) was isolated by column chromatography.
Methyl (3R,3aR,7aS)-3-oxo-octahydrobenzofuran-1-carboxylate (20): Tet-
rahydrofuran 19 (87 mg, 0.47 mmol) was oxidized by the method described
by Sharpless,[42] by using a solvent mixture of tetrachloromethane (1.0 mL),
acetonitrile (1.0 mL), and water (1.5 mL) to which was added sodium
periodate (786 mg, 3.7 mmol) and ruthenium trichloride hydrate (69 mg,
0.33 mmol). The mixture was stirred at room temperature for 12.5 h,
washed with dichloromethane (5 Â 10 mL), and dried over Na2SO4.
Column chromatography (Et2O/hexanes 1:2) afforded 20 (58 mg; 62%)
ˆ
174.42 (NC O); C13H25NO4 (259.35): calcd C 60.21, H 9.72, N 5.40; found C
60.15, H 9.78, N 5.53.
Deprotection of the Dicarbamates 11. Method B:[38] Methyl (1S,6R,7R)-8-
oxabicyclo[4.3.0]nonan-7-carboxylate (19): Compound 11d (1.83 g,
3.6 mmol) was refluxed in HCl (5n, 30 mL) for 14 h. The reaction mixture
was extracted with Et2O (4 Â 30 mL), dried over MgSO4, the solvent was
evaporated, and the residue esterified with diazomethane, as described for
11d. Column chromatography afforded 19 (539 mg (82%), dr> 98:2, ee ˆ
1
as a colorless solid. M.p. 668C (hexanes); IR (KBr): nÄ ˆ 1775 and 1750 cm
21
ˆ
(C O); [a]D
ˆ
11.4 (c ˆ 0.52 in CH2Cl2); 1H NMR (300 MHz, CDCl3):
d ˆ 1.11 ± 1.36 (m, 3H, CH2), 1.52 ± 1.77 (m, 3H; CH2), 1.91 ± 2.19 (m, 2H;
CH2), 2.61 (ddt, 3J(H,H) ˆ 1.4 Hz, 6.3 Hz, 11.0 Hz, 1H, CH), 2.77 ± 2.82 (m,
1H, CH), 3.79 (s, 3H, OCH3), 4.50 (d, 3J(H,H) ˆ 1.4 Hz, 1H, HCO);
13C NMR (75 MHz, CDCl3): d ˆ 22.21 (CH2), 22.58 (CH2), 23.22 (CH2),
28.07 (CH2), 37.24 (CH), 39.36 (CH), 51.50 (OCH3), 78.92 (HCO), 169.87
1
21
ˆ
94%) as a slightly yellow liquid. IR (film): nÄ ˆ 1750 cm (C O); [a]D
ˆ
42.2 (c ˆ 0.85 in CH2Cl2); 1H NMR (200 MHz, CDCl3): d ˆ 1.20 ± 1.80 (m,
8H, CH2), 2.10 ± 2.50 (m, 2H; CH), 3.75 (s, 3H, OCH3), 3.76 (dd,
2J(H,H) ˆ 7.9 Hz, 3J(H,H) ˆ 4.7 Hz, 1H, CH2O), 4.03 (dd, 3J(H,H) ˆ
5.9 Hz, 1H, CH2O), 4.27 (d, 3J(H,H) ˆ 6.1 Hz, 1H, CHO); 13C NMR
(50 MHz, CDCl3): d ˆ 22.36 (CH2), 23.11 (CH2), 25.35 (CH2), 25.49 (CH2),
37.89 (CH), 43.12 (CH), 51.90 (OCH3), 73.44 (CH2O), 79.88 (CHO), 174.19
ˆ
(OC O), 177.02 (CO2CH3); C10H14O4 (198.22): calcd C 60.59, H 7.12; found
C 60.44, H 7.35.
‡
ˆ
Methyl [1R,1(1R,2S)]-2-acetoxy-2-{2-[1-(acetoxy)methyl]cyclohexyl}ace-
tate (21): Following the method of Ganem and Small, Jr.,[44] the
tetrahydrofuran 19 (222 mg, 1.2 mmol) was stirred in dry acetic anhydride
(3 mL) with a suspension of iron(iii) chloride (419 mg, 2.6 mmol) in dry
acetic anhydride (2 mL) for 43 h at 808C. The mixture was worked up with
HCl (2n, 10 mL) and Et2O (20 mL), extracted with Et2O (3 Â 20 mL), and
the combined organic layers were dried over NaHCO3/Na2SO4. Chromato-
graphic purification (silica gel, Et2O/hexanes 1:3, then 1:1) afforded 21
(OC O); HRMS (EI) calcd for C10H16O3 [M ]: 184.1099; found: 184.1096.
Method C1:[38b, 39] A solution of the carbamates 11 (1.00 mmol) in dry THF
(5 mL) was added dropwise to a stirred suspension of LiAlH4 (156 mg,
4.1 mmol) in dry THF (10 mL). The reaction mixture was refluxed for 4 ±
5 h and then worked up with water (0.16 mL), aqueous NaOH (0.16 mL,
15%), and water (0.48 mL). Column chromatography (silica gel, EtOAc/
cyclohexane 2:1) gave the diols 16 and 2,2,3,4,4-pentamethyl-1,3-oxazolidine.
1
rac-16e: rac-11e (467 mg, 1.00 mmol) was diluted in THF (6 mL) and
added to a suspension of LiAlH4 (158 mg, 4.16 mmol) in THF (10 mL). The
mixture was heated for 5 h, worked up, and purified to give rac-16e
(137 mg; 87%, drˆ 99:1) as well as N-2,2,3,4,4-pentamethyloxazolidine as
a colorless liquid. IR (film): nÄ ˆ 2940, 2910, 2840 (C H), 2780 (N-CH3),
(202 mg; 59%) as a slightly yellow oil. IR (film): nÄ ˆ 1740 ± 1715 cm
21
(C O); [a]D ˆ ‡31.2 (c ˆ 0.87 in CH2Cl2); 1H NMR (200 MHz, CDCl3):
ˆ
d ˆ 1.20 ± 1.90 (m, 8H, CH2), 2.02 and 2.13 (s, 6H, O(CO)CH3), 2.05 ± 2.29
2
3
(m, 2H, CH), 3.76 (s, 3H, OCH3), 4.08 (dd, J(H,H) ˆ 11.3 Hz, J(H,H) ˆ
3
7.7 Hz, 1H, CH2OAc), 4.28 (dd, J(H,H) ˆ 6.4 Hz, 1H, CH2OAc), 4.89 (d,
1
3J(H,H) ˆ 8.4 Hz, 1H, CHOAc); 13C NMR (50 MHz, CDCl3): d ˆ 20.45,
20.84 (2C; O(CO)CH3), 21.10 (CH2), 24.40 (CH2), 25.27 (CH2), 27.88
(CH2), 34.20 (CH), 40.36 (CH), 52.02 (OCH3), 63.31 (CH2OAc), 74.74
1450 (C H), 1365, 1355 (-CH3), 1260 (-C-N), 1110, 1050 cm (C-O-C);
1H NMR (360 MHz, CDCl3): d ˆ 1.09 (s, 6H; NC(CH3)2CH2), 1.24 (s, 6H;
NC(CH3)2O), 2.24 (s, 3H; NCH3), 3.64 (s, 2H; CH2O); 13C NMR (90 MHz,
CDCl3): d ˆ 22.71 (2C; NC(CH3)2CH2); 26.02 (2C; NC(CH3)2O), 27.49
(NCH3), 59.38 (NC(CH3)2CH2), 76.35 (CH2O), 94.95 (NC(CH3)2O);
ˆ
(CHOAc), 170.89, 170.48, 170.33 (3C; OC O); HRMS (EI) calcd for
C12H19O4 [M CO2CH3]: 227.1283; found: 227.1290.
‡
HRMS (EI) calcd for C8H17NO [M ]: 143.1310; found: 143.1329.
Methyl [1R,1(1R,2S)]-2-acetoxy-2-{2-[1-(trifluoromethylsulfonyloxyme-
thyl)cyclohexyl]}acetate (22): According to the method described by
Effenberger et al.,[45] the mixed acetic acid (trifluormethanesulfonic acid)
anhydride was generated from silver trifluoromethanesulfonate (912 mg,
3.6 mmol) and acetyl chloride (283 mg, 3.6 mmol) in dry dichloromethane
(10 mL) at 788C. The mixture was stirred for 17.5 h at this temperature,
then a solution of 19 (420 mg, 2.3 mmol) in dry dichloromethane (8 mL)
was added. The reaction mixture was stirred for 4 h at room temperature.
HCl (2n, 20 mL) was added and the mixture was filtered. The aqueous
layer was extracted and the solvent evaporated to give crude 22 (846 mg) as
a brown oil, which was used without further purification in the preparation
of 23.
[1S,1(1R,2S)]- and [1R,1(1R,2S)]-1-[2-(Hydroxymethyl)cyclohexyl]-but-
3-en-1-ol (16 f): The 68:32 mixture of 11 f and 12 f (203 mg, 0.41 mmol) was
treated with LiAlH4 (72 mg, 1.90 mmol) in THF (10 mL) to give 16 f
(49 mg; 67%, drˆ 65:35) as a viscous colorless oil. IR (film): nÄ ˆ 3400 ±
ˆ
ˆ
3200 (O H), 3085 (C C H), 2935, 2860 (C H), 1645 (C C), 1045 (C-O),
1
ˆ
1005, 920 cm ( C H); C11H20O2 (184.28), mixture: calcd C 71.70, H 10.94;
found C 71.57, H 11.05.
[1S,1(1R,2S)]-16 f: 1H NMR (300 MHz, CDCl3): d ˆ 1.12 ± 1.98 (m, 9H;
1CH, 4CH2), 2.11 ± 2.27 (m, 2H; CH2CH CH2), 2.41 (ddt, 3J(H,H) ˆ
ˆ
1.4 Hz, 3J(H,H) ˆ 6.2 Hz, 3J(H,H) ˆ 3.6 Hz, 1H; CH), 3.32 ± 4.12 (br, 2H;
OH), 3.50 (dd, 2J(H,H) ˆ 11.0 Hz, 3J(H,H) ˆ 3.6 Hz, 1H; CH2OH),
3.61 (ddd, 3J(H,H) ˆ 8.1 Hz, 3J(H,H) ˆ 1.7 Hz, 1H; CHOH), 3.90
(1S,5R,6R)-3-Benzyl-5-hydroxy-3-azabicyclo[4.4.0]decan-4-one (23): Ben-
zylamine (10 mL) was added dropwise at room temperature to neat, crude
22 (1.68 g, 4.5 mmol). The reaction mixture was stirred for 13 h and was
then poured into saturated aqueous NaHCO3 (20 mL) and Et2O (20 mL).
The aqueous layer was extracted with Et2O (3 Â 20 mL) and the combined
(dd, 3J(H,H) ˆ 9.3 Hz, 1H; CH2OH), 5.12 (dd, 2J(H,H) ˆ 1.1 Hz,
3
J(H,H) ˆ 10.3 Hz, 1H; CH2CH CH2), 5.13 (dd, 3J(H,H) ˆ 16.9 Hz, 1H;
ˆ
CH2CH CH2), 5.87 (dddd, 3J(H,H) ˆ 7.7 Hz, 3J(H,H) ˆ 6.5 Hz, 1H;
ˆ
CH2CH CH2); 13C NMR (75 MHz, CDCl3): d ˆ 22.54 (CH2), 25.57
ˆ
1914
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0506-1914 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6

Efficient Desymmetrization
1905±1916
organic layers were dried over MgSO4. Chromatographic purification
(silica gel, Et2O/hexanes 1:2) yielded 23 (867 mg; 74% from 19, dr> 98:2)
as a colorless solid. M.p. 1188C (hexanes); IR (KBr): nÄ ˆ 3310 cm 1 (OH),
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Ed. Engl. 1982, 21, 654.
[26] The configurations could not be established owing to the presence of
small amounts of the minor diastereomers 12 or ent-12. Formation of
12 requires the abstraction of (R)-H(R), which creates a doubly
mismatched situation.
[27] L. M. Tolbert, J. Bedloek, M. Terapane, J. Kowalik, J. Am. Chem. Soc.
1997, 119, 2291 ± 2292, and references therein.
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Angew. Chem. Int. Ed. Engl. 1993, 32, 394 ± 396.
1
20
1
ˆ
1645 cm (C O); [a]D ˆ ‡3.0 (c ˆ 0.83 in CH2Cl2); H NMR (300 MHz,
CDCl3): d ˆ 1.16 ± 1.93 (m, 8H, CH2), 2.14 ± 2.25 (m, 1H, CH), 2.39 (quint.,
3J(H,H) ˆ 6.1 Hz, 1H, CH), 3.73 (dd, 2J(H,H) ˆ 8.1 Hz, 3J(H,H) ˆ 5.5 Hz,
1H, CH2N), 3.87 (dd, 3J(H,H) ˆ 6.2 Hz, 1H, CH2N), 4.20 (d, 3J(H,H) ˆ
6.1 Hz, 1H, CHOH), 4.44 (d, 2J(H,H) ˆ 6.0 Hz, 2H; CH2Ph), 6.95 ± 7.10
(br., 1H; OH), 7.23 ± 7.38 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3): d ˆ
22.34 (CH2), 22.98 (CH2), 25.11 (CH2), 25.88 (CH2), 37.84 (CH), 42.70
(CH2Ph), 42.86 (CH), 72.75 (CH2N), 80.94 (CHOH), 127.34, 127.55 and
128.59 (CH, arom.), 138.23 (Cquart, arom.); C16H21NO2 (259.35): calcd C
74.10, H 8.16, N 5.40; found C 73.95, H 8.17, N 5.49.
rac-3-Methyl-octahydrobenzofuran-1-one (rac-24): According to the meth-
od described by Ley et al.[46a, 46c] and Bloch et al.,[46b] tetrapropylammonium
perruthenate (35 mg, 0.10 mmol) was added at room temperature to a
stirred suspension of molecular sieve (498 mg, 4 Š), diol 16e (161 mg,
1.02 mmol), and N-methylmorpholine N-oxide (358 mg, 3.06 mmol) in dry
CH2Cl2 (10 mL). The reaction mixture was stirred for 4 h, the solvent
evaporated, and the residue purified by column chromatography (CH2Cl2)
to afford rac-24[47] (113 mg (72%)) as a colorless oil.
Acknowledgments
Generous support by the Deutsche Forschungsgemeinschaft and the Fonds
der Chemischen Industrie is gratefully acknowledged.
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Chem. Eur. J. 1999, 5, No. 6
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1915

D. Hoppe et al.
FULL PAPER
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[43] X-ray crystal structure analysis of 20: formula C10H14O4, M ˆ 198.21;
colorless crystal, 0.70  0.40  0.30 mm; a ˆ 5.723(1), b ˆ 10.694(1),
c ˆ 17.074(1) Š, Vˆ 1045.0(4) Š3, 1calcd ˆ 1.260 gcm 3, F(000) ˆ 424 e,
m ˆ 8.13 cm 1, Z ˆ 4, orthorhombic, space group P212121 (No. 19), l ˆ
1.54178 Š, Tˆ 293 K, w/2q scans, 1886 reflections collected (‡h, k,
1
Æl), [(sinq)/l] ˆ 0.62 Š
,
1617 independent and 1518 observed
reflections [I ꢂ 2s(I)], 129 refined parameters, R ˆ 0.041, wR2 ˆ
0.119, max. residual electron density 0.12 ( 0.15) eŠ 3, hydrogens
calculated and refined as riding atoms. Data set was collected with an
Enraf ± Nonius CAD4 diffractometer. Programs used: data reduction
MolEN, structure solution SHELXS-86, structure refinement
SHELXL-93, graphics SCHAKAL-92. Crystallographic data (exclud-
ing structure factors) for the structure reported in this paper has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-100883. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
[48] Surprisingly, according to a literature search in Chemical Abstracts,
only racemic 24 has already been reported.
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Received: October 19, 1998 [F 1399]
1916
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0947-6539/99/0506-1916 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 6