Stereoselective synthesis of conformationally constrained cyclohexanediols: A set of molecular scaffolds for the synthesis of glycomimetics

Article abstract of DOI:10.1021/jo015570b

The practical, stereoselective synthesis of the three diastereoisomeric 1,2-trans-dicarboxy-4,5-cyclohexanediols 1-3 (DCCHDs) is described, starting from a common precursor, easily available in both enantiomeric forms. The regioselective derivatization of all functional groups of 1 is also reported. The three DCCHDs are locked in a single chair conformation and thus can be used to mimic vicinally disubstituted monosaccharides of any relative configuration.

Full text of DOI:10.1021/jo015570b

VOLUME 66, NUMBER 19
SEPTEMBER 21, 2001
© Copyright 2001 by the American Chemical Society
Articles
Ster eoselective Syn th esis of Con for m a tion a lly Con str a in ed
Cycloh exa n ed iols: A Set of Molecu la r Sca ffold s for th e Syn th esis
of Glycom im etics
Anna Bernardi,*,† Daniela Arosio,† Leonardo Manzoni,† Fabrizio Micheli,‡
Alessandra Pasquarello,‡ and Pierfausto Seneci‡,§
Universita’ di Milano, Dipartimento di Chimica Organica e Industriale, via Venezian 21, 20133 Milano,
Italy, GlaxoWellcome SpA, Medicines Research Centre, via Fleming 4, 37100 Verona, Italy
anna.bernardi@unimi.it
Received February 14, 2001
The practical, stereoselective synthesis of the three diastereoisomeric 1,2-trans-dicarboxy-4,5-
cyclohexanediols 1-3 (DCCHDs) is described, starting from a common precursor, easily available
in both enantiomeric forms. The regioselective derivatization of all functional groups of 1 is also
reported. The three DCCHDs are locked in a single chair conformation and thus can be used to
mimic vicinally disubstituted monosaccharides of any relative configuration.
In tr od u ction
that functional mimics of carbohydrates may be designed
by replacing these seemingly inactive fragments with
simpler, non-carbohydrate scaffolds. Such replacements
could decrease the molecular, and hence synthetic,
complexity of the construct and simultaneously increase
its metabolic stability.2 In particular, carbocyclic diols of
the appropriate configuration can be used as substitutes
of branching units in complex oligosaccharides. For
instance, the 3,4-disubstituted N-acetyl glucosamine
(GlcNAc) of the sialylLewisX tetrasaccharide (sLex, Chart
1), a residue that does not contain any groups critical
for binding to the sLex target, has been successfully
replaced using 1,2-trans-cyclohexanediol in the synthesis
of a highly effective mimic.3
In recent years much interest has been devoted to the
synthesis of so-called glycomimetics, i.e., functional and
structural mimics of oligosaccharides, as promising thera-
peutic agents.1 Analysis of the characteristic properties
of sugar-binding sites shows that many of the lectins bind
carbohydrates weakly, using shallow depressions exposed
to the solvent on the protein surface. Thus, despite the
great structural complexity of many bioactive oligosac-
charides, often only small portions of these molecules are
actually recognized by their receptors. The remaining
part appears to act as a scaffold that orients the binding
determinants in the appropriate conformation and pro-
vides a connection to the aglycons. This analysis suggests
The use of simple cyclohexanediols, though, is limited
by two factors. First and foremost, simple 1,2-cyclohex-
anediols are conformationally flexible. Hence, they cannot
be used to replace those branching motifs that incorpo-
* Corresponding author.
† Universita′ di Milano.
‡ GlaxoWellcome.
§ Present address: Nucleotide Analog Design AG, Landsberger-
strasse 50, 80339 Mu¨nchen, Germany.
(1) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300-
2324.
(2) Simanek, E. E.; McGarvey, G. J .; J ablonowski, J . A.; Wong, C.-
H., Chem. Rev. 1998, 98, 833-862, and references therein.
(3) Kolb, H. C.; Ernst, B. Chem. Eur. J . 1997, 3, 1571-1578.
10.1021/jo015570b CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/25/2001

6210 J . Org. Chem., Vol. 66, No. 19, 2001
Bernardi et al.
Ch a r t 1. High -Activity Mim ics of Oligosa cch a r id es Bu ilt on Cycloh exa n ed iol Sca ffold s
Ch a r t 2. Com m on Ar r a ys of Br a n ch in g Un its in
Bioa ctive Oligosa cch a r id es
Sch em e 1. Con for m a tion a l Equ ilibr ia of DCCHDs
1-3 (MM3* r ela tive en er gies in k ca l/m ol)
Ch a r t 3. Con for m a tion a lly Con str a in ed
Dica r boxy Cycloh exa n ed iols (DCCHD) 1-3 a n d
Th eir Com m on P r ecu r sor 4
rate one or more axial substituents, and that are fre-
quently encountered in bioactive oligosaccharides (see
Chart 2). Such motifs include, for example, the 3,4-
galacto and 2-ManR-1 arrays shown in Chart 2, that are
commonly found in glycolipids and glycopeptides. Second,
in biological systems the bioactivity of oligosaccharides
is often expressed by multivalent clusters of glycoconju-
gates (glycoside cluster effect).4 Simple cyclohexanediols
that cannot be conjugated to polyvalent aglycons thus
lack an important attribute, which could help to produce
highly effective and specific ligands.
The stereoisomeric 1,2-trans-dicarboxy-4,5-cyclohex-
anediols (DCCHDs) 1-3 (Chart 3 and Scheme 1) over-
come both the above-mentioned drawbacks and thus
appear a very attractive alternative as mimics of scaffold
monosaccharides.
substituted.5 This was experimentally confirmed for 16
1
and 27 by analysis of their H NMR spectra. Accordingly,
the diol functionality is also locked in the lowest energy
conformation shown in Scheme 1 and can be used to
reproduce vicinally disubstituted monosaccharides of any
relative configuration.
In fact, we recently succeeded in mimicking the cis diol
of the 3,4-disubstituted galactose residue in the GM1
oligosaccharide (Chart 1) using diol 1, and the resulting
pseudo-GM1 molecule (Chart 1) was shown to accurately
replicate the three-dimensional structure and cholera
toxin-binding activity of its natural model.6,8 In addition,
Indeed, DCCHDs are highly conformationally stable,
thanks to the 1,2-trans-dicarboxy substitution that acts
as a conformational lock for the cyclohexane ring. MM3*
calculations show (Scheme 1) that for all isomers the
chair featuring two equatorial carboxy groups is at least
2.7 kcal/mol more stable than the isomeric one, diaxially
(5) Calculations were run in vacuo, using MacroModel 5.5: Moha-
madi, F., Richards, N. G. J .; Guida, W. C.; Liskamp, R.; Lipton, M.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput. Chem.
1990, 11, 440-467.
(6) Bernardi, A.; Checchia, A.; Brocca, P.; Sonnino, S.; Zuccotto, F.
J . Am. Chem. Soc. 1999, 121, 2032-2036.
(7) Samoshin, V. V.; Chertkov, V. A.; Vatlina, L. P.; Dobretsova, E.
K.; Simonov, N. A.; Kastorsky, L. P.; Gremyachinsky, D. E.; Schneider,
H.-J . Tetrahedron Lett. 1996, 37, 3981-3984.
(4) Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 1-327. Lis, H.;
Sharon, N. Chem. Rev. 1998, 98, 637-674. Kiessling, L. L.; Pohl, N.
L. Chem. Biol. 1996, 3, 71-77. Roy, R. Curr. Opin. Struct. Biol. 1996,
6, 692-702.
(8) (a) Bernardi, A.; Boschin, G.; Checchia, A.; Lattanzio, M.;
Manzoni, L.; Potenza, D.; Scolastico, C. Eur. J . Org. Chem. 1999, 1311-
1317. (b) Bernardi, A.; Carrettoni, L.; Grosso Ciponte, A.; Monti, D.;
Sonnino, S. Bioorg., Med. Chem. Lett. 2000, 10, 2197-2200.

Conformationally Constrained Cyclohexanediols
J . Org. Chem., Vol. 66, No. 19, 2001 6211
Sch em e 2a
a
Conditions: (a) For 1a : Me2NCH(OtBu)2, benzene; OsCl3/Et3NO. (b) For 1b: MeOH/H2SO4; OsCl3/Et3NO. (c) Bu2SnO, refl. benzene;
R1Br. (d) From 1b: Bu2SnO; allylBr, CsF, refl. toluene. (e) From 1b: LiOH (2.5 mol equiv) or NaOH, (1.5 mol equiv).
Sch em e 3. Selective Op en in g of La cton e 6
the carboxy groups of DCCHDs could be exploited for
conjugation to various supports, thus allowing the syn-
thesis of polyvalent pseudo-glycoconjugates.
The three diastereisomeric diols should be easily
synthesized from a common precursor, the 1,2-dicarboxy-
4-cyclohexene 4. Since we have recently described the
facile, large-scale synthesis of both enantiomers of 1,2-
dicarboxy-4-cyclohexene,9 the three diols could, in prin-
ciple, be synthesized in both enantiomeric forms.
Here we report the stereoselective synthesis of DCCHD
1-3 starting from 4, and some regioselective manipula-
tions of their functional groups.
takes place on the lactone, leaving the methyl ester
unchanged and yielding the monoacid 8 as the major
product (40%) (Scheme 3).
Resu lts a n d Discu ssion
Syn th esis a n d Regioselective F u n ction a liza tion
of th e cis-Diol 1. We have described the synthesis of
the cis-diol 1a as an intermediate en route to pseudo-
GM1.8a Starting from 4, the tert-butyl ester was synthe-
sized with dimethylformamide di-tert-butyl acetal (Scheme
2), and OsO4 dihydroxylation gave 1a . Likewise, the
methyl ester 1b can be obtained by Fischer esterification
in MeOH, followed by dihydroxylation using Poli’s pro-
tocol10 (Scheme 2).
Selective alkylation of the equatorial hydroxy group
can be achieved via the intermediate stannylene.11 The
Bu2SnO-mediated synthesis of the monobenzyl ether 5a
from the di-tert-butyl ester 1a (Scheme 2, route c) has
already been described.8a The same procedure was also
effective for the synthesis of the equatorial allyl ether
5b from the dimethyl ester 1b, using allyl bromide and
Bu2SnO (Scheme 2). In this case the alkylation step must
be carried out at room temperature, to avoid the Sn-
assisted lactonization11 of the methyl ester. The latter
reaction becomes prevalent in refluxing toluene, leading
to lactone 6 as the only product, in 60% yield (Scheme 2,
route d). This compound provides an easy entry to
carboxy group differentiation in DCCHD 1. In fact,
reaction of 6 with 1 mol equiv of benzylamine in CH2Cl2
at room temperature selectively occurs on the lactone
carboxy group, affording the amide 7 in 75% yield
(Scheme 3). Similarly, Me3SiOK hydrolysis preferentially
Alternatively, carboxy group differentiation can also
be achieved by direct, regioselective hydrolysis of 1b with
2.5 mol equiv of LiOH in MeOH/H2O (Scheme 2, route
e). This reaction appears to proceed initially to yield a
70:30 ratio of the regioisomeric monoacids, which cannot
be separated by flash chromatography. However, if the
reaction is protracted for 5-6 h at room temperature,
the minor isomer is preferentially consumed to give the
diacid, and the monoacid 9 is isolated in 64% yield and
90-95% isomeric purity after flash chromatography. The
identity of this compound was established on the basis
of its NOESY spectrum in D2O, which showed medium-
intensity cross-peaks between the methyl ester protons
and both H-6eq and H-6ax (see Scheme 2 for numbering).
Eventually, the same selective transformation was more
efficiently achieved with 1.5 mol equiv of 0.07 M NaOH
at room temperature for 45 min. Under these conditions,
only the monoacid 9 is formed and can be isolated in 80%
yield.
Syn th esis of th e Tr a n s-Dia xia l Diol 2. The trans-
diaxial diol 2 was obtained by acid-catalyzed hydrolysis
of the epoxide 10,7 which in turn was synthesized by
MCPBA oxidation of the bis tert-butyl ester of 4 (Scheme
4). Selective trans-diaxial opening of 10 could also be
achieved by catalyzed alcoholysis, using either allyl
alcohol as the solvent (to give the allyl ether 11), or excess
PhCH2OH in dioxane or CH2Cl2 (to give the benzyl ether
12) (Scheme 4). The diastereoisomeric composition of the
mixture and the product characterization were deter-
mined after acetylation of the crude with Ac2O/DMAP to
give 13 and 14, respectively.
(9) Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli, F. Tetrahe-
dron: Asymmetry 1999, 40, 3403-3407.
(10) Poli, G. Tetrahedron Lett. 1989, 30, 7385-7388
(11) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663.

6212 J . Org. Chem., Vol. 66, No. 19, 2001
Bernardi et al.
Ta ble 2. Syn th esis of Ben zyl Eth er 12 fr om Ep oxid e 10
Sch em e 4. Syn th esis of th e Dia xia l Diol 2 a n d of
Its Mon oeth er s 11 a n d 12a
entry catalyst
solvent
dioxane
temperature time (h) yield (%)
1
2
3
4
5
DDQa
TCNEb
TCNb
rt
72
48
15
24
24
0
0
dioxane
CH2Cl2
Cu(OTf)2 CH2Cl2
rt
rt
rt
80 °C
22
83
60
b
c
Mg(OTf)2 ClCH2CH2Cl
a
c
See ref 12a. bSee ref 12d. See ref 12a.
Sch em e 5. Syn h esis of Keton e 15
reaction, but required high temperatures and prolonged
12e
reaction times. Yb(OTf)3 (Table 1, entry 8) catalyzed
rapid epoxide opening, but also resulted in extensive
decomposition of the tert-butyl esters.
The best promoters were then tested in the synthesis
of the benzyl ether 12. In this case, only 5 mol equiv of
nucleophile were employed, and the reaction was carried
out in an inert solvent. Using dioxane as the solvent the
opening reaction did not take place in the presence of
either DDQ or TCNE (Table 2, entries 1 and 2). In
CH2Cl2, TCNE does catalyze the reaction, but after 15 h
only 22% of ether is formed (entry 3). On the contrary,
good results were achieved using Cu(OTf)2 (entry 4) or
Mg(OTf)2 (entry 5).13
Syn th esis of th e Tr a n s-Diequ a tor ia l Diol 3. For
the synthesis of the diequatorial diol 3, Mitsunobu
inversion14 of the alcohol 5a was initially attempted.
However, using benzoic acid or the more reactive picolinic
acid,15 no reaction occurred, and the starting material
was recovered unchanged. Therefore the ketone 15 was
prepared by Sn-mediated selective oxidation of diol 1a
with NBS (Scheme 5),16 and its stereoselective reduction
was studied.
a
Conditions: (a) Me2NCH(OtBu)2; (b) MCPBA; (c) H2O, H+; (d)
ROH, cat.; (e) Ac2O, DMAP.
Ta ble 1. Ca ta lyzed Rea ction of Ep oxid e 10 w ith Allyl
Alcoh ol a s Solven t
entry
catalyst
temperature
rt
rt
rt
rt
rt
rt
time
yield (%)
a
1
2
3
4
5
6
7
8
FeCl3
2 h
2 h
60b
74
64
43e
75
67
69
4e
TCNEc
DDQd
3 days
15 h
CANc
d
Cu(OTf)2
3 h
4 h
f
Ce(OTf)4
a
f
Mg(OTf)2
Yb(OTf)3
60 °C f 80 °C
rt
15 h + 4 h
5 h
See ref 12a. b10% of inseparable chloride opening product was
a
also obtained. cSee ref 12c. dSee ref 12b. eByproducts were also
obtained (see text). See ref 12e.
f
The steric outcome of the hydride reduction of simple
cyclohexanones is known to depend on the size of the
reducing agent.17 Axial attack of the hydride is normally
favored for torsional (Felkin)18 or electronic (Cieplak)19
reasons and leads to the equatorial alcohol with modest
stereoselectivity. This selectivity is overridden by steric
effects when using sterically hindered reducing agents,
such as the selectrides.17 In this case, equatorial attack
of the hydride efficiently leads to the axial alcohol. Steric
hindrance from the R-substituents of the carbonyl group
is also known to favor equatorial attack. Accordingly,
ketone 15 exhibited a modest preference for axial hydride
attack in the reactions with NaBH4 (Table 3, entry 2, 60:
40 trans:cis ratio), with BH3.THF (Table 3, entry 3, 66:
34 t:c), and exclusive equatorial attack in the reaction
with Li-selectride (Table 3, entry 1), which led to the
starting cis-diol 1a .
The alcoholysis of epoxides can be catalyzed by a
number of Lewis acids, or by electron-transfer catalysts,12
and some of these were examined in order to achieve
maximum yield and selectivity in the allyl alcohol open-
ing reaction (Table 1). Owing to the conformational
stability of the 1,2-trans-dicarboxycyclohexane frame-
work, only the ether arising from axial attack was
obtained under all sets of conditions. FeCl3 catalysis12a
led to rapid reaction of the epoxide at room temperature,
but, in addition to the desired allyl ether 11, ca. 20% of
inseparable chloride opening product was also formed.
(Table 1, entry 1). Better results were achieved using
other electron-transfer catalysts, such as tetracyano-
ethylene12d (TCNE, Table 1, entry 2) or DDQ12b (Table 1,
entry 3). However, with the latter catalyst the alcoholysis
reaction became sluggish and required 3 days at room
temperature. CAN-catalyzed opening12c was also slow and
gave a number of byproducts (Table 1, entry 4). Good
reactivity and selectivity were obtained using 10%
Cu(OTf)2 (Table 1, entry 5) or 5% Ce(OTf)4 (Table 1,entry
6) at room temperature. Lewis acidic conditions were also
explored. Mg(OTf)2 (Table 1, entry 7) did promote the
(13) The Cu(OTf)2-promoted reaction appears to be rather general,
as exemplified by cyclohexanol opening of 10, which occurs in 40 h at
RT in 60% yield.
(14) Mitsunobu, O. Synthesis 1981, 1. Hughes, D. L. Org. React.
1992, Chapter 2.
(15) Sammakia, T.; J acobs, J . S. Tetrahedron Lett. 1999, 40, 2685.
(16) Kong, X.; Grindley, T. B. J . Carbohydr. Chem. 1993, 12, 557-
571.
(12) (a) Iranpoor, N.; Salehi, P. Synthesis 1994, 1152. (b) Iranpoor,
N.; Baltork, I. M. Tetrahedron Lett. 1990, 31, 735. (c) Iranpoor, N.;
Baltork, I. M. Synth. Commun. 1990, 20, 2789. (d) Masaki, Y.; Miura,
T.; Ochiai, M. Bull. Chem. Soc. J pn. 1996, 69, 195. (e) Iranpoor, N.;
Shekarriz, M.; Shirini, F. Synth. Commun. 1998, 28, 347. (f) De, A.;
Ghosh, S.; Iqbal, J . Tetrahedron Lett. 1997, 38, 8379.
(17) Greeves, N. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds., 1991; vol. 8, chap. 1.1. Carey, F. A.; Sundberg, R. J .
Advanced Organic Chemistry B; Plenum Press: New York, 1990.
(18) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2205. Wu, Y.-D.; Houk, K. J . Am. Chem. Soc. 1987, 109, 908.
(19) Cieplak, A. S. J . Am. Chem. Soc. 1981, 103, 4540.

Conformationally Constrained Cyclohexanediols
J . Org. Chem., Vol. 66, No. 19, 2001 6213
Ta ble 3. Red u ction of Keton es 15-19. Syn th esis of th e Tr a n s-Diequ a tor ia l Diol 3a
entry
substrate
reducing agent
solvent
THF
MeOH
THF
MeCN/AcOH
MeCN
MeCN
MeOH
MeCN/AcOH
MeCN
T (oC)
t (h)
t:c ratioa
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
15
15
15
15
15
15
16
16
16
17
17
18
18
Li-selectride
NaBH4
BH3
NaBH(OAc)3
NaBH(OAc)3
Me4NBH(OAc)3
NaBH4
NaBH(OAc)3
NaBH(OAc)3
NaBH4
-78
2.5
0.5
5
22
5
20
1.5
1.5
17
0.5
6.5
2
0:100
60:40
66:34
62:38
74:26
70:30
40:60
84:16
81:19
50:50
82:18
60:40c
98: 2
98
94
81
89
77
50b
85
95
96
80
85
81c
70
0 f 25
0
-40
-20
25
0
-40
-20
0
MeOH
MeCN/AcOH
MeOH
NaBH(OAc)3
NaBH4
NaBH(OAc)3
-40
0
MeCN/AcOH
-40
36
a
c
As determined by 1H NMR at 300 MHz. bReaction is incomplete. Deacetylation occurs. Diastereomeric ratio and yields determined
after peracetylation of the reduction crude.
Sch em e 6. Ster eoselective Red u ction of Keton es
In conclusion, we have described the straightforward
stereoselective synthesis of enantiomerically pure, con-
formationally constrained DCCHD 1-3, starting from an
easily available common precursor, which can be readily
synthesized in both enantiomeric forms.9 These molecules
should be useful as building blocks in the synthesis of
mimics of complex oligosaccharides in solution or on solid
phase, either using classical synthetic methods or apply-
ing parallel or combinatorial methodologies leading to
oligosaccharide libraries. Their use in the design and
synthesis of glycomimetics is underway in our laborato-
ries6,8 and will be reported in due course.
15-18: Syn th esis of th e Tr a n s-Diequ a tor ia l Diol 3a
a
Conditions: (a) BnBr, Ag2O (70%); (b) TBSCl, DMF, imidazole
(64%); (c) Ac2O, DCM, pyridine, DMAP (86%); (d) reducing agents,
see Table 3.
Exp er im en ta l Section
Directing effects from hydroxy groups have been
reported by Evans and Chapman in the stereoselective
reduction of â-hydroxy ketones, using NaBH(OAc)3 or
Me4NBH(OAc)3.20 Their results are consistent with dis-
placement of one of the OAc ligands by the substrate
hydroxy group, followed by internal delivery of the
hydride through a six-membered transition state. Indeed,
a modest improvement of the trans selectivity was
achieved upon treating 15 with NaBH(OAc)3 (Table 3,
entry 5, 74:26 t:c) or Me4NBH(OAc)3 (Table 3, entry 6,
70:30 t:c) in MeCN at -20 °C. Addition of AcOH to the
reaction mixture, as in the original Evans-Chapman
protocol, allowed the reaction to proceed at -40 °C, but
was detrimental for the stereoselectivity (Table 3, entry
4, 62:38 t:c). Thus it appears that internal hydride
delivery from the R-hydroxy group, which would require
a five-membered transition structure, is occurring much
less efficiently than from the â position. In an effort to
improve the trans selectivity, the effect of different
hydroxy protecting groups was examined, in the series
16-18 (Scheme 6, Table 3). Protection of the alcohol did
not have any influence on the NaBH4 reduction, which
remained essentially stereorandom (Table 3, entries 2,
7 10, 12). On the contrary, the trans selectivity of
NaBH(OAc)3 reduction increased upon protection of the
hydroxy group going from 3:1 for the free alcohol 15 to
5:1 for the benzyl ether 16 (Table 3, entry 8) and the silyl
ether 17 (Table 3, entry 11) and reached synthetically
useful values (98:2, Table 3, entry 13) for the acetate 18.21
Gen er a l. Solvents: pyridine, DMF, CCl4, and dichloro-
ethane were dried over 4-A molecular sieves. The other dry
solvents were distilled under nitrogen shortly before use. THF,
Et2O, dioxane, benzene, and toluene were distilled from Na;
MeCN, EtCN, MeOH, Et3N, CH2Cl2 were distilled from CaH2.
Flash chromatography: Silica gel (Kieselgel 60, 230-400
mesh). Mps: Kleinfeld Labortechnik apparatus, uncorrected
values. NMR: Bruker Ac-200, Ac-300, and Avance-400, for 13C
spectra only selected values are reported, internal standard
TMS. IR: Perkin-Elmer FTIR 1600 spectrometer. Optical
rotations: Perkin-Elmer 241 at 589 nm, using 1 mL cells.
Known compounds: 1a ,8a 4,9 5a .8a
Syn th esis of (1S,2S)-Cycloh ex-4-en e-1,2-d ica r boxylic
Acid Dim eth yl Ester . To a solution of the diacid 4 (7.02 g,
0.041 mol, 1 mol equiv) in dry MeOH (100 mL) was added
H2SO4 (0.5 mL, 0.009 mol, 0.2 mol equiv). The solution was
stirred at reflux for ca. 20 h and then concentrated under
vacuum to about half of the original volume. AcOEt was added,
the organic phase was washed with saturated NaHCO3 and
dried with Na2SO4, and the solvent was evaporated under
reduced pressure to yield 7.8 g of dimethyl ester (95%). [R]20
:
D
+127.3 (c ) 1.23, CHCl3); Microanalysis: Found, C 60.62%,
H 7.10%; C10H14O4 requires C 60.59%, H 7.12%. 1H NMR (200
MHz, CDCl3): 2.6-2.1 (m, 4H, CH2), 2.85 (m, 2H, H1, H2), 3,7
(s, 6H, OCH3), 5,7 (m, 2H, H4, H5); 13C NMR (50.3 MHz,
CDCl3): 24.5, 40.96, 51.45, 124.66, 174.79.
Syn th esis of (1S,2S)-Cycloh ex-4-en e-1,2-d ica r boxylic
Acid Di-ter t-Bu tyl Ester . To a refluxing solution of the diacid
4 (1.0 g, 5.88 mmol, 1 mol equiv), under N2, in dry benzene
(15 mL), was added N,N-dimethylformanide di-tert-butyl acetal
(8.5 mL, 35.4 mmol, 1 mol equiv). The solution was refluxed
for 36 h monitoring by TLC. The organic phase was washed
with H2O (20 mL) and then with saturated NaHCO3 and
finally with brine. The solvent, dried with Na2SO4, was
evaporated under reduced pressure. The crude was used for
(20) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(21) The reduction of 16 with chiral oxazaborolidines was also
studied, using (R) or (S) diphenylprolinol (Corey, E. J .; Bakshi, R. K.;
Shibata, S. J . Am. Chem. Soc. 1987, 109, 5551. Quallich, G. J .; Woodall,
T. M. Synth. Lett. 1993, 929). Both reagents yielded a 85:15 trans:cis
ratio. For the enantioselective reduction of hydroxymethylene ketones
with oxazaborolidine, see: Cho, B. T.; Chun, Y. S. J . Org. Chem. 1998,
63, 5280. Tetrahedron: Asymmetry 1999, 10, 1843.
1
the following reactions with no further purification. H NMR
(200 MHz, CDCl3): 1.5 (s, 18H, COOC(CH3)3); 2.0-2.52 (m, 4H,
H
3ax, H3eq, H6ax, H6eq); 2.6-2.78 (m, 2H, H1, H2); 5.65 (d, 2H,
H4, H5, J 4-5 ) 3.7 Hz); 13C NMR (50.3 MHz, CDCl3): 28.01,
28.22, 42.16, 80.12, 124.59, 174.18.

6214 J . Org. Chem., Vol. 66, No. 19, 2001
Bernardi et al.
Syn th esis of th e cis-Diol 1b. To a solution of the dimethyl
ester of 4 (208 mg, 1.05 mmol, 1 mol equiv) in wet CH2Cl2 (5
mL) were added trimethylamine N-oxide (152 mg, 1.37 mmol,
1.3 mol equiv) and osmium(III) chloride (5 mg,0.02 mmol, 0.02
mol equiv). The solution was stirred at room temperature for
ca. 15 h. After reaction completion, the solvent was evaporated
under reduced pressure. The crude can be used for the
following reactions with no further purification (99%). An
analytical sample was purified by flash chromatography (3:7
hexane:AcOEt). [R]20D: +18.3 (c ) 1, CHCl3); Microanalysis:
Found, C 51.31%, H 7.19%; C10H16O6 requires C 51.72%, H
2H, CH2dCHCH2O); 4.1 (m, 1H, H5); 4.4 (d, 2H, NHCH2C6H5,
J gem ) 6 Hz); 5.1-5.35 (m, 2H, CH2dCHCH2O); 5.8-6.08 (m,
2H, CH2dCHCH2O, NH); 7.2-7.4 (m, 5H, C6H5); 13C NMR
(75.4 MHz, CDCl3): 28.0, 33.2, 38.9, 43.5, 45.1, 51.8, 65.6, 69.3,
77.0, 117.2, 127.4, 127.8, 128.6, 134.5.
Syn th esis of th e Mon oa cid 8. To a suspension of potas-
sium trimethylsilanoate (9 mg, 0.07 mmol, 1 mol equiv) in dry
CH2Cl2 (0.25 mL) was added a solution of lactone 6 (16 mg,
0.07 mmol, 1 mol equiv) in dry CH2Cl2 (0.25 mL) under N2.
The reaction mixture was stirred at room temperature for 4
h. After completion, the solution was diluted with AcOEt. The
organic phase was washed with 6 N HCl and then with H2O,
dried with Na2SO4, and evaporated under reduced pressure.
The crude was purified by flash chromatography on silica gel
(hexane/AcOEt 3:7 + 1% AcOH) to yield pure 8 (40%).
Microanalysis: Found, C 60.08%, H 7.17%; C12H18O6 requires
1
6.94%. H NMR (400 MHz, CDCl3): 1.6-1.4 (m, 1H, H6ax), 1.8
(q, 1H, H6ax), 2.0 (dt, 1H, H3eq), 2.0 (bm, 1H, OH), 2.1 (bm, 1H,
OH), 2.25 (dt, 1H, H6eq), 2.7 (m, 1H, H2), 3.0 (m, 1H, H1), 3.69
(s, 3H, OCH3),), 3.7 (s, 3H, OCH3), 3.7 (m, 1H, H4), 4.0 (m,
1H, H5); 13C NMR (50.3 MHz, CDCl3): 29.9, 32.9, 38.2, 42.9,
51.9, 52.0, 67.7, 70.1, 174.3, 175.4.
1
C 59.81%, H 7.02%. H NMR (200 MHz, CDCl3): 1.3-1.5 (m,
Syn th esis of th e Mon oa llyl Eth er 5b. A solution of
dimethyl ester 1b (1.32 g, 5.69 mmol, 1 mol equiv) in dry
benzene (30 mL) was refluxed for 6 h under N2, in the presence
of Bu2SnO (1.42 g, 5.69 mmol, 1 mol equiv), and the water
was continuously removed. After concentrating to 10 mL, allyl
bromide (0.46 mL, 6.83 mmol, 1.2 mol equiv), Bu4NI (2.07 g,
5.69 mmol, 1 mol equiv), and CsF (1.21 g, 7.96 mmol, 1.4 mol
equiv) were added, and the suspension was stirred at room-
temperature monitoring by TLC. After completion (ca. 48 h),
the solvent was evaporated under reduced pressure and the
crude was purified by flash chromatography on silica gel
(hexane/AcOEt 6:4) to yield pure 5b (73%). [R]20D: -7.36 (c )
1.25, CHCl3); Microanalysis: Found, C 57.55%, H 7.26%;
1H, H6ax); 1.4-1.6 (m, 1H, H3ax); 1.8-2.2 (m, 2H, H6eq, H3eq);
2.5 (m, 1H, H2); 2.9 (m, 1H, H1); 3.2 (dm, 1H, H4); 3.5 (s, 3H,
OCH3); 3.9 (s, 3H, H5, OCH2); 5.0-5.2 (m, 2H, CH2CHCH2O);
5.6-5.9 (m, 1H, CHCH2O).
Syn th esis of th e Mon oa cid 9. (1) Selective Hyd r olysis
w ith LiOH. To a solution of dimethyl ester 1b (505 mg, 2.17
mmol, 1 mol equiv) in a 4:1 mixture of MeOH/H2O (10 mL)
was added LiOH‚H2O (228 mg, 5.34 mmol, 2.5 mol equiv). The
solution was stirred at rt for 5.5 h. After this time, 6 N HCl
was added to pH 1, and then the solvent was evaporated under
reduced pressure. The crude was purified by flash chroma-
tography on silica gel (CHCl3/MeOH 9:1 + 1% AcOH) to yield
300 mg of 9 (60%) as 20:1 mixture with the regioisomeric
monomethyl ester.
C
13H20O6 requires C 57.34%, H 7.40%. 1H NMR (400 MHz,
CDCl3): 1.4-1.6 (m, 1H, H6ax), 1.7-1.9 (q, 1H, H3ax), 2.0-2.1
(dm, 1H, H6eq), 2.2-2.3 (dm, 1H, H3eq), 2.6-2.7 (tm, 1H, H2),
3.0-3.1 (m, 1H, H1), 3.4 (dq, 1H, H4), 3.69 (s, 3H, OCH3), 3.7
(s, 3H, OCH3), 4.0 (m, 1H, H5), 4.1 (m, 2H, OCH2), 5.1-5.4
(m, 2H, CH2CHCH2O), 5.7-6.0 (m, 1H, CHCH2O); 13C NMR
(50.3 MHz, CDCl3): 27.27, 32.25, 38.19, 42.78, 51.82, 51.90,
65.62, 69.29, 76.77, 117.18, 134.33, 173.86, 155.33.
(2) Selective Hyd r olysis w ith Na OH. To a solution of
dimethyl ester 1b (505 mg, 2.17 mmol, 1 mol equiv) was added
a 0.07 M solution of NaOH (46.5 mL, 3.26 mmol, 1.5 mol
equiv). The solution was stirred at rt for 45 min, 6 N HCl was
added to pH 1, and the solvent evaporated under reduced
pressure. The crude was purified as described above, to yield
378 mg (80%) of pure 9.
Syn th esis of th e La cton e 6. A solution of dimethyl ester
1b (406 mg, 1.75 mmol, 1 mol equiv) in dry toluene (10 mL)
was refluxed for 6 h under N2, in the presence of Bu2SnO (436
mg, 1.75 mmol, 1 mol equiv), and the water was continuously
removed. After concentrating to 5 mL, allyl bromide (0.18 µL,
2.1 mmol, 1.2 mol equiv), Bu4NI (638 mg, 1.75 mmol, 1 mol
equiv), and CsF (372 mg, 2.45 mmol, 1.4 mol equiv) were
added, and the suspension was refluxed monitoring by TLC.
After completion (ca. 5 h), the reaction mixture was filtered,
and the collected salts were washed with Et2O. The organic
phase was evaporated under reduced pressure, and the crude
was purified by flash chromatography on silica gel (toluene/
AcOEt 8:2) to yield 240 mg of pure lactone 6 (60%). Mi-
croanalysis: Found, C 59.73%, H 7.05%; C12H16O5 requires C
[R]20 +17.5 (c ) 1.05, MeOH); Microanalysis: Found, C
D
49.78%, H 6.12%; C9H14O6 requires C 49.54%, H 6.47%. 1H
NMR (400 MHz, D2O): 1.6-1.8 (m, 2H, H3ax, H6ax); 2.0 (m, 1H,
H
3eq); 2.1 (m, 1H, H6eq); 2.08 (m, 1H,); 2.71 (m, 1H, H2); 2.88
(m, 1H, H1); 3.65 (m, 1H, OCH3); 3.71 (m, 1H, H4); 3.74 (m,
1H, H5); 4; 13C NMR (50.3 MHz, CDCl3) : 29.8; 33.2; 39.2; 44.0;
53.3; 68.3; 70.5; 178.4;179.0.
Syn th esis of th e Ep oxid e 10. To a solution of the di-tert-
butyl ester of 4 (1.5 g, 5.5 mmol, 1 mol equiv) in CH2Cl2 (13
mL) was added MCPBA (1.85 g, 7.6 mmol, 1.4 mol equiv). The
solution was stirred at room temperature for 3 h, and then
the organic phase was washed with saturated NaHCO3, dried
with Na2SO4, and evaporated under reduced pressure. The
crude was purified by flash chromatography on silica gel
(hexane/AcOEt 85:15) to yield 1.54 g of pure 10 as a white
solid (97%). Mp: 98 °C. [R]20D: +55.78 (c ) 1.01, CHCl3);22
Microanalysis: Found, C 64.58%, H 8.50%; C16H26O5 requires
59.99%, H 6.71%. IR (Nujol): ν 1735 cm-1; ν 1758 cm-1
;
1H
NMR (500 MHz, CDCl3): 1.82 (m, 1H, H3eq); 2.13 (ddd, 1H, H6ax
,
J 6ax-5 ) 5 Hz, J 6ax-6eq ) 14.6 Hz); 2.2-2.3 (m, 2H, H3ax, H6eq);
2.98 (m, 1H, H1); 3.03 (dd, 1H, H2, J 2-1 ) 3 Hz, J 2-3eq ) 5.5
Hz); 3.62-3.74 (dq, 1H, H4, J 4-5 ) 1.5 Hz, J 4-3eq ) 3 Hz, J 4-3ax
) 10 Hz); 3.76 (s 3H, COOCH3); 4.0-4.1 (m, 2H, CH2d
CHCH2O); 4.82 (d, 1H, H5, J 5-4 ) 1.5 Hz, J 5-6ax ) 5 Hz); 5.15-
5.35 (m, 2H, CH2dCHCH2O); 5.89 (m, 1H, CH2dCHCH2O);
13C NMR (125.7 MHz, CDCl3): 25.0; 25.9; 37.9; 38.1; 52.9; 69.6;
73.1; 76.3; 117.8; 134.4; 172.7; 173.6.
1
C 64.41%, H 8.78%. IR (Nujol): ν 3005 cm-1; ν 1722 cm-1. H
NMR (300 MHz, C6D6): 1.4 (s, 18 H, COOC(CH3)3); 1.58 (m,
1H, H6ax, J 6ax-5 ) 2.1 Hz, J 6ax-1 ) 10.9 Hz, J 6ax-6eq ) 14.5 Hz);
1.95-2.06 (m, 2H, H3ax, H6eq); 2.35 (ddd, 1H, H3eq, J 3eq-4 ) 1.7
Hz, J 3eq-2 ) 10.9 Hz, J 3eq-3ax ) 14.5 Hz); 2.52 (dt, 1H, H2, J 2-1
= J 2-3eq ) 2.7 Hz, J 2-3ax ) 10.3 Hz); 2.71 (m, 1H, H4); 2.79 (m,
1H, H5); 3.0 (dt, 1H, H1, J 1-2 = J 1-6ax ) 10.6 Hz, J 1-6eq ) 4.8
Hz). 13C NMR (50.3 MHz, CDCl3): 26.4; 27.2; 27.8; 38.5; 41.0;
50.4; 51.9; 90.4; 172.9; 173.9.
Syn th esis of th e Am id e 7. To a solution of lactone 6 (22
mg, 0.092 mmol, 1 mol equiv) in CH2Cl2 (0,5 mL) was added
benzylamine (10 mg, 0.092 mmol, 1 mol equiv) under N2. The
reaction mixture was stirred at room-temperature monitoring
by TLC. After reaction completion (ca. 20 h), the solvent was
evaporated, and the crude was taken up with AcOEt. The
organic phase was washed with 6 N HCl and H2O, dried with
Na2SO4, and evaporated under reduced pressure to yield 7 as
a yellow oil (75%). Microanalysis: Found, C 65.34%, H 7.40%;
Syn th esis of th e Tr a n s-Dia xia l Diol 2a . To a solution of
the epoxide 10 (41 mg, 0.14 mmol, 1mol equiv) in 1:1 CH3CN:
H2O (1 mL) was added Ce(OTf)4 (7 mg, 0.013 mmol, 0.09 mol
equiv). The solution was stirred at room temperature for ca.
15 h, monitoring by TLC. After reaction completion, water was
added, and the crude extracted with AcOEt. The organic layer,
dried with Na2SO4, was evaporated under reduced pressure.
C
19H25NO5 requires C 65.69%, H 7.25%, N 4.03%. 1H NMR
(200 MHz, CDCl3): 1.25 (m, 1H, H6ax); 1.4-1.6 (m, 1H, H3ax);
1.8-1.95 (m, 1H, H3eq); 2.1-2.5 (m, 2H, H6eq, H2); 3.0-3.2 (m,
1H, H1); 3.3-3.45 (m, 1H, H4); 3.6 (s, 3H, COOCH3); 4.04 (m,
(22) This compound was prepared starting from a batch of 4 with
82% ee.

Conformationally Constrained Cyclohexanediols
J . Org. Chem., Vol. 66, No. 19, 2001 6215
The crude was purified by flash chromatography on silica gel
5.2 (m, 1H, H5); 7.0-7.3 (m, 5H, C6H5);13C NMR (50.3 MHz,
CDCl3): 21.2; 27.9; 28.3; 39.8; 40.4; 68.5; 70.9; 72.6; 80.4; 80.5;
104.5; 127.4; 127.6; 128.3; 174.0.
(hexane/AcOEt 4:6) to yield 39 mg of pure 2a (89%). [R]20
:
D
+16.2 (c ) 1.8, EtOH),22 Microanalysis: Found, C 61.03%, H
8.60%; C16H28O6 requires C 60.74%, H 8.92%. 1H NMR (200
Syn th esis of Keton e 15. The diol 1a (201 mg,0.64 mmol,
1 mol equiv) was refluxed with Bu2SnO (159 mg, 0.64 mmol,
1 mol equiv) for 12 h in anhydrous toluene (14 mL) while
continuously removing water. After this time, toluene was
evaporated, and the residue was dried for 30 min under
reduced pressure. The residue was taken up in dry chloroform
(7 mL), and N-bromosuccinimide (123 mg, 0.69 mg, 1.1 mol
equiv) was added. The reaction mixture was stirred at room
temperature for ca. 1.5 h, the solvent was evaporated, and the
crude was purified by flash chromatography on silica gel
(hexane/AcOEt 7:3) to yield 169 mg of pure 15 (84%) as a white
solid. Mp: 120 °C. [R]20D: +26.9 (c ) 1.1, CHCl3);23 Microanaly-
sis: Found, C 61.35%, H 8.12%; C16H26O6 requires C 61.13%,
MHz, CDCl3): 1.45 (s, 18H, COOC(CH3)3); 1.6-1.8 (m, 2H, H3ax
,
H
6ax); 2.08-2.24 (m, 2H, H3eq, H6eq); 2.4 (bs, 1H, OH); 2.9-
3.05 (m, 2H, H1, H2); 3.55-3.72 (m, 1H, H4, H5). 13C NMR (50.3
MHz, CDCl3): 27.88; 30.53; 40.73; 70.36; 80.84; 173.45.
Syn th esis of (1S,2S,4S,5S)-4-Allyloxy-5-h yd r oxy-cyclo-
h exa n e-1,2-d ica r boxylic Acid Di-ter t-bu tyl Ester 11. To
a solution of the epoxide 10 (15 mg, 0.05 mmol, 1 mol equiv)
in allyl alcohol (150 µL, 2.2 mmol, 44 mol equiv) was added
the catalyst. The reaction mixture was stirred at the indicated
temperature, for the indicated time (Table 1), monitoring by
TLC. After reaction completion, water (or a saturated solution
of NH4Cl and NH3) was added, and the mixture was extracted
with Et2O. The organic layer was dried with Na2SO4 and
evaporated under reduced pressure.
1
H 8.34%. IR (Nujol): ν 3502 cm-1; ν 1725 cm-1. H NMR (400
MHz, CDCl3): 1.4 (m, 18H, COOC(CH3)3); 2.45 (t, 1H, H1, J 1-2
= J 1-6ax ) 13.9 Hz); 2.62-2.76 (m, 2H, H3ax, H3eq); 2.82 (dd,
The crude mixtures were purified by flash chromatography
on silica gel (hexane/AcOEt 8:2) to give 11 with the yield
reported in Table 1. [R]20D: +14.2 (c ) 1.1, CHCl3);22 Mi-
croanalysis: Found, C 64.17%, H 8.83%; C19H32O6 requires C
64.02%, H 9.05%. 1H NMR (400 MHz, CDCl3): 1.4 (s, 18H,
COOC(CH3)3); 1.7-1.8 (m, 4H, H3ax, H6ax,);2.0-2.16 (m, 2H,
1H, H6ax, J 6ax-1 = J 6ax-6eq ) 13.9 Hz);2.9 (dt, 1H, H2, J 2-1
)
13.9 Hz, J 2-3ax ) 9.2 Hz, J 2-3eq ) 2.2 Hz); 3.2 (dt, 1H, H6eq
,
J 6eq-1 ) 3.3 Hz, J 6eq-6ax ) 12.9 Hz); 3.52 (d, 1H, OH, J ) 4.9
Hz); 4.2 (m, 1H, H4, J 4-3ax = J 4-3eq ) 9.05 Hz); 13C NMR (50.3
MHz, CDCl3): 27.8; 36.9; 39.9; 43.3; 46.3; 73.5; 81.5; 171.3;
207.6.
H
3eq, H6eq); 2.95-3.0 (m, 2H, H1, H2); 3.35 (dt, 1H, H4, J 4-5 =
J 4-3eq ) 3.4 Hz, J 4-3ax ) 9.95 Hz), 3.75 (dt, 1H, H5, J 5-4 = J 5-6eq
) 3.4 Hz, J 5-6ax ) 10.1); 3.8-4.15 (m, 2H, CH2dCHCH2O);
5.1-5.3 (m, 2H,CH2dCHCH2O); 5.8-6 (m, 1H, CH2dCHCH2O).
13C NMR (50.3 MHz, CDCl3): 27.3; 27.9; 30.2; 40.2; 40.6; 68.1;
68.8; 76.9; 80.8; 116.7; 134.9; 173.5.
Syn th esis of (1S,2S,4R)-4-Ben zyloxy-5-oxocycloh ex-
a n e-1,2-d ica r boxylic Acid Di-ter t-bu tyl Ester 16. To a
solution of ketone 15 (100 mg, 0.32 mmol, 1 mol equiv) and
benzyl bromide (60 µL, 0,5 mmol, 1.6 mol equiv) in dry Et2O
(3.5 mL) was slowly added Ag2O (118 mg, 0.5 mmol, 1.6 mol
equiv), heating after the first addition to start the reaction.
The reaction mixture was refluxed for 5 h. After this time the
salts were filtered and washed several times with AcOEt. The
organic layer was evaporated under reduced pressure, and the
crude was purified by flash chromatography on silica gel
(toluene:Et2O 95:5) to yield 100 mg of pure 16 (76%) as a white
solid. Mp:137 °C; [R]20D: +49.8 (c ) 1.0, CHCl3);23 Microanaly-
sis: Found, C 68.37%, H 8.06%; C23H32O6 requires C 68.29%,
Syn th esis of (1S,2S,4S,5S)-4-Ben zyloxy-5-h yd r oxy-cy-
cloh exa n e-1,2-d ica r boxylic Acid Di-ter t-bu tyl Ester 12.
To a solution of the epoxide 10 (20 mg, 0.067 mmol, 1 mol
equiv) and benzyl alcohol (35 µL, 0.34 mmol, 5 mol equiv) in
dry solvent (100 µL) was added the catalyst (Table 2). The
reaction mixture was stirred at the indicated temperature, for
the indicated time (Table 2), monitoring by TLC. After reaction
completion, water (or a saturated NH4Cl/NH3 buffer) was
added, and the mixture was extracted with Et2O. The organic
layer was dried with Na2SO4 and evaporated under reduced
pressure. The crude mixtures were purified by flash chroma-
tography on silica gel (hexane/AcOEt 8:2) to give 12 with the
yield reported in Table 2. [R]20D: +7.5 (c ) 1.32, CHCl3);22
Microanalysis: Found, C 67.74%, H 8.72%; C23H34O6 requires
C 67.96%, H 8.43%. 1H NMR (200 MHz, CDCl3): 1.45 (m, 18H,
COOC(CH3)3); 1.6-1.95 (m, 2H, H3ax,H6ax); 2.0-2.3 (m, 2H,
1
H 7.97%. IR (Nujol): ν 1721 cm-1; ν 1606 cm-1. H NMR (200
MHz, CDCl3): 1.5 (s, 18H, COOC(CH3)3); 1.7-2.0 (m, 1H, H3ax);
2.3-2.65 (m, 2H, H6ax, H3eq); 2.75 (m, 1H, H6eq); 2.84-3.1 (m,
2H, H1, H2); 4.0 (m, 1H, H4); 4.5 (d, 1H, CH2C6H5, J gem )10
Hz); 4.85 (d, 1H, CH2C6H5, J gem ) 10 Hz); 7.3-7.5 (m, 5H,
C6H5); 13C NMR (50.3 MHz, CDCl3): 27.8; 34.9; 41.3; 43.8; 46.0;
72.0; 79.4; 81.3; 81.4; 127.8; 128.4; 173:3; 205.7.
Syn th esis of (1S,2S,4R)-4-(ter t-Bu tyld im eth ylsilyloxy)-
5-oxocycloh exa n e-1,2-d ica r boxylic Acid Di-ter t-bu tyl Es-
ter 17. To a solution of ketone 15 (29 mg, 0.092 mmol, 1 mol
equiv) and imidazole (34 mg, 0.5 mmol, 5.5 mol equiv) in dry
DMF (500 µL) was added tBuMe2SiCl (21 mg, 0.14 mmol, 1.5
mol equiv) under N2. The reaction mixture was stirred at room
temperature for ca. 15 h (monitoring by TLC), the solvent was
evaporated under reduced pressure, and the residue was
dissolved in AcOEt. The organic phase was washed first with
saturated NH4Cl and then with H2O, dried with Na2SO4, and
evaporated. The crude was purified by flash chromatography
on silica gel (hexane/AcOEt 95:5) to yield 25 mg of pure 17
(64%).23 Microanalysis: Found, C 61.20%, H 9.57%; C22H40O6-
H
3eq, H6eq); 3.2-3.3 (m, 2H, H1, H2); 3.38 (m, 1H, H4); 3.75 (m,
1H, H5); 4.22 (d, 1H, CH2C6H5, J gem ) 11.5 Hz);4.42 (d, 1H,
CH2C6H5, J gem ) 11.5 Hz) 7.3-7.5 (m, 5H, C6H5); 13C NMR
(50.3 MHz, CDCl3): 27.2; 27.9; 30.7; 40.3; 40.7; 68.2; 70.8; 77.2;
90.6; 127.6; 128.3; 173.5.
Syn tesis of th e Aceta tes 13 a n d 14. To a solution of
product 11 or 12 (12.3 mg, 0.035 mmol, 1 mol equiv) in dry
CH2Cl2 (0.25 mL) were added Ac2O (60 µL, 0.54 mmol, 15 mol
equiv), TEA (30 µL, 0.22 mmol, 6 mol equiv), and a catalytic
amount of DMAP. The solution was stirred at room temper-
ature for ca. 2 h. After reaction completion, the organic phase
was washed first with saturated NaHCO3 and then with H2O,
dried with Na2SO4, and evaporated under reduced pressure.
The crude was purified by flash chromatography on silica gel
(hexane/AcOEt 9:1) to yield the desired product (95%).
13: [R]20D: +8.26 (c ) 1.32, CHCl3);22 Microanalysis: Found,
C 63.52%, H 8.24%; C21H34O7 requires C 63.30%, H 8.60%. 1H
NMR (300 MHz, C6D6): 1.4 (s, 18H, COOC(CH3)3); 1.75-1.9
(m, 2H, H3ax, H6ax); 2.1-2.25 (m, 5H, H3eq, H6eq, OCOCH3); 3.1-
3.3 (m, 2H, H1, H2); 3.5 (m, 1H, H4); 3.95-4.1 (m, 2H, CH2d
CHCH2O); 4.98 (m, 1H, H5); 5:15-5.32 (m, 2H, CH2d
CHCH2O); 5.6 (m, 1H, CH2dCHCH2O); 13C NMR (50.3 MHz,
CDCl3):21.1; 27.8; 27.9; 28.3; 39.7; 40.4; 68.6; 69.9; 72.4; 77.5;
116.8; 134.6.
1
Si requires C 61.65%, H 9.41%. H NMR (200 MHz, CDCl3):
0.08 (s, 3H, OSi(CH3)2C(CH3)3);0.16 (s, 3H, OSi(CH3)2C(CH3)3)
0.93 (s, 9H, Si(CH3)2C(CH3)3); 1.45 (s, 18H, COOC(CH3)3); 1.82
(m, 1H, H3ax); 2.35-2.5 (m, 2H, H6ax, H3eq); 2.68 (m, 1H, H6eq);
2.85-3.0 (m, 1H, H1); 2.95 (m, 1H, H2); 4.24 (m, 1H, H4); 13C
NMR (50.3 MHz, CDCl3): -5.6, -4.7, 18.3, 25.6, 27.8, 34.5,
41.1, 44.2, 46.1, 75.2, 81.4, 171.4, 205.4.
Syn th esis of (1S,2S,4R)-4-Acetoxy-5-oxocycloh exa n e-
1,2-d ica r boxylic Acid Di-ter t-bu tyl Ester 18. To a solution
of ketone 15 (51 mg, 0.16 mmol, 1 mol equiv) and pyridine (65
µL, 0.8 mmol, 5 mol equiv) in dry CH2Cl2 (1 mL) were added
Ac2O (270 µL, 2.4 mmol, 15 mol equiv) and a catalytic amount
of DMAP. The solution was stirred at room temperature for
14: [R]20D: +7.5(c ) 1.32, CHCl3);22 Microanalysis: Found,
C 66.74%, H 8.13%; C25H36O7 requires C 66.94%, H 8.09%. 1H
NMR (300 MHz, C6D6): 1.4 (s, 18H, COOC(CH3)3); 1.65-1.9
(m, 2H, H3ax, H6ax); 2.0-2.3 (m, 5H, H3eq, H6eq, OCOCH3); 3.1-
3.4 (m, 2H, H1, H2); 3.55 (m, 1H, H4); 4.3 (m, 2H, CH2C6H5);
(23) This compound was prepared starting from a batch of 4 with
60% ee.

6216 J . Org. Chem., Vol. 66, No. 19, 2001
Bernardi et al.
ca. 1 h. After reaction completion, the organic phase was
washed first with saturated NaHCO3 and then with H2O, dried
with Na2SO4, and evaporated under reduced pressure. The
crude was purified by flash chromatography on silica gel
(hexane/AcOEt 8:2) to yield 49 mg of pure 18 (86%) as a white
solid. Microanalysis: Found, C 60.73%, H 7.85%; C18H28O7
1.55 (m, 2H, H3ax, H6ax); 2.2-2.35 (m, 2H, H3eq, H6eq); 2.5-2.6
(m, 2H, H1, H2); 3.4-3.55 (m, 2H, H4, H5); 13C NMR (50.3
MHz,CDCl3): 27.3; 34.3; 44.1; 74.0; 80.8.
19: [R]20D: -11.3 (c ) 1.8, EtOH);23 Microanalysis: Found,
C 68.01%, H 8.37%; C23H34O6 requires C 67.96%, H 8.43%. 1H
NMR (400 MHz, CDCl3): 1.2-1.4 (m, 2H, H3ax,H6ax); 1.45 (m,
18H, COOC(CH3)3); 2.25-2.5 (m, 2H, H3eq, H6eq); 2.5-2.6 (m,
2H, H1, H2); 3.25 (m, 1H, H4); 3.55 (m, 1H, H5); 4.48 (d, 1H,
CH2C6H5, J gem ) 11.4 Hz); 4.75 (d, 1H, CH2C6H5, J gem ) 11.4
Hz); 7.35 (s, 5H, C6H5). 13C NMR (75.5 MHz, CDCl3): 11.1; 27.9;
31.2; 33.8; 44.0; 44.3; 71.3; 72.5; 80.7; 80.8; 81.8; 127.8; 127.9;
128.7; 138.1; 172.7.
1
requires C 60.66%, H 7.92%. H NMR (200 MHz, CDCl3): 1.5
(s, 18H, COOC(CH3)3); 1.75-2.15 (m, 2H, H6ax, H3ax); 2.2 (s,
3H, OOCCH3); 2.45-2.6 (m, 2H, H6eq, H3eq); 2.7-3.2 (m, 2H,
H1, H2); 5.25 (dd, 2H, H4); 13C NMR (50.3 MHz, CDCl3): 20.5,
27.8, 33.4, 41.1, 43.7, 46.0, 74.3, 81.6, 170.9, 171.0, 200.7.
Gen er a l P r oced u r e for th e Red u ction of Keton es 15-
18. To a solution (or a suspension, if no AcOH is present) of
Na(OAc)3BH (117 mg, 0.55 mmol,5 mol equiv) in anhydrous
CH3CN (400 µL) at the indicated temperature was added a
solution of ketone (40 mg, 0.11, 1 mol equiv) in anhydrous
solvent (800µL). After the reaction mixture was stirred for the
indicated time at the indicated temperature (Table 3), it was
quenched by addition of 0.5 N aqueous sodium potassium
tartrate with vigorous stirring for 30 min. The mixture was
then diluted with AcOEt and washed with saturated NaHCO3.
The aqueous layer was back extracted several times with
AcOEt, and the combined organic layers were dried with
Na2SO4 and evaporated under reduced pressure. The crude
was purified by flash chromatography on silica gel to yield the
pure product.
20: 1H NMR (200 MHz, CDCl3): 0.1 (s, 6H, (CH3)2C(CH3)3-
Si); 0.9 (s, 9H, (CH3)2C(CH3)3Si); 1.45 (s, 18H, COOC(CH3)3);
2.05-2.15 (m, 2H, H3ax, H6ax); 2.24-2.35 (m, 2H, H3eq, H6eq);
2.42 (bs, 1H, OH); 2.55-2.64 (m, 2H, H1, H2); 3.34-3.5 (m,
2H, H4, H5).
21: [R]20D: -27.5 (c ) 1.02, CHCl3);23 Microanalysis: Found,
C 60.08%, H 8.28%; C18H30O7 requires C 60.32%, H 8.44%. 1H
NMR (200 MHz, CDCl3): 1.2-1.6 (m, 2H, H3ax, H6ax); 1.45 (s,
18H, COOC(CH3)3); 2.1 (s, 3H, OCOCH3); 2.2-2.4 (m, 2H, H3eq
,
H
6eq); 2.33-2.55 (m, 2H, H1, H2); 3.65 (m, 1H, H5); 4.65 (m,
1H, H4); 13C NMR (75.4 MHz, CDCl3): 21.1, 27.9, 31.7, 34.8,
43.9, 44.1, 71.6, 76.4, 80.9, 171.0, 172.3.
Ack n ow led gm en t. This work was supported in part
by COFIN2000 (prot. MM03155477)
3: [R]20D: +64.6 (c ) 0.7, EtOH);23 Microanalysis: Found,
C 60.97%, H 9.03%; C16H28O6 requires C 60.74%, H 8.92%. 1H
NMR (200 MHz, CDCl3): 1.45 (s, 18H, COOC(CH3)3); 1.25-
J O015570B