Chemoenzymatic synthesis of enantiopure α-substituted cyclohexanones from aromatic compounds

Article abstract of DOI:10.1016/j.tetasy.2005.02.012

A series of chiral α-substituted cyclohexanones have been synthesized from chemoenzymatically produced chlorocyclohexadienediol. These highly functionalized ketones can be used in the total synthesis of diverse natural products, such as bengamides. A study of the reactivity of α- chlorooxiranes, common intermediates in the synthetic scheme, showed that under nucleophilic opening conditions an intermediate chloroketone may or may not form, depending on the nature of the nucleophiles present in the reaction medium. The stereochemical outcome of this reaction is presented.

Full text of DOI:10.1016/j.tetasy.2005.02.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1393–1402
Chemoenzymatic synthesis of enantiopure a-substituted
cyclohexanones from aromatic compounds
*
´
German Fonseca and Gustavo A. Seoane
´ ´ ´ ´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de la Republica, General Flores 2124, Montevideo, Uruguay
Received 5 January 2005; accepted 7 February 2005
Abstract—A series of chiral a-substituted cyclohexanones have been synthesized from chemoenzymatically produced chlorocyclo-
hexadienediol. These highly functionalized ketones can be used in the total synthesis of diverse natural products, such as beng-
amides. A study of the reactivity of a-chlorooxiranes, common intermediates in the synthetic scheme, showed that under
nucleophilic opening conditions an intermediate chloroketone may or may not form, depending on the nature of the nucleophiles
present in the reaction medium. The stereochemical outcome of this reaction is presented.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Cl
1. Introduction
O
Cl
Pseudomonas
O
O
OH
OH
L
putida F39/D
a-Heterosubstituted ketones are important synthons
for the asymmetric syntheses of natural products, fine
chemicals, and medicines.1 Of them, a-hydroxy- and
a-aminoketones are the most used and, consequently,
numerous studies have been aimed at their stereoselec-
tive synthesis.2 The a-aminoketones are generally pre-
pared by the reaction of organometallic reagents with
a-amino acid derivatives.3 Other methods, such as the
Neber rearrangement, the reaction of a-haloketones
with amines, and the Dakin–West reaction are less used
because of diminished yields and/or poor control of re-
gio- and/or enantioselectivity.4 a-Hydroxyketones, on
the other hand, can be prepared by both oxidative and
non-oxidative methods.5 Among the latter transform-
ations, representative methods include the enzymatic
kinetic resolution of a-hydroxyketones and derivatives.6
1
2
L : O- or N- containing
functional group;
Cl
Scheme 1.
oxidation of aromatics has been extensively used in
organic synthesis.9
2. Results and discussion
2.1. Synthesis of ketones 3 and 4
Halogen-derived diene diols 1 are currently being stud-
ied in our laboratory as potential starting materials in
the asymmetric synthesis of bengamides and its deriva-
tives. The proposed retrosynthetic pathway shows that
both the polyoxygenated side chain and the e-caprolac-
tam nucleus can be obtained from compounds of type 1
In connection with our work on the biotransformation
of aromatic substrates,7 we herein report a chemoenzy-
matic route to a series of chiral a-heterosubstituted cyc-
lic ketones starting from monohalogenated aromatic
compounds such as chlorobenzene. These simple aro-
matics are converted to chiral cyclohexadienediols 1,
through whole-cell oxidation using Pseudomonas putida
F/39D,8 and then carried out to the desired ketones of
type 2 (Scheme 1). The methodology of the microbial
10
(Scheme 2).
Hydroxyketone 4 was obtained from chlorobenzene, via
diol 1, through a concise sequence (Scheme 3). Regiose-
lective reduction of 1 with a diimide prepared in situ11
gave diol 5, which was then protected to give acetonide
6. After treatment of vinylic chloride 6 with m-CPBA, a-
chlorooxirane 7 was obtained as a single isomer in 65%
*
Corresponding author. Tel.: +598 2 924 4066; fax: +598 2 9241906;
e-mail: gseoane@fq.edu.uy
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.02.012

1394
G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
O
O
O
H
H2N
H
O
O
O
O
N3
HO
N
O
OH OCH
3 H
N
H
R
OR
3
4
1
N
H
OR1 OH
O
Cl
Me(CH2)12COO
OH OCH3
OH
OH
OH
General structure of bengamides
OH OH
O
Scheme 2.
Cl
Cl
Cl
O
Cl
O
OH
OH
OH
O
O
O
HO
O
O
i
ii
i
O
OH
1
5
6
4
7
iii
iii
ii, iii
O
O
O
Cl
N
O
O
O
O
N
3
O
3
O
O
HO
O
O
iv
8
3
4
7
Scheme 4. Reagents and conditions: (i) NaHCO3, H2O, 100 ꢁC, 5 min,
85%; (ii) MsCl, Et3N, CH2Cl2, 80%; (iii) NaN3, DMF, rt, 40%.
Scheme 3. Reagents and conditions: (i) KO2CN@NCO2K, AcOH,
MeOH, rt, 90%; (ii) 2,2-dimethoxypropane, p-TsOH (catalytic),
acetone, rt, 95%; (iii) m-CPBA, CH2Cl2, rt, 65%; (iv) NaHCO3,
H2O, 100 ꢁC, 5 min, 85%.
obtained ketone 3 as the only azide containing product.
Even though the crude of reaction showed clean conver-
sion to the azide, the reaction mixture proved to be dif-
ficult to handle and azide 3 was obtained in an isolated
yield ranging between 30% and 40% (Scheme 4).
yield. The choice of the protecting group was determi-
nant in the selectivity of the epoxidation. Thus, whereas
the acetonide gave complete diastereoselection, the use
of silyl ethers and acylating agents, or even the free diol
5, resulted in mixtures of isomeric epoxides (vide infra).
We were concerned about the behavior of the acetonide
group in the subsequent hydrolysis of the halogenoepox-
ide since its instability under hydrolytic conditions in
related systems is known.12 However, after careful opti-
mization ketone 4 was obtained in 85% yield. The best
conditions proved to be refluxing 7 in aqueous bicarbon-
ate for 5 min. Prolonged reaction times resulted in a loss
of the acetonide integrity.
The discrepancy in the results of the chlorooxirane
openings raised some doubts on the stereochemical out-
come of this reaction and thus, the structure of ketone 4
had to be reconsidered. The point to be confirmed was
the configuration of the a-carbon bearing the free
hydroxyl group in 4.
2.2. Absolute configuration determination of ketone 4
The configuration at the a-carbon was determined by
converting 4 into a derivative of known configuration
prepared by independent methods. Thus, ketone 4 was
reduced with NaBH4 in MeOH to give a near 1:1 mix-
ture of diprotected tetraols 9 and 10, differing only at
the configuration of the new chiral stereogenic (epimers
at C3) (Scheme 5).
The stereochemistry of the newly formed hydroxyl in ke-
tone 4 was, in principle, assigned by analogy to that re-
ported for basic openings of a-chlorooxiranes in closely
related systems.12
With hydroxyketone 4 in hand, prepared in 50% overall
yield from diol 1, we turned our attention to the synthe-
sis of a-azidoketone 3 (Scheme 4). The free hydroxyl
group in 4 was transformed into a mesylate, and then
3 obtained through inversion with sodium azide in
DMF at room temperature. In our synthetic scheme
for the preparation of derivatives of bengamides, it
was convenient to have access to both epimers of the azi-
do group. To this end, chlorooxirane 7 was subjected to
opening conditions using sodium azide in DMF to
cleave the epoxide and produce the epimeric azide 8.
Unexpectedly, these conditions afforded the previously
On the other hand, two diprotected tetraols 11 and 12
(epimers at C4) were prepared starting from bromobenz-
ene, to be used as standards (Scheme 6). The configura-
tion of 11 and 12 was unequivocally set since both were
obtained from known compounds 16 and 1713 by olefin
reduction with concomitant dehalogenation, via cata-
lytic hydrogenation over Raney nickel. In addition, 11
1
is a known compound.14 When the H and 13C NMR
spectra of products 9 and 10 were compared against
those from standard diprotected tetraols 11 and 12,

G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
1395
X = Cl, Br
O
OH
Cl
O
X
O
O
O
HO
Cl
O
OH
9
O
O
HO
i
18
19
20
OH
+
Cl
Cl
OH
O
O
4
O
O
O
O
O
O
HO
HO
10
21
7
OH
Scheme 5. Reagents and conditions: (i) NaBH4, MeOH, rt, 40% 9 and
45% 10.
Scheme 7.
Compound 7 possesses a number of features that
deserve attention, namely its stability and capacity to
undergo an epoxide–carbonyl rearrangement. Halo-
geno-substituted oxiranes are generally unstable and
rearrange easily unless they are stabilized by suitable
substitution.17 Thus, chloroepoxide 18 reported by
Gasteiger rearranges at room temperature to 1918 and
also the more functionalized haloepoxides 20 are unsta-
ble at room temperature (Scheme 7).19 However, the
highly oxygenated chlorooxirane 21 reported by Hud-
licky is remarkably stable.12
Br
Br
OH
OH
O
O
i
13
1b
ii
v
Br
Br
O
O
O
O
O
O
14
15
We observed that compound 7 shows an intermediate
stability (t1/2 in toluene at 110 ꢁC is ca. 10 h). Regarding
the rearrangement (such as 18 to 19), the conversion of
a-halogenooxiranes to a-halocarbonyl compounds is
generally easy, as a consequence of the release of the
three-membered ring strain.17a Thus, 7 could function
as a synthon for the preparation of a-substituted cyclo-
hexanones, thus taking advantage of its high reactivity.
However, halogenooxiranes do not only offer higher
reactivity than a-halocarbonyl compounds, their reac-
tions may also follow different pathways. For example,
18 reacts with sodium methoxide in methanol to give
in quantitative yield, 2-methoxycyclohexanone,20
whereas 2-chlorocyclohexanone 19 affords products
from both Favorski rearrangements and attacks to the
carbonyl group.20 In addition, the reactions of phosph-
ites with a-chlorocarbonyl compounds give variable
amounts of Arbuzov- and Perkow-products, whereas
2-chlorooxiranes only give b-ketophosphonic acid
esters.21 Consequently, it seems to be necessary to gain
some insight into the mechanism of reaction of 7 to
the carbonyl compounds 3 and 4. In one of the most
complete studies about the mechanism of the epoxide–
carbonyl rearrangement, McDonald postulated that
the thermal rearrangement proceeds by disrotatory
Cb–O bond opening to an a-ketocarbonium–chloride
ion pair of type 22.22 Further kinetic attack of the chlo-
ride produces an axial C–Cl bond in the final a-chloro-
ketone (Scheme 8). If necessary, the chloride ion could
migrate from one face of the epoxide to the opposite
face to yield the product through an axial attack.22,23
To minimize the 1,3-diaxial interaction between the
incoming nucleophile and the protecting group, the pro-
posed mechanism yields chloroketone 23 from 7, as
shown. If strong nucleophiles are present, it would be
expected that they would compete with the chloride
ion for the carbocation.
iii
iii
Br
Br
O
O
O
O
HO
HO
OH
OH
17
16
iv
O
iv
O
O
O
HO
HO
OH
OH
11
12
Scheme 6. Reagents and conditions: (i) 2,2-dimethoxypropane,
p-TsOH (catalytic), acetone, rt, 95%; (ii) m-CPBA, CH2Cl2, rt, 80%;
(iii) 10% KOH, THF, reflux, 60%; (iv) H2/Raney-Ni, MeOH, rt, 50%;
(v) NBS, THF–H2O, rt; then 5 N NaOH, Et2O–H2O, 40 ꢁC, 55%.
the spectra of 9 turned out to be exactly the same as
those of 11, indicating that both compounds possess
the same relative configuration.15 Therefore, the relative
configuration at C4 in 9 was established, which is the
same as the configuration of the a-carbon bearing the
free hydroxyl group in 4. In this way, our original
assumption about the stereochemistry of ketone 4 was
confirmed. The identity of azidoketone 3 was also con-
firmed, since it was obtained from 4 through a simple
and well-documented inversion sequence.16
2.3. Nucleophilic opening of a-chlorooxirane 7
Considering the different stereochemical results
of the a-chlorooxirane openings, when using different
nucleophiles, to give 3 or 4, a closer examination of
the stereochemical course of this reaction was required.

1396
G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
Cl
Cl
O
O
OAc
O
O
i
i
OTHS
7
26
O
OAc
N3
Cl
O
H
O
O
OAc
OTHS
O
28
O
O
OTHS
27
O
Cl
22
Cl
Scheme 10. Reagents and conditions: (i) NaN3, acetone–H2O, rt, 85%
from 26, 65% from 27.
Cl
O
O
O
O
O
ketone 4 was obtained uneventfully after the treatment
of 23 with H2O–NaHCO3 at 100 ꢁC, whereas the condi-
tions used for azide displacement (NaN3 in DMF at
room temperature) did not afford a noticeable reaction
after 24 h. Heating the reaction mixture at 90 ꢁC instead
produced 50% of the ring-contracted product 25, via a
formal Favorski rearrangement (Scheme 9).18
Cl
O
23
24
O
O
Cl
Cl
O
O
O
O
Scheme 8.
In consequence, chloroketone 23 is not an intermediate
in the formation of azidoketone 3 from chlorooxirane 7,
in agreement with the proposed mechanism. Moreover,
the observed formation of the kinetic product resulting
from the axial attack of the nucleophile to the a-ketocar-
bonium–chloride ion pair is reinforced by the reactions
of isomeric chlorooxiranes 26 and 27 with sodium azide
(Scheme 10).25 When treated with sodium azide, both
compounds afforded the same azidoketone, 28, as the
only product. This outcome is again in agreement with
the proposed mechanism.
Our data are consistent with the proposed mechanism
(Scheme 8). In polar media with poor nucleophiles, such
as the conditions we used (H2 O–NaHCO3 at 100 ꢁC),
chlorooxirane 7 forms the chloroketone, which reacts
further to produce a-hydroxyketone 4 via an SN2 mech-
anism.16,24 On the other hand, in the presence of stron-
ger nucleophiles such as the azide ion in DMF, the
a-azidoketone 3 is obtained instead. This compound re-
sults from the kinetic attack of the azide ion to the car-
bocation forming an axial C–N bond in an analogous
way as for the formation of chloroketone 23. To test this
hypothesis, the corresponding chloroketone 23 was pre-
pared via thermal rearrangement of a-chlorooxirane 7
and subjected to the reaction conditions previously used
to obtain hydroxyketone 4 and azidoketone 3 (Scheme
9). Heating 7 at 110 ꢁC in DMF produced chloroketone
23 in moderate yield. Compound 23 can be easily depro-
tected in acidic conditions to give diol 34. As expected,
O
O
O
O
O
O
N3
HO
3
4
iv
i
O
O
OH
OH
O
O
N3
BzO
v
Cl
O
O
31
29
O
O
Cl
O
O
i
ii
23
7
O
O
O
ii
OTBS
OH
O
O
N3
TBSO
iv
O
O
O
OH
OH
Cl
N3
32
30
O
O
iii
iv
iii
34
3
O
OTBS
N3
N3
O
O
HO
O
O
OMOM
33
4
25
Scheme 11. Reagents and conditions: (i) Dowex 50 WX8-200, MeOH–
H2O, rt, 90%; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 85%; (iii)
chloromethylmethyl ether, DIPEA, CH2Cl2, rt, 85%; (iv) BzCl,
Et3N, CH2Cl2, rt, 70%; (v) TBSCl, imidazole, DMF, 4 ꢁC, 85%.
Scheme 9. Reagents and conditions: (i) 110 ꢁC, DMF, 50%; (ii) Dowex
50 WX8-200, MeOH–H2O, rt, 90%; (iii) NaHCO3, H2O, 100 ꢁC,
5 min, 75%; (iv) NaN3, DMF, 90 ꢁC, 50%.

G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
1397
2.4. Synthesis of other ketones
to the center line of the CDCl3 triplet (77.0 ppm). Ele-
mental analyses were performed by Atlantic Microlab
Inc., Norcross, GA, USA. Optical rotations were mea-
sured on a Zuzi 412 polarimeter using a 1 dm cell. [a]D
Considering the outcome of the reaction using an azide
ion, other N-containing nucleophiles were tested. Chlo-
rooxirane 7 was thus treated with succinimide, hydr-
azine hydrate, benzylamine, and methylamine in an
attempt to obtain the corresponding ketones. Unfortu-
nately in all cases, the reaction was extremely sluggish
and only decomposition products were obtained.
Although there is a precedent in the literature about
the opening of the halogenooxirane using sulfur con-
taining nucleophiles,18 Hudlicky had reported that the
use of amines as nucleophiles was unsuccessful and the
use of aqueous ammonia conducted to condensation
to form pirazines.12 On the other hand, regarding the
oxygen-containing series, hydroxyketone 4 is easily acyl-
ated or silylated. For example, either benzoylated deriv-
ative 29 or silyl ether 30 are made in high yield from 4
(Scheme 11). Ketone 3 can be easily deprotected to give
31. The diol functionality can also be selectively pro-
tected as shown.
values are given in units of 10ꢀ1 deg cm2 gꢀ1
.
Diols 1 and 1b were obtained by fermentation of the cor-
responding arenes.7 Analytical TLC was performed on
silica gel 60F-254 plates and visualized with UV light
(254 nm) and/or p-anisaldehyde in acidic ethanolic solu-
tion. Flash column chromatography was performed
using silica gel (Kieselgel 60, EM reagent, 230–400 mesh).
4.2. (1S,2S)-3-Chlorocyclohex-3-ene-1,2-diol, 5
To a solution of diol 1 (1.0 g, 6.8 mmol) in MeOH
(50 mL) at room temperature was added PAD (5.0 g,
27 mmol) and AcOH (5 mL) in portions. After 4 h of
stirring, the solvent was evaporated and the residue
was taken in Et2O. The ethereal solution was neutralized
with saturated aqueous NaHCO3, washed with brine
(2·), and dried over MgSO4. After filtration of the sol-
ids, the solvent was evaporated to give a residue, which
was chromatographed (silica, EtOAc/hexanes 1:1) to
yield 5 (0.9 g, 90%). This compound was fully character-
ized as the acetonide 6.
3. Conclusions
A series of enantiopure a-substituted cyclohexanones, 3,
4, 23, and 28–34, with potential applications as synthetic
intermediates have been successfully prepared through
simple reactions. The yields and the conciseness of the
sequences allow for the preparation of these synthons
in multigram quantities. Their use in the synthesis of
the nucleus of bengamides will be reported in due
course. All the preparations have a chlorooxirane as a
common intermediate, and the conditions for the epox-
ide opening using both nitrogen- and oxygen-containing
nucleophiles were investigated. Our results are consis-
tent with the proposed mechanism of an a-halogeno-
oxirane opening through an epoxide–carbonyl rear-
rangement. Depending on the presence of strong nucle-
ophiles in the reaction medium, an intermediate
haloketone may or may not form, since the nucleophiles
compete with the chloride ion to form kinetic products.
4.3. (1S,2S)-3-Chloro-1,2-O-isopropylidenecyclohex-3-
ene-1,2-diol, 6
To a solution of diol 5 (0.5 g, 3.4 mmol) in acetone
(10 mL) at rt was added 2,2-dimethoxypropane (0.4 g,
4.0 mmol) and a catalytic amount of p-TsOH. After stir-
ring for 1 h at rt, Amberlist A-21 (0.1 g) was added and
the mixture was stirred for an additional 15 min period.
The resin was filtered off and the resulting solution was
concentrated under reduced pressure to afford a light
yellow oil. Column chromatography (SiO2; hexanes/
EtOAc, 90:10) gave pure 6 as a colorless oil (0.6 g,
25
D
(c 1.1, acetone); IR (KBr) 2986, 2934, 1651, 1381,
95%). Rf = 0.4 (hexanes/EtOAc, 90:10); ½aꢁ ¼ þ64:6
1369, 1242, 1221 cmꢀ1 1H NMR (CDCl3) d 1.41 (s,
;
3H), 1.44 (s, 3H), 1.76 (m, 1H), 2.00 (m, 3H), 2.29 (m,
1H), 4.40 (m, 2H), 5.98 (m, 1H); 13C NMR (CDCl3) d
21.5 (CH2), 24.8 (CH2), 26.6 (CH3), 27.8 (CH3), 74.3
(CH), 75.6 (CH), 109.6 (C), 128.1 (CH), 131.3 (C); MS
(CI, CH4) m/z (relative intensity): 188 (3), 175 (53),
173 (100), 149 (51), 113 (65); EA calculated for
C9H13O2Cl: C, 57.30%, H, 6.95%. Found: C, 57.21%,
H, 7.11%.
4. Experimental
4.1. General
All non-hydrolytic reactions were carried out in a nitro-
gen atmosphere with standard techniques for the exclu-
sion of air. All solvents were distilled prior to use.
Melting points were determined on a Gallenkamp capil-
lary melting point apparatus and are uncorrected. Mass
spectra were recorded on a Shimadzu GC–MS QP 1100
EX instrument using the electron impact mode (70 or
20 eV) or chemical ionization (if indicated). Infrared
spectra were recorded either on neat samples (KBr
disks) or in solution on Perkin–Elmer 1310 or Bomem,
Hartmann & Braun FTIR spectrometers. NMR spectra
were obtained in CDCl3 on a Bruker Avance DPX-400
instrument. Proton chemical shifts (d) are reported in
ppm downfield from TMS as an internal reference,
and carbon chemical shifts are reported in ppm relative
4.4. (1S,2S,3R,4S)-3-Chloro-3,4-oxy-1,2-O-isopropyl-
idenecyclohexane-1,2-diol, 7
To a solution of 6 (0.1 g, 0.53 mmol) in CHCl3/CH2Cl2
(1:2, 20 mL) heated to reflux, was added m-CPBA (0.4 g,
2.2 mmol). After 5 h at reflux, the mixture was diluted
with CH2Cl2 (50 mL), and successively washed with
10% NaHSO3 (2 · 50 mL), 50% NaHCO3 (2 · 50 mL),
and brine (1 · 20 mL). The organic layer was dried
and concentrated in vacuo to give an oil, which was
purified by column chromatography (SiO2; hexanes/
EtOAc, 90:10) to afford 7 as a white solid (70 mg,

1398
G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
65%). Rf = 0.5 (hexanes/EtOAc, 90:10); mp = 71.0–
(CH), 80.0 (CH), 81.0 (CH), 110.6 (C), 201.9 (C). To a
solution of the mesyl derivative (69 mg, 0.26 mmol) in
DMF (15 mL) was added NaN3 (19 mg, 0.78 mmol).
After 3 h of stirring at rt, the reaction mixture was
quenched with water, and the mixture was extracted
with Et2O (3 · 20 mL), dried, and concentrated under
reduced pressure. The residue was purified by column
chromatography (SiO2; hexanes/EtOAc, 70:30) to give
25
D
73.3 ꢁC; ½aꢁ ¼ þ50:5 (c 0.62, acetone); IR (KBr)
2993, 2936, 2899, 1246, 1228, 1159, 1082, 903 cmꢀ1
;
1H NMR (CDCl3) d 1.41 (s, 3H), 1.52 (s, 3H), 1.66
(m, 1H), 1.70 (m, 1H), 1.95 (m, 1H), 2.21 (m, 1H),
3.58 (d, J = 3 Hz, 1H), 4.32 (m, 1H), 4.38 (m, 1H); 13C
NMR (CDCl3) d 18.3 (CH2), 18.6 (CH2), 25.8 (CH3),
27.4 (CH3), 62.1 (CH), 72.2 (CH), 74.5 (CH), 78.0 (C),
109.8 (C); MS (CI, CH4) m/z (relative intensity): 205
(8), 203 (39), 156 (36), 139 (100), 129 (26), 111 (33);
EA calculated for C9H13O3Cl: C, 52.82%; H, 6.40%.
Found: C, 51.55%; H, 5.50%.
3 as a white solid (21 mg, 40%). Rf = 0.6 (hexanes/
25
D
acetone); IR (KBr) 2995, 2986, 2878, 2106, 1726, 1381,
EtOAc, 1:1); mp = 66.5–70.0 ꢁC; ½aꢁ ¼ þ94:4 (c 0.30,
1226, 1022 cmꢀ1 1H NMR (CDCl3) d 1.41 (s, 3H),
;
1.45 (s, 3H), 2.08 (m, 2H), 2.15 (m, 1H), 2.34 (m, 1H),
3.91 (m, 1H), 4.41 (d, J = 5 Hz, 1H), 4.59 (m, 1H); 13C
NMR (CDCl3) d 24.1 (CH2), 26.1 (CH3), 27.1 (CH2),
27.2 (CH3), 65.0 (CH), 76.8 (CH), 79.7 (CH), 110.4
(C), 202.9 (C); MS (EI, 20 eV) m/z (relative intensity):
211 (20), 196 (21), 183 (3), 97 (49), 59 (100). Due to
the instability of the azido group, it was not possible
to obtain an analytically pure sample suitable for com-
bustion analysis.
4.5. (2S,3S,6R)-6-Hydroxy-2,3-isopropylidenedioxy-
cyclohexanone, 4
To an aqueous solution of NaHCO3 (18 mg, 0.21 mmol
in 5 mL) was added 7 (42 mg, 0.21 mmol) and the result-
ing solution was heated to reflux for 5 min. After cooling
down to rt, the solution was extracted with EtOAc
(3 · 10 mL), dried and concentrated under reduced pres-
sure to obtain a crude solid which was purified by col-
umn chromatography (SiO2; hexanes/EtOAc, 1:1) to
furnish 4 as a white solid (33 mg, 85%). Rf = 0.3 (hex-
anes/EtOAc, 1:1); mp = 112.3–114.9 ꢁC; IR (KBr) 3200
(broad), 2978, 2955, 2936, 1745, 1167, 1142,
4.7. (2S,3S,6S)-6-Chloro-2,3-isopropylidenedioxycyclo-
hexanone, 23
A stirred solution of epoxide 7 (71 mg, 0.35 mmol) in
DMF (3 mL) was heated to 110 ꢁC. After 30 min, the
reaction mixture was quenched with water, and the mix-
ture was extracted with Et2O (3 · 20 mL), dried, and
concentrated under reduced pressure. Purification of
the residue by column chromatography (SiO2; hexanes/
EtOAc, 70:30) gave 23 as a white solid (35 mg, 50%).
Rf = 0.6 (hexanes/EtOAc, 1:1); mp = 80–82 ꢁC; IR
1
1024 cmꢀ1; H NMR (CDCl3) d 1.40 (s, 3H), 1.43 (s,
3H), 1.85 (m, 1H), 2.02 (m, 1H), 2.23 (m, 2H), 3.61 (s,
broad, OH, 1H), 4.18 (dd, J = 12, 6 Hz, 1H), 4.45 (d,
J = 5 Hz, 1H), 4.60 (broad, 1H); 13C NMR (CDCl3) d
22.6 (CH2), 26.1 (CH3), 27.1 (CH3), 29.8 (CH2), 74.4
(CH), 77.5 (CH), 79.1 (CH), 110.3 (C), 208.9 (C); MS
(EI, 20 eV) m/z (relative intensity): 186 (5), 171 (34),
143 (80), 128 (29), 111 (17), 43 (100). Further character-
ization was done on the silylated derivative 30.
(KBr) 2950, 2938, 1743, 1157, 1136, 1010 cmꢀ1 1H
;
NMR (CDCl3) d 1.41 (s, 3H), 1.45 (s, 3H), 2.12 (m,
1H), 2.28 (m, 3H), 4.45 (m, 2H), 4.61 (m, 1H); 13C
NMR (CDCl3) d 25.3 (CH2), 26.2 (CH3), 27.1 (CH3),
32.1 (CH2), 62.3 (CH), 76.8 (CH), 80.2 (CH), 110.5
(C), 199.8 (C); MS (EI, 70 eV) m/z (relative intensity):
204 (2), 189 (28), 161 (36), 83 (19), 59 (34), 43 (100).
Further characterization was done on the deprotected
derivative 34.
4.6. (2S,3S,6S)-6-Azido-2,3-isopropylidenedioxycyclo-
hexanone, 3
From epoxide 7: To a solution of 7 (30 mg, 0.15 mmol)
in THF–EtOH–H2O (1:1:1, 20 mL) was added NaN3
(15 mg, 0.22 mmol) in one portion. After stirring at rt
for 6 h the mixture was diluted with H2O, extracted with
EtOAc (3 · 20 mL), dried, and concentrated under re-
duced pressure. The residue was purified by chromato-
graphy (SiO2; hexanes/EtOAc, 70:30) to give 3 as a white
solid (13 mg, 40%). From alcohol 4: To a stirred solu-
tion of 4 (22 mg, 0.12 mmol) in CH2Cl2 (5 mL) at
0 ꢁC, was added MsCl (67 mg, 0.59 mmol in 5 mL of
CH2Cl2), and Et3N (60 mg, 0.59 mmol in 3 mL of
CH2Cl2). The mixture was left to warm up to rt and
after 30 min at this temperature the reaction mixture
was quenched with water. The mixture was extracted
with CH2Cl2 (3 · 15 mL), dried, and concentrated under
reduced pressure to give an oil, which was further puri-
fied by chromatography (SiO2; hexanes/EtOAc, 1:1) to
afford the corresponding mesylate as a colorless oil
4.8. (2S,3S,6S)-6-Chloro-2,3-dihydroxycyclohexanone,
34
To a solution of 23 (90 mg, 0.44 mmol) in MeOH–H2O
(2:1, 30 mL) was added a spatula tip of acidic resin
(Dowex 50W8-200, previously washed with the same
solvent system, 3 · 10 mL). After 4 h of stirring, the re-
sin was filtered off and washed with EtOAc. The com-
bined organic layers were concentrated under reduced
pressure and the residue was purified by chromatogra-
phy (SiO2; hexanes/EtOAc, 1:1) to furnish 34 as a white
solid (70 mg, 95%). Rf = 0.2 (hexanes/EtOAc, 1:1);
25
D
IR (KBr) 3390 (broad), 2934, 1741, 1130, 1099, 1028,
½aꢁ ¼ þ81:6 (c 0.50, acetone); mp = 144.2–145.5 ꢁC;
1
1
(22 mg, 80%). Rf = 0.5 (hexanes/EtOAc, 1:1); H NMR
779 cmꢀ1; H NMR (DMSO-d6) d 1.80 (m, 1H), 1.90
(CDCl3) d 1.41 (s, 3H), 1.45 (s, 3H), 2.11 (m, 1H),
2.23 (m, 1H), 2.30 (m, 1H), 2.40 (m, 1H), 3.25 (s, 3H),
4.46 (d, J = 5 Hz, 1H), 4.58 (m, broad, 1H), 5.12 (dd,
J = 12, 6 Hz, 1H); 13C NMR (CDCl3) d 23.1 (CH2),
26.1 (CH3), 27.1 (CH3), 27.7 (CH2), 39.8 (CH3), 76.6
(m, 1H), 2.09 (m, 1H), 2.22 (m, 1H), 4.14 (s, broad,
1H), 4.27 (m, 1H), 4.91 (ddd, J = 7, 6, <1, Hz, 1H),
4.96 (d, J = 2 Hz, OH, 1H), 5.01 (d, J = 7 Hz, OH,
1H); 13C NMR (DMSO-d6) d 29.0 (CH2), 32.6 (CH2),
63.0 (CH), 73.1 (CH), 78.1 (CH), 202.2 (C); MS (EI,

G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
1399
20 eV) m/z (relative intensity): 164 (1), 128 (51), 120
(100), 82 (55), 57 (78); EA calculated for C6H9O3Cl:
C, 43.79%; H, 5.51%. Found: C, 43.92%; H, 5.84%.
centrated in vacuo to give an oil, which was purified by
column chromatography (SiO2; hexanes/EtOAc, 98:2) to
afford the isomeric epoxides 26 and 27. Compound 26
(colorless oil, 112 mg, 60%), Rf = 0.5 (hexanes/EtOAc,
25
D
2980, 2945, 1730, 1370, 1262, 1228, 1120, 1088,
4.9. (1R,2S)-1,2-Isopropylidenedioxycyclopentanecarb-
onylazide, 25
90:10); ½aꢁ ¼ þ57:8 (c 0.30, acetone); IR (KBr) 2996,
1
890 cmꢀ1; H NMR (CDCl3) d 0.08 (s, 3H), 0.12 (s,
To a solution of chloroketone 23 (20 mg, 0.10 mmol) in
DMF (5 mL) was added NaN3 (20 mg, 0.30 mmol) in
one portion at rt and then the mixture heated to
90 ꢁC. After 1 h of heating, the reaction mixture was
quenched with water, and the mixture extracted with
Et2O (3 · 20 mL), dried, and concentrated under re-
duced pressure. Purification of the residue by column
chromatography (SiO2; hexanes/EtOAc, 90:10) gave 25
as a colorless oil (11 mg, 50%). Rf = 0.4 (hexanes/
EtOAc, 90:10); IR (KBr) 2941, 2116, 1732, 1458,
3H), 0.83 (s, 6 H), 0.87 (s, 3H), 0.89 (s, 3H), 1.44 (m,
1H), 1.58 (m, 2H), 1.60 (m, 1H), 1.95 (m, 1H), 2.14 (s,
3H), 2.20 (m, 1H), 3.51 (m, 1H), 3.90 (m, 1H), 5.50 (d,
J = 3 Hz, 1H); 13C NMR (CDCl3) d ꢀ2.62 (CH3),
ꢀ2.59 (CH3), 18.8 (CH3), 18.9 (CH3), 20.6 (2 · CH3),
21.2 (CH3), 21.6 (CH2), 24.0 (CH2), 25.3 (C), 34.6
(CH), 61.7 (CH), 67.2 (CH), 72.1 (CH), 78.4 (C), 169.9
(C); MS (CI, CH4) m/z (relative intensity): 348 (16),
306 (16), 207 (12), 148 (20), 132 (100), 114 (28); EA cal-
culated for C16H29SiO4Cl: C, 55.07%; H, 8.38%. Found:
C, 54.93%; H, 8.29%. Compound 27 (white solid, 56 mg,
1
1385 cmꢀ1; H NMR (CDCl3) d 1.54 (s, 3H), 1.57 (s,
3H), 1.84 (m, 2H), 1.95 (m, 1H), 2.06 (m, 1H), 2.49
(m, 1H), 2.63 (m, 1H), 4.31 (t, 1H); 13C NMR (CDCl3)
d 17.9 (CH2), 25.9 (CH3), 27.2 (CH2), 27.1 (CH3), 37.2
(CH2), 81.8 (CH), 92.6 (C), 112.3 (C), 202.2 (C); MS
(EI, 20 eV) m/z (relative intensity): 183 (0.5, M+ꢀN2),
169 (7, M+ꢀN2ꢀCH2), 149 (7), 125 (8), 113 (21), 95
(30). Due to the instability of the azido group, it was
not possible to obtain an analytically pure sample suit-
able for combustion analysis.
30%), Rf = 0.4 (hexanes/EtOAc, 90:10); mp = 63–65 ꢁC;
25
½aꢁ ¼ þ32:3 (c 0.30, acetone); IR (KBr) 2992, 2978,
D
2947, 1726, 1356, 1270, 1230, 1140, 1100, 860 cmꢀ1
;
1H NMR (CDCl3) d 0.07 (s, 3H), 0.08 (s, 3H), 0.82 (s,
6 H), 0.87 (s, 3H), 0.88 (s, 3H), 1.43 (m, 1H), 1.59 (m,
1H), 1.66 (m, 1H), 1.96 (m, 1H), 2.13 (m, 1H), 2.19 (s,
3H), 3.50 (m, 1H), 3.87 (m, 1H), 5.52 (d, J = 3 Hz,
1H); 13C NMR (CDCl3) d ꢀ2.74 (CH3), ꢀ2.66 (CH3),
18.8 (CH3), 18.9 (CH3), 20.5 (2 · CH3), 21.2 (CH3),
22.2 (CH2), 24.3 (CH2), 25.3 (C), 34.5 (CH), 61.9
(CH), 68.2 (CH), 75.3 (CH), 75.7 (C), 170.5 (C); MS
(CI, CH4) m/z (relative intensity): 348 (5), 306 (17),
207 (10), 148 (22), 132 (100), 114 (37); EA calculated
for C16H29SiO4Cl: C, 55.07%; H, 8.38%. Found: C,
54.01%; H, 8.25%.
4.10. (1S,2R,3S,6S)-2-Chloro-6-(dimethylthexylsilyloxy)-
2,3-oxycyclohexyl acetate, 26 and (1S,2S,3R,6S)-2-
chloro-6-(dimethylthexylsilyloxy)-2,3-oxycyclohexyl
acetate, 27
To a stirred solution of 5 (0.100 g, 0.68 mmol) in DMF
(10 mL) cooled to 0 ꢁC, was added imidazole (100 mg,
1.46 mmol) and THSCl (1.33 g, 0.75 mmol) in portions.
The reaction mixture was kept at 4 ꢁC during 24 h and
then was diluted with Et2O (50 mL) and quenched with
water (40 mL). The organic layer was successively
washed with aqueous 10% CuSO4 (2 · 50 mL) and
brine, dried, and concentrated under reduced pressure
to give the monoprotected diol as an oily residue
(170 mg, 85%), which was pure enough for the next step.
The crude was dissolved in Ac2O (5 mL) and Et3N
(90 mg, 0.88 mmol) and a catalytic amount of DMAP
(5 mg) was added in portions. After 24 h of stirring at
rt, the reaction mixture was diluted with Et2O (50 mL)
and quenched by the addition of ice–H2O (30 mL).
The pH of the aqueous layer was made slightly basic (lit-
mus paper) by the addition of solid NaHCO3. The aque-
ous layer was extracted with Et2O (3 · 20 mL) and
the combined organic layer was successively washed
with aqueous 10% CuSO4 (3 · 50 mL) and brine
(2 · 30 mL), dried, and concentrated under reduced
pressure. The oily residue was purified by column chro-
matography (SiO2; hexanes/EtOAc, 90:10) to give the
diprotected diol in 90% yield. To a stirred solution of
the diprotected diol (175 mg, 0.53 mmol) in CH2Cl2
(50 mL) was added m-CPBA (110 mg, 0.63 mmol) in
portions. After 48 h at rt, the mixture was diluted with
CH2Cl2 (50 mL), and successively washed with 10%
NaHSO3 (2 · 50 mL), 50% NaHCO3 (2 · 50 mL), and
brine (1 · 20 mL). The organic layer was dried and con-
4.11. (2S,3S,6S)-2-Acetoxy-6-azido-3-(dimethylthexyl-
silyloxy)cyclohexanone, 28
From chlorooxirane 26: To a solution of 26 (30 mg,
0.09 mmol) in acetone–H2O (1:1, 10 mL) was added
NaN3 (15 mg, 0.22 mmol) in one portion. After 1 h of
stirring at rt the reaction mixture was quenched with
water, and the mixture extracted with Et2O
(3 · 10 mL), dried, and concentrated under reduced pres-
sure. Purification of the residue by column chromatogra-
phy (SiO2; hexanes/EtOAc, 90:10) gave 28 as a colorless
oil (26 mg, 85%). From chlorooxirane 27: To a solution
of 27 (30 mg, 0.09 mmol) in acetone–H2O (1:1, 10 mL)
was added NaN3 (15 mg, 0.22 mmol) in one portion.
After 2 days of stirring at rt, the reaction mixture was
quenched with water, and the mixture was extracted with
Et2O (3 · 10 mL), dried, and concentrated under re-
duced pressure. Purification of the residue by column
chromatography (SiO2; hexanes/EtOAc, 90:10) gave 28
as a colorless oil (20 mg, 65%). Rf = 0.5 (hexanes/EtOAc,
25
70:30); ½aꢁ ¼ þ89:7 (c 0.60, acetone); IR (KBr) 2993,
D
2985, 2950, 1748, 1732, 1388, 1250, 1115, 880 cmꢀ1; H
NMR (CDCl3) d 0.10 (s, 3H), 0.15 (s, 3H), 0.83 (s, 6
H), 0.86 (d, 3H), 0.87 (d, 3H), 1.59 (m, 1H), 1.96 (m,
2H), 2.18 (m, 5 H), 3.92 (t, J = 10 Hz, 1H), 4.45 (m,
1H), 5.12 (m, 1H); 13C NMR (CDCl3) d ꢀ2.58 (CH3),
ꢀ2.45 (CH3), 18.8 (CH3), 19.0 (CH3), 20.3 (CH3), 20.6
(CH3), 20.9 (CH3), 25.4 (C), 25.4 (CH2), 27.6 (CH2),
34.5 (CH), 65.1 (CH), 72.5 (CH), 78.8 (CH), 170.1 (C),
1

1400
G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
197.5 (C). Due to the instability of the azido group, it was
not possible to obtain an analytically pure sample suit-
able for combustion analysis.
(Dowex 50W8-200, previously washed with the same
solvent system, 3 · 10 mL). After 4 h of stirring, the re-
sin was filtered off and washed with EtOAc. The com-
bined organic layers were concentrated under reduced
pressure and the residue was purified by chromatogra-
phy (SiO2; hexanes/EtOAc, 1:1) to afford 34 as a white
solid (73 mg, 90%). Rf = 0.2 (hexanes/EtOAc, 1:1);
mp = 121–123 ꢁC; IR (KBr) 3370 (broad), 2990, 2982,
4.12. (2S,3S,6R)-6-Benzoyloxy-2,3-isopropylidenedioxy-
cyclohexanone, 29
To a stirred solution of 4 (40 mg, 0.22 mmol) in CH2Cl2
was added Et3N (44 mg, 0.44 mmol), followed by ben-
zoyl chloride (45 mg, 0.33 mmol). After 2 h of stirring
at rt the reaction mixture was diluted with CH2Cl2,
washed successively with 5% HCl (2 · 10 mL), water
(2 · 10 mL), and brine (1 · 10 mL), dried and concen-
trated under reduced pressure. The residue was purified
by chromatography (SiO2; hexanes/EtOAc, 70:30) to
1
2880, 1738, 1395, 1240 cmꢀ1; H NMR (CDCl3) d 1.90
(m, 1H), 2.20 (m, 3H), 2.74 (s, OH, 1H), 3.87 (s, OH,
1H), 4.00 (m, 1H), 4.21 (m, 1H), 4.40 (m, 1H); 13C
NMR (CDCl3) d 26.5 (CH2), 27.7 (CH2), 64.7 (CH),
72.5 (CH), 77.4 (CH), 205.1 (C). Due to the instability
of the azido group, it was not possible to obtain an ana-
lytically pure sample suitable for combustion analysis.
give 29 as a colorless oil (44 mg, 70%). Rf = 0.7 (hex-
25
D
anes/EtOAc, 1:1); ½aꢁ ¼ þ61:8 (c 0.40, acetone); IR
4.15. (2S,3S,6S)-6-Azido-2-(tert-butyldimethylsilyloxy)-
3-hydroxycyclohexanone, 32
(KBr) 2986, 2937, 1751, 1720, 1290, 1124 cmꢀ1
;
1H
NMR (CDCl3) d 1.42 (s, 3H), 1.46 (s, 3H), 2.17 (m,
1H), 2.27 (m, 2H), 2.42 (m, 1H), 4.54 (d, J = 4 Hz,
1H), 4.62 (m, 1H), 5.40 (m, 1H), 7.46 (m, 2H), 7.59
(m, 1H), 8.09 (m, 2H); 13C NMR (CDCl3) d 23.6
(CH2), 26.4 (CH3), 26.7 (CH2), 27.4 (CH3), 75.9 (CH),
77.2 (CH), 80.2 (CH), 110.6 (C), 128.8 (CH), 129.8
(CH), 130.3 (CH), 133.7 (CH), 165.8 (C), 201.7 (C);
MS (EI, 20 eV) m/z (relative intensity): 290 (3), 247
(10), 105 (100), 99 (11), 77 (20). Due to its instability,
it was not possible to obtain an analytically pure sample
of this compound.
To a stirred solution of 31 (30 mg, 0.16 mmol) in
CH2Cl2 (3 mL) was added 2,6-lutidine (90 mg,
0.85 mmol) and TBSOTf (90 mg, 0.34 mmol) in portions
at 0 ꢁC. The reaction was then left to stand at rt for 4 h,
after which time was diluted with Et2O (10 mL) and
quenched with 10% HCl (20 mL). The aqueous layer
was extracted with Et2O (2 · 10 mL) and the combined
organic layer washed with brine (2 · 10 mL), dried,
and concentrated under reduced pressure. The solid res-
idue was purified by column chromatography (SiO2;
hexanes/EtOAc, 90:10) to give 32 as a white solid
(41 mg, 85%). Rf = 0.8 (hexanes/EtOAc, 1:1);
mp = 110–112 ꢁC; IR (KBr) 3290 (broad), 2980, 2965,
4.13. (2S,3S,6R)-6-(tert-Butyldimethylsilyloxy)-2,3-
isopropylidenedioxycyclohexanone, 30
2949, 2860, 1740, 1390, 1210, 890 cmꢀ1 1H NMR
;
To a stirred solution of 4 (40 mg, 0.22 mmol) in DMF
(0.5 mL) cooled to 0 ꢁC, was added imidazole (50 mg,
0.73 mmol) and TBSCl (95 mg, 0.66 mmol) in portions.
The reaction mixture was kept at 4 ꢁC for 24 h and then
diluted with Et2O (10 mL) and quenched with water
(20 mL). The aqueous layer was extracted with Et2O
(2 · 10 mL) and the combined organic layer was succes-
sively washed with aqueous 10% CuSO4 (2 · 10 mL)
and brine, then dried and concentrated under reduced
pressure. The oily residue was purified by column chro-
matography (SiO2; hexanes/EtOAc, 90:10) to give 30 as
(CDCl3) d 0.06 (s, 3H), 0.20 (s, 3H), 0.93 (s, 9H), 1.84
(m, 1H), 2.16 (m, 3H), 2.71 (s, OH, 1H), 3.81 (m, 1H),
4.24 (m, 2H); 13C NMR (CDCl3) d ꢀ5.2 (CH3), ꢀ4.2
(CH3), 18.7 (C), 26.1 (3 · CH3), 26.9 (CH2), 27.5
(CH2), 65.3 (CH), 74.3 (CH), 78.8 (CH), 202.5 (C).
Due to the instability of the azido group, it was not pos-
sible to obtain an analytically pure sample suitable for
combustion analysis.
4.16. (2S,3S,6S)-6-Azido-2-(tert-butyldimethylsilyloxy)-
3-(methoxymethyloxy)cyclohexanone, 33
a white solid (56 mg, 85%). Rf = 0.3 (hexanes/EtOAc,
25
D
IR (KBr) 2986, 2945, 2926, 2899, 2855, 1736, 1253,
90:10); mp 96.0–100.1 ꢁC; ½aꢁ ¼ þ64:2 (c 0.30, acetone);
To a stirred solution of 32 (25 mg, 0.09 mmol) in
CH2Cl2 (5 mL) was added diisopropylethylamine
(13 mg, 0.1 mmol) and MOMCl (8 mg, 0.1 mmol) in
portions. After 12 h of stirring at rt, the solution was
concentrated under reduced pressure and the residue
was taken in Et2O (10 mL). The solution was extracted
with 10% HCl 10% (20 mL) and the aqueous layer was
extracted with Et2O (2 · 10 mL). The combined organic
layer was successively washed with 5% NaHCO3
(2 · 10 mL) and brine (2 · 10 mL), dried, and concen-
trated under reduced pressure. The oily residue was
purified by column chromatography (SiO2; hexanes/
EtOAc, 90:10) to afford 33 as a colorless oil (25 mg,
85%). Rf = 0.3 (hexanes/EtOAc, 90:10); IR (KBr) 2995,
2970, 2935, 2820, 1742, 1385, 1263, 1140, 1085,
1
794 cmꢀ1; H NMR (CDCl3) d 0.04 (s, 3H), 0.13 (s,
3H), 0.92 (s, 9H), 1.38 (s, 3H), 1.44 (s, 3H), 2.02 (m,
3H), 2.25 (m, 2H), 4.21 (m, 1H), 4.34 (d, J = 4 Hz, 1H),
4.54 (m, 1H); 13C NMR (CDCl3) d ꢀ4.9 (CH3), ꢀ4.1
(CH3), 18.9 (C), 23.7 (CH2), 26.2 (3 · CH3), 26.4 (CH3),
27.4 (CH3), 30.9 (CH2), 76.5 (CH), 77.3 (CH), 80.2
(CH), 110.3 (C), 206.5 (C). MS (EI, 70 eV) m/z (relative
intensity): 285 (10), 245 (8), 244 (19), 243 (100), 185 (50),
167 (18), 157(38), 129 (51); EA calculated for C15H28O4Si:
C, 59.96%; H, 9.39%. Found: C, 59.21%; H, 9.35%.
4.14. (2S,3S,6S)-6-Azido-2,3-dihydroxycyclohexanone,
31
1
795 cmꢀ1; H NMR (CDCl3) d 0.04 (s, 3H), 0.17 (s,
To a solution of 3 (90 mg, 0.43 mmol) in MeOH/H2O
(2:1, 30 mL), was added a spatula tip of acidic resin
3H), 0.94 (s, 9H), 1.84 (m, 1H), 2.16 (m, 3H), 3.37 (s,
3H), 3.80 (m, 1H), 4.25 (m, 2H), 4.67 (d, J = 4 Hz,

G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
1401
1H), 4.82 (d, J = 4 Hz, 1H); 13C NMR (CDCl3) d ꢀ5.1
(CH3), ꢀ4.2 (CH3), 18.8 (C), 26.1 (3 · CH3), 27.2
(CH2), 27.8 (CH2), 55.9 (CH3), 65.2 (CH), 79.1 (CH),
79.4 (CH), 97.0 (CH2), 202.1 (C). Due to the instability
of the azido group, it was not possible to obtain an ana-
lytically pure sample suitable for combustion analysis.
Prof. T. Hudlicky for providing the cultures of P. putida
F39/D.
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1981, 103, 6157; (b) Roemmele, R. C.; Rapoport, H.
J. Org. Chem. 1989, 54, 1866; (c) Klix, R. C.; Chamberlin,
S. A.; Bhatia, A. V.; Davis, D. A.; Hayes, T. K.; Rojas,
F. G.; Koops, R. W. Tetrahedron Lett. 1995, 36, 1791.
4. (a) OÕBrien, C. Chem. Rev. 1964, 64, 81; (b) Jung, M. E.;
Love, B. E. J. Chem. Soc., Chem. Commun. 1987, 1288; (c)
Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969,
8, 981.
5. (a) Kawai, Y.; Hida, K.; Tsujimoto, M.; Kondo, S.;
Kitano, K.; Nakamura, K.; Ohno, A. Bull. Chem. Soc.
Jpn. 1999, 72, 99; (b) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y.
Tetrahedron Lett. 1998, 39, 7819; (c) Adam, W.; Fell, R.
T.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahedron: Asym-
metry 1998, 9, 4117; (d) Horiuchi, C. A.; Takeda, A.; Chai,
W.; Ohwada, K.; Ji, S.-J.; Takahashi, T. T. Tetrahedron
Lett. 2003, 44, 9307.
4.17. (1S,2S,3S,4R)-1,2-O-Isopropylidenecyclohexane-
1,2,3,4-tetraol, 9 and (1S,2S,3R,4R)-1,2-O-isopropylid-
enecyclohexane-1,2,3,4-tetraol, 10
To a solution of ketone 4 (0.4 g, 2.2 mmol) in MeOH
(30 mL) was added NaBH4 (90 mg, 2.4 mmol) in por-
tions at rt. After 15 min of stirring, the mixture was con-
centrated under reduced pressure and the residue was
taken in Et2O (50 mL). The organic layer was succes-
sively washed with 10% NaHCO3 (2 · 25 mL) and brine
(2 · 10 mL), dried, and concentrated under reduced
pressure. The residue was purified by column chroma-
tography (SiO2; EtOAc) to afford 9 and 10 as white sol-
1
ids. Compound 9 (0.26 g, 40%), Rf = 0.2 (EtOAc); H
NMR (CDCl3) d 1.37 (s, 3H), 1.54 (s, 3H), 1.72 (m,
2H), 1.80 (m, 1H), 2.16 (m, 1H), 3.28 (s, OH, 2H),
3.42 (m, 1H), 3.52 (m, 1H), 3.90 (m, 1H), 4.26 (m,
1H); 13C NMR (CDCl3) d 24.1 (CH2), 26.6 (CH3),
26.9 (CH2), 28.7 (CH3), 71.8 (CH), 74.4 (CH), 78.7
(CH), 81.2 (CH), 109.5 (C); Compound 10 (0.29 g,
1
45%), Rf = 0.3 (EtOAc); H NMR (CDCl3) d 1.36 (s,
3H), 1.57 (s, 3H), 1.67 (m, 2H), 1.81 (m, 1H), 1.90 (m,
1H), 2.75 (s, OH, 1H), 3.05 (s, OH, 1H), 3.75 (m, 1H),
3.88 (m, 1H), 4.24 (m, 1H), 4.33 (m, 1H); 13C NMR
(CDCl3) d 23.0 (CH2), 25.7 (CH3), 26.1 (CH2), 28.0
(CH3), 69.1 (CH), 69.3 (CH), 73.7 (CH), 77.0 (CH),
109.4 (C).
4.18. (1R,2R,3S,4R)-1,2-O-Isopropylidenecyclohexane-
1,2,3,4-tetraol, 12
To
a
solution of vinylic bromide 1713 (95 mg,
0.26 mmol) in MeOH (50 mL) was added Raney-Ni
(under aqueous NaOH, 100 mg). Hydrogen was bub-
bled through the mixture for 1 min to evacuate the air
and then the mixture was stirred in a hydrogen atmo-
sphere. After 30 min, the catalyst was filtered off and
the solution was concentrated under reduced pressure.
The residue was taken in EtOAc (40 mL), washed with
brine (2 · 20 mL), dried, and concentrated under re-
duced pressure to give a crude which was purified by
chromatography (SiO2; EtOAc) to furnish 12 as a white
solid (40 mg, 50%). Rf = 0.2 (EtOAc); 1H NMR (CDCl3)
d 1.28 (m, 1H), 1.34 (s, 3H), 1.49 (s, 3H), 1.62 (m, 1H),
1.83 (m, 1H), 1.96 (m, 1H), 3.20 (s, OH, 2H), 3.54 (m,
1H), 3.82 (m, 1H), 4.21 (m, 1H), 4.42 (m, 1H); 13C
NMR (CDCl3) d 26.1 (CH2), 26.5 (CH3), 27.5 (CH2),
28.0 (CH3), 70.2 (CH), 74.6 (CH), 75.1 (CH), 78.1
(CH), 109.7 (C).
6. (a) Adam, W.; Diaz, M. T.; Fell, R. T.; Saha-Moller, C. R.
Tetrahedron: Asymmetry 1996, 7, 2207; (b) Tanyeli, C.;
Turkut, E.; Akhmedov, I. M. Tetrahedron: Asymmetry
2004, 15, 1729.
7. (a) Schapiro, V.; Cavalli, G.; Seoane, G. A.; Faccio, R.;
Mombru, A. W. Tetrahedron: Asymmetry 2002, 13, 2453;
(b) Brovetto, M.; Schapiro, V.; Cavalli, G.; Padilla, P.;
Sierra, A.; Seoane, G. A.; Suescun, L.; Mariezcurrena, R.
New J. Chem. 1999, 23, 549.
8. (a) Gibson, D. T.; Koch, J. R.; Kallio, R. E. Biochemistry
1968, 7, 2653; (b) Gibson, D. T.; Hensley, M.; Yhosiota,
H.; Mabry, T. J. Biochemistry 1970, 9, 1626; (c) Gibson,
D. T.; Kobak, V. M.; Davis, R. E.; Garza, A. J. Am.
Chem. Soc. 1973, 95, 4120.
9. Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichim. Acta
1999, 32, 35, and references cited therein.
10. Whereas no reports have been found on the use of this
strategy to prepare the nucleous. The synthesis of a
representative side chain of bengamides has recently been
disclosed starting from bromobenzene: Banwell, M. G.;
Mc Rae, K. J. J. Org. Chem. 2001, 66, 6768.
Acknowledgements
11. Hamersma, J. W.; Snyder, E. I. J. Org. Chem. 1965, 30,
3985.
Support of this work from the Universidad de la Repu´b-
lica-CSIC (Uruguay) and PEDECIBA (Project URU/
97/016) is gratefully acknowledged. The authors thank
12. Hudlicky, T.; Mandel, M.; Rouden, J.; Lee, R. S.;
Bachmann, B.; Dudding, T.; Yost, K. J.; Merola, J. S.
J. Chem. Soc., Perkin Trans. 1 1994, 1553.

1402
G. Fonseca, G. A. Seoane / Tetrahedron: Asymmetry 16 (2005) 1393–1402
13. Compound 16: Banwell, M. G.; Mc Rae, K. J. J. Org.
Chem. 2001, 66, 6768; compound 17: Hudlicky, T.;
Restrepo-Sanchez, N.; Kary, P. D.; Jaramillo-Gomez, L.
M. Carbohydr. Res. 2000, 324, 200.
19. Ganey, M. V.; Padykula, R. E.; Berchtold, G. A. J. Org.
Chem. 1989, 54, 2787.
20. Gasteiger, J.; Herzig, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 868.
14. Hu, Y.; Meuillet, E. J.; Quiao, L.; Berggren, M. M.;
Powis, G.; Kozikowski, A. P. Tetrahedron Lett. 2000, 41,
7415.
21. Gasteiger, J.; Herzig, C. Tetrahedron Lett. 1980, 21, 2687.
22. McDonald, R. N.; Cousins, R. C. J. Org. Chem. 1980, 45,
2976.
15. Also, the NMR spectra of 10 are different than those of 12.
16. (a) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry, Part A, 4th ed.; Plenum: New York, 2000, pp
300–302; (b) Bordwell, F. G.; Brannen, W. T. J. Am.
Chem. Soc. 1964, 86, 4645.
17. (a) McDonald, R. N. In Mechanisms of Molecular
Migrations; Thyagarajan, B. S., Ed.; Wiley: New York,
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CA, 1972, pp 313–314.
23. McDonald, R. N.; Tabor, T. E. J. Am. Chem. Soc. 1967,
89, 6573.
24. The preparation of a closely related a-hydroxyketone was
reported by Hudlicky et al.12 by heating an a-chloroox-
irane in water in the presence of aluminum oxide.
25. Oxiranes 26 and 27 were prepared in a similar way as 7 by
epoxidation of a differentially protected vinylic chloride.
The replacement of the acetonide by other protecting
groups allows for the preparation of isomeric chloro-
oxiranes due to the diminished facial selectivity of the
system.
18. Gasteiger, J.; Herzig, C. Tetrahedron 1981, 37, 2607.