Selectivity in the halohydroxylation of cyclohexadienediols

Article abstract of DOI:10.1016/j.tet.2007.02.109

The halohydroxylation of a number of cyclohexadienediol derivatives has been investigated. The selectivity of the reaction as a function of the type of substituent on the diene, protecting group of the diol functionality, halonium donor, medium polarity,

Full text of DOI:10.1016/j.tet.2007.02.109

Tetrahedron 63 (2007) 4095–4107
Selectivity in the halohydroxylation of cyclohexadienediols
*
Ignacio Carrera, Margarita C. Brovetto and Gustavo Seoane
Departamento de Quꢀımica Orgaꢀnica, Facultad de Quꢀımica, Universidad de la Repuꢀblica, C.C. 1157, Montevideo, Uruguay
Received 30 December 2006; revised 21 February 2007; accepted 23 February 2007
Available online 28 February 2007
Abstract—The halohydroxylation of a number of cyclohexadienediol derivatives has been investigated. The selectivity of the reaction as
a function of the type of substituent on the diene, protecting group of the diol functionality, halonium donor, medium polarity, and temperature
is described. Best selectivity is obtained for iodohydrin formation. The course of the reaction for these dienic systems is heavily dependent on
steric factors.
Ó 2007 Elsevier Ltd. All rights reserved.
CH3
2
CH3
HO CH3
HO
1. Introduction
3
4
5
O
O
O
O
O
OsO4
NIS,
H2O
In connection with our ongoing efforts to prepare marine
natural products from cis-cyclohexadienediols of microbial
origin, we have tested a number of electrophilic additions
to these dienes. This type of compounds, readily available
in our laboratory by biotransformation of substituted benz-
enes,1 presents interesting features for the study of these re-
actions on dienes. The protected cis-diol functionality and
the presence of a conjugated dienic system including di-
and trisubstituted double bonds allows for the consideration
of both the stereo- and regioselectivity of the reactions, re-
spectively. We have previously disclosed the osmylation
and the iodohydroxylation of a number of these dienic com-
pounds.1,2 Both reactions have found repeated application in
organic synthesis.3,4 They are widely used in industrial pro-
cesses for the synthesis of drugs, pharmaceuticals, agro-
chemicals, pigments, and photographic materials.5
O
1
HO
6
major
Scheme 1.
major
1
I
For other electrophilic additions, such as oxymercuration12
and halohydroxylation,9,14 the volume of available data is
more limited. The results of the cohalogenation study for
the dienic system and some mechanistic considerations are
described here.
2. Results and discussion
2.1. Regioselectivity: effect of the substituents on the
diene
The study was started by varying the electronic environment
around the dienic system. Thus, the halohydroxylations of
electron deficient (2, R1¼Br), alkyl substituted (1 and 3,
R1¼Me and Et, respectively), and electron rich dienes (4,
R1¼OMe) were studied (Table 1).
In our dienic system, both reactions showed different (oppo-
site) regioselectivity, whereas the osmylation took place
preferentially in the more electron rich double bond of 1,1
the iodohydrin was formed exclusively on the disubstituted
,
olefin (Scheme 1).y 2 Motivated by the difference in selectiv-
ity we decided to investigate further the cohalogenation of
these dienes, studying mainly the effect of the source of
halonium ion and the steric requirements for both regio-
and stereoselectivity. In conjugated dienic systems the pos-
sibility of 1,2- versus 1,4-addition is another variable to be
considered, which has been studied mainly for addition of
halogens (particularly in brominations and chlorinations)
and electrophilic hydrogen.6,7–13
There are a number of reports on halohydrin formation for
electron deficient dienes such as 2,15,16 the attack being
always on the more electron rich olefin, following the gener-
alized Markownikoff’s rule.
The halohydroxylation was performed using two different
halogens, under standard conditions for each one, namely
acetyl hypoiodite (Prevost reaction)17 and/or N-iodosuccin-
ꢀ
imide (NIS)–H2O for iodine,18 and N-bromosuccinimide
(NBS)–H2O for bromine.19 The regioselectivity was investi-
gated by considering two parameters: the ratio of electro-
philic attack on trisubstituted versus disubstituted olefin,
* Corresponding author. Tel.: +598 2 924 4066; fax: +598 2 924 1906;
e-mail: gseoane@fq.edu.uy
The numbering scheme shown in Scheme 1 for the parent compound is
y
used throughout the text for all compounds.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.109

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I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
Table 1. Effect of the substituents on the diene
R1
R1
R1
R1
R1
HO
I
AcO
+
O
O
O
O
O
O
O
O
O
O
Conditions
R2O
+
+
R2O
X
X
Br
5a R1= Br, R2=Ac, X=I
6a R1= Br, R2=H, X=I
7a R1= Br, R2=H, X=Br
8a R1= Me, R2=Ac, X=I
10a R1= Me, R2=H, X=I
5b R1= Br, R2=Ac, X=I
6b R1= Br, R2=H, X=I
7b R1= Br, R2=H, X=Br
8b R1= Me, R2=Ac, X=I
10b R1= Me, R2=H, X=I
1 R1= Me
2 R1= Br
3 R1= Et
9
R1= Me
4 R1= OMee
11a R1= Me, R2=H, X=Br 11b R1= Me, R2=H, X=Br
12 R1=Me
16 R1=Et
13a R1= Et, R2=Ac, X=I
15a R1= Et, R2=H, X=Br
13b R1= Et, R2=Ac, X=I
15b R1= Et, R2=H, X=Br
14 R1= Et
Entry
R1
Conditionsa
Timeb (h)
Product, yield (%)
Tri/di-Olefinc
Ratio a/b
1,4- versus
1,2-addition
Overall
yield (%)
1
2
3
4
5
6
7
8
9
10
Br
Br
Br
Me
Me
Me
Et
AcOAg, I2, AcOH
2
2
2
1.8
1
1
2
1.5
5a, 89
6a, 75
7a, 60
8a, 57
10a, 79
11a, 59
13a, 60
15a, 52
5b, 1
0
0
0
0.16
0
0
0.07
0
89
0
0
0
0
0
0.37
0
90
85
74
74d
94
88
72
75
NIS, DME–H2O (1:1)
NBS, DME–H2O (1:1)
AcOAg, I2, AcOH
NIS, DME–H2O (1:1)
NBS, DME–H2O (1:1)
AcOAg, I2, AcOH
NBS, DME–H2O (1:1)
AcOAg, I2, AcOH
NBS, DME–H2O (1:1)
6b, 10
7b, 14
8b, 3
10b, 15
11b, 5
13b, 7
15b, 7
7.5
4.3
9.6
5.3
2.0
9.3
2.4
9, 10
12, 24
14, 5
16, 16
Et
0.27
OMee
OMee
Aromatization products
Polymerization products
a
All reactions were run from 0 ꢀC to rt.
Time for disappearance of starting material (1 mmol). Conversion data points were taken after every 10 min by TLC.
Ratio of addition to trisubstituted versus disubstituted olefin.
Includes 4% of diiodohydrin derivatives, see Table 3.
b
c
d
e
Used as unprotected diol, because of its unstability toward acetonization.
ꢀ
and the ratio of 1,4- versus 1,2-addition. In addition the
stereoselectivity was defined by the ratio of electrophilic
attack on the a-face to the attack on the b-face (ratio a/b).
Iodoacetate 5a, the major product from Prevost reaction on
2, presented a coupling pattern for H-6 (geminal to the
iodine) consisting of a triplet with J 7.8 Hz, suggesting
a trans-diaxial relationship with its neighbors. The same
type of pattern is observed for all the major stereoisomers
of halohydrins, vide infra.
The reaction of compound 2 proceeded in good to excellent
yields for both halogens, with exclusive selectivity toward
the disubstituted olefin (entries 1–3).
The results were completely different for electron rich di-
enes (entries 9 and 10). Strongly electron donor groups,
namely the methoxyl in 4, activated the compound in such
a way that polymerization and/or aromatization took place.
For this system, less active electrophilic donors would be
needed in order to obtain the desired addition products.z
The stereoselectivity was excellent for iodine (entries 1 and
2) and good for bromine (entry 3). The mixture of iodoace-
tates 5a and 5b was very difficult to separate by chromato-
graphy, in contrast to the readiness of separation of the
iodo- and bromohydrin 6 and 7. Therefore, the minor stereo-
isomer 5b was characterized as the iodohydrin 6b, after hy-
drolysis of the acetate and further separation. The regio- and
stereochemistry of the products was established by 1H NMR
analysis and, in all cases, the structures were confirmed by
base-catalyzed conversion to the known bromoepoxides
17a and 17b (Scheme 2).15b,20
For alkyl-substituted dienes such as 1 and 3, different results
were found. In this type of dienes the regioselectivity was
complicated by the presence of electrophilic attack on either
olefin and also by the competition between 1,2- and 1,4-
ꢀ
addition. Prevost reaction of 1 and 3 afforded products
resulting from electrophilic attack on either olefin, but 1,4-
addition was not observed (entries 4 and 7). Conversely,
the reaction of these dienes with NBS–H2O gave products
from 1,2- and 1,4-addition, although electrophilic attack
on the trisubstituted olefin was not found (entries 6 and 8).
The stereochemistry of the 1,4-addition products, 12 and
16, indicates that they arise exclusively from b-halonium
ions. Also, in agreement with the results for electron defi-
cient dienes of type 2, better stereoselectivity was obtained
for iodine, which gave higher a/b ratios than bromine under
Br
Br
O
O
O
NaOH,
DME-H2O (3:1)
O
HO
HO
O
O
X
6a, X= I
7a, X= Br
17b
Br
Br
O
O
O
NaOH,
DME-H2O (3:1)
O
X
6b, X= I
7b, X= Br
17a
z
For diene 4, all attempts to control the reaction failed, the overoxidation
being the main outcome even when reacted with NBS and 1 equiv of
H2O in DME at ꢁ10 ꢀC.
Scheme 2.

I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
4097
ꢀ
both Prevost and NIS–H2O conditions (entries 4, 5, and 7 vs
increasing amounts of shift reagent (higher nEu/n12). In ad-
dition, H-2, H-6, and CH3 are more sensitive to europium co-
ordination than H-1, H-4, and H-5. This is in agreement with
the proposed a stereochemistry for the tertiary alcohol, on
the opposite face to the O-containing protecting group. If
this alcohol was in b-position, the complexation would
take place only on this face, and a negligible variation in
chemical shifts for H-1, H-2, and H-6 would have been
seen (Scheme 3).
6 and 8). Similar to the electron deficient case, the halohy-
drins from 1 or 3 with N-haloimides were readily separable
by column chromatography.
The structures of the products were determined as follows.
For the products resulting from 1,2-addition to the disubsti-
tuted olefin (8, 10, 11, 13, and 15), the major diastereomer
presented the signal corresponding to the H-6 (geminal
to the halogen, at d 4.00, 4.21, 4.06, 4.03, and 4.05 for
8a, 10a, 11a, 13a, and 15a, respectively) as a doublet of
doublets, with coupling constants between 6.9 and 9.7 Hz
in all the cases, suggesting a trans-diaxial relationship
between this proton and their immediate neighbors. In the
analogous spectra of the minor isomers the magnitudes of
the vicinal couplings associated with the signals due to
H-6 (at d 4.13, 4.08, 4.00, 4.13, and 3.98 for 8b, 10b, 11b,
13b, and 15b, respectively) suggest a trans-diaxial arrange-
ment between these protons and H-5 (J between 7.4 and
9.3 Hz), together with a cis-relationship to H-1 (J between
2.2 and 2.3 Hz). Then, both types of halohydrins correspond
to the structures of the known iodohydrins 10a and 10b.2
The observed difference in the product distribution for halo-
hydroxylation of dienes 1 and 3 deserves some comments.
There are a number of reports about the dependence of the
reactions between dienes and positive halogen donors on
the steric requirements of the substrate.6 Specifically, Dalton
found a strong dependence of the regiochemistry and rate of
addition on the bulkiness of the substrate,14,21 and also sev-
eral authors refer to this point in their work (see Section 2.4).
The ethyl derivative, 3,22 was prepared to probe this phe-
nomenon in our dienic system. Then, diene 3 was reacted
ꢀ
with acetyl hypoiodite (Prevost) and NBS to give the corre-
sponding cohalogenated products (Table 1, entries 7 and 8).
The products 9 and 14, resulting from electrophilic attack
on the trisubstituted olefin, presented a noticeable homo-
allylic coupling between H-1 and H-4 of 1–5J 1.9 Hz, for
both cases, which is due to a cis-di-pseudoaxial relationship
between these protons, presumably through a twisted-boat
conformation.
The yields were comparable, although somewhat lower than
those for the methyl substituted diene 1. The stereoselectiv-
ity (ratio a/b) remained unchanged, within the experimental
error (entries 7 vs 4 and 8 vs 6). However, the regioselectiv-
ity displayed by 3 was higher for the two parameters con-
sidered (ratios 1,4/1,2-addition and tri/disubstituted olefin
attack). In this context, the relative amount of 1,4-addition
product in 3 diminished considerably for bromine. For
iodine, it is worth to mention that no 1,4-addition products
were observed in the reaction of 1 or 3. Regarding the 1,4-
addition products, the introduction of a bulkier substituent
in the dienic system decreased the attack at that position, re-
sulting in a higher ratio. Thus, for diene 1 the b-bromonium
ion gave a ratio of 1,2- to 1,4-addition of 11b–12¼0.21; di-
ene 3, in turn, gave a ratio of 1,2- to 1,4-addition more than
doubled, 15b–16¼0.44.
Regarding the 1,4-addition products (12 and 16), the cou-
pling between H-1 and H-6 (J 2.0 and 1.9 Hz, respectively)
suggests a cis-relationship between them. In addition the ter-
tiary methyl group shows a low enhancement (<1%) in the
NOE experiment when one of the methyls from the isopro-
pylidene group is irradiated, thus suggesting a b-disposition
for the tertiary methyl group on C-3. To confirm the
stereochemistry at C-3, an experiment with NMR shift
reagents (using tris(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-
4,6-octanedionato) europium) was performed on 12. The
plot of the molar ratio europium reagent/compound 12
versus chemical shift shown in Scheme 3 presents the pro-
gressive deshielding of all the protons on the ring with
For iodine, although no 1,4-products were detected, a further
difference in regioselectivity was observed, depending on
the attack on the tri- or disubstituted olefin. Again, ethyl de-
rivative 3 was more selective, since the ratio for the attack on
the trisubstituted over the disubstituted olefin, which was
0.16 for 1, dropped to 0.07 for 3, representing less than
one half of the former value.
Eu
O
1
H
O
4
2
O
CH3
OH
Br
1H
5
4
O
H
CH3
OH
Br
6
It seems that a more crowded steric environment on C-3 re-
tards attack on the trisubstituted olefin (for both 1,2- and 1,4-
addition). These findings are in agreement with the proposed
strong dependence of the reaction on steric requirements,
which makes the preferred site of attack the more accessible,
although less electron rich, disubstituted olefin of the dienic
system.
5
H
H
6
H
Eu
2
0.8
0.4
0
4
CH3
2
1
5
2.2. Stereoselectivity: effect of the protecting group
6
To study the stereoselectivity of the halohydroxylation reac-
tion several dienes with protecting groups of different sizes
on the diol functionality were prepared (Table 2). To avoid
regioselectivity issues the reactions were performed on
ppm
1.2
3.2
5.2
Scheme 3.

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I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
Table 2. Effect of the protecting group
Cl
Cl
Cl
Conditions
OR
OR
OR
+
OR´
OR´
OR´
HO
HO
18 R=R'= H
19 R=R'= Ac
Br
Br
22a R=R´=Ac,
23a R=R´=C(CH3)2
22b R=R´=Ac,
23b R=R´=C(CH3)2
20 R=R´= C(CH3)2
21 R= COCF3, R'= THS
Entry
Protecting groups
Conditionsa
Product, yield (%)
Ratio a/b
2.6
6.9
Overall yield (%)
1
2
3
R¼R0¼Ac
NBS, acetone–H2O (4:1)
NBS, DME–H2O (1:1)
NBS, DME–H2O (1:1)
22a, 54
23a, 48
22b, 21
23b, 7
75
55
R, R0¼C(CH3)2
R¼COCF3, R0¼THS
Decompositionb
a
All reactions were run from 0 ꢀC to rt.
Decomposition products with losses of the protecting groups.
b
derivatives of chlorocyclohexadienediol 18,23 an electron
deficient diene analogous to 2.
formation preferentially occurred on the a-face, with the
exception of the reaction of chlorohydrin formation, which
gave roughly equal amounts of products resulting from a-
and b-chloronium ions (entry 4, Table 3). The ratio a/b in-
creased with the size of the halogen considered, reaching
preparatively useful values (greater than 4) for the iodine
atom (entries 1 and 2, Table 3). On the other hand, the ratio
of 1,4- to 1,2-addition increased significantly from the iodo-
hydrins, where no 1,4-addition products were detected, to
bromo- and chlorohydrin (0.37 and 1.0, respectively, entries
3 and 4, Table 3). The stereochemistry of the 1,4-addition
products (12 and 25) indicates that they arise exclusively
from b-halonium ions. This preference is more noticeable
in chlorohydrins: all of the products derived from the
b-chloronium ion correspond to 1,4-addition (25, entry 4,
Table 3). For the case of bromohydrins, in turn, the 1,4-
addition product, 12, represents 82% of the products arising
from the b-bromonium ion (11b and 12), and finally both
methods of iodohydrin formation did not afford any 1,4-
addition products. Again, the most selective halogen is the
iodine, giving high preference for a-halonium ions.
The easily prepared diacetate 192 gave low yields of bromo-
hydrins (less than 35%) when treated with NBS in DME–
H2O and, therefore, several different solvent systems were
tried. Best results were obtained in acetone–H2O (4:1),
yielding a ratio a/b¼2.6 with an overall yield of 75%.
This low stereoselectivity was greatly improved by using
the bulkier isopropylidene group in 20,24a with the former
solvent system, which afforded a ratio a/b¼6.9 in 55% yield
(Table 2, entry 2).24b
Finally, the differently protected compound 2125a decom-
posed under the reaction conditions, presumably via NBS-
mediated oxidation of the silylated protecting group.25b
From these results, we decided to carry out further reactions
using the large isopropylidene protecting group.
2.3. Effect of the halonium source
To complete the study on the effect of the halonium source,
the reaction of diene 1 with N-chlorosuccinimide (NCS) was
also tried, in addition to the other N-halosuccinimides and
ꢀ
the Prevost reaction. All of them are presented in Table 3,
for comparison. In all cases studied the halonium ion
The yields of bromo- and iodohydroxylation were good to
excellent; conversely, the chlorohydroxylation gave a dis-
appointing 30% yield after disappearance of starting diene,
together with aromatization products.
Table 3. Effect of the halonium source
CH3
CH3
CH3
CH3
CH3
HO
X
RO
O
O
O
O
O
O
O
O
O
Conditions
+
+
+
O
RO
RO
X
X
X
1
8a R= Ac, X= I
10a R= H, X= I
11a R= H, X= Br
24a R= H, X= Cl
8b R= Ac, X= I
10b R= H, X= I
11b R= H, X= Br
9 R= Ac, X= I
12 X= Br
25 X= Cl
Entry
Conditionsa
Timeb
(h)
Product, yield (%)
Ratio
a/b
1,4- Versus
1,2-addition
Overall
yield (%)
1
2
3
4
AcOAg, I2, AcOH
1.8
1
1
40
8a, 57
8b, 3
9, 10
—
—
12, 24
25, 15
26, 4c
—
—
—
9.6
5.3
2.0
1.0
0
0
0.37
1.0
74
94
88
30
NIS, DME–H2O (1:1)
NBS, DME–H2O (1:1)
NCS, DME–H2O (1:1)
10a, 79
11a, 59
24a, 15
10b, 15
11b, 5
—
—
—
—
a
All reactions were run from 0 ꢀC to rt.
Time for disappearance of starting material.
Mixture of monoacetates from dihalohydrins, see Scheme 4.
b
c

I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
4099
1.6 Hz
H
It is interesting to note that when the iodohydroxylation was
ꢀ
performed with acetyl hypoiodite (Prevost reaction) another
Br
H
product was observed, 26, isolated as an inseparable 1.5:1
mixture of monoacetates (Scheme 4). This product resulted
from electrophilic attack on both double bonds, always
through the corresponding b-iodonium ion. The regiochem-
istry obtained can be rationalized invoking, for the second
attack, an anchimeric assistance of the allylic pseudoequato-
rial acetate introduced in the first attack, in a similar way as
reported by Sweeney for iodohydrin formation on acyloxy-
cyclohexenes.26 The order of events is not relevant to the
final stereochemistry, giving the same mixture of monoace-
tates 26. However, according to the isolated products result-
ing from mono-iodohydroxylation, it seems likely that the
first step was the formation of iodoacetate 8b, and further
attack afforded 26.
O
Me
H
HO
O
HO
8.7 Hz
Br
H
3.3 Hz
5.1 Hz
H
11.1 Hz
27
Scheme 5.
Table 4. Effect of the medium polarity
CH3
X
CH3
CH3
CH3
HO
O
O
O
O
O
O
O
Conditions
HO
+
+
O
HO
X
Br
1
10a X= I
10b X= I
CH3
CH3
I
I
11a X= Br
11b X= Br
12
HO
AcO
HO
O
O
Entry Conditionsa
H2O (equiv)/
1 (equiv)
Product, ratiob
O
O
AcO
I
I
1.5 : 1
26
1c
2c
3c
4
5
6
NIS, 1:1 DME–H2O
NIS, 25:1 DME–H2O
NIS, 140:1 DME–H2O
140
10
2
10a, 84 10b, 16
10a, 92 10b, 8
10a, 97 10b, 3
11a, 64 11b, 6 12, 30
11a, 67 11b, 7 12, 26
11a, 69 11b, 6 12, 25
—
—
—
Scheme 4.
NBS, 1:1 DME–H2O 140
NBS, 5:1 DME–H2O 50
NBS, 25:1 DME–H2O 10
Next, the effect of the temperature over the reaction of N-
haloimides on diene 1 was studied, performing the iodo-
and bromohydroxylation at ꢁ30, 0, and 50 ꢀC.
a
b
c
All reactions were run in 5 mL of DME–H2O as specified, from 0 ꢀC to rt.
Determined by integration of 1H NMR signals in the reaction mixture.
From Ref. 2.
Within the experimental error the product distribution, deter-
mined by integration of the 1H NMR signals in the mixtures
of reaction, did not vary with temperature. Also, to study the
behavior toward equilibration, one of the mixtures of reac-
tion, corresponding to entry 3, Table 3, was left reacting
overnight once the starting material had disappeared, the
starting product ratio being 11a–11b–12¼67:6:27, as deter-
As previously reported,2 the stereoselectivity of the iodohy-
droxylation showed a modest enhancement for the a-attack
with decreasing amounts of water, which could be ascribed
to the diminished polarity of the solvent system. For the
bromohydroxylation, however, the data are not conclusive,
showing a slight variation in the same sense, although within
the experimental error. Regarding the regioselectivity, the
change in the ratio of 1,4- to 1,2-addition is small, within
the experimental error.
1
mined by H NMR. In this event, a new product was ob-
served, which was identified as a dibromohydrin, 27. The
final ratio of products was 11a–11b–12–27¼59:6:27:8, sug-
gesting that the new product resulted exclusively from reac-
tion of bromohydrin 11a and no equilibration occurred. To
confirm this further, major bromohydrin 11a was isolated
and subjected to the same reaction conditions overnight.
Neither compound 12 nor 11b was detected, thus confirming
the absence of equilibration among bromohydrins under
these conditions. The spectroscopic data of dibromohydrin
27 were in full accord with the proposed structure. The
magnitudes of the observed coupling between H-6 and its
immediate neighbors (J6,1 8.7 Hz and J6,5 11.1 Hz) suggest
a trans-diaxial relationship between this proton and
H-1 and H-5. A long distance coupling between H-2 and
H-4 (1–4J 1.6 Hz) is suggestive of a cis-diequatorial arrange-
ment on a cyclohexane ring (Scheme 5). The formation of
product 27 can be rationalized through a second electro-
philic attack on the major product, 11a, producing a b-
bromonium ion that opens to afford the Markownikoff’s
product.
2.4. Mechanistic considerations
The results presented herein indicate that halohydroxylation
of substituted cyclohexadienediols proceeds with variable
selectivity.
The selectivity of alkene additions using electrophilic halo-
gen donors depends on a number of factors including, in ad-
dition to the structure of reactants and nature of the solvent,
the bridged or unbridged structure of the intermediate halo-
nium ion, its association with nucleophilic partners, and its
lifetime.27,6 The controversial question about the equilib-
rium between bridged and unbridged structures of the ionic
intermediates is further complicated in conjugated dienes by
the possibility of resonance and extensive charge delocaliza-
tion into the second double bond, thus allowing the compe-
tition between 1,2- and 1,4-addition and also between each
particular double bond for addition.
The effect of modifying the solvent polarity was also inves-
tigated, by changing the amount of H2O in mixtures DME–
H2O. Data for the reaction of diene 1 with NBS or NIS in
mixtures of DME and decreasing amounts of water are
presented in Table 4.
Regarding the cyclohexadienediols, there is a clear-cut dif-
ference between the additions to electron deficient dienes
such as 2, 19, and 20, and to alkyl-substituted ones, namely

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I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
1 and 3. For dienes 2, 19, and 20 the addition took place ex-
clusively on the disubstituted and more electron rich olefin.
This behavior was also observed for other electrophilic
reactions, such as osmylations, thus suggesting that the
halogeno-olefin is too deactivated to undergo this type of
additions.1 For epoxidations, the use of peroxyacids pro-
duced exclusively the disubstituted epoxide,28,29 but stron-
ger conditions using permanganate ions result in attack on
the entire dienic system (possibly through a cyclic 1,4
intermediate).30
chloronium ion. For cyclohexene-derived syn-halonium
ions, molecular models indicate a good antiperiplanar orbital
overlap between the C–H and C–X s*-bonds (Scheme 7).
The preference for the pseudoequatorial disposition of the
allylic substituent during halohydrin formation in acyloxy-
cyclohexenes was recently mentioned.26
X
H
O
O
Me
Me
H
O
O
eq
ax
X
On the other hand, dienes 1 and 3 show a more complicated
behavior toward electrophilic additions. The formal HOX
addition afforded products resulting from attack on one
or both olefins. Reactions of NIS–H2O, NBS–H2O, and
NCS–H2O with dienes 1 and 3 gave addition products
derived from initial electrophilic attack exclusively on the
disubstituted, less electron rich, double bond. The reaction
H
H
Scheme 7.
In the reaction of dienes such as 1 and 3 with N-halosuccin-
imides, a preference for the formation of products resulting
from the a-halonium ion is observed, which increases with
the size of the halogen atom (ratio a/b, Tables 1 and 3). Con-
sidering the steric crowding given by the acetonide on the
b-face of the dienic system, this selectivity in reactions
involving the attack of bulky halogen ions is expected. What
is surprising, however, is the low values obtained for the ratio
of a/b products in the chloro- and bromohydrin cases. It
seems that other factors are involved, including the general-
ized anomeric effect. This effect, that favors b-halonium
ions, is stronger for the more electronegative halogen atoms
and may account for the diminished selectivity found for
these two halogens.
ꢀ
under Prevost conditions, however, produced a mixture of
products resulting from attack on both double bonds. This
reaction is, therefore, regiochemically less selective than
the corresponding iodohydroxylation using NIS.
The regiochemical outcome of the electrophilic additions
using N-halosuccinimides is different from other related
additions, namely osmylation and peroxyacid epoxidation.
In these latter reactions the electrophilic attack on diene 1
took place mainly on the trisubstituted, more electron rich,
olefin, giving products 28 and 29 (Scheme 6).1,28 Clearly,
there are differences between these electrophilic additions
and the formal addition of HOX to olefins. Some of them
will be discussed below.
The dependence of electrophilic additions on steric effects is
related to the nature of the incoming electrophile and the
structure of the transition state. Thus, whereas the bromina-
tions are independent of the steric effects (higher rates in
more highly substituted olefins),12 the sensitivity of halohy-
droxylations to steric effects is well documented.9,14,21,35
For unsymmetrical dienes, in particular, a large influence
of the steric factor was described by Dalton, affecting the
rate and the selectivity (regiochemistry) of addition.14,21
CH3
HO CH3
OsO4(cat)
O
O
HO
O
+
NMO
CH3
HO
2 : 1
28
O
ref 1
OH
O
O
CH3
O
O
O
MCPBA
(exclusive)
The halohydroxylation of dienes 1 and 3 proved to be highly
dependent on steric factors, which made the products result-
ing from a-halonium ions to predominate (Tables 1 and 3).
In addition to this effect on the stereoselectivity, the replace-
ment of the methyl group on C-3 of diene 1 for the ethyl
group in diene 3 enhanced the regioselectivity of the reaction
(Table 1). The bulkier ethyl group effectively retarded the at-
tack (both electrophilic and nucleophilic) on the trisubsti-
tuted olefin, producing higher preference for reaction at
the disubstituted olefin and slower overall reaction rates
(Table 1, entries 4–8). As expected, the ratio a/b did not
change, within the experimental error, when passing from
1 to 3 (Table 1, entries 4–8).
ref 28
29
Scheme 6.
Our system also presents allylic substitution, which adds
another parameter to be considered for the selectivity. The
regio- and stereochemistry of electrophilic addition to allylic
double bonds has been modeled by Kahn et al. some years
ago.31 Those models indicate, for allylic hydroxy or alkoxy
substituent, a preference for the addition of the electrophile
syn to the substituent, which is based on electrostatic argu-
ments.32 This selectivity for the syn adduct was recently
rationalized by Ganem et al.,33 mentioning that, for 1,2-ad-
dition of HOX to alkenes, an additional stabilization of the
intermediate syn-halonium ion might be obtained through
a hyperconjugative generalized anomeric effect.34 In this
case, if the polar allylic substituent is oriented in pseudo-
equatorial position, the corresponding pseudoaxial allylic
C–H s-bond can serve as an electron releasing group to sta-
bilize the electronegative halonium ion by back-donation
into the C–X s*-bond. This effect would be more pro-
nounced in the formation of the more electronegative
In the theoretical model developed by Kahn for electrophilic
additions,31 the experimental results for osmium tetroxide
dihydroxylation and peroxyacid epoxidation of allylic ethers
showed discrepancies with the proposed model (i.e., the ma-
jor addition product is not syn to the allylic substituent). For
dienes 1 and 3, we also obtain differences in the selectivity,
but this time related specifically to the regiochemistry of ad-
dition. The preference of osmium tetroxide and peroxyacids
to attack the more electron rich olefin of diene 1, which is

I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
4101
opposite to that for halohydroxylations, points out the differ-
ence between the operating mechanisms and seems to indi-
cate that the former reactions are closer to brominations,
where steric factors are less important due to a reactant-
like transition state.12
were derived exclusively from the b-halonium ions, the
a-ions giving only 1,2-addition. The more delocalized
chloronium gives the highest ratio of 1,4-addition products,
followed by bromine, and iodine does not give 1,4-addition
products (Table 3). The exclusive 1,2-addition resulting
from a-halonium ions (Table 1, entries 4–8, and Table 3)
could be explained by a minimum delocalization of charge
and the absence of SN20 due to deficient overlap (and also
due to the steric hindrance of the b-face, in case of anti
attack).
Another point deserving attention is the 1,2- versus 1,4-addi-
tion in the dienic system. Regardless of the existence of
a bridged or unbridged ion, the actual intermediate would
be more reactive with a better overlap of the orbitals in-
volved, namely the C–X bond and the p cloud of the vicinal
double bond. Inspection of molecular models of our dienic
system indicates that the geometrical requirements for
a good overlap are more easily met when the halonium ion
is on the b-face. In this arrangement, better overlap is ob-
tained for the b-halonium ion with both the neighbor olefin
and the vicinal pseudoaxial C–H (generalized anomeric
effect), through a twisted-boat conformation (see Scheme 7).
This qualitative picture agrees with preliminary theoretical
calculations, performed at semiempirical level using the
AM1 Hamiltonian.36 The structures of a- and b-halonium
ions were modeled for the bromonium and chloronium
cases, using semiempirical methods. The reliability of the
data obtained using this type of methods is moderate, but
the information is easily obtained and is useful to indicate
qualitative trends, which was the purpose for its use. The
calculations showed a large difference between the bond
distances of the C–X bonds for each particular halonium
ion, being longer for the C–X bond next to the double
bond (Scheme 8).
In all the cases of 1,4-addition, the nucleophilic attack on C-
3 is always a, suggesting an effective shielding of the b-face
by the protecting group or an anti attack on the b-halonium
ion through an SN20 reaction.
Another observation is related to the difference in the mode
of attack on dienes 1 and 3 to give 1,2-addition products
ꢀ
when using Prevost or NXS–H2O conditions. The regio-
selectivity of the Prevost reaction is intermediate between
ꢀ
the NXS-mediated halohydroxylations and other electro-
philic additions (osmylations and epoxidations), giving mi-
nor products resulting from attack on the more electron
rich trisubstituted olefin. Also, there is a dependence on
the steric environment of the olefin, since the attack on the
more hindered trisubstituted olefin of diene 3 represents
less than one half of the attack on the corresponding olefin
in 1 (Table 1, entries 7 vs 4). Undoubtedly, several factors
influence the mechanism of formation and collapse of the
halonium ions and, therefore, determine the regiochemical
ratios of products. Such factors may involve differences in
the association state and bridging of the halonium ions and
differences in anion structures and reactivities.27,31,38
These factors play different roles in both types of halo-
hydroxylations.
3
3
d C5-Cl= 2.607 A
d C6-Cl= 1.759 A
Δ = 0.848 A
Δ/d = 0.39
d C5-Br= 2.736 A
d C6-Br= 1.948 A
Δ = 0.788 A
Δ/d = 0.34
O
O
O
O
5
5
6
6
1
1
Cl
Br
alpha-Chloro
alpha-Bromo
In addition, in an attempt to better understand the parameters
affecting the selectivity in this dienic system, some reactions
were performed at different temperatures and in solvent
mixtures of different polarities.
3
3
d C5-Cl= 2.667 A
d C5-Br= 2.827 A
O
O
O
O
5
5
d C6-Cl= 1.748 A
Δ = 0.919 A
Δ/d = 0.42
d C6-Br= 1.941 A
Δ = 0.886 A
Δ/d = 0.37
6
6
1
1
Cl
Br
All conditions tried involved polar media, although of vari-
able polarity ranging from aqueous mixtures (mainly with
DME) to AcOH. The data from Table 4 show that for
NBS- and NIS-mediated halohydroxylations in polar media,
the polarity of the solvent may vary significatively without
causing major changes in the product distribution. The effect
could be analyzed taking into account two factors, the
stereo- and the regioselectivity of attack. The stereoselectiv-
ity is dependent primarily on the degree of dissociation of
the incoming electrophile and the possibility of interaction
with the directing group. The dissociation of the electrophile
is related to the polarity of the medium, which governs its
effective size, and thus a less polar system favors the
electrophilic attack from the less hindered a-face. Although
satisfactory for the reaction of NIS (Table 4, entries 1–3),
the dependence of the electrophile’s size with polarity can-
not explain alone the small variation observed for NBS
(Table 4, entries 4–6). In this latter case, the solvent may
influence another feature of the system, namely the relative
stability of the isomeric halonium ions via the anomeric
effect. The polarity affects the magnitude of the anomeric
effect, which is more noticeable for the more polar halonium
beta-Bromo
beta-Chloro
Scheme 8.
Because of dispersal of charge in the allylic system, the bond
between the halogen and C-5 is weakened so that an unsym-
metrical intermediate is formed. The relative difference be-
tween the C–X bonds for each structure is given by the D/
d parameter, which takes into account the different size of
the halogens. This parameter indicates that the chloronium
is the more unsymmetrical ion, suggesting a higher delocal-
ization of charge. This is more noticeable for the b-halonium
ions, in which both halogens display higher values. Then,
these results are in agreement with the fact that bridged halo-
nium ions are better supported by halogen atoms following
the order iodine>bromine>chlorine,37 and also indicate
that bridging is less effective (producing more charge dis-
persal) for the b-halonium ions.
The experimental results seem to agree with this description.
For the three halogens studied, the 1,4-addition products

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I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
ion (bromonium) in low polarity media,34a thus favoring the
b-bromonium ion with decreasing polarity. For the bromo-
hydroxylation, then, the effect of polarity on the electro-
phile’s size (higher a/b ratio with decreasing polarity) is
counter balanced by its effect on the stability of the b-bro-
monium ion, favoring the attack on the b-face with dimin-
ished polarity. The overall result of these opposite trends is
a small variation in the a/b ratio (Table 4, entries 4–6). Re-
garding the regioselectivity, our data are in agreement with
the proposed no dependence of bridging with the polarity
of the solvent.6,27
preliminary calculations. In addition, the nucleophilic
attack on the intermediate halonium ion is always a,
in agreement with an ion with charge dispersal in the
allylic system and a hindered b-face, thus favoring an
a-nucleophilic attack. A less hindered anti nucleophilic
opening of a bridged b-halonium ion, via an SN20 mech-
anism, cannot be ruled out, although this is less likely
since it would imply greater proportion of this mecha-
nism in chloronium (and also bromonium) ions, which
are those with lower bridging ability. The behavior of
N-haloimide-mediated halohydroxylations in different
solvents is in agreement with the proposed no depen-
dence of bridging with solvent variations.
The effect of the temperature on NBS- and NIS-mediated
halohydroxylations indicates that the temperature does not
influence the product distribution within the range ꢁ30 to
50 ꢀC.
(iii) Steric and stereoelectronic effects play different roles in
these reactions when compared to related electrophilic
additions, such as epoxidation and osmylations (and
also brominations12). The N-haloimide-mediated halo-
hydroxylations are highly dependent on steric require-
ments (precluding the attack on the more hindered,
although more electron rich olefin) whereas in the
related additions the preferential attack is on the more
Finally, the data obtained in this study seem to suggest that
the halohydroxylations of cyclohexadienediols follow a reac-
tion path including an irreversible electrophilic attack on
form the halonium ion, which is determined by the relative
stability of these ions. In these systems, the steric factors
are predominant, conferring greater stability to the a-halo-
nium ion (less crowded) over the corresponding b-isomer
(more crowded, although stabilized by anomeric effect).
The interplay between steric and stereoelectronic factors,
among others, determines the relative stability of intermedi-
ate species and, therefore, the final product distribution. If
the halonium ions were formed reversibly, the product distri-
bution in formal HOX additions would be determined not by
the thermodynamically more stable ion, but by the rate of
opening of this intermediate, as pointed out by several
authors.26,31,32d,33 For our cyclohexadienediol system, this
would imply a higher selectivity for the b-product, resulting
from a faster a-nucleophilic opening of the b-halonium ion,
which is favored based on steric grounds. The experimental
results show an opposite selectivity for all cases, in agree-
ment with an irreversible formation of the halonium ion.
The sensitivity to the steric requirements seems to be consis-
tent with a product-like transition state, as opposed to other
related electrophilic additions, such as brominations.
ꢀ
alkyl-substituted olefin. The Prevost reaction, in turn,
shows an intermediate behavior, being more stereo-
selective but less regioselective than the corresponding
NIS-mediated iodohydroxylation.
3. Conclusion
The halohydroxylations of cyclohexadienediol derivatives
have been investigated using different conditions and halo-
nium sources. The importance of the steric factors in the
course of the reaction is highlighted. Best overall selectivity
is achieved using iodine, although bromine is also syntheti-
cally useful, especially in deactivated systems. On the other
hand, for the chlorine case the reaction was neither selective
nor efficient, unsuitable for preparative purposes. Strongly
activated systems (enol ethers) require less active electro-
philic halogen donors in order for the reaction to be useful
under standard conditions. Investigations in this area are in
progress and will be disclosed in due course.
In summary several considerations on the mechanism of
the halohydroxylations of cyclohexadienediol derivatives
emerge:
4. Experimental
4.1. General techniques
(i) The selectivity of the reaction is determined primarily
by the steric requirements of the reactants. All reactions
showed a marked preference for products derived from
a-halonium ions, except in the reaction with NCS
where equal amounts of a- and b-product are obtained.
For alkyl-substituted dienes, the steric effects also influ-
ence the ratio of disubstituted versus trisubstituted ole-
fin attack, retarding the attack on the more crowded
double bond.
(ii) The ratio of 1,4- versus 1,2-addition follows an inverse
relationship to the bridging ability of the halonium ions:
the most bridged iodonium ions do not afford 1,4-addi-
tion products, whereas chloronium ions give roughly
the same amounts of each addition mode. All 1,4-addi-
tion products were derived from b-halonium ions,
which are the isomers exhibiting best overlap and
charge dispersal with the vicinal olefin, according to
All non-hydrolytic reactions were carried out in a nitrogen
atmosphere with standard techniques for the exclusion of
air. All solvents were distilled prior to use. Melting points
were determined on a Gallenkamp capillary 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). Infrared spectra were
recorded either on neat samples (KBr disks) or in solution
on Perkin–Elmer 1310 or Shimadzu FT-IR 8101A spectro-
meters. NMR spectra were obtained in CDCl3 on a Bruker
Avance DPX-400 instrument. Proton chemical shifts (d)
are reported in parts per million downfield from TMS as
an internal reference, and carbon chemical shifts are re-
ported in parts per million relative to the centerline of the
CDCl3 triplet (77.0 ppm). Elemental analyses were per-
formed by Atlantic Microlab Inc., Norcross, GA, USA, or
determined on a Fisions EA 1108 CHNS-O microanalyzer.

I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
4103
Optical rotations were measured on a Zuzi 412 polari-
meter using a 0.5 dm cell. [a]D values are given in units
of deg cm2/g and concentration values are expressed in
g/100 mL. Diols 1–4, and 18 were obtained by fermentation
of the corresponding arenes. Analytical TLC was performed
on silica gel 60 F254 plates and visualized with UV light
(254 nm) and/or p-anisaldehyde in acidic ethanolic solution.
Flash column chromatography was performed using silica
gel (Kieselgel 60, EM reagent, 230–400 mesh).
1.53 (s, 3H), 3.04 (br s, 1H), 4.36 (dd, 1H, J 4.0, 4.3 Hz),
4.40 (t, 1H, J 4.3 Hz), 4.70 (m, 2H), 6.39 (d, 1H, J 4.5 Hz);
13C NMR (100 MHz, CDCl3): d 26.3 (HC–I), 26.9 (CH3),
28.4 (CH3), 72.4 (HC–O), 76.9 (HC–O), 79.9 (HC–O),
112.6 (C), 124.7 (C), 131.3 (CH]); IR nmax (KBr)/cmꢁ1
:
3400 (br), 2986, 2932, 1641, 1221, 1157, 1062, 1007,
866; EIMS m/z (%): 361–359 (100, M+ꢁCH3), 301–299
(47, M+ꢁC3H6O2), 220 (13, M+ꢁC3H6O2–Br), 191–189
(21, M+ꢁC3H7O–I), 174–172 (95, M+ꢁC3H6O2–I), 110
(65, M+ꢁC3H7O–I–Br), 81 (100, Br+), 59 (88, C3H7O);
[a]2D5 +20 (c 0.44, CH2Cl2). Anal. required for C9H12O3BrI:
C, 28.83; H, 3.23%. Found: C, 29.10; H, 3.35%.
ꢀ
4.2. General procedure for Prevost reaction
To a stirred solution of cyclohexadienediol acetonide
(1.9 mmol) and silver acetate (657 mg, 3.9 mmol) in acetic
acid (20 mL) was added iodine (500 mg, 1.9 mmol) in small
lots for 3 h. The mixture was protected from light and stirred
at ambient temperature for 3 h. The precipitated silver iodide
was filtered off; the filtrate was diluted with CH2Cl2
(50 mL), neutralized with saturated aqueous NaHCO3
(2ꢂ30 mL), washed with water (2ꢂ30 mL), 20% aqueous
solution of NaHSO3 (2ꢂ30 mL,), again with water (2ꢂ
30 mL), and dried over Na2SO4. After filtration of the solids,
solvent was removed in vacuo. The crude product was puri-
fied by column chromatography on silica gel using hexanes–
ethyl acetate as eluant.
4.3.4. (1R,2S,5R,6S)-3-Bromo-6-iodo-1,2-O-isopropyl-
idenecyclohex-3-ene-1,2,5-triol (6b). White solid, mp
75.4–76.0 ꢀC; 1H NMR (400 MHz, CDCl3): d 1.43 (s, 3H),
1.45 (s, 3H), 3.07 (br s, 1H), 4.12 (dd, 1H, J 2.2, 9.3 Hz),
4.53 (td, 1H, J 1.8, 9.2 Hz), 4.56 (dd, 1H, J 1.7, 5.0 Hz),
4.71 (m, 1H), 6.28 (d, 1H, J 1.8 Hz); 13C NMR (100 MHz,
CDCl3): d 26.7 (CH3), 27.7 (CH3), 32.0 (HC–I), 71.4
(HC–O), 77.2 (HC–O), 79.6 (HC–O), 110.0 (C), 124.5
(C), 132.7 (CH]); IR nmax (KBr)/cmꢁ1: 3400 (br), 1258,
1138, 1096, 1043, 932, 866, 822, 737; EIMS m/z (%):
361–359 (13, M+ꢁCH3), 191–189 (50, M+ꢁC3H7O–I),
174–172 (49, M+ꢁC3H6O2–I), 110 (100, M+ꢁC3H7O–I–
Br), 127 (31, I+), 81 (34, Br+), 59 (52, C3H7O); [a]2D5 ꢁ31
(c 0.72, CH2Cl2). Anal. required for C9H12O3BrI: C,
28.83; H, 3.23%. Found: C, 29.14, H, 3.43%.
4.3. General procedure for halohydrin preparation with
NXS in DME–H2O
To a 0 ꢀC stirred solution of cyclohexadienediol acetonide
(1.9 mmol) dissolved in the corresponding mixture of
DME–H2O (5 mL/mmol of alkene) was added 1.1 equiv of
NXS. The mixture protected from light was stirred and let
to warm up to ambient temperature. After the specified
time, it was diluted with saturated solution of NaHSO3 and
extracted with methylene chloride. The combined organic
layers were washed with saturated NaCl, dried over
MgSO4, and then the solvent was removed in vacuo. The
crude product was purified by column chromatography on
silica gel using hexanes–ethyl acetate as eluant.
4.3.5. (1R,2S,5S,6R)-3,6-Dibromo-1,2-O-isopropylidene-
cyclohex-3-ene-1,2,5-triol (7a).16a White crystalline solid;
1H NMR (400 MHz, CDCl3): d 6.37 (d, 1H, J 4.8 Hz),
4.69 (m, 1H), 4.62 (m, 1H), 4.29 (m, 2H), 2.99 (br s, 1H),
1.55 (s, 3H), 1.44 (s, 3H).
4.3.6. (1R,2S,5S,6R)-3,6-Dibromo-1,2-O-isopropylidene-
cyclohex-3-ene-1,2,5-triol (7b). White crystalline solid;
1H NMR (400 MHz, CDCl3): d 6.27 (d, 1H, J 1.8 Hz),
4.63 (m, 2H), 4.57 (m, 1H), 4.04 (m, 1H), 2.99 (br s, 1H),
1.46 (s, 3H), 1.28 (s, 3H). Characterized by conversion to
known epoxide 17a.
4.3.1. (1R,2S,5S,6S)-3-Bromo-6-iodo-1,2-isopropylidene-
cyclohex-3-ene-5-yl acetate (5a). Yellow crystalline solid;
4.3.7. (1R,2R,5S,6R)-6-Iodo-1,2-O-isopropylidene-3-
methylcyclohex-3-ene-5-yl acetate (8a). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.40 (s, 3H), 1.48 (s, 3H), 1.85
(s, 3H), 2.12 (s, 3H), 4.00 (dd, 1H, J 9.5 Hz), 4.35 (d, 1H,
J 5.8 Hz), 4.48 (dd, 1H, J 5.8 Hz), 5.44 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 20.6 (CH3), 21.4 (CH3), 26.4 (CH3),
27.9 (CH3), 31.5 (HC–I), 73.5 (HC–O), 75.5 (HC–O), 79.4
(HC–O), 110.9 (C), 125.6 (HC]), 170.3 (C]O); IR nmax
(KBr)/cmꢁ1: 2986, 2856, 1746, 1372, 1233, 1219, 1161,
1026, 970, 876; EIMS m/z (%): 211 (36, M+ꢁCH3–I), 168
(7, M+ꢁC3H6O–I), 151 (2, M+ꢁC3H6O2–I), 109 (100,
M+ꢁC3H6O–I–OAc); [a]D20 0.6 (c 1.02, CH2Cl2). Anal.
required for C12H17O4I: C, 40.90; H, 4.82%. Found: C,
41.62; H, 4.95%.
1
mp 112.0–113.5 ꢀC; H NMR (400 MHz, CDCl3): d 1.45
(s, 3H), 1.54 (s, 3H), 2.14 (s, 3H), 4.16 (t, 1H, J 7.8 Hz),
4.61 (dd, 1H, J 5.6, 7.9 Hz), 4.66 (d, 1H, J 5.6 Hz), 5.57
(dd, 1H, J 3.0, 7.5 Hz), 6.22 (d, 1H, J 3.1 Hz); 13C NMR
(100 MHz, CDCl3): d 21.2 (CH3), 26.5 (HC–I), 26.6
(CH3), 28.4 (CH3), 73.2 (HC–O), 76.8 (HC–O), 79.4 (HC–
O), 112.2 (C), 123.8 (C), 130.8 (]CH), 170.2 (C]O); IR
nmax (KBr)/cmꢁ1: 2924, 2851, 1740, 1373, 1265, 738;
EIMS m/z (%): 416–418 (2, M+), 401–403 (77, M+ꢁCH3),
299–301 (54, M+ꢁOAc–C3H6O), 189–191 (38, M+ꢁOAc–
C3H6–I), 172–174 (60, M+ꢁOAc–C3H6O–I), 127 (8, I+),
81 (5, Br+), 43 (100, Ac+); [a]D25 +58.4 (c 1.5, CHCl3).
4.3.2. (1R,2S,5R,6R)-3-Bromo-6-iodo-1,2-isopropylid-
enecyclohex-3-ene-5-yl acetate (5b). Characterized as its
unprotected iodohydrin 6b.
4.3.8. (1R,2R,5R,6S)-6-Iodo-1,2-O-isopropylidene-3-
methylcyclohex-3-ene-5-yl acetate (8b). Characterized as
its unprotected iodohydrin 10b.
4.3.3. (1R,2S,5S,6R)-3-Bromo-6-iodo-1,2-O-isopropyl-
idenecyclohex-3-ene-1,2,5-triol (6a). White solid, mp
71.3–72.9 ꢀC; 1H NMR (400 MHz, CDCl3): d 1.42 (s, 3H),
4.3.9. (1S,2S,3R,4R)-3-Iodo-1,2-O-isopropylidene-3-
methylcyclohex-5-ene-4-yl acetate (9). Yellow oil; 1H

4104
I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
NMR (400 MHz, CDCl3): d 1.39 (s, H), 4.2 (d, 1H, J 5.2 Hz),
4.68 (m, 1H), 5.40 (dd, 1H, J 1.9, 3.5 Hz), 5.6 (m, 1H), 5.84
(m, 1H); 13C NMR (100 MHz, CDCl3): d 21.4 (CH3), 24.4
(CH3), 26.9 (CH3), 28.2 (CH3), 72.8 (HC–O), 72.8 (C),
73.3 (HC–O), 79.9 (HC–O), 110.2 (C), 126.1 (HC]),
129.4 (HC]); 170.6 (C]O); IR nmax (KBr)/cmꢁ1: 3040,
2988, 2882, 1747, 1373, 1244, 518; EIMS m/z (%): 227
(37, M+ꢁI), 169 (12, M+ꢁC3H6O–I), 167 (3, M+ꢁAcOH–
I), 141 (18), 127 (4, I+), 125 (100), 59 (9, AcO); [a]2D0 92
(c 0.3, CH2Cl2).
1.81 (s, 3H), 2.18 (br s, 1H), 4.00 (dd, 1H, J 2.3, 9.0 Hz),
4.42 (d, 1H, J 5.1 Hz), 4.56 (ddd, 1H, J 1.4, 1.9, 9.0 Hz),
4.63 (dd, 1H, J 2.3, 5.1 Hz), 5.58 (d, 1H, J 1.4 Hz);
13C NMR (100 MHz, CDCl3): d 19.5 (CH3), 26.8 (CH3),
27.7 (CH3), 55.9 (HC–Br), 69.5 (HC–O), 77.2 (HC–O),
77.8 (HC–O), 110.2 (C), 126.5 (CH]), 135.6 (C]); IR
nmax (KBr)/cmꢁ1: 3400 (br), 2986, 2916, 2849, 1367,
1219, 1037, 764; EIMS m/z (%): 247–249 (87, M+ꢁCH3),
187–189 (57, M+ꢁC3H7O2), 159–161 (27), 125 (29,
M+ꢁC3H6O–Br), 108 (100, M+ꢁC3H7O2–Br), 79 (54), 59
(16, C3H7O); [a]1D8 ꢁ99 (c 0.13, CH2Cl2). Anal. required
for C10H15O3Br: C, 45.62; H, 5.70%. Found: C, 45.23;
H, 5.53%.
4.3.10. (1R,2R,5S,6R)-6-Iodo-1,2-O-isopropylidene-3-
methylcyclohex-3-ene-1,2,5-triol (10a). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.40 (s, 3H), 1.47 (s, 3H),
1.86 (s, 3H), 2.77 (br s, 1H), 4.21 (t, 1H, J 6.9 Hz), 4.31
(m, 1H), 4.42 (d, 1H, J 5.2 Hz), 4.56 (dd, 1H, J 5.5,
7.4 Hz), 5.70 (d, 1H, J 1.4 Hz); 13C NMR (100 MHz,
CDCl3): d 20.2 (CH3), 26.7 (CH3), 28.6 (CH3), 34.5 (HC–
I), 71.5 (HC–O), 75.7 (HC–O), 79.2 (HC–O), 111.3 (C),
126.0 (CH]), 134.0 (C); IR nmax (KBr)/cmꢁ1: 3450 (br),
2986, 2984, 2856, 1448, 1371, 1219, 1061, 868; EIMS m/z
(%): 295 (20, M+ꢁCH3), 235 (15, M+ꢁC3H7O2), 125 (87,
M+ꢁC3H6O–I), 108 (100, M+ꢁC3H7O2–I), 79 (68), 59
(29, C3H7O); [a]2D9 ꢁ35 (c 1.07, CH2Cl2). Anal. required
for C10H15O3I: C, 38.73; H, 4.88%. Found: C, 38.30; H,
5.15%.
4.3.14. (1R,2R,3S,6S)-6-Bromine-1,2-O-isopropylidene-
3-methylcyclohex-4-ene-1,2,3-triol (12). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.37 (s, 3H), 1.38 (s, 3H),
1.42 (s, 3H), 2.34 (br s, 1H), 4.39 (dd, 1H, J 1.0, 6.0 Hz),
4.56 (dd, 1H, J 2.0, 5.4 Hz), 4.88 (ddd, 1H, J 1.1, 2.2,
6.7 Hz), 5.95 (d, 1H, J 1.0, 9.8 Hz), 6.10 (ddd, 1H, J 0.8,
5.4, 9.7 Hz); 13C NMR (100 MHz, CDCl3): d 25.0 (CH3),
26.0 (CH3), 27.1 (CH3), 44.9 (C–Br), 68.5 (C–O), 79.8
(HC–O), 81.6 (HC–O), 109.2 (C), 129.0 (HC]), 137.4
(HC]); IR nmax (KBr)/cmꢁ1: 3450 (br), 2988, 2916, 2849,
1375, 1217, 1063, 775; EIMS m/z (%): 247–249
(68, M+ꢁCH3), 205–207 (3, M+ꢁCH3–C3H6), 187–189
(30, M+ꢁCH3–C3H6–H2O), 159–161 (17), 125 (100,
M+ꢁCH3–C3H6–Br), 108 (67, M+ꢁCH3–C3H6–H2O–Br),
79 (27), 59 (20, C3H7O); [a]1D8 ꢁ239 (c 0.76, CH2Cl2).
4.3.11. (1R,2R,5R,6S)-6-Iodo-1,2-O-isopropylidene-3-
methylcyclohex-3-ene-1,2,5-triol (10b). White solid, mp:
1
101.2–103.4 ꢀC; H NMR (400 MHz, CDCl3): d 1.37 (s,
3H), 1.42 (s, 3H), 1.79 (s, 3H), 2.05 (br s, 1H), 4.08 (dd,
1H, J 2.2, 9.3 Hz), 4.34 (d, 1H, J 4.9 Hz), 4.51 (dt, 1H, J
1.9, 7.4 Hz), 4.66 (dd, 1H, J 2.1, 5.1 Hz), 5.70 (d, 1H, J
1.4 Hz); 13C NMR (100 MHz, CDCl3): d 19.6 (CH3), 27.0
(CH3), 27.8 (CH3), 35.3 (HC–I), 70.3 (HC–O), 75.8 (HC–
O), 79.2 (HC–O), 109.5 (C), 126.1 (CH]), 135.6 (C); IR
nmax (KBr)/cmꢁ1: 3400 (br), 2986, 1383, 1246, 1215,
1136, 1099, 1034, 871; EIMS m/z (%): 295 (23,
M+ꢁCH3), 235 (10, M+ꢁC3H7O2), 211 (9), 165 (5), 127
(I+)125 (100, M+ꢁC3H6O–I), 108 (62, M+ꢁC3H7O2–I), 97
(27), 79 (45), 59 (33, C3H7O); [a]2D9 ꢁ81 (c 0.70, CH2Cl2).
Anal. required for C10H15O3I: C, 38.73; H, 4.88%. Found:
C, 39.10; H, 5.26%.
4.3.15. (1R,2R,5S,6S)-3-Ethyl-6-iodo-1,2-O-isopropyl-
idenecyclohex-3-ene-5-yl acetate (13a). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.10 (t, 3H), 1.43 (s, 3H), 1.51
(s, 3H), 2.16 (s, 3H), 2.17 (m, 1H), 2.25 (m, 1H), 4.03 (t,
1H, J 9.7 Hz), 4.44 (d, 1H, J 5.8 Hz), 4.48 (dd, 1H, J 5.8,
9.8 Hz), 5.47 (dd, 1H, J 1.6, 3.3 Hz), 5.51 (dd, 1H, J 3.3,
9.6 Hz); 13C NMR (100 MHz, CDCl3): d 11.8 (CH3),
21.4 (CH3), 26.4 (CH3), 26.9 (CH2), 28.6 (CH3), 32.0
(HC–I), 73.8 (HC–O), 74.5 (HC–O), 79.5 (HC–O), 110.8
(C), 124.0 (HC]), 140.0 (C]), 170.5 (C]O); IR nmax
(KBr)/cmꢁ1: 2986, 2936, 2878, 1745, 1371, 1219, 1232;
EIMS m/z (%): 351 (27, M+ꢁCH3), 249 (34, M+ꢁC3H6O–
CH3–C2H6), 239 (30, M+ꢁI), 197 (10, M+ꢁAc–I), 181
(21.5), 139 (100), 122 (74, M+ꢁC3H6O–CH3–C2H6–I),
111 (27), 93 (26); [a]D19 ꢁ9 (c 2.44, CH2Cl2). Anal. required
for C13H19O4I: C, 42.62; H, 5.19%. Found: C, 42.58; H,
5.26%.
4.3.12. (1R,2R,5S,6R)-6-Bromo-1,2-O-isopropylidene-3-
methylcyclohex-3-ene-1,2,5-triol (11a). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.43 (s, 3H), 1.51 (s, 3H),
1.88 (s, 3H), 2.56 (d, 1H, J 6.2 Hz), 4.06 (m, 1H), 4.26 (m,
1H), 4.47 (m, 2H), 5.68 (d, 1H, J 1.3 Hz); 13C NMR
(100 MHz, CDCl3): d 20.2 (CH3), 26.5 (CH3), 28.5 (CH3),
56.3 (HC–Br), 70.7 (HC–O), 76.0 (HC–O), 78.1 (HC–O),
4.3.16. (1S,2S,3R,4R)-3-Ethyl-3-iodo-1,2-O-isopropyl-
idenecyclohex-5-ene-4-yl acetate (14). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.03 (t, 3H, J 7.5 Hz), 1.38 (s,
3H), 1.39 (s, 3H), 1.69 (m, 1H), 1.79 (m, 1H), 2.16 (s,
3H), 4.29 (d, 1H, J 4.9 Hz), 4.65 (ddd, 1H, J 1.9, 3.0,
5.0 Hz), 5.40 (dd, 1H, J 1.9, 3.2 Hz), 5.54 (dd, 1H, J 3.3,
10.3 Hz), 5.82 (dd, 1H, J 3.2, 10.3 Hz); 13C NMR
(100 MHz, CDCl3): d 6.8 (CH3), 21.4 (CH3), 26.9 (CH2),
28.2 (CH3), 30.0 (CH3), 72.7 (HC–O), 72.9 (HC–O), 74.8
(C), 75.9 (C–O), 110.0 (C), 125.9 (HC]), 129.2 (C]),
170.5 (C]O); IR nmax (KBr)/cmꢁ1: 2984, 2936, 1738,
1371, 1238, 1055, 1028; EIMS m/z (%): 241(21, M+2ꢁI),
181 (3, M+2ꢁI–AcOH), 169 (15, M+2ꢁI–C3H6–C2H6),
139 (100), 129 (57), 109 (30), 99 (34); [a]1D9 96 (c 0.16,
CH2Cl2).
111.2 (C), 126.5 (CH]), 133.8 (C); IR nmax (KBr)/cmꢁ1
:
3400 (br), 3057, 2986, 2918, 2849, 1373, 1217, 1063, 739;
EIMS m/z (%): 247–249 (95, M+ꢁCH3), 187–189 (10,
M+ꢁC3H7O2), 159–161 (29), 125 (35, M+ꢁC3H6O–Br),
108 (100, M+ꢁC3H7O2–Br), 79 (52), 59 (17, C3H7O);
[a]1D8 ꢁ46 (c 3.09, CH2Cl2). Anal. required for
C10H15O3Br: C, 45.62; H, 5.70%. Found: C, 45.77; H,
5.85%.
4.3.13. (1R,2R,5R,6S)-6-Bromine-1,2-O-isopropylidene-
3-methylcyclohex-3-ene-1,2,5-triol (11b). Yellow oil; H
NMR (400 MHz, CDCl3): d 1.38 (s, 3H), 1.43 (s, 3H),
1

I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
4105
4.3.17. (1R,2R,5S,6R)-6-Bromo-3-ethyl-1,2-O-isopropyl-
idenecyclohex-3-ene-1,2,5-triol (15a). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.12 (t, 3H, J 7.4 Hz), 1.43 (s,
3H), 1.50 (s, 3H), 2.17 (m, 1H), 2.28 (m, 1H), 4.05 (dd, 1H,
J 7.6, 7.6 Hz), 4.30 (m, 1H), 4.44 (m, 1H), 4.56 (d, 1H, J
3.72 Hz), 5.65 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 11.9 (CH3), 26.4 (CH2), 26.4 (CH3), 28.5 (CH3), 57.1
(HC–Br), 71.0 (HC–O), 75.0 (HC–O), 78.2 (HC–O), 111.1
(C), 124.7 (CH]), 139.0 (C); IR nmax (KBr)/cmꢁ1: 3400
(br), 3030, 2988, 1454, 1372, 1217, 1136, 1099, 1035, 871,
746, 698; EIMS m/z (%): 261–263 (28, M+ꢁCH3), 201–
203 (28, M+ꢁC3H6O2), 173–175 (13, M+ꢁC3H6O2–C2H5),
122 (63, M+ꢁC3H6O–Br), 93 (100, M+ꢁC3H7O2–C2H5–
Br); [a]2D9 ꢁ73 (c 0.73, CH2Cl2). Anal. required for
C11H17O3Br: C, 47.65; H, 6.13%. Found: C, 47.40; H, 5.90%.
4.3.21. (1R,2S,5R,6S)-6-Bromo-3-chloro-5-hydroxy-
cyclohex-3-ene-1,2-diyl diacetate (22b). White solid; mp
1
143–144 ꢀC; H NMR (400 MHz, CDCl3): d 2.07 (s, 3H),
2.16 (s, 3H), 3.09 (s, 1H), 4.14 (d, 1H, J 8.7 Hz), 4.63 (d,
1H, J 8.3 Hz), 5.73 (s, 2H), 6.13 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 20.7 (CH3), 20.8 (CH3), 52.8 (HC–
Br), 68.9 (HC–O), 71.0 (HC–OH), 71.9 (HC–O), 129.8
(CH), 130.5 (C), 169.8 (C]O), 170.2 (C]O); IR nmax
(KBr)/cmꢁ1: 3440 (br), 1751, 1649, 1236, 1219, 1144;
EIMS m/z (%): 187 (35, M+ꢁHBr–OAc), 145 (100,
M+ꢁHBr–OAc–COCH3), 109 (46), 81 (18), 65 (23).
4.3.22. (1R,2S,5S,6R)-6-Bromo-3-chloro-1,2-O-isopropyl-
idenecyclohex-3-ene-1,2,5-triol (23a).16b White crystalline
solid; 1H NMR (400 MHz, CDCl3): d 6.10 (d, 1H, J 4.4 Hz),
4.61 (m, 2H), 4.35 (m, 1H), 4.27 (m, 1H), 2.88 (d, 1H, J
9.1 Hz), 1.51 (s, 3H), 1.41 (s, 3H).
4.3.18. (1R,2R,5R,6S)-6-Bromo-3-ethyl-1,2-O-isopropyl-
idenecyclohex-3-ene-1,2,5-triol (15b). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.08 (t, 3H, J 7.4 Hz), 1.51 (s,
3H), 1.52 (s, 3H), 2.22 (m, 2H), 3.98 (dd, 1H, J 9.1,
2.3 Hz), 4.50 (m, 1H), 4.56 (m, 1H), 4.64 (dd, 1H, J 2.9,
3.3 Hz), 5.57 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 12.0 (CH3), 25.5 (CH3), 25.7 (CH3) 27.8 (CH2) 56.0
(HC–Br), 69.5 (HC–O), 70.8 (HC–O), 78.3 (HC–O), 111.1
(C), 124.2 (CH]), 140.8 (C); IR nmax (KBr)/cmꢁ1: 3400,
2916, 2849, 1412, 1232, 1043, 758; EIMS m/z (%): 261–
263 (13, M+ꢁCH3), 201–203 (21, M+ꢁC3H6O2), 173–175
(13, M+ꢁC3H6O2–C2H5), 139 (100), 122 (50,
M+ꢁC3H6O–Br), 93 (43, M+ꢁC3H7O2–C2H5–Br); [a]1D9
ꢁ11 (c 0.13, CH2Cl2). Anal. required for C11H17O3Br: C,
47.65; H, 6.13%. Found: C, 47.35; H, 5.97%.
4.3.23. (1R,2S,5R,6S)-6-Bromo-3-chloro-1,2-O-isopropyl-
idenecyclohex-3-ene-1,2,5-triol (23b).19 White crystalline
solid; 1H NMR (400 MHz, CDCl3): d 6.00 (d, 1H, J
1.8 Hz), 4.70 (dd, 1H, J 9.0, 2.2 Hz), 4.60 (br d, 1H, J
9.7 Hz), 4.57 (dd, 1H J 5.1, 2.1 Hz), 4.00 (dd, 1H, J 9.0,
2.21 Hz), 2.42 (br s, 1H), 1.42 (s, 3H).
4.3.24. (1R,2R,5S,6R)-6-Chloro-1,2-O-isopropylidene-3-
methylcyclohex-3-ene-1,2,5-triol (24a). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.43 (s, 3H), 1.52 (s, 3H), 1.89
(s, 3H), 3.96 (dd, 1H, J 7.6, 7.7 Hz), 4.19 (d, 1H, J 6.9 Hz),
4.33 (dd, 1H, J 6.0, 8.0 Hz), 4.47 (d, 1H, J 5.9 Hz), 5.66
(m, 1H); 13C NMR (100 MHz, CDCl3): d 20.2 (CH3), 26.4
(CH3), 28.4 (CH3), 63.9 (HC–Cl), 70.7 (HC–O), 75.9 (HC–
O), 77.9 (HC–O), 111.1 (C), 126.5 (HC]), 133.7 (C]);
IR nmax (KBr)/cmꢁ1: 3450 (br), 2916, 2849, 1657, 1219,
1064; EIMS m/z (%): 203–205 (83, M+ꢁCH3), 143–145
(100, M+ꢁC3H7O2), 125 (21, M+ꢁCH3–C3H6–Cl), 115–
117 (40), 107 (23, M+ꢁC3H7O2–Cl), 79 (46), 59 (14,
C3H7O); [a]1D8 ꢁ63 (c 0.29, CH2Cl2). Anal. required for
C10H15O3Cl: C, 54.94; H, 6.86%. Found: C, 54.67; H, 6.88%.
4.3.19. (1R,2R,3S,6S)-6-Bromo-3-ethyl-1,2-O-isopropyl-
idenecyclohex-4-ene-1,2,3-triol (16). Yellow oil; 1H NMR
(400 MHz, CDCl3): d 1.08 (t, 3H, J 7.4 Hz), 1.51 (s, 3H),
1.52 (s, 3H), 2.22 (m, 2H), 3.98 (dd, 1H, J 9.1, 2.3 Hz),
4.50 (m, 1H), 4.56 (m, 1H), 4.64 (dd, 1H, J 2.9, 3.3 Hz),
5.57 (m, 1H); 13C NMR (100 MHz, CDCl3): d 12.0 (CH3),
25.5 (CH3), 25.7 (CH3), 27.8 (CH2), 56.0 (HC–Br), 69.5
(HC–O), 70.8 (HC–O), 78.3 (HC–O), 111.1 (C), 124.2
(CH]), 140.8 (C); IR nmax (KBr)/cmꢁ1: 3400, 2916,
2849, 1412, 1232, 1043, 758; EIMS m/z (%): 261–263 (13,
M+ꢁCH3), 201–203 (21, M+ꢁC3H6O2), 173–175 (13,
M+ꢁC3H6O2–C2H5), 139 (100), 122 (50, M+ꢁC3H6O–Br),
93 (43, M+ꢁC3H7O2–C2H5–Br); [a]1D9 ꢁ11 (c 0.13,
CH2Cl2). Anal. required for C11H17O3Br: C, 47.65; H,
6.13%. Found: C, 47.35; H, 5.97%.
4.3.25. (1R,2R,3S,6S)-6-Chloro-1,2-O-isopropylidene-3-
methylcyclohex-4-ene-1,2,3-triol (25). Yellow oil; 1H
NMR (400 MHz, CDCl3): d 1.38 (s, 3H), 1.39 (s, 3H), 1.40
(s, 3H), 2.25 (br s, 1H), 4.36 (d, 1H, J 6.9 Hz), 4.46 (dd,
1H, J 1.8, 2.8 Hz), 4.66 (dd, 1H, J 2.8, 6.9 Hz), 5.99
(m, 2H); 13C NMR (100 MHz, CDCl3): d 24.9 (CH3), 25.4
(CH3), 27.0 (CH3), 54.7 (HC–Cl), 69.1 (C–O), 79.5 (HC–
O), 81.6 (HC–O), 109.2 (C), 128.3 (HC]), 137.9 (HC]);
IR nmax (KBr)/cmꢁ1: 3450 (br), 2988, 2916, 2849, 1375,
1215, 1065, 864; EIMS (IE, 70 eV) m/z (%): 203–205 (27,
M+ꢁCH3), 143–145 (47, M+ꢁC3H7O2), 131–133 (100),
125 (72, M+ꢁCH3–C3H6–Cl), 107 (20, M+ꢁC3H7O2–Cl),
95 (100), 59 (46, C3H7O); [a]1D8 ꢁ97 (c 0.44, CH2Cl2).
4.3.20. (1R,2S,5S,6R)-6-Bromo-3-chloro-5-hydroxy-
cyclohex-3-ene-1,2-diyl diacetate (22a). White crystalline
1
solid; mp 143.0–144.0 ꢀC; H NMR (400 MHz, CDCl3):
d 2.09 (s, 3H), 2.17 (s, 3H), 2.61 (d, 1H, J 4.9 Hz), 4.61
(dd, 1H, J 8.2, 11.7 Hz), 4.52 (m, 1H), 5.24 (dd, 1H, J 4.1,
11.7 Hz), 5.74 (d, 1H, J 4.1 Hz), 6.16 (d, 1H, J 2.5 Hz);
13C NMR (100 MHz, CDCl3): d 20.8 (CH3), 20.9 (CH3),
52.7 (HC–Br), 69.6 (HC–OH), 69.9 (HC–O), 73.1 (HC–
O), 130.1 (C), 131.7 (CH), 169.6 (C]O), 170.1 (C]O);
IR nmax (KBr)/cmꢁ1: 3524, 1759, 1728, 1655, 1254, 1192,
860; EIMS m/z (%): 311 (10, M+ꢁCH3), 269 (9), 251 (20,
M+ꢁOAc–H2O), 209 (57, M+ꢁ2(OAc)), 187 (47), 145
(66), 43 (100); [a]2D8 ꢁ191 (c 0.05, CH2Cl2). Anal. required
for C10H12O5ClBr: C, 36.70; H, 3.66%. Found: C, 37.01; H,
4.00%.
4.3.26. (1R,2S,3R,4S,5R,6R)-4-Hydroxy-3,6-diiodo-1,2-
O-isopropylidene-3-methylcyclohex-5-yl acetate (26).
Viscous oil; H NMR (400 MHz, CDCl3): d 1.29 (s, 3H),
1
1.40 (s, 6H), 2.20 (s, 3H), 4.01 (d, 1H J 6.7 Hz), 4.17 (d,
1H, J 7.2 Hz), 4.63 (dd, 1H, J 7.2, 3.8 Hz), 4.88 (dd, 1H, J
11.1, 3.3 Hz), 5.37 (dd, 1H, J 11.1, 6.6 Hz); 13C NMR
(100 MHz, CDCl3): d 24.2 (CH3), 26.5 (CH3), 26.7 (CH3),
27.2 (C–I), 30.8 (C), 31.3 (CH3), 70.3 (HC–O), 73.2 (HC–
O), 77.9 (HC–O), 79.5 (HC–O), 109.2 (C), 171.0 (C]O).

4106
I. Carrera et al. / Tetrahedron 63 (2007) 4095–4107
12. Nelson, D. J.; Cooper, P. J.; Soundararajan, R. J. Am. Chem.
Soc. 1989, 111, 1414.
13. Heasley, G. E.; Hayse, D. C.; McClung, G. R.; Strickland, D. K.
J. Org. Chem. 1976, 41, 334.
4.3.27. Minor product: (1R,2S,3S,4S,5R,6S)-5-hydroxy-
3,6-diiodo-1,2-O-isopropylidene-3-methylcyclohex-4-yl
1
acetate (260). Viscous oil; H NMR (400 MHz, CDCl3):
d 1.29 (s, 3H), 1.55 (s, 6H), 2.19 (s, 3H), 4.06 (d, 1H J
7.2 Hz), 4.51(dd, 1H, J 8.6, 7.0 Hz), 4.66 (dd, 1H, J 7.2,
2.8 Hz), 4.81 (dd, 1H, J 8.6, 2.8 Hz), 5.05 (d, 1H, J
6.9 Hz); 13C NMR (100 MHz, CDCl3): d 15.0 (C), 21.0
(CH3), 23.5 (CH3), 24.3 (CH3), 25.0 (CH3), 31.8 (C–I),
72.2 (C–O), 72.8 (C–O), 77.0 (C–O), 79.7 (C–O), 109.2
(C), 170.6 (C]O).
14. Dalton, D. R.; Davis, R. M. Tetrahedron Lett. 1972, 13, 1057.
15. (a) Nguyen, B. V.; York, C.; Hudlicky, T. Tetrahedron 1997, 53,
8807; (b) Hudlicky, T.; Restrepo-Sanchez, N.; Kary, P. D.;
Jaramillo-Gomez, L. M. Carbohydr. Res. 2000, 324, 200.
16. (a) Hudlicky, T.; Tian, X.; Konigsberger, K.; Maurya, R.;
Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118, 10752; (b)
Banwell, M. G.; Haddad, N.; Hudlicky, T.; Nugent, T. C.;
Mackay, M. F.; Richards, S. L. J. Chem. Soc., Perkin Trans. 1
1997, 1779; (c) Nugent, T. C.; Hudlicky, T. J. Org. Chem.
1998, 63, 510.
4.3.28. (1R,2R,3R,4S,5S,6R)-4,6-Dibromo-1,2-O-isopro-
pylidene-3-methylcyclohexane-1,2,3,5-tetraol (27). Yel-
low oil; H NMR (400 MHz, CDCl3): d 1.40 (s, 3H), 1.57
1
17. (a) Bedekar, A. V.; Nair, K. B.; Soman, R. Synth. Commun.
1994, 24, 2299; (b) Mangoni, L.; Adinolfi, M.; Barone, G.;
Parrilli, M. Tetrahedron Lett. 1973, 14, 4485; (c) Campbell,
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40, 5063.
(s, 3H), 1.74 (s, 3H), 3.96 (dd, 1H, J 1.6, 5.1 Hz), 4.12
(dd, 1H, J 3.2, 11.1 Hz), 4.26 (dd, 1H, J 1.7, 3.6 Hz), 4.29
(dd, 1H, J 8.8, 11.2 Hz), 4.52 (dd, 1H, J 5.1, 8.7 Hz); 13C
NMR (100 MHz, CDCl3): d 26.3 (CH3), 27.9 (CH3), 28.4
(CH3), 59.7 (C–Br), 60.1 (C–Br), 68.9 (HC–O), 73.2 (C–
O), 81.6 (HC–O), 83.4 (HC–O), 110.6 (C).
18. Smietana, M.; Gouverneur, V.; Mioskowski, C. Tetrahedron
Lett. 2000, 41, 193.
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59, 7944.
Acknowledgements
20. Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am. Chem.
Soc. 1990, 112, 9439.
21. Dalton, D. R.; Dutta, V. P.; Jones, D. C. J. Am. Chem. Soc. 1968,
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22. Diene 3 was prepared by acetonization (DMP, p-TsOH
(cat.)) of the cis-diol derived from microbial oxidation of ethyl-
benzene. The cis-diol was obtained with a yield of 3–4 g/L via
the same procedure as reported for toluene.1
Support of this work from DINACYT (PDT 54, Ministerio
ꢀ
edged. The authors thank Professor T. Hudlicky for provid-
ing the cultures of Pseudomonas putida F39/D. I.C. thanks
PEDECIBA (Project URU/97/016) for a scholarship.
de Educacion y Cultura, Uruguay) is gratefully acknowl-
23. Gibson, D.; Hensley, M.; Yoshika, H.; Mabry, R. Biochemistry
1970, 9, 1626.
Supplementary data
24. (a) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem.
1990, 55, 4683; (b) If benzyl alcohol is used as the solvent, the
corresponding O-benzylated derivative of bromohydrin 23a is
isolated as a single isomer in 60% yield.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.02.109.
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