Hydroxyselanylation of acyloxycyclohex-3-enes

Article abstract of DOI:10.1016/j.tet.2006.12.035

In contrast to the corresponding hydroxyiodination reactions, the reaction of acetoxycyclohex-2-ene 1 with N-PSP in the presence of water shows little regiocontrol, but is highly diastereoselective. However, the same reaction of the (R)-phenylglycinate de

Full text of DOI:10.1016/j.tet.2006.12.035

Tetrahedron 63 (2007) 2729–2737
Hydroxyselanylation of acyloxycyclohex-3-enes
b
b
a
J. B. Sweeney,a,b, Alan F. Haughan, J. R. Knight and Smita Thobhani
*
aDepartment of Chemistry, University of Reading, Reading RG1 5JN, UK
bSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Received 11 August 2006; revised 24 November 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—In contrast to the corresponding hydroxyiodination reactions, the reaction of acetoxycyclohex-2-ene 1 with N-PSP in the presence
of water shows little regiocontrol, but is highly diastereoselective. However, the same reaction of the (R)-phenylglycinate derivative of (ꢀ)-
cyclohexen-3-ol is highly diastereoselective, and regioselective. A hydrogen-bonding interaction is proposed to rationalize these differing
selectivities.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
dioxolonium ion 6 (derived from the corresponding a-iodo-
nium ion) one could rationalize the obtention of isomers.
We have previously described our studies on the reactions
of acyloxycyclohexenes (such as 1 and 2, Scheme 1) with
iodinating agents.1 Thus, these alkenes react under a range
of conditions in the presence of water and an iodonium
source, to give trans-1,2-hydroxyiodides, often with excel-
lent regio- and stereocontrol; we have used this reaction in
an iterative manner to prepare tetraacetylconduritol D 3
(Scheme 1).2
This observation contrasted with the similarly diastereo- and
regioselective addition of phenyselanyl chloride to 1, which
Liotta et al. reported to give a single regio- and stereoisomer
7, arising from a b-selanonium ion.5 NMR studies by Cooper
and Ward6 later revealed that 7 was accompanied by a
small amount of a diastereomer, 8 (Scheme 3). Presumably,
in this case, any influence of the carbonyl lone pair is con-
fined to an electrostatic interaction with the selenium posi-
tive charge.
We have also reported3 that phenylselanylation of 1 is dia-
stereoselective but not regioselective, in stark contrast to
the highly selective hydroxyiodination process, but the
hydroxyselanylation reaction is intimately related to the
structure of the acyl group: phenylglycinates analogous to
1 undergo reaction with N-PSP with excellent stereo- and re-
giocontrol.4 We report here in full the data arising from these
hydroxyselanylations, with a comment on the underlying
mechanistic features of the processes.
Thus, we were intrigued to observe the reaction of 1 with
selanylating reagents in the presence of water. In our initial
studies, we exposed 1 to PhSeCl, in chloroform containing
a few drops of water, whereupon we isolated only chloro-
selanide 7, but these reactions were inefficient (starting ma-
terial was never fully consumed in the processes) and often
difficult to purify.y We turned our attention to an alternative
electrophilic selanylating reagent, N-PSP,7 and found that re-
action with 1 in the presence of 1 equiv of camphor sulfonic
acid was a much smoother process. From the reaction, iso-
meric hydroxyselanides 9 and 10 were isolated in good yield
and in w50:50 ratio (Scheme 4). We identified CSA as the
source of water by carrying out the reaction in the presence
of molecular sieves, whereupon starting material was recov-
ered unchanged from the reaction; thus we added a few drops
of water8 to subsequent reactions.
2. Results and discussion
2.1. Hydroxyselanylation of acetoxycyclohex-3-ene
Thus, we had previously observed that hydroxyiodination
of 1 proceeded to give a single adduct, 4, on small scale and
an additional regioisomeric monoacetate 5 in larger scale
reactions (Scheme 2). This confirmed our postulate that
the acetate group was providing anchimeric assistance in
the addition of oxygen to the alkene: only by invoking
y
Cooper and Ward subsequently reported (op. cit.) that similar reactions
using a larger excess of water gave 9 and 10 instead of 7 (85% yield,
w50:50 ratio), indicating that concentration effects exert a powerful influ-
ence upon the reaction.
* Corresponding author. E-mail: j.b.sweeney@rdg.ac.uk
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.12.035

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J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
OAc
OAc
OAc
OAc
OAc
OH
I
OAc
OAc
OAc
OAc
OAc
ii, iii
i-iii
30% yield
i-iii
30% yield
i
74% yield
48% yield
1
2
OAc
3
via:
AcO
I
O
O
AcO
O
OAc
HO
H2O
O
OAc
I
I
Scheme 1. Reagents: (i) N-iodosuccinimide, water, MeCN; (ii) Ac2O, pyridine, DMAP; (iii) DBU, toluene, reflux.
OAc
OAc
OH
via:
path a
O
OH
I
OAc
I
OH
O
path b
i
4
5
a
O
+
O
O
O
b
1
4
5
I
I
I
6
74% yield
4% yield
Scheme 2. Reagents: (i) N-iodosuccinimide, water, MeCN.
OAc
OAc
OAc
O
via:
SePh
SePh
Cl
SePh
Cl
Ph
i
Se
O
Cl
OAc
+
Cl
1
7
8
90:10
Scheme 3. Reagents: (i) PhSeCl, d-chloroform.
separated by flash chromatography. Analysis of the 1H
NMR spectra for the monoesters confirmed the original
assignments.
OAc
OAc
OAc
OH
SePh
OH
i
+
71% yield
SePh
1
9
10
Compound 14 was then prepared unambiguously by a se-
quential hydroxyiodination–reductive deiodination process:
11 reacted under typical hydroxyiodination conditions (vide
supra) to give hydroxyiodide 16, as a single product (Scheme
6). Thermolytic reduction again gave 14, and we were able to
confirm the original structural assignment.
46:54
Scheme 4. Reagents: (i) N-phenylselanylphthalimide (2 equiv), CSA, room
temperature.
The regio- and stereochemical assignments, based on the
observed coupling constants for the downfield resonances,
were straightforward (Fig. 1).
Finally in this series of compounds, we performed a rigorous
chemical correlation. Thus, the acetoxy compounds 9 and
10 were reductively dechalcogenated: 9 gave (ꢀ)-cis-1-
acetoxy-2-hydroxycyclohexane 17,9 directly (Scheme 7).
Under a wide range of different conditions, the 9/10 ratio
was unchanged; we next examined the effect of substitution
at the acetate subunit, by carrying out the hydroxyselanyl-
ation on phenylacetate 11.z This compound was hydroxy-
selanylated in a slightly better yield, to give hydroxyselenides
12 and 13 (Scheme 5): however, these compounds were not
easily separable chromatographically. By analogy with the
chemical shifts observed for the acetate analogues, the ratio
12/13 was judged to be w50:50, paralleling to that seen in
the reaction of 1.
To confirm this tentative analysis, 12 and 13 were desela-
nylated under thermolytic conditions, to give the corre-
sponding monoesters 14 and 15, which were easily
z
Other esters did not react cleanly in these additions; we are currently
investigating the reasons for this observation.
Figure 1.

J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
2731
O
O
O
O
O
Ph
Ph
OH
Ph
Ph
OH
Ph
O
O
O
O
O
SePh
i
ii
+
+
74% yield
74% yield
SePh
12
OH
OH
15
11
13
14
~50:50
51:49
Scheme 5. Reagents: (i) N-phenylselanylphthalimide, CSA, water, room temperature; (ii) Bu3SnH, AIBN, PhH, reflux.
O
O
O
OAc
OAc
OH
Ph
Ph
OH
Ph
OH
SePh
OH
O
O
O
ii, iii
82% yield
i
77% yield
i
ii
OH
OTBDMS
66% yield
71% yield
10
18
I
11
16
14
Scheme 8. Reagents: (i) Bu3SnH, AIBN, PhH, reflux; (ii) TBDMSOTf, 2,6-
lutidine, CH2Cl2; (iii) LiOH$H2O, THF/H2O (8:1, reflux).
Scheme 6. Reagents: (i) N-iodosuccinimide, water, CH2Cl2; (ii) Bu3SnH,
AIBN, PhH, reflux.
of the absolute configurations of the cyclohexenyl substitu-
ent over the other. In fact the reaction proceeded to give
roughly equal amounts of two hydroxyselanides, in im-
proved yields compared to the corresponding acetate and
phenylacetates (Scheme 9). The process was complicated
by the fact that the two products could (except on small
scale) be chromatographically separated only with difficulty,
but it quickly became apparent that the two products were
diastereomers, not regioisomers; the compounds were again
obtained in roughly equal amounts. Thus, in contrast to the
acetate reactions, it seemed that each of the two diastereoiso-
meric esters had a preference for a single selenonium ion,
since it is the structure of the selenonium ion, which controls
the course of the reaction (assuming the process proceeds
by trans-diaxial ring-opening). By analogy with the data col-
lected from previous products, we tentatively assigned struc-
tures 20 and 21 to the products of the phenylglycinate
reaction.
1H decoupling experiments confirmed the cis-arrangement
in this molecule.
Upon deselanylation (Scheme 8), 10 gave (ꢀ)-trans-1-ace-
toxy-3-hydroxycyclohexane, which was converted in two
stepsto(ꢀ)-trans-3-hydroxy-1-(tert-butyldimethylsilyl)oxy-
cyclohexane 18, previously prepared by Evans et al.10
2.2. Hydroxyselanylation of (phenylglycinoyl)oxycyclo-
hex-3-ene
Having seen no dominant acetate directing effect on these
hydroxyselanylation processes, and being cognizant of the
known effects of hydrogen-bonding upon selanylation reac-
tions,4,5 we next sought to introduce an H-bonding compo-
nent into the acyl substituent. Since we eventually required
access to the single enantiomers of some of the hydroxy-
selenides and iodides from these reactions, we chose to use
a chiral H-bonding acyl species and (primarily for the rela-
tively simple NMR spectra of such compounds) settled
upon the (R)-phenylglycinoyl substituent. Thus, phenylgly-
cinoate 19, prepared as an inseparable 1:1 mixture of diaste-
reomers (by reaction of the DBU salt of R-phenylglycine
with (ꢀ)-bromocyclohex-3-ene), was reacted with N-PSP
in the presence of water. In addition to observing the effect
of the branched acyl substituent pattern, we were also keen
to ascertain whether or not the asymmetric centre of the
side chain would effect a kinetic resolution, favouring one
O
Ph
O
OC(O)R
SePh
OC(O)R
SePh
Ph
NHCbz
i
R =
+
NHCbz
89% yield
OH
OH
19
20
21
49:51
Scheme 9. Reagents: (i) N-phenylselanylphthalimide, CSA, water, room
temperature.
OAc
OH
OAc
OH
i
75% yield
SePh
9
17
OAc
OAc
OAc
4.89
ddd
4.89
dd J 8.3, 3.0
OH
OH
irradiated
OH
3.82-3.90 m
J 8.3, 3.0, 3.0
Scheme 7. Reagents: (i) Bu3SnH, AIBN, PhH, reflux.

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J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
O
O
Ph
Ph
OC(O)R
SePh
OC(O)R
SePh
O
O
NHCbz
NHCbz
i
+
+
82% yield
OH
OH
OH
OH
20
21
Ph
NHCbz
22
23
R =
~50:50
49:51
INSEPARABLE
SEPARABLE
Scheme 10. Reagents: (i) Bu3SnH, AIBN, PhH, reflux.
OH
OH
i, ii
74% yield
i, ii
71% yield
22
23
OTBDMS
OTBDMS
(+)-18
(–)-18
[ ]D + 4.85
[ ]D - 4.55
Scheme 11. Reagents: (i) TBDMSOTf, 2,6-lutidine, CH2Cl2; (ii) LiOH$H2O, THF/H2O (8:1, reflux).
Faced with the inability to separate diastereomers 20 and 21,
we carried out a chemical correlation process analogous to
that described above for the phenylacetate adduct: 20 and
21 were protiodeselanylated to give hydroxyesters 22 and
23 (Scheme 10). The latter compounds were now easily sep-
arated by chromatography and analysis of the associated 1H
NMR spectra supported the original structural assignment
we had made for 20 and 21.
selenonium ions, 24 and 25; these undergo trans-diaxial
ring-opening to give hydroxyselenides 9 and 10, respectively
(Scheme 12). The fact that roughly equal amounts of these
isomers are obtained implies the formation of selanonium
ion is rate-determining; ion 24 can undergo intramolecular
ring-opening (as seen in the corresponding hydroxyiodina-
tion process, Scheme 2), whereas ion 25 experiences an elec-
trostatic effect (cf. the Liotta reaction, Scheme 3), but neither
of the latter processes affect the overall course of the reac-
tion. This implies, in turn, that iodination of 1 is controlled
by the ring-opening of the iodonium intermediate, and that
formation of iodonium is reversible, which is well-prece-
dented.
To confirm that only two diastereoisomers were present, we
next prepared chiral derivatives of the separated deselenated
products. Thus, 22 ([a]D ꢁ31.96) and 23 ([a]D ꢁ41.02) were
converted into the corresponding (R)-MTPA esters, and
analyzed by chromatography and NMR. Frustratingly, the
compounds could not be completely separated by any chro-
matographic means, though 1H NMR did indicate that single
enantiomers (ꢂ90%) were present in each of the MTPA es-
ters. However, despite this disappointing diversion, we still
had available to us the chemical correlation applied for
(ꢀ)-18: thus, sequential silylation and hydrolysis of 22 and
23 gave (+)-18 and (ꢁ)-18, respectively. Gratifyingly, the
specific rotation of each compound was of the same magni-
tude, within experimental error (Scheme 11).
Giventhat increased steric bulkin the acylunit does not affect
the course of the reaction (Scheme 5), it seems unlikely that
the rate-limiting step involves dissociation of the N–Se bond:
if such a process was in operation, one would reasonably pre-
dict a larger ester group to have more steric repulsions with
the relatively bulky phthalimido subunit, leading to a prefer-
ence for (presumably) the a-selenonium intermediate. No
discernable improvement in regioselectivity is observed in
the reaction of phenylacetate 11, again implying that the for-
mation of selenonium is the rate-determining step.
Thus, it was shown that hydroxyselanylation of cyclo-
hexenyl phenylglycinates is regiospecific (only 3-hydroxy-
2-phenylselanyl products were obtained), and that the
reactions are highly diastereoselective (each diastereomer
of the starting material give only one hydroxyselanide prod-
uct). There is, therefore, an inherently high face selectivity:
the selenium electrophile is delivered only from the b-face of
the alkene, syn to the acyloxy substituent. The mechanistic
features of the reaction are discussed below.
The reaction of the phenylglycinate 19 is surprising, against
this mechanistic background. Each diastereomer forms a
single selenonium ion, where the selenium is located syn to
the acyloxy substituent (Scheme 13); trans-diaxial ring-
opening gives 20 and 21 and in this case there is no intramo-
lecular ring-opening by the acyl oxygen. This implies
immediately that the asymmetric centre of the acyl side chain
does not have any influence upon the stereoselectivity of
2.3. Mechanistic discussion
OAc
OAc
O
O
Ph
OH
SePh
OH
Se
O
O
It is well-known that addition reactions of cyclohexenes
often proceed via apparently less stable intermediates, under
Curtin–Hammett11 control, due to the low energy barrier for
interconversion between the available half-chair con-
formers. In the case of 1, the product profile indicates that
reaction with N-PSP gives equal amounts of both possible
SePh
Se
Ph
9
24
25
10
intramolecular
electrostatic
oxygen delivery
stabilization
Scheme 12.

J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
2733
hydrogen bonding
SePh
directs electrophile
O
Ph
N
Se
Se
OC(O)R
O
OC(O)R
H
N
Ph
HO
Ph
O
single selenonium
O
C=O anti to alkene
Scheme 13.
Ph
Se
Ph
Se
OC(O)R
OC(O)R
OC(O)R
OC(O)R
Se
Ph
Se
Ph
acyloxy pseudoequatorial
acyloxy pseudoequatorial
acyloxy pseudoaxial
acyloxy pseudoaxial
cis acetate and selenonium
trans acetate and selenonium
trans acetate and selenonium cis acetate and selenonium
OC(O)R
OC(O)R
HO
OC(O)R
PhSe
HO
SePh
PhSe
OC(O)R
HO
OH
SePh
NOT OBSERVED
Acetate
Phenylglycinate
Acetate 3
Phenylglycinate 3
NOT OBSERVED
Scheme 14.
the reaction: both diastereomers react in roughly the same
yield and with high levelsof stereoselectivity.x The only other
significant structural difference in this acyl group, which can
influence the reaction is the N–H bond: we assume, therefore,
that formation of selanonium is again rate-determining but
now hydrogen-bonding delivers the selenium electrophile
to the syn-face of the alkene (Scheme 13).
4. Experimental section
4.1. General techniques
All organic solvents were distilled prior to use and all
reagents were purified by standard procedures.12 ‘Petrol’ re-
fers to the fraction of petroleum ether with the boiling range
40–60 ꢃC and ‘ether’ refers to diethyl ether. Ether was dis-
tilled from sodium benzophenone ketyl; dichloromethane
from calcium hydride. Other chemicals were purchased from
Aldrich Chemical Co. and purified prior to use, or prepared
by literature methods.
Though further study is needed to confirm the hypotheses,
we can tentatively predict the preferences for these acyloxy
cyclohexenes as follows (Scheme 14): upon reaction with
N-PSP, simple acyl moieties cannot influence the course of
the reaction, because the rate-determining step is formation
of the selanonium ion. Only two of the four possible con-
formers are in operation, those in which the acyloxy substit-
uent is pseudoequatorial. Hydrogen bond donors in the acyl
group are likely to direct the incoming electrophiles to form
b-selanonium ions. Asymmetry present adjacent to the H-
bond has no influence upon the course of the reaction, and
only one of the four possible conformers is of importance.
Melting points were recorded on either a Kofler hot-stage
apparatus and are corrected, or an Electrothermal melting
point apparatus and are uncorrected. Infra-red spectra were
recorded on a Perkin–Elmer 881 spectrophotometer. Mass
spectra were recorded on a Fisons Autospec spectrometer
or a VG 9090 mass spectrometer. NMR spectra were
carried out on JEOL PMX 60, GX 270, GX 400 or GX
500 spectrometer using tetramethylsilane, chloroform, di-
chloromethane or acetone as an internal standard. Chemical
shifts in 1H NMR spectra are expressed in parts per million
downfield from tetramethylsilane, and, in 13C NMR, relative
to the internal solvent standard. Coupling constants (J) are
quoted in hertz.
3. Conclusion
In summary, we have found that hydroxyselanylation of
acyloxycyclohexenes can be a highly diastereoselective
process, when the acyl substituent contains an H-bond do-
nor. We are currently exploring the scope of these processes
and carrying out a detailed study on the mechanistic factors
responsible for these phenomena.
Reactions involving chemicals or intermediates sensitive
to air and/or moisture were conducted under a nitrogen or
argon atmosphere in flame- or oven-dried apparatus. Column
chromatography was performed using Merck Kieselgel 60 or
Fluka Kieselgel 60 silica gel. Analytical thin layer chroma-
tography was carried out using either precoated Merck
Kieselgel 60 F254 glass-backed plates, or precoated Merck
x
When a single equivalent or substoichiometric amount of N-PSP is used in
the reaction, kinetic resolution has, to date, not been observed; yields are
merely diminished.

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J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
Kieselgel 60 F254 aluminium backed plates and were visual-
ized under UV at 346 nm by staining with iodine and an
acidic ammonium molybdate stain (20% w/v ammonium
molybdate(VI) tetrahydrate in 10% sulfuric acid).
12 h. The white precipitate, which had formed was filtered
and washed with dichloromethane. The combined filtrate
and washings were evaporated in vacuo to give a pale yellow
solid. Flash column chromatography (ether/petrol, 1:1)
yielded an inseparable mixture of 12 and 13, as a colourless
solid (290 mg, 74%). By analogy with the spectra obtained
for 9 and 10, 1H NMR data were assigned as follows:
4.2. ( )-1,2-trans-2,3-cis-3-Acetoxy-2-hydroxy-1-phen-
selanylcyclohexane 9 and ( )-1,2-cis-2,6-trans-2-ace-
toxy-6-hydroxy-1-phenselanylcyclohexane 10
Hydroxyselenide 12: dH (270 MHz; CDCl3) 1.30–2.20 (6H,
m), 3.16–3.27 (1H, m), 3.47 (1H, dd, J 9.9 and 2.8), 3.68
(2H, s), 5.28–5.34 (1H, m), 7.21–7.38 (3H, m), 7.55–7.61
(2H, m); m/z 390 (M+, 18.5%), 254 (5.4), 233 (9.6), 157
(7.4), 147 (22.8), 104 (15.3), 91 (100).
Acetoxycyclohex-2-ene 1 (140 mg, 1 mmol), N-phenyl-
selanylphthalimide (604 mg, 2 mmol), (ꢀ)-camphor-10-
sulfonic acid (232 mg, 1 mmol), water (3 drops) and
dichloromethane (30 ml) were combined and stirred at
room temperature for 17 h. The white precipitate, which
had formed was filtered and washed with dichloromethane.
The combined filtrate and washings were evaporated in va-
cuo to give a pale yellow solid. Flash column chromato-
graphy (ether/petrol, 1:1) yielded 9, as a colourless solid
(103 mg, 33%). nmax (CCl4)/cmꢁ1 3350, 1721, 1572, 1470;
dH (270 MHz; CDCl3) 1.38–2.20 (6H, m), 2.11 (3H, s),
2.76 (1H, br s), 3.38 (1H, ddd, J 9.6, 9.6 and 3.7), 3.52
(1H, dd, J 9.6 and 2.8), 5.28–5.34 (1H, m), 7.24–7.38 (3H,
m), 7.58–7.64 (2H, m); dC (67.5 MHz; CDCl3) 170.66,
136.15, 134.24, 129.02, 128.23, 72.29, 71.81, 46.28,
31.36, 28.24, 21.24, 20.92 (2ꢄCH2); m/z 314 (M+, 23.7%),
157 (67.7), 147 (60.1), 104 (31.7), 97 (77.6), 43 (100). Hy-
droxyselenide 10 was also obtained as a colourless solid
(120 mg, 38%). nmax (CCl4)/cmꢁ1 3335, 1717, 1599, 1465;
dH (270 MHz; (CD3)2CO) 1.40–2.00 (6H, m), 1.90 (3H, s),
3.47 (1H, dd, J 7.7 and 3.3), 3.97–4.06 (1H, m), 5.25–5.32
(1H, m), 7.23–7.28 (3H, m), 7.57–7.62 (2H, m); dC
(67.5 MHz; (CD3)2CO) 170.12, 135.00, 134.69, 129.81,
123.73, 73.60, 70.80, 55.61, 33.07, 20.83, 19.69 (2ꢄCH2);
m/z 314 (M+, 22.1%), 158 (10.7), 147 (100), 104 (64.2),
97 (41.6), 76 (60.5), 50 (23.5), 43 (60.2).
Hydroxyselenide 13: dH (270 MHz; CDCl3) 1.30–2.20 (6H,
m), 3.05 (1H, dd, J 10.1 and 2.9), 3.61 (2H, s), 3.78 (1H, ddd,
J 10.1, 10.1 and 4.0), 5.42–5.47 (1H, m), 7.21–7.38 (3H, m),
7.55–7.61 (2H, m); m/z 390 (M+, 18.5%), 254 (5.4), 233
(9.6), 157 (7.4), 147 (22.8), 104 (15.3), 91 (100).
The mixture was not characterized further, but reacted di-
rectly in the next step.
4.5. ( )-cis-1-(Phenyl)acetyloxy-2-hydroxycyclohexane
14 and ( )-trans-1-(phenyl)acetyloxy-3-hydroxycyclo-
hexane 15
The mixture of selanides 12 and 13 (215 mg, 0.55 mmol),
tri-n-butyltin hydride (0.3 ml, 1.1 mmol), a,a0-azobisiso-
butyronitrile (50 mg) and dry benzene (20 ml) was combined
and heated to reflux for 12 h. The solution was allowed
to cool to room temperature and evaporated in vacuo to give
a colourless liquid. Purification by flash column chromato-
graphy (ether/petrol, 1:1) yielded 14 as a colourless
liquid (49 mg, 38%) and 15, also as a colourless liquid
(46 mg, 36%).
4.3. (Phenylacetyl)oxycyclohex-2-ene 11
Data for 14: nmax (CCl4)/cmꢁ1 3611, 1737; dH (270 MHz;
CDCl3) 1.22–1.90 (8H, m), 3.66 (2H, s), 3.77–3.85 (1H, m),
4.93 (1H, dt, J 7.9 and 2.9), 7.25–7.37 (5H, m); dC
(67.5 MHz; CDCl3) 171.20, 134.11, 129.11, 128.61, 127.11,
74.49, 69.14, 41.71, 30.16, 26.92, 21.70, 21.14; m/z 234 (M+,
0.5%), 136 (2.5), 118 (9.8), 98 (100), 91 (94.6), 81 (78.0).
3-Bromocyclohexene (7.00 g, 43.47 mmol), phenylacetic
acid (4.08 g, 30 mmol) and diazobicyclo[5.4.0]undec-7-ene
(4.49 ml, 30 mmol) were reacted in benzene (100 ml) to give
a tan liquid, which on flash column chromatography afforded
11, as a clear colourless liquid (4.88 g, 76%). (Found: C,
77.87; H, 7.51. C14H16O2 requires C, 77.75; H, 7.46%.)
nmax (CCl4)/cmꢁ1 1727 (CO); dH (270 MHz; CDCl3) 1.53–
2.15 (6H, m, CH2CH2CH2), 3.61 (2H, s, CH2Ph), 5.24–
5.31 (1H, m, OCH), 5.69 (1H, ddt, J 10.07, 3.66 and 2.2,
OCHCHCH), 5.94 (1H, ddt, J 10.08, 3.85 and 1.28,
OCHCH), 7.22–7.35 (5H, m, Ph); dC (67.5 MHz; CDCl3)
171.20 (C), 134.21 (C), 132.73 (CH), 129.16 (CH), 128.45
(CH), 126.91 (CH), 124.48 (CH), 68.46 (CH), 41.60
(CH2), 28.14 (CH2), 24.78 (CH2), 18.73 (CH2); m/z 216
(M+, 6%), 136 (3.3), 118 (1.8), 97 (4.1), 91 (42.3), 81 (100).
Data for 15: (found: 234.1241; C14H18O3 requires
234.1256); nmax (CCl4)/cmꢁ1 3623, 1735; dH (270 MHz;
CDCl3) 1.20–1.95 (8H, m), 3.59 (2H, s), 3.86–3.97 (1H,
m), 5.10–5.20 (1H, m), 7.22–7.36 (5H, m); dC (67.5 MHz;
CDCl3) 170.86, 134.18, 129.11, 128.48, 126.97, 70.83,
66.67, 41.76, 38.74, 33.82, 29.81, 19.01; m/z 234 (M+,
10.6%), 205 (5.3), 136 (3.4), 118 (4.7), 98 (23.2), 91
(49.0), 81 (100).
4.6. ( )-1,2-trans-2,3-cis-3-(Phenyl)acetyloxy-2-hydr-
oxy-1-iodocyclohexane 16
4.4. ( )-1,2-trans-2,3-cis-3-(Phenyl)acetyloxy-2-
hydroxy-1-phenselanylcyclohexane 12 and ( )-1,2-trans-
2,3-cis-3-(Phenyl)acetyloxy-2-hydroxy-1-phenselanyl-
cyclohexane 13
Phenylacetate 11 (50 mg, 0.23 mmol), N-iodosuccinimide
(63 mg, 0.28 mmol), water (2 drops) and dichloromethane
(5 ml) were combined and stirred at room temperature for
17 h. The product was absorbed onto silica gel, by adding
silica gel and evaporating in vacuo. Flash column chromato-
graphy (ether/petrol, 1:1) yielded 16, as a colourless solid
(55 mg, 66%). (Found: C, 46.88; H, 4.84. C14H17IO3
Phenylacetate 11 (216 mg, 1 mmol), N-phenylselanylphthal-
imide (604 mg, 2 mmol), (ꢀ)-camphor-10-sulfonic acid
(232 mg, 1 mmol), water (3 drops) and dichloromethane
(30 ml) were combined and stirred at room temperature for

J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
2735
requires C, 46.68; H, 4.76%.) (Found: 342.0091. C14H15IO2
requires 342.0119.) nmax (CCl4)/cmꢁ1 3569, 1742; dH
(270 MHz; CDCl3) 1.15–2.35 (7H, m), 3.60 (2H, s), 3.64–
3.72 (1H, m), 4.06–4.18 (1H, m), 5.16–5.24 (1H, m),
7.16–7.30 (5H, m); dC (67.5 MHz; CDCl3) 170.96, 133.92,
129.16, 128.59, 127.18, 75.48, 71.98, 41.59, 36.63, 34.00,
28.28; m/z 360 (M+, 0.5%), 342 (2.0), 233 (21.4), 137
(20.0), 97 (76.9), 91 (100).
42.85, 34.63, 33.72, 25.81, 18.92, 18.06, –4.83, ꢁ4.86; m/z
230 (M+, 1.2%), 213 (2.4), 173 (31.1), 171 (43.7), 97
(100), 81 (45.3), 75 (51.4).
4.9. [N-Cbz-(R)-Phenylglycinoyl]oxycyclohex-2-ene 19
3-Bromocyclohexene (3.55 g, 22 mmol), (R)-N-Cbz-phenyl-
glycine (5.65 g, 19.8 mmol) and diazobicyclo[5.4.0]undec-
7-ene (2.96 ml, 19.8 mmol) were reacted in refluxing
benzene (100 ml) to give a tan liquid, which on flash col-
umn chromatography afforded 19, as a colourless solid
(4.77 g, 67%), as a mixture of diastereoisomers; mp 73–
77 ꢃC. (Found: C, 72.15; H, 6.51; N, 3.82. C22H23NO4
requires C, 72.31; H, 6.34; N, 3.83%.) nmax (CCl4)/cmꢁ1
3436, 1729; dH (270 MHz; CDCl3) 1.44–2.12 (6H, m),
5.02–5.17 (2H, m), 5.20–5.32 (1H, m), 5.32–5.39 (1H, m,
OCH), 5.41–5.76 (1H, m), 5.82–6.00 (1H, m), 7.25–7.40
(10H, m); dC (67.5 MHz; CDCl3) 170.35, 155.31, 155.28,
136.90, 136.78, 136.12, 133.53, 133.23, 128.78, 128.50,
128.37, 128.15, 126.98, 124.72, 124.59, 69.96, 69.65,
67.04, 58.03, 28.06, 27.71, 24.69, 18.67, 18.30; m/z 240
(4.8%), 196 (24.9), 91 (100).
4.7. ( )-cis-1-Acetoxy-2-hydroxycyclohexane 17
Selanide 9 (100 mg, 0.32 mmol), tri-n-butyltin hydride
(0.17 ml, 0.64 mmol), a,a0-azobisisobutyronitrile (50 mg)
and dry benzene (20 ml) were combined and heated to reflux
for 15 h. The solution was allowed to cool to room temper-
ature and evaporated in vacuo to give a white gel. Purifica-
tion by flash column chromatography (ether/petrol, 1:1)
yielded 17, as a colourless viscous liquid (38 mg, 75%).
nmax (CCl4)/cmꢁ1 3612, 1737; dH (270 MHz; CDCl3)
1.20–1.88 (8H, m), 2.01 (1H, br s), 2.07 (3H, s), 3.82–3.90
(1H, m), 4.89 (1H, dt, J 8.3 and 3.0) (upon irradiation at
d 3.86, signal became dd, J 8.3 and 3.0); dC (67.5 MHz;
CDCl3) 170.77, 74.17, 69.05, 30.25, 26.79, 22.00, 21.27,
20.89; m/z 116 (3.9%), 115 (3.9), 98 (98.3), 97 (32.6), 79
(32.3), 70 (52.3), 58 (35.0), 43 (100).
4.10. 1,2-cis-2,6-trans-2-[N-Cbz-(R)-Phenylglycinoyl]-
oxy-6-hydroxy-1-phenselanylcyclohexanes 20 and 21
4.8. ( )-trans-(tert-Butyldimethylsilyl)oxy-3-hydroxy-
cyclohexane 18
N-Phenylselanylphthalimide (2.71 g, 8.95 mmol) and 19
(2.81 g, 5.97 mmol) were combined in dry dichlorometh-
ane (150 ml).6 (ꢀ)-Camphor-10-sulfonic acid (1.39 g,
5.97 mmol) was added to the mixture, which was stirred at
room temperature for 16 h. The white precipitate of phthal-
imide was filtered, washed with dichloromethane (2ꢄ20 ml)
and combined filtrate and washings were evaporated in
vacuo to give an orange solid. Purification by flash column
chromatography (ether/petrol, 1:1) yielded 20 and 21, as
a white gum (2.87 g, 89%). (Found: C, 62.72; H, 5.62; N,
2.95. C28H29NO5Se requires C, 62.45; H, 5.43; N, 2.60%.)
nmax (CCl4)/cmꢁ1 3437, 1732; dH (270 MHz; CDCl3) 1.17–
1.80 (6H, m), 1.96 (0.5H, br s of one diastereoisomer), 2.16
(0.5H, br s of other diastereoisomer), 2.90–3.01 (1H, m),
3.60–3.76 (1H, m), 5.03–5.24 (3H, m), 5.36–5.42 (1H, m),
5.88–5.95 (1H, m), 7.27–7.89 (15H, m); m/z 539 (M+,
3.8%), 431 (1.9), 240 (23.7), 196 (22.1), 147 (65.9), 91 (100).
(1) The selanide 10 (110 mg, 0.35 mmol), tri-n-butyltin
hydride (0.19 ml, 0.70 mmol), a,a0-azobisisobutyronitrile
(50 mg) and dry benzene (20 ml) were combined and heated
to reflux for 15 h. The solution was allowed to cool to room
temperature and evaporated in vacuo to give a white gel.
Purification by flash column chromatography (ether/petrol,
1:1) yielded (ꢀ)-trans-1-acetoxy-3-hydroxycyclohexane, as
a colourless viscous liquid (42 mg, 77%). nmax (CCl4)/cmꢁ1
3622 and 3473, 1739; dH (270 MHz; CDCl3) 1.32–1.94 (8H,
m), 2.01 (3H, s), 3.95–4.07 (1H, m), 5.07–5.17 (1H, m); dC
(67.5 MHz; CDCl3) 170.53, 70.32, 66.75, 38.79, 33.71,
30.03, 21.33, 19.05; m/z 140 (1.6%), 115 (2.9), 104 (1.7),
98 (77.5), 80 (34.5), 70 (39.8), 54 (27.9), 43 (100).
(2) (ꢀ)-trans-1-Acetoxy-3-hydroxycyclohexane (80 mg,
0.51 mmol) and 2,6-lutidine (90 ml, 0.76 mmol) were com-
bined in dry dichloromethane (16 ml) and cooled on an ice
bath. (tert-Butyldimethylsilyl)methanesulfonate (0.23 ml,
1.01 mmol) was added and stirring was continued for 5 h
at room temperature. The reaction mixture was washed
with 5% hydrochloric acid (1ꢄ5 ml), saturated aqueous
sodium hydrogen carbonate (1ꢄ5 ml), dried (MgSO4) and
evaporated in vacuo to give a colourless liquid.
4.11. (1R,10S,3S)-(L)-3-Hydroxy-1-[N-Cbz-(R)-phenyl-
glycinoyl]oxycyclohexane 22 and (1R,10R,30R)-(L)-3-hy-
droxy-1-[N-Cbz-(R)-phenylglycinoyl]oxycyclohexane 23
A mixture of 20 and 21 (1.27 g, 2.37 mmol), tri-n-butyltin
hydride (1.27 ml, 4.74 mmol), a,a0-azobisisobutyronitrile
(50 mg) and dry benzene (30 ml) was combined and heated
to reflux for 16 h.7 The solution was allowed to cool to room
temperature and evaporated in vacuo, to give a white gel.
Purification by flash column chromatography eluting with
ether/petrol (3:1) yielded 22 as a colourless solid (382 mg,
42%) and 23 also as a colourless solid (400 mg, 44%).
(3) The crude product from above (110 mg, 0.40 mmol),
lithium hydroxide monohydrate (19 mg, 0.44 mmol), water
(3 ml) and tetrahydrofuran (24 ml) were combined and
refluxed for 15 h. The solution was allowed to cool to room
temperature and evaporated in vacuo to give a colourless liq-
uid. Purification by flash column chromatography yielded
(ꢀ)-18, as a colourless liquid (93 mg, 82%). nmax (CCl4)/
cmꢁ1 3623; dH (500 MHz; CDCl3) 0.02 (3H, s), 0.03 (3H,
s), 0.87 (9H, s), 1.26–1.82 (8H, m), 4.01–4.06 (1H, m),
4.07–4.11 (1H, m); dC (125 MHz; CDCl3) 67.62, 67.12,
Data for 23: mp 79 ꢃC. (Found: C, 68.89; H, 6.91; N, 3.52.
C22H25NO5 requires C, 68.91; H, 6.57; N, 3.65%.) [a]D24
ꢁ31.96; nmax (CCl4)/cmꢁ1 3621, 3435, 1728; dH
(270 MHz; (CD3)2CO) 1.21–1.95 (8H, m), 3.85–3.96 (1H,
m), 5.06–5.17 (3H, m), 5.31–5.37 (1H, m), 7.14 (1H, d,
J 7.7), 7.27–7.49 (10H, m); dC (67.5 MHz; (CD3)2CO)

2736
J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
170.73, 156.57, 138.03, 129.41, 129.12, 128.98, 128.60,
128.30, 72.63, 66.87, 66.29, 59.33, 39.47, 34.47, 31.17,
18.93; m/z 383 (M+, 0.6%), 240 (48.6), 196 (33.6), 91 (100).
silyl ether, as a colourless viscous liquid (272 mg, 85%).
(Found: C, 67.32; H, 7.64; N, 2.54. C28H39NO5Si requires
C, 67.57; H, 7.90; N, 2.81%.) [a]2D2 ꢁ18.01; nmax (CCl4)/
cmꢁ1 3434, 1727; dH (270 MHz; (CD3)2CO) 0.06 (3H, s),
0.07 (3H, s), 0.89 (9H, s), 1.25–1.85 (8H, m), 3.99–4.10
(1H, m), 5.08 (2H, 2ꢄd, J 3.8), 5.06–5.15 (1H, m), 5.34
(1H, d, J 7.7), 7.10 (1H, d, J 7.7), 7.30–7.50 (10H, m); dC
(67.5 MHz; (CD3)2CO) 170.62, 156.51, 138.09, 137.89,
129.39, 129.09, 128.95, 128.60, 128.25, 72.55, 68.09,
66.87, 59.34, 39.86, 34.59, 30.47, 26.15, 19.43, 18.50,
Data for 22: mp 120 ꢃC. (Found: C, 68.91; H, 6.66; N,
3.69. C22H25NO5 requires C, 68.91; H, 6.57; N, 3.65%.)
[a]2D4 ꢁ24.02; nmax (CCl4)/cmꢁ1 3621, 3435, 1729; dH
(270 MHz; CDCl3) 1.10–1.95 (8H, m), 3.65–3.76 (1H, m),
5.03–5.16 (3H, m), 5.34 (1H, d, J 7.8), 7.14 (1H, d, J 7.8),
7.29–7.48 (10H, m); dC (67.5 MHz; (CD3)2CO) 170.74,
156.6, 138.01, 129.46, 129.17, 129.01, 128.66, 128.31,
72.64, 66.90, 66.12, 59.41, 39.18, 34.45, 30.86, 19.78; m/z
383 (M+, 0.3%), 240 (24.0), 196 (19.8), 91 (100).
t
ꢁ4.66; m/z 440 (M+ꢁ Bu, 5.9%), 342 (26.9), 234 (37.0),
91 (100), 81 (55.2).
(2) The ester from step 1 (230 mg, 0.46 mmol), lithium
hydroxide monohydrate (20 mg, 0.46 mmol), water (3 ml)
and tetrahydrofuran (24 ml) were combined and refluxed
for 12 h. Upon cooling to room temperature Merck Kieselgel
60 (0.5 g) was added and the mixture was evaporated to dry-
ness in vacuo. Flash column chromatography, eluting with
ether/petrol (3:7), yielded (+)-18, as a colourless viscous liq-
uid (92 mg, 87%). (Found: 230.1722. C12H26O2Si requires
230.1702.) [a]2D4 +4.85 (c 1, EtOAc); other data as above,
for (ꢀ)-18.
4.12. (1R,3R)-(L)-1-(tert-Butyldimethylsilyl)oxy-3-
hydroxycyclohexane (L)-18
(1) Hydroxyester 23 (310 mg, 0.81 mmol) and 2,6-lutidine
(0.14 ml, 1.21 mmol) were combined in dry dichlorometh-
ane (30 ml) and cooled on an ice bath. tert-Butyldimethyl-
silylmethanesulfonate (0.37 ml, 1.62 mmol) was added and
stirring was continued for 15 h at room temperature. The
reaction mixture was washed with 5% hydrochloric acid
(1ꢄ10 ml) and saturated aqueous sodium hydrogen carbon-
ate (1ꢄ10 ml), dried (MgSO4) and evaporated in vacuo to
give a colourless viscous liquid. Purification by flash column
chromatography eluting with ether/petrol (1:4) yielded the
silyl ether, as a colourless viscous liquid (338 mg, 84%).
(Found: C, 67.94; H, 7.80; N, 3.11. C28H39NO5Si requires
C, 67.57; H, 7.90; N, 2.81%.) [a]2D2 ꢁ29.34; nmax (CCl4)/
cmꢁ1 3434, 1728; dH (270 MHz; (CD3)2CO) 0.05 (3H, s),
ꢁ0.04 (3H, s), 0.84 (9H, s), 1.20–1.75 (8H, m), 3.77–3.89
(1H, m), 5.08 (2H, s), 5.05–5.16 (1H, m), 5.34 (1H, d,
J 7.7), 7.12 (1H, d, J 7.7), 7.32–7.49 (10H, m); dC
(67.5 MHz; (CD3)2CO) 170.66, 156.54, 138.12, 137.96,
129.49, 129.14, 129.01, 128.63, 128.27, 72.61, 67.96,
66.88, 59.28, 39.63, 34.80, 30.80, 26.12, 19.74, 18.45,
ꢁ4.71; m/z 440 (M+ꢁ57, 5.0%), 342 (29.8), 240 (14.6),
234 (14.5), 196 (10.7), 91 (100).
Acknowledgements
We acknowledge the financial support of the EPSRC (A.F.H.,
J.R.K.). We also acknowledge the advice of Mr. E. Blair
and the technical contributions of Mr. T. McDermott.
References and notes
1. Knight, J.; Sweeney, J. B. Tetrahedron Lett. 1998, 39, 8703.
2. Bange, J.; Haughan, A. F.; Knight, J. R.; Sweeney, J. B.
J. Chem. Soc., Perkin Trans. 1 1998, 1039; For a review on other
syntheses of conduritols and other cyclitols, see: Gultekin,
M. S.; Celik, M.; Balci, M. Curr. Org. Chem. 2004, 8, 1159;
For recent syntheses, see: Cere, V.; Minzoni, M.; Pollicino,
S.; Ricci, A.; Gasparrini, F.; Ciogli, A.; D’Acquarica, I.
J. Comb. Chem. 2006, 8, 74; Serrano, P.; Llebaria, A.;
Delgado, A. J. Org. Chem. 2005, 70, 7829; Podeschwa,
M. A. L.; Plettenburg, O.; Altenbach, H. J. Eur. J. Org. Chem.
2005, 3116; Podeschwa, M. A. L.; Plettenburg, O.;
Altenbach, H. J. Eur. J. Org. Chem. 2005, 3101; Orsini, F.;
Sello, G.; Bernasconi, S.; Fallacara, G. Tetrahedron Lett.
2004, 45, 9253; Saito, S.; Shimazawa, R.; Shirai, R. Chem.
Pharm. Bull. 2004, 52, 727; Freeman, S.; Hudlicky, T.
Bioorg. Med. Chem. Lett. 2004, 14, 1209 and references cited
therein.
(2) The ester from step 1 (307 mg, 0.62 mmol), lithium
hydroxide monohydrate (26 mg, 0.62 mmol), water (3 ml)
and tetrahydrofuran (24 ml) were combined and refluxed
for 12 h. Upon cooling to room temperature Merck Kieselgel
60 (0.5 g) was added and the mixture was evaporated
to dryness in vacuo. Flash column chromatography eluting
with ether/petrol (3:7) yielded (ꢁ)-18, as a colourless vis-
cous liquid (120 mg, 84%). (Found: 230.1727. C12H26O2Si
requires 230.1702); [a]2D4 ꢁ4.55 (c 1, EtOAc); other data as
above, for (ꢀ)-18.
3. Haughan, A. F.; Knight, J. R.; Sweeney, J. B. Tetrahedron Lett.
1994, 35, 1781.
4. Haughan, A. F.; Sweeney, J. B. Tetrahedron: Asymmetry 1994,
5, 177.
4.13. (1S,3S)-(D)-1-(tert-Butyldimethylsilyl)oxy-3-
hydroxycyclohexane (D)-18
(1) Hydroxyester 22 (246 mg, 0.64 mmol), 2,6-lutidine
(0.11 ml, 0.96 mmol) and (tert-butyldimethylsilyl)methane-
sulfonate (0.29 ml, 1.28 mmol) were reacted in dry dichloro-
methane (30 ml) with stirring for 15 h at room temperature.
The reaction mixture was washed with 5% hydrochloric acid
(1ꢄ10 ml) and saturated aqueous sodium hydrogen carbon-
ate (1ꢄ10 ml), dried (MgSO4) and evaporated in vacuo, to
give a colourless viscous liquid. Purification by flash column
chromatography, eluting with ether/petrol (1:4), yielded the
5. Liotta, D.; Zima, G.; Saindane, M. J. Org. Chem. 1982, 47,
1258.
6. Cooper, M. A.; Ward, A. D. Tetrahedron 2004, 60, 7963.
7. Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P.
J. Am. Chem. Soc. 1979, 101, 3704.
8. Nicolaou, K. C. Tetrahedron 1981, 37, 4097.
9. Anchisi, C.; Maccioni, A.; Maccioni, A. M.; Podda, G. Gazz.
Chim. Ital. 1983, 113, 73; Pedersen, C. Tetrahedron Lett.
1967, 511.

J. B. Sweeney et al. / Tetrahedron 63 (2007) 2729–2737
2737
10. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc.
1988, 110, 6917.
P. R.; Spencer, N.; Philp, D. Org. Lett. 2001, 3, 353;
Chandrasekhar, S. Res. Chem. Intermed. 1998, 24, 625;
Cavalier, J. F.; Fotiadu, F.; Verger, R.; Buono, G. Synlett
1998, 73; Chandrasekhar, S. Res. Chem. Intermed. 1997, 23,
55; Roth, M.; Damm, W.; Giese, B. Tetrahedron Lett. 1996,
37, 351; Pearson, A. J.; Neagu, I. B.; Pinkerton, A. A.;
Kirschbaum, K.; Hardie, M. J. Organometallics 1997, 16,
4346.
11. For recent discussion on reactions controlled by the Curtin–
Hammett principle, see: Wu, H.; Loeppky, R. N.; Glaser, R.
J. Org. Chem. 2005, 70, 6790; Yoon, U. C.; Kwon, H. C.;
Hyung, T. G.; Choi, K. H.; Oh, S. W.; Yang, S. R.; Zhao,
Z. M.; Mariano, P. S. J. Am. Chem. Soc. 2004, 126, 1110;
Adam, W.; Librera, C.; Trofimov, A. V. J. Am. Chem. Soc.
2004, 125, 5741; Adam, W.; Librera, C.; Trofimov, A. V.
J. Am. Chem. Soc. 2002, 124, 11936; Howell, S. J.; Ashton,
12. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: Oxford, 1988.