Ketone homologation to produce α-methoxyketones: Application to conduritol synthesis

Article abstract of DOI:10.1039/a703073h

The scope of Trost's sulfone homologation procedure for the conversion of ketones into their α-methoxylated higher homologues has been dramatically expanded. The use of zirconium (or hafnium) tetrachloride in the hydroxy sulfone rearrangement step gives g

Full text of DOI:10.1039/a703073h

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Ketone homologation to produce á-methoxyketones: application to
conduritol synthesis
Neil Phillipson,a Michael S. Anson,b John G. Montana †,b and
Richard J. K. Taylor *,‡,a
a
Department of Chemistry, University of York, York, UK Y01 5DD
b Glaxo Group Research, Ware, Herts, UK SG12 0DJ
The scope of Trost’s sulfone homologation procedure for the conversion of ketones into their á-
methoxylated higher homologues has been dramatically expanded. The use of zirconium (or hafnium)
tetrachloride in the hydroxy sulfone rearrangement step gives good yields with the adducts of aryl alkyl
ketones, dialkyl ketones and cycloalkanones, and the rearrangement occurs with total regioselectivity.
M echanistic observations are presented which account for the formation of á-hydroxy aldehydes as by-
products and which indicate an efficient method for their preparation. Application of the homologation
methodology to the stereoselective synthesis of dihydroconduritols is described.
acid-induced ring expansion to give the α-alkoxy ketone homo-
Introduction
logue 2. We decided to screen a variety of Lewis acids in an
attempt to extend the scope of the procedure beyond cyclobutyl
and cyclopentyl substrates. We therefore commenced our stud-
ies by investigating the homologation of acyclic ketones, and
chose 2Ј-methylacetophenone for the preliminary studies
(Scheme 2).
Procedures for the homologation of cyclic ketones with the
concomitant introduction of a substituent on the new carbon
atom 1,2 are extremely useful in natural product synthesis. The
sulfone-based alkoxymethylene homologation methodology
introduced by Trost and Mikhail (Scheme 1)3 has considerable
SO2Ph
MeO
O
MeO
O
SO2Ph
HO
OH
i. MeOCH(Li)SO2Ph
ii. H3O+
i
4 & 5
only
4a
1
ii
Bui2AlCl
O
OMe
OH
OHC
OMe
5 & 6
only
+
O
2
6a
5a
Scheme 1
Scheme 2 Reagents and conditions: i, PhSO2CH2OMe 3, BuLi, THF,
Ϫ78 ЊC (83%); ii, Lewis acid (see Table 1)
synthetic potential; for example, we4 and others,5 have applied
the method for the preparation of novel prostaglandins. The
scope of the published procedure is limited, however, in that it
has only been successfully applied to bicyclic cyclobutanones
and cyclopentanones (although the corresponding phenylthio
reagent is more versatile3). We decided to re-investigate this
reaction with a view to expanding its scope to include larger
cycloalkanones and acyclic ketones. Herein, we describe this
methodological study,6 and demonstrate the utility of the pro-
cedure for conduritol synthesis.
The lithium salt of [(methoxymethyl)sulfonyl]benzene 3
underwent smooth addition to 2Ј-methylacetophenone giving
β-hydroxy sulfones 4a as a separable 1:1 mixture of diastereo-
isomers in good yield. Treatment of 4a with excess diisobutyl-
aluminium chloride in dichloromethane at Ϫ78 ЊC produced a
complex product mixture (Table 1, entry i). However, other
Lewis acids proved to be more successful. Boron trifluoride–
diethyl ether gave 5a in 44% yield (entry ii), and magnesium()
chloride, mercury() trifluoroacetate and zinc() chloride all
gave the same product in even higher yields (entries iii–v).
Cerium() chloride gave no observable product but haf-
nium() and zirconium() chlorides gave particularly clean
transformations (entries vi–viii). The use of ZrCl4 at room tem-
perature (RT) gave a quantitative yield of the homologated
Results and discussion
Trost’s procedure involves the formation of a β-hydroxy sulfone
intermediate 1 (Scheme 1) followed by aluminium-based Lewis
1
ketone 5a according to H NMR spectroscopy (77% isolated
† Current address: Chiroscience, Cambridge Science Park, Milton
Road, Cambridge, UK CB4 4WE.
‡ E-Mail: rjkt1@york.ac.uk
yield after distillation). It is noteworthy that there was no
sign of the alternative regioisomer, arising from methyl group
J. Chem. Soc., Perkin Trans. 1, 1997
2821

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migration, in any of the reactions (although the by-product 6a
was observed in most cases—see later).
In all examples, the addition of the α-sulfonyl anion derived
from 3 proceeded efficiently giving sulfones 4b–f. Application
of the ZrCl4 rearrangement conditions to adduct 4b derived
from 4Ј-methylacetophenone (entry i) gave another encour-
aging result with the efficient, regioselective formation of 5b.
Whilst we had now succeeded in extending the Trost method-
ology to acyclic systems, aryl groups are well known to undergo
facile migration to an electron deficient centre.8 More signifi-
cant indications of the generality of this process came with the
successful homologation of aliphatic ketones (entries ii and iii).
The migrating group in entry ii is a saturated, primary alkyl
chain which offers little stabilisation of the electron deficient
centre in the reaction intermediate. The system also possesses
no ring strain to act as a driving force, and yet rearrangement
occurs to give 5c in a total yield of 85% (partial demethylation
was observed in this example). The efficient formation of 5d
(entry iii) provided a further example of alkyl group migration;
total regioselectivity was observed with the exclusive migration
of the secondary centre. The first examples of monocyclic ring
expansion with the simultaneous incorporation of an α-
oxygenated centre were provided by the successful formation of
cycloheptanone 5e and cyclooctanone 5f in acceptable yields
for medium size ring formation. In all of the cases illustrated in
Table 2, only the expected 1,8 regioisomer was formed: the novel
discovery is that, with the correct choice of Lewis acid, the
Trost homologation procedure has a far greater scope than was
originally realised.
Zirconium tetrachloride has not received very much atten-
tion as a Lewis acid 7 but the efficiency and regioselectivity of
this process are enhanced by its practical simplicity: the ZrCl4
is added as a powder to a solution of the sulfone in dichloro-
methane at room temperature, and the heterogeneous mixture
is stirred for 10 min before treatment with aqueous
NaHCO3. The use of fewer than six equivalents of the Lewis
acid gave a slower and less clean reaction. With this procedure
in hand, the scope of the methodology in terms of substrate
structure was investigated as illustrated in Table 2.
Table 1a,b
Entry
Lewis acid (equiv.)
Temperature
Ϫ78 ЊC
Ϫ78 ЊC to RT
RT
Ϫ78 ЊC to RT
RT
40 ЊC
RT
RT
Yieldof 5a b,c
i
ii
Bui2AlCl (6)
BF3ؒOEt2 (6)
MgBr2 (6)
Hg(COCF3)2 (6)
ZnCl2 (10)
CeCl3 (10)
HfCl4 (6)
d
44%
50%
70%
iii
iv
v
vi
vii
viii
75%
No reaction
80%e
99%f,g
ZrCl4 (6)
a
All reactions were carried out in dry CH2Cl2 under an inert atmos-
phere and followed by TLC; RT reactions were complete in a few min-
utes whereas those carried out at Ϫ78 ЊC took up to 5 h. b Varying
amounts of 6a were observed in most reactions (see text). c Estimated
by 1H NMR spectroscopy. d Complex mixture of products observed.
e 40% at Ϫ78 ЊC. f 77% isolated yield after distillation. g When the reac-
tion was carried out and quenched at Ϫ78 ЊC, the main product was 6a
(5a :6a = 1:7).
Mechanistic studies
Many of the reactions described above produced α-hydroxy
aldehydes (e.g. 6a) as minor by-products, and they often became
Table 2 Ketone homologation using ZrCl4 for homologation a
Entry
Ketone
Sulfone adduct 4
Homologated ketone 5
OMe
SO2Ph
OMe
Me
O
HO
i
Me
Me
O
5b, 75%
O
Me
Me
Me
4b, 90%
OMe
O
O
SO2Ph
CHMe2
Me2CH
HO
ii
CHMe2
Me2CH
Me2CH
CHMe2
OR
4c, 82%
5c, R = Me, 61%
R = H, 24%
OMe
SO2Ph
OMe
Me
HO
iii
Me
Me
Me
Me
Me
Me
O
Me
Me
O
5d, 87%
4d, 91%
OMe
O
HO
SO2Ph
OMe
iv
v
4e, 83%
5e, 51%
OMe
SO2Ph
O
O
HO
OMe
5f, 60%
4f, 92%
a
Carried out using 6 equiv. of ZrCl4 in dry CH2Cl2 at RT for 15 min under an inert atmosphere. Yields are of isolated, analytically pure, material.
2822
J. Chem. Soc., Perkin Trans. 1, 1997

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the major product if the reaction was carried out at low tem-
perature. We rationalise these observations in terms of a
semipinacol-type mechanism, as a concerted rearrangement–
sulfone cleavage sequence seems unlikely.
Thus, Lewis acid-mediated carbon–sulfur bond cleavage
would lead to the formation of the resonance-stabilised cation
7, which could be in equilibrium with epoxide 8 (Scheme 3).9 It
was isolated in 79% yield from a sample of the lithiated hydroxy
sulfone 4c-Li which had been allowed to warm to RT. An
authentic sample of 8c was prepared from enol ether 9, as
shown in Scheme 4, and was found to have identical properties
to the original sample. When attempts were made to pre-
pare other epoxides related to 8c using the same procedures,
the oxidation products were extremely labile undergoing
hydrolysis to the corresponding aldehydes over a period of
minutes. The unusual stability of epoxide 8c is therefore note-
worthy.
HO SO2Ph
R1
H
When epoxide 8c was treated with ZrCl4 in dichloromethane
at RT, ketones 5c (R = Me and H) were isolated in yields similar
to those obtained from rearrangement of hydroxy sulfone 4c
(Table 2). When epoxide 8c was treated with aqueous acid, α-
hydroxy aldehyde 6c was formed rapidly according to NMR
spectroscopy (although the reaction was not clean). A more
straightforward route to aldehyde 6c was to treat sulfone 4c
with ZrCl4 at Ϫ78 ЊC and quench at the same temperature.
Given the synthetic utility of α-hydroxy aldehydes,10 this new
method for their preparation warrants further study.
R2 OCH3
4
ZrCl4
– O
O
H
R1
R1
H
OCH3
OCH3
R2
R2
+
7
8
Application of the Trost homologation methodology to conduritol
synthesis
H3O +
RT
In order to demonstrate the potential of this methodology,
the conduritol synthesis, illustrated in retrosynthetic form
in Scheme 5, was investigated. We first established that
OH
O
O
H
R1
R2
OCH3
R1
R2
(a)
SO2Ph
OH
OH
O
OP
OH
OP
5
6
Scheme 3
HO
PO
OP
PO
OH
OP
seems likely that at low temperature the rearrangement pro-
ceeds slowly and an aqueous work-up generates significant
quantities of aldehyde 6. When the reaction is carried out at RT,
the rearrangement product 5 is the major, or exclusive, product.
Support for this proposal was obtained when, in a non-
reproducible reaction (Scheme 4), epoxide 8c (R1 = R2 = Pri)
10
Conduritols
O
PO
OP
(b)
i
SO2Ph
OMe
LiO
O
O
i
SO2Ph
MeO
ii
4c-Li
OH
OMe
OMe
OMe
ii
iii
OMe
5g
O
4g
O
OCH3
OCH3
Scheme 5 (a) Retrosynthetic route for conduritol synthesis; (b)
Reagents and conditions: i, PhSO2CH2OMe 3, BuLi, THF, Ϫ78 ЊC
(67%); ii, ZrCl4, CH2Cl2, RT (ca. 40%; see text); or HfCl4, CH2Cl2, RT
(65%; cis:trans = 2.4:1)
9
8c
v
iv
O
2-alkoxycyclopentanones underwent the ring expansion effi-
ciently and with the required regiochemistry (Scheme 5). Add-
ition of the lithium salt of [(methoxymethyl)sulfonyl]benzene
3 to 2-methoxycyclopentanone11 proceeded efficiently to give
adduct 4g, but the standard zirconium tetrachloride procedure
produced a mixture of the required product 5g (ca. 40% by
NMR estimate) and an aldehydic by-product. Changing to haf-
nium tetrachloride, however, gave the separable cis- and trans-
2,3-dimethoxycyclohexanones (5g, 65%) with only a trace of
aldehyde being present according to an NMR analysis of the
crude reaction product. The process was totally regioselective
with the oxygenated centre migrating preferentially (as
expected 12).
HO
CHO
vi
OR
6c
5c
R = Me, H
HO
SO2Ph
MeO
4c
Scheme 4 Reagents and conditions: i, 3, BuLi, THF, Ϫ78 ЊC to RT
(79%); ii, Ph3PCH2OCH3ؒCl, BuLi, diethyl ether, Ϫ12 ЊC (21%); iii,
dimethyldioxirane, acetone, Ϫ12 ЊC (69%); iv, 6 equiv. ZrCl4, CH2Cl2,
RT (R = Me, 51%; R = H, 18%); v, AcOH–H2O, acetone, RT (see text);
vi, 6 equiv. ZrCl4, CH2Cl2, Ϫ78 ЊC then aq. NaHCO3 (81%)
With this promising model study successfully completed we
went on to prepare an adduct of type 10. This chemistry, which
J. Chem. Soc., Perkin Trans. 1, 1997
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SO2Ph
OCH3
O
O
ii
i
OH
X
OCH3
O
O
O
O
O
O
11
12
13
iii
SO2Ph
OCH3
O
OH
O
iv
OH
v
vi
O
OCH3
O
OCH3
O
O
O
O
O
O
17
14
15
16
[α]D – 50
viii
vii
OH
OH
OH
OH
ix
O
OCH3
HO
HO
OH
O
OH
OH
20
19
18
[α]D – 36 (Lit.,16 – 35.8)
Scheme 6 Reagents and conditions: i, PhSO2CH2OCH3, BuLi, THF, Ϫ78 ЊC (77%); ii, range of Lewis acids/reaction conditions; iii, H2, 10% Pd/C,
EtOAc (95%); iv, as i (87%); v, 6 equiv. ZrCl4, CH2Cl2 (51–84%; see text); vi, NaBH4, MeOH, Ϫ12 ЊC (81%); vii, 40 equiv. BCl3, CH2Cl2, Ϫ78 ЊC to
RT (97%); viii, 2 equiv. PPh3, 2 equiv. DEAD, 2 equiv. p-NO2C6H4CO2H, C6H6, then 2 equiv. LiOHؒH2O, MeOH (22%); ix, as vii (91%)
commences with the known 13,14 chiral pool derived cyclopent-
enone 11, is shown in Scheme 6. Addition of the anion derived
from [(methoxymethyl)sulfonyl]benzene 3 proceeded with total
β-stereoselectivity to give hydroxy sulfone 12 as a separable
mixture of two diastereoisomers. Treatment of 12 with six
equivalents of zirconium tetrachloride in dichloromethane at
RT in an attempt to prepare 13 gave an inseparable mixture of
several products. The low material recovery after aqueous
work-up was also disappointing, suggesting loss of the acetal
protecting group. Several sets of conditions were screened in an
attempt to overcome this problem, but to date it seems that α,β-
unsaturated ketones are not suitable substrates for the Trost
ring expansion methodology.
We therefore adapted the synthetic route by operating on the
saturated system 14, readily prepared by hydrogenation of 11.
Formation of β-hydroxy sulfones 15 proceeded in excellent
yield, the product again being a separable mixture of two dia-
stereoisomers. Treatment of either diastereoisomer, or a mix-
ture, with excess zirconium tetrachloride in dichloromethane at
RT gave clean formation of the desired ring-expanded ketone
16. The regioselectivity was expected from the model studies; a
little more surprising was the fact the process was also stereo-
selective giving only the all syn-diastereoisomer 16. The
recovery from the zirconium tetrachloride-mediated reaction
was disappointing, and some effort was required to optimise the
yield. It was eventually found that by using zirconium tetra-
chloride which had been sublimed in an inert atmosphere
immediately before use, and by quenching the reaction with
aqueous THF instead of NaHCO3, a good yield was obtained.
The use of more robust protecting groups should alleviate the
need for these special conditions. NOE studies failed to provide
conclusive evidence for the stereochemistry at C-2, although
the proposed structure was ultimately confirmed by subsequent
transformation to a known compound.
Reduction of the ketone 16 with sodium borohydride in
methanol gave alcohol 17 as a single stereoisomer. Deprotec-
tion of 17 was achieved using boron trichloride in dichloro-
methane:15 NMR studies showed that the acetal was rapidly
removed at Ϫ78 ЊC whereas demethylation required warming to
RT. This sequence gave meso-dihydroconduritol D 18. The sim-
plicity of the NMR spectra reflected the symmetry of the mol-
ecule and provided final confirmation of the earlier, tentative
stereochemical assignments. Mitsunobu inversion of 17 gave
the epimeric alcohol 19, albeit in low, unoptimised yield.
Deprotection using boron trichloride gave (Ϫ)-dihydrocon-
duritol C 20. Compound 20 is known and its physical and
spectroscopic properties were in good agreement with those
reported in the literature.16
Summary
The use of zirconium tetrachloride facilitates a high yielding
homologation of ketones into α-methoxy ketones via the inter-
mediacy of β-hydroxy sulfones. The procedure is operationally
simple, totally regioselective, and is applicable to a wide range
of substrates including bicyclic, monocyclic and acyclic
ketones. The homologation procedure has been applied to pre-
pare (Ϫ)-dihydroconduritol C and meso-dihydroconduritol D
and, with the use of more robust protecting groups this new
method should prove to be of general synthetic utility. The suc-
cessful regioselective homologation of α-oxygenated ketones
suggests that the process should be capable of iteration (Scheme
7) and therefore prove useful in the construction of polyoxy-
genated carbon frameworks.
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once with brine and then dried (MgSO4). The solvent was evap-
OR
O
O
orated at reduced pressure to give a colourless liquid (22.0 g)
which was purified by distillation at reduced pressure to give
[(methoxymethyl)thio]benzene17 (17.8 g, 83%) as a colourless
liquid, bp 85–90 ЊC/3 mmHg; Rf 0.2 (petrol); δH (60 MHz) 3.40
(3 H, s, CH3), 4.95 (2 H, s, CH2) and 7.20–7.60 (5 H, m, ArH).
(b) A solution of Oxone (72.0 g, 117 mmol) in H2O (400 ml)
was added to a stirred solution of [(methoxymethyl)thio]ben-
zene (13.0 g, 84 mmol) in methanol (200 ml) at 5 ЊC. The result-
ant slurry was stirred at 5 ЊC for 1 h and at RT for 3 h before the
excess Oxone was dissolved in water. The mixture was
extracted three times with ether and the combined extracts were
washed with brine and dried (MgSO4). The solvent was evapor-
ated at reduced pressure to give a waxy white solid (15.7 g)
which was purified by recrystallisation from ethanol–petrol to
give the title compound 3 (14.0 g, 89%) as a white crystalline
solid, mp 74 ЊC (lit.,18 74–75 ЊC); Rf 0.6 (ethyl acetate–petrol,
1:1) which was fully characterised.
HO
SO2Ph
OR
OR
OR
ZrCl4
OR
repeat
n times
O
OR
n+1
OR
Scheme 7
Experimental
Preparation of â-hydroxy sulfones
General
Representative procedure: 1-methoxy-2-(2-methylphenyl)-1-
(phenylsulfonyl)propan-2-ol 4a. BuLi (1.52  in hexane, 3.89
ml, 5.91 mmol) was added dropwise to a stirred solution of
sulfone 3 (1.10 g, 5.91 mmol) in dry THF (70 ml) at Ϫ78 ЊC
under a nitrogen atmosphere. The resulting yellow solution was
stirred at Ϫ78 ЊC for 15 min before a solution of 2Ј-methyl-
acetophenone (790 mg, 5.89 mmol) in dry THF (20 ml) at
Ϫ78 ЊC was added via a double tipped needle under pressure
of nitrogen. After stirring for a further 30 min at Ϫ78 ЊC the
mixture was allowed to warm to RT and saturated aqueous
NH4Cl (20 ml) was added. Standard aqueous work-up (ethyl
acetate) gave a pale yellow oil (1.95 g) which was purified by
chromatography (petrol–ether, 3:1) to give the title compound
4a (1.56 g, 83%) as two separable diastereoisomers.
Diastereoisomer 1 (775 mg, 41%) was obtained as a white
solid, Rf 0.4 (petrol–ether, 1:1) (Found: C, 63.8; H, 6.2; S, 10.25.
C17H20O4S requires C, 63.7; H, 6.3; S, 10.0%); νmax(CDCl3)/cmϪ1
3509, 1304 and 1143; δH (270 MHz) 1.85 (3 H, s, CH3CO), 2.56
(3 H, s, ArCH3), 2.90 (3 H, s, OCH3), 4.13 (1 H, s, OH), 4.56 (1
H, s, 1-H) and 7.06–7.92 (9 H, m, ArH); δC(22.4 MHz) 22.8,
25.4, 62.6, 78.0, 100.6, 125.8, 127.8, 128.0, 129.1, 132.6, 134.0,
136.1, 139.1 and 140.35; m/z (EI) 135 (M Ϫ CH3OCHSO2Ph,
100%).
Diastereoisomer 2 (780 mg, 41%) was obtained as a colourless
oil, Rf 0.3 (petrol–ether, 1:1) (Found: C, 63.4; H, 6.2; S, 10.0.
C17H20O4S requires C, 63.7; H, 6.3; S, 10.0%); νmax(CDCl3)/cmϪ1
3502, 1304 and 1141; δH (90 MHz) 1.91 (3 H, s, CH3CO), 2.53 (3
H, s, ArCH3), 3.15 (3 H, s, OCH3), 4.58 (1 H, s, 1-H) and 7.01–
7.85 (9 H, m, ArH); δC(22.4 MHz) 22.4, 26.5, 62.6, 77.5, 101.9,
125.6, 127.5, 128.6, 129.0, 129.25, 132.5, 133.6, 133.9, 134.0 and
134.7; m/z (EI) 135 (M Ϫ CH3OCHSO2Ph, 100%).
1-Methoxy-2-(4-methylphenyl)-1-phenylsulfonylpropan-2-ol
4b. Using the representative procedure with sulfone 3 (1.44 g,
7.73 mmol) and 4Ј-methylacetophenone (1.02 g, 7.61 mmol)
gave a crude product (2.67 g) as a pale yellow oil. Purification
by chromatography (petrol–ethyl acetate, 6:1) gave the title
compound 4b (2.18 g, 90%) as two separable diastereoisomers.
Diastereoisomer 1 (912 mg, 38%) was obtained as a white
solid, Rf 0.3 (petrol–ether, 1:1) (Found: C, 63.75; H, 6.2;
S, 10.05. C17H20O4S requires C, 63.7; H, 6.3; S, 10.0%);
νmax(CDCl3)/cmϪ1 3494, 1296 and 1139; δH (270 MHz) 1.69 (3 H,
s, CH3CO), 2.27 (3 H, s, ArCH3), 3.49 (3 H, s, OCH3), 4.19 (1 H,
s, OH), 4.46 (1 H, s, 1-H), 6.91 (2 H, AB d, J 8.65, ArH), 7.20–
7.32 (4 H, m, ArH) and 7.43–7.53 (3 H, m, ArH); δC(67.8 MHz)
20.9, 28.3, 63.0, 75.6, 104.4, 125.2, 128.2, 128.45, 129.3, 133.1,
136.7, 136.9 and 139.5; m/z (CI) 338 ([M ϩ NH4]ϩ, 100%).
Diastereoisomer 2 (1.27 g, 52%) was obtained as a white
solid, Rf 0.3 (petrol–ether, 1:1) (Found: C, 63.8; H, 6.1; S, 10.1.
C17H20O4S requires C, 63.7; H, 6.3; S, 10.0%); νmax(CDCl3)/cmϪ1
3500, 1297 and 1144; δH (270 MHz) 1.76 (3 H, s, CH3CO), 2.31
NMR spectra were recorded on JEOL PMX 60 (60 MHz),
JEOL EX 90 (90 MHz), JEOL GX-270 (270 MHz), JEOL GX-
400 (400 MHz), Bruker WM 250 (250 MHz) and Bruker AMX
500 (500 MHz) instruments using CDCl3 as solvent unless
otherwise stated. Tetramethylsilane (TMS) or CDCl3–CHCl3
was used as the internal standard. Coupling constants (J ) are
in Hz to the nearest 0.5 Hz. Melting points were recorded on a
Kopfler hot-stage or Electrothermal melting point apparatus
and are uncorrected. Infrared (IR) spectra were recorded on
Perkin-Elmer 1720-X or ATI Mattson Genesis FT-IR spectro-
meters. Low resolution electron impact (EI) mass spectra were
recorded on a Kratos MS 25 spectrometer. Chemical ionisation
(CI) and high resolution mass spectra were recorded on a Fisons
Analytical (VG) Autospec spectrometer. Optical rotations were
recorded at ambient temperature on a Jasco DIP-370 polar-
imeter and values are given in units of 10Ϫ1 deg cm2 gϪ1. Con-
centration (c) is expressed in g 100 mlϪ1. Standard aqueous
work-up was performed as follows: the mixture was diluted
with water and extracted three times with the specified solvent;
the combined extracts were washed with brine, dried (MgSO4
unless stated) and concentrated at reduced pressure. Chroma-
tography is flash column chromatography and was performed
using May and Baker Sorbsil C60 silica gel under pressure
of nitrogen using the eluent specified. Ether is diethyl ether.
Where necessary ether and THF were distilled from sodium–
benzophenone ketyl immediately before use. Dichloromethane
was distilled from calcium hydride. Petrol refers to the fraction
of light petroleum boiling in the range 40–60 ЊC and was re-
distilled prior to use. Brine is saturated aqueous sodium chlor-
ide. Water is distilled water. Except where specified, all reagents
were purchased from commercial sources and were used
without further purification. 2-Methoxycyclopentanone11a was
obtained by pyridinium chlorochromate oxidation of the
corresponding alcohol (which was prepared by modification of
a literature procedure11b used for 2-alkoxycyclohexanones).
[(Methoxymethyl)sulfonyl]benzene 3
(a) Potassium tert-butoxide (30.7 g, 274 mmol) was added por-
tionwise to a stirred solution of thiophenol (30.14 g, 28.1 ml,
274 mmol) in dry DMF (250 ml) at 5 ЊC under a nitrogen
atmosphere. When addition was complete the solution was
allowed to warm quickly to room temperature (RT) and stirred
for 1 h. A solution of chloromethoxymethane (CAUTION:
known carcinogen) (11.27 g, 11.5 ml, 140 mmol) in dry DMF
(150 ml) was added via a double tipped needle under pressure of
nitrogen. Stirring was continued for a further 3 h before satur-
ated aqueous ammonium chloride (100 ml) was added. The
aqueous phase was extracted twice with ether and the combined
organic phases washed twice with water, twice with 10% NaOH,
J. Chem. Soc., Perkin Trans. 1, 1997
2825

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(3 H, s, ArCH3), 2.91 (3 H, s, OCH3), 4.13 (1 H, s, OH), 4.20 (1
H, s, 1-H), 7.11 (2 H, AB d, J 8.5, ArH), 7.36 (2 H, AB d, J 8.5,
ArH), 7.51–7.56 (2 H, m, ArH), 7.62–7.68 (1 H, m, ArH) and
7.88–7.92 (2 H, m, ArH); δC(67.8 MHz) 20.95, 24.2, 62.7, 76.0,
102.6, 125.8, 128.7, 129.0, 133.9, 137.3, 138.9 and 140.4; m/z
(CI) 338 ([M ϩ NH4]ϩ, 100%).
8.0. C11H14O2 requires C, 74.1; H, 7.9%); νmax(neat)/cmϪ1 1717;
δH (90 MHz) 2.10 (3 H, s, CH3CO), 2.38 (3 H, s, ArCH3), 3.35 (3
H, s, OCH3), 4.84 (1 H, s, 1-H) and 7.16–7.45 (4 H, m, ArH);
δC(22.4 MHz) 19.45, 25.3, 57.1, 86.9, 126.4, 127.3, 128.5, 131.0,
134.3, 136.9 and 206.25; m/z (EI) 178 (Mϩ, 1%), 135
(M Ϫ COCH3, 100).
2,6-Dimethyl-4-[(methoxy)(phenylsulfonyl)methyl]heptan-4-ol
4c. Using the representative procedure with sulfone 3 (1.95 g,
10.5 mmol) and 2,6-dimethylheptan-4-one (1.49 g, 10.5 mmol)
gave a crude product (3.40 g) as a pale yellow oil. Purification
by chromatography (petrol–ethyl acetate, 6:1) gave the title
compound 4c (2.82 g, 82%) as a colourless oil, Rf 0.5 (petrol–
ether, 1:1); νmax(neat)/cmϪ1 3517, 1300 and 1137; δH (270 MHz)
0.91 (3 H, d, J 6.5, CH3), 0.94 (3 H, d, J 6.5, CH3), 1.00 (3 H, d, J
6.5, CH3), 1.02 (3 H, d, J 6.5, CH3), 1.57–1.69 (4 H, m, CH2),
1.72–1.95 (2 H, m, CH), 3.36 (3 H, s, OCH3), 3.57 (1 H, br s,
OH), 4.35 (1 H, s, OCHS), 7.50–7.74 (3 H, m, ArH) and 7.96 (2
H, m, ArH); δC(67.8 MHz) 23.6, 23.7, 24.0, 24.35, 24.7, 24.8,
44.2, 44.3, 62.1, 78.7, 102.5, 128.9, 129.0, 133.8 and 139.7.
1-Methoxy-1-(4-methylphenyl)propan-2-one 5b. Using the
representative procedure with sulfone 4b (880 mg, 2.75 mmol)
gave a crude product (550 mg) as a yellow liquid. Purification
by chromatography (petrol–ether, 5:1) gave the title compound
5b (367 mg, 75%) as a colourless liquid which was fully charac-
terised and exhibited data corresponding to literature19 values.
2,7-Dimethyl-5-methoxyoctan-4-one 5c. Using the representa-
tive procedure with sulfone 4c (359 mg, 1.09 mmol) gave a crude
product (230 mg) as a yellow liquid. Purification by chrom-
atography (petrol–ether, 10:1) gave the title compound 5c
(R = Me) (123 mg, 61%) as a colourless liquid, Rf 0.3 (petrol–
ethyl acetate, 4:1) (Found: C, 70.95; H, 11.65. C11H22O2
requires C, 70.9; H, 11.9%); νmax(neat)/cmϪ1 1714 (C᎐O); δ (270
᎐
H
1-Methoxy-2,3-dimethyl-1-phenylsulfonylpentan-2-ol
4d.
MHz) 0.98 (3 H, d, J 6.5, CH3), 0.99 (3 H, d, J 6.5, CH3), 1.00 (6
H, d, J 6.5, 2 × CH3), 1.38 (1 H, ddd, J 4.5, 8.5 and 14.5, 6-H),
1.58 (1 H, ddd, J 5.5, 9.0 and 14.5, 6-H), 1.71–1.88 (1 H, m, 7-
H), 2.19 (1 H, septet, J 6.5, 2-H), 2.35 and 2.41 (1 H, dd and 1
H, dd, J 17.0 and 6.5, ABX, 3-H), 3.34 (3 H, s, OCH3) and 3.60
(1 H, dd, J 4.5 and 9.0, 5-H); δC(67.8 MHz) 21.8, 22.6, 22.6,
23.1, 23.6, 24.5, 40.8, 46.0, 58.1, 86.05 and 213.0; m/z (EI)
186 (Mϩ, 0.3%) and 101 (M Ϫ C5H9O, 100). 2,7-Dimethyl-5-
hydroxyoctan-4-one 5c (R = H)20 (45 mg, 24%) was also isol-
ated as a colourless liquid, Rf 0.2 (petrol–ethyl acetate, 4:1) and
was fully characterised.
Using the representative procedure with sulfone 3 (2.79 g, 15.0
mmol) and 3-methylpentan-2-one (1.50 g, 15.0 mmol) gave a
crude product (4.35 g) as a yellow oil. Purification by chrom-
atography (cyclohexane–ethyl acetate, 5:1) gave the title com-
pound 4d (3.90 g, 91%) as a colourless oil and as a mixture of
diastereoisomers, Rf 0.28 and 0.31 (petrol–ethyl acetate, 3:1);
m/z (CI) 304 [(M ϩ NH4)ϩ, 65%], 287 ([M ϩ H]ϩ, 5) and 162
(100). This mixture decomposed over a period of days at
Ϫ20 ЊC and was therefore used immediately.
1-[(Methoxy)(phenylsulfonyl)methyl]cyclohexan-1-ol
4e.
Using the representative procedure with sulfone 3 (1.00 g, 5.37
mmol) and cyclohexanone (527 mg, 5.37 mmol) gave a crude
product (1.59 g) as a yellow oil. Purification by chromatography
(petrol–ethyl acetate, 3:1) gave the title compound 4e (1.27 g,
83%) as a colourless oil, Rf 0.2 (petrol–ethyl acetate, 2:1);
νmax(neat)/cmϪ1 3527, 1302 and 1149; δH (270 MHz) 1.50–1.91
(10 H, m, remainder), 3.08 (1 H, br s, OH), 3.29 (3 H, s, OCH3),
4.06 (1 H, s, OCHS), 7.56–7.71 (3 H, m, ArH) and 7.95–7.99
(2 H, m, ArH); δC(67.8 MHz) 20.95, 25.2, 32.8, 33.95, 62.7,
74.9, 103.0, 129.0, 129.2, 133.9 and 139.0; m/z (CI) 302
[(M ϩ NH4]ϩ, 50%), 285 ([M ϩ H]ϩ, 20) and 143 (M Ϫ
SO2Ph, 100) (Found: 285.115 734. C14H21O4S requires [M ϩ
H]ϩ, 285.116 056; 1.1 ppm error).
3-Methoxy-4-methylhexan-2-one 5d. Using the representative
procedure with sulfone 4d (116 mg, 0.41 mmol) gave a crude
product (56.7 mg) as a yellow liquid. Purification by chrom-
atography (petrol–ether, 10:1) gave the title compound 5d (50.6
mg, 87%) as a colourless liquid and as an inseparable mixture
of diastereoisomers (ca. 1.5:1 by NMR), Rf 0.3 (petrol–ethyl
acetate, 3:1); νmax(neat)/cmϪ1 1716; δH (270 MHz) (data for the
minor isomer is listed first) 0.76 (3 H, d, J 7.0, 4-CH3 minor),
0.79 (3 H, d, J 6.5, 4-CH3 major), 0.83 (6 H, t, J 7.5, 2 × 6-CH3),
0.88–1.69 (6 H, m, 2 × H-4 and 2 × 5-CH2), 2.05 (3 H, s, 1-CH3
minor), 2.06 (3 H, s, 1-CH3 major), 3.16 (1 H, d, J 7.5, 3-H
minor), 3.34 (1 H, d, J 5.0, 3-H major), 3.25 (3 H, s, OCH3
minor) and 3.27 (3 H, s, OCH3 major); δC(67.8 MHz) (data for
the minor isomer is listed first) 11.1 and 11.6, 14.8 and 14.2,
25.5 and 24.7, 26.1 and 25.8, 37.0 and 37.5, 58.6 and 58.85, 92.0
and 90.6, and 210.9 and 211.9; m/z (CI) 162 ([M ϩ NH4]ϩ, 98%),
145 ([M ϩ H]ϩ, 100) [Found (CI): 162.149 824. C8H16O2
requires [M ϩ NH4]ϩ, 162.149 404; 2.6 ppm error].
2-Methoxycycloheptan-1-one 5e. Using the representative
procedure with sulfone 4e (580 mg, 2.04 mmol) gave a crude
product (319 mg) as a yellow liquid. Purification by column
chromatography on silica gel using petrol–ether (7:1) as eluent
gave the title compound 5e21 (147 mg, 51%) as a colourless
liquid, Rf 0.4 (petrol–ethyl acetate, 4:1); νmax(neat)/cmϪ1 1712;
δH (270 MHz) 1.45–1.92 (8 H, m, remainder), 2.39–2.62 (2 H, m,
7-CH2), 3.36 (3 H, s, OCH3) and 3.89 (1 H, dd, J 3.0 and 8.0,
H-2); δC(67.8 MHz) 23.2, 25.5, 28.4, 31.1, 40.7, 57.5, 86.4
and 212.4; m/z (CI) 160 ([M ϩ NH4]ϩ, 40%), 143 ([M ϩ H]ϩ,
85) (Found: 160.133 244. C8H14O2 requires [M ϩ NH4]ϩ,
160.133 754; 3.2 ppm error).
1-[(Methoxy)(phenylsulfonyl)methyl]cycloheptan-1-ol
4f.
Using the representative procedure with sulfone 3 (1.50 g, 8.05
mmol) and cycloheptanone (900 mg, 8.03 mmol) gave a crude
product (2.50 g) as a yellow oil. Purification by chromatography
(petrol–ethyl acetate, 3:1) gave the title compound 4f (2.20 g,
92%) as a colourless oil, Rf 0.3 (petrol–ethyl acetate, 2:1);
νmax(neat)/cmϪ1 3513, 1306 and 1151; δH (270 MHz) 1.48–2.03
(12 H, m, remainder), 3.08 (1 H, br s, OH), 3.30 (3 H, s, OCH3),
4.13 (1 H, s, OCHS), 7.53–7.72 (3 H, m, ArH) and 7.95–8.00 (2
H, m, ArH); δC(67.8 MHz) 21.7, 21.8, 29.4, 29.7, 36.7, 38.8,
62.7, 78.4, 104.2, 129.0, 129.2, 133.9 and 139.1; m/z (CI) 316
([M ϩ NH4]ϩ, 50%), 299 ([M ϩ H]ϩ, 30), 157 (M Ϫ SO2Ph,
100) (Found: 316.158 363. C15H26NO4S requires [M ϩ NH4]ϩ,
316.158 255; 0.3 ppm error).
Preparation of homologated ketones using ZrCl4
Representative procedure: 1-methoxy-1-(2-methylphenyl)prop-
an-2-one 5a. ZrCl4 (1.25 g, 5.36 mmol) was added to a stirred
solution of β-hydroxy sulfone 4a (300 mg, 0.94 mmol) in dry
CH2Cl2 (40 ml) at RT under a nitrogen atmosphere. The result-
ing brown mixture was stirred for 15 min before TLC analysis
showed complete conversion to a single product. Saturated
aqueous NaHCO3 (15 ml) was added. The mixture was diluted
with ethyl acetate and filtered through a plug of Celite, and the
filtrate was washed with water. Standard aqueous work-up
(ethyl acetate) gave the title compound 5a (165 mg, 99%) as a
pale yellow liquid, Rf 0.6 (petrol–ether, 1:1) (Found: C, 74.3; H,
2-Methoxycyclooctan-1-one 5f. Using the representative pro-
cedure with sulfone 4f (561 mg, 1.88 mmol) gave a crude prod-
uct (308 mg) as a yellow liquid. Purification by chromatography
(petrol–ether, 9:1) gave the title compound 5f (176 mg, 60%) as
a colourless liquid, Rf 0.2 (petrol–ethyl acetate, 9:1) which was
fully characterised and exhibited data corresponding to liter-
ature values.22
2,2-Diisobutyl-3-methoxyoxirane 8c. (a) BuLi (1.55  in hex-
ane, 5.64 ml, 8.74 mmol) was added dropwise to a stirred solu-
tion of (methoxymethyl)triphenylphosphonium chloride (3.00
2826
J. Chem. Soc., Perkin Trans. 1, 1997

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g, 8.75 mol) in dry ether (150 ml) at Ϫ10 ЊC under a nitrogen
atmosphere. The resulting orange solution was stirred at
Ϫ10 ЊC for 30 min before a solution of 2,6-dimethylheptan-4-
one (1.13 g, 7.94 mmol) in dry ether (50 ml) at RT was added via
a double tipped needle under pressure of nitrogen. The mixture
was allowed to warm slowly to RT and stirred overnight. After
a total of 15 h the yellow mixture was poured into a separatory
funnel containing saturated aqueous NH4Cl (100 ml). Standard
aqueous work-up (ethyl acetate) gave a deep yellow oil which
was purified by chromatography (petrol) to give the enol ether 9
(290 mg, 21%) as a colourless liquid, Rf 0.5 (petrol) which was
fully characterised.
(b) Dimethyldioxirane (ca. 0.09  in acetone, 15 ml, 1.35
mmol) was rapidly added to enol ether 9 (1.90 mg, 1.12 mmol)
at 2 ЊC. After standing for 5 min TLC analysis showed the start-
ing material to have been consumed. The solvent was evapor-
ated at reduced pressure and the residue dissolved in CH2Cl2
and dried (Na2SO4). Filtration and concentration gave the title
compound 8c (143 mg, 69%) as a colourless liquid (which could
be further purified by chromatography using petrol–ether, 5:1),
Rf 0.3 (petrol); νmax(neat)/cmϪ1 2957, 1466, 1151 and 1098;
δH (270 MHz) 0.91, 0.93, 0.95 and 0.98 (12 H, d, J 6.5, 4 × CH3),
1.17 (1 H, dd, J 14.0 and 8.0, CH2), 1.53–1.63 (3 H, m, CH2),
1.68–1.91 (2 H, m, CH), 3.50 (3 H, s, OCH3) and 4.21 (1 H, s,
1-H); δC(67.8 MHz) 22.7, 22.8, 22.9, 23.2, 24.9, 25.0, 37.1, 42.3,
56.2, 63.65 and 87.1; m/z (CI) 204 ([M ϩ NH4]ϩ, 18%), 187
([M ϩ H]ϩ, 85) [Found (CI): 187.169 280. C11H23O2 requires
[M ϩ H]ϩ, 187.169 805; 2.8 ppm error].
2,7-Dimethyl-5-methoxyoctan-4-one 5c from epoxide 8c. Zir-
conium tetrachloride (230 mg, 0.99 mmol) was added to a
stirred solution of epoxide 8c (37 mg, 0.20 mmol) in dry CH2Cl2
(10 ml) at RT under a nitrogen atmosphere. The resulting bright
pink mixture was stirred for 30 min before saturated aqueous
NaHCO3 (10 ml) was added. The mixture was diluted with
CH2Cl2 and filtered through a plug of Celite, and the filtrate
was washed with water. Standard aqueous work-up (ethyl acet-
ate, Na2SO4) gave the crude product as a yellow liquid which was
purified by chromatography (petrol–ethyl acetate, 10:1) to give
the title compound 5c (R = Me) (19 mg, 51%) as a colourless
liquid. 2,7-Dimethyl-5-hydroxyoctan-4-one 5c (R = H) (6 mg,
18%) was also isolated as a colourless liquid. Spectroscopic data
for these compounds were consistent with that reported above.
2,6-Dimethyl-4-formylheptan-4-ol 6c. Zirconium tetra-
chloride (600 mg, 2.57 mmol) was added to a stirred solution of
β-hydroxy sulfone 4c (213 mg, 0.65 mmol) in dry CH2Cl2 at
Ϫ78 ЊC under a nitrogen atmosphere. The mixture was stirred
for 30 min before saturated aqueous NaHCO3 (10 ml) was
added. The mixture was diluted with ethyl acetate and filtered
through a plug of Celite, and the filtrate was washed with water.
The aqueous phase was extracted twice with ethyl acetate and
the combined organic phases washed with brine and dried
(MgSO4). The solvent was evaporated at reduced pressure to
give a pale yellow liquid (120 mg) which was purified by column
chromatography on silica gel using petrol–ethyl acetate (10:1)
as eluent to give the title compound 6c (91 mg, 81%) as a colour-
less liquid, Rf 0.3 (petrol); νmax(neat)/cmϪ1 3509 and 1727;
δH (270 MHz) 0.76 (3 H, d, J 5.5, CH3), 0.77 (3 H, d, J 6.5, CH3),
0.87 (3 H, d, J 5.5, CH3), 0.89 (3 H, d, J 6.5, CH3), 1.48–1.71
(6 H, m, 2 × CH2 and 2 × CH), 3.25 (1 H, s, OH) and 9.51
(1 H, s, CHO); δC(67.8 MHz) 23.5, 23.8, 24.35, 46.1, 81.2 and
205.0; m/z (CI) 190 ([M ϩ NH4]ϩ, 100%) and 173 ([M ϩ H]ϩ,
20%) (Found: 190.180 282. C10H20O2 requires [M ϩ NH4]ϩ,
190.180 704; 2.2 ppm error).
was purified by chromatography (petrol–ether, 5:1) to give the
title compound 4g (1.14 g, 67%) (Found: C, 56.2; H, 6.7; S, 10.4.
C14H20O5S requires C, 56.0; H, 6.7; S, 10.7%) as two separable
diastereoisomers.
Diastereoisomer 1 (625 mg, 37%) was obtained as a white
solid, mp 80–81 ЊC; Rf 0.4 (ethyl acetate–petrol, 1:1);
νmax(CHCl3)/cmϪ1 3525, 1305 and 1140; δH (400 MHz) 1.47–2.03
(6 H, m, 3-H, 4-H and 5-H), 3.38 (3 H, s, OCH3), 3.45 (3 H, s,
OCH3), 3.89 (1 H, dd, J 6.5 and 7.0, 2-H), 4.22 (1 H, s, 1Ј-H),
7.55–7.58 (2 H, m, ArH), 7.65 (1 H, tt, J 1.5 and 7.5, ArH) and
7.96–7.99 (2 H, m, ArH); δC(22.4 MHz) 19.8, 29.0, 35.3, 57.3,
62.3, 80.8, 81.6, 101.7, 128.3, 129.0, 133.2 and 138.9; m/z (EI) 71
(100%).
Diastereoisomer 2 (512 mg, 30%) was obtained as a colourless
oil, Rf 0.3 (ethyl acetate–petrol, 1:1); νmax(neat)/cmϪ1 3501, 1305
and 1145; δH (400 MHz) 1.33–1.89 (6 H, m, 3-H, 4-H and 5-H),
2.91 (1 H, br s, OH), 3.29 (3 H, s, OCH3), 3.41 (3 H, s, OCH3),
3.51 (1 H, dd, J 7.5 and 9.5, 2-H), 4.21 (1 H, s, 1Ј-H), 7.44–7.48
(2 H, m, ArH), 7.57 (1 H, tt, J 1.5 and 7.5, ArH) and 7.82–7.90
(2 H, m, ArH); δC(100 MHz) 18.8, 26.1, 29.7, 57.4, 62.45,
80.9, 83.1, 99.5, 128.7, 129.3, 133.6 and 138.8; m/z (EI) 71
(100%).
cis- and trans-2,3-Dimethoxycyclohexan-1-one 5g. HfCl4 (2.45
g, 7.64 mmol) was added to a stirred solution of β-hydroxy
sulfone 4g (418 mg, 1.39 mmol) in dry CH2Cl2 (50 ml) at RT
under a nitrogen atmosphere. The resulting brown mixture was
stirred for 30 min before TLC analysis showed the starting
material to have been consumed. Saturated aqueous NaHCO3
(15 ml) was added. The mixture was diluted with ethyl acetate
and filtered through a plug of Celite, and the filtrate was
washed with water. Standard aqueous work-up (ether) gave a
yellow liquid (223 mg) which was purified by chromatography
(petrol–ether, 3:1) to give the title compound 5g (144 mg, 65%)
as two separable diastereoisomers.
cis-2,3-Dimethoxycyclohexan-1-one (102 mg, 46%) was
obtained as a colourless liquid, Rf 0.2 (petrol–ether, 1:2)
(Found: C, 60.9; H, 8.9. C8H14O3 requires C, 60.7; H, 8.9%);
νmax(neat)/cmϪ1 1728; δH (400 MHz) 1.67–1.76 (2 H, m, 5-H),
1.89–1.99 (1 H, m, 4-H), 2.11–2.18 (1 H, m, 4-H), 2.24 (1 H,
dddd, J 1.0, 6.0, 11.0 and 13.5, 6-H ax), 2.49 (1 H, dtd, J 1.5, 5.0
and 13.5, 6-H eq), 3.35 (3 H, s, OCH3), 3.45 (3 H, s, OCH3), 3.80
(1 H, dd, J 1.0 and 2.5, 2-H) and 3.86 (1 H, td, J 2.5 and 5.5,
3-H); m/z (EI) 158 (Mϩ, 22%), 71 (100).
trans-2,3-Dimethoxycyclohexan-1-one (42 mg, 19%) was
obtained as a colourless liquid, Rf 0.3 (petrol–ether, 1:2);
νmax(neat)/cmϪ1 1730; δH (270 MHz) 1.47–1.75 (2 H, m, 5-H),
1.90–2.02 (1 H, m, 4-H), 2.15–2.27 (1 H, m, 4-H), 2.28 (1 H,
dddd, J 1.5, 5.5, 11.0 and 13.5, 6-H ax), 2.49 (1 H, dtd, J 1.5, 5.0
and 13.5, 6-H eq), 3.38–3.47 (1 H, m, 3-H), 3.46 (3 H, br s,
OCH3), 3.48 (3 H, s, OCH3) and 3.68 (1 H, dd, J 1.5 and 8.0, 2-
H); δC(67.8 MHz) 20.6, 28.3, 39.5, 57.9, 58.9, 82.8, 88.65 and
207.8; m/z (EI) 158 (Mϩ, 15%), 71 (100).
(؊)-(2R,3R)-2,3-(Cyclohexylidenedioxy)cyclopentan-1-one
14. 10% Pd on activated carbon (110 mg) was weighed into a
hydrogenation flask which was sequentially evacuated and
flushed with nitrogen three times. A solution of ketone (Ϫ)-1113
(610 mg, 3.14 mmol) in ethyl acetate (50 ml) was added to the
evacuated flask. The flask was flushed with nitrogen, re-
evacuated and flushed with hydrogen. The reaction was stirred
at RT for 4 h after which time the flask was evacuated, flushed
with nitrogen and the catalyst filtered off over Celite. The solv-
ent was evaporated at reduced pressure to give the title com-
pound (Ϫ)-14 (585 mg, 95%) as a white solid, mp 94 ЊC; Rf 0.4
(petrol–ether, 1:2); [α]D Ϫ242 (c 0.4, CH2Cl2) (Found: C, 67.6;
H, 8.6. C11H16O3 requires C, 67.3; H, 8.2%); νmax(CHCl3)/cmϪ1
1753; δH (400 MHz) 1.33–1.38 (2 H, m, CH2), 1.50–1.64 (8 H, m,
4 × CH2), 1.99 (1 H, dddd, J 5.0, 9.5, 11.5 and 14.5, 4-H), 2.18–
2.30 (2 H, m, 4-H and 5-H), 2.50–2.61 (1 H, m, 5-H), 4.14 (1
H, d, J 5.0, 2-H) and 4.82 (1 H, t, J 5.0, 3-H); m/z 214
([M ϩ NH4]ϩ, 100%) and 197 ([M ϩ H]ϩ, 80).
Synthesis of dihydroconduritols C and D and related model
studies
(1S *,2R*,1ЈRS )-2-Methoxy-1-[(methoxy)(phenylsulfonyl)-
methyl]cyclopentan-1-ol 4g. Using the representative procedure,
sulfone 3 (1.05 g, 5.64 mmol) and 2-methoxycyclopentan-1-one
6d11 (643 mg, 5.63 mmol) gave a pale yellow oil (1.72 g) which
J. Chem. Soc., Perkin Trans. 1, 1997
2827

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(1S,2R,3R,1ЈRS )-2,3-(Cyclohexylidenedioxy)-1-[(methoxy)-
(phenylsulfonyl)methyl]cyclopentan-1-ol 15. Using the repre-
sentative procedure with sulfone 3 (2.00 g, 10.7 mmol) and
ketone (Ϫ)-14 (2.00 g, 10.2 mmol) gave a pale yellow oil
(4.2 g) which was purified by chromatography (petrol–ethyl
acetate, 4:1) to give the title compound 15 (3.41 g, 87%) as two
separable diastereoisomers.
Diastereoisomer 1 (1.88 g, 48%) was obtained as a colourless
oil, Rf 0.3 (petrol–ethyl acetate, 2:1); νmax(CHCl3)/cmϪ1 3505,
1307 and 1144; δH (250 MHz) 1.35–1.76 (10 H, m, 5 × CH2),
1.83–1.96 (3 H, m, 4-H and 5-H), 2.10–2.25 (1 H, m, 5-H), 3.29
(1 H, s, OH), 3.46 (3 H, s, OCH3), 4.19 (1 H, s, 1Ј-H), 4.64–4.72
(2 H, m, 2-H and 3-H), 7.53–7.69 (3 H, m, ArH) and 7.99 (2 H,
d, J 7.0, ArH); δC(67.8 MHz) 23.4, 23.9, 24.95, 28.5, 33.2, 34.0,
35.8, 63.0, 79.6, 79.6, 81.0, 100.8, 113.9, 128.7, 129.6, 133.7
and 138.8; m/z (CI) 400 ([M ϩ NH4]ϩ, 15%) and 383 ([M ϩ
H]ϩ, 5).
Diastereoisomer 2 (1.53 g, 39%) was obtained as a white
solid, mp 84 ЊC; Rf 0.3 (petrol–ethyl acetate, 2:1) (Found: C,
59.7; H, 6.7; S, 8.4. C19H26O6S requires C, 59.7; H, 6.85; S,
8.4%); νmax(CHCl3)/cmϪ1 3505, 1306 and 1143; δH (250 MHz)
1.50–1.72 (10 H, m, 5 × CH2),1.84–1.92 (2 H, m, 4-H), 1.98–
2.21 (2 H, m, 5-H), 3.30 (1 H, s, OH), 3.63 (3 H, s, OCH3), 4.22
(1 H, s, 1Ј-H), 4.50 (1 H, d, J 6.5, 2-H), 4.66 (1 H, dd, J 6.5 and
9.5, 3-H), 7.51–7.69 (3 H, m, ArH) and 7.97–8.02 (2 H, m, ArH);
δC(67.8 MHz) 23.5, 24.0, 25.05, 28.3, 34.1, 35.9, 36.6, 62.75,
79.0, 80.1, 80.2, 102.0, 113.8, 128.6, 129.7, 133.65 and 138.9;
m/z (CI) 400 ([M ϩ NH4]ϩ, 15%) and 383 ([M ϩ H]ϩ, 10).
(؊)-(2R,3R,4R)-3,4-(Cyclohexylidenedioxy)-2-methoxycyclo-
hexan-1-one 16. Freshly sublimed ZrCl4 (540 mg, 2.32 mmol)
was added to a solution of β-hydroxy sulfone 15 (diastereo-
isomer 2, 157 mg, 0.41 mmol) in dry CH2Cl2 (15 ml) at RT
under a nitrogen atmosphere. After stirring for 15 min the mix-
ture was cooled to 3 ЊC and a 1:1 mixture of THF and water
(4 ml) was added. The mixture was diluted with CH2Cl2 and
filtered over a plug of Celite, and the filtrate was washed with
water. Standard aqueous work-up (dichloromethane, Na2SO4)
gave a pale yellow liquid (94 mg) which was purified by chrom-
atography (petrol–ether, 2:1) to give the title compound 16 (50
mg, 51%) as a colourless liquid, Rf 0.2 (hexane–ethyl acetate,
1:1); [α]D Ϫ50.0 (c 0.5, CH2Cl2); νmax(CDCl3)/cmϪ1 1735, 1123
and 1088; δH (270 MHz) 1.26–1.69 (10 H, m, 5 × CH2), 1.96
(1 H, dddd, J 2.5, 5, 13.5 and 15.5, 5-H ax), 2.05–2.14 (1 H, m,
5-H eq), 2.34 (1 H, ddd, J 2.5, 3.5 and 19, 6-H eq), 2.61 (1 H,
ddd, J 6, 13.5 and 19, 6-H ax), 3.58 (3 H, s, OCH3), 3.92 (1 H, d,
J 3.5, 2-H), 4.65–4.69 (1 H, m, 4-H) and 4.77 (1 H, dd, J 3.5 and
7.5, 3-H); δC(100 MHz) 23.5, 23.8, 24.0, 25.1, 33.2, 33.5, 35.4,
59.2, 75.2, 72.4, 83.1, 109.6 and 206.4; m/z (CI) 241 ([M ϩ H]ϩ,
80%) and 143 (100) [Found (CI): 241.1435. C13H20O4 requires
[M ϩ H]ϩ, 241.1440; 2.1 ppm error]. Yields as high as 84% were
obtained for this reaction, although 50–60% yields were more
typical. Diastereoisomer 1 gave similar results.
260 ([M ϩ NH4]ϩ, 5%), 243 ([M ϩ H]ϩ, 100) [Found (CI):
243.159 550. C13H22O4 requires [M ϩ H]ϩ, 243.159 634; 0.3
ppm error).
(؊)-(1R,2S,3R,4R)-3,4-(Cyclohexylidenedioxy)-2-methoxy-
cyclohexan-1-ol 19. DEAD (0.144 ml, 159 mg, 0.92 mmol)
was added to a mixture of PPh3 (240 mg, 0.92 mmol), 4-
nitrobenzoic acid (153 mg, 0.92 mmol) and alcohol 17 (111 mg,
0.46 mmol) in dry benzene (5 ml) at RT under a nitrogen atmos-
phere. The reaction was stirred at RT for 3 h after which time
TLC analysis showed the starting material to have been con-
sumed. The mixture was diluted with ethyl acetate (15 ml) and
poured into water (30 ml). Standard aqueous work-up (ethyl
acetate, Na2SO4) gave a pale yellow liquid which was chromato-
graphed (petrol–ether, 2:1) to remove 1,2-bis(ethoxycarbonyl)-
hydrazine. The resulting inseparable mixture (261 mg) was
dissolved in MeOH (10 ml) and LiOHؒH2O (38 mg, 0.91
mmol) was added. The deep yellow mixture was stirred at RT
for 2 h. The methanol was removed at reduced pressure
and the residue dissolved in ether and filtered through a plug
of Celite. The filtrate was concentrated at reduced pressure
to give a pale yellow oil which was purified by chromato-
graphy (ether–petrol, 1:1) to give the title compound 19 (24
mg, 22%) as a colourless liquid, Rf 0.2 (petrol–ethyl acetate,
1:2); [α]D Ϫ44 (c 0.16, methanol); νmax(neat)/cmϪ1 3404, 1112,
1091, 1070 and 1021; δH (270 MHz) 1.21–2.02 (14 H, m,
7 × CH2), 2.44 (1 H, br s, OH), 3.17 (1 H, dd, J 3.5 and 9.0, 2-
H), 3.53 (3 H, s, OCH3), 3.91 (1 H, dt, J 5.5 and 9.0, 1-H), 4.23
(1 H, dt, J 8.0 and 5.5, 4-H) and 4.56 (1 H, dd, J 3.5 and 5.5,
3-H); δC(67.8 MHz) 23.6, 24.0, 25.05, 26.6, 26.85, 34.9, 37.5,
57.0, 68.3, 72.0, 74.2, 83.1 and 109.8; m/z (CI) 243 ([M ϩ H]ϩ,
100%) [Found (CI): 243.160 100. C13H22O4 requires [M ϩ H]ϩ,
243.159 634; 1.9 ppm error].
meso-(1S,2S,3R,4R)-Cyclohexane-1,2,3,4-tetrol (dihydrocon-
duritol-D) 18. BCl3 (1.0  in CH2Cl2, 3.0 ml, 3.0 mmol) was
added to a solution of alcohol 17 (18 mg, 0.074 mmol) in
dry CH2Cl2 (3 ml) at Ϫ78 ЊC under a nitrogen atmosphere.
The mixture was stirred at Ϫ78 ЊC for 10 h and then allowed
to warm slowly to RT and stirred for a further 16 h (after which
time TLC analysis showed a single product). The solvent was
evaporated at reduced pressure to give a brown residue (13
mg) which was purified by chromatography (ethyl acetate–
methanol, 5:1) to give a colourless oil which was rapidly eluted
from a short column of reversed-phase silica gel (octadecyl
coating) using methanol as eluent to give the title compound 18
(10.7 mg, 97%) as a colourless oil, Rf 0.3 (ethyl acetate–
methanol, 1:1); δH (270 MHz; CD3OD) 1.45–1.55 (2 H, br m, 5-
H and 6-H), 1.81–1.92 (2 H, br m, 5-H and 6-H) and 3.70 (4 H,
br s, 1-H, 2-H, 3-H and 4-H); δC(67.8 MHz; CD3OD) 26.0,
71.6 and 74.0; m/z (CI) 166 ([M ϩ NH4]ϩ, 100%) and 149
([M ϩ H]ϩ, 10); m/z (EI) 130 (Mϩ Ϫ H2O, 7%) [Found (CI):
166.108 245. C6H12O4 requires [M ϩ NH4]ϩ, 166.107 933; 1.9
ppm error].
(؊)-(1S,2S,3R,4R)-3,4-(Cyclohexylidenedioxy)-2-methoxy-
cyclohexan-1-ol 17. NaBH4 (12 mg, 0.32 mmol) was added
to a solution of ketone 16 (59 mg, 0.25 mmol) in methanol
(10 ml) at Ϫ12 ЊC (salt–ice bath) under a nitrogen atmos-
phere. The reaction was stirred at this temperature for 30 min
after which time TLC analysis showed complete conversion
into a single product. Saturated aqueous NH4Cl (2 ml) was
added and the mixture was diluted with ethyl acetate (50 ml)
and water (20 ml). Standard aqueous work-up (ethyl acetate,
Na2SO4) gave a pale yellow liquid (60 mg) which was purified by
chromatography (petrol–ethyl acetate, 2:1) to give the title
compound 17 (48 mg, 81%) as a colourless liquid, Rf 0.2 (petrol–
ethyl acetate, 1:1); [α]D Ϫ33 (c 0.23 methanol); νmax(neat)/cmϪ1
3472, 1120, 1104, 1079 and 1034; δH (270 MHz) 1.26–2.05 (14 H,
m, 7 × CH2), 2.97 (1 H, d, J 8.0, OH), 3.32 (1 H, t, J 4.0, 2-H),
3.54 (3 H, s, OCH3), 4.14–4.28 (2 H, m, 1-H and 4-H) and 4.43
(1 H, t, J 4.0, 3-H); δC(67.8 MHz) 22.8, 23.5, 24.0, 25.0, 26.6,
35.1, 37.8, 56.9, 65.1, 73.75, 74.6, 78.0 and 110.05; m/z (CI)
(؊)-(1R,2S,3R,4R)-Cyclohexane-1,2,3,4-tetrol (dihydrocon-
duritol-C) 20. BCl3 (1.0  in CH2Cl2, 2.64 ml, 2.64 mmol) was
added to a solution of alcohol 19 (16 mg, 0.066 mmol) in dry
CH2Cl2 (2 ml) at Ϫ78 ЊC under a nitrogen atmosphere. The
mixture was stirred at Ϫ78 ЊC for 8 h and then allowed to
warm slowly to RT and stirred for a further 16 h (after which
time TLC analysis showed a single product). The solvent was
evaporated at reduced pressure to give a brown residue (13
mg) which was purified by chromatography (ethyl acetate–
methanol, 5:1) to give a colourless oil which was rapidly
eluted from a short column of reversed-phase silica gel
(octadecyl coating) using methanol as eluent to give the title
compound 20 (8.9 mg, 91%) as a white solid, mp 154 ЊC (lit.,16
157–158 ЊC); Rf 0.3 (ethyl acetate–methanol, 1:1); [α]D Ϫ36 (c
0.08, H2O, 25 ЊC) [lit.,16 Ϫ35.8 (c 4.7, H2O, 20 ЊC) and Ϫ39 (c
1.0, H2O, 25 ЊC)] which also gave consistent NMR data [Found
(CI): 166.107 746. Calculated for C6H12O4 as [M ϩ NH4]ϩ,
166.107 933; 1.1 ppm error].
2828
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
10 D. Enders and U. Reinhold, Synlett, 1994, 792; M. Hayashi, T.
Acknowledgements
Yoshiga, K. Nakatani, K. Ono and N. Oguni, Tetrahedron, 1994, 50,
2821.
We are grateful to the SERC and Glaxo Group Research (Ware)
for a CASE studentship (N. P.). We also thank Professor S. M.
Roberts for helpful advice and interest.
11 (a) A. Barco, G. de Giuli and G. P. Pollini, Synthesis, 1972, 626; (b)
see also B. C. McKusic, J. Am. Chem. Soc., 1948, 70, 1976.
12 N. Chida, T. Tobe and S. Ogawa, Tetrahedron Lett., 1994, 35, 7251.
13 D. R. Borcherding, S. A. Scholtz and R. T. Borchardt, J. Org.
Chem., 1987, 52, 5457; see also C. L. Mariën, E. L. Esmans,
F. Lemière and R. A. Dommisse, Synth. Commun., 1997, 27, 205
and C. R. Johnson, J. L. Esker and M. C. van Zandt, J. Org. Chem.,
1994, 59, 5854.
14 D. Beer, R. Meuwly and A. Vasella, Helv. Chim. Acta, 1982, 65,
2570.
15 S. D. Géro, Tetrahedron Lett., 1966, 591.
16 L. Pingli and M. Vandewalle, Tetrahedron, 1994, 50, 7061; C. Le
Drian, E. Vieira and P. Vogel, Helv. Chim. Acta, 1989, 72, 338.
17 B. M. Trost and C. H. Miller, J. Am. Chem. Soc., 1975, 97, 7182.
18 K. Schank and H.-G. Scmitt, Chem. Ber., 1977, 110, 3235.
19 H. R. Sonawane, B. S. Nanjundiah, D. G. Kulkarni and J. R. Ahuja,
Tetrahedron, 1988, 44, 7319.
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21 This compound has been described several times in the literature
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Paper 7/03073H
Received 6th May 1997
Accepted 2nd June 1997
J. Chem. Soc., Perkin Trans. 1, 1997
2829