Novel versatile approach to an enantiopure 19-nor, des-C,D vitamin D3 derivative

Article abstract of DOI:10.1016/S0040-4020(00)01035-8

A short and efficient de novo route to the des-C,D vitamin D₃ derivative 3 (Ro 65-2299), a potential antipsoriatic, has been developed. This route features an assembly strategy so far unexplored in vitamin D chemistry involving a modified Julia olefination of the A-ring ketone 30 and the 2-benzothiazolyl sulfone 60. Construction of the A-ring building block was accomplished by an efficient three-step route starting from the meso trans-1,3,5-cyclohexane triol (26), which was desymmetrized by a highly selective enzymatic mono-hydrolysis of the corresponding triacetate 27 followed by oxidation of the alcohol 29 to give the homochiral diacetoxy ketone 30 (ee=99.5%) in 83% overall yield. Furthermore, we found efficient and practical syntheses of the 5-acetoxy-2-cyclohexenone (31) and its enantiomer 32, both new building blocks useful for natural product synthesis.

Full text of DOI:10.1016/S0040-4020(00)01035-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 681±694
Novel versatile approach to an enantiopure 19-nor, des-C,D
vitamin D3 derivativeq
Hans Hilperta,p and Beat Wirzb
aNon-Clinical DevelopmentÐProcess Research, F. Hoffmann-La Roche Ltd., Pharmaceuticals Division,
Grenzacherstr. 124, CH-4070, Basel, Switzerland
bPharmaceutical Research, Biological Sciences, F. Hoffmann-La Roche Ltd., Pharmaceuticals Division,
Grenzacherstr. 124, CH-4070, Basel, Switzerland
Received 6 September 2000; accepted 6 November 2000
AbstractÐA short and ef®cient de novo route to the des-C,D vitamin D3 derivative 3 (Ro 65-2299), a potential antipsoriatic, has been
developed. This route features an assembly strategy so far unexplored in vitamin D chemistry involving a modi®ed Julia ole®nation of the
A-ring ketone 30 and the 2-benzothiazolyl sulfone 60. Construction of the A-ring building block was accomplished by an ef®cient three-step
route starting from the meso trans-1,3,5-cyclohexane triol (26), which was desymmetrized by a highly selective enzymatic mono-hydrolysis
of the corresponding triacetate 27 followed by oxidation of the alcohol 29 to give the homochiral diacetoxy ketone 30 (eeˆ99.5%) in 83%
overall yield. Furthermore, we found ef®cient and practical syntheses of the 5-acetoxy-2-cyclohexenone (31) and its enantiomer 32, both new
building blocks useful for natural product synthesis. q 2001 Elsevier Science Ltd. All rights reserved.
1Introduction
hardly explored modi®cation ®rst published by Kutner et
al.6 involves the retiferol 2, a compound that lacks the
C,D-ring substructure. Based on molecular modelling,
Kutner hypothesised that for receptor binding the 3D
arrangement of the three hydroxy groups should be suf®-
ciently preserved. Subsequently, Mohr et al.7 from Roche,
Basel, prepared a variety of des-C,D vitamin D3 derivatives
from which the compounds with terminal CF3 groups
showed improved activities. The molecular structure was
Vitamin D research has attracted much attention in recent
years with the ®nding that calcitriol 1 (Fig. 1), the pharma-
cologically active metabolite of vitamin D3, exhibits a far
broader activity beyond regulating calcium and phosphorus
metabolism.1,2 As a result, structurally modi®ed compounds
are currently being explored extensively, e.g. in the area of
oncology,3 bone diseases,4 and skin diseases.5 A recent and
Figure 1. Selected structures of vitamin-D3 derivatives.
q
Part of these results were previously communicated: Hilpert, H., CU-Roche Colorado Symposium, May 25th, 2000, Boulder, Colorado, USA.
Keywords: cyclohexanones; enzyme reactions; sulfones; vitamins.
* Corresponding author. Tel.: 141-61-688-7264; fax: 141-61-688-1670; e-mail: hans.hilpert@roche.com
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01035-8

682
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
Scheme 1. Retrosynthesis of the retiferol 3.
further modi®ed in the side chain and simpli®ed in the
A-ring segment by omitting the exocyclic methylene
group ®nally leading to the 19-nor, des-C,D vitamin D3
derivative 3, a compound to be considered as a locked vitamin
D3 analogue incapable of equilibrating with the corresponding
pre-vitamin.8 Retiferol 3 (Ro 65-2299) represents a potent
activator of the vitamin D receptor hardly displaying any
undesired hypercalcemia relevant for therapeutic applications,
and was therefore selected as a clinical candidate for the
evaluation of a potential oral therapy for psoriasis.
introduced by the disconnection A (Scheme 1) leading to the
key intermediate phosphinoxide 6 and the corresponding
carbonyl building block. For the retiferol 3, the required
TMS-protected aldehyde 4 was prepared in 11 steps starting
from 4,4-dimethyl-2-cyclohexenone (5).7 Three routes to
the phosphinoxide 6 are known in the literature, the shortest
one developed by DeLuca9 involving a ten-step synthesis
starting from (2)-quinic acid (8) (overall yield 13%). More
recently Mikami11 and Uskokovic12 published elegant 13-
and 12-step syntheses, respectively, starting from achiral
acyclic precursors (overall yields 6% and 14%, respec-
tively). Both routes are based on a highly stereoselective
carbonyl-ene cyclization as the key steps.
Various syntheses of 19-nor analogues are documented in
the literature.9,10 In all cases the diene substructure has been
Scheme 2. Reagents and conditions: (a) (i) 9, Mg, THF, 658C, 3.5 h; (ii) CuI cat., 10, THF, 2208C, 1 h; (b) (i) LDA, diethyl chlorophosphate, THF, 278 to
228C, 2 h; (ii) LDA, hexa¯uoro acetone, 2788C, 30 min; (c) H2 (1 bar), Pd/CaCO3/Pb (4.5%), tert-butyl methyl ether, 228C, 1.5 h; (d) H2SO4, H2O/i-PrOH,
808C, 2 h; (e) NaOCl, TEMPOcat., CH2Cl2/H2O, 08C, 1 h; (f) Et3SiCl, NEt3, DMAPcat., THF, 228C, 1.5 h.

H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
683
Due to our interest in the clinical development of retiferol 3,
we evaluated new routes to the aldehyde 4 and to the phos-
phinoxide 6 via a suitably protected ketone 7. In addition,
alternative coupling strategies (B- and C-disconnections)
requiring a facile preparation of the corresponding A-ring
precursors were also considered. Herein, we report an
ef®cient and practical route to both enantiomers of the
phosphinoxide 6 and to the retiferol 3 based on enzymatic
transformations and on a new coupling strategy. Further-
more, as a result of our investigations, short and high
yielding routes to both enantiomers of the 5-acetoxy-2-
cyclohexenones (31) and (32), versatile building blocks
for natural product synthesis were also discovered.
the reaction was achieved in THF yielding 16 in a 91%. This
completed the short 6-step route of the side chain affording a
good overall yield of 46% of the protected aldehyde 16 with
minimal puri®cation operations of the intermediates
involving only two chromatographic separations and one
crystallization.
2.2. Facile synthesis of the phosphinoxide 6 and its
enantiomer 40
In search of a shorter route to a suitably protected ketone 7
(Scheme 1), we evaluated an enzyme catalysed desymme-
trization of the meso-diol 18 (Scheme 3) to the mono acetate
19. The selective and high yielding protection (84%) of
the cis-triol 17 to the mono TBS-ether 18 reported in the
literature16 was not reproducible in our hands due to the lack
of selectivity leading also to the bis- and tris-TBS ethers.
High yield and selectivity, however, was achieved using a
mixture of NaH and NEt3 as the bases, the latter one
inducing a signi®cant acceleration of the reaction thus
enhancing the selectivity, although the role of NEt3 is not
fully understood. This process reproducibly provided 18 in a
high yield of 93% after crystallization on a 70 g scale.
Asymmetric acylation of the meso-diol 18 was extensively
investigated by Wirz et al.17 involving a broad panel of
commercially available enzymes. Lipase QL from Meito
Sangyo proved to be the most rapid catalyst furnishing the
required enantiomer (vide infra) of the alcohol 19 in a quan-
titative yield and high enantiomeric purity (eeˆ.99%).
Alcohol 19 served as a common intermediate to synthesise
the desired ketone 22 and its diacetyl protected enantiomer
25, representing potential new intermediates of general
interest and expanding the scope of preparing vitamin D
analogues. Thus, the con®guration of the hydroxy group
in 19 was inverted by Mitsunobu reaction affording the
fully protected pivaloate 20, which was selectively
deacetylated and oxidised with bleach to give the ketone
22 in a high overall yield (90% from 19).
2. Results and discussion
2.1. Synthesis of the aldehyde side-chain 16
A convenient route to the aldehyde side-chain 16 incorpor-
ating the more stable triethylsilyl protecting group
compared to TMS (Scheme 2) was elaborated. The Grignard
reagent derived from 1-tert-butyloxy-4-chloro-butane (9)13
was subjected to a conjugate addition to mesityl oxide (10)
furnishing the ketone 11 in 68% yield. Dehydration of 11
was accomplished via in situ formation of the enol phos-
phate14 followed by trapping of the intermediate alkyne
lithium species with hexa¯uoro acetone affording the alkyne
12 in good yield (92%). Hydrogenation of the triple bond in
12 with Lindlar's catalyst proceeded with high diastereo-
selectivity to give a 98.6:1.4 mixture in favour of the
Z-con®gurated alkene 13, which was deprotected to the
diol 14 in a 90% overall yield (from 12).
Oxidation of the primary alcohol group in 14 was readily
accomplished by a TEMPO15 catalysed bleach oxidation
providing the aldehyde 15 in good yield (90%). In search
of a more stable protecting group the pivaloyl, tert-butyl-
dimethylsilyl and the triethylsilyl groups were evaluated,
but only the latter could be installed with Et3SiCl/DMAP
in dichloromethane to give the protected aldehyde 16 in a
modest yield of 60%. A remarkable ten-fold acceleration of
Alternatively, the Mitsunobu reaction of 19 with acetic acid
provided the diacetate 23, which after cleavage of the tert-
butyldimethylsilyl protecting group with TBAF furnished
Scheme 3. Reagents and conditions: (a) TBSCl, NaH, NEt3, THF, 408C, 2 h; (b) Lipase QL, vinyl acetate, AcOEt, 228C, 46 h; (c) PPh3, i-PrO2CNvNCO2i-Pr,
tert-BuCO2H, THF, 08C, 1 h; (d) K2CO3, MeOH/H2O, 228C, 7 h; (e) NaOCl, TEMPOcat., CH2Cl2/H2O, 08C, 1 h; (f) PPh3, i-PrO2CNvNCO2i-Pr, AcOH, THF,
08C, 2 h; (g) TBAF (1 M, THF), THF, 08C, 3 h; (h) NaOCl, TEMPOcat., CH2Cl2/H2O/HCl, pH 6.5 27.5, 08C, 1 h.

684
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
Scheme 4. Reagents and conditions: (a) Ac2O, pyridine, 458C, 4 h, 77:18 mixture of 27 and 28; (b) Lipase OF, cyclohexane, NaOH/H2O, pH 7.0, 5±68C,
21.5 h; (c) NaOCl, TEMPOcat., CH2Cl2/H2O/HCl, pH 6.5 27.5, 08C, 1 h; (d) Al2O3, THF, 228C, 1 h.
the alcohol 24 in good yield (87%) but lower enantiomeric
excess of 87±95%. This partial racemization is attributable
to a 1,3-migration of the acetyl group located cis to the
hydroxy group in 24. Bleach/TEMPO oxidation of the
alcohol 24 under pH control (vide infra) ®nally provided
access to the ketone 25 (eeˆ87±95%) in a 80% overall
yield from 19. The enantiomeric purity of 25 was suf®cient
for further processing since improvements were observed
for later stage intermediates. Alternatively, the enantiomeric
purity was improved to an ee of 99% by a single crystal-
lization.
30 (Scheme 4) is based on the selective enzymatic
hydrolysis of the trans-triacetate 27 to the trans-diacetate
29. trans-Cyclohexane-1,3,5-triol (26), commercially avail-
able from Tokyo Kasei as a 1:1 mixture of the trans- and
cis-triol 26 and 17, was prepared by hydrogenation of 1,3,5-
trihydroxy benzene.18 A one-pot method providing an
improved 2:1 mixture of 26 and 17 was recently presented
by Roessler et al.19 involving the Raney nickel catalysed
hydrogenation of 1,3,5-trihydroxy benzene and subsequent
isomerization of the cis-triol 17 to the thermodynamically
more stable trans-isomer 26 at elevated temperature. The
trans-isomer 26 was further enriched by preferential crystal-
lization of the cis-triol 17 from ethanol/water affording a
An even shorter route to the enantiomeric diacetoxy ketone
Scheme 5. Reagents and conditions: (a) 33: TMSCH2CO2tert-Bu, LDA, THF, 2788C, 15 min, then 30, 2788C, 2 h; (b) 34: TMSCH2CO2Et, LDA, THF,
2788C, then 30, 2788C, 1.5 h; (c) K2CO3, MeOH/H2O, 228C, 6 h; (d) TBSCl, imidazole, DMF, 228C, 3 h; (e) Red-Alw, toluene, 2158C, 1 h;
(f) (i) 2-mercaptobenzothiazole, PPh3, then 37, i-PrO2CNvNCO2i-Pr, THF, 08C, 30 min; (ii) H2O2/H2O, (NH4)6Mo7O24´4H2Ocat., EtOH, 228C, 10 h; (g) (i)
37, n-BuLi, THF, 08C, then TsCl, 08C, 2.5 h; (ii) HPPh2, n-BuLi, THF, 08C, 1 h; (iii) H2O2, CH2Cl2/H2O, 228C, 3.5 h; (h) (i) 6, n-BuLi, THF, 2788C, 30 min;
(ii) 16, 278 to 228C, 64 h; (iii) TBAF (1 M, THF), 458C, 12 h; (iv) HPLC, Kromasil 10±100, heptane/i-PrOH 92:8.

H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
685
Figure 2. Monoview of the tert-butyl ester 33 with thermal ellipsoids at 20% probability level.
mother liquor containing a 4:1 mixture favouring the trans-
triol 26.
the diacetoxy ketone enantiomer 25 (eeˆ87%) in 70% yield
and 98.8% ee after crystallization from tert-butyl methyl
ether.
The conversion of the meso trans-1,3,5-triacetoxy cyclo-
hexane (27) to the homochiral diacetate 29 requires the
selective enzymatic hydrolysis of only one of the three
stereo-different acetoxy groups and limitation to mono-
hydrolysis. Futhermore, the identi®cation of an enzyme
preventing at the same time the hydrolysis of the cis-
triacetate 28 completely would easily allow the separation
of the desired product 29 from unreacted 28 after the
enzymatic reaction. Surprisingly, these highly demanding
selectivity requirements were achieved by using cheap
lipase OF ($15/kg 29) isolated from Candida rugosa as
demonstrated by Wirz et al.17 providing the desired
diacetate enantiomer 29 (vide infra) in high enantiomeric
excess of 99.5% and good yield (84%, based on trans-26
present in the mixture) after chromatographic ®ltration of
the reaction mixture. Oxidation of the alcohol 29 to the
ketone 30 with bleach/TEMPO proved to be highly sensitive
to the basic conditions resulting in an approximately 9:1
mixture of the ketone 30 and the enone 31. However, the
formation of 31 was completely suppressed by keeping the
pH at 7 during addition of the bleach furnishing the crystal-
line ketone 30 in quantitative yield, which is stable at
2208C for months but slowly decomposes at ambient
temperature.
With the short and high yielding synthesis of the diacetoxy
ketone 30 (three steps, 83% overall from 26) at hand we
developed a practical route to the phosphinoxide 6 and its
enantiomer 40 as outlined in Scheme 5 in analogy to the
chemistry developed by DeLuca.9
Peterson ole®nation of 30 with tert-butyl- or ethyl-
trimethylsilyl-acetate provided the esters 33 and 34, respec-
tively. The crystalline tert-butyl ester 33 was used to deter-
mine the absolute con®guration by X-ray analysis (Fig. 2)25
which in turn allowed now to assign the absolute con®gura-
tion of the alcohols 19 and 29 resulting from the enzymatic
reactions (vide supra): Since the tert-butylester 33 was
prepared from the alcohol 29, the absolute con®guration
of 29 is also con®rmed. In addition, the alcohol 19 was
converted to the alcohol 24, spectroscopically identical to
29 but clearly separated from 29 on a chiral GLC column
(BGB-175). This corroborates the enantiomeric relationship
of the two compounds and therefore allows the assignment
of the absolute con®guration of the alcohol 19.
Removal of the acetoxy groups in the ester 34, not resistant
to the forthcoming reducing conditions (36!37), was
achieved with K2CO3 in MeOH/H2O providing the ethyl
ester 35 in good yield (82%, from 30) containing approxi-
mately 25% of the corresponding methyl ester formed by
partial trans-esteri®cation with MeOH. All attempts,
however, to replace MeOH by EtOH resulted in a sluggish
reaction. Reprotection of the hydroxy groups in 35 as the
TBS ether 36 and subsequent reduction with sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Alw) furnished the
allylic alcohol 37 in excellent yield (92% from 35). This
material was converted to the phosphinoxide 6 via in situ
formation of the labile allyl tosylate in analogy to a method
developed by DeLuca et al.26 thus avoiding the isolation of
the hitherto used allyl chloride 38,9 which in our hands
proved to be unstable during chromatography on a larger
scale. Likewise, the enantiomeric ketone 25 was converted
to the new phosphinoxide enantiomer 40. Both enantiomers
6 and 40 were obtained in a high enantiomeric purity of
.99.9% after crystallization as determined by chiral
HPLC. In summary, phosphinoxide 6 is now available in
only eight steps and 47% overall yield comparing favour-
ably with all methods (vide supra) known up to date.
The remarkable stability of the enone 31 towards aromati-
zation under basic conditions not instantly leading to phenol
prompted us to investigate the preparation of the chiral
5-acetoxy enone 31, an unknown building block potentially
useful for natural product synthesis.20 Various chiral
5-substituted 2-cyclohexenones are known in the literature
including the trimethylsilyl,21,22 the benzyloxy23,24 and the
tert-butyldimethylsilanyloxy20 derivative, the latter one
extensively investigated by Sato et al. Conversion of the
diacetoxy ketone 30 to the acetoxy enone 31 was investi-
gated with various bases, basic alumina proving to be the
base of choice affording 31 in 84% yield. Preliminary results
indicated that 31 undergoes conjugate additions of higher-
and lower-order cuprates with trans- and cis-selectivity,
respectively, as recently described by Sato et al.20 for the
corresponding tert-butyldimethylsilanyloxy derivative. As
an unexpected extension of our investigations, this new
chiral building block 31 is now readily accessible from
cheap 26 in four steps and a high overall yield of 70%. In
addition, the enantiomeric enone 32 was also prepared from

686
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
2.3. Final assembly of the aldehyde 16 with the
phosphinoxide 6
exocyclic enal 42 as a 9:1 mixture of E- and Z-isomers but
only in a poor yield of ca. 45% along with the dienal 43
(E/Zˆ2:1, 40%) resulting from elimination of pivalic acid.
An exploratory investigation attempting a Suzuki coupling
(disconnection B) was also undertaken, requiring the vinyl
bromide 44 (or dibromide 45) or the pinacol alkeneboronate
47. Attempts to prepare compounds 44 or 45 with bromo-
methyltriphenyl phosphonium bromide or PPh3/CBr4,
respectively, resulted in complex product mixtures. The
reaction of the diacetoxy ketone 30 and pinacol (trimethyl-
silyl)methaneboronate 4636 gave a mixture of the pinacol
alkeneboronate 47 (15%) and the enone 31 (45%). With
the only C-disconnection remaining, we tried to prepare
the phosphinoxide 51 and the sulfone 52. Thus, alcohol 29
was mesylated to 48 (quant.), followed by attempted dis-
placement with LiPPh2 and oxidation with H2O2. However,
instead of the expected phosphinoxide formation, cleavage
of one of the acetoxy groups of the mesylate 48 was
observed. Therefore, mesylate 48 was deprotected to form
the alcohol 49 and reprotected as the TBS ether 50 (77%
overall), which upon the reaction with LiPPh2 followed by
oxidation with H2O2 furnished the phosphinoxide 51 in low
yield (29%) together with the ole®n 53 as the major compo-
nent (65%). Likewise, the reaction of the TBS-protected
mesylate 50 with the sodium salt of 2-mercaptobenzo-
thiazole followed by oxidation with H2O2 afforded the
sulfone 52 in low yield (36%) accompanied by the ole®n
53 (35%). Exploratory experiments towards deprotonation
of the phosphinoxide 51 or the sulfone 52 with n-BuLi at
2788C revealed that neither of the compounds was stable to
strong bases.
For the assembly of the side chain 16 with the A-ring
segment (Scheme 5) we evaluated a modi®ed Julia ole®na-
tion27±29 involving the sulfone 39 and the Horner reaction9,30
employing the phosphinoxide 6. The sulfone 39 was
prepared from the allyl alcohol 37 by Mitsunobu
reaction with 2-mercaptobenzothiazole31,32 and subsequent
ammonium heptamolybdate tetrahydrate catalysed
oxidation32,33 of the thioether intermediate using hydrogen
peroxide. The coupling of 39 or 6 with the aldehyde 16
using n-BuLi at 2788C provided the expected intermediate
diene as a mixture of partly deprotected intermediates. This
mixture was subjected to TBAF conditions providing the
retiferol isomers (2E)- and (2Z)-3 as a 7:3 and 9:1 mixture,
respectively, as determined by HPLC. Obviously, the
highest selectivity was obtained with the phosphinoxide
activating group originally developed by Lythgoe et al.30
Separation of the isomers was not straightforward requiring
a tedious HPLC chromatography yielding isomerically pure
(2E)-retiferol 3 in approximately 60% yield (from 6) as a
resin.
2.4. Alternative coupling strategies
The modest yield of the ole®nation step and the cumber-
some HPLC puri®cation of the retiferol 3 prompted us to
evaluate alternative coupling strategies such as the discon-
nection A with `inverted' functional groups (Scheme 1) and
the disconnections B and C. Expedient routes to the more
complex A-ring building blocks were ®rst evaluated starting
from the ketones 22 and 30 (Scheme 6).
Since all attempts functionalizing the sensitive A-ring
ketones 22 or 30 proved unsuccessful so far we explored
the challenging C-disconnection with `inverted' functional
groups requiring the diacetoxy ketone 30 and a C2 elongated
Ole®nation of the A-ring ketone precursor 22 with N-tert-
butyl-2-(triethylsilyl)acetaldimine (41)34,35 gave the desired
Scheme 6. Reagents and conditions: (a) 41, LDA, THF, 08C, 15 min, then 22, 2908C, 1 h; (b) 44: BrCH2PPh31Br2, tert-BuOK, THF, 2788C, 30 min, then 30,
2788C, 2 h; (c) 45: 30, CBr4, PPh3, CH2Cl2, 2158C; (d) (i) 46, n-BuLi, 2,2,6,6-tetramethylpiperidine, N,N,N0,N0-tetramethylethyldiamine, THF, 08C, 3 h, then
30, 2788C; (e) CH3SO2Cl, NEt3, CH2Cl2, 08C, 1 h; (f) K2CO3, MeOH/H2O, 228C, 5 h; (g) TBSCl, imidazole, DMF, 228C, 24 h; (h) 51: (i) 50, HPPh2, n-BuLi,
THF, 08C, 10 h; (ii) H2O2, CH2Cl2/H2O, 228C, 3 h; (i) 52: (i) 2-mercaptobenzothiazole, NaH, DMF, 228C, 15 min, then 50, 1108C, 1 h; (ii) H2O2/H2O,
(NH4)6Mo7O24´4H2Ocat., EtOH, 228C, 10 h.

H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
687
Scheme 7. Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, tert-BuOK, toluene, 228C, 1 h, then 16, 2108C, 2.5 h; (b) DIBAH, toluene, 2788C, 2.5 h;
(c) CBr4, PPh3, CH2Cl2, 08C, 1 h; (d) 57: 56, PPh3, CH3CN, 708C, 4.5 h; (e) 58: (i) 55, n-BuLi, THF, 08C, 10 min, then TsCl, 08C, 3 h; (ii) HPPh2, n-BuLi, THF,
08C, 6 h; (iii) H2O2, CH2Cl2/H2O, 228C, 2 h; (f) 59: (i) 1-phenyl-5-mercapto-tetrazole, PPh3, then 55, i-PrO2CNvNCO2i-Pr, THF, 08C, 1.5 h; (ii) H2O2/H2O,
(NH4)6Mo7O24´4H2Ocat., EtOH, 228C, 10 h; (g) 60: (i) 2-mercaptobenzothiazole, PPh3, then 55, i-PrO2CNvNCO2i-Pr, THF, 08C, 1.5 h; (ii) H2O2/H2O,
(NH4)6Mo7O24´4H2Ocat., EtOH, 228C, 17 h.
side chain with an appropriate activating group. To the best
of our knowledge this coupling strategy remained
unexplored in vitamin D chemistry presumably due to the
lability of the A-ring ketone towards the elimination/
aromatization anticipated or rapid enolization. On the
other hand, this strategy bene®ts from the advantage of
the C2 symmetry of the diacetoxy ketone 30 generating an
exocyclic double bond after ole®nation with no need for
control of the geometry. Additionally, the con®guration of
the second trans double bond required in the side chain
should also be more easily controllable than during the
®nal assembly of the building blocks as for the previous
strategy employed above.
the 2-benzothiazolyl sulfone 60 according to Scheme 7;
the potential precursors to the Wittig, Horner or modi®ed
Julia coupling envisaged. An ef®cient and stereoselective
synthesis to the C2 elongated ester 54 was established by
the Horner reaction of the aldehyde 16 with triethyl-
phosphonoacetate affording a 97:3 mixture in favour of
the desired E-isomer 54, which was readily separable by
chromatography on silica gel to provide the pure E-isomer
54 in 96% yield. DIBAH reduction of 54 furnished the allyl
alcohol 55 (quant.), which was converted to the target
molecules 57 (via 56, 77% overall), 58 (64%), 59 (38%)
and 60 (77%).
In the synthesis of the sulfone 59, the allyl alcohol 61 (11%)
was also formed, presumably by an initial [2,3]-sigmatropic
rearrangement of the intermediate sulfoxide to the allyl
sulfenate ester.37 This side reaction was not observed in
For a thorough evaluation of the ®nal assembly strategy we
prepared the triphenyl phosphonium bromide 57, the
phosphinoxide 58, the 2-phenyltetrazolyl sulfone 59 and
Scheme 8. Reagents and conditions: (a) (i) 60, LiN(TMS)2, THF, 2788C, 35 min, then 30, 2788C, 4 h and 228C, 18 h; (ii) K2CO3, MeOH/H2O, 228C, 22 h.

688
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
the case of the sulfone 60 under identical conditions,
attributable to the more electron withdrawing property of
the 2-phenyltetrazolyl compared to the benzothiazolyl
residue, accelerating the rearrangement.
Laufenrainweg 139, CH-4469 Anwil; GLC-column
Optima-240: Macherey Nagel AG, P.O. 224, CH-4702
Oensingen. HPLC-column Chiracel OD-H: Daicel or
Merck. Cis-Triol 17: Fluka; 1:1-mixture of 17/26: Tokyo
Kasei; Al2O3, basic, activity I: CAMAG; Lipases QL and
OF: Meito Sangyo Co., Tokyo.
A ®rst ole®nation screening of activated methylene compo-
nents 57 and 58 with the diacetoxy ketone 30 using n-BuLi
at 2788C preferentially led to phenol as the major product
resulting from aromatization of the base sensitive ketone 30.
With the sulfones 59 and 60, however, we obtained for the
®rst time the desired diene 62 (Scheme 8) albeit only in a
low yield of 30±40%. For further optimization the more
readily accessible 2-benzothiazolyl sulfone 60 was selected,
which after deprotonation with LiN(TMS)2 was smoothly
converted to the still TES-protected and not isolated
retiferol 62 readily transformed into the pure retiferol 3 in
a high overall yield of 85% (from 30 and 60) using K2CO3/
MeOH/H2O. These results indicate that the modi®ed Julia
ole®nation represents a highly ef®cient method compatible
with the base sensitive ketone 30 presumably due to the
lower basicity of the sulfone anion compared to the
phosphorus ylides.
4.2.1. 8-tert-Butyloxy-4,4-dimethyl-octan-2-one (11). A
tenth of a solution of 1-tert-butyloxy-4-chloro-butane (9)
(67.84 g, 412 mmol) in THF (400 ml) was added dropwise
to a suspension of magnesium powder (10.33 g, 425 mmol)
in THF (20 ml). The reaction was started by the addition of a
small amount of iodine, the remaining solution was added at
re¯ux temperature over 40 min and stirring was continued at
re¯ux temperature for 3.5 h. The black suspension was
cooled to 228C and added at 2108C to a suspension of
CuI (8.58 g, 45 mmol) in THF (90 ml) over 40 min. The
mixture was cooled to 2208C and treated with mesityl
oxide (44.93 g, 90% pure, 412 mmol) over 15 min and stir-
ring was continued at 2208C for 1 h. The reaction mixture
was washed with aqueous NH4Cl (15%, 600 ml) and with
brine (600 ml), the organic layer was dried and the solvent
evaporated to give the crude title compound 11 (84.49 g,
75.8% GLC purity, 68% yield) as a pale brown oil, which
was further processed without puri®cation. For analytical
purposes a sample was puri®ed over silica gel (hexane/
AcOEt 10:1). IR (neat): 1718 s (CvO). 1H NMR
(250 MHz, CDCl3): 3.33 (t, Jˆ6.5 Hz, 2H, OCH2), 2.32
(s, 2H, H2C(3)), 2.13 (s, 3H, CH3CO), 1.49 and 1.30 (m
each, 2H and 4H, 3£CH2), 1.19 (s, 9H, (CH3)3C, 0.98 (s,
6H, (CH3)2C). MS: 213/3 [M2CH3]1, 171/10, 155/25, 97/
95, 57/85, 43/100. C16H23F6O2 requires for [M2CH3]1:
361.1602; found for [M2CH3]1: 361.1592.
3. Summary
Novel practical approaches to both enantiomers of the phos-
phinoxides 6 and 40, useful building blocks to access 19-nor
vitamin D derivatives, were developed based on highly
selective enzymatic desymmetrizations of the meso-1,3,5-
trihydroxy cyclohexane derivatives 27 and 18, respectively.
These routes also provided ef®cient access to the enantio-
pure (S)- and (R)-5-acetoxy-2-cyclohexenone (31) and (32),
previously unknown but highly potential building blocks for
natural product synthesis applying stereoselective conjugate
organo cuprate addition reactions. From a variety of
assembly strategies evaluated, the uncommon C-disconnec-
tion, realised by application of a modi®ed Julia ole®nation
involving the ketone 30 and the sulfone 60, emerged as the
most ef®cient strategy completing a new short and high
yielding route (Scheme 8) to the retiferol 3.
4.2.2. 10-tert-Butyloxy-1,1,1-tri¯uoro-6,6-dimethyl-2-tri-
¯uoromethyl-dec-3-yn-2-ol (12). To a solution of diiso-
propyl amine (27.62 g, 273 mmol) in THF (28 ml) was
added at 2788C n-BuLi (1.6 M, 171 ml, 273 mmol), the
solution was warmed to 08C for 30 min and cooled to
2788C. To this solution was added a solution of the crude
ketone 11 (59.38 g, 74.4% GLC purity, 193.5 mmol) in THF
(20 ml) over 40 min and stirring was continued at 2788C for
1 h. The yellow solution was treated at 2788C with diethyl
chlorophosphate (47.11 g, 262 mmol) over 30 min, the solu-
tion was allowed to warm to 228C over 2 h and stirring was
continued for 2 h. The pale yellow suspension containing
the intermediate enol phosphate was added at 2788C to a
solution of LDA, prepared from diisopropyl amine (52.62 g,
520 mmol) and n-BuLi (1.6 M, 325 ml, 520 mmol) in THF
(60 ml) as described above, over 20 min and stirring was
continued at 2788C for 2 h. The orange suspension was
treated at 2788C with hexa¯uoro acetone (60.0 g, 97%
purity, 351 mmol) and stirring was continued at 2788C
for 30 min. The suspension was washed with sat. aqueous
NH4Cl (400 ml) and with brine (400 ml), the organic layer
was dried and the solvent was evaporated. To remove traces
of THF, the residue was dissolved in n-hexane (300 ml) and
evaporated again. The residue was dissolved in n-hexane
(300 ml), the solution cooled to 08C and the suspension
was stirred at 08C for 1 h and at 2208C for 16 h. The suspen-
sion was ®ltered, the residue was washed with cold (2208C)
n-hexane (150 ml) and dried to give the pure title compound
12 (43.00 g, 59% yield) as white crystals, mp 66±678C. The
4. Experimental
4.1. General
Mp: Tottoli or BuÈchi 535, uncorrected. Optical rotations:
Perkin±Elmer Polarimeter 241. IR-spectra: Nicolet, FT-IR
20 SXB. H NMR-spectra: Bruker AC 250 or AM 400,
1
internal standard TMS, J values in Hz. MS-spectra:
Finnigan MAT SSQ 7000, EI at 70 eV. GLC: Perkin
Elmer AutoSystem and HP5890-II. HPLC: Agilent 1100.
Monitoring of reactions by GLC with PS-088 capillary
column (5% phenyl- 95% methyl-polysiloxane): 9±16,
18±19; OV-1-OH: 19±20, 27/28±29; remaining reactions
monitored by TLC on silica gel (Merck) with n-hexane/
AcOEt of various ratios. Chromatographic puri®cations on
silica gel Si 60 (40±63 mm) from Merck.
4.2. Materials
GLC-columns BGB (b-cyclodextrin): BGB-Analytik AG,

H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
689
mother liquor was puri®ed over silica gel (hexane/AcOEt
19:1) to give a further portion of 12 (23.82 g, 33% yield) as
white crystals, mp 60±648C. IR (nujol): 3157 m (OH), 2242
br., 1H, OH), 2.45, 1.60 and 1.20 (m each, 4H, 2H and 2H
4£CH2), 0.93 (s, 6H, (CH3)2C). MS: 287/3
[M2CH32H2O]1, 231/10, 113/15, 95/100, 69/75.
C13H18F6O2 requires: C 48.75%, H 5.67%, F 35.59%;
found: C 48.95%, H 5.74%, F 35.43%.
1
m (C,C triple bond). H NMR (250 MHz, CDCl3): 4.6 (s,
br., 1H, OH), 3.40 (t, Jˆ6.5 Hz, 2H, OCH2), 2.16 (s, 2H,
H2C(5)), 1.52 and 1.32 (m each, 2H and 4H, 3£CH2), 1.20
(s, 9H, (CH3)3C), 0.97 (s, 6H, (CH3)2C). MS: 361/20
[M2CH3]1, 115/30, 57/100. C13H25O2 requires for
[M2CH3]1: 213.1855; found for [M2CH3]1: 213.1854.
4.2.6. (7Z)-10,10,10-Tri¯uoro-5,5-dimethyl-9-triethyl-
silanyloxy-9-tri¯uoromethyl-dec-7-en-1-al (16). To a
solution of the aldehyde 15 (6.73 g, 85.2% GLC purity,
17.9 mmol) in THF (67 ml) was subsequently added at
228C NEt3 (2.55 g, 25.2 mmol), 4-dimethylamino pyridine
(128 mg, 1.05 mmol) and triethylsilyl chloride (3.92 g, 97%
pure, 25.2 mmol) and stirring was continued at 228C for
1.5 h. The suspension was evaporated, the residue dissolved
in dichloromethane (90 ml) and washed with hydrochloric
acid (0.1N, 90 ml) and brine (90 ml). The organic layer was
dried, the solvent evaporated and the residue puri®ed over
silica gel (hexane/AcOEt 9:1) to give the title compound 16
(7.50 g, 94.5% GLC purity, 91% yield) as a colourless oil.
IR (neat): 1729 s (CvO), 1661 w (CvC). 1H NMR
(250 MHz, CDCl3): 9.77 (t, Jˆ1.7 Hz, 1H, CHO), 5.97
(td, Jˆ7.3, 12.4 Hz, 1H, H±C(7)), 5.45 (d, br., Jˆ12.4 Hz,
1H, H±C(8)), 2.38, 1.60 and 1.20 (m each, 4H, 2H and 2H,
4£CH2), 0.96 and 0.73 (t and q, Jˆ8.2 Hz each, 9H and 6H,
Si(CH2CH3)3), 0.91 (s, 6H, (CH3)2C). MS: 405/10
[M2C2H5]1, 95/100, 69/7. C19H32F6O2Si requires: C
52.52%, H 7.42%, F 26.23%; found: C 52.39%, H 7.46%,
F 26.17%.
4.2.3. (3Z)-10-tert-Butyloxy-1,1,1-tri¯uoro-6,6-dimethyl-
2-tri¯uoromethyl-dec-3-en-2-ol (13). A suspension of
alkyne 12 (20.00 g, 53.1 mmol) in tert-butyl methyl ether
(200 ml) and Lindlar's catalyst (Pd/CaCO3/Pb (4.5%),
3.00 g) was hydrogenated at 228C and 1 bar of hydrogen
for 1.5 h after which time hydrogen up-take ceased. The
suspension was ®ltered and the ®ltrate evaporated to dryness
to give the pure title compound (3Z)-13 (20.11 g, 100%
yield) as a colourless oil, containing (3E)-13 (1.4% GLC,
1
Optima-240). IR (neat): 3260 m (OH), 1665w (CvC). H
NMR (250 MHz, CDCl3): 6.08 (td, Jˆ8.1, 12.3 Hz, 1H,
H±C(4)), 5.48 (d, br., Jˆ12.3 Hz, 1H, H±C(3)), 3.40 (s,
br., 1H, OH), 3.34 (t, Jˆ6.5 Hz, 2H, OCH2), 2.39 (d, br.,
Jˆ8.1 Hz, 2H, H2C(5)), 1.55±1.20 (m, 6H, 3£CH2), 1.19 (s,
9H, (CH3)3C), 0.90 (s, 6H, (CH3)2C). MS: 363/5
[M2CH3]1, 115/30, 57/100. C17H28F6O2 requires: C
53.96%, H 7.46%, F 30.12%; found: C 54.12%, H 7.43%,
F 30.25%.
4.2.4. (7Z)-10,10,10-Tri¯uoro-5,5-dimethyl-9-tri¯uoro-
methyl-dec-7-ene-1,9-diol (14). A mixture of the alkene
13 (20.11 g, 53.1 mmol) in i-PrOH (40 ml) and sulfuric
acid (50%, 20.7 g) was heated to re¯ux temperature for
2 h and evaporated to dryness. The residue was dissolved
in dichloromethane (100 ml) and washed with sat. NaHCO3
(100 ml) and brine (100 ml), the organic layer was dried and
the solvent evaporated to give the crude title compound 14
(16.44 g, 93.6% GLC purity, 90% yield) as a colourless oil,
which was further processed without puri®cation. IR (neat):
3253 m (OH), 1650 w (CvC). 1H NMR (250 MHz, CDCl3):
6.08 (td, Jˆ7.6, 12 Hz, 1H, H±C(7)), 5.49 (d, br., Jˆ12 Hz,
1H, H±C(8)), 4.1 and 1.8 (s br. each, 2H, 2£OH), 3.66 (t,
Jˆ6 Hz, 2H, OCH2), 2.40 (d, br., Jˆ7.6 Hz, 2H, H2C(6)),
1.55, 1.35 and 1.20 (m each, 2H each, 3£CH2), 0.92 (s, 6H,
(CH3)2C). MS: (neg. ion spray): 321/100 [M2H]2.
C13H20F6O2 requires: C 48.45%, H 6.26%, F 35.37%;
found: C 48.41%, H 6.39%, F 35.34%.
4.2.7. cis-5-(tert-Butyldimethylsilanyloxy)-cyclohexane-
1,3-diol (18). To a suspension of the cis-triol 17 (74.01 g,
560.0 mmol) in THF (1480 ml) was added subsequently at
228C tert-butyldimethylsilyl chloride (95.72 g, 97% pure,
616 mmol) and NEt3 (62.33 g, 616 mmol) and the suspen-
sion was treated in one portion with NaH (24.64 g, 60% in
oil, 616 mmol) whereby the temperature rose slowly to 458C
over 30 min. After 2 h at 408C the suspension was cooled to
108C and ®ltered. The ®ltrate was evaporated and the resi-
due triturated at 228C with n-hexane (750 ml). Filtration of
the suspension and drying of the residue afforded the pure
title compound 18 (128.0 g, 93% yield) as a white solid, mp
121±1228C. IR (nujol): 3418 m, 3337 m and 3256 m (OH).
1H NMR (250 MHz, CDCl3): 3.78 (m, 3H, 3£H±CO),
2.28±1.93 and 1.55 (m each, 5H and 3H, 3£CH2 and
2£OH), 0.89 (s, 9H, (CH3)3C), 0.08 (s, 6H, (CH3)2Si).
MS: 189/2 [M2C(CH3)3]1, 171/45, 129/30, 119/28, 75/
100. C12H26O3Si requires: C 58.49%, H 10.64%; found: C
58.53%, H 10.51%.
4.2.5. (7Z)-10,10,10-Tri¯uoro-9-hydroxy-5,5-dimethyl-9-
tri¯uoromethyl-dec-7-en-1-al (15). To a solution of the
diol 14 (3.39 g, 95.9% GLC purity, 10.1 mmol) in dichloro-
methane (15 ml) was added a solution of KBr (90 mg) and
NaHCO3 (336 mg) in water (14 ml) followed by addition of
TEMPO (8.5 mg, 0.054 mmol) and the mixture was treated
at 08C under vigorous stirring with NaOCl (10.8%, 8.00 g,
11.57 mmol) over 1 h. The aqueous layer was extracted
twice with dichloromethane (15 ml each), the organic layers
were washed with brine (15 ml), dried and the solvent
evaporated to give the pure title compound 15 (2.92 g,
90% yield) as a pale yellow oil. IR (neat): 3360m (OH),
1718 s (CvO), 1665 w (CvC). 1H NMR (250 MHz,
CDCl3): 9.75 (s, br. 1H, CHO), 6.09 (td, Jˆ8.0, 12.2 Hz,
1H, H±C(7)), 5.53 (d, br., Jˆ12.2 Hz, 1H, H±C(8)), 3.80 (s,
4.2.8. (1R,3S,5S)-1-Acetoxy-3-hydroxy-5-(tert-butyldi-
methylsilanyloxy)-cyclohexane (19). To a solution of the
diol 18 (8.95 g, 36.3 mmol) in vinyl acetate (90 ml) and
ethyl acetate (810 ml) was added at 228C Lipase QL
(895 mg) and stirring was continued at 228C for 46 h. The
reaction mixture was ®ltered, the ®ltrate concentrated and
the residue dried at 0.01 mbar overnight to give the pure title
compound 19 (10.55 g, 98.5% GLC purity, 99% yield) as a
pale yellow oil. eeˆ.99% (GLC, BGB-172). [a]Dˆ14.988
1
(CHCl3, 1%). IR (neat): 3431 m (OH), 1738s (CvO). H
NMR (250 MHz, CDCl3): 4.76 (m, 1H, H±C(1)), 3.73 (m,
2H, H±C(3) and H±C(5)), 2.22±2.03 and 1.54±1.37 (m
each, 4H and 3H, 3£CH2 and OH), 2.04 (s, 3H, COCH3),
0.88 (s, 9H, (CH3)3C), 0.07 and 0.06 (s each, 3H each,

690
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
(CH3)2Si). MS: 289/1 [M1H]1, 171/100, 129/33, 117/55,
79/45, 75/60, 43/47. C14H28O4Si requires: C 58.29%, H
9.78%; found: C 57.93%, H 9.48%.
159/20, 57/100. C17H32O4Si requires: C 62.15%, H 9.82%;
found: C 62.52%, H 9.81%.
4.2.12. (1R,3R)-1,3-Diacetoxy-5-(tert-butyldimethylsil-
anyloxy)-cyclohexane (23). A solution of the alcohol 19
(40.38 g, 98.5% GLC purity, 137.9 mmol) and triphenyl-
phosphine (55.08 g, 210.0 mmol) in THF (400 ml) was
cooled to 08C and treated with a solution of diisopropyl
azodicarboxylate (44.69 g, 95% purity, 210.0 mmol) and
acetic acid (12.61 g, 210.0 mmol) in THF (220 ml) over
2 h and stirring was continued at 08C for 2 h. The yellow
solution was evaporated, the residue triturated with
n-hexane/AcOEt (4:1, 300 ml), the suspension was ®ltered
and the ®ltrate evaporated. The residue was puri®ed over
silica gel (n-hexane/AcOEt, 9:1) to give the pure title
compound 23 (42.26 g, 93% yield) as a colourless oil.
4.2.9. (1R,3R,5R)-1-Acetoxy-3-tert-butylcarbonyloxy-5-
(tert-butyldimethylsilanyloxy)-cyclohexane (20). A solu-
tion of the alcohol 19 (10.67 g, 98.5% GLC purity,
36.4 mmol) and triphenylphosphine (14.55 g, 55.5 mmol)
in THF (107 ml) was cooled to 08C and treated with a solu-
tion of diisopropyl azodicarboxylate (11.81 g, 95% purity,
55.5 mmol) and pivalic acid (5.67 g, 55.5 mmol) in THF
(85 ml) over 1 h and stirring was continued at 08C for 1 h.
The yellow solution was evaporated, the residue triturated
with n-hexane/AcOEt (9:1, 130 ml), the suspension was
®ltered and the ®ltrate evaporated. The residue was puri®ed
over silica gel (n-hexane/AcOEt, 19:1) to give the pure title
compound 20 (12.63 g, 93% yield) as a colourless oil.
1
[a]Dˆ114.638 (CHCl3, 1%). IR (neat): 1740s (CvO). H
1
[a]Dˆ111.778 (CHCl3, 1%). IR (neat): 1733s (CvO). H
NMR (250 MHz, CDCl3): 5.27 and 5.02 (m each, 1H each,
H±C(1) and H±C(3)), 3.97 (m, 1H, H±C(5)), 2.25±1.85 and
1.61±1.36 (m each, 3H each, 3£CH2), 2.05 and 2.03 (s each,
3H each, 2£CH3CO), 0.87 (s, 9H, (CH3)3CSi), 0.06 (s, 6H,
(CH3)2Si). MS: 273/5 [M2C(CH3)3]1, 213/5, 171/10, 117/
100. C16H30O5Si requires: C 58.15%, H 9.15%; found: C
58.09%, H 9.12%.
NMR (250 MHz, CDCl3): 5.24 and 4.99 (m each, 1H each,
H±C(1) and H±C(3)), 3.97 (m, 1H, H±C(5)), 2.30±1.85 and
1.60±1.35 (m each, 3H each, 3£CH2), 2.03 (s, 3H, CH3CO),
1.20 (s, 9H, (CH3)3C), 0.88 (s, 9H, (CH3)3CSi), 0.05 (s, 6H,
(CH3)2Si). MS: 371/1 [M2H]1, 315/10, 159/45, 117/100.
C19H36O5Si requires: C 61.25%, H 9.74%; found: C 61.26%,
H 9.70%.
4.2.13. (1S,3S)-1,3-Diacetoxy-5-hydroxy-cyclohexane (24).
To a solution of the diacetate 23 (34.70 g, 105.0 mmol) in
THF (350 ml) was added at 08C tetrabutylammonium
¯uoride (1 M in THF, 115.5 ml, 115.5 mmol) over 30 min
and stirring was continued at 08C for 3 h. The solution was
evaporated and the residue puri®ed over silica gel (n-hexane/
AcOEt, 1:2) to give the title compound 24 (20.05 g, 97.9%
GLC purity, 87% yield), as a pale yellow oil. eeˆ87.2%
(GLC, BGB-174). IR (neat): 3451 m, br. (OH), 1734s
4.2.10. (1R,3R,5R)-1-Hydroxy-3-tert-butylcarbonyloxy-
5-(tert-butyldimethylsilanyloxy)-cyclohexane (21). To a
solution of the pivaloate 20 (7.45 g, 20.0 mmol) in MeOH
(52 ml) was added at 228C a solution of K2CO3 (2.76 g,
20.0 mmol) in water (23.5 ml) and stirring was continued
at 228C for 7 h. The pale yellow solution was evaporated
and the residue partitioned between dichloromethane
(50 ml) and water (50 ml). The organic layer was dried
and evaporated to give the pure title compound 21
(6.49 g, 98% yield) as a colourless oil, which solidi®ed at
228C, mp 41±42.58C. IR (nujol): 3240 m, br. (OH),1731s
(CvO). 1H NMR (250 MHz, CDCl3): 5.31 (m, 1H, H±C(3),
4.18 and 4.06 (m each, 1H each, H±C(1) and H±C(5)), 2.97
(d, br. Jˆ6.4 Hz, 1H, OH), 1.94±1.64 (m, 6H, 3£CH2), 1.19
(s, 9H, (CH3)3C), 0.91 (s, 9H, (CH3)3CSi), 0.11 and 0.09 (s
each, 3H each, (CH3)2Si). MS: 273/10 [M2C(CH3)3]1, 171/
100, 159/35, 79/45, 75/90. C17H34O4Si requires: C 61.77%,
H 10.37%; found: C 61.90%, H 10.62%.
1
(CvO). H NMR (250 MHz, CDCl3): 5.29 and 5.05 (m
each, 1H each, H±C(1) and H±C(3)), 4.04 (m, 1H, H±
C(5)), 2.31±2.05 and 1.65±1.43 (m each, 3H each,
3£CH2), 2.05 and 2.04 (s each, 3H each, 2£CH3CO), 1.85
(s, br., 1H, OH). MS: 156/2 [M2AcOH]1, 96/75, 43/100.
C10H16O5 (containing 0.81% of H2O) requires: C 55.55%,
H 7.46%; found: C 55.59%, H 7.43%.
4.2.14. (3R,5R)-3,5-Diacetoxy-cyclohexan-1-one (25). To
a solution of the alcohol 24 (30.0 g, 97.9% GLC purity,
135.8 mmol) in dichloromethane (400 ml) was added a
solution of KBr (1.16 g) in water (200 ml) followed by addi-
tion of TEMPO (325 mg, 2.1 mmol) and the mixture was
treated at 08C under vigorous stirring simultaneously with
NaOCl (10.6%, 107.1 g, 152.6 mmol) and with hydro-
chloric acid (0.1N, 520 ml) over 1 h keeping the pH at
6.5±7.5. The aqueous layer was extracted once with
dichloromethane (200 ml), the organic layers were washed
with brine (300 ml), dried and the solvent evaporated to give
the pure title compound 25 (28.93 g, 99% yield) as a pale
yellow oil. eeˆ87% (GLC, BGB-174). A sample was
crystallized from tert-butyl methyl ether/n-hexane at
2208C to give white crystals, mp 51±528C. eeˆ99.0%
(GLC, BGB-174). [a]Dˆ156.58 (CHCl3, 1%). IR
(nujol): 1728s (CvO). 1H NMR (400 MHz, CDCl3):
5.37 (m, 2H, H±C(3) and H±C(5)), 2.73 and 2.52 (dd
each, Jˆ14.614, 14.616.8 Hz, 2H each, H2C(2) and
H2C(6)), 2.19 (t, Jˆ5.6 Hz, 2H, H2C(4)), 2.05 (s, 6H,
2£CH3CO). MS: 154/5 [M2AcOH]1, 112/20, 94/25,
4.2.11. (3S,5S)-3-tert-Butylcarbonyloxy-5-(tert-butyldi-
methylsilanyloxy)-cyclohexan-1-one (22). To a solution
of the alcohol 21 (27.50 g, 83.2 mmol) in dichloromethane
(250 ml) was added a solution of KBr (0.71 g) and NaHCO3
(2.66 g) in water (250 ml) followed by addition of TEMPO
(200 mg, 1.25 mmol) and the mixture was treated at 08C
under vigorous stirring with NaOCl (11%, 61.93 g,
91.52 mmol) over 1 h. The aqueous layer was extracted
once with dichloromethane (250 ml), the organic layers
were washed with aqueous NH4Cl (15%, 250 ml) and
brine (250 ml), dried and the solvent evaporated to give
the pure title compound 22 (27.24 g, 100% yield) as a
yellow oil. [a]Dˆ220.378 (CHCl3, 1%). IR (neat): 1728 s,
1
br. (CvO). H NMR (250 MHz, CDCl3): 5.37 (m, 1H,
H±C(3), 4.30 (m, 1H, H±C(5)), 2.63, 2.43 and 2.06 (m
each, 2H each, 3£CH2), 1.18 (s, 9H, (CH3)3C), 0.97 (s,
9H, (CH3)3CSi), 0.08 and 0.07 (s each, 3H each,
(CH3)2Si). MS: 271/3 [M2C(CH3)3]1, 227/15, 169/30,

H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
691
43/100. C10H14O5 requires: C 56.07%, H 6.59%; found:
C 55.93%, H 6.76%.
4.2.18. (5S)-5-Acetoxy-cyclohex-2-en-1-one (31). A sus-
pension of the ketone 30 (5.00 g, 23.35 mmol) in THF
(50 ml) and aluminium oxide (basic, activity I, 25.0 g)
was stirred at 228C for 1 h and the reaction was followed
by 1H NMR. The suspension was ®ltered, the ®ltrate evapo-
rated and the residue triturated with tert-butyl methyl ether
(4 ml) at 228C for 1 h. The suspension was ®ltered and the
residue dried to give the pure title compound 31 (2.75 g,
76% yield) as white crystals, mp 84±868C. The mother
liquor was evaporated and subsequently triturated with
n-pentane (1.5 ml) and with tert-butyl methyl ether (2 ml)
at 228C to give a further portion of pure 31 (0.28 g, 8%
yield). eeˆ.99.9% (GLC, BGB-176). [a]Dˆ143.68
(CHCl3, 1%). IR (nujol): 1731s and 1671s (CvO), 1625
4.2.15. 77:18 Mixture of trans-1,3,5-triacetoxy-cyclo-
hexane (27) and cis-1,3,5-triacetoxy-cyclohexane (28).
A solution of a 1:1 mixture of the trans-triol 26 and the
cis-triol 17 (87.34 g) in ethanol (870 ml) was diluted at
228C with water (38 ml) and cooled to 08C. The solution
was seeded with pure 17 and stirring was continued at 08C
for 1 h and at 2208C for 4 h. The suspension was ®ltered,
the ®ltrate evaporated, the residue was suspended in toluene
(440 ml) and evaporated again to give a water free 76:18
mixture of the trans-triol 26 and the cis-triol 17 (44.00 g,
333.0 mmol) as a white solid. This mixture was treated at
228C with pyridine (110 ml) and with acetic anhydride
(157 ml, 1665 mmol) over 45 min after which time the
temperature rose to 458C and stirring was continued at
458C for 4 h. The mixture was evaporated to dryness, the
residue dissolved in dichloromethane (300 ml) and washed
with hydrochloric acid (0.2N, 300 ml) and water (200 ml).
The organic layer was dried and evaporated to give a 77:18
mixture (GLC) of the title compounds 27 and 28 (85.73 g,
100% yield) as a pale yellow oil. IR (neat): 1736s br.
1
m (CvC). H NMR (400 MHz, CDCl3): 6.88 (td, Jˆ4,
10.2 Hz, 1H, H±C(3)), 6.12 (td, Jˆ1.6, 10.2 Hz, 1H, H±
C(2)), 5.35 (m, 1H, H±C(5)), 2.80±2.48 (m, 4H, 2£CH2),
2.05 (s, 3H, CH3CO). MS: 154/3 [M]1, 111/10, 94/37, 68/
40, 43/100. C8H10O3 requires: C 62.33%, H 6.54%; found: C
62.12%, H 6.57%.
4.2.19. (5R)-5-Acetoxy-cyclohex-2-en-1-one (32). The
elimination was carried out with the ketone 25 (eeˆ87%)
according to the preparation of the enantiomer 31 to give the
pure title compound 32 (70% yield) as white crystals, mp
84±868C. eeˆ98.8% (GLC, BGB-176). [a]Dˆ243.08
1
(CvO). H NMR (400 MHz, CDCl3): 5.31, 5.09 and 4.78
(m each, 3£H±CO of trans-27 and cis-28), 2.07 and 2.04 (s
each, 3£CH3), 2.35±2.07 and 1.65±1.35 (m each, 3£CH2).
MS: 199/7 [M2AcO]1, 138/20, 96/90, 78/35, 43/100.
C12H18O6 requires: C 55.81%, H 7.03%; found: C 55.94%,
H 7.10%.
1
(CHCl3, 1%). IR, H NMR and MS are identical with 31.
C8H10O3 requires: C 62.33%, H 6.54%; found: C 62.05%, H
6.64%.
4.2.16. (1R,3R)-1,3-Diacetoxy-5-hydroxy-cyclohexane (29).
To a 77:18 mixture of the crude triacetates 27 and 28 (81.74 g,
243.7 mmol 27) in cyclohexane (200 ml) was added under
vigorous stirring a solution of sodium chloride (0.1 M,
1300 ml) and sodium phosphate buffer (0.1 M, pHˆ7.0,
50 ml). The resulting mixture was cooled to 5±68C and the
pH re-adjusted to 7.0 with aqueous sodium hydroxide (1N,
few drops). The reaction was started by adding a solution of
Lipase OF (1.60 g) in aqueous sodium chloride (0.1 M, 15 ml)
to the vigorously stirred mixture and the pH was kept constant
at 7.0 by the controlled addition (pH-stat) of aqueous sodium
hydroxide (1N, 260 ml, 1.07 equiv. with respect to 27) over
21.5 h keeping the temperature at 5±68C. The reaction
mixture was extracted twice with dichloromethane (1500 ml
each), the organic, very turbid layers were ®ltered over
Dicalite Speedex (100 g, prewashed with water) dried and
evaporated. The residue (66.1 g) was puri®ed over silica gel
(700 g, n-hexane/ethyl acetate 3:2) to give the title compound
29 (46.3 g 95.7% GLC purity, 84% yield with respect to 27) as
4.2.20. Ethyl ((3R,5R)-3,5-diacetoxy-cyclohexylidene)-
acetate (34). To a solution of LDA (0.2 M in THF,
1000 ml, 200 mmol) was added at 2788C a solution of
ethyl (trimethylsilyl)±acetate (33.05 g, 97% pure,
200.0 mmol) in THF (100 ml) over 1 h followed by addition
of a solution of the ketone 30 (21.42 g, 100.0 mmol) in THF
(150 ml) and stirring was continued at 2788C for 1.5 h. The
yellow solution was washed with aqueous sat. NH4Cl
(500 ml) and brine (500 ml), the organic layer was dried
and evaporated. Puri®cation of the residue over silica gel
(hexane/AcOEt 4:1) gave the pure title compound 34
(23.57 g, 83% yield) as a pale yellow. IR (neat): 1734 s
1
and 1712 s (CvO), 1656m (CvC). H NMR (400 MHz,
CDCl3): 5.78 (s, br., 1H, HCvC), 5.20 and 5.14 (m each,
1H each, H±C(3) and H±C(5)), 4.16 (q, Jˆ7.2 Hz, 2H,
COOCH2), 3.07, 2.56, 2.33 and 2.00 (m, dd, dd, and m,
Jˆ13.414.4, 13.417.6 Hz, 2H, 1H, 1H and 2H, 3£CH2),
2.05 and 2.02 (s each, 3H each, 2£CH3CO), 1.28 (t,
Jˆ7.2 Hz, 3H, CH3). MS: 284/1 [M]1, 225/5
[M2CH3CO2]1, 164/85, 136/80, 118/55, 91/60, 43/100.
C14H20O6 requires: C 59.15%, H 7.09%; found: C 58.88%,
H 7.09%.
1
a colourless oil. eeˆ99.5% (GLC, BGB-174). IR, H NMR
and MS are identical with the enantiomer 24. C10H16O5
requires: C 55.55%, H 7.46%; found: C 55.76%, H 7.37%.
4.2.17. (3S,5S)-3,5-Diacetoxy-cyclohexan-1-one (30). The
oxidation was carried out with the alcohol 29 according to
the preparation of the enantiomer 25 to give the pure title
compound 30 (99% yield) as a pale yellow oil which
solidi®ed at 2208C. For analytical purposes a sample was
recrystallized from tert-butyl methyl ether/n-hexane at
2208C to give white crystals, mp 51±528C. eeˆ99.5%
(GLC, BGB-174). [a]Dˆ256.18 (CHCl3, 1%). IR, 1H
NMR and MS are identical with 25. C10H14O5 requires: C
56.07%, H 6.59%; found: C 55.98%, H 6.65%.
4.2.21. 3:1 Mixture of ethyl ((3R,5R)-3,5-dihydroxy-
cyclohexylidene)-acetate (35) and its methyl acetate. To
a solution of the ethyl ester 34 (21.60 g, 75.97 mmol) in
methanol (160 ml) was added at 08C a solution of K2CO3
(21.0 g, 152 mmol) in water (74 ml) and the solution was
stirred vigorously at 228C for 6 h. The mixture was evapo-
rated, the residue partitioned between dichloromethane
(300 ml) and brine (300 ml) and the aqueous layer was
extracted four times with dichloromethane (300 ml each).
The combined organic layers were dried and evaporated to

692
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
give a 3:1 mixture (1H NMR) of the title compound 35 and
its methyl acetate (14.75 g, 99% yield) as a yellow oil. IR
4.2.24. [(3R,5R)-3,5-Bis-(tert-butyldimethylsilanyloxy)-
cyclohexylidene]-ethyl-diphenylphosphine oxide (6). To
a solution of the allyl alcohol 37 (9.67 g, 25.0 mmol) in THF
(97 ml) was subsequently added at 08C n-BuLi (1.6 M in
hexane, 16.4 ml, 26.2 mmol) over 20 min and a solution of
toluene-4-sulfonyl chloride (5.00 g, 26.2 mmol) in THF
(50 ml) over 30 min and stirring was continued at 08C for
2.5 h. The pale yellow solution was treated at 08C over 1 h
with a solution of lithium diphenylphosphide, prepared by
addition of n-BuLi (1.6 M in hexane, 17.2 ml, 27.5 mmol)
to a solution of diphenylphosphine (5.12 g, 27.5 mmol) in
THF (40 ml) over 1 h, and the orange solution was stirred at
08C for 1 h. The mixture was slowly diluted with 5 ml of
water and evaporated. The residue was diluted with
dichloromethane (200 ml) and water (200 ml) and the
vigorously stirred mixture was treated at 228C with hydro-
gen peroxide (35%, 24.3 g, 250 mmol) and stirring was
continued for 3.5 h. The organic layer was washed with
aqueous sat. NaHCO3 (300 ml) and water (300 ml), dried
and evaporated. The residue was puri®ed over silica gel
(n-hexane/AcOEt 2: 1) to give the pure title compound 6
(10.71 g, 75% yield) as a white solid. For analytical
purposes a sample was recrystallized from n-hexane at
2508C, mp 73±758C. eeˆ.99.9% (HPLC, Chiracel OD±
H, n-hexane/EtOH 9:1). [a]Dˆ113.88 (CHCl3, 1%). IR
1
(neat): 3392s, br. (OH), 1712s (CvO), 1651s (CvC). H
NMR (400 MHz, CDCl3): 5.82 (s, br., HCvC), 4.30±4.17
(m, H±C(3) and H±C(5)), 4.15 (q, Jˆ6.8 Hz, COOCH2),
3.70 (s, COOCH3), 3.12, 2.88, 2.55 and 2.25±1.75 (m
each, 3£CH2 and 2£OH), 1.28 (t, Jˆ6.8 Hz, CH3 of ethyl
acetate). MS: 200/5 [M]1 of 35, 182/20 [M2H2O]1 of 35,
155/80, 82/100. C10H16O4 requires: 200.1049; found:
200.1039.
4.2.22. 3:1 Mixture of ethyl [(3R,5R)-3,5-bis-(tert-butyl-
dimethylsilanyloxy)-cyclohexylidene]-acetate (36) and
its methyl acetate. To a solution of a 3:1 mixture of the
ethyl acetate 35 and its methyl acetate (13.80 g,
70.14 mmol) in DMF (70 ml) was added in one portion at
228C tert-butyldimethylsilyl chloride (23.56 g, 97% pure
151.6 mmol) and in ®ve portions imidazole (10.32 g,
151.6 mmol) and stirring of the suspension was continued
at 228C for 3 h. The mixture was diluted at 108C with
toluene (150 ml) and water (150 ml), the organic layer
was washed several times with water, dried and evaporated
to give a 3:1 mixture (1H NMR) of the title compound 36
and its methyl acetate (29.05 g, 97% yield) as a pale yellow
oil. For analytical purposes a sample was puri®ed over silica
gel (n-hexane/AcOEt 50:1). IR (neat): 1721s (CvO), 1655
m (CvC). 1H NMR (400 MHz, CDCl3): 5.70 (s, br.,
HCvC), 4.20±4.10 (m, H±C(3) and H±C(5)), 4.15 (q,
Jˆ7 Hz, COOCH2), 3.68 (s, COOCH3), 3.03, 2.80, 2.38,
2.16, 1.80 and 1.70 (m each, 3£CH2), 1.27 (t, Jˆ7 Hz,
CH3 of ethyl acetate), 0.87 and 0.85 (s each, 2£(CH3)3C),
0.05 (s, 2£(CH3)2Si). MS: 371/100 [M2C(CH3)3]1 of 36,
357/40 [M2C(CH3)3]1 of methyl acetate, 73/55.
C22H44O4Si21C21H42O4Si2 (3:1) requires: C 61.43%, H
10.31%; found: C 61.41%, H 10.43%.
1
(KBr): 1180s (PvO). H NMR (400 MHz, CDCl3): 7.72
and 7.47 (m each, 4H and 6H, H-ar.), 5.28 (q, Jˆ7.2 Hz,
1H, HCvC), 3.98 (m, 2H, H±C(3) and H±C(5)), 3.10 (m,
2H, CH2P), 2.21, 2.00, 1.90 and 1.64 (m each, 1H, 2H, 1H
and 2H, 3£CH2), 0.85 and 0.83 (s each, 9H each,
2£(CH3)3C), 0.00 and 20.01 (s each, 12H, 2£(CH3)2Si).
MS: 555/3 [M2CH3]1, 513/100 [M2C(CH3)3)]1, 381/80,
1
202/75, 73/87. IR, H NMR and MS are identical with 6
prepared according to lit.9. C32H51O3PSi2 requires: C
67.32%, H 9.00%, P 5.43%; found: C 67.22%, H 8.96, P
5.32%.
4.2.23. [(3R,5R)-3,5-Bis-(tert-butyldimethylsilanyloxy)-
cyclohexylidene]-ethanol (37). To a solution of a 3:1
mixture of the ethyl acetate 36 and its methyl acetate
(27.00 g, 63.5 mmol) in toluene (270 ml) was added at
2158C Red-Alw (3.5 M in toluene, 43 ml, 150.5 mmol)
over 30 min and stirring was continued at 2158C for 1 h.
The yellow solution was slowly diluted at 215 to 08C with
water (140 ml) and the emulsion was further diluted with
aqueous NaOH (1N, 135 ml). The organic layer was washed
several times with water, dried and evaporated to give the
title compound 37 (23.36 g, 95% yield) as a colourless wax,
which was further processed without puri®cation. For
analytical purposes a sample was puri®ed over silica gel
(n-hexane/AcOEt 7:1), mp 63±658C. [a]Dˆ118.48
(CHCl3, 1%). Prepared according to lit.:9 [a]Dˆ118.78
(CHCl3, 1%). IR (nujol): 3240s, br. (OH), 1675w (CvC);
4.2.25. [(3S,5S)-3,5-Bis-(tert-butyldimethylsilanyloxy)-
cyclohexylidene]-ethyl-diphenylphosphine oxide (40).
The preparation of the enantiomer 40 from the ketone 25
(eeˆ86%) was carried out in analogy to 6 to give the title
compound 40, which was recrystallized from n-hexane at
2508C, mp 73±758C. eeˆ.99.9% (HPLC, Chiracel OD±
H, n-hexane/EtOH 9:1). [a]Dˆ213.48 (CHCl3, 1%). IR, 1H
NMR and MS are identical with 6. C32H51O3PSi2 requires: C
67.32%, H 9.00%, P 5.43%; found: C 67.11%, H 9.00, P
5.55%.
4.2.26. (2E,9Z)-12,12,12-Tri¯uoro-7,7-dimethyl-11-triethyl-
silanyloxy-11-tri¯uoromethyl-dodeca-2,9-dienoic acid
ethyl ester (54). To a suspension of tert-BuOK (16.83 g,
150 mmol) in toluene (450 ml) was added at 58C a solution
of triethyl phosphonoacetate (33.60 g, 150 mmol) in toluene
(120 ml) over 30 min and stirring was continued at 228C for
1 h. The suspension was cooled to 2158C and treated with a
solution of the aldehyde 16 (50.00 g, 95.4% GLC purity,
109.8 mmol) in toluene (120 ml) over 30 min and stirring
was continued at 2108C for 2.5 h. The reaction mixture was
quenched with aqueous NH4Cl (15%, 500 ml), the organic
layer was washed twice with water (500 ml each), dried
and evaporated. The residue was puri®ed over silica gel
(n-hexane/AcOEt 40:1) to give a minor fraction containing
the pure (2Z,9Z)-isomer of 54 (1.38 g, 2.5% yield). IR
1
MS (EI): 371/3 (M2CH3). H NMR (400 MHz, CDCl3):
5.60 (t, Jˆ7.3 Hz, 1H, HCvC), 4.13 and 4.03 (m each,
2H each, H±C(3), H±C(5) and CH2O), 2.35, 2.18, 2.06,
1.82, 1.64 and 1.30 (m, dd, dd, m, m and t, Jˆ1312.4,
1318.1, 6.5 Hz Hz, 2H, 1H, 1H, 1H, 1H and 1H, 3£CH2
and OH), 0.89 (s, br., 18H, 2£(CH3)3C), 0.06, 0.05 and 0.04
(s each, 6H, 3H and 3H, 2£(CH3)2Si). MS: 371/3
[M2CH3]1, 237/45, 211/40, 197/50, 171/100, 75/90. IR,
1H NMR and MS are identical with 37 prepared according
to lit.9. C20H42O3Si2 requires: C 62.12%, H 10.95%; found:
C 62.23%, H 11.03%.

H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
693
(neat): 1723s (CvO), 1645m (CvC). 1H NMR (400 MHz,
CDCl3): 6.19 (td, Jˆ7.6, 11.4 Hz, 1H, H±C(3)), 5.96 (td,
Jˆ7.0, 12.4 Hz, 1H, H±C(9)), 5.76 (td, Jˆ1, 11.4 Hz, 1H,
H±C(2)), 5.43 (d, br., Jˆ12.4 Hz, 1H, H±C(10)), 4.17 (q,
Jˆ6.8 Hz, 2H, CH2O), 2.62 (qd, Jˆ7.6, 1.6 Hz, 2H,
H2C(4)), 2.32 (dd, Jˆ7, 2 Hz, 2H, H2C(8)), 1.39 and 1.25
(m each, 2H each, 2£CH2), 1.30 (t, Jˆ6.8 Hz, 3H, CH3),
0.96 and 0.72 (t and q, Jˆ8 Hz each, 9H and 6H,
Si(CH2CH3)3), 0.88 (s, 6H, (CH3)2C(7)). MS: 505/1
[M1H]1, 475/20 [M2C2H5)]1, 325/10, 183/15, 137/40,
109/100. C21H33F6O3Si requires for [M2C2H5)]1:
475.2103; found for [M2C2H5)]1: 475.2090.
evaporated to dryness, the residue dissolved in EtOH
(425 ml) and treated at 08C with a solution of ammonium
heptamolybdate tetrahydrate (16.31 g, 13.2 mmol) in H2O2
(35%, 64.15 g, 660 mmol) over 15 min and stirring was
continued at 228C for 17 h. The mixture was treated with
a solution of Na2SO3 (76 g) in water (760 ml), the ethanol
was distilled off and the aqueous layer was extracted twice
with dichloromethane (500 ml each). The organic layers
were washed with water (500 ml), dried and evaporated.
The residue was puri®ed over silica gel (n-hexane/AcOEt,
15:1) to give the title compound 60 (32.90 g, 77%) as a pale
yellow oil. IR (neat): 1663w (CvC), 1335 1148s (SO2). 1H
NMR (400 MHz, CDCl3): 8.23, 8.00 and 7.61 (d, d and m,
Jˆ7.6 Hz each, 1H, 1H and 2H, H-ar), 5.88 (td, Jˆ7,
12.4 Hz, 1H, H±C(9)), 5.72 and 5.49 (td each, Jˆ7,
15.6 Hz each, 1H each, H±C(2) and H±C(3)), 5.40 (d, br.,
Jˆ12.4 Hz, 1H, H±C(10)), 4.18 (d, Jˆ7 Hz, 2H, H2C(1)),
2.24 (d, Jˆ7 Hz, 2H, H2C(8)), 1.96 (q, Jˆ7 Hz, 2H,
H2C(4)), 1.12 (m, 4H, 2£CH2), 0.95 and 0.71 (t and q,
Jˆ8 Hz each, 9H and 6H, Si(CH2CH3)3), 0.76 (s, 6H,
(CH3)2C(7)). MS: 643/1 [M]1, 614/50 [M2C2H5)]1 182/
100. C28H39F6NO3S2Si requires: C 52.24%, H 6.11%, N
2.18%, S 9.96%, F 17.71%; found: C 52.39%, H 6.24%,
N 2.20%, S 10.18%, F 17.58%.
The main fraction contained the pure title compound 54
(53.15 g, 96% yield) as a colourless oil. IR (neat): 1724s
(CvO), 1655m (CvC). 1H NMR (400 MHz, CDCl3): 6.95
(td, Jˆ7.0, 15.6 Hz, 1H, H±C(3)), 5.95 (td, Jˆ7.0, 12.4 Hz,
1H, H±C(9)), 5.81 (d, br., Jˆ15.6 Hz, 1H, H±C(2)), 5.43 (d,
br., Jˆ12.4 Hz, 1H, H±C(10)), 4.18 (q, Jˆ6.8 Hz, 2H,
CH2O), 2.32 and 2.17 (d and q, Jˆ7.0 Hz each, 2H and
2H, 2£CH2), 1.42 and 1.25 (m each, 2H each, 2£CH2),
1.28 (t, Jˆ6.8 Hz, 3H, CH3), 0.97 and 0.72 (t and q,
Jˆ7.6 Hz each, 9H and 6H, Si(CH2CH3)3), 0.89 (s, 6H,
(CH3)2C(7)). MS: 505/1 [M1H]1, 475/15 [M2C2H5)]1,
325/10, 183/5, 137/10, 109/100. C21H33F6O3Si requires for
[M2C2H5)]1: 475.2103; found for [M2C2H5)]1: 475.2088.
4.2.29. (1R,3R)-5-[(2E,9Z)12,12,12-Tri¯uoro-11-hydroxy-
7,7-dimethyl-11-tri¯uoromethyl-dodeca-2,9-dienylidene]-
cyclohexane-1,3-diol (3). A solution of the sulfone 60
(21.89 g, 34.0 mmol) in THF (130 ml) was treated at
2788C with LiN(TMS)2 (1.0 M in THF, 34 ml,
34.0 mmol) over 45 min and stirring of the orange solution
was continued for 35 min. The solution was treated at 2788
with a solution of the ketone 30 (7.28 g, 34.0 mmol) in THF
(36 ml) over 20 min and stirring was continued at 2788C for
4 h and at 228C for 18 h. The mixture was evaporated to
dryness and the residue dissolved in MeOH (440 ml). To the
orange solution was added at 228C a solution of K2CO3
(14.1 g) in water (110 ml) and stirring was continued at
228C for 22 h. The orange emulsion was evaporated to
dryness and the residue partitioned between dichloro-
methane (200 ml) and water (100 ml). The aqueous layer
was extracted twice with dichloromethane (200 ml each)
and the organic layers were washed with brine (100 ml),
dried and evaporated. The residue was puri®ed over silica
gel (n-hexane/AcOEt 1:4) to give the pure title compound 3
(12.81 g, 85%) as a pale yellow resin, which is sensitive to
air. [a]D18.348 (CHCl3, 1%). IR (neat): 3348 m (OH), 1662
4.2.27. (2E,9Z)-12,12,12-Tri¯uoro-7,7-dimethyl-11-tri-
ethylsilanyloxy-11-tri¯uoromethyl-dodeca-2,9-dien-1-ol
(55). To a solution of the ester 54 (53.10 g, 105.2 mmol) in
toluene (650 ml) was added at 2788C diisobutyl aluminium
hydride (1.2 M in toluene, 240 ml, 288 mmol) over 40 min
and stirring of the colourless mixture was continued at
2788C for 2.5 h. The reaction was quenched with aqueous
NH4Cl (15%, 500 ml), the suspension was ®ltered and the
aqueous layer extracted once with toluene (500 ml). The
organic layers were washed twice with water (500 ml
each), dried and evaporated to give the title compound 55
(48.52 g, 100%) as a pale yellow oil, which was further
processed without puri®cation. For analytical purposes a
sample was puri®ed over silica gel (n-hexane/AcOEt 4:1).
IR (neat): 3328m (OH), 1669w (CvC). 1H NMR
(400 MHz, CDCl3): 5.97 (td, Jˆ6.5, 12.4 Hz, 1H, H±
C(9)), 5.66 (m, 2H, H±C(2) and H±C(3)), 5.43 (d, br.,
Jˆ12.4 Hz, 1H, H±C(10)), 4.09 (t, Jˆ5,2 Hz, 2H,
H2C(1)), 2.32 (d, Jˆ6.5 Hz, 2H, H2C(8)), 2.02 (q,
Jˆ6.5 Hz, 2H, H2C(4)), 1.35 and 1.25 (m each, 2H and
3H, 2£CH2 and OH), 0.96 and 0.73 (t and q, Jˆ8 Hz
each, 9H and 6H, Si(CH2CH3)3), 0.88 (s, 6H, (CH3)2C(7)).
MS: 433/4 [M2C2H5)]1, 231/25, 123/85, 81/100.
C21H36F6O2Si requires: C 54.53%, H 7.84%, F 24.64%;
found: C 54.76%, H 7.78%, F 24.84%.
1
w (CvC). H NMR (400 MHz, CDCl3): 6.26 (dd, Jˆ10.8,
15.2 Hz, 1H, H±C(2)), 6.05 (td, Jˆ8, 12.4 Hz, 1H, H±
C(9)), 5.98 (d, br., Jˆ10.8 Hz, 1H, H±C(1)), 5.68 (td,
Jˆ6.8, 15.2 Hz, 1H, H±C(3)), 5.45 (d, br., Jˆ12.4 Hz,
1H, H±C(10)), 4.34 (s, br., 1H, HO±C(11)), 4.08 (m, 2H,
2£H±CO)), 2.60, 2.50±1.70, 1.38 and 1.22 (dd and m each,
1H, 11H, 2H and 2H, Jˆ3.6, 13.6 Hz, 7£CH2 and 2£OH),
0.89 (s, 6H, (CH3)2C(7)). MS: 444/25 [M]1, 426/15
[M2H2O]1, 231/55, 95/100. C21H30F6O3 (containing
0.29% of water and 2.92% of AcOEt) requires: C 56.69%,
H 6.87%, F 24.90%; found: C 56.39%, H 7.09%, F 24.94%.
4.2.28. (2E,9Z)-2-(12,12,12-Tri¯uoro-7,7-dimethyl-11-tri-
ethylsilanyloxy-11-tri¯uoromethyl-dodeca-2,9-diene-1-
sulfonyl)-benzothiazole (60). To
a
suspension of
2-mercaptobenzothiazole (16.56 g, 99 mmol) in dichloro-
methane (165 ml) was subsequently added at 08C in one
portion triphenylphosphine (25.97 g, 99 mmol), a solution
of the allyl alcohol 55 (30.53 g, 66 mmol) in dichloro-
methane (90 ml) over 20 min and diisopropyl azodicar-
boxylate (21.07 g, 95% pure, 99 mmol) over 30 min and
stirring was continued at 08C for 1.5 h. The mixture was
Acknowledgements
We express our cordial thanks to Jean-Pierre Gaertner,

694
H. Hilpert, B. Wirz / Tetrahedron 57 (2001) 681±694
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Asymmetry 1997, 8, 181±184.
Roland Humm, Patrick Stocker and Maya Zur¯uh for their
skilful technical assistance, to our colleagues from the
analytical service labs, especially to Sabine Ulrike Mayer,
Gottfried Oesterhelt and Willy Walther for analysing
numerous samples and to Michael Hennig for the X-ray
analysis. The reading of the manuscript by Martin Karpf,
Mark Rogers-Evans and Ulrich Widmer is kindly acknowl-
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