Development and applications of remote stereocontrol using allylic organobismuth reagents

Article abstract of DOI:10.1039/c3ob41931b

Reactions of 5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane with aldehydes promoted by bismuth(iii) iodide were usefully stereoselective in favour of the (E)-1,5-anti-6-benzyloxy-5-methylalk-3-en-1-ols. Similar stereoselectivity was observed for reactions of analogous 5-benzyloxy-4- methylpent-2-enyl bromides with aldehydes when promoted by a low valency bismuth species prepared by reduction of bismuth(iii) triiodide with powdered zinc so providing a "tin-free" procedure. The analogous reactions of 4-benzyloxypent-2-enyl(tributyl)stannane with aldehydes promoted by bismuth(iii) iodide were also stereoselective but gave lower yields. Attempted 1,6-stereocontrol using these reactions resulted in only modest stereoselectivities. Aspects of the chemistry of the products were studied in particular their stereoselective conversion into aliphatic compounds with methyl bearing stereogenic centres at 1,5,9,13- and 1,3,5-positions along the aliphatic chain. Mechanistically, allylic organobismuth species may be involved in both sets of reactions but this was not confirmed although the similar stereoselectivities observed for both the bismuth(iii) iodide mediated reactions of the pent-2-enylstannanes and the low-valency bismuth promoted reactions of the pent-2-enyl bromides are consistent with participation of similar intermediates.

Full text of DOI:10.1039/c3ob41931b

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Development and applications of remote stereocontrol
using allylic organobismuth reagents†
Norazah Basar,a Sam Donnelly,b Hasnah M. Sirata and Eric J. Thomas*b
Cite this: Org. Biomol. Chem., 2013, 11,
8476
Reactions of 5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane with aldehydes promoted by bismuth(III)
iodide were usefully stereoselective in favour of the (E)-1,5-anti-6-benzyloxy-5-methylalk-3-en-1-ols.
Similar stereoselectivity was observed for reactions of analogous 5-benzyloxy-4-methylpent-2-enyl bro-
mides with aldehydes when promoted by a low valency bismuth species prepared by reduction of
bismuth(III) triiodide with powdered zinc so providing a “tin-free” procedure. The analogous reactions of
4-benzyloxypent-2-enyl(tributyl)stannane with aldehydes promoted by bismuth(III) iodide were also
stereoselective but gave lower yields. Attempted 1,6-stereocontrol using these reactions resulted in only
modest stereoselectivities. Aspects of the chemistry of the products were studied in particular their
stereoselective conversion into aliphatic compounds with methyl bearing stereogenic centres at 1,5,9,13-
and 1,3,5-positions along the aliphatic chain. Mechanistically, allylic organobismuth species may be
involved in both sets of reactions but this was not confirmed although the similar stereoselectivities
observed for both the bismuth(III) iodide mediated reactions of the pent-2-enylstannanes and the low-
valency bismuth promoted reactions of the pent-2-enyl bromides are consistent with participation of
similar intermediates.
Received 23rd September 2013,
Accepted 30th October 2013
DOI: 10.1039/c3ob41931b
www.rsc.org/obc
Following on from this work, it was of interest to study
transmetallation of the allylstannanes with other Lewis acids
Introduction
Transmetallation of 4- and 5-heterosubstituted alk-2-enyl- to see whether similar or complementary stereoselectivity was
(trialkyl)stannanes using tin(IV) halides is stereoselective and observed. The development of “tin-free” procedures would also
generates allyltin trihalides that react with aldehydes and with be of interest. We here report studies of reactions of allylstan-
imines with useful 1,5-, 1,6- and 1,7-stereocontrol.1,2 For nanes, including the pent-2-enylstannane 1, with aldehydes
example the 5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane promoted by bismuth(III) iodide together with analogous reac-
1 gives the (Z)-1,5-anti-alkenols 2 following transmetallation tions of alk-2-enyl bromides promoted by a low valency
with tin(IV) chloride at −78 °C and reaction of the intermediate bismuth species prepared by reduction of bismuth(III) iodide
allyltin trichloride with aldehydes.2b This chemistry has been with powdered zinc.7,8
used to complete syntheses of several natural products3–5 and
analogous chemistry has been developed for the corres-
ponding organogermanium compounds so avoiding the use of
Results and discussion
Preliminary studies and 1,5-stereocontrol in reactions of
organotin starting materials.6
4- and 5-benzyloxypent-2-enylstannanes with aldehydes
promoted by bismuth(III) iodide
Strong Lewis acids catalyse reactions of allylstannanes with
aldehydes by coordination to the aldehyde leading to an SE′
reaction with the stannane. BF3·Et2O has been widely used in
this context with useful 1,2-syn-stereoselectivities found for
reactions of but-2-enylstannanes with aldehydes at −78 °C.9
aChemistry Department, Faculty of Science, Universiti Teknologi Malaysia Skudai,
81310 Skudai, Johor Bahru, Malaysia
bSchool of Chemistry, The University of Manchester, Manchester, M13 9PL, UK.
The BF3·Et2O promoted reaction of the racemic stannane 1
with benzaldehyde followed this pattern and gave a mixture of
E-mail: e.j.thomas@manchester.ac.uk; Fax: +44 (0)161 275 4939;
two SE′ products identified as the 1,2-syn-adducts 3 and 4,
Tel: +44 (0)161 275 4613
ratio 70 : 30, see Scheme 1. The relative configurational assign-
ments shown were provisionally assigned on the basis of the
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob41931b
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Scheme 1 Reaction of stannane 1 with benzaldehyde catalysed by BF3·Et2O.
Reagents and conditions: (i) PhCHO, BF3·Et2O, DCM, −78 °C, 10 min, add 1,
−78 °C to 0 °C (51%, 3 : 4 = 70 : 30).
1,2-syn-stereoselectivity usually observed for BF3·Et2O catalysed
reactions of alk-2-enylstannanes with aldehydes9 and the facial
selectivities found for reactions of analogous allylsilanes, but
these were not confirmed.10 The regioselectivity was estab-
lished by 1H NMR.
Scheme 3 Confirmation of the structures of hexenols 5a and 6a. Reagents
and conditions: (i) Dess Martin periodinane, DCM, r.t., 30 min (75%); (ii) Ph3P,
4-NO2C6H4CO2H, THF, DIAD, 0 °C, 10 min then r.t., 30 min (8 with 30% epimer,
63%; 10, 68%); (iii) NaOAc, TsNHNH2, DME, reflux, 6 h (9 with 30% 11, 68%;
11, 62%).
Transmetallation of allyl- and allenylstannanes with indium(III)
chloride has been widely studied and subsequent reactions of
the organo-indium species with aldehydes developed into a
useful synthesis of 1,2-anti-products.11 Moreover 1,6-remote
stereocontrol was observed in reactions of butadienyl 2,3-di-
indium compounds with aldehydes.11l Preliminary studies of
the reaction of the racemic stannane 1 with benzaldehyde pro-
moted by indium(III) chloride were carried out at room temp-
erature with the stannane added to a mixture of indium(III)
chloride and benzaldehyde in either DCM, acetonitrile or
acetone as the solvent. Mixtures of linear products were
formed with the major products being the (E)-hex-3-enols 5a
and 6a, ratio ca. 70 : 30, together with a small amount of the
separable (Z)-isomer 2a,2b see Scheme 2. The best yield, 72%,
was obtained in DCM at room temperature with lower temp-
eratures resulting in lower yields. Indium(III) bromide and
iodide in acetonitrile, gave slightly better stereoselectivities,
78 : 22 and 80 : 20, respectively, but with slightly lower yields.
Although these indium(III) halide promoted reactions of the
stannane 1 with benzaldehyde were of interest in that the
(E)-hexenol 5a was the major product, the relatively modest
1,5-stereoselectivity observed mitigated against these reactions
being useful in synthesis. Bismuth(III) bromide and triflate
have been used to promote reactions of allylstannanes with
aldehydes with the advantage that organobismuth compounds
are supposedly relatively non-toxic.12
gave a 90 : 10 mixture of the epimeric 1,5-anti- and 1,5-syn-(E)-
hexenols 5a and 6a together with ca. 5% of the (Z)-1,5-anti-
alkenol 2a.2b Since indium(III) iodide had given slightly
improved stereoselectivity for the reaction between the stannane
1 and benzaldehyde, the use of bismuth(III) iodide was investi-
gated. A reasonable yield of the (E)-products was obtained and
the stereoselectivity was slightly improved, 5a:6a = 92 : 8.
The hexenols 5a and 6a could not be separated. The 1H
NMR spectrum of the ketone 7 prepared by oxidation of a
70 : 30 mixture of these alcohols using the Dess Martin period-
inane, see Scheme 3, showed a distinctive 16 Hz coupling
between the vinylic protons consistent with the (E)-configur-
ation shown. The 1,5-anti-configuration of the major hexenol
5a was established via the 4-nitrobenzoate 8 prepared with
inversion of configuration from the 70 : 30 mixture of products
5a and 6a by a Mitsunobu reaction.13 Reduction of the alkene
8 containing ca. 30% of its epimer using diimide gave the satu-
rated hexane 9 as the major product together with a minor
1
component. This minor component was shown by H and 13C
NMR to be the 4-nitrobenzoate 11 prepared from the 1,5-anti-
(Z)-product 2a2b via its inverted 4-nitrobenzoate 10 followed by
reduction using diimide.
The reactions of other aldehydes with the stannane 1 pro-
moted by bismuth(III) iodide were studied and in all cases
useful stereoselectivities in favour of the 1,5-anti-(E)-products
were obtained. Most reactions were carried out in acetonitrile
as solvent, but later it was found that significantly better yields
were obtained using a mixed solvent system of acetonitrile and
DCM without any loss of stereoselectivity, see Table 1.
The reaction between the racemic stannane 1 and benz-
aldehyde in acetonitrile promoted by bismuth(III) bromide
The product ratios were determined by integration of the
CHCH3 peaks in 1H NMR spectra. The 1,5-anti-configuration of
the major product 5f from the reaction with butanal was con-
firmed by Mitsunobu esterification with inversion of configur-
ation using 4-nitrobenzoic acid followed by reduction of the
resulting unsaturated ester 12 with diimide. The saturated
ester 13 so obtained was compared with the anti-isomer 15 pre-
pared using the same chemistry from the known 1,5-anti-(Z)-
alkenol 2f.2b The two epimers 13 and 15 could not be distin-
guished using 1H NMR but there were slight differences in
Scheme 2 Reactions of stannane 1 with benzaldehyde promoted by indium(III)
and bismuth(III) halides. Reagents and conditions: (i) InX3, PhCHO, r.t., add 1, r.t.
(X = Cl, DCM, 5a:6a = 70 : 30, 72%; X = Br, MeCN, 5a:6a = 78 : 22, 66%; X = I,
DCM, 5a:6a = 80 : 20, 42%; 2a, ca. 5% in all cases); (ii) BiX3, PhCHO, MeCN,
15 min, r.t., add 1, r.t., 30 min (X = Br, 5a:6a = 90 : 10, 58%; X = I, 5a:6a = 92 : 8,
72%; 2a, ca. 5% in both cases).
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Table 1 Reactions of stannane 1 with aldehydes promoted by bismuth(III) halides
X
R
Solvent
Yielda (%)
Productsb
1,5-anti : 1,5-syn
Br
I
I
I
I
I
I
I
I
Ph
Ph
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN–DCM
MeCN–DCM
MeCN–DCM
58
72 (66)
53
56
45
55
61 (82)
80
87
92
5a, 6a
5a, 6a
5b, 6b
5c, 6c
5d, 6d
5e, 6e
5f, 6f
5a, 6a
5e, 6e
5f, 6f
90 : 10
92 : 8
95 : 5
92 : 8
90 : 10
93 : 7
93 : 7
92 : 8
93 : 7
93 : 7
4-O2NC6H4
4-MeOC6H4
MeCHvCH
iPr
nPr
Ph
iPr
nPr
I
a Yields based on the stannane with stannane–aldehyde–BiI3 = 1 : 3 : 1. Yields in parenthesis are based on the aldehyde with stannane–aldehyde–
BiI3 = 1.3 : 1 : 1.4. b In all cases ca. 5% of anti-(Z)-alkenols 2 were isolated.
Scheme 4 Confirmation of the structure of alkenol 5f. Reagents and con-
ditions: (i) Ph3P, 4-NO2C6H4CO2H, THF, DIAD, 0 °C, 10 min then r.t., 30 min (12,
92%; 14, 68%); (ii) NaOAc, TsNHNH2, DME, reflux, 6 h (13, 64%; 15, 51%).
their 13C NMR spectra with six peaks being distinguished in a
spectrum of a mixture. The 1,5-anti-configurations of the other
major products 5 were assigned by analogy (Scheme 4).
Scheme 5 Reactions of the 4-benzyloxypent-2-enylstannane 16 with alde-
High 1,5-stereocontrol in favour of the (Z)-1,5-syn-products
hydes promoted by bismuth(III) iodide. Reagents and conditions: (i) RCHO, BiI3,
17 had been observed for the tin(IV) chloride promoted reac-
DCM, MeCN, r.t., add stannane in DCM, 30 min (18a/19a, 56%, 18a:19a =
tions of the 4-benzyloxypent-2-enyl(tributyl)stannane 16 with 93 : 7; 18b/19b, 48%, 18b:19b = 93 : 7; 18c/19c, 62%; 18c:19c = 92 : 8); (ii)
aldehydes,2a and so it was of interest to study the bismuth(III)
iodide promoted reaction of this stannane with aldehydes.
Ph3P, 4-NO2C6H4CO2H, DIAD, THF, 0 °C to r.t., 30 min (21, 49%; 23, 63%); (iii)
NaOAc, TsNHNH2, DME, H2O, reflux, 16 h (22, 40%; 24, 48%).
These bismuth(III) iodide promoted reactions of the pent-2-
enylstannanes 1 and 16 with aldehydes are of interest since they
proceed with stereoselectivity different from that observed for
the tin(IV) halide promoted reactions. However, this chemistry is
still based on the use of an organotin starting material and the
Useful stereoselectivities, ca. 93 : 7, in favour of the (E)-1,5-
development of a “tin-free” procedure remained of interest.
syn-products 18 were observed, see Scheme 5, although the
yields were only modest. In the reaction with benzaldehyde a
minor side-product was identified as a branched isomer 20.
The relative 1,5-configuration was established by conversion of
1,5-Stereocontrol in reactions of 4- and 5-benzyloxypent-2-enyl
bromides with aldehydes
the benzaldehyde derived products 18a(19a) to the 4-nitro- Reactions of allylic bromides with aldehydes have been pro-
benzoate 21 by esterification with inversion using a Mitsunobu moted by activated bismuth(0) prepared by reduction of
reaction. Reduction using diimide gave the 1,5-anti-5-benzyloxy- bismuth(III) iodide using powdered zinc, iron or aluminium.14
hex-1-yl 4-nitrobenzoate 22 that was compared with the syn- Since allylic organobismuth intermediates related to those gen-
epimer 24, prepared from the known (Z)-1,5-syn-5-benzyloxy-1- erated in the bismuth(III) iodide promoted reactions of stannane
phenylhex-3-enol 17a using the same chemistry, see Scheme 5. 1 with aldehydes may be involved, vide infra, it was of interest to
1
The esters 22 and 24 were distinguishable by H and 13C NMR. repeat this chemistry using 4-methylpent-2-enyl bromide 26 to
Structures were assigned to the other products 18b,c by analogy. see whether useful 1,5-stereocontrol could be achieved.
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Table 2 Reactions of aldehydes with (R)-pent-2-enyl bromide 26 mediated by
Bi(0)
R
Yield (%)
Products
1,5-anti : 1,5-syn
Ph
83
86
82
92
63
87
66
63
5a, 6a
5d, 6d
5e, 6e
5f, 6f
5g, 6g
5h, 6h
5i, 6i
96 : 4
93 : 7
95 : 5
93 : 7
87 : 13
95 : 5
95 : 5
95 : 5
MeCHvCH
iPr
Scheme 6 Reactions of benzaldehyde with the (R)-pent-2-enyl bromide 26
promoted by bismuth(0). Reagents and conditions: (i) Ph3P, CBr4, DCM, r.t., 2 h
(92%); (ii) BiI3, activated zinc powder, THF, r.t., 1 h, then add 26 and PhCHO,
reflux 2 h or r.t., 16 h (83%; 5a:6a = 96 : 4); (iii) (R)- or (S)-O-acetylmandelyl
chloride, py., DMAP, DCM, 0 °C, r.t. 2 h (27, 60%; 28, 39%).
nPr
BnOCH2
BnOCH2CH2
TBSOCH2
TBSOCH2CH2
5j, 6j
the (E)-1,5-anti- and (E)-1,5-syn-hex-3-enols 31a and 32a, 65%,
31a : 32a = 95 : 5, together with ca. 10% of the known (Z)-1,5-
anti-product 33a,2b was obtained, see Scheme 7.
Following the published procedure, activated zinc powder
was suspended in a solution of bismuth(III) iodide in THF and
the mixture stirred vigorously at room temperature for 1 h
during which time a black precipitate developed. The (R)-4-
methylpent-2-enyl bromide 26 was prepared from the known
alcohol 25,2b see Scheme 6. It was added to the black suspen-
sion followed by benzaldehyde and the mixture was heated
under reflux for 2 h. After work-up and chromatography, an
83% yield of the (E)-hex-3-enols 5a and 6a was obtained with a
useful diastereoselectivity, 96 : 4, in favour of the (E)-1,5-anti-
product 5a. Lower yields were obtained if iron or aluminium
were used to reduce the bismuth(III) iodide. At room tempera-
ture, the reaction of the pent-2-enyl bromide 26 with benz-
aldehyde gave similar yields and stereoselectivity, but 16 h was
required for completion.
The structures of these products were initially assigned by
analogy with the reactions of the pent-2-enyl bromide 26. The
1
products 31a and 32a could be distinguished by H NMR, the
doublets attributed to the 5-CH3 groups being used to estimate
the 1,5-stereoselectivity. The (E)-double-bond geometry of the
major product 31a and the (Z)-double-bond geometry of the
minor product 33a were confirmed by nOe studies. The minor
(E)-product 32a was prepared from the major epimer 31a by a
Mitsunobu reaction with inversion of configuration followed
The products 5a and 6a were identified by comparison with
samples prepared earlier but, in this case, as enantiomerically
enriched (R)-pent-2-enyl bromide 26 had been used, the major
product 5a, still containing ca. 4% of its syn-epimer 6a, was
converted into the (R)- and (S)-O-acetylmandelates 27 and 28.
The relative chemical shifts of these derivatives were consistent
with the major product 5a from the bismuth promoted reac-
tion being the (1R,5R)-diastereoisomer as shown.15
The reactions of other aldehydes with the pent-2-enyl
bromide 26 mediated by bismuth(0) were then investigated.
In all cases usefully stereoselective reactions in favour of the
(E)-1,5-anti-products 5 were observed, see Table 2. In this work,
the products that had been made previously were identified by
comparison with earlier samples. The structures of the new
products were assigned by analogy and the ratios of the pro-
1
ducts 5 and 6 were estimated by H NMR using their CHCH3
doublets.
As the bismuth(0) promoted reactions of the pentenyl
bromide 26 with aldehydes proceeded with useful 1,5-stereo-
control it was of interest to see whether structurally related alk-
2-enyl bromides also reacted with viable stereoselectivity and
the 2,4-dimethylpent-2-enyl bromide 30 was selected for study.
This bromide was prepared both as its racemate and as its
(R)-and (S)-enantiomers (ca. 95% ee) from the corresponding
alcohol 29.2b With benzaldehyde, an inseparable mixture of
Scheme 7 1,5-Stereocontrol in reactions of the (R)-2,4-dimethylpent-2-enyl
bromide 30 with benzaldehyde. Reagents and conditions: (i) Ph3P, CBr4, DCM,
r.t., 2 h (90%); (ii) BiI3, activated zinc powder, THF, r.t., 1 h, then add 30 and
PhCHO, reflux 2 h or r.t., 16 h (65%, 31a:32a = 95 : 5; 33a, 10%); (iii) Ph3P,
4-NO2C6H4CO2H, DIAD, THF, 0 °C to r.t., 30 min (60%); (iv) NaOH, MeOH, r.t., 2 h
(43%); (v) (R)- or (S)-O-acetylmandelic acid, py., DMAP, DCC, DCM, 0 °C, r.t. 16 h
(35, 78%; 36, 75%).
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Table 3 Reactions of aldehydes with (R)-2,4-dimethylpent-2-enyl bromide 30
mediated by Bi(0)
R
Yield (%)
Products
1,5-anti : 1,5-syna
Ph
65
80
72
78
63
50
31a, 32a
31b, 32b
31c, 32c
31d, 32d
31e, 32e
31f, 32f
95 : 5
91 : 9
90 : 10
96 : 4
95 : 5
95 : 5b
MeCHvCH
iPr
nPr
4-O2NC6H4
TBSOCH2
a In all cases 5–10% of the (Z)-1,5-anti-isomer 33 was isolated. b In this
case, ca. 20% of the (Z)-1,5-anti-isomer 33f was isolated.
Scheme 8 Reaction of the bromide (S)-30 with tert-butyldimethylsilyloxyetha-
nal. Reagents and conditions: (i) BiI3, activated zinc powder, THF, r.t., 1 h, then
add (S)-30 and TBSOCH2CHO, reflux 2 h (50%, 31f:32f = 95 : 5; 33f, 20%); (ii)
(R)- or (S)-O-acetylmandelyl chloride, py., DMAP, DCM, 0 °C, r.t. 2 h (37, 62%; 38,
76%; 39, 72%; 40, 80%).
by saponification of the resulting 4-nitrobenzoate ester 34. The
1,5-anti-configuration of the major product 31a prepared using
the (R)-enantiomer of the pent-2-enyl bromide (R)-30 was
1
established by comparison of the H NMR spectra of the (R)-
Scheme 9 The bismuth(0) promoted reaction of the pent-2-enyl bromide 42
with benzaldehyde. Reagents and conditions: (i) Ph3P, CBr4, DCM, r.t., 2 h (90%);
(ii) BiI3, activated zinc powder, THF, r.t., 1 h, then add 42 and PhCHO, reflux 2 h
(46%, 18a:19a = 94 : 6).
and (S)-O-acetylmandelates 35 and 36, see Scheme 7.15
Reactions of the 2,4-dimethylpent-2-enyl bromide 30 with
other aldehydes were then investigated, see Table 3. In all
cases the major products were the (E)-products 31 and 32
formed with useful stereoselectivities, >90 : 10, in favour of the
1,5-anti-epimers 31. The ratios of the products 31 and 32 in
the (E)-alkene manifold were determined by 1H NMR using
their CHCH3 doublets. Typically, 5–10% of the (Z)-1,5-anti-alke-
nols 33 were also isolated and identified by comparison with
known compounds.2b The only exception to this useful stereo-
selectivity was the reaction with 2-tert-butyldimethylsilyl-
oxyethanal. In this case the 1,5-stereoselectivity in the
(E)-manifold was 95 : 5 as expected, but the yield was only 50%
and about 20% of the (Z)-1,5-anti-isomer 33f was isolated.
Because of this reduced (E)/(Z)-stereoselectivity, the structures
of the (E)- and (Z)-1,5-anti-isomers 31f and 33f, in this case pre-
pared from the (S)-enantiomer of the 2,4-dimethylpentenyl
bromide (S)-30, were confirmed by comparison of the 1H NMR
spectra of their (R)- and (S)-O-acetylmandelates 37/38 and
39/40, see Scheme 8.15 The structures of the other products
were assigned by analogy.
1,6-Stereocontrol in reactions of allylic organobismuth
reagents with aldehydes
Useful 1,6-stereocontrol in favour of the (Z)-1,6-syn-isomers 45
and 46 was observed for tin(IV) bromide promoted reactions of
the 5-hydroxy- and 5-methoxy-hex-2-enylstannanes 43 and 44
with aldehydes.2b The bismuth(III) iodide promoted reactions
of these stannanes, and the bismuth(0) induced reaction of
the bromide 48, with aldehydes, were therefore briefly investi-
gated.
The bismuth(III) iodide promoted reaction of the (R)-5-
methoxyhex-2-enylstannane 44, and the bismuth(0) induced
reaction of the (R)-bromide 48, available from the alcohol 47,2b
with benzaldehyde, gave only modest 1,6-stereocontrol, 80 : 20
Following the studies of the reactions of 4-benzyloxypent-2-
enylstannane 16 with aldehydes it was of interest to study the
bismuth(0) promoted reactions with aldehydes of the corres- and 74 : 26, respectively, in favour of the (E)-1,6-syn-diastereo-
ponding bromide 42. This was prepared from the alcohol 412a
and was found to undergo the bismuth(0) mediated reaction
with benzaldehyde to give mainly the (E)-1,5-syn-hex-3-enol 18a configuration was deduced from the H NMR chemical shifts
isomer 49, see Scheme 10. The (E)-configuration of the major
1
product followed from its H NMR spectrum and the 1,6-syn-
1
prepared earlier. Although useful stereoselectivity, 1,5-syn : 1,5-
anti = 94 : 6, was observed, the yield was only 46%, perhaps
due to a competing elimination, see Scheme 9.
of the (R)- and (S)-O-acetyl mandelates 51 and 52. The ratio of
the epimers 49 and 50 was estimated by integration of the
7-H3 peaks in the 1H NMR spectra of the product mixtures.
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Scheme 10 1,6-Stereocontrol in bismuth-mediated reactions of the hex-2-
enylstannane 44 and the hex-2-enyl bromide 48 with benzaldehyde. Reagents
and conditions: (i) Ph3P, CBr4, DCM, r.t., 2 h (92%); (ii) BiI3, activated zinc
powder, THF, r.t., 1 h, then add 48 and PhCHO, reflux 2 h (69%; 49 : 50 =
74 : 26); (iii) PhCHO, BiI3, DCM, MeCN, r.t., add 44 in DCM, 30 min (80%;
49 : 50 = 80 : 20); iv, (R)- or (S)-O-acetylmandelyl chloride, py., DMAP, DCM, 0 °C,
r.t. 2 h (51, 59%; 52, 62%).
Similar results were observed for the bismuth(III) iodide
promoted reactions of the 5-hydroxyhex-2-enylstannane 43
with several aldehydes, see Table 4. In this series, the ratios of
the products were estimated by 13C with the 1,5-syn-(E)-stereo-
chemistry of the major product 53 assigned by analogy with
the analogous reaction of the 5-methoxyhexenylstannane 44
with benzaldehyde.
Scheme 11 Reactions of the pent-2-enyl bromide 26 with chiral aldehydes.
Reagents and conditions: (i) BiI3, activated zinc, THF, r.t., 1 h, then add 26 and
RCHO, reflux 2 h (56, 53%, 1,5-anti:1,5-syn = 78 : 22; 57, 63%, 1,5-anti : 1,5-syn
= 83 : 17; 61, 60%, 1,5-anti : 1,5-syn = 60 : 40; 62, 67%, 1,5-anti : 1,5-syn =
60 : 40; 64, 51%, 1,5-anti : 1,5-syn = 78 : 22); (ii) (R)- or (S)-O-acetylmandelyl
chloride, py., DMAP, DCM, 0 °C, r.t. 2 h (58, 68%; 59 76%; 65, 58%; 66, 69%);
(iii) Dess Martin periodinane, DCM, r.t., 2 h (74%).
Low valency bismuth promoted reactions of the (R)-pent-2-enyl
bromide 26 with chiral aldehydes
The low valency bismuth promoted reactions between the (R)-
pent-2-enyl bromide 26 and chiral α- and β-alkoxyaldehydes
were briefly examined to see whether the chirality of the alde-
hyde or that of the bromide influenced the diastereoselectivity
of the reaction. Rather disappointingly, only modest stereo-
selectivities, 83 : 17 at best, were observed for these reactions
and no significant matching or mismatching was observed for
enantiomeric aldehydes, see Scheme 11.
alkenol 56 and its 1,5-syn-epimer were confirmed by oxidation
of the mixture of products to the enone 67. The 1,5-anti-con-
figurations of the major products 57 and 64 from the reactions
of the (S)-3-benzyloxy- and (R)-tert-butyldimethylsilyloxy-buta-
nals (S)-55 and (R)-63, were confirmed by comparison of the
1H NMR spectra of their (R)- and (S)-O-acetylmandelates. The
configurations of the other major products were assigned as
the 1,5-anti-epimers 56, 61 and 62 by analogy, see Scheme 11.
The minor products from these reactions were not separated
from the major products. They were assumed to be the (E)-1,5-
syn-isomers by comparison with earlier work. The ratios of the
The structures of these products were initially assigned by
analogy with the earlier reactions of the pent-2-enyl bromide
26 with achiral aldehydes. The (E)-configurations of the
Table 4 Reactions of aldehydes with the 5-hydroxyhex-2-enylstannane 43
mediated by bismuth(III) iodide
1
products were estimated from the H and 13C NMR spectra of
product mixtures.
Applications of remote stereocontrol using pent-2-enyl
bromides in synthesis
R
Yield (%)
Products
1,6-syn : 1,6-anti
Ph
63
71
74
78
78
53a, 54a
53b, 54b
53c, 54c
53d, 54d
53e, 54e
80 : 20
80 : 20
68 : 32
50 : 50
82 : 28
Many natural products are known that have all syn-methyl sub-
stituents at 1,5,9-positions along an aliphatic chain, e.g. the
all-syn-16-tert-butyldimethylsilyloxy-3,7,11,15-tetramethylhexa-
decan-1-ol 68 is a potential intermediate for the synthesis of
tBu
iPr
nPr
4-O2NC6H4
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lipids found in archaeal cell membranes.16 It was of interest the racemic aldehyde ( )-72 and the (S)-ketophosphonate 73. A
to see whether this motif could be prepared using organo- comparison of the 1H NMR spectrum of the mixture of 2,6-syn-
bismuth chemistry.
and 2,6-anti-dimethylheptanes 71 and 77 with that of the syn-
2,6-dimethylheptane 71 showed that one each of the diastereo-
topic hydrogens at C(1) and C(7) was doubled up in the 1H
NMR spectrum of the mixture whereas clean double-doublets
were observed for these hydrogens in the 1H NMR of the single
epimer 71. It was confirmed that the syn-2,6-dimethylheptane
71 prepared from the toluene p-sulfonate 70 contained less
than 5% of its 2,6-anti-epimer 77, see Scheme 12.
The incorporation of the syn-2,6-dimethylheptane 71 into a
synthesis of the all syn-2,6,10,14-tetramethylpentadecan-1-ol
84 is shown in Scheme 13. Selective deprotection gave the alco-
hols 78 and 80 that were converted into the iodides 79 and 81.
Alkylation of 1,3-dithiane with iodide 81 and then with the
iodide 79 gave the bis-alkylated dithiane 83. Desulfurisation
using RANEY® nickel was accompanied by hydrogenolysis of
the benzyl group and gave the all-syn-tetramethylpentadecanol
84. This appeared to be essentially a single diastereoisomer, as
indicated by the double-doublets observed for the diastereo-
topic hydrogens at C(1) and C(15) in the 1H NMR spectra of
the dialkylated dithiane 83 and the pentadecanol 84 (>10% of
an epimer should have been detected by a doubling up of one
or other of these peaks).
Compounds with methyl substituents at 1,3,5-positions
along an aliphatic chain, e.g. the syn,syn- and anti,anti-isomers
85 and 86, are of interest. Several iterative procedures that
deliver excellent stereoselectivity involving conjugate
addition,19 displacement,20 hydrogenation21 and alkene
methylation,22 have been developed for the synthesis of these
compounds. Although the 1,5-anti-stereocontrol observed for
the reactions of the pent-2-enyl bromide 30 with aldehydes is
less than the stereoselectivities of these iterative methods, the
use of the products so obtained for the synthesis of com-
The (E)-1,5-anti-product 5i prepared from 2-tert-butyldi-
methylsilyloxyethanal and the (R)-4-methylpent-2-enyl bromide
(R)-26, see Table 2, was reduced using diimide and the result-
ing saturated alcohol 69 converted into its toluene p-sulfonate
70. Substitution of the toluene p-sulfonyl group by a methyl
group with inversion of configuration was achieved using the
cuprate formed from methyllithium and copper(I) cyanide,17
and gave the 2,6-syn-dimethylheptane 71. A minor elimination
product was formed during this displacement and was
removed by treatment of the crude product mixture with
osmium tetraoxide and N-methylmorpholine-N-oxide, see
Scheme 12.
The 2,6-syn-configuration of the 2,6-dimethylheptane 71
was confirmed by preparation of an authentic sample by an
alternative route. Condensation of the (S)-ketophosphonate
7318 with the (R)-aldehyde (R)-72 gave the 2,6-syn-dimethyl-
heptenone 74 that was reduced to give the saturated alcohol 75
as a mixture of epimers at C(3). Deoxygenation using the
Barton procedure then gave the syn-2,6-dimethylhexane 71 so
confirming the structure of the 2,6-dimethylheptane prepared
by substitution of the sulfonate 70.
The spectroscopic data of the 2,6-syn-dimethylheptanes pre-
pared by the two routes were identical and appeared to corres-
pond to a single diastereoisomer. However to be certain of this
it remained to show that the 2,6-anti- and 2,6-syn-dimethylhep-
tanes could be distinguished. A mixture of the syn- and anti-
2,6-dimethylheptanes 71 and 77 was therefore prepared using
pounds with 1,3,5-methyl substituents would provide
a
Scheme 12 Synthesis of (2S,6R)-1-tert-butyldimethylsilyloxy-7-benzyloxy-2,6-dimethylheptane 7l and confirmation of its stereochemistry. Reagents and conditions:
(i) NaOAc, TsNHNH2, DME, H2O, reflux, 16 h (92%); (ii) TsCl, DMAP, DCM, r. t., 16 h (90%); (iii) MeLi, CuCN, tol., ether, 0 °C, 15 min, 70, 0 °C, 5 h; NMO, OsO4,
acetone, r.t., 16 h (73%); (iv) 73, Ba(OH)2, THF, r.t., 30 min, add 72, r,t., 16 h (74, 84%; 74 + 76, 82%); (v) NaBH4, MeOH, 0 °C, 2 h (70%); (vi) (a) PhOC(SCl, py., DCM,
r.t., 16 h) (b) Bu3SnH, AIBN (cat.), reflux, 16 h (74%); (vii) (a) NaBH4, MeOH, 2 h (68%) (b) PhOC(S)Cl, py., DCM, r.t., 16 h (c) Bu3SnH, AIBN (cat.), reflux, 16 h (78%
from 74 + 76).
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analogy with the literature.23 The analogous hydrogenation of
the secondary alcohol 91 was less stereoselective and gave a
mixture of two epimeric products, ratio 85 : 15, although these
were relatively easy to separate by chromatography. The minor
product, isolated in a yield of 10%, was identified as the syn-
dimethyl-epimer 98 by comparison with an authentic sample
prepared from the nonan-1-ol 96 by desilylation and regio-
selective silylation of the resulting diol 97. The major product,
isolated in a yield of 56%, was therefore identified as the
epimer 92 in which the two methyl groups are anti-disposed,
see Scheme 15.
To introduce the remaining methyl substituent to prepare
open-chain compounds with either syn,syn- or anti,anti-1,3,5-
disposed methyl substituents, it remained to substitute the
secondary hydroxyl groups in the nonanols 92 and 98 by
a methyl group with inversion of configuration. The toluene
p-sulfonate 93 prepared from the alcohol 92 was converted
into the anti,anti-2,4,6-trimethylnonane 94 using a higher
order methyl cuprate.17 This gave the required product 94
together with small amounts of elimination products that were
removed by oxidation using osmium tetraoxide. Desilylation
then gave the anti,anti-2,4,6-trimethylnonan-1-ol 95. Similarly
the alcohol 98 was converted to its toluene p-sulfonate 99 that
gave the syn,syn-2,4,6-trimethylnonan-1-ol 101 on treatment
Scheme 13 Synthesis of the pentadecanol 84. Reagents and conditions: (i)
TBAF, THF, r.t., 16 h (98%); (ii) PPh3, I2, imid., THF, r.t., 2 h (79, 94%; 81, 97%);
(iii) 10% Pd/C, ethanol, H2, r.t., 1 h (98%); (iv) nBuLi, 1,3-dithiane, THF −20 °C,
1 h, add 81, 0 °C, 16 h (89%); (v) nBuLi, THF, HMPA, −78 °C, 30 min, add 79,
−78 °C, 1 h (88%); (vi) W-2 RANEY® nickel, THF, reflux, 16 h (95%).
conceptually different approach that may be useful.
Preliminary studies of reduction of the 2,6-anti-4,6-
dimethylheptenol 31f using Pd/C catalysed hydrogenation or
diimide were non-stereoselective, see Scheme 14. It was there-
fore decided to study the hydroxyl directed hydrogenation of
homoallylic alcohols developed by Evans.23,24
Protection of the (E)-1,5-anti-product 31d derived from
butanal as its tri-isopropylsilyl ether 88 followed by removal of
the benzyl group using lithium naphthalenide gave the
primary alcohol 89. Reversing these two steps, i.e. selective sily-
lation of the diol 90 formed by removal of the benzyl ether
under Birch conditions, gave the secondary alcohol 91. Homo-
geneous hydrogenation of homoallylic alcohols using the
achiral catalyst, [Rh(NBD)DIPHOS-4]BF4 is known to be use-
fully stereoselective for primary alcohols.23 Indeed, hydrogen-
ation of the primary alcohol 89 gave the nonan-1-ol 96 in
which the two methyl groups are syn-disposed with excellent
stereoselectivity. The structure of this product was assigned by
Scheme 15 Synthesis of the all-anti- and all syn-2,4,6-trimethylnonan-1-ols 95
i
and 101. Reagents and conditions: (i) Pr3SiOTf, 2,6-lutidine, DCM, 0 °C to r.t.,
16 h (89%); (ii) Li, naphthalene, THF, r.t. then −25 °C, add benzyl ether, −25 °C,
i
2 h (90%); (iii) Na, liq. NH3, EtOH, NH4Cl (75%); iv, Pr3SiCl, imid., DCM, r.t., 1 h
(91, 90%; 98, 90%); v, Rh(diphos-4), DCM, H2, 950 psi, r.t., 5 h (92, 56% plus
10% of its C(6)-epimer 98; 96, 82%); (vi) TsCl, DMAP, DCM, r.t., 16 h (93, 91%;
99, 91%); (vii) MeLi, CuCN, Et2O, toluene, 0 °C, 15 min, add toluene p-sulfonate,
0 °C, 5 h (94, 48%; 100, 45%); (viii) TBAF, THF, r.t., 16 h (95, 90%; 97, 91%; 101,
91%).
Scheme 14 Reduction of 31f. Reagents and conditions: (i) NaOAc, TsNHNH2,
DME, reflux, 16 h (82%, 2 : 1); (ii) Pd/C, H2, MeOH, r.t. 1 h (90%; 2 : 1).
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both processes. One possibility is that the transmetallation of
the pent-2-enylstannanes, e.g. stannane 1, is generating an
allylic organobismuth species perhaps 104 (X = I) and that a
similar species is being formed from the pent-2-enyl bromide
26 and the low-valency bismuth species formed from the
bismuth(III) iodide and activated zinc. Reduction of bismuth(III)
by zinc can give bismuth(0) although an alternative inter-
mediate might be the zinc–bismuth(III) iodide insertion
species 103. Precisely what is coordinated to the bismuth in
the allylic organobismuth intermediates is not known, the
σ-bonded structure 104 is drawn for simplicity although there
may be some Π-allyl character in the intermediate. However,
once formed these intermediates could react with aldehydes
either via an open-chain process or via the six-membered
chair-like transition structure 105 to give the observed
products.
Scheme 16 Hydrogenation of diol 90. Reagents and conditions: (i) Rh(diphos-4),
DCM, H2, 950 psi, r.t., 5 h (97, 48%; 102, 10%).
with the higher order methyl cuprate followed by deprotection
of the resulting product 100, see Scheme 15.
Evans hydrogenation of the diol 90 was also investigated
and found to give a mixture of two products, see Scheme 16.
The major product was the syn-2,4-dimethylnonanediol 97.
The minor product was therefore the anti-dimethyl epimer
102.
Bismuth has a lone-pair and therefore the same coordi-
nation number as tin. Moreover carbon–tin and carbon–
Summary and conclusions
This work has shown that bismuth(III) iodide mediated reac- bismuth bond lengths are similar. So if similar σ-bonded
tions of pent-2-enyl(tributyl)stannanes 1 and 16 with achiral allylic organic metallic species are involved why there are
aldehydes take place with useful levels of (E)-1,5-stereocontrol. different stereochemical outcomes in the reactions with alde-
This stereoselectivity is complementary to that observed for hydes of the allyltin trihalide 106 and the allylbismuth species
the analogous tin(IV) halide promoted processes.2a,b Moreover, 104 generated from the pent-2-enylstannane 1? Typically the
the pent-2-enyl bromides 26, 30 and 42 undergo reactions with lone-pair and the bismuth–carbon bond are apical in pentaco-
aldehydes mediated by the low valency bismuth species gener- ordinated organobismuth compounds25 and this is indicated
ated from bismuth(III) iodide and activated zinc, a tin-free in the structure 104. If the bismuth–oxygen coordination is
process, to give (E)-alk-3-enols with useful 1,5-stereoselectivity. retained in the reaction with the aldehyde, then in the cyclic
However, only modest 1,6-syn-(E)-stereoselectivity was observed process 105 the bismuth would be octahedral. In the analo-
in the bismuth(III) iodide mediated reactions of the stannanes gous reactions of allyltin trichlorides with aldehydes, it is
43 and 44 with aldehydes and for the lower valency bismuth believed that the tin is trigonal bypyramidal as indicated in
promoted reaction of the 5-methoxyhex-2-enyl bromide 48 with transition structure 107.26 The different geometry around the
benzaldehyde.
metal in these transition structures may be responsible for
These bismuth-mediated reactions were carried out in THF their different stereochemical outcomes. However in the
either at room temperature or under reflux. The stannane was absence of clarification of the types of intermediates involved
added last in the bismuth(III) iodide-mediated reactions of the in the bismuth mediated processes, this dichotomy cannot
pent-2-enylstannanes. The pent-2-enyl bromide and the alde- really be resolved.
hyde were added simultaneously to the low valency bismuth
Indeed this mechanistic discussion is only speculative. In
species in the case of the tin-free procedure. Therefore, in the case of the low-valency bismuth mediated reactions of the
these reactions the generation of any organobismuth species is pent-2-enyl halides, the reactions fail if any of the components,
taking place in the presence of the aldehyde under very i.e. the zinc powder or the bismuth(III) iodide, is omitted but
different conditions from the tin(IV) halide mediated reactions full details of the nature of the participation of all of the com-
of the pent-2-enylstannanes, where transmetallation of the ponents, e.g. the zinc, are not clear. The mechanism outlined
stannane at −78 °C occurs before the addition of the aldehyde. in Fig. 1 is likely to be a significant oversimplification.
Nevertheless, a transmetallation of the pent-2-enylstannanes
Under the reaction conditions, the reactive intermediates in
by bismuth(III) iodide is believed to be taking place in these the bismuth mediated reactions may be able to equilibrate
bismuth(III) iodide mediated reactions of the pentenylstan- unlike the kinetically controlled process believed to be
nanes since the alternative process, involving the bismuth(III) involved in the tin(IV) halide mediated reactions.26 The lower
iodide acting as a Lewis acid promoting the reactions by yields observed for reactions of the 4-alkoxypent-2-enylstan-
coordination to the aldehyde, would give rise to the regio- nanes and the 4-alkoxypent-2-enyl bromides with aldehydes,
isomeric products observed in the boron trifluoride etherate may be due to a competing elimination, see structure 108 in
promoted reactions, see Scheme 1.9 These products were either Fig. 1.
not observed at all or were only detected in trace amounts.
The (E)-1,5-anti-stereoselectivity observed for the 5-alkoxy-
The formation of the same products in both the bismuth(III) pent-2-enylstannanes and the analogous pent-2-enyl bromides
iodide promoted reactions of the pent-2-enylstannanes and in may be useful in synthesis. This is illustrated by the stereo-
the low valency bismuth induced reactions of the pent-2-enyl selective syntheses of open-chain compounds with methyl
bromides, suggests that similar species may be involved in groups at 1,3,5- and 1,5,9,13-positions along the aliphatic
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so it may be possible to use allylic alcohols, e.g. 25, 29 and 41,
directly for remote stereocontrol, although this has yet to be
confirmed. Alternatively the stereoselective generation of
allylic organometallic intermediates by oxidation of suitable
alkenes may be of interest and would be “atom efficient.”
These options have yet to be investigated.
Experimental
General experimental procedures
1H and 13C NMR spectra were recorded on Varian Unity 500,
Varian Unity Inova 400 and Varian Unity Inova 300 spectro-
meters with residual non-deuterated solvent as the internal
standard. Coupling constants are rounded to the nearest 0.5
Hz. IR spectra were recorded on an ATI Mattson Genesis FTIR
as thin films produced by evaporation of a DCM solution on
sodium chloride plates unless otherwise stated. Mass spectra
were recorded on Fison VG Trio 2000 and Kratos Concept
spectrometers. Chemical ionisation (CI) was performed using
ammonia. Chromatography refers to flash column chromato-
graphy using Merck silica gel 60H (230–300 mesh).
Tetrahydrofuran (THF) was dried and distilled from sodium
metal using benzophenone as an indicator under an atmos-
phere of nitrogen. Dichloromethane (DCM) was dried and dis-
tilled from calcium hydride under an atmosphere of nitrogen.
Ether refers to diethyl ether, which was dried and distilled
from sodium metal using benzophenone as an indicator
under an atmosphere of nitrogen. Light petroleum refers to
the fraction of petroleum ether distilled between 40–60 °C.
Benzene and hexane were dried over sodium metal. Butyl-
lithium (1.6 M in hexanes) was titrated against a solution of
propan-2-ol in xylene with 2,2′-bipyridine as an indicator. Tri-
ethylamine and diisopropylamine were dried over potassium
hydroxide pellets. Brine refers to saturated aqueous sodium
chloride. Anhydrous cerium(III) chloride was prepared by
heating the heptahydrate overnight at 80 °C under reduced
pressure and was stored under an atmosphere of N2.
Fig. 1 Possible mechanisms for the bismuth-mediated reactions of allylstan-
nanes and allyl bromides with aldehydes.
chain. The (R)-pentenyl bromide (R)-26 was the only chiral
starting material used in the synthesis of the pentadecanol 84.
Two of its stereogenic centres were derived directly from the
pent-2-enyl bromide and the other two from its reaction with
2-tert-butyldimethylsilyloxyethanal. Similarly, the 2,4-dimethyl-
pent-2-enyl bromide 30 was the only chiral starting material
used in the synthesis of the syn,syn- and anti,anti-2,4,6-tri-
methylnonanols 95 and 101. Although the (R)-enantiomer of
the dimethylpent-2-enyl bromide 30 was used in this synthesis,
the use of racemic bromide would have led to a diastereoselec-
tive synthesis of the racemic syn,syn- and anti,anti-trimethyl-
nonanols. Stereoselective syntheses of racemic compounds of
this type would be difficult by other routes and could be of
interest. Finally this chemistry has since been applied to com-
plete stereoselective syntheses of (4S,6R,8R,10S,16S)- and
(4S,6R,8R,10S,16R)-pentamethyldocosanes so confirming the
relative stereochemistry of the pentamethyldocosane isolated
from the cuticular extract of the cane beetle Antitrogus parvu-
lus.27 The one-pot formation of allylic halides from the corres-
ponding alcohols and their low valency bismuth induced
reactions with aldehydes has been found to be useful14c and
2-(1-Benzyloxyprop-2-yl)-1-phenylbut-3-en-1-ols
3
and
4. Boron trifluoride diethyletherate (40 μL, 0.31 mmol) cooled
to −78 °C was added to benzaldehyde (30 μL, 0.31 mmol) in
DCM at −78 °C. After 10 min, stannane 1 (150 mg, 0.31 mmol)
was added at −78 °C and the mixture was allowed to warm to
0 °C. Methanolic ammonium chloride (10 mL) was added and
the aqueous phase extracted with DCM (3 × 10 mL). The
organic extracts were washed with brine (30 mL), dried
(MgSO4) and concentrated under reduced pressure. Chromato-
graphy of the residue (4 : 1 light petroleum–ether) afforded the
title compounds 3 and 4 as a colourless oil (46 mg, 51%), a
70 : 30 mixture of epimers. These were separated by chromato-
graphy. The less polar isomer was the major product (21 mg,
23%); νmax/cm−1 3387, 3029, 2958, 2924, 2871, 1638, 1453,
1365, 1075, 1029, 1000 and 915; δH (CDCl3, 300 MHz) 0.91
(3 H, d, J 7, 3′-H3), 2.24 (1 H, m, 2′-H), 2.48 (1 H, m, 2-H), 3.32
(1 H, dd, J 7.5, 4, 1′-H), 3.48 (1 H, t, J 7.5, 1′-H′), 4.15 (1 H, d,
J 6, OH), 4.60 (2 H, s, PhCH2O), 4.80 (1 H, t, J 7, 1-H), 4.97
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(1 H, dd, J 16 and 3, 4-H), 5.12 (1 H, dd, J 10 and 3, 4-H′), 5.77 containing ca. 4% of its epimer 6a, Rf = 0.25 (4 : 1, light pet-
(1 H, dt, J 17 and 10, 3-H) and 7.20–7.50 (10 H, m, ArH); m/z roleum–ether), [α]2D0 +47.3 (c 1.8, CHCl3) (Found: M+ + NH4,
(CI) 314 (M+ + 18, 5%), 296 (M+, 3) and 279 (M+ − 17, 100). The 314.2118. C20H28NO2 requires M, 314.2120). Spectroscopic
more polar isomer was the minor product; νmax/cm−1 3375, data were identical to those of the racemate.
2959, 2925, 2871, 1602, 1453, 1365, 1075, 1029, 916 and 736;
(3E,1SR,5SR)-6-Benzyloxy-5-methyl-1-(4-nitrophenyl)-hex-3-
δH (CDCl3, 300 MHz) 0.84 (3 H, d, J 7, 3′-H3), 2.13 (1 H, d, J 4, en-1-ol 5b. Following the standard procedure, 4-nitrobenzal-
OH), 2.32 (1 H, m, 2′-H), 2.59 (1 H, dt, J 10 and 4, 2-H), 3.28 dehyde (93 mg, 0.42 mmol), BiI3 (120 mg, 0.21 mmol) in
(2 H, m, 1′-H2), 4.43 (2 H, s, PhCH2O), 4.60 (1 H, m, 1-H), 4.69 MeCN (2.0 mL) and the racemic stannane 1 (100 mg,
(1 H, dd, J 17 and 2, 4-H), 4.84 (1 H, dd, J 10 and 2, 4-H′), 5.39 0.21 mmol) in MeCN (0.4 mL) and DCM (0.3 mL), after chrom-
(1 H, dt, J 17 and 10, 3-H) and 7.25 (10 H, m, ArH); m/z (CI) atography (3 : 1, light petroleum–ether with 1% Et3N) afforded
314 (M+ + 18, 8%), 296 (M+, 6), 279 (M+ − 17, 100) and the title compound 5b as a colourless oil (38 mg, 53%) contain-
111 (100).
ing ca. 5% of its (E)-1,5-syn-epimer 6b (1H NMR) (Found: M+ +
Standard procedure for the bismuth(III) iodide promoted NH4, 359.1975. C20H27N2O4 requires M, 359.1971); νmax/cm−1
reactions of alk-2-enylstannanes with aldehydes. (3E,1RS,5RS)- 3434, 2958, 2928, 2869, 1603, 1519, 1346, 1072 and 855, 749;
6-benzyloxy-5-methyl-1-phenylhex-3-en-1-ol 5a. Benzaldehyde δH (CDCl3, 300 MHz) major 1,5-anti-epimer 5b 1.03 (3 H, d, J 7,
(0.1 mL, 0.93 mmol) was added to BiI3 (182 mg, 0.31 mmol) in 5-CH3), 2.36 (1 H, dt, J 13.5, 8, 2-H), 2.50–2.60 (2 H, m, 2-H′
MeCN (2 mL) and the solution stirred for 15 min at room and 5-H), 2.66 (1 H, d, J 3, OH), 3.25 (2 H, m, 6-H2), 4.54 (2 H,
temperature. Racemic stannane 1 (150 mg, 0.31 mmol) in s, PhCH2O), 4.78 (1 H, m, 1-H), 5.48 (1 H, ddd, J 15.5, 7.5 and
MeCN (0.5 mL) and DCM (0.3 mL) was added dropwise and 5.5, 3-H), 5.56 (1 H, dd, J 15.5 and 6, 4-H), 7.36 (5 H, m, ArH),
the mixture stirred for 30 min. Saturated aqueous ammonium 7.54 (2 H, d, J 9, ArH) and 8.22 (2 H, d, J 9, ArH); minor 1,5-
chloride (5 mL) was added and the aqueous phase extracted syn-epimer 6b 1.05 (3 H, d, J 7, 5-CH3); δC (CDCl3, 75 MHz)
with DCM (3 × 15 mL). The organic extracts were washed with 16.8, 37.2, 43.0, 71.9, 73.0, 74.7, 123.5, 124.5, 126.5, 127.6,
brine (40 mL), dried (MgSO4) and concentrated under reduced 128.3, 138.2, 139.0, 147.1 and 151.3; m/z (CI) 359 (M+ + 18,
pressure. Chromatography of the residue (4 : 1, light pet- 100%), 342 (M+ + 1, 4), 294 (60), 206 (24) and 108 (38).
roleum–ether with 1% Et3N) afforded the title compound 5a as
(3E,1SR,5SR)-6-Benzyloxy-1-(4-methoxyphenyl)-5-methyl-hex-
a colourless oil (67 mg, 72%) containing ca. 8% of its syn- 3-en-1-ol 5c. Following the standard procedure, 4-methoxy-
epimer 6a (1H NMR) (Found: M+ + NH4, 314.2118. C20H28NO2 benzaldehyde (0.15 mL, 0.93 mmol), BiI3 (243 mg, 0.41 mmol)
requires M, 314.2120); νmax/cm−1 3424, 3029, 2857, 1494, 1453, in MeCN (3.0 mL) and the racemic stannane 1 (200 mg,
1361, 1201, 1091, 976 and 737; δH (CDCl3, 300 MHz) major 0.41 mmol) in MeCN (0.7 mL) and DCM (0.5 mL) after
epimer 5a 1.14 (3-H, d, J 7, 5-CH3), 2.55 (3 H, m, 2-H2 and chromatography (3 : 1, light petroleum–ether with 1% Et3N)
5-H), 3.34 (2 H, m, 6-H2), 4.55 (2 H, s, PhCH2O), 4.70 (1 H, dd, afforded the title compound 5c as a colourless oil (76 mg, 56%)
J 8 and 5, 1-H), 5.54 (2 H, m, 3-H and 4-H) and 7.36 (10 H, m, containing about 8% of its 1,5-syn-epimer 6c (1H NMR)
ArH); minor epimer 6a 1.15 (3 H, d, J 7, 5-CH3); (C6D6, (Found: M+ + H, 327.1965. C21H27O3 requires M, 327.1962);
300 MHz) 1.09 (3-H, d, J 7, 5-CH3 major) and 1.12 (3-H, d, J 7, νmax/cm−1 3426, 2956, 2928, 1612, 1513, 1454, 1247, 1094,
5-CH3 minor); δC (CDCl3, 75 MHz) 17.1, 32.3, 38.5, 73.0, 73.2, 1036 and 832; δH (CDCl3, 300 MHz) major 1,5-anti-epimer 5c
74.6, 125.6, 126.1, 127.1, 127.6, 127.8, 128.2, 128.3, 136.7, 0.95 (3 H, d, J 7, 5-CH3), 2.07 (1 H, d, J 3, OH), 2.41 (3 H, m,
137.9 and 144.7; m/z (CI) 314 (M+ + 18, 22%), 296 (M+, 50), 2-H2 and 5-H), 3.13 (2 H, m, 6-H2), 3.23 (3 H, s, OCH3), 4.31
279 (74), 261 (24), 173 (38) and 85 (100). Minor amounts of the (2 H, s, PhCH2O), 4.50 (1 H, td, J 6 and 3, 1-H), 5.44 (2 H, m,
(Z)-anti-isomer 2a (<5 mg, <6%) were isolated.
3-H and 4-H), 6.81 (2 H, d, J 9, ArH) and 7.20 (7 H, m, ArH);
The reactions using indium(III) halides were carried out minor 1,5-syn-epimer 6c 0.98 (3 H, d, J 7, 5-CH3); δC (CDCl3,
using similar procedures except that equimolar amounts of 75 MHz) 17.1, 36.7, 36.8, 41.7, 55.1, 72.8, 75.4, 77.9, 113.4,
the indium(III) halide, stannane 1 and benzaldehyde were 126.3, 127.3, 127.4, 128.2, 134.3, 134.7, 138.6 and 158.8; m/z
used.
Standard procedure for the bismuth(III) iodide/zinc pro- 137 (32).
moted reactions of allyl bromides with aldehydes: (3E,1R,5R)- 4-MeOC6H4) was also isolated (7 mg, 5%).
6-benzyloxy-5-methyl-1-phenylhex-3-en-1-ol 5a. Activated zinc (2E,6E,4SR,8SR)-9-Benzyloxy-8-methylnona-2,6-dien-4-ol 5d.
(CI) 327 (M+ + 1, 14%), 326 (M+, 30), 309 (100), 203 (48) and
sample of the (Z)-1,5-anti-isomer 2c (R
A
=
powder (31 mg, 0.48 mmol) was suspended in a solution of Following the standard procedure, crotonaldehyde (0.076 mL,
bismuth(III) iodide (248 mg, 0.42 mmol), in THF (1.5 mL) and 0.93 mmol), BiI3 (182 mg, 0.31 mmol) in MeCN (2.0 mL) and
the mixture stirred vigorously at room temperature for 1 h the racemic stannane 1 (150 mg, 0.31 mmol) in MeCN
during which time the orange/grey suspension turned black. (0.5 mL) and DCM (0.3 mL), after chromatography of the
The (R)-bromide 26 (75 mg, 0.28 mmol) in THF (0.5 mL) and residue (3 : 1, light petroleum–ether with 1% Et3N) afforded
benzaldehyde (29 μL, 0.28 mmol) were added and the resulting the title compound 5d as a colourless oil (37 mg, 45%) contain-
mixture heated under reflux for 2 h. After cooling and concen- ing ca. 10% of its syn-epimer 6d (1H NMR) (Found: M+ + NH4,
tration under reduced pressure, chromatography of the residue 278.2123. C17H28NO2 requires M, 278.2134); νmax/cm−1 3420,
(4 : 1, light petroleum–ether) gave the (1R,5R)-enantiomer of 2958, 2928, 2854, 1453, 1376, 1093, 1029, 966 and 736;
the title compound 5a as a colourless oil (69 mg, 83%) δH (CDCl3, 300 MHz) major anti-epimer 5d 1.06 (3 H, d, J 7,
8486 | Org. Biomol. Chem., 2013, 11, 8476–8505
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8-CH3), 1.73 (3 H, d, J 7, 1-H3), 2.26 (2 H, m, 5-H2), 2.54 (1 H, m, 2-H2 and 3-H2), 1.83 (1 H, m, OH), 2.09 (1 H, m, 5-H), 2.29
m, 8-H), 3.35 (2 H, dd, J 7 and 3, 9-H2), 4.07 (1 H, m, 4-H), 4.55 (1 H, m, 5-H′), 2.54 (1 H, m, 8-H), 3.35 (2 H, d, J 6, 9-H2), 3.62
(2 H, s, PhCH2O), 5.53 (3 H, m, 2-H, 6-H and 7-H), 5.71 (1 H, (1 H, m, 4-H), 4.55 (2 H, s, PhCH2O), 5.52 (2 H, m, 6-H and
m, 3-H) and 7.35 (5 H, m, ArH); minor syn-epimer 6d 1.08 7-H) and 7.35 (5 H, m, ArH); minor syn-epimer 6f 1.08 (3 H, d,
(3 H, d, J 7, 8-CH3); δC (CDCl3, 75 MHz) 17.0, 17.6, 37.1, 41.0, J 7, 8-CH3); δC (C6D6, 75 MHz) 13.9, 16.8, 18.9, 37.2, 39.0, 41.1,
71.6, 72.9, 75.1, 125.5, 126.1, 126.6, 127.5, 128.3, 133.3, 137.1 69.9, 72.7, 74.9, 126.3, 127.2, 127.6, 128.1, 136.4 and 138.8; m/z
and 138.4; m/z (CI) 278 (M+ + 18, 36%), 260 (M+, 64), 243 (100) (CI) 280 (M+ + 18, 100%), 263 (M+ + 1, 66), 245 (32), 174 (34)
n
and 225 (20).
and 91 (44). A small amount of the (Z)-anti-isomer 2f (R = Pr)
Following the standard procedure, bromide 26 (100 mg, (5 mg, 6%) was also isolated.
0.374 mmol) and crotonaldehyde (31 μL, 0.374 mmol)
Following the standard procedure, bromide 26 (100 mg,
afforded the (4R,8R)-enantiomer of the title compound 5d as a 0.374 mmol) and butanal (34 μL, 0.374 mmol) afforded the
colourless oil (84 mg, 86%) containing ca. 7% of its (4S)- (4S,8R)-enantiomer of the title compound 5f as a colourless oil
epimer 6d, Rf = 0.3 (3 : 1, light petroleum–ether), [α]2D0 +9 (c 1.7, (90 mg, 92%) containing ca. 7% of its 4-epimer 6f, Rf = 0.3
CHCl3) (Found: M+ + NH4, 278.2123. C17H28NO2 requires M, (3 : 1, light petroleum–ether), [α]D20 +9 (c 1.5, CHCl3) (Found: M+
278.2134). Spectroscopic data were identical to those of the + NH4, 280.2279. C17H30NO2 requires M, 280.2290). Spectro-
racemate.
scopic data were identical to those of the racemate.
(5E,3SR,7SR)-8-Benzyloxy-2,7-dimethyloct-5-en-3-ol 5e. Fol-
(4E,2R,6R)-1,7-Bis-benzyloxy-6-methylhept-4-en-2-ol 5g. Fol-
lowing the standard procedure, 2-methylpropanal (90 μL, lowing the standard procedure, the (R)-bromide 26 (100 mg,
0.93 mmol), BiI3 (182 mg, 0.31 mmol) in MeCN (2.0 mL) and 0.374 mmol) and benzyloxyacetaldehyde (53 μL, 0.374 mmol)
the racemic stannane 1 (150 mg, 0.31 mmol) in MeCN afforded the title compound 5g as a colourless oil (80 mg, 63%)
(0.5 mL) and DCM (0.3 mL), after chromatography (3 : 1, light containing ca. 13% of its (2S)-epimer 6g (1H NMR) Rf = 0.4
petroleum–ether with 1% Et3N) afforded the title compound 5e (3 : 1, light petroleum–ether), [α]2D0 +10 (c 0.9, CHCl3) (Found:
as a colourless oil (43 mg, 55%) containing 7% of its syn- M+ + NH4, 358.2382. C22H32NO3 requires M, 358.2377); νmax
/
epimer 6e (1H NMR) (Found: M+ + NH4, 280.2279. C17H30NO2 cm−1 3445, 3028, 2856, 1602, 1453, 1363, 1204, 1092, 1028 and
requires M, 280.2290); νmax/cm−1 3443, 2958, 2930, 2872, 1454, 973; δH (CDCl3, 400 MHz) major anti-epimer 5g 0.92 (3 H, d, J
1365, 1094, 1029, 973 and 736; δH (C6D6, 300 MHz) major anti- 7, 6-CH3), 2.14 (2 H, m, 3-H2), 2.31 (1 H, m, OH), 2.40 (1 H, m,
epimer 5e 0.89 (3 H, d, J 7, 7-CH3), 0.97 (6 H, d, J 7, 1-H3 and 6-H), 3.20 and 3.24 (each 1 H, dd, J 9, 6.5, 7-H), 3.30 and 3.40
2-CH3), 1.60 (1 H, m, 2-H), 1.64 (1 H, d, J 4, OH), 1.98 (1 H, m, (each 1 H, dd, J 9.5, 7, 1-H), 3.74 (1 H, m, 2-H), 4.42 and 4.46
4-H), 2.12 (1 H, m, 4-H′), 2.44 (1 H, m, 7-H), 3.13 (2 H, dd, J (each 2 H, s, OCH2Ph), 5.39 (2 H, m, 4-H and 5-H) and 7.23 (10
7 and 3, 8-H2), 3.18 (1 H, m, 3-H), 4.31 (2 H, s, PhCH2O), 5.41 H, m, ArH); minor syn-epimer 6g 0.93 (3 H, d, J 7, 6-CH3), 2.27
(2 H, m, 5-H and 6-H), 7.10 (1 H, m, ArH), 7.19 (2 H, m, ArH) (1 H, m, OH) and 4.45 (2 H, s, OCH2Ph); δC (CDCl3, 100 MHz)
and 7.29 (2 H, m, ArH); minor syn-epimer 6e 1.41 (1 H, d, J 4, 17.9, 37.7, 37.7, 70.7, 73.7, 74.1, 74.6, 76.0, 125.9, 128.3, 128.3,
OH); m/z (CI) 280 (M+ + 18, 100%), 263 (M+ + 1, 45) and 245 128.5, 129.1, 129.2, 129.4, 137.3, 138.8 and 139.3; m/z (CI) 358
(24). A small amount of the (Z)-anti-isomer 2e (5 mg, 7%) was (M+ + 18, 38%), 168 (66) and 108 (100).
also isolated.
(5E,3R,7R)-1,8-Bis-benzyloxy-7-methyloct-5-en-3-ol 5h. Fol-
Following the standard procedure, the (R)-bromide 26 lowing the standard procedure, the (R)-bromide 26 (100 mg,
(100 mg, 0.374 mmol) and 2-methylpropanal (34 μL, 0.374 mmol) and 3-benzyloxypropanal (61 mg, 0.374 mmol)
0.37 mmol) afforded the (3R,7R)-enantiomer of the title com- afforded the title compound 5h as a colourless oil (115 mg,
pound 5e as a colourless oil (80 mg, 82%) containing ca. 5% of 87%) containing ca. 5% of its (3S)-epimer 6h (1H NMR), Rf =
its 3-epimer 6e, Rf = 0.3 (3 : 1, light petroleum–ether), [α]2D0 +14 0.4 (3 : 1, light petroleum–ether), [α]D20 +11 (c 0.9, CHCl3)
(c 1.9, CHCl3) (Found: M+ + NH4, 280.2279. C17H30NO2 requires (Found: M+, 355.2268. C23H31O3 requires M, 355.2268); νmax
/
M, 280.2290); δC (C6D6, 75 MHz) 16.9, 17.2, 17.4, 18.6, 32.8, cm−1 3387, 3029, 2925, 2861, 1453, 1365, 1206, 1096 and 1027;
37.0, 37.6, 72.7, 74.9, 127.3, 127.6, 127.9, 128.2, 136.5 and δH (CDCl3, 400 MHz) major anti-epimer 5h 1.01 (3 H, d, J 7,
138.4; m/z (CI) 280 (M+ + 18, 100%), 263 (M+ + 1, 45) and 245 7-CH3), 1.74 (2 H, m, 2-H2), 2.19 (2 H, m, 4-H2), 2.47 (1 H, m,
(24).
7-H), 2.77 (1 H, s, OH), 3.28 and 3.33 (each 1 H, dd, J 9, 8,
(6E,4RS,8SR)-Benzyloxy-8-methylnon-6-en-4-ol 5f. Following 8-H), 3.60 3.70 (2 H, m, 1-H2), 3.78 (1 H, m, 3-H), 4.50 and 4.51
the standard procedure, butanal (84 μL, 0.93 mmol), BiI3 (each 2 H, s, OCH2Ph), 5.47 (2 H, m, 5-H and 6-H) and 7.31
(182 mg, 0.31 mmol) in MeCN (2.0 mL) and the racemic stan- (10 H, m, ArH); minor syn-epimer 6h 1.02 (3 H, d, J 7, 7-CH3);
nane 1 (150 mg, 0.31 mmol) in MeCN (0.5 mL) and DCM δC (CDCl3, 100 MHz) 19.4, 38.1, 39.3, 43.1, 71.1, 72.5, 75.2,
(0.3 mL), after chromatography (3 : 1, light petroleum–ether 75.6, 77.6, 128.2, 129.8, 129.9, 129.9, 130.0, 130.6, 130.7, 138.9,
with 1% Et3N) afforded the title compound 5f as a colourless oil 140.4 and 140.9; m/z (CI) 372 (M+ + 18, 4%), 354 (M+, 8), 182
(50 mg, 61%) containing about 7% of its syn-epimer 6f (1H (6), 108 (64) and 91 (100).
NMR) (Found: M+ + NH4, 280.2280. C17H30NO2 requires M,
(4E,2R,6R)-7-Benzyloxy-6-methyl-1-tert-butyldimethylsilyloxy-
280.2291); νmax/cm−1 3426, 2957, 2928, 2871, 1455, 1361, 1094, hept-4-en-2-ol 5i. Following the standard procedure, the (R)-
1028, 973 and 736; δH (CDCl3, 300 MHz) major anti-epimer 5f bromide 26 (100 mg, 0.374 mmol) and tert-butyldimethylsilyl-
0.97 (3 H, t, J 7, 1-H3), 1.06 (3 H, d, J 7, 8-CH3), 1.35–1.60 (4 H, oxyacetaldehyde (71 μL, 0.374 mmol) afforded the title
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compound 5i as a colourless oil (90 mg, 66%) containing <5% dissolved in dry THF at 0 °C. DIAD (0.18 mL, 0.94 mmol) was
of its (2S)-epimer 6i, Rf = 0.4 (3 : 1, light petroleum–ether), [α]2D0 added dropwise and, after 10 min, the mixture was allowed to
+4 (c 1.5, CHCl3) (Found: M+ + H, 365.2514. C21H37O3Si warm to room temperature over 30 min. The solution was con-
requires M, 365.2506); νmax/cm−1 3461, 2928, 2857, 1461, 1361, centrated under reduced pressure and chromatography of the
1254, 1114, 1096, 972, 837 and 778; δH (CDCl3, 400 MHz) 0.00 viscous yellow residue (30 : 1 then 15 : 1, light petroleum–ether)
(6 H, s, 2 × SiCH3), 0.83 [9 H, s, SiC(CH3)3], 0.96 (3 H, d, J 7, 6- afforded the title compound 8 as a pale yellow oil (69 mg, 63%)
CH3), 2.11 (2 H, m, 3-H2), 2.31 (1 H, d, J 4, OH), 2.42 (1 H, m, containing ca. 30% of its 1,5-anti-epimer (Found: M+,
6-H), 3.21 and 3.28 (each 1 H, dd, J 9 and 7, 7-H), 3.39 (1 H, 445.1889. C27H27NO5 requires M, 445.1889); νmax/cm−1 3032,
dd, J 10 and 7, 1-H), 3.55 (2 H, m, 1-H′ and 2-H), 4.44 (2 H, s, 2855, 1725, 1607, 1529, 1454, 1346, 1272, 1102 and 973;
OCH2Ph), 5.41 (2 H, m, 4-H and 5-H) and 7.25 (5 H, m, ArH); δH (CDCl3, 300 MHz) major 1,5-syn-epimer 8 0.98 (3 H, d, J 7,
δC (CDCl3, 100 MHz) −5.1, 18.8, 20.0, 27.6, 38.2, 38.6, 68.2, 5-CH3) 2.46 (1 H, m, 5-H), 2.75 (2 H, m, 2-H2), 3.26 (2 H, m,
73.1, 74.6, 77.0, 127.2, 129.1, 129.2, 129.3, 137.8 and 140.3; m/z 6-H2), 4.47 (2 H, s, PhCH2O), 5.51 (2 H, m, 3-H and 4-H), 6.06
(CI) 382 (M+ + 18, 6%), 365 (M+ + 1, 6), 108 (46) and 91 (100).
(1 H, dd, J 7.5 and 6, 1-H), 7.36 (10 H, m, ArH) and 8.34 (4 H,
(5E,3R,7R)-8-Benzyloxy-7-methyl-1-tert-butyldimethylsilyloxy- m, ArH); minor 1,5-anti-epimer 0.95 (3 H, d, J 7, 5-H3); δC
oct-5-en-3-ol 5j. Following the standard procedure, the (R)- (CDCl3, 75 MHz) 17.0, 36.8, 39.8, 72.8, 75.1, 77.1, 123.4, 123.9,
bromide 26 (100 mg, 0.374 mmol) and 3-tert-butyldimethylsilyl- 126.4, 127.3, 128.2, 128.3, 128.5, 130.6, 135.8, 137.3, 138.4,
oxypropanal (70 mg, 0.374 mmol) afforded the title compound 139.4 and 163.8; m/z (CI) 463 (M+ + 18, 100%), 296 (50) and
5j as a colourless oil (89 mg, 63%) containing <5% of its (3S)- 279 (54).
epimer 6j, Rf = 0.4 (3 : 1, light petroleum–ether), [α]2D0 +9 (c 1.7,
Standard procedure for diimide reduction of alkenes;
CHCl3) (Found: M+, 378.2577. C22H38O3Si requires M, (1RS,5SR)-6-benzyloxy-5-methyl-1-phenylhex-1-yl 4-nitrobenzo-
378.2585); νmax/cm−1 3445, 2930, 2857, 1455, 1361, 1255, 1092, ate 9. Sodium acetate (370 mg, 2.64 mmol) in water (1.4 mL)
973, 836 and 777; δH (CDCl3, 400 MHz) 0.00 (6 H, s, 2 × SiCH3), was added dropwise to the alkene 8 (37 mg, 0.08 mmol) and
0.82 [9 H, s, SiC(CH3)3], 0.95 (3 H, d, J 7, 7-CH3), 1.55 (2 H, m, toluene 4-sulfonylhydrazine (260 mg, 1.6 mmol) in DME
2-H2), 2.12 (2 H, m, 4-H2), 2.41 (1 H, m, 7-H2), 3.21 and 3.27 (3.1 mL) heated under reflux over 2 h. The mixture was heated
(each 1 H, dd, J 9, 6.5, 8-H), 3.65–3.80 (3 H, m, 1-H2 and 3-H), under reflux for a further 4 h then allowed to cool to room
4.43 (2 H, s, OCH2Ph), 5.40 (2 H, m, 5-H and 6-H) and 7.24 temperature. The aqueous phase was extracted with ether (2 ×
(5 H, m, ArH); δC (CDCl3, 100 MHz) −5.1, 18.7, 19.7, 27.4, 38.5, 10 mL) and the organic extracts were washed with water
39.4, 42.4, 63.9, 72.6, 74.4, 76.8, 127.6, 129.0, 129.1, 129.8, (15 mL), brine (15 mL), dried (MgSO4) and concentrated under
137.6 and 140.1; m/z (CI) 396 (M+ + 18, 6%), 379 (M+ + 1, 18), reduced pressure. Chromatography of the residue (3 : 1, light
189 (16), 108 (22) and 91 (100).
petroleum–ether) afforded the title compound 9 as a colourless
(3E)-6-Benzyloxy-5-methyl-1-phenylhex-3-en-1-one 7. Alcohol oil (25 mg, 68%) containing about 30% of its 1,5-anti-epimer
5a (30 mg, 0.103 mmol containing ca. 30% of 6a) in DCM 11 (1H NMR) (Found: M+ + NH4, 465.2388. C27H33N2O5
(0.4 mL) was added dropwise to the Dess Martin periodinane requires M, 465.2389); νmax/cm−1 3031, 2927, 2855, 1723, 1528,
(218 mg, 0.515 mmol) in DCM (0.8 mL) at room temperature. 1453, 1347, 1270, 1100 and 1014; δH (CDCl3, 300 MHz) major
After 30 min, aqueous sodium hydroxide (1.3 M; 3 mL) was 1,5-syn-epimer 9 0.81 (3 H, d, J 7, 5-CH3), 1.05–1.50 (4 H, m,
added and the aqueous layer was extracted with ether (2 × 3-H2 and 4-H2), 1.65 (1 H, m, 5-H), 1.86 (1 H, m, 2-H) 2.00
15 mL). The combined organic extracts were washed with (1 H, m, 2-H′), 3.17 (2 H, m, 6-H2), 4.39 (2 H, s, PhCH2O), 5.92
aqueous sodium hydroxide (1.3 M; 20 mL) and water (20 mL), (1 H, t, J 7, 1-H), 7.27 (5 H, m, ArH), 8.14 (2 H, d, J 9, ArH) and
dried (MgSO4) and then concentrated under reduced pressure. 8.19 (2 H, d, J 9, ArH); minor 1,5-anti-epimer 11 0.82 (3 H, d,
Chromatography of the residue (6 : 1, light petroleum–ether) J 7, 5-CH3); δC (CDCl3, 75 MHz) both epimers (70 : 30) 16.9,
afforded the title compound 7 as a colourless oil (27 mg, 75%) 22.9, 23.0, 33.2, 33.3, 36.4, 36.5, 72.9, 75.7, 77.9, 123.5, 126.5,
(Found: M+ + H, 295.1699. C20H23O2 requires M, 295.1698); 127.4, 128.2, 128.5, 130.6, 135.8, 138.6, 140.0(2), 150.5 and
νmax/cm−1 3029, 2961, 2858, 1686, 1449, 1275, 1208, 1097, 973 163.9; m/z (CI) 465 (M+ + 18, 18%), 298 (100), 263 (56), 108 (38)
and 746; δH (CDCl3, 300 MHz) 0.97 (3 H, d, J 7, 5-CH3), 2.46 and 91 (42).
(1 H, m, 5-H), 3.26 (2 H, m, 6-H2), 3.63 (2 H, d, J 7, 2-H2), 4.42
(3Z,1SR,5SR)-6-Benzyloxy-5-methyl-1-phenylhex-3-en-1-yl 4-nitro-
(2 H, s, PhCH2O), 5.52 (1 H, dd, J 16 and 7, 4-H), 5.69 (1 H, dt, benzoate 10. Following the standard procedure, the alcohol 2a
J 16 and 7, 3-H), 7.24 (5 H, m, ArH), 7.38 (2 H, m, ArH), 7.49 (75 mg, 0.26 mmol), triphenylphosphine (260 mg, 1.02 mmol),
(1 H, m, ArH) and 7.88 (2 H, m, ArH); δC (CDCl3, 75 MHz) 16.9, 4-nitrobenzoic acid (170 mg, 0.96 mmol) and DIAD (0.2 mL,
36.9, 42.5, 72.9, 75.1, 122.2, 127.4, 127.5, 128.2, 128.5, 128.6, 1.02 mmol), after chromatography (30 : 1 then 15 : 1, light pet-
133.0, 136.6, 137.1, 138.5 and 198.4; m/z (CI) 312 (M+ + 18, roleum–ether), afforded the title compound 10 as a pale yellow
71%) and 295 (M+ + 1, 100).
Standard procedure for Mitsunobu reactions: (3E,1RS,5SR)- requires M, 463.2233); νmax/cm−1 3063, 3030, 2855, 1725, 1606,
6-benzyloxy-5-methyl-1-phenylhex-3-en-1-yl 4-nitrobenzoate 1528, 1453, 1345, 1272, 1102, 1014 and 720; δH (CDCl3,
8. The alcohol 5a [70 mg, 0.24 mmol containing ca. 30% of its 200 MHz) 0.98 (3 H, d, J 7, 5-CH3), 2.86 (3 H, m, 2-H2 and 5-H),
(E)-1,5-syn-epimer 6a], triphenylphosphine (240 mg, 3.24 (2 H, m, 6-H2), 4.50 (2 H, s, PhCH2), 5.41 (2 H, m, 3-H and
0.94 mmol) and 4-nitrobenzoic acid (160 mg, 0.94 mmol) were 4-H), 6.07 (1 H, t, J 7, 1-H), 7.39 (10 H, m, ArH) and 8.29 (4 H,
oil (77 mg, 68%) (Found: M+ + NH4, 463.2226. C27H31N2O5
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m, ArH); δC (CDCl3, 75 MHz) 17.6, 32.6, 34.6, 72.9, 74.9, 77.0, (R = nPr, 60 mg, 0.23 mmol), triphenylphosphine (230 mg,
123.5, 123.8, 126.5, 127.4, 128.2, 128.5, 130.7, 135.7, 136.1, 0.92 mmol), 4-nitrobenzoic acid (178 mg, 0.92 mmol) and
138.5, 139.5, 150.5 and 163.8; m/z (CI) 463 (M+ + 18, 100%) DIAD (0.17 mL, 0.92 mmol), after chromatography (30 : 1 then
and 279 (35).
(1SR,5SR)-6-Benzyloxy-5-methyl-1-phenylhex-1-yl
15 : 1, light petroleum–ether), afforded the title compound 14 as
4-nitro- a pale yellow oil (98 mg, 68%) (Found: M+ + NH4, 429.2388.
benzoate 11. Following the standard procedure, sodium C24H33N2O5 requires M, 429.2404); νmax/cm−1 2957, 2930,
acetate (190 mg, 1.35 mmol) in water (0.7 mL), the alkene 10 2872, 1721, 1608, 1529, 1349, 1274, 1116, 1102 and 720; δH
(30 mg, 0.06 mmol) and toluene 4-sulfonylhydrazine (130 mg, (CDCl3, 300 MHz) 0.94 (6 H, m, 1-H3 and 8-CH3), 1.30–1.50
0.8 mmol) in DME (1.6 mL), after chromatography (3 : 1, light (2 H, m, 2-H2), 1.60–1.80 (2 H, m, 3-H2), 2.38–2.62 (2 H, m,
petroleum–ether), afforded the title compound 11 as a colour- 5-H2), 2.81 (1 H, m, 8-H), 3.28 (2 H, dd, J 7 and 7, 9-H2), 4.48
less oil (23 mg, 62%) (Found: M+ + NH4, 465.2383. C27H33N2O5 (2 H, s, PhCH2O), 5.20 (1 H, pent, J 6.5, 4-H), 5.33 (1 H, t, J 10,
requires M, 465.2389); νmax/cm−1 3031, 2927, 2855, 1723, 1606, 7-H), 5.44 (1 H, dt, J 11, 7, 6-H), 7.30 (5 H, m, ArH) and 8.19
1528, 1453, 1347, 1270, 1100 and 1014; δH (CDCl3, 300 MHz) and 8.28 (each 2 H, d, J 9, ArH); δC (CDCl3, 75 MHz) 13.8, 17.7,
0.82 (3 H, d, J 7, 5-CH3), 1.05–1.55 (4 H, m, 3-H2 and 4-H2), 18.6, 32.3, 32.6, 35.8, 72.9, 75.0, 75.6, 123.4, 124.4, 127.3,
1.67 (1 H, m, 5-H), 1.85 (1 H, m, 2-H) 2.02 (1 H, m, 2-H′), 3.17 128.2, 130.6, 135.6, 136.0, 138.5 and 164.3; m/z (CI) 429 (M+ +
(2 H, m, 6-H2), 4.39 (2 H, s, PhCH2O), 5.92 (1 H, t, J 7, 1-H), 18, 100%), 412 (M+ + H, 36), 382 (68), 245 (100) and 91 (80).
7.27 (5 H, m, ArH), 8.14 (2 H, d, J 9, ArH) and 8.19 (2 H, d, J 9,
(4SR,8RS)-9-Benzyloxy-8-methylnon-4-yl
4-nitrobenzoate
ArH); δC (CDCl3, 75 MHz) 17.3, 23.3, 33.6(2), 36.8, 73.2, 76.0, 15. Following the standard procedure, sodium acetate
78.2, 123.8, 126.8, 127.7, 128.5, 128.6, 128.9, 131.0, 136.1, (270 mg, 2.0 mmol) in water (0.9 mL), the alkene 14 (40 mg,
138.9, 140.4, 150.8 and 164.3; m/z (CI) 465 (M+ + 18, 20%), 298 0.1 mmol) and toluene 4-sulfonylhydrazine (210 mg,
(100), 263 (52), 108 (34) and 91 (48).
1.2 mmol) in DME (3 mL), after chromatography (3 : 1, light
(6E,4SR,8SR)-9-Benzyloxy-8-methylnon-6-en-4-yl
4-nitro- petroleum–ether), afforded the title compound 15 as a colour-
benzoate 12. Following the standard procedure, the alcohol 5f less oil (21 mg, 51%) (Found: M+ + NH4, 431.2550. C24H35N2O5
(90 mg, 0.34 mmol), triphenylphosphine (350 mg, 1.37 mmol), requires M, 431.2560); νmax/cm−1 2957, 2936, 2871, 1719, 1528,
4-nitrobenzoic acid (270 mg, 1.37 mmol) and DIAD (0.26 mL, 1349, 1274, 1114, 1102 and 720; δH (CDCl3, 300 MHz) 0.90
1.37 mmol), after chromatography (30 : 1 then 15 : 1, light pet- (6 H, m, 1-H3 and 8-CH3), 1.18–1.90 (11 H, m, 2-H2, 3-H2, 5-H2,
roleum–ether), afforded the title compound 12 as a pale yellow 6-H2, 7-H2 and 8-H), 3.28 (2 H, m, 9-H2), 4.49 (2 H, s,
oil (130 mg, 92%) (Found: M+ + NH4, 429.2393. C24H33N2O5 PhCH2O), 5.19 (1 H, m, 4-H), 7.32 (5 H, m, ArH) and 8.32 (4 H,
requires M, 429.2404); νmax/cm−1 2958, 2928, 2872, 1723, 1608, m, ArH); δC (CDCl3, 75 MHz) 14.2, 17.2, 18.9, 23.0, 33.6, 33.7,
1530, 1349, 1274, 1116, 1102 and 720; δH (CDCl3, 300 MHz) 34.6, 36.6, 73.2, 76.1, 76.4, 123.8, 127.7, 128.6, 130.9, 136.4,
0.98 (6 H, m, 1-H3 and 8-CH3), 1.25–1.50 and 1.65–1.78 (each 139.0, 150.7 and 164.7; m/z (CI) 431 (M+ + 18, 60%), 414 (M+ +
2 H, m, 2-H2 and 3-H2), 2.40–2.55 (3 H, m, 5-H2 and 8-H), 3.29 1, 22), 247 (86), 108 (78) and 91 (100).
(2 H, m, 9-H2), 4.50 (2 H, s, PhCH2O), 5.24 (1 H, m, 4-H), 5.52
Samples of the nitrobenzoates 13 and 15 were mixed
(2 H, m, 6-H and 7-H), 7.33 (5 H, m, ArH) and 8.23 and 8.29 together: δC (CDCl3, 75 MHz) mixture of 13 and 15 17.249/
(each 2 H, d, J 9, ArH); δC (CDCl3, 75 MHz) 13.8, 17.0, 18.6, 17.321, 22.982/23.013, 33.744/33.786, 36.457/36.560, 76.041/
35.7, 36.9, 37.6, 72.8, 75.1, 75.3, 123.4, 124.4, 127.3, 128.2, 76.102 and 76.426/76.484 (signals italicised assigned to isomer
130.5, 136.1, 136.8, 138.5, 150.3 and 164.2; m/z (CI) 429 15).
(M+ + 18, 100%), 412 (M+ + 1, 18), 245 (16) and 106 (100).
(4SR,8SR)-9-Benzyloxy-8-methylnon-4-yl
(3E,1RS,5RS)-5-Benzyloxy-1-phenylhex-3-en-1-ol 18a. Follow-
4-nitrobenzoate ing the standard procedure, benzaldehyde (63 μL, 0.63 mmol),
13. Following the standard procedure, sodium acetate (0.53 g, BiI3 (123 mg, 0.21 mmol) in MeCN (1 mL) and DCM (1 mL)
3.8 mmol) in water (1.8 mL), the alkene 12 (81 mg, 0.19 mmol) and the racemic stannane 16 (100 mg, 0.21 mmol) in DCM
and toluene 4-sulfonylhydrazine (0.42 g, 2.3 mmol) in DME (0.3 mL), after chromatography (3 : 1, light petroleum–ether
(4.5 mL), after chromatography (3 : 1, light petroleum–ether), with 1% Et3N), gave the title compound 18a as a colourless oil
afforded the title compound 13 as a colourless oil (52 mg, 64%) (33 mg, 56%) containing ca. 7% of the anti-epimer 19a, Rf =
(Found: M+
+
NH4, 431.2552. C24H35N2O5 requires M, 0.3 (3 : 1, light petroleum–ether) (Found: M+ + NH4, 300.1962.
431.2560); νmax/cm−1 2957, 2936, 2871, 1720, 1528, 1349, 1274, C19H26NO2 requires M, 300.1963); νmax/cm−1 3397, 3028, 2974,
1114, 1102 and 720; δH (CDCl3, 300 MHz) 0.90 (6 H, m, 1-H3 2863, 1602, 1494, 1453, 1370, 1069 and 735; δH (CDCl3,
and 8-CH3), 1.18–1.90 (11 H, m, 2-H2, 3-H2, 5-H2, 6-H2, 7-H2 300 MHz) 1.27 (3 H, d, J 7, 6-H3), 2.55 (2 H, m, 2-H2), 3.90 (1 H,
and 8-H), 3.28 (2 H, m, 9-H2), 4.49 (2 H, s, PhCH2O), 5.19 (1 H, m, 5-H), 4.35 and 4.52 (each 1 H, d, J 12, OHCHPh), 4.77 (1 H,
m, 4-H), 7.32 (5 H, m, ArH) and 8.32 (4 H, m, ArH); δC (CDCl3, t, J 6, 1-H), 5.51 (1 H, dd, J 16 and 6, 4-H), 5.61 (1 H, dt, J 16
75 MHz) 14.2, 17.3, 18.9, 23.0, 33.6, 33.8, 34.6, 36.5, 73.2, 76.0, and 6, 3-H) and 7.30 (10 H, m, ArH); δC (CDCl3, 75 MHz) 21.9,
76.5, 123.8, 127.7, 128.6, 130.9, 136.4, 139.0, 150.7 and 164.7; 42.4, 70.1, 74.0, 75.7, 126.2, 127.7, 128.0, 128.1, 128.3, 128.6,
m/z (CI) 431 (M+ + 18, 44%), 414 (M+ + 1, 14), 247 (46), 108 (74) 128.7, 136.1, 139.1 and 144.1; m/z (CI) 300 (M+ + 18, 84%), 192
and 91 (100).
(96), 157 (100) and 124 (56). A less polar minor fraction was
(6Z,4RS,8SR)-9-Benzyloxy-8-methylnon-6-en-4-yl
4-nitro- 2-(2-benzyloxyethyl)-1-phenylbut-3-en-1-ol 20, Rf = 0.35 (3 : 1,
benzoate 14. Following the standard procedure, the alcohol 2f light petroleum–ether) (Found: M+
+
NH4, 300.1966.
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C19H26NO2 requires M, 300.1963); νmax/cm−1 3468, 2964, 2925,
(3E,1SR,1RS)-5-Benzyloxy-1-phenylhex-3-en-1-yl
4-nitro-
1639, 1452, 1260, 1098, 1073, 1027 and 799; δH (CDCl3, benzoate 21. Following the standard procedure, the alcohol
300 MHz) 1.19 (3 H, d, J 6, 2′-H3), 2.27 (1 H, m, 2-H), 3.20 (1 H, 18a (100 mg, 0.35 mmol), triphenylphosphine (0.35 g,
br. s, OH), 3.68 (1 H, m, 2′-H), 4.33 and 4.65 (each 1 H, d, J 12, 1.38 mmol), 4-nitrobenzoic acid (0.23 g, 1.38 mmol) and DIAD
OHCHPh), 4.97 (1 H, d, J 6, 1-H), 5.05 (1 H, dd, J 17 and 2, (0.26 mL, 1.38 mmol), after chromatography (30 : 1 then 15 : 1,
4-H), 5.32 (1 H, dd, J 10 and 2, 4-H′), 6.11 (1 H, dt, J 17 and 10, light petroleum–ether), afforded the title compound 21 as a
3-H) and 7.34 (10 H, m, ArH); δC (CDCl3, 75 MHz) 17.9, 59.2, pale yellow oil (74 mg, 49%), Rf = 0.4 (3 : 1, light petroleum–
70.6, 76.0, 76.6, 121.0, 127.0, 127.8, 127.9, 127.9, 128.2, 129.0, ether) (Found: M+ + NH4, 449.2071. C26H29N2O5 requires M,
133.8, 138.7 and 142.8; m/z (CI) 281 (M+ − 1, 6%), 265 (22), 108 449.2076); νmax/cm−1 2957, 2923, 2854, 1724, 1606, 1528, 1345,
(84) and 91 (100).
1264, 1100 and 799; δH (CDCl3, 300 MHz) 1.23 (3 H, d, J 6,
Following the standard procedure, the (S)-bromide 42 6-H3), 2.86 (2 H, m, 2-H2), 3.86 (1 H, m, 5-H), 4.24 and 4.42
(100 mg, 0.394 mmol) and benzaldehyde (34 μL, 0.394 mmol) (each 1 H, d, J 12, OHCHPh), 5.50–5.70 (2 H, m, 3-H and 4-H),
gave the (1S,5S)-enantiomer of the title compound 18a as a col- 6.16 (1 H, t, J 7, 1-H), 7.10–7.50 (10 H, m, ArH) and 8.28 (4 H,
ourless oil (51 mg, 46%) containing ca. 6% of its 1-epimer 19a, m, ArH); m/z (CI) 449 (M+ + 18, 1%), 324 (2) and 157 (100).
Rf = 0.3 (3 : 1, light petroleum–ether), [α]2D0 +8 (c 1.4, CHCl3)
(Found: M+
300.1963). Spectroscopic data were identical to those of the 0.32 mmol) in water (1.5 mL), the alkene 21 (67 mg,
racemate. 0.15 mmol) and toluene 4-sulfonylhydrazine (0.35 g,
(1RS,5SR)-5-Benzyloxy-1-phenylhex-1-yl
4-nitrobenzoate
+
NH4, 300.1962. C19H26NO2 requires M, 22. Following the standard procedure, sodium acetate (0.44 g,
(5E,3RS,7RS)-7-Benzyloxy-2-methyloct-5-en-3-ol 18b. Follow- 1.90 mmol) in DME (4 mL) with heating under reflux for 16 h,
ing the standard procedure, 2-methylpropanal (57 μL, after chromatography (3 : 1, light petroleum–ether), afforded
0.63 mmol), BiI3 (123 mg, 0.21 mmol) in MeCN (1 mL) and the title compound 22 as a colourless oil (28 mg, 40%), Rf = 0.3
DCM (1 mL) and the racemic stannane 16 (100 mg, (3 : 1, light petroleum–ether) (Found: M+ + NH4, 451.2238.
0.21 mmol) in DCM (0.3 mL), after chromatography (3 : 1, light C26H31N2O5 requires M, 451.2233); νmax/cm−1 2963, 2929,
petroleum–ether with 1% Et3N), gave the title compound 18b as 2863, 1723, 1606, 1528, 1346, 1270, 1100 and 719; δH (CDCl3,
a colourless oil (25 mg, 48%) containing ca. 7% of its epimer 300 MHz) 1.21 (3 H, d, J 6.5, 6-H3), 1.30–1.75 (4 H, m, 3-H2 and
19b (13C NMR), Rf
(Found: M+
NH4, 266.2113. C16H28NO2 requires M, 4.43 and 4.60 (each 1 H, d, J 12, OHCHPh), 6.04 (1 H, t, J 6,
= 0.3 (3 : 1, light petroleum–ether) 4-H2), 1.98 and 2.13 (each 1 H, m, 2-H), 3.53 (1 H, m, 5-H),
+
266.2119); νmax/cm−1 3443, 2965, 2929, 2871, 1602, 1494, 1453, 1-H), 7.38 (10 H, m, ArH) and 8.30 (4 H, m, ArH); δC (CDCl3,
1368, 1071, 975 and 732; δH (CDCl3, 300 MHz) 0.96 and 0.98 75 MHz) 19.9, 21.9, 30.6, 36.6, 70.5, 74.6, 78.3, 123.8, 126.8,
(each 3 H, d, J 6.5, 1-H3 or 2-CH3), 1.32 (3 H, d, J 6.5, 8-H3), 127.7, 127.9, 128.5, 128.6, 128.9, 131.0, 136.1, 139.2, 140.3 and
1.71 (1 H, m, 2-H), 2.10–2.40 (2 H, m, 4-H2), 3.42 (1 H, m, 3-H), 164.3; m/z (CI) 451 (M+ + 18, 6%), 391 (18), 284 (30), 175 (14)
3.96 (1 H, m, 7-H), 4.42 and 4.59 (each 1 H, d, J 12, OHCHPh), and 99 (100).
5.55 (1 H, dd, J 16 and 7, 6-H), 5.68 (1 H, dt, J 16 and 7, 5-H)
(3Z,1RS,5RS)-5-Benzyloxy-1-phenylhex-3-en-1-yl 4-nitrobenzo-
and 7.26 (5 H, m, ArH); δC (CDCl3, 75 MHz) major syn-epimer ate 23. Following the standard procedure, the alcohol 17a
18b 17.7, 19.0, 21.9, 33.4, 37.5, 70.1, 75.9, 76.0, 127.7, 127.9, (80 mg, 0.28 mmol), triphenylphosphine (0.28 g, 1.10 mmol),
128.6, 129.4, 135.6 and 139.1; minor anti-epimer 19b 32.8, 4-nitrobenzoic acid (0.19 g, 1.10 mmol) and DIAD (0.21 mL,
38.6 and 68.4; m/z (CI) 266 (M+ + 18, 96%), 216 (24), 158 (100) 1.10 mmol), after chromatography (30 : 1 then 15 : 1, light pet-
and 123 (42).
(6E,4SR,4RS)-8-Benzyloxynon-6-en-4-ol 18c. Following the oil (77 mg, 63%). Rf = 0.4 (3 : 1, light petroleum–ether) (Found:
standard procedure, butanal (86 μL, 0.96 mmol), BiI3 (185 mg, M+ + NH4, 449.2080. C26H29N2O5 requires M, 449.2076); νmax
roleum–ether), afforded the title compound 23 as a pale yellow
/
0.32 mmol) in MeCN (1.25 mL) and DCM (1.25 mL) and the cm−1 3029, 2971, 2864, 1725, 1606, 1528, 1344, 1271, 1101 and
racemic stannane 16 (150 mg, 0.32 mmol) in DCM (0.4 mL), 719; δH (CDCl3, 300 MHz) 1.22 (3 H, d, J 6, 6-H3), 2.70–2.95
after chromatography (3 : 1, light petroleum–ether with 1% (2 H, m, 2-H2), 4.24 (1 H, d, J 12, OHCHPh), 4.30 (1 H, m, 5-H),
Et3N), gave the title compound 18c as a colourless oil (47 mg, 4.41 (1 H, d, J 12, OHCHPh), 5.59 (2 H, m, 3-H and 4-H), 6.09
62%) containing ca. 8% of its epimer 19c, Rf = 0.3 (3 : 1, light (1 H, t, J 7, 1-H), 7.30 (10 H, m, ArH) and 8.30 (4 H, m, ArH); δC
petroleum : ether) (Found: M+ + NH4, 266.2115. C16H28NO2 (CDCl3, 75 MHz) 21.7, 35.0, 70.1, 70.5, 77.4, 123.9, 126.0,
requires M, 266.2119); νmax/cm−1 3403, 2958, 2929, 2870, 1602, 126.8, 127.9, 128.2, 128.7, 128.8, 129.0, 129.2, 131.0, 135.9,
1494, 1453, 1370, 1071, 976 and 733; δH (CDCl3, 300 MHz) 0.90 138.9, 139.5, 150.9 and 164.1; m/z (CI) 449 (M+ + 18, 4%), 324
(3 H, m, 1-H3), 1.34 (3 H, d, J 6, 9-H3), 1.30–1.60 (4 H, m, 2-H2 (7), 265 (3) and 157 (100).
and 3-H2), 2.00–2.40 (2 H, m, 5-H2), 3.69 (1 H, m, 4-H), 3.98
(1RS,5RS)-5-Benzyloxy-1-phenylhex-1-yl
4-nitrobenzoate
(1 H, m, 8-H), 4.10 (1 H, d, J 4, OH), 4.60 and 4.69 (each 1 H, d, 24. Following the standard procedure, sodium acetate (0.44 g,
J 12, OHCHPh), 5.56 (1 H, dd, J 15 and 7, 7-H), 5.66 (1 H, dt, 0.32 mmol) in water (1.5 mL), the alkene 23 (70 mg,
J 15 and 7, 6-H) and 7.31 (5 H, m, ArH); δC (CDCl3, 75 MHz) 0.16 mmol) and toluene 4-sulfonylhydrazine (0.35 g,
14.4, 19.1, 21.9, 39.3, 40.6, 70.2, 71.1, 75.9, 127.8, 127.9, 128.7, 1.90 mmol) in DME (4 mL) with heating under reflux for 16 h,
135.7 and 139.1; m/z (CI) 266 (M+ + 18, 100%), 216 (36), 158 after chromatography (3 : 1, light petroleum–ether), afforded
(98) and 123 (38).
the title compound 24 as a colourless oil (28 mg, 48%), Rf = 0.3
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(3 : 1, light petroleum–ether) (Found: M+ + NH4, 451.2237. CHCl3) (Found: M+ + NH4, 490.2597. C30H36NO5 requires M,
C26H31N2O5 requires M, 451.2233); νmax/cm−1 2963, 2928, 490.2593); νmax/cm−1 3032, 2927, 2853, 1746, 1453, 1371, 1231,
2864, 1724, 1606, 1528, 1346, 1271, 1101 and 720; δH (CDCl3, 1173, 1084 and 1057; δH (CDCl3, 300 MHz) 0.87 (3 H, d, J 7,
300 MHz) 1.22 (3 H, d, J 6, 6-H3), 1.30–1.75 (4 H, m, 3-H2 and 5-CH3), 2.19 (3 H, s, CH3), 2.24 (1 H, m, 5-H), 2.46 (2 H, m,
4-H2), 1.98 and 2.13 (each 1 H, m, 2-H), 3.54 (1 H, m, 5-H), 2-H2), 3.18 (2 H, m, 6-H2), 3.47 (2 H, s, OCH2Ph), 5.08 (1 H, dt,
4.43 and 4.60 (each 1 H, d, J 12, OHCHPh), 6.04 (1 H, t, J 6, J 16 and 7, 3-H), 5.29 (1 H, dd, J 16 and 7, 4-H), 5.76 (1 H, t,
1-H), 7.38 (10 H, m, ArH) and 8.30 (4 H, m, ArH); δC (CDCl3, J 7, 1-H), 6.01 (1 H, s, 2′-H), 7.35 (13 H, m, ArH) and 7.51 (2 H,
75 MHz) 19.9, 21.9, 30.6, 36.6, 70.6, 74.7, 78.2, 123.8, 126.8, m, ArH); m/z (CI) 490 (M+ + 18, 4%), 174 (12), 157 (16) and
127.7, 127.9, 128.5, 128.6, 128.9, 131.0, 136.1, 139.2, 140.3 and 91 (100).
164.3; m/z (CI) 451 (M+ + 18, 6%), 284 (14), 267 (19), 175 (16),
(2E,4S)-5-Benzyloxy-1-bromo-2,4-dimethylpent-2-ene 30. Tri-
157 (16), 99 (68) and 59 (100).
phenylphosphine (3.3 g, 12.74 mmol) was added at room
(4R,2E)-5-Benzyloxy-1-bromo-4-methylpent-2-ene 26. Triphenyl- temperature in three portions over 30 min to a solution of (S)-
phosphine (0.42 g, 1.62 mmol) was added at room temperature alcohol (S)-29 (1.7 g, 7.72 mmol) and carbon tetrabromide
in three portions over 30 min to the (R)-alcohol 25 (0.20 g, (3.3 g, 10.04 mmol) in DCM (50 mL). The reaction mixture was
0.98 mmol) and carbon tetrabromide (0.42 g, 1.27 mmol) in stirred at this temperature for 2 h then concentrated under
DCM (12 mL). The mixture was stirred for 2 h then concen- reduced pressure. Chromatography of the residue (15 : 1, light
trated under reduced pressure. Chromatography of the residue petroleum–ether) gave the title compound (S)-30 as a colourless
(15 : 1, light petroleum–ether) gave the title compound 26 as a oil (2.0 g, 90%), Rf = 0.8 (2 : 1, light petroleum–ether), [α]2D0 +11
colourless oil (242 mg, 92%), Rf = 0.25 (15 : 1, light petroleum– (c 1.1, CHCl3) (Found: M+ + NH4, 300.0959. C14H23ON79Br
ether), [α]2D0 +11.7 (c 2.5, CHCl3) (Found: M+, 268.0460. requires M, 300.0958); νmax/cm−1 2959, 2927, 2854, 1599, 1453,
C13H17O79Br requires M, 268.0463); νmax/cm−1 3030, 2962, 1365, 1202, 1094, 1027 and 736; δH (CDCl3, 300 MHz) 1.04
2855, 1658, 1453, 1361, 1204, 1095, 967 and 736; δH (CDCl3, (3 H, d, J 7, 4-CH3), 1.83 (3 H, s, 2-CH3), 2.75 (1 H, m, 4-H),
300 MHz) 1.10 (3 H, d, J 6, 4-CH3), 2.60 (1 H, m, 4-H), 3.38 and 3.35 (2 H, m, 5-H2), 4.01 (2 H, s, 1-H2), 4.55 (2 H, s, OCH2Ph),
3.42 (each 1 H, dd, J 6 and 4, 5-H), 4.01 (2 H, m, 1-H2), 4.57 5.48 (1 H, d, J 9, 3-H) and 7.34 (5 H, m, ArH); δC (CDCl3,
(2 H, s, OCH2Ph), 5.80 (2 H, m, 2-H and 3-H) and 7.38 (5 H, m, 300 MHz) 15.2, 17.4, 33.8, 41.9, 73.2, 75.0, 127.8, 128.6, 132.7,
ArH); δC (CDCl3, 75 MHz) 16.9, 33.7, 36.8, 73.3, 75.0, 126.4, 134.3 and 138.8; m/z (CI) 302, 300 (M+ + 18, 72%), 205 (70), 130
127.8, 128.7, 138.8 and 138.9; m/z (CI) 288, 286 (M+ + 18, (48), 108 (94) and 82 (100).
100%).
Standard procedure for the preparation of O-acetyl mande- 15.1 (c 1.8, CHCl3), was prepared from the (R)-alcohol (R)-29.
lates from O-acetylmandelyl chlorides: (3E,1R,5R)-6-benzyloxy- (3E,1RS,5RS)-6-Benzyloxy-3,5-dimethyl-1-phenylhex-3-en-1-ol
Following this procedure, the (R)-enantiomer (R)-30, [α]2D0-
5-methyl-1-phenylhex-3-en-1-yl (2R)-2-acetoxy-2-phenylacetate 31a. Following the standard procedure, zinc powder (30 mg,
27. Pyridine (0.27 mL, 3.9 mmol) and DMAP (cat.) were added 0.46 mmol), bismuth(III) iodide (234 mg, 0.4 mmol) in THF
to the alcohol 5a (100 mg, 0.34 mmol) in DCM (0.9 mL) before (1.65 mL), the racemic bromide 30 (75 mg, 0.26 mmol) and
cooling to 0 °C. A solution of (R)-O-acetylmandelyl chloride benzaldehyde (27 μL, 0.26 mmol), after chromatography
(212 mg, 1.01 mmol) in DCM (0.9 mL) was added dropwise (10 : 1, light petroleum–ether) gave the title compound 31a
before warming the mixture to room temperature and stirring (53 mg, 65%) as a colourless oil containing ca. 5% of its
for 2 h. Ether (2 mL) and saturated aqueous ammonium chlor- 1-epimer 32a (1H NMR), Rf = 0.25 (3 : 1, light petroleum–ether)
ide (2 mL) were added and the aqueous phase extracted with (Found: M+
+ NH4, 328.2273. C21H30O2N requires M,
ether (3 × 5 mL). The organic extracts were washed with brine 328.2271); νmax/cm−1 3431, 3063, 3030, 2961, 2868, 1604, 1453,
(15 mL), dried (MgSO4) and concentrated under reduced 1375, 1089 and 750; δH (300 MHz, CDCl3) major isomer 31a
pressure. Chromatography (6 : 1, light petroleum–ether) of the 0.98 (3 H, d, J 7, 5-CH3), 1.77 (3 H, d, J 1, 3-CH3), 2.33 (1 H, dd,
residue gave the title compound 27 as a colourless oil (95 mg, J 13 and 9, 2-H), 2.44 (1 H, dd, J 13 and 4, 2-H′), 2.82 (1 H, m,
60%), Rf = 0.4 (3 : 1, light petroleum–ether), [α]2D0 −15.3 (c 2.2, 5-H), 3.30 (1 H, dd, J 9 and 8, 6-H), 3.34 (1 H, dd, J 9 and 6,
CHCl3) (Found: M+ + NH4, 490.2599. C30H36NO5 requires M, 6-H′), 4.55 and 4.59 (each 1 H, d, J 12, OHCHPh), 4.77 (1 H, dd,
490.2593); νmax/cm−1 3032, 2926, 2853, 1746, 1454, 1371, 1231, J 10 and 4, 1-H), 5.13 (1 H, dd, J 9 and 1, 4-H) and 7.39 (10 H,
1173, 1084 and 1057; δH (CDCl3, 300 MHz) 1.01 (3 H, d, J 7, m, ArH); minor epimer 32a 1.04 (3 H, d J 7, 5-CH3); δC
5-CH3), 2.21 (3 H, s, CH3), 2.40–2.70 (3 H, m, 2-H2 and 5-H), (75 MHz, CDCl3) 16.6, 17.5, 33.5, 51.0, 71.0, 73.3, 75.4, 126.1,
3.30 (2 H, m, 6-H2), 3.53 (2 H, s, OCH2Ph), 5.42 (2 H, m, 3-H 127.5, 127.8, 127.9, 128.6, 128.6, 132.4, 133.1, 138.7 and 144.4;
and 4-H), 5.77 (1 H, t, J 7, 1-H), 6.04 (1 H, s, 2′-H), 6.99 (2 H, m/z (CI) 328 (M+ + 18, 59%), 310 (M+, 71), 293 (84), 275 (14)
m, ArH), 7.20 (3 H, m, ArH) and 7.38 (10 H, m, ArH); m/z (CI) and 99 (100). A less polar fraction, Rf = 0.28 (3 : 1, light pet-
490 (M+ + 18, 6%), 174 (18), 157 (24) and 91 (100).
(3E,1R,5R)-6-Benzyloxy-5-methyl-1-phenylhex-3-en-1-yl (2S)- less oil.
roleum–ether), was the (Z)-isomer 33a (8 mg, 10%), a colour-
2-acetoxy-2-phenylacetate 28. Following the standard pro-
Using the (R)-bromide (R)-30, the (1R,5R)-enantiomer of the
cedure, alcohol 5a (100 mg, 0.34 mmol) and (S)-acetylmandelyl title compound 31a was obtained, [α]2D0 +48 (c 0.7, CHCl3)
chloride gave the title compound 28 as a colourless oil (61 mg, (Found: M+
+
NH4, 328.2273. C21H30O2N requires M,
39%), Rf = 0.4 (3 : 1, light petroleum ether), [α]2D0 +50.2 (c 1.5, 328.2271). Using the (S)-bromide (S)-30, the (1S,5S)-
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enantiomer of the title compound 31a was obtained, [α]2D0 −50 dicyclohexylcarbodiimide (25.1 mg, 0.12 mmol in DCM
(c 0.8, CHCl3) (Found: M+ + NH4 − H2O, 310.2162. C21H28ON (0.5 mL)) at 0 °C. During the addition, a white precipitate was
requires M, 310.2165).
observed. The reaction mixture was allowed to warm to room
(3E,1SR,5RS)-6-Benzyloxy-3,5-dimethyl-1-phenylhex-3-en-1-yl
temperature, stirred for 16 h, then diluted with ether (2 mL)
4-nitrobenzoate 34. The racemic alcohol 31a (90 mg, and filtered through celite. The resulting solution was washed
0.29 mmol), triphenylphosphine (183 mg, 0.70 mmol) and with aqueous hydrogen chloride (0.5 N, 2 × 5 mL), saturated
4-nitrobenzoic acid (58 mg, 0.35 mmol) were dissolved in THF aqueous sodium hydrogen carbonate (2 × 5 mL) and brine
at 0 °C. Di-isopropyl azodicarboxylate (0.14 mL, 0.7 mmol) was (5 mL), then dried (MgSO4) and concentrated under reduced
added dropwise and, after 10 min, the mixture was allowed to pressure. Chromatography of the residue (10 : 1, light pet-
warm to room temperature for 30 min. After concentration roleum–ether) gave the title compound 35 as a colourless oil
under reduced pressure, chromatography of the residue (30 : 1 (31 mg, 78%), Rf
=
0.42 (4 : 1, light petroleum–ether),
18, 504.2750.
to 15 : 1, light petroleum–ether) gave the title compound 34 con- [α]2D0 −16.3 (c 0.5, CHCl3) (Found: M+
+
taining ca. 10% of its epimer (80 mg, 60%) as a pale yellow oil, C31H38O5N requires M, 504.2744); νmax/cm−1 3065, 3033, 2958,
Rf = 0.37 (2 : 1, light petroleum–ether) (Found: M+, 459.2049 2927, 2856, 1744, 1605, 1454, 1372, 1232, 1208, 1175, 1084,
C28H29O5N requires M, 459.2046); νmax/cm−1 3033, 2858, 1728, 1058, 738 and 698; δH (500 MHz, CDCl3) major isomer 35 0.76
1608, 1532, 1455, 1348, 1273, 1102, 720 and 699; δH (500 MHz, (3 H, d, J 7, 5-CH3), 1.54 (3 H, s, COCH3), 2.08 (3 H, d, J 1,
CDCl3) major epimer 34 0.65 (3 H, d, J 7, 5-CH3), 1.61 (3 H, s, 3-CH3), 2.29 (1 H, dd, J 14 and 7, 2-H), 2.47 (1 H, dd, J 14 and
3-CH3), 2.44 (1 H, dd, J 14 and 5, 2-H), 2.53 (1 H, m, 5-H), 2.66 8, 2-H′), 2.56 (1 H, m, 5-H), 3.07 (1 H, dd, J 9 and 7, 6-H), 3.17
(1 H, dd, J 14 and 9, 2-H′), 3.03 (1 H, dd, J 7 and 5, 6-H), 3.06 (1 H, dd, J 9 and 6, 6-H′), 4.38 and 4.42 (each 1 H, d, J 12,
(1 H, dd, J 9 and 6, 6-H′), 4.34 (2 H, s, OCH2Ph), 4.92 (1 H, d, OHCHPh), 4.77 (1 H, d, J 9, 4-H), 5.75 (1 H, t, J 7, 1-H), 5.90
J 9, 4-H), 6.06 (1 H, dd, J 9 and 5, 1-H), 7.18 (10 H, m, ArH) and (1 H, s, 2′-H), 6.84 (2 H, m, ArH), 7.05 (3 H, m, ArH) and 7.25
8.08 (4 H, m, ArH); minor 1-epimer 0.78 (3 H, d, J 7, 5-CH3) (10 H, m, ArH); δC (125 MHz, CDCl3) 17.2, 17.9, 21.1, 33.4,
and 4.90 (1 H, d, J 9, 4-H); δC (125 MHz, CDCl3) 17.0, 17.9, 46.8, 73.2, 74.8, 75.5, 76.8, 126.4, 127.8, 128.1, 128.4, 128.6,
33.5, 47.6, 73.4, 75.4, 76.1, 123.9, 126.8, 127.9, 128.6, 128.7, 128.7, 129.0, 129.6, 130.7, 132.2, 134.1, 139.2, 140.0, 168.3
128.9, 131.1, 132.8, 136.3, 139.0, 140.3, 150.8 and 164.2; minor and 170.5; m/z (CI) 504 (M+ + 18, 2%), 310 (19), 293 (14) and
1-epimer 47.5, 73.3 and 76.3 m/z (CI) 477 (M+ + 18, 3%), 310 99 (100).
(16), 293 (18), 155 (30) and 199 (100).
(3E,1R,5R)-6-Benzyloxy-3,5-dimethyl-1-phenylhex-3-en-1-yl (S)-
(3E,1SR,5RS)-6-Benzyloxy-3,5-dimethyl-1-phenylhex-3-en-1-ol 2-acetoxy-2-phenylacetate 36. Following the standard procedure
32a. The nitrobenzoate 34 (80 mg, 0.17 mmol) and sodium for the synthesis of O-acetyl mandelates from O-acetylmandelic
hydroxide in methanol (1%, 3 mL) were stirred for 2 h then acid, alcohol 31a (20 mg, 0.065 mmol) and (S)-O-acetylmande-
extracted with DCM (2 × 6 mL) and the extracts dried (Na2SO4). lic acid (19 mg, 0.098 mmol), after chromatography (10 : 1,
Chromatography of the residue (10 : 1, light petroleum–ether) light petroleum–ether), gave the title compound 36 as a colour-
gave the title compound 32a as a pale yellow oil (23 mg, 43%) less oil (24 mg, 75%), Rf = 0.42 (4 : 1, light petroleum–ether),
containing ca. 15% of the 1-epimer 31a (1H NMR), Rf = 0.28 [α]2D0 +32.4 (c 0.5, CHCl3) (Found: M+ + NH4, 504.2751.
(3 : 1, light petroleum–ether) (Found: M+ + NH4, 328.2273. C31H38O5N requires M, 504.2744); νmax/cm−1 3065, 3033, 2959,
C21H30O2N requires M, 328.2271); νmax/cm−1 3417, 3070, 2961, 2927, 2856, 1749, 1605, 1454, 1372, 1056, 738 and 698; δH
2925, 2863, 1604, 1454, 1370, 1201, 1090, 753 and 699; (500 MHz, CDCl3) 0.67 (3 H, d, J 7, 5-CH3), 1.35 (3 H, s,
δH (500 MHz, CDCl3) major epimer 32a 1.04 (3 H, d, J 7, COCH3), 2.07 (3 H, d, J 1, 3-CH3), 2.19 (1 H, dd, J 14 and 7,
5-CH3), 1.72 (3 H, d, J 1, 3-CH3), 2.15 (1 H, br. s, OH), 2.35 2-H), 2.36 (1 H, dd, J 14 and 8, 2-H′), 2.42 (1 H, m, 5-H), 2.94
(1 H, dd, J 14 and 9, 2-H), 2.44 (1 H, dd, J 14 and 4, 2-H′), 2.81 (1 H, dd, J 9 and 7, 6-H), 3.03 (1 H, dd, J 9 and 6, 6-H′), 4.34
(1 H, m, 5-H), 3.31 (1 H, dd, J 9 and 7, 6-H), 3.34 (1 H, dd, J 9 and 4.39 (each 1 H, d, J 12, OHCHPh), 4.63 (1 H, d, J 9, 4-H),
and 6, 6-H′), 4.53 and 4.55 (each 1 H, d, J 12, OHCHPh), 4.80 (1 5.73 (1 H, t, J 7, 1-H), 5.89 (1 H, s, 2′-H), 7.18 (13 H, m, ArH)
H, dd, J 9 and 4, 1-H), 5.15 (1 H, d, J 9, 4-H) and 7.35 (10 H, m, and 7.38 (2 H, m, ArH); δC (125 MHz, CDCl3) 17.0, 17.8, 21.1,
ArH); minor epimer 31a 0.98 (3 H, d, J 7, 5-CH3), 1.75 (3 H, d, 33.3, 46.5, 73.3, 74.8, 75.4, 126.8, 127.8, 127.9, 128.1, 128.4,
J 1, 3-CH3) and 4.75 (1 H, dd, J 9 and 4, 1-H); δC (175 MHz, 128.6, 128.7, 129.0, 129.6, 130.8, 131.9, 134.3, 139.1, 140.0,
CDCl3) 16.6, 17.5, 33.4, 51.0, 71.0, 73.3, 75.4, 126.1, 127.5, 168.5 and 170.4; m/z (CI) 504 (M+ + 18, 16%), 310 (25),
127.8, 127.9, 128.6, 128.7, 132.4, 133.0, 138.7 and 144.4; minor 293 (36), 171 (40) and 99 (100).
epimer 37 16.9, 18.2, 50.5 and 71.6; m/z (CI) 328 (M+ + 18,
(2E,6E,4RS,8RS)-9-Benzyloxy-6,8-dimethylnona-2,6-dien-4-ol
31b. Following the standard procedure, racemic bromide 30
10%), 310 (M+, 6), 293 (13) and 99 (100).
Standard procedure for the preparation of O-acetyl mande- (75 mg, 0.26 mmol) and (E)-but-2-enal (22 μL, 0.26 mmol),
lates from O-acetylmandelic acid: (3E,1R,5R)-6-benzyloxy-3,5- after chromatography (10 : 1, light petroleum–ether) gave the
dimethyl-1-phenylhex-3-en-1-yl
35. (R)-O-Acetylmandelic acid (24 mg, 0.12 mmol) and ca. 9% of its 4-epimer 32b (1H NMR), Rf = 0.25 (3 : 1, light pet-
4-dimethylaminopyridine (1 mg) were added to the alcohol roleum–ether) (Found: M+
NH4, 292.2266. C18H30O2N
31a (25 mg, 0.081 mmol, containing ca. 5% of its epimer 32a) requires M, 292.2271); νmax/cm−1 3429, 3030, 2960, 2927, 2855,
(R)-2-acetoxy-2-phenylacetate title compound 31b as a colourless oil (58 mg, 80%) containing
+
in DCM (0.5 mL) followed by
a
solution of N,N′- 1453, 1377, 1092, 966, 737 and 698; δH (300 MHz, CDCl3)
8492 | Org. Biomol. Chem., 2013, 11, 8476–8505
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major isomer 31b 1.00 (3 H, d, J 7, 8-CH3), 1.75 (6 H, m, 1-H3 4-epimer 32d (1H NMR), Rf = 0.25 (3 : 1, light petroleum–ether)
and 6-CH3), 2.15 (1 H, dd, J 13, 9, 5-H), 2.26 (1 H, dd, J 13, 6, (Found: M+ + H, 277.2155. C18H29O2 requires M, 277.2162);
5-H′), 2.80 (1 H, m, 8-H), 3.30 (2 H, m, 9-H2), 4.16 (1 H, m, νmax/cm−1 3443, 3031, 2956, 2929, 2870, 1454, 1367, 1093,
4-H), 4.50 and 4.56 (each 1 H, d, J 12, OHCHPh), 5.10 (1 H, d, 1026, 737 and 698; δH (500 MHz, CDCl3) major epimer 31d
J 9, 7-H), 5.50 (1 H, ddd, J 17, 7 and 3, 3-H), 5.75 (1 H, m, 2-H) 0.86 (3 H, t, J 6, 1-H3), 0.88 (3 H, d, J 7, 8-CH3), 1.25–1.45 (4 H,
and 7.35 (5 H, m, ArH); minor epimer 32b 1.04 (3 H, d, J 7, m, 2-H2 and 3-H2), 1.59 (3 H, d, J 1, 6-CH3), 1.90 (1 H, dd, J 13
8-CH3); δC (75 MHz, CDCl3) 16.7, 17.6, 18.0, 33.4, 48.7, 69.6, and 10, 5-H), 1.98 (1 H, br. s, OH), 2.11 (1 H, dd, J 13 and 3,
73.3, 75.5, 126.8, 127.8, 127.9, 128.6, 132.3, 132.6, 133.7 and 5-H′), 2.67 (1 H, m, 8-H), 3.15 (1 H, dd, J 9 and 8, 9-H), 3.22 (1
138.8; m/z (CI) 292 (M+ + 18, 7%), 274 (M+, 10), 257 (20), 149 H, dd, J 9 and 7, 9-H′), 3.55 (1 H, m, 4-H), 4.41 and 4.44 (each
(10) and 99 (100). A less polar fraction was (2E,6Z,4SR,8RS)-9- 1 H, d, J 12, OHCHPh), 4.98 (1 H, d, J 9, 7-H) and 7.35 (5 H, m,
benzyloxy-6,8-dimethylnona-2,6-dien-4-ol 33b as a colourless ArH); minor epimer 32d 1.02 (3 H, d,
oil (10 mg, 7%), Rf = 0.28 (3 : 1, light petroleum–ether) (Found: δC (1255 MHz, CDCl3) 14.2, 16.4, 17.3, 19.0, 33.1, 39.1, 48.2,
M+ + NH4, 292.2266. C18H30O2N requires M, 292.2271); νmax
67.7, 73.0, 75.2, 127.5, 127.6, 128.4, 131.9, 132.6 and 138.5; m/z
J 7, 8-CH3);
/
cm−1 3439, 3031, 2960, 2927, 2855, 1454, 1376, 1090, 966, 737 (ES) 299 (M+ + 23, 100%), 294 (63), 277 (M+ + 1, 8) and 205
and 698; δH (300 MHz, CDCl3) 0.88 (3 H, d, J 7, 8-CH3), 1.74 (3 (10). A less polar fraction was the (Z)-isomer 33d isolated as a
H, d, J 7, 1-H3), 1.81 (3 H, s, 6-CH3), 2.04 (1 H, dd, J 13 and 2, colourless oil (4 mg, 5%), Rf = 0.28 (3 : 1, light petroleum–
5-H), 2.55 (1 H, dd, J 13 and 6, 5-H′), 2.82 (1 H, m, 8-H), 3.12 (1 ether); νmax/cm−1 3444, 3031, 2951, 2921, 2872, 1604, 1454,
H, t, J 9, 9-H), 3.38 (1 H, dd, J 9 and 6, 9-H′), 3.43 (1 H, br. s, 1368, 1094 and 1028; δH (300 MHz, CDCl3) 0.88 (3 H, d J 7,
OH), 4.20 (1 H, m, 4-H), 4.53 and 4.59 (1 H, d, J 12, OHCHPh), 8-CH3), 0.98 (3 H, t, J 7, 1-H3), 1.30–1.60 (4 H, m, 2-H2 and
5.11 (1 H, d, J 9, 7-H), 5.68 (1 H, ddd, J 17, 7 and 3, 3-H), 5.75 3-H2), 1.78 (3 H, d, J 1, 6-CH3), 1.99 (1 H, dd, J 14 and 2, 5-H),
(1 H, m, 2-H) and 7.36 (5 H, m, ArH); δC (75 MHz, CDCl3) 17.7, 2.45 (1 H, dd, J 14 and 10, 5-H′), 2.86 (1 H, m, 8-H), 3.16 (1 H,
18.0, 24.0, 33.2, 41.1, 70.0, 73.2, 75.1, 126.0, 127.9, 128.2, t, J 8, 9-H), 3.37 (1 H, dd, J 8 and 5, 9-H′), 3.75 (1 H, m, 4-H),
128.6, 132.4, 132.6, 134.6 and 138.3; m/z (CI) 292 (M+ + 18, 4.52 and 4.59 (each 1 H, d, J 12, OHCHPh), 5.08 (1 H, d, J 9,
5%), 274 (M+, 5), 257 (36), 151 (34) and 99 (100).
7-H) and 7.35 (5 H, m, ArH); δC (75 MHz, CDCl3) 14.5, 17.7,
Following the standard procedure, the (S)-bromide 30 19.3, 24.1, 33.2, 40.4, 40.7, 68.8, 73.3, 75.2, 127.8, 128.1, 128.6,
(75 mg, 0.265 mmol) and but-2-enal (22 μL, 0.265 mmol) 132.3.
afforded the (4S,8S)-enantiomer of the title compound 31b as
Following the standard procedure, (S)-bromide 30 (75 mg,
a colourless oil (57 mg, 78%) containing ca. 9% of its 4-epimer 0.265 mmol) and butanal (24 μL, 0.265 mmol) gave the
32b, Rf = 0.25 (3 : 1, light petroleum–ether), [α]2D0 −5 (c 0.8, (4R,8S)-enantiomer of the title compound 31d as a colourless
CHCl3) (Found: M+, 274.1931. C18H26O2 requires M, 274.1927).
oil (57 mg, 78%) containing ca. 7% of its 4-epimer 32d, Rf =
(5E,3R,7R)-8-Benzyloxy-2,5,7-trimethyloct-5-en-3-ol 31c. Fol- 0.25 (3 : 1, light petroleum–ether), [α]2D0 +9 (c 1.1, CHCl3)
lowing the standard procedure, the (R)-bromide 30 (75 mg, (Found: M+ + H, 277.2163. C18H29O2 requires M, 277.2162).
0.26 mmol) and 2-methylpropanal (24 μL, 0.26 mmol), after
(3E,1RS,5RS)-6-Benzyloxy-3,5-dimethyl-1-(4-nitrophenyl)hex-
chromatography (10 : 1, light petroleum–ether), gave the title 3-en-1-ol 31e. Following the standard procedure, racemic
compound 31c as a colourless oil (55 mg, 75%) containing bromide 30 (75 mg, 0.26 mmol) and 4-nitrobenzaldehyde
ca. 10% of its 3-epimer 32c (1H NMR), Rf = 0.25 (3 : 1, light (40 mg, 0.26 mmol), after chromatography (10 : 1, light pet-
petroleum–ether) (Found: M+ + NH4, 294.2428. C18H32O2N roleum–ether), gave the title compound 31e as a colourless oil
requires M, 294.2428); νmax/cm−1 3487, 2961, 2929, 2871, 1454, (59 mg, 63%) containing ca. 5% of its 1-epimer 32e (1H NMR),
1365, 1092, 993, 735 and 697; δH (500 MHz, CDCl3) major Rf = 0.25 (3 : 1, light petroleum–ether) (Found: M+ + NH4,
isomer 31c 0.85 and 0.89 (each 3 H, d, J 7, 1-H3 or 2-CH3), 0.95 373.2125. C21H29O4N2 requires M, 373.2122); νmax/cm−1 3426,
(3 H, d, J 7, 7-CH3), 1.74 (3 H, d, J 1, 5-CH3), 1.81 (1 H, m, 2-H), 3066, 2928, 2871, 1605, 1520, 1455, 1348, 1198, 1072, 854, 750
2.01 (1 H, dd, J 13 and 10, 4-H), 2.43 (1 H, dd, J 13 and 3, 4-H′), and 699; δH (300 MHz, CDCl3) major epimer 31e 0.98 (3 H, d,
2.84 (1 H, m, 7-H), 3.16 (1 H, dd, J 9 and 8, 8-H), 3.40 (1 H, dd, J 7, 5-CH3), 1.79 (3 H, s, 3-CH3), 2.22 (1 H, dd, J 14 and 10,
J 9 and 7, 8-H′), 3.43 (1 H, m, 3-H), 4.55 and 4.58 (each 1 H, d, 2-H), 2.42 (1 H, dd, J 14 and 4, 2-H′), 2.85 (1 H, m, 5-H), 2.90
J 12, OHCHPh), 5.16 (1 H, dd, J 9 and 1, 6-H) and 7.35 (5 H, m, (1 H, br. s, OH), 3.26 (1 H, t, J 9, 6-H), 3.38 (1 H, dd, J 9 and 6,
ArH); minor epimer 32c 0.98 (3 H, d, J 7, 7-CH3); δC (125 MHz, 6-H′), 4.50 and 4.54 (each 1 H, d, J 12, OHCHPh), 4.80 (1 H, dd,
CDCl3) 16.3, 17.3, 18.0, 18.6, 33.2, 33.3, 44.8, 72.4, 73.0, 75.2, J 10 and 6, 1-H), 5.17 (1 H, d, J 9, 4-H), 7.36 (5 H, m, ArH) and
127.5, 127.6, 128.3, 131.9, 132.9 and 138.5; m/z (CI) 294 (M+ + 7.53 and 8.18 (each 2 H, d, J 9, ArH); minor epimer 32e 1.01 (3
18, 21%), 277 (M+ + 1, 31), 205 (100), 108 (44), 99 (37) and H, d, J 7, 5-CH3); δC (75 MHz, CDCl3) 16.5, 17.2, 33.5, 51.1,
91 (56). A less polar fraction was the (Z)-isomer 33c (5 mg, 6%) 69.9, 73.3, 75.3, 123.8, 126.7, 127.9, 128.6, 131.5, 134.3, 138.5,
as a colourless oil.
147.3 and 152.0; m/z (CI) 373 (M+ + 18, 74%), 356 (M+ + 1), 12),
(6E,4S,8R)-9-Benzyloxy-6,8-dimethylnon-6-en-4-ol 31d. Fol- 338 (12), 308 (21), 205 (25), 108 (31) and 99 (100). A less polar
lowing the standard procedure, (R)-bromide 30 (75 mg, fraction was (3Z,1SR,5RS)-6-benzyloxy-3,5-dimethyl-1-(4-nitro-
0.26 mmol) and butanal (24 μL, 0.26 mmol), after chromato- phenyl)hex-3-en-1-ol 33e as a colourless oil (9 mg, 10%), Rf =
graphy (10 : 1, light petroleum–ether), gave the title compound 0.28 (3 : 1, light petroleum–ether) (Found: M+ + NH4, 373.2125.
31d as a colourless oil (57 mg, 78%) containing <5% of its C21H29O4N2 requires M, 373.2122); νmax/cm−1 3411, 2960,
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2873, 1602, 1520, 1455, 1347, 1074, 856, 749 and 698; δH 1178, 1091, 1056 and 838; δH (300 MHz, CDCl3) 0.08 (6 H, s,
(300 MHz, CDCl3) 0.96 (3 H, d, J 7, 5-CH3), 1.78 (3 H, s, 3-CH3), 2 × SiCH3), 0.94 (12 H, m, SiC(CH3)3 and 6-CH3), 1.52 (3 H, d,
2.17 (1 H, dd, J 14 and 3, 2-H), 2.63 (1 H, dd, J 14 and 11, 2-H′), J 1, 4-CH3), 2.10 (1 H, dd, J 10 and 7, 3-H), 2.22 (3 H, s, CH3),
2.83 (1 H, m, 5-H), 3.19 (1 H, dd, J 10 and 8, 6-H), 3.42 (1 H, 2.32 (1 H, dd, J 10 and 6, 3-H′), 2.62 (1 H, m, 6-H), 3.12 (1 H,
dd, J 8 and 4, 6-H′), 4.58 (2 H, s, OCH2Ph), 4.91 (1 H, dd, J 11 dd, J 11 and 7, 7-H), 3.23 (1 H, dd, J 11 and 6, 7-H′), 3.68 (2 H,
and 2, 1-H), 5.18 (1 H, d, J 10, 4-H), 7.36 (5 H, m, ArH) and d, J 5, 1-H2), 4.50 (2 H, s, OCH2Ph), 5.02 (2 H, m, 2-H and 5-H),
7.44 and 8.19 (each 2 H, d, J 9, ArH); δC (75 MHz, CDCl3) 17.5, 5.96 (1 H, s, 2′-H) and 7.34 (10 H, m, ArH); m/z (CI) 572 (M+ +
23.6, 33.3, 43.4, 70.5, 73.5, 75.2, 123.8, 126.5, 128.2, 128.4, 18, 6%), 272 (34), 229 (36) and 123 (100).
128.7, 131.8, 133.8, 137.7, 147.2 and 153.6; m/z (CI) 373 (M+ +
18, 21%), 356 (M+ + 1, 53), 338 (14), 205 (30), 122 (30), 108 (51) hept-4-en-2-yl (2S)-2-acetoxy-2-phenylacetate 38. Following the
(4E,2S,6S)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-4,6-dimethyl-
and 99 (100).
standard procedure, alcohol 31f (20 mg, 0.053 mmol) and
(4E,2S,6S)-
and
(4Z,2R,6S)-7-(Benzyloxy)-1-tert-butyldi- (S)-O-acetylmandelyl chloride gave the title compound 38 as a
methylsilyloxy-4,6-dimethylhept-4-en-2-ols 31f and 33f. Follow- colourless oil (22 mg, 76%), Rf = 0.3 (6 : 1, light petroleum–
ing the standard procedure, the (S)-bromide 30 (75 mg, ether), [α]2D0 +65 (c 1.8, CHCl3) (Found: M+ + NH4, 572.3403.
0.265 mmol) and tert-butyldimethylsilyloxyethanal (56 μL, C32H50O6NSi requires M, 572.3402); νmax/cm−1 2955, 2929,
0.265 mmol), after chromatography, afforded the title com- 2857, 1746, 1454, 1372, 1247, 1178, 1093, 1056 and 838; δH
pound 33f as a colourless oil (20 mg, 20%), Rf = 0.4 (3 : 1, light (300 MHz, CDCl3) major isomer −0.08 (6 H, s, 2 × SiCH3), 0.83
petroleum–ether), [α]2D0 +11 (c 0.8, CHCl3) (Found: M+ + H, [9 H, s, SiC(CH3)3], 1.02 (3 H, d, J 7, 6-CH3), 1.72 (3 H, d, J 1,
379.2660. C22H39O3Si requires M, 379.2663); νmax/cm−1 3443, 4-CH3), 2.22 (3 H, s, CH3), 2.35 (2 H, m, 3-H2), 2.74 (1 H, m,
2954, 2928, 2857, 1586, 1456, 1362, 1254, 1118 and 837; δH 6-H), 3.25 (1 H, dd, J 11 and 7, 7-H), 3.37 (1 H, dd, J 11 and 6,
(300 MHz, CDCl3) 0.11 (6 H, s, 2 × SiCH3), 0.92 (3 H, d, J 7, 7-H′), 3.53 (2 H, d, J 5, 1-H2), 4.54 and 4.56 (each 1 H, d, J 12,
6-CH3), 0.95 [9 H, s, SiC(CH3)3], 1.80 (3 H, d, J 1, 4-CH3), 2.21 OHCHPh), 5.03 (2 H, m, 2-H and 5-H), 5.94 (1 H, s, 2′-H) and
(1 H, dd, J 13 and 4, 3-H), 2.39 (1 H, dd, J 13 and 9, 3-H′), 2.81 7.34 (10 H, m, ArH); m/z (CI) 572 (M+ + 18, 8%), 271 (100) and
(1 H, m, 6-H), 3.19 (1 H, t, J 9, 7-H), 3.33 (1 H, dd, J 9 and 5, 123 (70).
7-H′), 3.54 (1 H, dd, J 10 and 6, 1-H), 3.64 (1 H, dd, 10 and 5,
(4Z,2R,6S)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-4,6-dimethyl-
1-H′), 3.78 (1 H, m, 2-H), 4.54 (2 H, s, OCH2Ph), 5.08 (1 H, d, hept-4-en-2-yl (2R)-2-acetoxy-2-phenylacetate 39. Following the
J 10, 5-H) and 7.34 (5 H, m, ArH); δC (75 MHz, CDCl3) −5.0, standard procedure, alcohol 33f (20 mg, 0.053 mmol) and (R)-
17.8, 18.6, 24.1, 26.2, 33.2, 36.8, 67.5, 70.0, 73.2, 75.2, 127.9, O-acetylmandelyl chloride gave the title compound 39 as a col-
128.0, 128.6, 131.9, 132.7 and 138.4; m/z (CI) 396 (M+ + 18, ourless oil (19 mg, 72%), Rf = 0.5 (3 : 1, light petroleum–ether),
40%), 379 (M+ + 1, 100) and 205 (72). Further chromatography [α]D20 −48 (c 0.6, CHCl3) (Found: M+
+ NH4, 572.3392.
afforded the title compound 31f as a colourless oil (50 mg, C32H50O6NSi requires M, 572.3402); νmax/cm−1 2956, 2928,
50%) containing ca. 5% of its 2-epimer 32f (1H NMR), Rf = 0.35 2857, 1746, 1595, 1455, 1372, 1231, 1120, 1090 and 838; δH
(3 : 1, light petroleum–ether), [α]2D0 +11 (c 1.2, CHCl3) (Found: (300 MHz, CDCl3) −0.08 (6 H, s, 2 × SiCH3), 0.80 [9 H, s, SiC-
M+ + H, 379.2663. C22H39O3Si requires M, 379.2663); νmax
/
(CH3)3], 1.02 (3 H, d, J 7, 6-CH3), 1.77 (3 H, s, 4-CH3), 2.22 (3 H,
cm−1 3468, 2956, 2857, 1455, 1362, 1254, 1121 and 838; s, CH3), 2.38 (1 H, dd, J 11 and 7, 3-H), 2.48 (1 H, dd, J 11 and
δH (300 MHz, CDCl3) major isomer 31f 0.01 (6 H, s, 2 × SiCH3), 7, 3-H′), 2.80 (1 H, m, 6-H), 3.20–3.60 (4 H, m, 1-H2 and 7-H2),
0.94 [9 H, s, SiC(CH3)3], 1.01 (3 H, d, J 7, 6-CH3), 1.74 (3 H, d, 4.54 (2 H, s, OCH2Ph), 5.08 (2 H, m, 2-H and 5-H), 5.95 (1 H, s,
J 1, 4-CH3), 2.15 (1 H, dd, J 13 and 8, 3-H), 2.23 (1 H, dd, J 13 2′-H) and 7.34 (10 H, m, ArH); m/z (CI) 572 (M+ + 18, 4%),
and 6, 3-H′), 2.45 (1 H, br. s, OH), 2.78 (1 H, m, 6-H), 3.31 (2 H, 271 (56), 123 (96) and 108 (100).
m, 7-H2), 3.52 (1 H, dd, J 10 and 6, 1-H), 3.62 (1 H, dd, J 10 and
(4Z,2R,6S)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-4,6-dimethyl-
4, 1-H′), 3.78 (1 H, m, 2-H), 4.52 and 4.57 (each 1 H, d, J 12, hept-4-en-2-yl (2S)-2-acetoxy-2-phenylacetate 40. Following the
OHCHPh), 5.08 (1 H, dd, J 9 and 1, 5-H) and 7.34 (5 H, m, standard procedure, alcohol 33f (20 mg, 0.053 mmol) and (S)-
ArH); minor 2-epimer 32f 1.80 (3 H, d, J 1, 4-CH3); δC (75 MHz, O-acetylmandelyl chloride gave the title compound 40 as a col-
CDCl3) −5.1, 16.8, 17.9, 18.6, 26.2, 33.4, 44.0, 67.0, 69.8, 73.2, ourless oil (23 mg, 80%), Rf = 0.5 (3 : 1, light petroleum–ether),
75.5, 127.7, 127.8, 128.6, 131.3, 132.5 and 138.9; m/z (CI) 396 [α]2D0 +67 (c 0.6, CHCl3) (Found: M+
+
NH4, 572.3394.
(M+ + 18, 12%), 379 (M+ + 1, 14), 205 (100) and 123 (50).
C32H50O6NSi requires M, 572.3402); νmax/cm−1 2955, 2928,
(4E,2S,6S)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-4,6-dimethyl- 2857, 1747, 1456, 1372, 1231, 1097, 1056 and 838; δH
hept-4-en-2-yl (2R)-2-acetoxy-2-phenylacetate 37. Following the (300 MHz, CDCl3) 0.10 (6 H, s, 2 × SiCH3), 0.93 [9 H, s, SiC-
standard procedure, alcohol 31f (20 mg, 0.053 mmol) in DCM (CH3)3], 0.96 (3 H, d, 6-CH3), 1.52 (3 H, s, 4-CH3), 2.22 (3 H, s,
(0.3 mL), pyridine (0.042 mL, 0.614 mmol), DMAP (cat.) and CH3), 2.38 (1 H, m, 6-H), 2.75 (2 H, m, 3-H2), 3.10–3.60 (4 H,
(R)-O-acetylmandelyl chloride (33 mg, 0.159 mmol) in DCM m, 1-H2 and 7-H2), 4.48 (2 H, s, OCH2Ph), 5.04 (2 H, m, 2-H
(0.3 mL), after chromatography (6 : 1, light petroleum–ether), and 5-H), 5.93 (1 H, s, 2′-H) and 7.34 (10 H, m, ArH); δC
gave the title compound 37 as a colourless oil (18 mg, 62%), (75 MHz, CDCl3) −5.1, 17.9, 18.1, 18.5, 21.0, 23.9, 26.1, 32.6,
Rf = 0.3 (6 : 1, light petroleum–ether), [α]2D0 −60 (c 0.9, CHCl3) 33.0, 63.6, 73.1, 74.9, 75.4, 127.7, 127.8, 128.1, 128.6, 129.0,
(Found: M+ + H, 555.3141. C32H47O6Si requires M, 555.3136); 129.0, 131.1, 131.5, 134.2, 139.0, 168.8 and 170.4; m/z (CI) 572
νmax/cm−1 2954, 2928, 2856, 1746, 1587, 1454, 1372, 1252, (M+ + 18, 4%), 271 (54), 123 (94) and 108 (100).
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Paper
(4S,2E)-4-Benzyloxy-1-bromopent-2-ene
42. Triphenylpho- (1.5 mL), the bromide 48 (53 mg, 0.28 mmol) in THF (0.5 mL)
sphine (1.76 g, 6.78 mmol) was added at room temperature in and benzaldehyde (29 μL, 0.28 mmol), after chromatography
three portions over 30 min to the alcohol 41 (0.79 g, (4 : 1, light petroleum–ether), gave the title compound 49 as a
4.11 mmol) and carbon tetrabromide (1.76 g, 5.34 mmol) in colourless oil (69 mg, 69%) containing ca. 26% of its 1-epimer
DCM (50 mL) and the mixture stirred at this temperature for 50.
2 h. After concentration under reduced pressure, chromato-
graphy (15 : 1, light petroleum–ether) of the residue gave the phenylacetate 51. Following the standard procedure, the
title compound 42 as a colourless oil (936 mg, 90%), Rf alcohol 49 (40 mg, 0.18 mmol) in DCM (0.5 mL), pyridine
0.3 (15 : 1, light petroleum–ether), [α]2D0 −27.6 (c 4.6, CHCl3) (0.15 mL, 2.1 mmol), DMAP (cat.) and (R)-O-acetylmandelyl
(3E,1S,6R)-6-Methoxy-1-phenylhept-3-en-1-yl(2R)-2-acetoxy-2-
=
(Found: M+
−
CH3, 239.0068. C11H12O79Br requires M, chloride (112 mg, 0.53 mmol) in DCM (0.9 mL), after
239.0072); νmax/cm−1 2975, 2928, 2863, 1601, 1453, 1370, 1205, chromatography (6 : 1, light petroleum–ether), afforded the
1101, 1073 and 968; δH (300 MHz, CDCl3) 1.32 (3 H, d, J 6, title compound 51 as a colourless oil (48 mg, 59%), Rf = 0.3
5-H3), 4.00 (3 H, m, 4-H and 1-H2), 4.44 and 4.61 (each 1 H, d, (6 : 1, light petroleum–ether), [α]2D0 −38 (c 1.1, CHCl3) (Found:
J 12, OHCHPh), 5.77 (1 H, dd, J 15 and 7, 3-H), 5.93 (1 H, dt, M+ + NH4, 414.2272. C24H32NO5 requires M, 414.2280); νmax
/
J 15 and 7, 2-H) and 7.36 (5 H, m, ArH); δC (75 MHz, CDCl3) cm−1 2971, 2929, 1747, 1455, 1373, 1231, 1175, 1085, 1056, 969
21.5, 32.3, 70.4, 74.7, 127.9, 128.3, 128.7, 137.3, 138.7 and and 743; δH (300 MHz, CDCl3) major isomer 1.00 (3 H, d, J 6,
138.8; m/z (CI) 274, 272 (M+ + 18, 1%), 239 (M+ − 15, 3), 7-H3), 1.87 (1 H, m, 5-H), 2.06 (1 H, m, 5-H′), 2.18 (3 H, s,
108 (14) and 91 (100).
CH3), 2.30–2.60 (2 H, m, 2-H2), 3.16 (1 H, m, 6-H), 3.27 (3 H, s,
(5R,2E)-1-Bromo-5-methoxyhex-2-ene
48. Triphenylpho- OCH3), 5.05 and 5.26 (each 1 H, dt, J 15, 7, 3-H or 4-H), 5.76
sphine (130 mg, 0.51 mmol) was added at room temperature (1 H, t, J 7, 1-H), 6.00 (1 H, s, 2′-H), 7.19 (1 H, m, ArH), 7.36
in three portions over 30 min to the alcohol 47 (40 mg, (7 H, m, ArH) and 7.51 (2 H, m, ArH); m/z (CI) 414 (M+ + 18,
0.31 mmol) and carbon tetrabromide (130 mg, 0.40 mmol) in 48%), 220 (58) and 203 (100).
DCM (4 mL) and the reaction mixture stirred at this tempera-
(3E,1S,6R)-6-Methoxy-1-phenylhept-3-en-1-yl (2S)-2-acetoxy-2-
ture for 2 h. After concentration under reduced pressure, phenylacetate 52. Following the standard procedure, the
chromatography (15 : 1, light petroleum–ether) of the residue alcohol 49 (40 mg, 0.18 mmol) and (S)-O-acetylmandelyl chlor-
gave the title compound 48 as a colourless oil (55 mg, 92%), ide gave the title compound 52 as a colourless oil (50 mg, 62%),
Rf = 0.9 (1 : 1, light petroleum–ether), [α]2D0 +14 (c 2.1, CHCl3); Rf = 0.3 (6 : 1, light petroleum–ether), [α]D20 +36 (c 1.5, CHCl3)
νmax/cm−1 2964, 2929, 1662, 1461, 1376, 1261, 1099, 1017 and (Found: M+
+ NH4, 414.2286. C24H32NO5 requires M,
802; δH (300 MHz, CDCl3) 1.14 (3 H, d, J 6, 6-H3), 2.15–2.45 414.2280); νmax/cm−1 2970, 2928, 1746, 1455, 1372, 1231, 1175,
(2 H, m, 4-H2), 3.33 (3 H, s, OCH3), 3.38 (1 H, m, 5-H), 3.98 1085, 1056, 971, 745 and 699; δH (300 MHz, CDCl3) major
(2 H, m, 1-H2) and 5.78 (2 H, m, 2-H and 3-H); δC (75 MHz, isomer 1.07 (3 H, d, J 6, 7-H3), 2.07 (1 H, m, 5-H), 2.19 (3 H, s,
CDCl3) 19.2, 33.5, 38.9, 56.3, 76.4, 128.9 and 132.6; m/z (CI) CH3), 2.23 (1 H, m, 5-H′), 2.40–2.70 (2 H, m, 2-H2), 3.22 (1 H,
212, 210 (M+ + 18, 100%), 180 (32) and 98 (52).
m, 6-H), 3.24 (3 H, s, OCH3), 5.34 and 5.48 (each 1 H, dt, J 15,
(3E,1S,6R)-6-Methoxy-1-phenylhept-3-en-1-ol 49. Following 7, 3-H or 4-H), 5.76 (1 H, t, J 7, 1-H), 6.00 (1 H, s, 2′-H), 6.98
the standard procedure, benzaldehyde (0.075 mL, 0.75 mmol), (1 H, m, ArH), 7.19 (2 H, m, ArH) and 7.38 (7 H, m, ArH); m/z
bismuth(III) iodide (144 mg, 0.25 mmol) in MeCN (1 mL) and (CI) 414 (M+ + 18, 1%), 259 (6) and 91 (100).
DCM (1 mL) and stannane 44 (100 mg, 0.25 mmol) in DCM
(3E,1S,6R)-1-Phenylhept-3-ene-1,6-diol 53a. Following the
(0.3 mL), after chromatography (3 : 1, light petroleum–ether standard procedure, stannane 43 (30 mg, 0.077 mmol) and
with 1% Et3N), gave the title compound 49 as a colourless oil benzaldehyde (24 μL, 0.231 mmol) afforded the title compound
(44 mg, 80%) containing ca. 20% of its 1-epimer 50 (1H and 53a as a colourless oil (10 mg, 63%) containing ca. 20% of its
13C NMR), Rf = 0.3 (3 : 1, light petroleum–ether), [α]2D0 −24 1-epimer 54a (13C NMR), Rf = 0.3 (1 : 4, light petroleum–ether),
(c 0.5, CHCl3) (Found: M+ + NH4, 238.1812. C14H24NO2 requires [α]D20 −18 (c 1.2, CHCl3) (Found: M+
+ NH4, 224.1651.
M, 238.1807); νmax/cm−1 3424, 2969, 2924, 1602, 1452, 1377, C13H22NO2 requires M, 224.1650); νmax/cm−1 3388, 2965, 2922,
1087, 1046, 971 and 756; δH (300 MHz, CDCl3) major epimer 1601, 1453, 1415, 1375, 1114, 1047, 972, 938 and 755;
49 1.13 (3 H, d, J 6, 7-H3), 2.10–2.35 and 2.40–2.50 (each 2 H, δH (300 MHz, CDCl3) 1.13 (3 H, d, J 6, 7-H3), 1.70 (2 H, br. s,
m, 2-H2 and 5-H2), 3.34 (3 H, s, OCH3), 3.35 (1 H, m, 6-H), 4.71 OH), 2.10–2.40 and 2.52 (each 2 H, m, 2-H2 or 5-H2), 3.76 (1 H,
(1 H, m, 1-H), 5.40–5.55 (2 H, m, 3-H and 4-H) and 7.34 (5 H, m, 6-H), 4.71 (1 H, dd, J 8 and 6, 1-H), 5.49 (2 H, m, 3-H and
m, ArH); minor epimer 50 1.14 (3 H, d, J 6.5, 7-H3); 4-H) and 7.34 (5 H, m, ArH); δC (75 MHz, CDCl3) major epimer
δH (300 MHz, C6D6) major epimer 49 0.91 (3 H, d, J 6.5, 7-H3); 53a 23.0, 42.7, 42.9, 67.2, 73.7, 126.0, 127.8, 128.7, 129.9, 130.5
minor epimer 50 0.93 (3 H, d, J 6.5, 7-H3); δC (75 MHz, CDCl3) and 144.3; minor epimer 54a 22.9, 42.9 and 73.6; m/z (CI) 224
major epimer 49 19.0, 39.6, 43.1, 56.2, 73.4, 76.5, 126.0, 127.6, (M+ + 18, 54%), 206 (M+, 26) and 117 (100).
128.4, 128.6, 131.1 and 144.1; minor epimer 50 39.4, 43.0 and
73.6; m/z (CI) 238 (M+ + 18, 100%), 220 (M+, 98), 203 (60) and the standard procedure, stannane 43 (60 mg, 0.154 mmol) and
117 (36). 2,2-dimethylpropanal (50 μL, 0.462 mmol) afforded the title
(4E,2R,7S)-8,8-Dimethylnon-4-ene-2,7-diol
53b. Following
Following the standard procedure, zinc powder (31 mg, compound 53b as a colourless oil (20 mg, 71%) containing
0.48 mmol), bismuth(III) iodide (248 mg, 0.42 mmol) in THF ca. 20% of its 7-epimer 54b (13C NMR), Rf = 0.2 (1 : 4, light
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petroleum–ether), [α]2D0 −18 (c 1.1, CHCl3) (Found: M+ + NH4, epimer 54e 23.1, 42.5, 43.0, 128.4 and 131.8; m/z (CI) 269 (M+ +
204.1964. C11H26NO2 requires M, 204.1963); νmax/cm−1 3368, 18, 100%) and 204 (56).
2963, 2913, 2871, 1479, 1428, 1364, 1304, 1127, 1069, 1040,
(6E,2R,4R,8R)-2,9-Bis-benzyloxy-8-methylnon-6-en-4-ol
56.
1014 and 967; δH (300 MHz, CDCl3) 0.91 (9 H, s, 2 × 8-CH3 and Following the standard procedure, activated zinc powder
9-H3), 1.20 (3 H, d, J 6, 1-H3), 1.80–2.40 (6 H, m, 3-H2, 6-H2 and (32 mg, 0.49 mmol), bismuth(III) iodide (258 mg, 0.44 mmol),
2 × OH), 3.22 (1 H, d, J 11, 7-H), 3.81 (1 H, m, 2-H) and 5.55 in THF (1.5 mL), (R)-bromide 26 (60 mg, 0.29 mmol) in THF
(2 H, m, 4-H and 5-H); δC (75 MHz, CDCl3) major epimer 53b (0.5 mL) and aldehyde (R)-5528 (70 mg, 0.39 mmol), after
23.1, 26.0, 34.9, 35.4, 42.8, 67.3, 78.6, 129.8 and 131.9; minor chromatography (4 : 1, light petroleum–ether), gave the title
epimer 54b 23.0. 42.7, 67.4, 129.7 and 132.0; m/z (CI) 204 compound 56 as a colourless oil (56 mg, 53%), a 78 : 22 mixture
(M+ + 18, 100%), 186 (M+, 6) and 109 (12).
of 4-epimers (1H and 13C NMR), Rf = 0.3 (4 : 1, light petroleum–
(4E,2R,7S)-8-Methylnon-4-ene-2,7-diol 53c. Following the ether), [α]2D0 −27 (c 1.4, CHCl3) (Found: M+ + H, 369.2423.
standard procedure, stannane 43 (70 mg, 0.18 mmol) and C24H33O3 requires M, 369.2429); νmax/cm−1 3464, 2929, 2868,
2-methylpropanal (50 μL, 0.72 mmol) afforded the title com- 1603, 1496, 1453, 1374, 1205, 1092 and 974; δH (300 MHz,
pound 53c as a colourless oil (23 mg, 74%) containing ca. 32% CDCl3) major epimer 56 1.07 (3 H, d, J 7, 8-CH3), 1.28 (3 H, d,
of its 7-epimer 54c (13C NMR), Rf = 0.2 (1 : 4, light petroleum– J 6, 1-H3), 1.68 (2 H, m, 5-H2), 2.20 (2 H, m, 3-H2), 2.54 (1 H,
ether), [α]2D0 −11 (c 1.1, CHCl3) (Found: M+ + NH4, 190.1811. m, 8-H), 3.42 (2 H, m, 9-H2), 3.78–4.03 (2 H, m, 2-H and 4-H),
C10H24NO2 requires M, 190.1806); νmax/cm−1 3368, 2976, 2927, 4.51 (1 H, d, J 12, OHCHPh), 4.56 (2 H, s, OCH2Ph), 4.66 (1 H,
1600, 1465, 1370, 1260, 1118, 1040, 970, 940 and 801; δH d, J 12, OHCHPh), 5.52 (2 H, m, 6-H and 7-H) and 7.38 (10 H,
(300 MHz, CDCl3) 0.84 (3 H, d, J 7, 9-H3), 0.86 (3 H, d, J 7, m, ArH); minor 4-epimer 1.06 (3 H, d, J 7, 8-CH3) and 4.49 and
8-CH3), 1.22 (3 H, d, J 6, 1-H3), 1.70 (1 H, m, 8-H), 1.80–2.00 4.67 (each 1 H, d, J 12, OHCHPh); δC (75 MHz, CDCl3) major
(2 H, br. s, 2 × OH), 2.05–2.35 (4 H, m, 3-H2 and 6-H2), 3.38 epimer 56 17.4, 19.7, 37.3, 41.3, 42.9, 68.0, 70.6, 71.0, 73.2,
(1 H, m, 7-H), 3.73 (1 H, m, 2-H) and 5.56 (2 H, m, 4-H and 75.5, 126.4, 127.8, 127.9, 128.0, 128.1, 128.6, 128.7, 136.7 and
5-H); δC (75 MHz, CDCl3) major epimer 53c 17.9, 19.0, 23.0, 138.8; minor 4-epimer 19.9, 37.3, 41.2, 43.3 and 71.2; m/z (CI)
33.5, 37.9, 42.7, 67.3, 75.9, 130.0 and 130.8; minor epimer 54c 369 (M+ + 1, 42%), 196 (34) and 106 (100).
23.1, 33.4, 42.8, 67.4 and 129.9; m/z (CI) 190 (M+ + 18, 100%),
(6E,2S,4R,8R)-2,9-Bis-benzyloxy-8-methylnon-6-en-4-ol
Following the standard procedure, (R)-bromide 26 (53 mg,
57.
172 (M+ + 1, 8) and 137 (6).
(5E,2R,7R)- and (5E,2R,7S)-Dec-4-ene-2,7-diols 53d and 54d. 0.256 mmol) and aldehyde (S)-5528 (35 mg, 0.197 mmol)
Following the standard procedure, stannane 43 (70 mg, afforded the title compound 57 as a colourless oil (90 mg, 63%),
0.18 mmol) and butanal (48 μL, 0.72 mmol) afforded the title an 83 : 17 mixture of epimers (1H and 13C NMR), Rf = 0.3 (4 : 1,
compounds 53d and 54d as a colourless oil (24 mg, 78%) as a light petroleum–ether), [α]2D0 +52 (c 1.9, CHCl3) (Found: M+ + 1,
50 : 50 mixture (13C NMR), Rf = 0.2 (1 : 4, light petroleum– 369.2423. C24H33O3 requires M, 369.2429); νmax/cm−1 3464,
ether) (Found: M+ + NH4, 190.1799. C10H24NO2 requires M, 2929, 2868, 1603, 1496, 1453, 1374, 1205, 1092, 974 and 736;
190.1806); νmax/cm−1 3349, 2961, 2927, 1645, 1457, 1430, 1374, δH (300 MHz, CDCl3) major epimer 57 1.04 (3 H, d, J 7, 8-CH3),
1121, 1073, 1025, 972 and 940; δH (300 MHz, CDCl3) both 1.26 (3 H, d, J 6, 1-H3), 1.50–1.75 (2 H, m, 5-H2), 2.27 (2 H, m,
epimers 0.93 (3 H, t, J 7, 10-H3), 1.20 (3 H, d, J 6, 1-H3), 3-H2), 2.50 (1 H, m, 8-H), 3.29 (1 H, dd, J 9 and 7, 9-H), 3.37
1.35–1.60 (4 H, m, 8-H2 and 9-H2), 1.90 (2 H, br. s, 2 × OH), (1 H, dd, J 9 and 7, 9-H′), 3.75–4.00 (2 H, m, 2-H and 4-H), 4.44
2.12 and 2.25 (each 2 H, m, 3-H2 or 6-H2), 3.63 (1 H, m, 7-H), (1 H, d, J 12, OHCHPh), 4.52 (2 H, s, OCH2Ph), 4.67 (1 H, d,
3.82 (1 H, m, 2-H) and 5.54 (2 H, m, 4-H and 5-H); δC (75 MHz, J 12, OHCHPh), 5.47 (2 H, m, 6-H and 7-H) and 7.35 (10 H, m,
CDCl3) both epimers 53d and 54d 14.3, 19.1, 23.0, 23.1, 39.2, ArH); minor 4-epimer 1.05 (3 H, d, J 7, 8-CH3) and 4.46 and
39.3, 40.9, 41.0, 42.7, 42.8, 67.3, 67.4, 70.8, 70.9, 130.0, 130.1 4.63 (each 1 H, d, J 12, OHCHPh); δC (75 MHz, CDCl3) major
and 130.3(2); m/z (CI) 190 (M+ + 18, 100%) and 172 (M+, 6).
epimer 57 17.4, 19.9, 37.3, 41.3, 43.4, 70.6, 71.2, 73.1, 75.5,
(3E,1S,6R)-1-(4-Nitrophenyl)hept-3-ene-1,6-diol 53e. Follow- 76.0, 126.2, 127.7, 127.8, 127.9, 128.0, 128.6, 128.8, 136.3,
ing the standard procedure, stannane 43 (60 mg, 0.154 mmol) 138.4 and 138.9; minor 4-epimer 19.7, 37.3, 42.9, 71.0 and 73.0
and 4-nitrobenzaldehyde (46 mg, 0.462 mmol) afforded the m/z (CI) 369 (M+ + 1, 12%), 196 (40) and 106 (100).
title compound 53e as a colourless oil (30 mg, 78%) containing
(6E,2S,4R,8R)-2,9-Bis-benzyloxy-8-methylnon-6-en-4-yl (2R)-
ca. 28% of its 1-epimer 54e (13C NMR), Rf = 0.3 (1 : 4, light pet- 2-acetoxy-2-phenylacetate 58. Following the standard pro-
roleum–ether), [α]D20 −42 (c 1.6, CHCl3) (Found: M+ + NH4, cedure, alcohol 57 (40 mg, 0.109 mmol) in DCM (0.7 mL), pyri-
269.1508. C13H21N2O4 requires M, 269.1501); νmax/cm−1 3387, dine (88 μL, 1.26 mmol), DMAP (cat.) and (R)-O-acetylmandelyl
2967, 2921, 1603, 1518, 1347, 1109, 1057, 973 and 855; δH chloride (68 mg, 0.327 mmol) in DCM (0.4 mL), after
(300 MHz, CDCl3) 1.16 (3 H, d, J 6, 7-H3), 1.80 (1 H, br. s, OH), chromatography (6 : 1, light petroleum–ether), gave the title
2.12 (1 H, dt, J 14, 6.5, 5-H), 2.23 (1 H, dt, J 14, 4.5, 5-H′), 2.40 compound 58 as a colourless oil (40 mg, 68%), Rf = 0.3 (6 : 1,
(1 H, dt, J 14, 8, 2-H), 2.52 (1 H, dt, J 14, 4, 2-H′), 2.85 (1 H, br. light petroleum–ether), [α]2D0 −81 (c 1.9, CHCl3) (Found: M+ +
s, OH), 3.81 (1 H, m, 6-H), 4.82 (1 H, dd, J 4 and 8, 1-H), 5.54 NH4, 562.3171. C34H44NO6 requires M, 562.3168); νmax/cm−1
(2 H, m, 3-H and 4-H) and 7.52 and 8.19 (each 2 H, d, J 9, 2964, 2925, 2853, 1744, 1603, 1453, 1373, 1232, 1210, 1178,
ArH); δC (75 MHz, CDCl3) major epimer 53e 23.2, 42.6, 43.1, 1091, 1058 and 737; δH (300 MHz, CDCl3) major isomer 1.02
67.3, 72.4, 123.9, 126.7, 128.5, 131.9, 147.4 and 151.7; major (3 H, d, J 6, 8-CH3), 1.05 (3 H, d, J 7, 1-H3), 1.58 (1 H, m, 3-H),
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1.89 (1 H, m, 3-H′), 2.22 (3 H, s, CH3), 2.34 (2 H, t, J 8, 5-H2), (50 mg, 0.25 mmol) afforded the title compound 64 as a colour-
2.50 (1 H, m, 8-H), 3.12 (1 H, m, 2-H), 3.30 (1 H, dd, J 8 and 7, less oil (45 mg, 51%), a 78 : 22 anti : syn mixture of 4-epimers
9-H), 3.39 (1 H, dd, J 7 and 6, 9-H′), 4.21 and 4.32 (each 1 H, d, (1H and 13C NMR), Rf = 0.3 (3 : 1, light petroleum–ether)
J 12, OHCHPh), 4.55 (2 H, s, OCH2Ph), 5.02 (1 H, m, 4-H), (Found: M+ + H, 393.2820. C23H41O3Si requires M, 393.2825);
5.35–5.53 (2 H, m, 6-H and 7-H), 5.92 (1 H, 2′-H), 7.34 (13 H, νmax/cm−1 3462, 2956, 2930, 2856, 1455, 1374, 1255, 1093, 836
m, ArH) and 7.48 (2 H, m, ArH); δC (75 MHz, CDCl3) major and 775; δH (300 MHz, CDCl3) major epimer 64 0.12 (6 H, s,
isomer 17.3, 19.4, 21.0, 37.1, 37.9, 40.2, 70.5, 72.0, 73.2, 74.9, 2 × SiCH3), 0.93 [9 H, s, SiC(CH3)3], 1.06 (3 H, d, J 7, 8-CH3),
75.6, 124.2, 127.7, 127.8, 127.8, 127.9, 128.6, 129.0, 129.5, 1.24 (3 H, d, J 7, 1-H3), 1.59 (2 H, m, 3-H2), 2.21 (2 H, m, 5-H2),
134.3, 137.1, 138.9, 139.0, 168.7 and 170.5; m/z (CI) 562 (M+ + 2.54 (1 H, m, 8-H), 3.32 (1 H, dd, J 9 and 7, 9-H), 3.38 (1 H, dd,
18, 16%), 206 (12), 150 (24) and 58 (100).
J 9 and 7, 9-H′), 3.97 (1 H, m, 4-H), 4.22 (1 H, m, 2-H), 4.56
(6E,2S,4R,8R)-2,9-Bis-benzyloxy-8-methylnon-6-en-4-yl(2S)- (2 H, s, OCH2Ph), 5.52 (2 H, m, 6-H and 7-H) and 7.36 (5 H, m,
2-acetoxy-2-phenylacetate 59. Following the standard pro- ArH); minor 4-epimer 0.15 and 0.16 (each 3 H, s, SiCH3), 1.21
cedure, alcohol 57 (40 mg, 0.109 mmol) and (S)-O-acetyl- (3 H, d, J 7, 1-H3), 3.8 (1 H, m, 4-H) and 4.10 (1 H, m, 2-H); δC
mandelyl chloride gave the title compound 59 as a colourless (75 MHz, CDCl3) major epimer 64 −4.7, −4.3, 17.5, 18.2, 23.3,
oil (45 mg, 76%), Rf = 0.3 (6 : 1, light petroleum–ether); 26.1, 37.3, 41.5, 44.2, 67.6, 68.1, 73.2, 75.6, 126.4, 127.8, 127.8,
δH (300 MHz, CDCl3) major isomer 0.92 (3 H, d, J 6, 8-CH3), 128.6, 136.4 and 138.9; minor 4-epimer −4.5, −3.6, 24.7, 41.2
1.25 (3 H, d, J 7, 1-H3), 1.67 (1 H, m, 3-H), 2.04 (1 H, m, 3-H′), and 45.3; m/z (CI) 410 (M+ + 18, 64), 393 (M+ + 1, 32%), 132
2.18 (2 H, m, 5-H2), 2.24 (3 H, s, CH3), 2.25 (1 H, m, 8-H), 3.18 (68) and 106 (100).
(1 H, dd, J 8 and 7, 9-H), 3.27 (1 H, dd, J 7 and 6, 9-H′), 3.63
(6E,2R,4R,8R)-9-Benzyloxy-2-tert-butyldimethylsilyloxy-8-
(1 H, m, 2-H), 4.45 (1 H, d, J 12, OHCHPh), 4.51 (1 H, s, methylnon-6-en-4-yl (2R)-2-acetoxy-2-phenylacetate 65. Follow-
OCH2Ph), 4.60 (1 H, d, J 12, OHCHPh), 5.06 (2 H, m, 4-H and ing the standard procedure, alcohol 64 (30 mg, 0.077 mmol)
6-H), 5.28 (1 H, dd, J 16 and 7, 7-H), 5.88 (1 H, s, 2′-H), 7.35 (13 and (R)-O-acetylmandelyl chloride afforded the title compound
H, m, ArH) and 7.50 (2 H, m, ArH); δC (75 MHz, CDCl3) major 65 as a colourless oil (25 mg, 58%), Rf = 0.3 (6 : 1, light pet-
isomer 17.1, 19.7, 21.0, 36.9, 37.4, 40.6, 70.5, 72.0, 73.1, 73.3, roleum–ether), [α]2D0 −74 (c 1.8, CHCl3) (Found: M+ + NH4,
75.0, 75.5, 124.1, 127.7, 127.8, 127.8, 127.9, 128.1, 128.6, 129.0, 586.3556. C33H52NO6Si requires M, 586.3563); νmax/cm−1 2928,
129.4, 134.2, 136.7, 138.9, 139.1, 168.6 and 170.6.
2855, 1746, 1603, 1454, 1373, 1233, 1096, 1058, 836, 776 and
(5E,2R,3RS,7R)- and (5E,2S,3RS,7R)-2,8-Bis-benzyloxy-7- 736; δH (300 MHz, CDCl3) major isomer −0.19 and −0.11 (each
methyloct-5-en-3-ols 61 and 62. Following the standard pro- 3 H, s, SiCH3), 0.84 [9 H, s, SiC(CH3)3], 0.97 (3 H, d, J 6,
cedure, the (R)-bromide 26 (44 mg, 0.214 mmol) and the alde- 8-CH3), 1.05 (3 H, d, J 7, 1-H3), 1.56 (2 H, m, 3-H2), 2.24 (3 H, s,
hyde (R)-602a (35 mg, 0.214 mmol) afforded the title compound CH3), 2.35 (2 H, t, J 6, 5-H2), 2.50 (1 H, m, 8-H), 3.30 (1 H, dd,
61 as a colourless oil (45 mg, 60%), a 60 : 40 mixture of J 10 and 7, 9-H), 3.40 (2 H, m, 2-H and 9-H′), 4.55 (2 H, s,
3-epimers (1H NMR), Rf = 0.4 (3 : 1, light petroleum–ether) OCH2Ph), 4.97 (1 H, m, 4-H), 5.47 (2 H, m, 6-H and 7-H), 5.91
(Found: M+
372.2539); νmax/cm−1 3424, 3029, 2870, 1495, 1453, 1370, 1093 (CI) 586 (M+ + 18, 34%), 152 (32) and 106 (100).
+ NH4, 372.2547. C23H34NO3 requires M, (1 H, s, 2′-H), 7.37 (8 H, m, ArH) and 7.51 (2 H, m, ArH); m/z
and 736; δH (300 MHz, CDCl3) major epimer 61 1.05 (3 H, d,
(6E,2R,4R,8R)-9-Benzyloxy-2-tert-butyldimethylsilyloxy-8-methyl-
J 7, 7-CH3), 1.22 (3 H, d, J 6, 1-H3), 2.20 (1 H, m, 4-H), 2.34 (1 non-6-en-4-yl (2S)-2-acetoxy-2-phenylacetate 66. Following the
H, m, 4-H′), 2.56 (1 H, m, 7-H), 3.37 (2 H, m, 8-H2), 3.50 (2 H, standard procedure, alcohol 64 (30 mg, 0.077 mmol) and (S)-
m, 2-H and 3-H), 4.43 (1 H, d, J 12, OHCHPh), 4.54 (2 H, s, O-acetylmandelyl chloride afforded the title compound 66 as a
OCH2Ph), 4.68 (1 H, d, J 12, OHCHPh), 5.52 (2 H, m, 5-H and colourless oil (31 mg, 69%), Rf = 0.3 (6 : 1, light petroleum–
6-H) and 7.34 (10 H, m, ArH); minor 3-epimer 1.06 (3 H, d, J 7, ether); δH (300 MHz, CDCl3) major isomer 0.02 and 0.06 (each
7-CH3); m/z (CI) 372 (M+ + 18, 88%) and 106 (100).
3 H, s, SiCH3), 0.91 [9 H, s, SiC(CH3)3], 0.93 (3 H, d, J 6,
Following the standard procedure, the (R)-bromide 26 8-CH3), 1.16 (3 H, d, J 7, 1-H3), 1.64 (2 H, m, 3-H2), 2.16 (2 H,
(44 mg, 0.214 mmol) and the aldehyde (S)-60 (35 mg, m, 5-H2), 2.24 (3 H, s, CH3), 2.32 (1 H, m, 8-H), 3.19 (1 H, dd,
0.214 mmol) afforded the title compound 62 as a colourless oil J 9 and 7, 9-H), 3.28 (1 H, dd, J 9 and 6, 9-H′), 3.87 (1 H, m,
(45 mg, 67%), a 60 : 40 mixture of 3-epimers (1H NMR), Rf = 0.4 2-H), 4.52 (2 H, s, OCH2Ph), 5.00–5.15 (2 H, m, 4-H and 6-H),
(3 : 1, light petroleum–ether); δH (300 MHz, CDCl3) major 5.29 (1 H, dd, J 16 and 7, 7-H), 5.94 (1 H, s, 2′-H), 7.37 (8 H, m,
isomer 62 1.05 (3 H, d, J 7, 7-CH3), 1.24 (3 H, d, J 6, 1-H3), ArH) and 7.51 (2 H, m, ArH); δC (75 MHz, CDCl3) −4.8, −4.0,
2.15–2.60 (3 H, m, 4-H2 and 7-H), 3.25–3.60 (3 H, m, 2-H and 17.2, 18.2, 21.0, 24.8, 26.1, 26.2, 36.9, 37.8, 43.9, 65.5, 73.1,
8-H2), 3.75 (1 H, m, 3-H), 4.54 (1 H, d, J 12, OHCHPh), 4.55 73.6, 74.9, 75.5, 124.2, 127.7, 127.8, 127.9, 128.6, 129.0, 129.4,
(2 H, s, OCH2Ph), 4.65 (1 H, d, J 12, OHCHPh), 5.53 (2 H, 134.3, 136.4, 138.9, 168.6 and 170.4.
m, 5-H and 6-H) and 7.34 (10 H, m, ArH); minor 3-epimer
1.06 (3 H, d, J 7, 7-CH3) and 4.50 and 4.68 (each 1 H, d, J 12, Dess–Martin periodinane (38 mg, 0.088 mmol) was added por-
OHCHPh); m/z (CI) 372 (M+ + 18, 78), 182 (22) and 106 (100).
tionwise to the alcohol 56 containing ca. 22% of its 4-epimer
(6E,2R,8R)-2,9-Bis-benzyloxy-8-methylnon-6-en-4-one
67.
(6E,2R,4R,8R)-9-Benzyloxy-2-tert-butyldimethylsilyloxy-8-methyl- (25 mg, 0.068 mmol) in DCM (1 mL) and the resulting suspen-
non-6-en-4-ol 64. Following the standard procedure, the (R)- sion stirred at room temperature for 2 h before addition of
bromide 26 (68 mg, 0.327 mmol) and the aldehyde (R)-6329 aqueous sodium hydroxide (2 mL, 1.3 M). The aqueous phase
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was extracted with ether (2 × 5 mL) and the organic extracts (2 H, m, 7-H2), 3.60 (2 H, m, 1-H2), 4.41 (1 H, m, 2-H), 4.42 (2
washed with aqueous sodium hydroxide (10 mL, 1.3 M) and H, s, OCH2Ph), 7.26 (7 H, m, ArH) and 7.75 (2 H, d, J 8, ArH);
water (10 mL), then dried (MgSO4) and concentrated under δC (75 MHz, CDCl3) −5.4, 17.0, 18.4, 21.7, 22.2, 25.9, 31.4, 33.3,
reduced pressure. Chromatography (15 : 1, light petroleum– 33.4, 64.2, 73.1, 75.8, 83.4, 127.6, 127.6, 127.9, 128.4, 129.8,
ether) of the residue afforded the title compound 67 as a pale 134.5, 138.8 and 144.6; m/z (CI) 538 (M+ + 18, 2%), 521 (M+ + 1,
yellow oil (19 mg, 74%), Rf = 0.7 (3 : 1, light petroleum–ether), 1), 259 (14), 201 (16) and 91 (100).
[α]2D0 −18 (c 1.0, CHCl3) (Found: M+ + 1, 367.2267. C24H31O3
(2S,6R)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-2,6-dimethyl-
in ether,
requires M, 367.2270); νmax/cm−1 3062, 3029, 2966, 2928, 2870, heptane 71. Methyllithium (1.44 mL, 1.6
M
1714, 1602, 1453, 1372, 1261, 1092, 971, 876 and 801; δH 2.31 mmol) was added dropwise to copper(I) cyanide (103 mg,
(300 MHz, CDCl3) 1.05 (3 H, d, J 7, 8-CH3), 1.25 (3 H, d, J 6, 1.15 mmol) in toluene (3 mL) at 0 °C and the mixture stirred
1-H3), 2.49 (1 H, dd, J 15 and 5, 3-H), 2.50 (1 H, m, 8-H), 2.83 at this temperature for 15 min. The toluene p-sulfonate 70
(1 H, dd, J 15 and 7, 3-H′), 3.16 (2 H, d, J 6, 5-H), 3.32 (1 H, dd, (120 mg, 0.23 mmol) in toluene (2 mL) was added and the
J 10 and 5, 9-H), 3.39 (1 H, dd, J 10 and 7, 9-H′), 4.46 (1 H, d, mixture stirred at 0 °C for 5 h. The mixture was then filtered
J 12, OHCHPh), 4.53 (2 H, s, OCH2Ph), 4.58 (1 H, d, J 12, through celite® that was washed with DCM (50 mL) and ether
OHCHPh) 5.52 (1 H, dd, J 16 and 6, 7-H), 5.62 (1 H, dt, J 16 (50 mL). The extracts were concentrated and the residue was
and 7, 6-H) and 7.32 (10 H, m, ArH); δC (75 MHz, CDCl3) 17.2, dissolved in acetone (1.5 mL) and water (0.3 mL). N-Methyl-
20.1, 37.1, 48.1, 49.5, 71.1, 71.9, 73.1, 75.3, 121.8, 127.7, 127.8, morpholine N-oxide (34 mg, 0.29 mmol) and osmium(IV) oxide
127.9, 128.5, 128.5, 137.7, 138.7 and 208.0; m/z (CI) 384 (M+ + (1 crystal, cat.) were added at room temperature and the solu-
18, 68%), 367 (M+ + 1, 4) and 276 (100).
tion stirred for 16 h. Saturated aqueous sodium sulfite (4 mL)
(2R,6R)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-6-methyl- was added and the mixture was stirred for 1 h before being
heptan-2-ol 69. Sodium acetate (462 mg, 3.3 mmol), in water extracted with ether (3 × 5 mL). The organic extracts were
(1.1 mL) was added dropwise to a solution of alkene 5i washed with brine (15 mL), dried (MgSO4) and concentrated
(100 mg, 0.28 mmol) and toluene p-sulfonylhydrazine (303 mg, under reduced pressure. Chromatography (10 : 1, light pet-
1.65 mmol) in DME (3.5 mL) under reflux over 30 min. The roleum–ether) of the residue gave the title compound 71 as a
solution was then heated under reflux for a further 16 h and colourless oil (61 mg, 73%), Rf = 0.8 (10 : 1, light petroleum–
allowed to cool to room temperature. The aqueous phase was ether), [α]2D0 +4 (c 1.7, CHCl3) (Found: M+ + 1, 365.2873.
extracted with ether (2 × 15 mL) and the organic extracts were C22H41O2Si requires M, 365.2870); νmax/cm−1 2928, 2855, 1589,
washed with water (20 mL) and brine (20 mL) then dried 1462, 1362, 1257, 1098, 1028, 836 and 775; δH (300 MHz,
(MgSO4) and concentrated under reduced pressure. Chromato- CDCl3) 0.08 (6 H, s, 2 × SiCH3), 0.91 (3 H, d, J 7, 2-CH3), 0.93
graphy of the residue (3 : 1, light petroleum–ether) afforded the [9 H, s, SiC(CH3)3], 0.97 (3 H, d, J 7, 6-CH3), 1.10–1.55 (6 H, m,
title compound 69 as a colourless oil (92 mg, 92%), Rf = 0.3 3-H2, 4-H2 and 5-H2), 1.61 (1 H, m, 2-H), 1.80 (1 H, m, 6-H),
(3–1, light petroleum–ether), [α]2D0 +3 (c 1.1, CHCl3) (Found: M+ 3.26 (1 H, dd, J 9 and 7, 1-H), 3.34 (1 H, dd, J 9 and 6,
+ 1, 367.2668. C21H39O3Si requires M, 367.2663); νmax/cm−1 1-H′), 3.37 (1 H, dd, J 10 and 6, 7-H), 3.45 (1 H, dd, J 10 and 6,
3465, 2929, 2857, 1587, 1462, 1362, 1255, 1099, 837 and 778; 7-H′), 4.55 (2 H, s, OCH2Ph) and 7.35 (5 H, m, ArH); δC
δH (300 MHz, CDCl3) 0.09 (6 H, s, 2 × SiCH3), 0.92 [9 H, s, SiC- (75 MHz, CDCl3) −5.1, 17.1, 17.5, 18.6, 24.6, 26.2, 33.7, 34.3,
(CH3)3], 0.96 (3 H, d, J 7, 6-CH3), 1.10–1.60 (6 H, m, 3-H2, 4-H2 36.0, 68.7, 73.2, 76.3, 127.7, 127.8 and 128.6; m/z (CI) 382
and 5-H2), 1.79 (1 H, m, 6-H), 2.46 (1 H, br. s, OH), 3.26 (1 H, (M+ + 18, 54%), 366 (30), 365 (M+ + 1, 22), 217 (38), 132 (52)
dd, J 9 and 7, 7-H), 3.35 (1 H, dd, J 9 and 6, 7-H′), 4.10 (1 H, and 108 (100).
m), 3.63 (2 H, m), 4.52 (2 H, s, OCH2Ph) and 7.34 (5 H, m,
Phenyl chlorothionoformate (65 μL, 0.473 mmol) was
ArH); δC (75 MHz, CDCl3) −5.1, 17.3, 18.5, 23.2, 26.1, 33.3, added to the alcohol 75 (150 mg, 0.394 mmol) and pyridine
33.7, 33.9, 67.5, 72.0, 73.2, 76.2, 127.7, 127.8, 128.6 and 139.0; (127 μL, 1.576 mmol) in DCM (1.3 mL) at room temperature
m/z (CI) 384 (M+ + 18, 12%), 367 (M+ + 1, 50) and 108 (100).
and the solution stirred at for 16 h. Water (2 mL) and ethyl
(2R,6R)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-6-methyl- acetate (2 mL) were added and the organic phase was washed
heptan-2-yl 4-methylbenzenesulfonate 70. Toluene p-sulfonyl with saturated aqueous sodium hydrogen carbonate (4 mL)
chloride (96 mg, 4.89 mmol) and DMAP (101 mg, 0.83 mmol) and brine (2 mL) then dried (MgSO4). After concentration
were added to the alcohol 69 (75 mg, 0.21 mmol) in DCM under reduced pressure, the residue was dissolved in toluene
(2 mL) at room temperature and the mixture stirred for 16 h. (8 mL). AIBN (cat.) and tributyltin hydride (0.38 mL) were
After concentration under reduced pressure, chromatography added at room temperature and the solution was then heated
(6 : 1, light petroleum–ether) of the residue gave the title com- under reflux for 16 h. After concentration under reduced
pound 70 as a colourless oil (97 mg, 90%), Rf = 0.3 (5 : 1, light pressure, chromatography (30 : 1, light petroleum–ether,
petroleum–ether), [α]2D0 +6 (c 0.8, CHCl3) (Found: M+ + 1, eluting with 1% TEA by volume) of the residue gave the title
521.2750. C28H45O5SiS requires M, 521.2751); νmax/cm−1 2928, compound 71 as a colourless oil (98 mg, 74%), Rf = 0.8 (10 : 1,
2855, 1598, 1461, 1363, 1255, 1177, 1098, 907, 836 and 778; δH light petroleum–ether), [α]2D0 +4 (c 1.5, CHCl3) (Found: M+ + 1,
(300 MHz, CDCl3) −0.06 (6 H, s, 2 × SiCH3), 0.79 (3 H, d, J 7, 365.2871. C22H41O2Si requires M, 365.2870) with spectroscopic
6-CH3), 0.80 [9 H, m, SiC(CH3)3], 0.90–1.40 (4 H, m, 4-H2 and data identical with those of the sample prepared from the
5-H2), 1.58 (3 H, m, 3-H2 and 6-H), 2.37 (3 H, s, ArCH3), 3.17 toluene p-sulfonate 70.
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(S)-Dimethyl 4-benzyloxy-3-methyl-2-oxobutylphosphonate 2954, 2929, 2856, 1461, 1362, 1253, 1093, 837, 775 and 736; δH
73.18 nButyllithium (12.33 mL, 1.7 M hexanes, 20.96 mmol) (300 MHz, CDCl3) −0.04 (6 H, s, 2 × SiCH3), 0.84 [15 H, m, SiC
was added to dimethyl methylphosphonate (2.92 g, (CH3)2, 2-CH3 and 6-CH3], 1.00–1.62 (5 H, m, 4-H2, 5-H2 and
23.56 mmol) in THF (48 mL) at −78 °C and the solution 6-H), 1.80 (1 H, m, 2-H), 2.53 (0.5 H, d, J 4, OH), 3.20–3.60
stirred at this temperature for 20 min. Methyl (S)-3-benzyloxy- (4.5 H, m, 1-H2, 3-H and 7-H2), 3.65 (0.5 H, m, 3-H), 4.45 (2 H,
2-methylpropanoate (2.45 g, 11.78 mmol) in THF (4 mL) was s, OCH2Ph) and 7.24 (5 H, m, ArH); m/z (CI) 381 (M+ + 1,
added and the solution was stirred at −78 °C for 15 min and 100%).
then allowed to warm to room temperature and stirred for 1 h.
(4E,2S,6S)- and (4E,2S,6R)-1-Benzyloxy-7-tert-butyldimethyl-
Saturated aqueous oxalic acid (25 mL) and ether (50 mL) were silyloxy-2,6-dimethylhept-4-en-3-one 74 and 76. A solution of
added and the organic layer was washed with brine (50 mL), the ketophosphonate 73 (750 mg, 2.50 mmol) and barium
dried (MgSO4) and concentrated under reduced pressure. hydroxide hexahydrate (activated by heating to 110 °C for 2 h)
Chromatography (ether) of the residue gave the title compound (1.18 g, 3.75 mmol) in THF (20 mL) was stirred at room temp-
73 as a colourless oil (3.11 g, 88%), Rf = 0.2 (ether) (Found: M+, erature for 30 min. Racemic 3-tert-butyldimethylsilyloxy-2-
300.1113. C14H21O5P requires M, 300.1121); νmax/cm−1 2955, methylpropanal ( )-72 (505 mg, 2.50 mmol) in THF (10 mL)
2855, 1713, 1454, 1366, 1259, 1185, 1032, 877, 810 and 742; δH and water (0.75 mL) was added and the mixture stirred at
(300 MHz, CDCl3) 1.13 (3 H, d, J 7, 3-CH3), 3.12 (1 H, m, 3-H), room temperature for 16 h. DCM (100 mL) was added and the
3.13 (1 H, dd, J 22 and 14, 1-H), 3.30 (1 H, dd, J 22.5 and 14, mixture filtered through celite® before being washed with
1-H′), 3.56 (1 H, dd, J 9 and 6, 4-H), 3.61 (1 H, dd, J 9 and 8, saturated aqueous sodium hydrogen carbonate (100 mL) and
4-H′), 3.77 and 3.81 (each 3 H, d, J 5, OCH3), 4.52 (2 H, s, brine (100 mL) then dried (MgSO4). The organic layer was con-
OCH2Ph) and 7.34 (5 H, m, ArH); δC (75 MHz, CDCl3) 13.3, centrated under reduced pressure and chromatography (5 : 1,
40.4, 42.1, 47.4, 53.2, 72.6, 73.5, 127.9, 128.0, 128.7, 138.1 and light petroleum–ether) of the residue gave a mixture of the title
205.0; m/z (CI) 318 (M+ + 18, 34%) and 301 (M+ + 1, 100).
compound 74 and 76 as a pale yellow oil (771 mg, 82%) as a
(4E,2S,6S)-1-Benzyloxy-7-tert-butyldimethylsilyloxy-2,6-dimethyl- 50 : 50 mixture of epimers (1H and 13C NMR), Rf = 0.3 (5 : 1,
hept-4-en-3-one 74.18 The ketophosphonate 73 (207 mg, light petroleum–ether); δH (300 MHz, CDCl3) both epimers
0.69 mmol) and barium hydroxide hexahydrate (activated by 0.08 (6 H, s, 2 × SiCH3), 0.93 [9 H, s, SiC(CH3)3], 1.09 and 1.10
heating at 110 °C for 2 h; 178 mg, 0.55 mmol) in THF (4 mL) (each 1.5 H, d, J 6, 6-CH3), 1.16 (3 H, d, J 7, 2-CH3), 2.55 (1 H,
were stirred at room temperature for 30 min. (R)-3-tert-Butyldi- m, 6-H), 3.19 (1 H, m, 2-H), 3.50 (1 H, dd, J 9 and 6, 1-H), 3.58
methylsilyloxy-2-methylpropanal (R)-72 (130 mg, 0.69 mmol) (2 H, d, J 6, 7-H2), 3.75 (1 H, dd, J 9 and 7, 1-H′), 4.51 and 4.56
in THF (2 mL) and water (0.05 mL) was added and the solution (each 1 H, d, J 12, OHCHPh), 6.24 (1 H, d, J 16, 4-H), 6.88 and
was stirred for 16 h. DCM (60 mL) was added and the mixture 6.90 (each 0.5 H, dd, J 16 and 7, 5-H) and 7.34 (5 H, m, ArH);
filtered through celite® before being washed with saturated δC (75 MHz, CDCl3) both epimers −5.1, 14.4, 15.9(2), 18.5,
aqueous sodium hydrogen carbonate (50 mL) and brine 26.1, 39.7, 44.2, 44.3, 67.2, 72.4, 73.5, 127.8, 128.6, 129.0(2),
(50 mL). The organic layer was dried (MgSO4) and concen- 138.5, 150.1, 150.2 and 202.5.
trated under reduced pressure. Chromatography (5 : 1, light
(2S,6R)- and (2R,6R)-7-Benzyloxy-1-tert-butyldimethylsilyl-
petroleum–ether) of the residue gave the title compound 74 as oxy-2,6-dimethylhexane 71 and 77. Sodium borohydride
a pale yellow oil (217 mg, 84%), Rf = 0.3 (5 : 1, light petroleum– (60 mg, 1.58 mmol) was added to a mixture of the ketones 74
ether) (Found: M+ + 1, 377.2502. C22H37O3Si requires M, and 76 (60 mg, 0.158 mmol) in methanol (2 mL) at 0 °C and
377.2506); νmax/cm−1 2930, 2857, 1695, 1671, 1627, 1455, 1362, the mixture allowed to warm to room temperature then stirred
1254, 1099, 838 and 777; δH (300 MHz, CDCl3) 0.08 (6 H, s, 2 × for 2 h. After concentration under reduced pressure, chromato-
SiCH3), 0.93 [9 H, s, SiC(CH3)3], 1.10 (3 H, d, J 6, 6-CH3), 1.16 graphy (4 : 1, light petroleum–ether) of the residue gave the
(3 H, d, J 7, 2-CH3), 2.55 (1 H, m, 6-H), 3.19 (1 H, m, 2-H), 3.50 corresponding 2,6-dimethylheptan-3-ol as a colourless oil
(1 H, dd, J 9 and 6, 1-H), 3.58 (2 H, d, J 6, 7-H2), 3.75 (1 H, dd, (40 mg, 68%), a mixture of diastereoisomers, Rf = 0.3 (3 : 1,
J 9 and 7, 1-H′), 4.51 and 4.56 (each 1 H, d, J 12, OHCHPh), light petroleum–ether).
6.24 (1 H, d, J 16, 4-H), 6.90 (1 H, dd, J 16 and 7, 5-H) and 7.34
Phenyl chlorothionoformate (65 μL, 0.473 mmol) was
(5 H, m, ArH); δC (75 MHz, CDCl3) −5.1, 14.4, 15.9, 18.5, 26.1, added to this alcohol (150 mg, 0.394 mmol) and pyridine
39.7, 44.2, 67.2, 72.4, 73.5, 127.8, 128.6, 129.0, 138.5, 150.2 (127 μL, 1.576 mmol) in DCM (1.3 mL) at room temperature
and 202.5; m/z (CI) 377 (M+ + 1, 100%).
and the solution stirred at room temperature for 16 h. Water
(2S,3RS,6S)-1-Benzyloxy-7-tert-butyldimethylsilyloxy-2,6-dimethyl- (2 mL) and ethyl acetate (2 mL) were added and the organic
heptan-3-ol 75. Sodium borohydride (30 mg, 0.79 mmol) was phase washed with saturated aqueous sodium hydrogen car-
added to the ketone 74 (30 mg, 0.079 mmol) in methanol bonate (4 mL) and brine (2 mL) then dried (MgSO4). The
(1 mL) at 0 °C over 5 min and the mixture allowed to warm to organic phase was then concentrated under reduced pressure
room temperature and then stirred for 2 h. After concentration to leave a residue that was dissolved in toluene (8 mL). AIBN
under reduced pressure, chromatography (4 : 1, light pet- (cat) and tributyltin hydride (0.38 mL) were added at room
roleum–ether) afforded the title compound 75 as a colourless temperature and the solution heated under reflux for 16 h.
oil (21 mg, 70%), Rf = 0.3 (3 : 1, light petroleum–ether) (Found: After concentration under reduced pressure, chromatography
M+ + 1, 381.2818. C22H41O3Si requires M, 381.2819); νmax/cm−1 (30 : 1, light petroleum–ether containing 1% Et3N) gave a
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mixture of the title compounds 71 and 77 as a colourless oil 33.7, 33.9, 35.0, 37.0, 73.3, 76.2, 127.7, 127.8, 128.6 and 139.1;
(98 mg, 78%), a 50 : 50 mixture of 2-epimers (1H and 13C m/z (CI) 378 (M+ + 18, 100%), 361 (M+ + 1, 8) and 108 (56).
NMR), Rf = 0.8 (10 : 1, light petroleum–ether); δH (300 MHz,
(2R,6S)-7-tert-Butyldimethylsilyloxy-2,6-dimethylheptan-1-ol
CDCl3) both epimers 0.08 (6 H, s, 2 × SiCH3), 0.91 (3 H, d, J 7, 80. Palladium (10% on carbon, 70 mg, 0.066 mmol) was
2-CH3), 0.93 [9 H, s, SiC(CH3)3], 0.98 and 0.99 (each 1.5 H, d, added to the benzyl ether 71 (155 mg, 0.46 mmol) in ethanol
J 7, 6-CH3), 1.00–1.90 (8 H, m, 2-H, 3-H2, 4-H2, 5-H2 and 6-H), (5 mL) at room temperature. The mixture was stirred under an
3.28 (1 H, dd, J 9 and 7, 1-H), 3.37 and 3.38 (each 0.5 H, dd, J 9 atmosphere of hydrogen for 1 h then filtered through celite®.
and 6, 1-H′), 3.40 (1 H, dd, J 10 and 6, 7-H), 3.48 and 3.49 The filtrate was washed with DCM (50 mL) and concentrated
(each 0.5 H, dd, J 10 and 6, 7-H′), 4.55 (2 H, s, OCH2Ph) and under reduced pressure to afford the title compound 80 as a col-
7.35 (5 H, m, ArH); δC (75 MHz, CDCl3) both epimers −5.1, ourless oil (123 mg, 98%), Rf = 0.8 (15 : 1, light petroleum–
17.0, 17.4, 17.8, 18.6, 24.6, 26.3, 27.1, 28.1, 33.7, 34.2, 34.3, ether), [α]2D0 +5 (c 1.4, CHCl3) (Found: M+ + 1, 275.2406.
36.0, 68.7, 73.2, 76.3(2), 127.7, 127.8, 128.6 and 139.1.
C15H35O2Si requires M, 275.2401); νmax/cm−1 3351, 2954, 2928,
(2S,6R)-7-Benzyloxy-2,6-dimethylheptan-1-ol
78. Tetra-n- 2857, 1463, 1388, 1254, 1098, 1038, 837 and 775; δH (300 MHz,
butylammonium fluoride (1 M in THF, 2.47 mL, 2.47 mmol) CDCl3) 0.03 (6 H, s, 2 × SiCH3), 0.85 (3 H, d, J 7, 6-CH3), 0.89
was added to the silyl ether 71 (600 mg, 1.47 mmol) in THF [9 H, s, SiC(CH3)3], 0.91 (3 H, d, J 7, 2-CH3), 1.06 (2 H, m),
(2 mL) and the solution was stirred at room temperature for 1.15–1.50 and 1.60 (each 3 H, m), 3.34 (1 H, dd, J 10 and 7),
16 h. Water (4 mL) was added and the mixture was stirred for 3.39 (1 H, dd, J 10.5 and 6.5) and 3.43 and 3.49 (each 1 H, dd,
1 h then extracted with ether (3 × 8 mL). The organic extracts J 10 and 6); δC (75 MHz, CDCl3) −5.1, 16.9, 17.0, 18.6, 24.6,
were washed with brine (20 mL), dried (MgSO4) and concen- 26.2, 33.6, 33.7, 33.7, 36.0, 68.5 and 68.6; m/z (CI) 292 (M+
+
trated under reduced pressure. Chromatography (3 : 1, light 18, 2%), 275 (M+ + 1, 100).
petroleum–ether) of the residue gave the title compound 78 as a
(2R,6S)-1-Iodo-7-tert-butyldimethylsilyloxy-2,6-dimethylhep-
colourless oil (403 mg, 98%), Rf = 0.3 (1 : 1, light petroleum– tane 81. Imidazole (149 mg, 2.19 mmol), triphenylphosphine
ether); [α]2D0 +2 (c 2.2, CHCl3) (Found: M+ + H, 251.2001. (285 mg, 1.09 mmol) and iodine (289 mg, 1.14 mmol) were
C16H27O2 requires M, 251.2006); νmax/cm−1 3385, 2928, 2857, added to the alcohol 80 (120 mg, 0.44 mmol) in THF (4 mL) at
1454, 1364, 1100, 1030 and 736; δH (300 MHz, CDCl3) 0.95 room temperature and the solution stirred at room tempera-
(3 H, d, J 7, 6-CH3), 0.98 (3 H, d, J 7, 2-CH3), 1.00–1.55 (6 H, m, ture for 2 h. Saturated aqueous sodium thiosulfate (5 mL) was
3-H2, 4-H2 and 5-H2), 1.64 (1 H, m, 6-H), 1.82 (1 H, m, 2-H), added and the mixture stirred until the colour of iodine disap-
1.95 (1 H, br. s, OH), 3.28 (1 H, dd, J 9 and 7, 7-H), 3.37 (1 H, peared. Ether (10 mL) was added and the aqueous phase was
dd, J 9 and 6, 7-H′), 3.44 (1 H, dd, J 11 and 7, 1-H), 3.52 (1 H, extracted with ether (3 × 5 mL). The organic extracts were
dd, J, 11 and 6, 1-H′), 4.54 (2 H, s, OCH2Ph) and 7.35 (5 H, m, washed with brine, dried (MgSO4), concentrated under
ArH); m/z (CI) 251 (M+ + 1, 8%), 107 (26) and 91 (100). Minor reduced pressure. Chromatography (15 : 1, light petroleum–
splitting of the dds at δ3.37 and δ3.52 indicated that ca. 15% ether) of the residue gave the title compound 81 as a colourless
of the 2-epimer was present, cf. 1H NMR data for 71 and 77. oil (178 mg, 97%), Rf = 0.8 (15 : 1, light petroleum–ether), [α]D20
This was not observed for any other compound along this +4 (c 0.9, CHCl3) (Found: M+ + 1, 385.1418. C15H34OSiI requires
series, i.e. intermediates 79–84.
M, 385.1418); νmax/cm−1 2954, 2928, 2855, 1462, 1377, 1254,
(2R,6S)-7-Iodo-1-benzyloxy-2,6-dimethylheptane
79. Imid- 1193, 1094, 837 and 775; δH (300 MHz, CDCl3) 0.08 (6 H, s, 2 ×
azole (259 mg, 3.80 mmol), triphenylphosphine (496 mg, SiCH3), 0.90 (3 H, J 7, 2-CH3), 0.93 [9 H, SiC(CH3)3], 1.01 (3 H,
1.90 mmol) and iodine (500 mg, 1.98 mmol) were added to the d, J 7, 6-CH3), 1.00–1.55 (7 H, m, 2-H, 3-H2, 4-H2 and 5-H2),
alcohol 78 (190 mg, 0.76 mmol) in THF (8 mL) at room temp- 1.62 (1 H, m, 6-H), 3.19 (1 H, dd, J 10 and 6, 1-H), 3.27 (1 H,
erature and the solution stirred at room temperature for 2 h. dd, J 10 and 5, 1-H′), 3.40 (1 H, dd, J 10 and 7, 7-H) and 3.47
Saturated aqueous sodium thiosulfate (10 mL) was added and (1 H, dd, J 10 and 6, 7-H′); δC (75 MHz, CDCl3) −5.1, 17.0, 18.2,
the mixture stirred until the colour of iodine disappeared. 18.6, 20.9, 24.6, 26.3, 33.4, 35.0, 35.9, 37.0 and 68.6; m/z (CI)
Ether was added, the layers were separated and the aqueous 402 (M+ + 18, 24%), 385 (M+ + 1, 100) and 132 (80). Slight split-
phase was extracted with ether (3 × 10 mL). The organic ting of the dd at δ3.27 indicated a small amount, <5% of an
extracts were washed with brine, dried (MgSO4) and concen- epimer was present.
trated under reduced pressure. Chromatography (15 : 1, light
2-[(2R,6S)-7-tert-Butyldimethylsilyloxy-2,6-dimethylhept-1-yl]-
petroleum–ether) of the residue gave the title compound 79 as a 1,3-dithiane 82. nButyllithium (1.7 M in hexanes, 10.4 mL,
colourless oil (257 mg, 94%), Rf = 0.8 (15 : 1, light petroleum– 0.63 mmol) was added dropwise to recrystallised (methanol)
ether), [α]2D0 +3 (c 2.8, CHCl3) (Found: M+ + NH4, 378.1285. dithiane (87 mg, 0.78 mmol), in THF (1 mL) at −20 °C. The
C16H29ONI requires M, 378.1288); νmax/cm−1 2956, 2927, 2853, solution was stirred at −20 °C for 1 h then allowed to warm to
1453, 1376, 1363, 1256, 1195, 1099, 1028 and 735; δH 0 °C. Iodide 81 (120 mg, 0.31 mmol) in THF (1 mL) was added
(300 MHz, CDCl3) 0.99 (3 H, d, J 7, 2-CH3), 1.02 (3 H, d, J 6, and the mixture was stirred at 0 °C for 16 h. Water (2 mL) and
6-CH3), 1.10–1.60 (7 H, m, 3-H2, 4-H2, 5-H2 and 6-H), 1.83 (1 H, ether (2 mL) were added and the aqueous phase was extracted
m, 2-H), 3.20 (1 H, dd, J 10 and 6, 7-H), 3.29 (2 H, m, 7-H′ and with ether (3 × 3 mL). The organic extracts were washed with
1-H), 3.37 (1 H, dd, J 9 and 6, 1-H′), 4.57 (2 H, s, OCH2Ph) and brine, dried (MgSO4) and concentrated under reduced
7.36 (5 H, m, ArH); δC (300 MHz, CDCl3) 17.5, 18.3, 21.0, 24.5, pressure. Chromatography (20 : 1, light petroleum–ether) of
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the residue gave the title compound 82 as a colourless oil and 6, 1-H′); δC (75 MHz, CDCl3) −5.1, 1.30, 16.9, 17.1, 18.6,
(100 mg, 89%), Rf = 0.8 (10 : 1, light petroleum–ether), [α]2D0 +7 20.0, 20.0, 24.7, 26.2, 30.0(2), 33.7, 33.8, 36.0, 37.6 and 68.7;
(c 2.3, CHCl3) (Found: M+ + 1, 377.2360. C19H41OS2Si requires m/z (CI) 432 (M+ + 18, 2%), 415 (M+ + 1, 100), 132 (46) and
M, 377.2363); νmax/cm−1 2952, 2928, 2855, 1592, 1462, 1252, 92 (54).
1094, 836 and 774; δH (300 MHz, CDCl3) 0.06 (6 H, s, 2 ×
(2R,4SR,6R)-7-Benzyloxy-1-tert-butyldimethylsilyloxy-4,6-dimethyl-
SiCH3), 0.89 (3 H, d, J 7, 2′-CH3), 0.95 [12 H, m, SiC(CH3)3 and heptan-2-ols 87. Following the standard procedure, sodium
6′-CH3], 1.00–2.00 (11 H, m, 5-H2, 2′-H, 3′-H2, 4′-H2, 5′-H2 and acetate (302 mg, 2.2 mmol) in water (0.8 mL), the alkene 31f
1′-H2), 2.13 (1 H, m, 6′-H), 2.87 (4 H, m, 4-CH2 and 6-CH2), (70 mg, 0.19 mmol) and toluene p-sulfonylhydrazine (207 mg,
3.38 (1 H, dd, J 10 and 7, 7′-H), 3.47 (1 H, dd, J 10 and 6, 7′-H′) 1.1 mmol) in DME (3 mL), after heating under reflux for 16 h
and 4.13 (1 H, dd, J 8 and 6, 2-H); δC (75 MHz, CDCl3) −5.1, and chromatography (10 : 1, light petroleum–ether) gave the
17.1, 18.6, 19.7, 24.4, 26.2, 26.4, 29.9, 30.7, 30.9, 33.6, 36.0, title compounds 87 as a colourless oil (48 mg, 82%), a
37.4, 42.8, 45.8 and 68.6; m/z (CI) 394 (M+ + 18, 32%), 377 2 : 1 mixture of epimers (1H and 13C NMR), Rf = 0.48 (2 : 1,
(M+ + 1, 100), 245 (40) and 132 (48). Less than 5% of any light petroleum–ether); νmax/cm−1 3471, 3031, 2935, 2859,
epimer was present, cf. the dd at δ3.47.
1462, 1255, 1103, 840, 779 and 697; δH (300 MHz, CDCl3)
(2R,6S,10R,14S)-1-Benzyloxy-15-tert-butyldimethylsilyloxy-8,8- major 4-epimer 0.12 (6 H, s, 2 × SiCH3), 0.83 [9 H, s, SiC-
(1,5-dithiatrimethylene)-2,6,10,14-tetramethylpentadecane 83. (CH3)3], 0.85 (3 H, d, J 7, 4-CH3), 0.87 (3 H, d, J 7, 6-CH3),
nButyllithium (1.7 M in hexanes, 0.19 mL, 0.113 mmol) was 1.10–2.00 (6 H, m, 3-H2, 4-H, 5-H2 and 6-H), 2.50 (1 H, br. s,
added dropwise to the 1,3-dithiane 82 (43 mg, 0.119 mmol), in OH), 3.28 (1 H, dd, J 9 and 7, 7-H), 3.35 (1 H, dd, J 9 and 7,
THF (1 mL) and HMPA (0.1 mL) at −78 °C. After 30 min, the 7-H′), 3.39 (1 H, dd, J 10 and 7, 1-H), 3.60 (1 H, dd, J 10 and 4,
iodide 79 in THF (0.5 mL) was added and the mixture was 1-H′), 3.80 (1 H, m, 2-H), 4.58 (2 H, s, OCH2Ph) and 7.35 (5 H,
stirred at −78 °C for 1 h. Saturated aqueous ammonium chlor- m, ArH); minor 4-epimer 2.41 (1 H, br. s, OH), 3.23 (1 H, dd,
ide (4 mL) was added and the aqueous phase was extracted J 9 and 7, 7-H), 3.40 (1 H, dd, J 10 and 7, 1-H) and 3.62 (1 H,
with ethyl acetate (3 × 5 mL). The organic extracts were washed dd, J 10 and 4, 1-H′); δC (75 MHz, CDCl3) major 4-epimer −5.1,
with brine (15 mL), dried (MgSO4) and concentrated under 17.1, 18.3, 20.5, 26.3, 27.1, 31.3, 41.0, 42.6, 67.9, 70.3, 73.4,
reduced pressure. Chromatography (30 : 1, light petroleum– 76.5, 127.8, 127.9, 128.7 and 139.1; minor 4-epimer 18.7, 26.9,
ether) of the residue gave the title compound 83 as a colourless 31.1, 40.0 and 69.9; m/z (CI) 398 (M+ + 18, 3%), 381 M+ + 1, 52),
oil (60 mg, 88%), Rf = 0.7 (10 : 1, light petroleum–ether); 108 (51) and 91 (100).
[α]2D0 +5 (c 1.5, CHCl3) (Found: M+
+
H, 610.4263.
Palladium (11 mg, 10% on activated carbon, 0.01 mmol)
C3413CH65O2S2Si requires M, 609.4258); νmax/cm−1 2927, 2854, was added to the alkene 31f (20 mg, 0.053 mmol) in MeOH
1598, 1460, 1297, 1251, 1210, 1097, 985, 836, 775 and 738; δH (1 mL) at room temperature. The mixture was stirred under an
(300 MHz, CDCl3) 0.07 (6 H, s, 2 × SiCH3), 0.91 (3 H, d, J 7, atmosphere of hydrogen for 1 h then filtered through celite.
10-CH3), 0.93 [9 H, s, SiC(CH3)3], 0.97 (3 H, d, J 7, 6-CH3), 1.05 The filtrate was washed with DCM (5 mL) and concentrated
(6 H, d, J 6, 2-CH3 and 14-CH3), 1.00–2.00 (22 H, m), 2.84 (4 H, under reduced pressure. Chromatography (10 : 1, light pet-
t, J 6, 2′-H2 and 4′-H2), 3.27 (1 H, dd, J 9 and 7, 15-H), 3.36 roleum–ether) also gave a 2 : 1 mixture of the 4-epimers of the
(1 H, dd, J 9 and 6, 15-H′), 3.39 (1 H, dd, J 10.5 and 6.5, 1-H), title compound 87 (18 mg, 90%) as a colourless oil.
3.48 (1 H, dd, J 9 and 6, 1-H′), 4.54 (2 H, s, OCH2Ph) and 7.34
(3E,2R,6S)-1-Benzyloxy-6-tri-isopropylsilyloxy-2,4-dimethyl-
(5 H, m, ArH); δC (75 MHz, CDCl3) −5.0, 17.1, 17.4, 17.5, 18.6, non-3-ene 88. 2,6-Lutidine (0.76 mL, 6.51 mmol) and tri-iso-
22.3, 22.4, 24.6, 24.7, 25.4, 26.3, 26.9, 30.0, 33.7, 33.8, 34.2, propylsilyl trifluoromethanesulfonate (0.70 mL, 2.60 mmol)
36.0, 39.7, 39.8, 47.2, 55.4, 68.7, 73.2, 76.3, 127.7, 127.8, 128.6 were added to the alcohol 31d (600 mg, 2.17 mmol) in DCM
and 139.1; m/z (CI) 610 (M+ + 2, 12%), 377 (12), 351 (16) and (5 mL) at 0 °C. The solution was allowed to warm to ambient
180 (100).
temperature and was stirred for 16 h. Saturated aqueous
(2R,6R,10S,14S)-15-tert-Butyldimethylsilyloxy-2,6,10,14-tetra- ammonium chloride (20 mL) was added and the mixture was
methylpentadecan-1-ol 84. Freshly activated (by washing with extracted with DCM (3 × 20 mL). The organic extracts were
deionised water under an inert atmosphere) W-2 RANEY® washed with brine (20 mL), dried (MgSO4) and concentrated
nickel (500 mg, 8.5 mmol) was added to the dithiane 83 under reduced pressure. Chromatography (10 : 1, light pet-
(20 mg, 0.033 mmol) in THF (2.5 mL) and the suspension was roleum–ether) of the residue gave the title compound 88 as a
stirred under reflux for 16 h. After cooling to room tempera- colourless oil (834 mg, 89%), Rf = 0.73 (3 : 1, light petroleum–
ture, the mixture was filtered through celite® to afford the title ether), [α]2D0 −6.4 (c 0.3, CHCl3) (Found: M+ + NH4, 450.3766.
compound 84 as a colourless oil (13 mg, 95%), Rf = 0.8 (10 : 1, C27H52O2NSi requires M, 450.3762); νmax/cm−1 2958, 2941,
light petroleum–ether), [α]2D0 +4 (c 1.0, CHCl3) (Found: M+ + 1, 2863, 1459, 1366, 1096, 1043, 883, 732 and 677; δH (500 MHz,
415.3966. C25H55O2Si requires M, 415.3966); νmax/cm−1 2954, CDCl3) 0.79 (3 H, t, J 7, 9-H3), 0.89 (3 H, d, J 7, 2-CH3), 0.99
2927, 2856, 1463, 1377, 1257, 1095, 1034, 836 and 775; δH [21 H, m, 3 × SiCH(CH3)2], 1.25–1.39 (4 H, m, 7-H2 and 8-H2),
(300 MHz, CDCl3) 0.07 (6 H, s, 2 × SiCH3), 0.80 (6 H, d, J 6, 1.57 (3 H, d, J 1, 4-CH3), 2.04 (1 H, dd, J 13 and 9, 5-H), 2.16
6-CH3 and 10-CH3), 0.93 [12 H, m, SiC(CH3)3 and 14-CH3], 0.96 (1 H, dd, J 13 and 5, 5-H′), 2.63 (1 H, m, 2-H), 3.13 (1 H, dd, J 9
(3 H, d, J 7, 2-CH3), 1.00–1.75 (22 H, m), 3.38 (1 H, dd, J 10 and and 8, 1-H), 3.23 (1 H, dd, J 9 and 6, 1-H′), 3.87 (1 H, m, 6-H),
7, 15-H), 3.46 (2 H, m, 1-H and 15-H′) and 3.55 (1 H, dd, J 11 4.41 and 4.44 (each 1 H, d, J 12, OHCHPh), 4.89 (1 H, d, J 9,
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3-H) and 7.26 (5 H, m, ArH); δC (125 MHz, CDCl3) 12.7, 14.4, 16.2, 16.8, 19.0, 34.2, 39.6, 48.3, 67.6, 67.8, 131.5 and 133.7;
16.9, 17.7, 17.8, 18.2, 33.0, 38.4, 47.6, 70.8, 72.9, 75.3, 127.4, m/z (ES+) 209 (M+ + 23, 100%). No minor isomer detected.
127.5, 128.3, 130.1, 133.0 and 138.7; m/z (ES+) 455 (M+ + 23,
(6E,4S,8R)-9-Tri-isopropylsilyloxy-6,8-dimethylnon-6-en-4-ol
91. Imidazole (274 mg, 4.03 mmol) and tri-isopropylsilyl
95%), 450 (M+ + 18, 100%) and 433 (M+ + 1, 3).
(3E,2R,6S)-6-Tri-isopropylsilyloxy-2,4-dimethylnon-3-en-1-ol chloride (0.45 mL, 2.097 mmol) were added to the diol 90
89. Lithium metal (88 mg, 12.50 mmol) was added in small (300 mg, 1.61 mmol) in DCM (8 mL) at 0 °C and the solution
portions to naphthalene (2.13 g, 16.64 mmol) in THF (30 mL). was stirred for 1 h at room temperature. Water was added
The reaction mixture was stirred at room temperature under (15 mL) and the mixture extracted using DCM (3 × 15 mL). The
an argon atmosphere until the lithium metal had completely organic extracts were washed with water (20 mL) and brine
dissolved. The resulting dark green solution of lithium (20 mL), dried (MgSO4) and concentrated under reduced
naphthalenide was then cooled to −25 °C and the alkene 88 pressure. Chromatography (10 : 1, light petroleum–ether) of
(900 mg, 2.08 mmol) in THF (15 mL) was added dropwise. The the residue gave the title compound 91 as a colourless oil
mixture was stirred at −25 °C for 2 h and then saturated (495 mg, 90%), Rf = 0.70 (1 : 1, light petroleum–ether),
aqueous ammonium chloride (30 mL) and water (30 mL) were [α]2D0 −6.3 (c 0.3, CHCl3) (Found: M+ + NH4, 360.3294.
added. The mixture was extracted with ether (3 × 40 mL) and C20H46O2NSi requires M, 360.3292); νmax/cm−1 3435, 2961,
the organic extracts were washed with water and brine, dried 2941, 2867, 1462, 1385, 1093, 882 and 787; δH (500 MHz,
(MgSO4) and concentrated under reduced pressure. Chromato- CDCl3) 0.86 and 0.87 (each 3 H, d, J 7, 1-H3 and 8-CH3), 0.98
graphy (4 : 1, light petroleum–ether) of the residue gave the [21 H, m, 3 × SiCH(CH3)2], 1.25–1.45 (4 H, m, 2-H2 and 3-H2),
title compound 89 (642 mg, 90% yield) as a light yellow oil, Rf = 1.59 (3 H, s, 6-CH3), 1.87 (1 H, br. s, 6-OH), 1.90 (1 H, dd, J 13
0.32 (2 : 1, light petroleum–ether), [α]2D0 −3.0 (c 0.3, CHCl3) and 10, 5-H), 2.09 (1 H, dd, J 13 and 3, 5-H′), 2.53 (1 H, m,
(Found: M+
+ NH4, 360.3301. C20H46O2NSi requires M, 8-H), 3.36 (1 H, dd, J 10 and 7, 9-H), 3.41 (1 H, dd, J 10 and 7,
360.3292); νmax/cm−1 3339, 2956, 2946, 2868, 1462, 1383, 9-H′), 3.56 (1 H, m, 4-H) and 4.96 (1 H, d, J 10, 7-H);
1108, 1040, 883 and 677; δH (500 MHz, CDCl3) 0.80 (3 H, t, J 6, δC (125 MHz, CDCl3) 12.0, 14.2, 16.5, 17.1, 18.0, 19.0, 35.8,
9-H3), 0.85 (3 H, d, J 7, 2-CH3), 0.99 [21 H, m, 3 × SiCH(CH3)2], 39.0, 48.2, 67.7, 68.4, 132.1 and 132.4; m/z (ES+) 365 (M+ + 23,
1.28–1.39 (4 H, m, 7-H2 and 8-H2), 1.61 (3 H, d J 0.5, 4-CH3), 100%).
2.09 (1 H, dd, J 13 and 8, 5-H), 2.19 (1 H, dd, J 13 and 5,
(2R,4S,6S)-6-Tri-isopropylsilyloxy-2,4-dimethylnonan-1-ol 96.
5-H′), 2.55 (1 H, m, 2-H), 3.25 (1 H, t, J 9, 1-H), 3.39 (1 H, m, To a steel screw-cap high-pressure bomb was added alcohol 89
1-H′), 3.90 (1 H, m, 6-H) and 4.85 (1 H, d, J 9, 3-H); (50 mg, 0.15 mmol) followed by [Rh(NBD)Diphos-4]BF4 (5 mg,
δC (125 MHz, CDCl3) 12.7, 14.4, 17.0, 17.1, 17.8, 18.3, 35.4, 0.0073 mmol, 5 mol%) and DCM (2.5 mL). The pressure gauge
38.5, 47.6, 67.9, 70.7, 129.7 and 135.2; m/z (ES+) 365 (M+ + 23, block was attached, and the bomb was flushed three times
100%) and 343 (M+ + 1, 10). No minor isomer detected, with hydrogen and then filled with hydrogen to a pressure of
i.e. <2%.
to 950 psi. After being stirred for 5 h at room temperature, the
(3E,2R,6S)-2,4-Dimethylnon-3-ene-1,6-diol 90. The alcohol solution was filtered through silica gel and concentrated under
31d (200 mg, 0.72 mmol) in ethanol (8 mL) was added to a reduced pressure. Chromatography (10 : 1, light petroleum–
50 mL, three-necked flask equipped with a stirrer, Dewar con- ether) of the residue gave the title compound 96 as a colourless
denser, and an ammonia inlet. The flask was cooled to −78 °C oil (41 mg, 82%), Rf = 0.35 (2 : 1, light petroleum–ether),
and ammonia was condensed until a final volume of 15 mL [α]2D0 +4.8 (c 0.3, CHCl3) (Found: M+
+ Na, 367.2987.
was achieved. Small pieces of sodium wire were added to the C20H44O2NaSi requires M, 367.3003); νmax/cm−1 3340, 2956,
solution until a characteristic deep blue colour persisted. Solid 2868, 1462, 1380, 1126, 1089, 1040, 883, 718 and 675; δH
ammonium chloride was added in portions until the mixture (500 MHz, CDCl3) 0.83 (3 H, t, J 7, 9-H3), 0.83 (3 H, d, J 7,
was white. The mixture was allowed to warm to room temp- 4-CH3), 0.85 (3 H, d, J 7, 2-CH3), 0.89 (1 H, dd, J 14 and 7, 3-H),
erature over a period of 1 h and ethyl acetate (30 mL) was 0.99 (21 H, m, 3 × SiCH(CH3)2], 1.05 (1 H, m, 3-H′), 1.17 (2 H,
added. Water (30 mL) was added and the aqueous layer m, 8-H2), 1.26 (1 H, m, 7-H), 1.32–1.46 (3 H, m, 5-H2 and 7-H′),
extracted with ethyl acetate (3 × 30 mL). The organic layers 1.62–1.70 (2 H, m, 2-H and 4-H), 3.27 (1 H, dd, J 10 and 7,
were dried (Na2SO4) and concentrated under reduced pressure. 1-H), 3.44 (1 H, dd, J 10 and 5, 1-H′) and 3.82 (1 H, m, 6-H); δC
Chromatography (1 : 1, light petroleum–ether) of the residue (125 MHz, CDCl3) 12.9, 14.4, 17.4, 17.7, 18.2, 20.7, 26.4, 33.0,
gave the title compound 90 as a colourless oil (101 mg, 75%), 40.3, 41.8, 44.2, 68.2 and 70.4; m/z (ES+) 367 (M+ + 23, 100%).
Rf = 0.17 (1 : 2, light petroleum–ether), [α]2D0 +2.7 (c 0.3, CHCl3)
(2R,4S,6S)- and (2R,4R,6S)-2,4-Dimethylnonane-1,6-diols 97
(Found: M+ + Na, 209.1505. C11H22O2Na requires M, 209.1512); and 102. To a steel screw-cap high-pressure bomb was added
νmax/cm−1 3338, 2957, 2929, 2872, 1455, 1124, 1073, 1036 and diol 90 (70 mg, 0.37 mmol) and [Rh(NBD)Diphos-4]BF4
830; δH (500 MHz, CDCl3) 0.83 (3 H, d, J 7, 2-CH3), 0.85 (3 H, t, (13 mg, 0.019 mmol, 5 mol%) and DCM (2.5 mL). The pressure
J 7, 9-H3), 1.28–1.43 (4 H, m, 7-H2 and 8-H2), 1.59 (3 H, s, gauge block was attached, and the bomb was flushed three
4-CH3), 1.90 (1 H, dd, J 13 and 10, 5-H), 2.09 (1 H, d, J 13, times with hydrogen and then was filled with hydrogen to a
5-H′), 2.55 (1 H, m, 2-H), 2.82 (1 H, br. s, 1-OH), 3.15 (1 H, br. pressure of to 950 psi. After being stirred for 5 h at room temp-
s, 6-OH), 3.17 (1 H, t, J 10, 1-H), 3.42 (1 H, m, 1-H′), 3.61 (1 H, erature, the solution was filtered through silica gel and con-
m, 6-H) and 4.89 (1 H, d, J 10, 3-H); δC (125 MHz, CDCl3) 14.1, centrated under reduced pressure. Chromatography (5 : 1, light
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petroleum–ether) of the residue gave the title compound 102 (Found: M+
+
Na, 367.3011. C20H44O2NaSi requires M,
(7 mg, 10%) as a colourless oil, Rf = 0.19 (1 : 2, light pet- 367.3003); νmax/cm−1 3346, 2956, 2927, 2867, 1462, 1382, 1103,
roleum–ether), [α]2D0 +4.8 (c 0.3, CHCl3) (Found: M+ − H, 1068, 997, 882, 787 and 681; δH (500 MHz, CDCl3) 0.80 (3 H, d,
187.1687. C11H23O2 requires M, 187.1693); νmax/cm−1 3336, J 7, 8-CH3), 0.81 (3 H, d, J 7, 6-CH3), 0.85 (3 H, t, J 7, 1-H3), 0.99
2958, 2925, 2873, 1462, 1379, 1124 and 1037; δH (500 MHz, [21 H, m, 3 × SiCH(CH3)2], 1.02–1.10 (2 H, m, 7-H2), 1.26–1.42
CDCl3) 0.83 (6 H, d, J 7, 2-CH3 and 4-CH3), 0.86 (3 H, t, J 7, (6 H, m, 2-H2, 3-H2 and 5-H2), 1.63–1.67 (2 H, m, 6-H and 8-H),
9-H3), 1.04–1.06 (2 H, m, 3-H2), 1.26–1.43 (6 H, m, 5-H2, 7-H2 3.36 (1 H, dd, J 10 and 7, 9-H), 3.41 (1 H, dd, J 10 and 6, 9-H′)
and 8-H2), 1.65–1.70 (2 H, m, 2-H and 4-H), 3.37 (1 H, dd, J 10 and 3.64 (1 H, m, 4-H); δC (125 MHz, CDCl3) 12.0, 14.1, 16.5,
and 6, 1-H), 3.40 (1 H, dd, J 10 and 6, 1-H′) and 3.65 (1 H, m, 6- 18.0, 18.8, 20.3, 26.8, 33.5, 40.1, 40.3, 46.2, 69.3 and 69.6; m/z
H); δC (125 MHz, CDCl3) 14.1, 16.2, 18.8, 20.4, 26.6, 33.2, 40.1, (ES−) 367 (M+ + Na, 100%).
46.1, 69.1 and 69.5; m/z (ES−) 188 (M+, 14%) and 187 (M+ − 1,
Imidazole (27 mg, 0.39 mmol) and tri-isopropylsilyl chlor-
100). The second fraction was the title compound 97 (34 mg, ide (40 μL, 0.21 mmol) were added to the diol 97 (30 mg,
48%) as a colourless oil, Rf = 0.17 (1 : 2, light petroleum–ether), 0.16 mmol) in DCM (1 mL) at 0 °C and the solution was
[α]2D0 +7.6 (c 0.2, CHCl3) (Found: M+ − H, 187.1687. C11H23O2 stirred for 1 h at room temperature. Water was added (3 mL)
requires M, 187.1693); νmax/cm−1 3339, 2957, 2923, 2872, 1461, and the mixture extracted into DCM (3 × 5 mL). The organic
1378, 1123 and 1037; δH (500 MHz, CDCl3) 0.84 (3 H, d, J 7, extracts were washed with water (5 mL) and brine (5 mL), dried
2- or 4-CH3), 0.85 (3 H, t, J 7, 9-H3), 0.86 (3 H, d, J 7, 4- or 2- (MgSO4) and concentrated under reduced pressure. Chromato-
CH3), 0.91 (1 H, m, 3-H), 1.01 (1 H, m, 3-H′), 1.24–1.39 (6 H, m, graphy (20 : 1, light petroleum–ether) of the residue gave the
5-H2, 7-H2, 8-H2), 1.62–1.73 (2 H, m, 2-H and 4-H), 1.84 (1 H, br. alcohol 98 as a colourless oil (49 mg, 90%).
s, OH), 2.10 (1 H, br. s, OH), 3.37 (1 H, dd, J 10 and 6, 1-H), 3.41
(2R,4R,6S)-1-Tri-isopropylsilyloxy-2,4-dimethylnonan-6-yl
(1 H, dd, J 10 and 5, 1-H′) and 3.62 (1 H, m, 6-H); δC (125 MHz, 4-methylbenzenesulfonate 93. Toluene p-sulfonyl chloride
CDCl3) 14.1, 17.5, 18.9, 20.1, 26.7, 32.9, 40.7, 41.9, 44.8, 67.8 (512 mg, 2.69 mmol) and 4-dimethylaminopyridine (460 mg,
and 69.5; m/z (ES−) 188 (M+, 14%) and 187 (M+ − 1, 100).
3.77 mmol) were added to the alcohol 92 (370 mg, 1.08 mmol)
Tetrabutylammonium fluoride (1.0 M in THF, 0.12 mL, in DCM (10 mL) at room temperature and the mixture was
0.41 mmol) was added to the silyl ether 96 (70 mg, 0.20 mmol) stirred for 16 h. The solution was concentrated under reduced
in THF (1 mL) and the mixture left to stir at room temperature pressure and chromatography (6 : 1, light petroleum–ether) of
for 16 h. Water (2 mL) was added and the mixture stirred for a the white solid residue gave the title compound 93 as a colour-
further 1 h. The mixture was then extracted with ether (3 × less oil (474 mg, 91%), Rf = 0.67 (2 : 1, light petroleum–ether),
3 mL) and the organic extracts washed with brine (5 mL), [α]2D0 +3.0 (c 1.5, CHCl3) (Found: M+
+ H, 499.3278.
dried (MgSO4) and concentrated under reduced pressure. C27H51O4SSi requires M, 499.3272); νmax/cm−1 2961, 2867,
Chromatography (1 : 2, light petroleum–ether to ether) of the 1600, 1463, 1363, 1177, 1099, 885 and 665; δH (500 MHz,
residue gave the diol 97 as a colourless oil (35 mg, 91%).
CDCl3) 0.73 and 0.74 (each 3 H, d, J 7, 2- or 4-CH3), 0.75 (3 H,
(4S,6R,8R)- and (4S,6S,8R)-9-Tri-isopropylsilyloxy-6,8- t, J 7.5, 9-H3), 0.98 [21 H, s, 3 × SiCH(CH3)2], 1.05–1.28 (4 H,
dimethylnonan-4-ols 92 and 98. To a steel screw-cap high- m, 3-H2 and 8-H2), 1.39–1.45 (5 H, m, 4-H, 5-H2 and 7-H2), 1.56
pressure bomb was added alcohol 91 (50 mg, 0.15 mmol) (1 H, m, 2-H), 2.37 (3 H, s, CH3Ar), 3.33 (1 H, dd, J 3 and 1, 1-
and [Rh(NBD)Diphos-4]BF4 (5 mg, 0.0073 mmol, 5 mol%) and H), 3.35 (1 H, dd, J 3 and 1, 1-H′), 4.59 (1 H, m, 6-H) and 7.24
DCM (2.5 mL). The pressure gauge block was attached, and and 7.71 (each 2 H, d, J 9, ArH); δC (125 MHz, CDCl3) 12.0,
the bomb was flushed three times with hydrogen and then was 13.8, 16.3, 17.8, 18.1, 19.4, 21.6, 26.7, 33.3, 36.5, 40.7, 42.7,
filled with hydrogen to a pressure of 950 psi. After being 69.1, 82.9, 127.7, 129.6, 135.0 and 144.3; m/z (CI) 499 (M+ + 1,
stirred for 5 h at room temperature, the solution was filtered 28%), 327 (100), 326 (24) and 283 (30).
through silica gel and concentrated under reduced pressure.
(2R,4S,6R)-1-Tri-isopropylsilyloxy-2,4,6-trimethylnonane 94.
Chromatography (10 : 1, light petroleum–ether) gave the title Methyllithium (1.6 M in Et2O, 3.14 mL, 5.02 mmol) was added
compound 98 (5 mg, 10%) as a colourless oil, Rf = 0.70 (1 : 1, dropwise to copper(I) cyanide (225 mg, 2.51 mmol) in toluene
light petroleum–ether), [α]2D0 +7.6 (c 1.1, CHCl3) (Found: M+ + (6.5 mL) at 0 °C and the mixture was stirred at this temperature
Na, 367.2999. C20H44O2NaSi requires M, 367.3003); νmax/cm−1 for 15 min. Toluene p-sulfonate 93 (250 mg, 0.50 mmol) in
3351, 2967, 2925, 2867, 1462, 1381, 1257, 1103, 1017, 883 and toluene (4.5 mL) was added dropwise and the mixture was
791; δH (500 MHz, CDCl3) 0.84 and 0.85 (each 3 H, d, J 7, 6- stirred at 0 °C for a further 5 h. The mixture was filtered
CH3 or 8-CH3), 0.86 (3 H, t, J 7, 1-H3), 0.88 (1 H, dd, J 14 and 7, through celite, washing the celite with DCM (10 mL) and Et2O
7-H), 0.99 [21 H, m, 3 × SiCH(CH3)2], 1.02 (1 H, m, 7-H′), (10 mL). The organic extracts were concentrated under reduced
1.25–1.39 (6 H, m, 2-H2, 3-H2 and 5-H2), 1.62–1.72 (2 H, m, 6-H pressure and the yellow residue was dissolved in acetone
and 8-H), 3.37 (1 H, dd, J 10 and 6, 9-H), 3.46 (1 H, dd, J 10 (7.5 mL) and water (1.5 mL). N-Methylmorpholine N-oxide
and 6, 9-H′) and 3.64 (1 H, m, 4-H); δC (125 MHz, CDCl3) 12.0, (75 mg, 0.20 mmol, 1.2 equiv.) and OsO4 (1 crystal, cat.) were
14.1, 17.5, 18.0, 18.9, 20.2, 26.6, 33.3, 40.6, 41.9, 44.8, 68.7 and added at room temperature and the solution was stirred for
69.3; m/z (ES−) 367 (M+ + Na, 100%). The more polar product 16 h. Saturated aqueous sodium sulfite (20 mL) was added and
was the title compound 92 (28 mg, 56%) as a colourless oil, Rf = the mixture was stirred for 1 h before being extracted with
0.68 (1 : 1, light petroleum–ether), [α]2D0 +7.8 (c 1.5, CHCl3) ether (3 × 30 mL). The organic extracts were washed with brine
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(30 mL), dried (MgSO4), and concentrated under reduced
(2R,4R,6R)-1-(Tri-isopropylsilyloxy)-2,4,6-trimethylnonane
pressure. Chromatography (10 : 1, light petroleum–ether) of 100. Following the standard procedure, methyllithium (1.6 M
the residue gave the title compound 94 (82 mg, 48%) as a in Et2O, 3.14 mL, 5.02 mmol), copper(I) cyanide (225 mg,
colourless oil, Rf = 0.43 (100% light petroleum), [α]2D0 +3.8 2.51 mmol) and the toluene p-sulfonate 99 (250 mg,
(c 1.0, CHCl3) (Found: M+ + NH4, 360.3648. C21H50ONSi 0.50 mmol), after chromatography (10 : 1, light petroleum–
requires M, 360.3656); νmax/cm−1 2956, 2927, 2868, 1464, ether), afforded the title compound 100 (77 mg, 45%) as a col-
1380, 1247, 1107, 1068, 1013, 996, 918, 883, 787 and 681; ourless oil, Rf = 0.41 (100% light petroleum), [α]2D0 +3.1 (c 0.3,
δH (500 MHz, CDCl3) 0.72 (3 H, d, J 7, 6-CH3), 0.74 (3 H, d, J 7, CHCl3) (Found: M+, 342.3311. C21H46OSi requires M,
4-CH3), 0.79 (3 H, t, J 7, 9-H3), 0.80 (3 H, d, J 7, 2-CH3), 0.88 342.3312); νmax/cm−1 2956, 2925, 2868, 1462, 1380, 1104, 882
(1 H, m, 3-H), 0.99 [21 H, m, 3 × SiCH(CH3)2], 1.04 (1 H, m, 3- and 682; δH (500 MHz, CDCl3) 0.76 (3 H, d, J 6.5, 6-CH3), 0.78
H′), 1.07–1.28 (6 H, m, 5-H2, 7-H2 and 8-H2), 1.39–1.53 (2 H, m, (3 H, d, J 6.5, 4-CH3), 0.81 (3 H, t, J 7, 9-H3), 0.84 (3 H, d, J 6.5,
4-H and 6-H), 1.65 (1 H, m, 2-H), 3.32 (1 H, dd, J 9 and 7, 1-H) 2-CH3), 0.92 (1 H, m, 3-H), 0.99 [21 H, m, 3 × SiCH(CH3)2], 1.02
and 3.43 (1 H, dd, J 9 and 6, 1-H′); δC (125 MHz, CDCl3) 12.0, (1 H, m, 3-H′), 1.10–1.31 (6 H, m, 5-H2, 7-H2 and 8-H2),
14.4, 16.8, 18.1, 19.4, 19.5, 20.1, 27.3, 29.7, 33.5, 40.2, 41.6, 1.40–1.53 (2 H, m, 4-H and 6-H), 1.60 (1 H, m, 2-H), 3.36 (1 H,
45.7 and 69.2; m/z (CI) 343 (M+ + 1, 100%), 342 (M+, 77) and dd, J 10 and 6, 1-H) and 3.47 (1 H, dd, J 10 and 5, 1-H′); δC
316 (20).
(2R,4S,6R)-2,4,6-Trimethylnonan-1-ol
(125 MHz, CDCl3) 12.1, 14.1, 14.4, 18.0, 20.0, 20.5, 21.0, 27.7,
95. Tetra-n-butyl- 29.8, 33.5, 38.9, 41.4, 45.5 and 68.4; m/z (CI) 343 (M+ + 1, 81%),
ammonium fluoride (1.0 M in THF, 0.29 mL, 0.29 mmol) was 316 (28), 110 (100), 83 (87) and 58 (76).
added to the silyl ether 94 (50 mg, 0.15 mmol) in THF (1 mL)
(2R,4R,6R)-2,4,6-Trimethylnonan-1-ol 101. Following the
and the mixture was stirred at room temperature for 16 h. standard procedure, tetra-n-butylammonium fluoride (1.0 M in
Water (2 mL) was added and the mixture was stirred for a THF, 0.29 mL, 0.29 mmol) and the silyl ether 100 (50 mg,
further 1 h then extracted with ether (3 × 3 mL). The organic 0.15 mmol), after chromatography (10 : 1 to 5 : 1, light pet-
extracts were washed with brine (5 mL), dried (MgSO4) and roleum–ether), afforded the title compound 101 (25 mg, 91%)
concentrated under reduced pressure. Chromatography (10 : 1 as a colourless oil, Rf = 0.33 (1 : 1, light petroleum–ether), [α]D20
to 5 : 1, light petroleum–ether) of the residue gave the title com- +7.3 (c 1.1, CHCl3) (Found: M+ − H2O, 168.1867. C12H24
pound 95 as a colourless oil (25 mg, 90%), Rf = 0.33 (1 : 1, light requires M, 168.1873); νmax/cm−1 3326, 2956, 2916, 2872, 2845,
petroleum–ether), [α]2D0 +4.1 (c 0.3, CHCl3) (Found: M+ − H2O, 1460, 1378 and 1040; δH (400 MHz, CDCl3) 0.77 (3 H, d, J 6.5,
168.1881. C12H24 requires M, 168.1873); νmax/cm−1 3325, 2956, 6-CH3), 0.80 (3 H, d, J 6.5, 4-CH3), 0.81 (3 H, t, J 7, 9-H3), 0.86
2916, 2872, 2845, 1460, 1378 and 1040; δH (400 MHz, CDCl3) (3 H, d, J 6.5, 2-CH3), 0.91 (1 H, m, 3-H), 1.11–1.31 (7 H, m, 3-
0.74 (3 H, d, J 6.5, 6-CH3), 0.75 (3 H, d, J 6.5, 4-CH3), 0.83 (3 H, H′, 5-H2, 7-H2 and 8-H2), 1.41–1.55 (2 H, m, 4-H and 6-H), 1.65
t, J 7, 9-H3), 0.83 (3 H, d, J 6.5, 2-CH3), 0.93–1.33 (8 H, m, 3-H2, (1 H, m, 2-H), 3.31 (1 H, dd, J 10 and 7, 1-H) and 3.47 (1 H, dd,
5-H2, 7-H2 and 8-H2), 1.39–1.55 (2 H, m, 4-H and 6-H), 1.66 J 10 and 5, 1-H′); δC (125 MHz, CDCl3) 14.4, 17.5, 19.9, 20.4,
(1 H, m, 2-H), 3.33 (1 H, m, 1-H) and 3.41 (1 H, m, 1-H′); δC 20.9, 27.5, 29.7, 33.1, 38.8, 41.3, 45.2 and 68.3; m/z (CI) 204
(125 MHz, CDCl3) 14.4, 16.4, 19.2, 19.5, 19.9, 27.2, 29.7, 33.2, (M+ + 18, 18%), 186 (M+, 4), 137 (23), 83 (41) and 58 (100).
40.1, 41.5, 45.7 and 69.0; m/z (CI) 204 (M+ + 18, 15%), 186 (M+,
9), 137 (92) and 57 (100).
(2R,4S,6S,)-1-Tri-isopropylsilyloxy-2,4-dimethylnonan-6-yl
4-methylbenzenesulfonate 99. Following the standard pro-
cedure, toluene p-sulfonyl chloride (104 mg, 0.55 mmol),
Notes and references
4-dimethylaminopyridine (101 mg, 0.83 mmol) and the
alcohol 98 (75 mg, 0.22 mmol), after chromatography (6 : 1,
light petroleum–ether) afforded the title compound 99 as a
colourless oil (99 mg, 91%), Rf = 0.67 (2 : 1, light petroleum–
ether), [α]2D0 +4.7 (c 1.7, CHCl3) (Found: M+ + H, 499.3273.
C27H51O4SSi requires M, 499.3272); νmax/cm−1 2961,
2867, 1600, 1463, 1364, 1177, 1098, 897, 683 and 665; δH
(500 MHz, CDCl3) 0.70 (3 H, d, J 7, 4-CH3), 0.74 (3 H, d, J 7,
2-CH3), 0.77 (3 H, t, J 7, 9-H3), 0.98 [21 H, s, 3 × SiCH(CH3)2],
1.05 (1 H, m, 3-H), 1.15–1.26 (3 H, m, 3-H′ and 8-H2), 1.39
(1 H, m, 4-H), 1.48–1.62 (5 H, m, 2-H, 5-H2 and 7-H2), 2.36
(3 H, s, CH3Ar), 3.31 (1 H, dd, J 10 and 6, 1-H), 3.38 (1 H, dd,
J 10 and 6, 1-H′), 4.60 (1 H, m, 6-H) and 7.23 and 7.71 (each
2 H, d, J 8, ArH); δC (125 MHz, CDCl3) 11.8, 12.2, 13.8, 17.3,
18.0, 20.3, 21.6, 26.3, 33.3, 37.3, 41.2, 41.4, 68.5, 82.6, 127.7,
129.6, 134.9 and 144.2; m/z (CI) 499 (M+ + 1, 27%), 327 (100)
and 283 (27).
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