Effective 1,5-, 1,6- and 1,7-remote stereocontrol in reactions of alkoxy- and hydroxy-substituted allylstannanes with aldehydes

Article abstract of DOI:10.1039/c0ob01084g

Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated stereoselectively with tin(iv) halides to generate allyltin trihalides which react with aldehydes to give (Z)-alk-3-enols with useful levels of 1,5-, 1,6- and 1,7-stereocontrol. Alk-2-enylstannanes with a stereogenic centre bearing a hydroxy or alkoxy group at the 4-, 5- or 6-position, react with overall (Z)-1,5-, 1,6- and 1,7-syn-stereoselectivity with respect to the hydroxy and alkoxy substituents. The analogous reactions of alkoxy- and -hydroxyalk-2-enylstannanes with a methyl bearing stereogenic centre at the 4- or 5-position react with overall (Z)-1,5- and 1,6-anti-stereoselectivity with respect to the hydroxy and methyl substituents.

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PAPER
Effective 1,5-, 1,6- and 1,7-remote stereocontrol in reactions of alkoxy- and
hydroxy-substituted allylstannanes with aldehydes†
John S. Carey, Somhairle MacCormick, Steven J. Stanway, Aphiwat Teerawutgulrag and Eric J. Thomas*
Received 25th November 2010, Accepted 24th February 2011
DOI: 10.1039/c0ob01084g
Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated
stereoselectively with tin(IV) halides to generate allyltin trihalides which react with aldehydes to give
(Z)-alk-3-enols with useful levels of 1,5-, 1,6- and 1,7-stereocontrol. Alk-2-enylstannanes with a
stereogenic centre bearing a hydroxy or alkoxy group at the 4-, 5- or 6-position, react with overall
(Z)-1,5-, 1,6- and 1,7-syn-stereoselectivity with respect to the hydroxy and alkoxy substituents. The
analogous reactions of alkoxy- and -hydroxyalk-2-enylstannanes with a methyl bearing stereogenic
centre at the 4- or 5-position react with overall (Z)-1,5- and 1,6-anti-stereoselectivity with respect to the
hydroxy and methyl substituents.
Introduction
4-Benzyloxypent-2-enylstannane 1 is transmetallated by tin(IV)
chloride to generate an allyltin trichloride which reacts with
aldehydes to give the (Z)-1,5-syn-5-benzyloxyalk-3-en-1-ols 2
with excellent 1,5-stereocontrol.1 This stereoselectivity usually
dominates the intrinsic stereochemical bias of a chiral aldehyde
and iterative reactions using an octa-2,7-dienylstannane have been
used to prepare aliphatic 1,5,9,13-polyols and ethers with useful
stereoselectivity.2
Fig. 1 Alk-2-enylstannanes selected for study.
Results and discussion
1,5-Stereocontrol using 5-alkoxyalk-2-enylstannanes I
It was of interest to see whether remote stereocontrol was
also observed for tin(IV) halide mediated reactions of alk-2-
enylstannanes which had alkoxy and hydroxy substituents at the
5- and 6-positions. We now report full details of the 1,5- and 1,6-
stereocontrol observed in the tin(IV) halide promoted reactions
between aldehydes and the 5-alkoxy(hydroxy)alk-2-enylstannanes
I and II, and 1,5-, 1,6- and 1,7-stereocontrol found for the
analogous reactions with aldehydes of the 6-alkoxy(hydroxy)alk-
2-enylstannanes III–V, see Fig. 1.3,4
The (R)-5-benzyloxy-4-methylpent-2-enylstannane 6 was synthe-
sized as outlined in Scheme 1. Treatment of (R)-5-benzyloxy-4-
methylpent-2-enol (3)5 (e.e. >85%, Mosher’s), an 80 : 20 mixture
of (E)- and (Z)-isomers, with sodium hydride, carbon disulfide
and methyl iodide gave the xanthate 4. This on heating in
toluene under reflux isomerised to give a 50 : 50 mixture of the
epimeric dithiocarbonates 5, which were converted into the 5-
benzyloxypent-2-enylstannane 6, as an 80 : 20 mixture of (E)- and
(Z)-isomers, by heating with tributyltin hydride in benzene under
free radical conditions.
Tin(IV) chloride was added to the mixture of (E)- and (Z)-
isomers of the alkenylstannane 6 in dichloromethane at -78 ◦C
to effect transmetallation. After 10 min, benzaldehyde was added
and after a further hour the reaction was worked up to give a
mixture of the 1,5-anti- and 1,5-syn-(Z)-hex-3-en-1-ols 7 and 8 in
a ratio of 96 : 4, see Scheme 2. (E)-Alk-3-enols were not isolated
and were only very minor products (<2%).
Address, School of Chemistry, University of Manchester, Manchester, UK
M13 9PL. E-mail: e.j.thomas@manchester.ac.uk; Fax: 00 44 161 275 4939;
Tel: 00 44 161 275 4613
† Electronic supplementary information (ESI) available: full experimental
details for the chemistry outlined in Schemes 3, 4, 5, 8, 10, 11, 12, 17,
and 18 and all compounds listed in Table 1–6 together with copies of
representative 1H and 13C NMR spectra. See DOI: 10.1039/c0ob01084g
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Scheme 3 Synthesis of a mixture of the epimeric alcohols 7 and 8.
Reagents and conditions: i, CBr4, Ph3P, Zn powder, DCM, r.t., 24 h, then
add 17, r.t., 2.5 h (74%); ii, n-BuLi in hexane, -78 ◦C, 2 h, then r.t., 1 h
(65%); iii, 19, n-BuLi, THF, -78 ◦C, 20 min, BF3. Et2O, -78 ◦C, 20 min,
add styrene oxide, -78 ◦C, 1.5 h (14%); iv, Lindlar’s cat., H2, r.t., 72 h (72%,
a 50 : 50 mixture of 7 and 8).
Scheme 1 Preparation of stannane 6. Reagents and conditions: i, NaH,
r.t., 1 h, CS2, r.t., 3 h, then MeI, r.t. 15 h [76%; (E) : (Z) = 80 : 20]; ii, heat
in toluene, 15 h (ca. 100%; 50 : 50 mixture); iii, Bu3SnH, AIBN (trace),
benzene, heat, 2.5 h [86%; (E) : (Z) = 80 : 20].
NMR spectra of the (R)- and (S)-acetylmandelates 9 and 107,8 and
was confirmed by ozonolysis of the acetate 11 with a reductive
work-up, which gave the (S)-3-acetoxy-3-phenylpropanol (S)-14,
[a]D -79 (c 0.61 in CHCl3)1a,9 and a mixture of the primary
acetate (S)-15, formed by 1,3-migration of the acetyl group,
and 3-benzyloxy-2-methylpropanol (R)-16, derived from the other
fragment of the ozonolysis. The 19F NMR spectra of the Mosher’s
derivatives 12 and 13 showed two products, in a ratio of ca.
91 : 9, the discrepancy from the 96 : 4 ratio of epimers 7 and 8
as estimated by 1H NMR being attributed to the e.e. of 85% of the
alkenylstannane 6 (cf . the e.e. of alcohol 3).
Tin(IV) chloride mediated reactions of allylstannane 6 with
several aldehydes were investigated and the results are shown
in Table 1. In all cases, useful diastereoselectivities in favour
of the (Z)-1,5-anti-products were observed even for reactions
1
of the stannane with enantiomeric chiral aldehydes. H NMR
confirmed the (Z)-configuration of the double-bonds of the
major products and the diastereoselectivities of the reactions
of the stannane with 4-methoxy- and 4-chloro-benzaldehyde.
Scheme 2 Tin(IV) chloride mediated reaction of stannane 6 with ben-
zaldehyde. Reagents and conditions: i, SnCl4, -78 ◦C, 10 min, then PhCHO,
1 h (83%; 7 : 8 = 96 : 4); ii, (R)- or (S)-O-acetyl-mandelic acid, DCC, DMAP
(cat), DCM, r.t., 15 h (9, 83%; 10, 88%); iii, Ac2O, DMAP (cat), Et3N,
DCM, r.t., 50 h (89%); iv, (S)- or (R)-Mosher’s acid chloride, py., CCl4, r.t.
(12, 86%; 13, 51%); v, O3, CHCl3, -60 ◦C, 30 min, DMS, r.t., then NaBH4,
MeOH, r.t., 3 h [(S)-14, 29%].
Table 1 1,5-Stereocontrol in tin(IV) chloride mediated reactions between
aldehydes and allylstannane 6
R
1,5-anti-producta
Yield (%)
1,2-anti : 1,5-syn
The major and minor products 7 and 8 could be distinguished
by H NMR, their ratio being estimated by integration of the
Ph
7
83
65
67
80
69
70
96 : 4
1
4-MeOC6H4
4-ClC6H4
Me2CH
Et
21
22
23
24
25
96 : 4b
96 : 4c
95 : 5d
95 : 5b
95 : 5d
doublets at d0.91 and 0.95 attributed to their 5-CH3 groups. To
confirm that the two products were the epimers 7 and 8, a mixture
was prepared by reacting racemic styrene oxide with the racemic
alkyne 19,6 which was available in two steps from 3-benzyloxy-2-
methylpropanal 17, see Scheme 3. This gave the hex-3-ynol 20 as
a mixture of diastereoisomers and hydrogenation using Lindlar’s
catalyst gave a 50 : 50 mixture of the epimeric alcohols 7 and 8.
Comparison with the products from the tin(IV) chloride mediated
reaction of stannane 6 with benzaldehyde confirmed that the (Z)-
1,5-syn-epimer 8 was the minor product.
26
73
95 : 5d
a In all cases, the vicinal 1H NMR vinylic coupling constant was ca. 10 Hz.
b Ratio by 1H NMR and from Mosher’s derivatives; configuration by anal-
The 3,4-vinylic coupling constant of the major product 7 from
the stannane reaction was 10 Hz consistent with the (Z)-geometry.
The 1,5-anti-configuration was assigned by comparison of the 1H
1
1
ogy. c Ratio by H NMR; configuration by analogy. d Ratio by H NMR
and/or Mosher’s; configuration assigned using O-acetylmandelates.
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The 19F spectra of the Mosher’s derivatives of the product 21
from 4-methoxybenzaldehyde were also consistent with the 1,5-
anti-configuration. Configurations were assigned to the major
products 23, 25 and 26 from 2-methylpropanal and (R)- and (S)-
1
2-benzyloxypropanal by comparison of the H NMR spectra of
their O-acetylmandelates, and the 19F spectra of their Mosher’s
derivatives, which also indicated the 1,5-stereoselectivity.
The minor product in each case was assigned the (Z)-1,5-syn-
configuration by analogy with the formation of the (Z)-1,5-syn-
isomer 8 in the reaction with benzaldehyde.
The use of other Lewis acids to promote reactions of allylstan-
nane 6 with aldehydes was briefly investigated. With dibutyltin
dichloride, titanium(IV) chloride, aluminium(III) chloride and
boron trifluoride diethyletherate, complex mixtures of products
were obtained. A modest, 40%, yield of the 1,5-anti- and 1,5-
syn-products 7 and 8, ratio 95 : 5, was obtained using butyltin
trichloride. However, with tin(IV) bromide, improved 1,5-(Z)-
anti : 1,5-(Z)-syn stereoselectivities of ca. 99 : 1 were obtained
for reactions of the allylstannane 6 with the arylaldehydes, and
improved stereoselectivities for reactions with 2-methylpropanal
and propanal. No (E)-isomers of the products were detected in
the product mixtures from these reactions.
The regio- and stereo-selectivities of these tin(IV) halide pro-
moted reactions of stannane 6 with aldehydes are consistent with
a kinetically controlled stereoselective intramolecular transmet-
allation, see Fig. 2. This generates the allyltin trihalide 28 in
which the vinyl and methyl substituents are trans-disposed, i.e.
pseudoequatorial, with respect to the 5-membered ring formed
by co-ordination of the oxygen of the benzyloxy group with the
electron deficient tin. The allyltin trihalide can then react with
an aldehyde via the chair-like six-membered transition state, 29 in
which the substituent next to the tin adopts the axial position to
give the 1,5-anti-(Z)-products after an aqueous work-up.
Fig. 2 Mechanism proposed to account for the stereoselectivity of tin(IV)
halide promoted reactions of allylstannane 6 and aldehydes.
3,3-sigmatropic rearrangement to give the dithiocarbonate 32
as a 60 : 40 mixture of epimers. On reaction with tributyltin
hydride under free radical conditions, these were converted into the
stannane 33. Following desilylation, O-alkylation of the resulting
hydroxystannane 34 then gave the 5-(methoxymethoxy)pent-2-
enylstannane 35.
To check its optical purity, hydroxystannane 34 was converted
into the Mosher’s derivatives 36 and 37, but the 19F NMR spectra
of these were complicated by the presence of geometrical isomers.
However, protonolysis gave the pent-4-enyl esters 38 and 39, which
by 19F NMR were estimated to have e.e.s of ca. 50%.
The tin(IV) chloride promoted reaction of the alk-2-
enylstannane 35 with benzaldehyde proceeded with excellent
stereoselectivity to give the 1,5-anti-(Z)-hex-3-en-1-ol 40 (69%).
Just one minor side-product was isolated and was identified as
the 6-(methoxymethoxymethoxy)hex-3-enol 41 (6%) attributed to
traces of (methoxymethoxy)methyl chloride in the MOM-chloride
used to prepare the stannnane 35.
The (Z)-configuration of the major product 40 was confirmed
by NOE, a significant enhancement of 4-H being observed on
irradiation of the 3-CH3. The configuration at C(1) was established
To check the compatibility of this chemistry with a 2-alkyl
substituent in the allylstannane, an (E,Z)-mixture of the 5-tert-
butyldimethylsilyl-2,4-dimethylpent-2-enylstannane 33 was pre-
pared, see Scheme 4. Thus the alcohol 30 (e.e. ca. 50%11) was
converted into the xanthate 31, which on heating underwent a
Scheme 4 Synthesis of 2,4-dimethylpent-2-enylstannanes and their reactions with benzaldehyde. Reagents and conditions: i, NaH, CS2, MeI (94%);
ii, heat in toluene, 18 h (75%; a 60 : 40 mixture of epimers); iii, Bu3SnH, AIBN, benzene 3 h; iv, TBAF (88% from the dithiocarbonate 32; a 55 : 45
i
mixture of geometric isomers); v, MeOCH2Cl, Pr2NEt (79%); vi, (S)- or(R)-Mosher’s acid chloride, py (36, 38%; 37, 66%); vii, HBr, EtOH (87–93%);
viii, SnCl4, -78 ◦C, 10 min then PhCHO, -78 ◦C, 1 h (40, 69%, 41, 6%); ix, (R)- or (S)-O-acetylmandelic acid, DCC, DMAP (42 and 43, both ca. 100%);
x, 4-NO2C6H4CO2H, Ph3P, DEAD (33%); xi, NaOH, MeOH (72%).
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Table 2 1,5-Stereocontrol in tin(IV) halide mediated reactions between aldehydes and allylstannanes 34 and 35
R1
Stannane
SnX4 (X)
1,5-anti-producta
R2
Yield (%)
1,5-anti : 1,5-syna
Ph
35
"
"
"
34
"
Cl
"
"
"
Br
"
40
46
47
48
49
50
MOM
"
"
"
H
"
69
49
57
68
92
89
≥98 : 2
≥98 : 2
≥98 : 2
≥98 : 2
≥98 : 2
≥98 : 2
4-MeOC6H4
iPr
MeCH CH
Ph
MeCH CH
a Ratio by 1H NMR.
by comparison of the 1H NMR chemical shifts of the O-
acetylmandelates 42 and 43.
To establish the stereoselectivity of this reaction, the 1,5-anti-
product 40 was converted into its 1,5-syn-diastereoisomer 45 via
a Mitsunobu reaction12 followed by saponification of the inverted
4-nitrobenzoate 44, see Scheme 4. Epimers 40 and 45 could be
distinguished by NMR, for example, the doublet due to the 5-CH3
group was seen at d0.87 in the 1H NMR spectrum of the 1,5-anti-
product 40 and at d1.03 in the 1H NMR spectrum of the 1,5-syn-
epimer 45. The 1,5-syn-alkenol 45 was not detected in the product
mixture from the reaction of allylstannane 35 with benzaldehyde,
and so the 1,5-anti : 1,5-syn selectivity was estimated to be
≥98 : 2.
The tin(IV) chloride promoted reactions of the allylstannane
35 with methoxybenzaldehyde, 2-methylpropanal and (E)-but-
2-enal were also highly stereoselective in favour of the (Z)-1,5-
anti-alkenols 46–48, see Table 2. Structures were assigned to
these products by analogy with the stereoselective formation of
the (Z)-1,5-alkenol 40 in the reaction with benzaldehyde. (Z)-
1,5-syn-Epimers were not detected from these reactions but to
check that 1,5-anti- and 1,5-syn-epimers could be distinguished,
the (Z)-1,5-anti-product 48 from the reaction with (E)-but-2-
enal was oxidised, and the resulting ketone 51 reduced to give a
mixture of the epimeric alkenols 48 and 52. These were clearly
different by 1H and 13C NMR and the (Z)-1,5-syn-epimer 52
was not detected in the product mixture from the tin(IV) chloride
promoted reaction of stannane 35 and (E)-but-2-enal. The only
side-products isolated from these reactions were the minor 6-
(methoxymethoxymethoxy)alk-3-en-1-ols due to the impurity in
the MOM-protected stannane 35.
The free hydroxystannane 34 was also found to react, after
transmetallation with tin(IV) bromide, with benzaldehyde and
(E)-but-2-enal to give the 1,5-anti-(Z)-alkenols 49 and 50 with
excellent yields, 92 and 89% and diastereoselectivities, >99 : 1.
The (Z)-1,5-anti-configuration assigned to the product 49 from
the reaction of stannane 34 with benzaldehyde was confirmed
by MOM-protection, which gave the known 1,5-anti-alkenol 40
together with a small amount of its regioisomer 53. The structure
of the product 50 was assigned by analogy.
additional 2-methyl substituent, with different alkoxy substituents,
and even with an unprotected 5-hydroxyl group in the stannane.
The next phase of this work was to study analogous reactions
of 5-substituted hexenylstannanes, cf . structure II, for 1,6-remote
stereocontrol.
1,6-Stereocontrol using 5-substituted alkenylstannnanes II
The 5-benzyoxyhex-2-enylstannane 59 was synthesized to eval-
uate the ability of a 5-benzyloxy substituent to deliver 1,6-
stereocontrol in reactions with aldehydes, see Scheme 5. (R)-3-
Benzyloxybutanol 54 was converted into the 5-benzyloxyhex-2-
enol 56 via oxidation,13 a Wittig reaction to give the (E)-ester 55
together with 5% of its (Z)-isomer, and reduction. Heating the
corresponding xanthate 57 gave the dithiocarbonate 58 which was
converted into the stannane 59, as a 2 : 1 mixture of (E)- and (Z)-
isomers, by treatment with tributyltin hydride under free-radical
conditions.
However, tin(IV) chloride and bromide promoted reactions of
stannane 59 with benzaldehyde gave mixtures of the 1,6-syn- and
1,6-anti-products 60 and 64. These products were shown to be
epimers since oxidation of the mixture gave a single ketone 68.
Their configurations at C(1) were established by comparison of
the 1H NMR spectra of their (R)-and (S)-O-acetylmandelates
62/63 and 66/67. The alkene geometry of the 1,6-syn-product
60 was established by the 3,4-vinylic coupling constant of ca. 10–
11 Hz observed for the acetate 61 and the O-acetylmandelates
62 and 63. The 1H NMR spectrum of the (S)-O-acetylmandelate
67 also established the double-bond geometry of the anti-epimer
64. Reasonable yields were obtained for these reactions, but the
5-Alkoxy-4-methylpent-2-enyl(tributyl)stannanes, cf . generic
structure I, appear to undergo highly stereoselective reactions with
aldehydes on transmetallation with tin(IV) halides to give 1,5-anti-
(Z)-alk-3-enols. This stereoselectivity, which can be promoted by
either tin(IV) chloride or tin(IV) bromide, is compatible with an
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Scheme 6 Preparation of 5-hydroxyhex-2-enylstannane 73. Reagents and
conditions: i, NaH, benzene, 40 ◦C, 2 h, CS2, r.t., 3 h, MeI, r.t., 15 h (92%);
ii, toluene, heat, 15 h (ca. 100%, 1 : 1); iii, Bu3SnH, AIBN (trace), benzene,
heat, 3.5 h [85%, (E) : (Z) = 2 : 1]; iv, TBAF, THF, r.t., 15 h (88%); v, NaH,
THF, 35 ◦C, 2 h, MeI, r.t., 15 h (85%); vi, TsNHNH2, NaOAc, EtOH,
heat, 4 h (83%); vii, (S)- or (R)-Mosher’s acid chloride, py., r.t. 15 h (76,
ca. 100%; 77, 70%).
converted into its Mosher’s derivatives 76 and 77. A comparison
of the 19F NMR spectra of these confirmed that the e.e. of stannane
73 was >98%, see Scheme 6.
Transmetallation of the 5-methoxyhex-2-enylstannane 74 using
tin(IV) bromide generated an allyltin tribromide, which reacted
with benzaldehyde to give a mixture of the inseparable (Z)-1,6-syn-
and (Z)-1,6-anti-6-methoxyhept-3-enols 78 and 81, ratio 91 : 9, see
Scheme 7. The use of tin(IV) chloride resulted in significantly lower
stereoselectivity, 78 : 81 = 70 : 30. The major product was converted
into the minor via a Mitsunobu reaction with inversion using 4-
nitrobenzoic acid followed by saponification of the resulting ester
86. The two alcohols were distinctly different by NMR and the
product ratio from the allylstannane reaction could be measured
by integration of peaks in its 13C NMR spectrum. Interestingly the
4-nitrobenzoate 79 prepared by esterification of the major alcohol
78 and its epimer 86 from the Mitsunobu reaction, could not be
Scheme 5 Chemistry of the 5-benzyloxyhex-2-enylstannane 59. Reagents
and conditions: i, DMSO, (COCl)2, DCM, -50 ◦C, 15 min, Et3N, -50 ◦C,
5 min, r.t., 20 min, then MeO2C. CHPPh3, DCM, r.t., 15 h [70% plus 5% of
its (Z)-isomer]; ii, DIBAL-H, hexane, DCM, -78 ◦C, 3 h (97%); iii, NaH,
benzene, r.t., 1 h, CS2, r.t., 3 h, MeI, r.t., 15 h (88%); iv, toluene, heat,
15 h (ca. 100%, 1 : 1); v, Bu3SnH, AIBN (trace), benzene, heat, 3 h [67%;
(E) : (Z) = 2 : 1]; vi, SnCl4 or SnBr4, -78 ◦C, 2–20 min, PhCHO, -78 ◦C,
1 h (44–76%); vii, Ac2O, DMAP (cat), Et3N, DCM, r.t., 15 h (61, 87%; 65,
88%); viii, (R)- or (S)-O-acetylmandelic acid, DCC, DMAP (cat), DCM,
r.t., 15 h (62, 82%; 63, 77%; 66, 80%; 67, 87%); ix, DMSO, (COCl)2, DCM,
-50 ◦C, 15 min, iPr2NEt, -50 ◦C, 5 min (49%).
proportions of the two products varied, typically with only modest
stereoselectivity in favour of the 1,6-syn-epimer 60.
The tert-butyldimethylsilyloxyhex-2-enylstannane 72 was pre-
pared to see whether stannanes analogous to the 5-
benzyloxyhexenylstannane 59, but with different O-substituents,
reacted with aldehydes with better remote stereocontrol, see
Scheme 6.
Xanthate 70, available from the alcohol 69, rearranged on
heating to give the dithiocarbonate 71 as a mixture of epimers.
Reaction with tributyltin hydride then gave the stannnane 72 as
a 2 : 1 mixture of (E)- and (Z)-isomers. Desilylation was achieved
using tetrabutylammonium fluoride to give the 5-hydroxyhex-2-
enylstannane 73, which was methylated to give the 5-methoxyhex-
2-enylstannane 74.
Scheme 7 1,6-Stereocontrol in the reaction of stannane 74 and benzalde-
hyde. Reagents and conditions; i, SnBr4, DCM, -78 ◦C, 10 min, PhCHO,
-78 ◦C, 1 h (78%; 78 : 81 = 91 : 9); ii, O2NC6H4COCl, DMAP, Et3N, DCM,
r.t., 72 h (79, 88%); iii, Ac2O, DMAP, Et3N, DCM, r.t., 15 h (92%);
iv, (S)- or (R)-Mosher’s acid chloride, py (82, 97%; 83, 78%); v, (R)- or
(S)-O-acetylmandelic acid, DCC, DMAP, DCM, r.t. 15 h (84, 80%; 85,
87%); vi, 78, 4-O2NC6H4CO2H, Ph3P, DEAD, tol, -35 ◦C to r.t., 2 h (80%);
vii, NaOH, MeOH, r.t., 2 h (84%); viii, O3, CHCl3, -78 ◦C, 15 min, DMS,
r.t., then NaBH4, MeOH, DCM, r.t., 1.5 h [(R)-14, 58%; (R)-15, 15%].
The optical purity of stannane 73 was checked by reduction
using di-imide to give the 5-hydroxyhexylstannane 75. This was
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distinguished by NMR. The high optical purity of the stannane,
and hence of the products in this series, meant that the ratio of the
epimers 78 and 81 could also be estimated using the 19F spectra of
the Mosher’s derivatives 82 and 83.
and the configurations of the hydroxyl bearing stereogenic centres
in the products.
The 5-hydroxyhex-2-enylstannane 73 was also found to undergo
stereoselective reactions with aldehydes in favour of (Z)-1,6-
syn-products after transmetallation with tin(IV) halides. With
benzaldehyde, a 90 : 10 mixture (59%) of the 1,6-syn- and 1,6-
anti-epimers 100 and 104 was obtained using tin(IV) chloride, with
a better yield (72%) and stereoselectivity, 94 : 6, being obtained
using tin(IV) bromide, see Scheme 9. The ratios of the products 100
and 104 were determined by integration of the benzylic protons
observed at d4.68 for the 1,6-syn-epimer 100, and at d4.77 for the
minor 1,6-anti-isomer 104. The configuration of the major product
100 at the benzylic position, C(1), was established by ozonolysis
of its bis-acetate 105 which, after reduction, gave the primary
alcohol (R)-14 (61%), together with the secondary alcohol (R)-15
(13%).1a O-Methylation also gave a mixture of the regioisomeric
monomethyl ethers 78 and 106, the former being identical to
the major product from the reaction of the 5-methoxyhex-2-
enylstannane 74 with benzaldehyde. The minor product 104 was
identified by analogy with earlier work.
The 1,6-syn-configuration assigned to the major product 78
was established by ozonolysis of its acetate 80, which gave (R)-3-
acetoxy-3-phenylpropanol (R)-14 together with the product (R)-
1
15 of acetate migration.1a Comparison of the H NMR spectra
of the (R)-and (S)-O-acetylmandelates 84 and 85 supported this
1
assignment. The vinylic coupling constant of 11 Hz in the H
NMR spectra of the Mosher’s derivatives 82 and 83 and the O-
acetylmandelates 84 and 85 confirmed the (Z)-geometry of the
alkene.
The tin(IV) bromide promoted reaction of the 5-methoxy-
hexenylstannane 74 with 2-methylpropanal was also stereoselec-
tive, the (Z)-3,8-syn-8-methoxynon-5-en-3-ol 87 being the major
product, see Scheme 8. To check that the major and minor
products were epimers, the major alkenol 87 was converted into the
minor 88 using a Mitsunobu reaction followed by saponification
1
of the resulting ester 93. Minor differences were seen in the H
and 13C NMR spectra of these epimers. The C(3) configuration
of the major product 87 was established by comparison of the
1H NMR data of O-acetylmandelates 89 and 90. The reaction
diastereoselectivity was estimated by 13C NMR spectra of the
product mixture and from the 19F NMR spectra of the Mosher’s
derivatives 91 and 92. The 10.5 Hz vinylic coupling constant in the
1H NMR spectrum of the (S)-Mosher’s derivative 92 confirmed
the (Z)-geometry.
Scheme 9 1,6-Stereocontrol in the reaction of the 5-hydroxyhexenylstan-
nane 73 and benzaldehyde. Reagents and conditions: i, SnX4, -78 ◦C,
10 min, PhCHO, -78 ◦C, 1 h (with SnCl4; 59%, 100 : 104 = 90 : 10; with
SnBr4, 72%, 100 : 104 = 94 : 6); ii, Ac2O, Et3N, DMAP, DCM, r.t., 15 h
(91%); iii, O3, CHCl3, -78 ◦C, 15 min, DMS, r.t., then NaBH4, MeOH,
DCM, r.t., 15 min [(R)-14, 61%, (R)-15, 13%]; iv, NaH, 18-crown-6, THF,
r.t., 15 min, diol 100, r.t., 45 min, MeI, r.t., 15 h (78, 11%, 106, 45%).
Scheme 8 1,6-Stereocontrol in the reaction of stannane 74 and 2-methyl-
◦
i
propanal. Reagents and conditions: i, SnBr4, -78 C, 10 min, PrCHO,
-78 ◦C, 1 h (72%; 87 : 88 = 85 : 15); ii, (R)- or (S)-O-acetylmandelic acid,
DCC, DMAP, DCM, r.t. 15 h (89, 81%; 90, 51%); iii, (S)- or (R)-Mosher’s
acid chloride, py (91, 89%; 92, 98%); iv, 4-O2NC6H4CO2H, Ph3P, DEAD,
tol, -35 ◦C to r.t., 18 h (45%); v, NaOH, MeOH, r.t., 2.5 h (92%).
Tin(IV) bromide promoted reactions of the 5-hydroxyhex-2-
enylstannane 73 and other aldehydes were investigated, see Table 3.
In all cases useful levels of (Z)-1,6-syn-stereoselectivity were
observed. The product ratios in these cases were determined
Tin(IV) bromide promoted reactions of the 5-methoxy-
hexenylstannane 74 with other aldehydes were investigated, see
Table 3. In all cases the (Z)-1,6-syn-isomers were the major prod-
ucts with useful stereoselectivity for achiral aldehydes. Matching
and mismatching was observed for the chiral aldehydes, (R)- and
(S)-2-benzyloxypropanal, with Felkin–Anh rather than chelation
control being preferred. The structures of the products from
these reactions were assigned by analogy with the products 78/81
and 87/88 from the reactions between alkenylstannane 74 and
benzaldehyde or 2-methylpropanal. Mosher’s derivatives and O-
acetylmandelates were used to establish the reaction selectivities
1
by H and 13C NMR. The structure of the major product 103
from 2-methylpropanal was confirmed by O-methylation, which
gave the regioisomeric monomethyl ethers 107 and 87, the latter
being identical to the major product from the reaction of 2-
methylpropanal with the 5-methoxyhexenylstannane 74.
The (Z)-1,6-syn-stereoselectivity observed for the tin(IV) bro-
mide mediated reactions of the 5-hydroxy- and 5-methoxy-hex-
2-enylstannanes 73 and 74 with aldehydes is consistent with
participation of the allyltin tribromides 108 in which the vinyl
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Table 3 1,6-Stereocontrol in tin(IV) bromide mediated reactions between aldehydes and allylstannanes 73 and 74
R1
Stannane
1,6-syn-producta
R2
Yield (%)
1,6-syn : 1,6-anti
Ph
74
"
"
"
"
"
"
78
94
95
96
97
87
98
Me
"
"
"
"
"
"
78
65
61
69
67
72
88
96 : 4
4-MeOC6H4
4-ClC6H4
Me
Et
Me2CH
93 : 7b
92 : 8b
91 : 9c
84 : 16b
85 : 15
75 : 25d
"
99
"
73
90 : 10d
Ph
73
"
"
100
101
102
103
H
"
"
72
71
60
59
94 : 6
94 : 6c
96 : 5c
93 : 7
4-O2NC6H4
Me
Me2CH
"
"
1
a In all cases the (Z)-configuration was confirmed by vicinal vinylic H couplings of ca. 10 Hz observed either for the products or for a derivative of
the products. b Ratio from 1H NMR, 13C NMR and Mosher’s 19F spectra; relative 19F chemical shifts for the Mosher’s derivatives were consistent with
1
1
1
the 1,6-syn-configuration. c Ratio by H and 13C NMR; structure by analogy. d Ratio from H NMR, 13C NMR and Mosher’s 19F spectra; H data of
O-acetylmandelates and the relative 19F chemical shifts for the Mosher’s derivatives established the 1,6-syn-configuration.
and methyl groups are cis-disposed, i.e. pseudo-equatorial, about
the five-membered ring formed by co-odination of the methoxy
or hydroxy group with the electron deficient tin, see Fig. 3.
Reaction of these allyltin tribromides with an aldehyde via the
six-membered, chair-like transition state 109, in which the group
next to tin adopts the axial position, would then account for the
overall (Z)-1,6-syn-stereocontrol. The use of tin(IV) bromide rather
than tin(IV) chloride led to improved 1,6-syn-stereoselectivity in
these reactions. Better stereoselectivity was also observed for
the 5-hydroxy- and 5-methoxy-alkenylstannanes 73 and 74, in
comparison with that found for the 5-benzyloxyhexenylstannane
59.
hydroxyalkenylstannanes should be studied, see generic structures
III, IV and V, for 1,5-, 1,6- and 1,7-stereocontrol. Hydroxy
substituted alkenylstannanes were selected for study, since the
hydroxyl group had proved to be an effective co-ordinating group
for 1,6-stereocontrol in 5-substituted systems.
1,5-Stereocontrol using 4-methyl-6-hydroxyhex-2-enylstannnane
III (R = H)
The racemic aldehyde 110 was available in two steps from
citronellol14 and was dehydrogenated to give the unsaturated
aldehyde 111, see Scheme 10.15 Reduction gave the alcohol 112
which was converted to the stannane 114 by displacement of its
mesylate 113.16 Desilylation then gave the racemic 6-hydroxy-4-
methylhexenylstannane 115.
Scheme 10 Synthesis of the racemic 6-hydroxy-4-methylhexenylstannane
115. Reagents and conditions; i, (EtO)2P(O)OCH2CH CH2, Pd(Ac)2,
NaHCO3, THF, heat, 72 h (95%); ii, DIBAL-H, THF, -78 ◦C to -45 ◦C,
3 h (84%); iii, MsCl, DCM, Et3N, -7 ◦C, 10 min; iv, Bu3SnLi, THF, -78 ◦C,
2 h, r.t., 15 h (53% from 112); v, TBAF, THF, r.t., 15 h (72%).
Fig. 3 Mechanism proposed to account for the 1,6-syn-stereoselectivity
in reactions of allylstannanes 73 and 74 with aldehydes.
Having studied reactions of 5-alkoxy(hydroxyl)alk-2-enyl-
stannanes for 1,5- and 1,6-stereocontrol, it was decided that 6-
The reaction between the racemic 6-hydroxy-4-methylhex-2-
enylstannane 115 and benzaldehyde mediated by tin(IV) bromide
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gave the (Z)-1,5-anti-hept-3-ene-1,7-diol 116 (64%) with excellent
stereoselectivity. With tin(IV) chloride, a lower yield, 40%, and
slightly reduced stereoselectivity, 95 : 5, was observed. The syn-
epimer 120 was prepared from diol 116 by selective silylation of
the primary hydroxyl group and esterification of the secondary
hydroxyl group of the resulting monosilyl ether 117 using a
Mitsunobu reaction to give the inverted 4-nitrobenzoate 118.
Saponification and desilylation gave the inverted 1,5-syn-diol 120,
see Scheme 11. Epimers 116 and 120 could be distinguished by
1H and 13C NMR, and the 10.5 Hz vinylic coupling observed
for the 1,5-anti-product 116 confirmed the (Z)-alkene geometry.
Only traces of the 1,5-syn-epimer 120 were present in the product
mixture from the allylstannane reaction.
series on the basis of the supposed mechanism and by analogy to
the other series, vide infra.
The 6-hydroxy-4-methylhexenylstannane 115 was then reacted
with a range of aldehydes using tin(IV) bromide to effect transmet-
allation, and the results obtained are shown in Table 4. In all cases
high levels of stereoselectivity were observed by NMR, and in
some cases, by glc. The 1,5-anti-configuration of the products was
assigned by analogy with earlier work and the (Z)-geometry of the
double-bond was confirmed by the vinylic 1H coupling constants
which were in the range of 10–11 Hz.
Table 4 1,5-Stereocontrol in tin(IV) bromide mediated reactions between
aldehydes and allylstannane 115
R
1,5-anti-producta
Yield (%)
1,5-anti : 1,5-syn
Ph
116
126
127
128
129
130
131
132
64
61
74
64
62
63
67
76
99 : 1
4-MeOC6H4
4-ClC6H4
3-ClC6H4
4-O2NC6H4
Me2CH
99 : 1b
98 : 2b
99 : 1b
99 : 1b
91 : 9c
96 : 4c
97 : 3c
Scheme 11 1,5-Stereocontrol in the reaction of 6-hydroxyhexenyl-stan-
nane 115 and benzaldehyde. Reagents and conditions: i, SnBr4, -78 ◦C,
5 min, PhCHO, -78 ◦C, 1 h (64%, 116 : 120 ≥ 98 : 2); ii, TBSCl, imid., DCM,
r.t., 30 min (67%); iii, 4-O2NC6H4CO2H, PPh3, DIAD, 0 ◦C, 10 min, r.t.,
30 min (63%); iv, NaOH, MeOH, r.t., 2 h; v, TBAF, THF, r.t., 15 h (89%).
nPr
MeCH CH
a In all cases the vicinal vinylic coupling constant was ca. 10 Hz. b Ratio by
As the compounds in this series were racemic, ozonolysis or
O-acetylmandelates couldn’t be used to establish their relative
configuration. The 1,5-anti-diol 116 was therefore taken through
to lactone 125 to see whether transannular nOe measurements
would confirm the assigned stereochemistry, see Scheme 12. The
diol was protected as its bis-tert-butyldimethylsilyl ether 121 which
was selectively monodesilylated using HF-pyridine to alcohol 122.
Oxidation via the corresponding aldehyde gave the carboxylic
acid 123 and, after desilylation to give the hydroxyacid 124,
lactonisation17 gave the lactone 125. This confirmed the (Z)-
geometry assigned to the double-bond, but nOe studies did not
establish the relative configuration of the stereogenic centres. The
1,5-anti-configuration was therefore assigned to products in this
1H NMR. c Ratio by glc.
1,6-Stereocontrol using 5-methyl-6-hydroxyhex-2-enylstannnane
IV (R = H)
A synthesis of the 6-hydroxy-5-methylhex-2-enylstannane 138 is
outlined in Scheme 13. Following lithiation, the allyl sulfide 13318
was alkylated using iodide 135, which is available from alcohol 134,
to give a mixture of the epimeric alkylated sulfides 136. Reaction of
this mixture with tributyltin hydride under free-radical conditions
gave the 6-silyloxyhexenylstannane 137 which was deprotected to
give the 6-hydroxy-5-methylhexenylstannane 138, (E) : (Z) = 2 : 1,
see Scheme 13. In this two step synthesis of alk-2-enylstannanes
from alkyl halides, the lithiated allylsulfide 139 is being used as the
synthetic equivalent of 3-(tributylstannyl)propenyllithium 140,19
see Fig. 4.
Scheme 12 Synthesis of lactone 125. Reagents and conditions: i, TBSCl,
imid., DMAP, r.t., 18 h (82%); ii, HF-py., THF, 18 h (72%); iii, Dess—
Martin periodinane, NaHCO3, DCM, r.t., 1 h; iv, NaClO2, NaH2PO4,
2-methylbut-2-ene,tBuOH, H2O, r.t., 2 h (76% from 122); v, HCl, MeOH,
r.t., 2 h (80%); vi, 2,4,6-Cl3C6H2COCl, Et3N, THF, r.t., 2 h, then DMAP,
toluene, reflux, 4.5 h (60%).
Scheme 13 Synthesis of the 6-hydroxy-5-methylhexenylstannane 138.
Reagents and conditions: i, (a) MsCl, Et3N, DCM, -20 ◦C to r.t., 1 h (ca.
100%) (b) NaI, acetone, heat, 18 h (70%); ii, 133, nBuLi, THF, HMDA,
-78 ◦C, 30 min, 135, -78 ◦C, 2.5 h (42%); iii, Bu3SnH, AIBN, benzene,
heat, 18 h [79%, (E) : (Z) = 2 : 1]; iv, TBAF, THF, r.t., 18 h (79%).
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Table 5 1,6-Stereocontrol in tin(IV) bromide mediated reactions between
aldehydes and allylstannane 138
R1
1,6-anti-producta
Yield (%)
1,6-anti : 1,6-syn
Fig. 4 The synthetic equivalence of the lithiated allylsulfide 139 and
3-(tributylstannylpropenyl)lithium 140.
Ph
141
149
150
151
152
84
58
76
56
80
93 : 7
4-MeOC6H4
4-O2NC6H4
Et
91 : 9b
91 : 9b
93 : 7c
91 : 9d
The tin(IV) bromide mediated reaction of the 5-
methylhexenylstannane 138 with benzaldehyde was stereo-
selective in favour of the (Z)-1,6-anti-heptenediol 141, 1,6-
anti : 1,6-syn = 93 : 7, see Scheme 14. With tin(IV) chloride, the
stereoselectivity dropped to 84 : 16 and the yield to 62%. To
establish the stereoselectivity of this reaction, the (Z)-1,5-anti-
product 141 was converted into its 1,6-syn-epimer 142 by selective
protection as its monosilyl ether 143, inversion of configuration
at C(1) using a Mitsunobu reaction, hydrolysis of the ester 147
and desilylation of the resulting (Z)-1,6-syn-silyloxyalcohol 148.
The 1,6-anti- and 1,6-syn-diols 141 and 142 were distinguishable
by 1H NMR and their ratio was measured by integration of
1-H, which was observed at d4.65 for the anti-diol 141 and at
d4.71 for its syn-epimer 142. The configuration of the major
Me2CH
a In all cases the vicinal vinylic coupling was 10 Hz. b Ratio by 1H NMR.
c Ratio by pulse delayed 13C NMR. d Ratio by pulse delayed 13C NMR;
stereochemistry by comparison of the H NMR spectra of the (R)- and
(S)-O-acetylmandelates 153 and 154.
1
1
The 6-hydroxyhexenylstannane 138 was also converted into its
methyl, MOM and benzyl ethers 156–158. However, tin(IV) bro-
mide mediated reactions ofthese withbenzaldehyde wereless stere-
oselective than those observed for the 6-hydroxyhexenylstannnane
138, the 1,6-anti : 1,6-syn ratios typically being of the order of
60 : 40, although (Z)-alkenols remained the dominant products.
product 141 at C(1) was initially assigned on the basis of the H
NMR chemical shifts of the (R)- and (S)-O-acetylmandelates
144 and 145 prepared from the monosilylether 143, and was
confirmed by ozonolysis of the diacetate 146 which gave the
(R)-3-acetoxy-3-phenylpropanol (R)-14 together with the product
(R)-15 of acetate migration.1a
1,7-Stereocontrol using 6-hydroxyhept-2-enylstannnane V (R = H)
1,7-Remote stereocontrol is rare in open-chain systems and so the
chemistry of 6-hydroxyhept-2-enylstannane 163, in which there
is potential for 1,7-stereocontrol determined by the stereogenic
centre at C(6), was investigated. This stannane was prepared
by alkylation of the allylsulfide 133 using the alkyl iodide 160
prepared from the alcohol 159,20 see Scheme 15. Reaction of
the alkylated sulfide 161 with tributyltin hydride under free-
radical conditions gave the 6-hydroxyheptenylstannane 163 after
desilylation of the silyl ether 162.
Scheme 14 1,6-Stereocontrol in the reaction of 6-hydroxyhexenylstan-
nane 138 and benzaldehyde. Reagents and conditions: i, SnBr4, DCM,
-78 ◦C, 10 min, PhCHO, -78 ◦C, 1 h (84%; 141 : 142 = 93 : 7); ii, TBSCl,
Et3N, DMAP, DCM, r.t., 3 h (92%); iii, Ac2O, Et3N, DMAP, DCM, r.t.,
18 h (90%); iv, (R)- or (S)-O-acetylmandelic acid, DCC, DMAP, DCM,
r.t. 18 h (144, 90%; 145, 80%); v, 4-O2NC6H4CO2H, Ph3P, DEAD, toluene,
-35 ◦C, 90 min (69%); vi, NaOH, MeOH, r.t., 3 h (73%); vii, TBAF, THF,
r.t., 18 h (88%); viii, O3, DCM, -78 ◦C, 40 min, DMS, then DCM, NaBH4,
MeOH, r.t., 2 h [(R)-14, 34%; (R)-15, 16%].
Tin(IV) bromide mediated reactions of the allylstannane 138
with several aldehydes were investigated, and the results are
summarised in Table 5. In all cases, useful stereoselectivities in
favour of the (Z)-1,6-anti-isomers were observed as estimated by
1H NMR. The 1,6-anti-configuration of the major product from
the reaction of the alkenylstannane 138 with 2-methylpropanal
Scheme 15 Synthesis of the 6-hydroxyhept-2-enylstannane 163. Reagents
and conditions: i, Ph3P, imid., ether, MeCN, I2, 0 ◦C, r.t., 2.5 h (75%); ii,
nBuLi, hexane, 133, -78 ◦C, 20 min, 160, -78 ◦C, 2.5 h (83%, a 1 : 1 mixture
of epimers); iii, Bu3SnH, AIBN (trace), benzene, heat, 1.5 h (92%); iv,
TBAF, THF, r.t., 50 h [80%, (E) : (Z) = 2 : 1].
1
was established by comparison of the H NMR spectra of the
(R)- and (S)-O-acetylmandelates 154 and 155 prepared from the
monosilyl ether 153. The structures of the other products were
assigned by analogy.
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The tin(IV) bromide mediated reaction of the heptenylstannane
163 with benzaldehyde gave the (Z)-1,7-syn and (Z)-1,7-anti-
products 164 and 165 with useful stereoselectivity, 164 : 165 =
92 : 8, together with a third product accounting for ca. 2%
of the product mixture, which was not identified. To confirm
that the minor product from the reaction of the stannane 163
with benzaldehyde was the (Z)-1,7-anti-isomer 165, an authentic
sample was prepared, see Scheme 16. Silylation of the 1,7-syn-diol
164 gave the regioisomeric monosilyl ethers 166 (63%) and 167
(5%), together with the bis-silyl ether 168 (15%). Inversion of the
monosilyl ether 166 at C(1) using a Mitsunobu reaction provided
the 1,7-anti-silyloxy ester 170 which was converted to the 1,7-
anti-diol 165 by saponification and deprotection of the resulting
monosilyl ether 171. Diols 164 and 165 were distinguishable by 1H
and 13C NMR e.g. 1-H was observed at d4.72 and at d4.63 in the
1H NMR spectra of the 1,7-syn and 1,7-anti-isomers 164 and 165,
respectively.
Scheme 17 1,7-Stereocontrol in the reaction of 6-hydroxy-
hept-2-enylstannane 163 and 2-methylpropanal. Reagents and conditions:
◦
i, 163, SnBr4, DCM, -78 C, 10 min, add PrCHO, -78 ◦C, 1 h (63%,
i
174 : 175 = 89 : 11); ii, TBSCl, imid., DMF, r.t., 15 h (176, 65%; 177, 1%;
178, 9%); iii, 4-O2NC6H4CO2H, Ph3P, DEAD, toluene, -35 ◦C, r.t., 5 h
(61%); iv, NaOH, MeOH, r.t., 3 h; v, TBAF, THF, r.t., 50 h (66% from
179); vi, (R)- or (S)-O-acetylmandelic acid, DCC, DMAP, DCM, r.t. 18 h
(181, 95%; 182, 74%).
amount, ca. 2%, of a third product was also isolated but was not
identified.
To check the structure of the minor product 175, a sample was
prepared by silylation of the major 1,7-syn-diol 174. This gave
a mixture of the regioisomeric monosilyl ethers 176 (65%) and
177 (1%), together with the bis-silyl ether 178 (9%). A Mitsunobu
reaction of the major monosilyl ether 176 using 4-nitrobenzoic
acid gave the inverted ester 179, which was converted into the 1,7-
anti-diol 175 by saponification and desilylation of the monosilyl
ether 180. The 1,7-syn- and 1,7-anti-diols 174 and 175 were
1
difficult to distinguish by H NMR but were distinguishable by
Scheme 16 1,7-Stereocontrol in the reaction of 6-hydroxy-
hept-2-enylstannane 163 and benzaldehyde. Reagents and conditions:
i, 163, SnBr4, DCM, -78 ◦C, 10 min, add PhCHO, -78 ◦C, 1 h (72%,
164 : 165 = 92 : 8); ii, TBSCl, imid., DMF, r.t., 15 h (166, 63%; 167,
5%; 168, 15%); iii, Ac2O, Et3N, DMAP, DCM, r.t., 15 h (96%); iv,
4-O2NC6H4CO2H, Ph3P, DEAD, toluene, -35 ◦C, r.t., 2 h (74%); v,
NaOH, MeOH, r.t., 2 h (93%); vi, TBAF, THF, r.t., 72 h (96%); vii, (R)-
or (S)-O-acetylmandelic acid, DCC, DMAP, DCM, r.t. 18 h (172, 78%;
173, 83%); viii, O3, DCM, -78 ◦C, 15 min, DMS, then DCM, NaBH4,
MeOH, r.t., 15 min [(S)-14, 27%; (S)-15, 13%].
13C NMR. Pulse delayed 13C NMR was used to measure their
ratio in the product mixture from the allylstannane reaction. The
configuration of the hydroxyl bearing stereogenic carbon in the
monosilyl ether 176 was established by comparison of the 1H
NMR spectra of the (R)- and (S)-O-acetylmandelates 181 and
182.
Tin(IV) bromide promoted reactions of the 6-hydroxyhept-2-
enylstannane 163 with several aromatic and aliphatic aldehydes
were investigated, and the results obtained are shown in Table 6.
In all cases useful levels of stereoselectivity in favour of the
(Z)-1,7-syn-products were observed. The structures of the major
products were consistent with spectroscopic data. The 1,7-syn-
diastereoselectivity and structures of the minor products were
assigned by analogy with the reactions of stannane 163 with ben-
zaldehyde and 2-methylpropanal. Product ratios were measured
by 1H NMR for the products from aromatic aldehydes and by 13
pulse delayed NMR for the products from aliphatic aldehydes.
The tin(IV) chloride mediated reaction of the 6-
hydroxyheptenylstannnane 163 with benzaldehyde gave the syn-
and (Z)-1,7-anti-products 164 and 165, but the stereoselectivity
was only 75 : 25 in favour of the 1,7-syn-diastereoisomer 164.
The hydroxyheptenylstannane 163 was also converted into the
The 1,7-syn-configuration was assigned to the major product
1
164 by comparison of the H NMR spectra of the (R)- and (S)-
O-acetylmandelates 172 and 173 prepared from the monosilyl
ether 166, and was confirmed by ozonolysis of the bis-acetate
169 which gave (S)-3-acetoxy-3-phenylpropan-1-ol (S)-14 and the
(S)-3-acetoxy-1-phenylpropan-1-ol (S)-15, formed by 1,3-acetate
migration,1a see Scheme 16. The (Z)-configuration of the double-
bond was consistent with the 10.5 Hz vinylic 1H coupling observed
for the 1,7-syn-diol 164.
The tin(IV) bromide promoted reaction of the 6-hydroxyhex-
2-enylstannane 163 with 2-methylpropanal was also stereose-
lective in favour of the (Z)-1,7-syn-product 174, (Z)-1,7-syn-
diol 174 : (Z)-1,7-anti-diol 175 = 89 : 11, see Scheme 17. A small
C
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Table 6 1,7-Stereocontrol in tin(IV) bromide mediated reactions between
aldehydes and allylstannane 163
R
1,7-syn-producta
Yield (%)
1,7-syn : 1,7-anti
Ph
164
183
184
185
174
186
187
188
189
72
47
71
65
63
36
61
58
38
92 : 8
4-MeOC6H4
4-ClC6H4
2-naphth.
Me2CH
Me
89 : 11b
92 : 8b
93 : 7b
89 : 11
90 : 10c
91 : 9c
85 : 15c
95 : 5c
Et
Me2CHCH2
Me3C
a Minor product assumed to be the (Z)-1,7–isomer by analogy with the
reactions of benzaldehyde and 2-methylpropanal with stannane 163; a
third very minor product, ca. 1%, also detected but not identified. b Ratio
by 1H NMR. c Ratio by pulse-delayed 13C NMR.
6-methoxy-, 6-(methoxymethoxy)- and 6-benzyloxystannanes
190–192, but preliminary studies of tin(IV) halide promoted
reactions of these with aldehydes gave mixtures of products, and
so were not studied further.
Scheme 18 Reactions of (S)- and (R)-2-benzyloxypropanal with the
6-hydroxyhept-2-enylstannane 163. Reagents and conditions: i, SnBr4,
-78 ◦C, 10 min, (S)- or (R)-MeCH(OBn)CHO, -78 ◦C, 1 h (193, 194,
56%; 199, 200, 67%); ii, TBSCl, imid., DMF. r.t., 15 h (195, 61%; 196, 5%;
201, 55%; 204, 33%); iii, (R)- or (S)-O-acetylmandelic acid, DCC, DMAP,
DCM, r.t. 18 h (197, 78%; 198, 75%; 202, 78%; 203, 75%; 205, 89%; 206,
88%).
Tin(IV) bromide promoted reactions of the 6-hydroxy-
heptenylstannane 163 with the chiral aldehydes (S)- and (R)-2-
benzyloxypropanal were also investigated, see Scheme 18. With
the (S)-enantiomer, the (Z)-1,7-syn- and (Z)-1,7-anti-products 193
and 194 were obtained, the 1,7-syn : 1,7-anti ratio of 85 : 15 being
measured by 13C pulse delayed NMR. The geometry of the double-
bond of the major product 193 followed from its vicinal vinylic 1H
NMR coupling constant (10.5 Hz) and its 1,7-syn-configuration
course of this work where the major product from a tin(IV) halide
promoted reaction of a heterofunctionalised alk-2-enylstannane
had an (E)-double-bond. It is likely that the formation of the
(E)-isomer 199 is indicative of an open-chain transition structure
in the reaction of the intermediate allyltin tribromide with
the aldehyde, but why this particular combination of reagents
proceeds via an open-chain process rather than via the more
usually observed 6-membered chair-like transition structure is not
clear.
1
was established by comparison of the H NMR spectra of the
(R)- and (S)-O-acetylmandelates 197 and 198 prepared from the
monosilyl ether 195. The structure of the minor product was
assigned by analogy with the identification of the (Z)-1,7-anti-
isomers 165/175 as the minor products from the reaction of
stannane 163 with benzaldehyde and 2-methylpropanal.
Apart from this exception, the stereoselectivities observed for
all the tin(IV) bromide promoted reactions of the 6-hydroxyalk-2-
enylstannanes 115, 138 and 163 with aldehydes are consistent with
kinetically controlled, stereoselective transmetallations generating
allyltin tribromides which react with aldehydes via six-membered
chair-like transition structures, see Fig. 5. It is proposed that the
stereogenic centre in the alk-2-enylstannane controls the facial
selectivity of the transmetallation to give the allyltin tribromides
207, 210 and 213, in which the methyl and ethenyl substituents
are pseudoequatorial about the six-membered oxastannane ring
formed by co-ordination of the hydroxyl group with the electron
deficient tin. These allyltin tribromides can then react with
aldehydes via the six-membered chair-like transition structures
208, 211 and 214 to give the (Z)-1,5-anti-, the (Z)-1,6-anti-
and the (Z)-1,7-syn-products 209, 212 and 215, respectively. The
formation of the (Z)-double-bonds in these products is consistent
with the known preference of a group next to tin to adopt the
axial position in analogous chair-like transition structures. This
preference together with the preference of the R group of the
aldehyde to adopt the equatorial position, explains how the allyltin
The tin(IV) bromide promoted reaction of the (R)-2-
benzyloxypropanal and the (R)-6-hydroxyheptenylstannane 163
was less stereoselective and gave two separable products, ratio
65 : 35. Unexpectedly, the major product was found by spin decou-
pling to have a vinylic coupling constant of 15 Hz, indicative of an
(E)-alkene. To establish their configuration at the newly introduced
hydroxyl bearing carbon, following selective monosilylation, both
products were converted into (R)- and (S)-O-acetylmandelates,
1
see Scheme 18. By comparison of the H NMR spectra of the
O-acetylmandelates 202/203 and 205/206 derived from each silyl
ether, and taking into account the double-bond geometries as
1
indicated by H NMR, the major product was identified as the
(E)-1,7-anti-diol 199 and the minor as the (Z)-1,7-anti-diol 200.
The reaction of the (R)-6-hydroxyheptenylstannane 163 with
(R)-2-benzyloxpropanal was the only example found during the
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in Fig. 5 with the structures of the products obtained from alk-2-
enylstannanes 115, 138 and 163 in Tables 4, 5 and 6.
Summary and conclusions
This work has shown that allylstannanes with an alkoxy or hydroxy
substituent at the 4-, 5- or 6-position react with tin(IV) halides at
-78 ◦C to generate intermediates, believed to be allyltin trihalides,
which react with aldehydes with useful levels of 1,5-, 1,6- and 1,7-
stereocontrol. Fig. 6 shows an overview of the results obtained.
Interestingly, stannanes1, 73/74 and 163 withastereogeniccarbon
bearing a secondary alkoxy- or hydroxy-substituent at either the
4-, 5- or 6-position react with overall (Z)-1,5-, (Z)-1,6- and (Z)-
1,7-syn-stereocontrol. In contrast, stannanes 6, 34/35, 115 and 138
with a terminal alkoxy- or hydroxy-substituent and a stereogenic
carbon bearing a methyl substituent at either the 4- or 5-position,
react with overall (Z)-1,5- or (Z)-1,6-anti-stereocontrol.
Details of mechanistic studies including studies into the trap-
ping of the allyltin trihalides 28 and 216 and evidence for kinetic
control of the transmetallation step will be reported in full
elsewhere. However, the overall remote stereoselectivity which is
reported here is believed to be due to two factors:
Fig. 5 Participation of allyltin tribromides which account for the
stereoselectivity observed for the tin(IV) bromide promoted reactions of
allylstannanes 116, 138 and 163 with aldehydes.
(a) the kinetically controlled, diastereofacially selective trans-
metallation of substituted allylstannanes by the tin(IV) halide to
form allyltin trihalides with high levels of stereoselectivity,21 and
tribromides 207, 210 and 213, deliver the remote stereocontrol
which is observed, cf . the generalised structures 209, 212 and 215
Fig. 6 Overview of remote stereocontrol using alkoxy and hydroxy-alk-2-enylstannanes.
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(b) the subsequent reaction of the allyltin trihalides with
aldehydes via six-membered chair-like transition structures in
which the group next to tin adopts an axial position.22
like transition structures, in which the tin is trigonal bipyramidal,
i.e. transition structures 29, 109, 208, 211 and 214.
1-Substituted alk-2-enylstannanes are known to react with
aldehydes on heating to give (Z)-alkenes; for example the highly
stereoselective synthesis of the (Z)-1,2-anti-alkenes 223 from
the non-catalysed reactions of 1-alkoxybut-2-enylstannanes 222
with aldehydes. The six-membered chair-like transition state 224
in which the group a to the tin is in the axial position, has
been suggested to explain the stereoselectivity observed in these
reactions.22
The allylstannanes used in this work were mixtures of (E)- and
(Z)-isomers, typically (E) : (Z) = 70 : 30. No attempts were made
to study reactions of the (E)- and (Z)-isomers separately although
studies of the analogous chemistry of alk-2-enylgermanium
compounds indicated that (Z)-isomers were transmetallated with
better stereoselectivity.23 To explain the high levels of stereocontrol
in the transmetallation step, even for 5- and 6-substituted alk-
2-enylstannanes, it is suggested that the tin halide initially co-
ordinates to the alkoxy or hydroxy group and is then delivered
to the double-bond of the allylstannane via an intramolecular
process. For example, formation of the allyltin trichloride 28
from both the (E)- and Z)-isomers of the (R)-4-methylpent-2-
enylstannane 6 via intramolecular delivery of the trichlorotin
moiety to the double-bond places the methyl substituent in the less
hindered “outside” position, see transition structures 217 and 219
in Fig. 7. Formation of the isomeric allyltin trichloride 221 in which
the vinyl and methyl groups are cis-disposed with respect to the
5-membered oxastannane ring would require the methyl group to
be in the more hindered “inside” position, see transition structures
218 and 220. Note that the stereochemistry of the tin(IV) halide
mediated transmetallation of allylstannanes by tin(IV) halides has
not been defined. An antarafacial process is depicted in Fig. 7 but
an alternative 6-membered, cyclic, suprafacial process could be
involved. However, the explanation given for the introduction of
the stereogenic centre bearing the tin into the intermediate allyltin
trihalides would still be valid.21
The transition structures 29, 109, 208, 211 and 214 which involve
a 1-substituted allyltin trichloride reacting with an aldehyde
with formation of an (Z)-alkene, are analogous to the transition
structure 224 proposed for the thermal process. In particular, is
suggested that the alkoxy or hydroxy group, which initially directed
the transmetallation, is no longer bound to the tin in these tran-
sition structures. The high preference for (Z)-alkene formation,
especially for reactions in which the co-ordinating group is at the 6-
position in the allylstannane, is difficult to reconcile with transition
structures in which the tin is hexacoordinated, i.e. octahedral.
This remote stereocontrol using tin(IV) halide mediated reac-
tions of alkoxy and hydroxy-functionalised alk-2-enylstannanes
would appear to be generally useful and reliable with better
stereoselectivity obtained using tin(IV) bromide and 6-hydroxyalk-
2-enylstannanes for 1,6- and 1,7-stereocontrol. Preliminary studies
to extend this work to include 1,8-stereocontrol using 7-hydroxy-
7-phenylhept-2-enylstannane 225 were unsuccessful, in that a
mixture of the (E)-1,8-syn-and 1,8-anti-diphenyloct-3-ene-1,8-
diols 225 was obtained (81%, 2 : 1). However, 1,8- and 1,9-
stereocontrol has been achieved by combining 1,5-stereocontrol
as discussed here, with subsequent stereoselective 2,3- and 3,3-
sigmatropic rearrangements.24,25
This chemistry has the limitation that it involves the use of
organotin reagents, indeed one equivalent of tributyltin chloride
or bromide is produced as the side-product in the transmetalla-
tion step. Analogous allylsilanes undergo transmetallation with
tin(IV) halides but, under the longer reaction times required,
the intermediate allyltin trihalides begin to equilibrate with their
epimers and only modest stereoselectivities are observed.26 How-
ever, allylgermanes undergo transmetallation at -78 ◦C relatively
quickly, and 1,5- and 1,6-remote stereocontrol has been shown for
reactions with aldehydes of 5- and 6-alkoxy and -hydroxy-alk-2-
enylgermanes. Indeed when using tin(IV) bromide and (Z)-alk-2-
enylgermanes higher stereoselectivities can be obtained than those
found using the corresponding allylstannanes.23
Fig.
7
Transmetallation of the (E)- and (Z)-isomers of the
alk-2-enylstannane 6.
In the second step, the reaction of the allyltin trihalide with the
aldehyde, thehighfidelity for formation of(Z)-double-bonds in the
products is consistent with the participation of 6-membered chair-
Bismuth tri-iodide also effects transmetallation of the allylstan-
nane 6 to generate an allylbismuth intermediate which reacts with
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aldehydes with useful 1,5-stereocontrol, albeit in favour of (E)-
alk-3-enols.27 Similar stereoselectivity has also been observed for
the bismuth(0) promoted reactions of 5-alkoxy-4-methylpent-2-
enyl bromides with aldehydes, a tin-free process, for example the
formation of the (E)-alkenols 228 from the bromide 227 and a
reduced bismuth species.28
General procedure for the reaction of an alkoxyalk-2-enylstannane
with an aldehyde in the presence of a Lewis acid
The tin(IV) halide (1.044 M in DCM, 958 ml, 1.00 mmol) was added
to the stannane (1.0 mmol) in DCM (10 ml) at -78 ◦C. After
10 min, the aldehyde (3.48 M in DCM, 287 ml, 1.00 mmol)
was added and the mixture was maintained at -78 ◦C for 1 h.
Saturated aqueous sodium hydrogen carbonate (5 ml) was added
and the mixture allowed to warm to room temperature. Ether
(50 ml) and water (50 ml) were added and the organic phase was
washed with aqueous ammonia (10%, 50 ml) and brine (50 ml),
then dried (MgSO4). Concentration under reduced pressure and
chromatography of the residue gave the products as colourless oils.
Finally, 1,5-stereocontrol has also been observed for tin(IV)
halide promoted reactions of amino- and phenylthio-substituted
alkenylstannanes with aldehydes, and for reactions of 4- and
5-alkoxyalk-2-enylstannanes with reactive imines.29–31 Details of
this work and of the application of remote stereocontrol using
tin(IV) halide mediated reactions of allylstannanes to complete
syntheses of the natural products, patulolide C,24 epothilones32
and pamamycin 607,33 will be reported in full elsewhere.
General procedure for the preparation of Mosher’s derivatives34
The alcohol (0.10 mmol) in carbon tetrachloride (300 ml) was
added to the 2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chlo-
ride (0.20 mmol) in pyridine (300 ml) at room temperature and
the mixture stirred until no starting material remained, typically
1–1.5 h (TLC). 3-Dimethylaminopropylamine (400 ml) was added
and the clear solution was stirred for 10 min. Ether (25 ml) and
water (25 ml) were added and the organic phase was washed with
dilute aqueous hydrogen chloride (1 M, 20 ml), saturated aqueous
sodium carbonate (20 ml) and brine (20 ml), then dried (MgSO4).
Concentration under reduced pressure gave the Mosher’s ester as
a colourless oil.
Experimental
General experimental procedures
NMR spectra were recorded on Varian Unity 500, Bruker AC-
300 or Varian XL spectrometers and IR spectra on a Perkin–Elmer
1710FT spectrometer. For minor diastereoisomers, >10%, present
in mixtures, just the distinctive peaks are reported. Low resolution
chemical ionisation (CI) and electron impact (EI) mass spectra
were recorded on a Kratos MS25 mass spectrometer coupled to a
DS 55 data system or on a VG Trio 2000 mass spectrometer. Fast
atom bombardment (FAB) mass spectra and all high resolution
mass spectra were recorded on a Kratos Concept 1S mass
spectrometer coupled to a Mach 3 data system. Compounds
containing tin or chlorine showed characteristic clusters of isotope
peaks in their mass spectra.
Optical rotations were recorded on an Optical Activity AA-100
polarimeter at 589 nm using chloroform as the solvent at ambient
temperature. Analytic high performance liquid chromatography
was carried out with a Waters Z module, 10 cm ¥ 8 mm cartridge,
C18 5 m stationary phase and detection by ultraviolet absorption
using a Perkin–Elmer IC-480 detector at 255 nm. Semi-preparative
high performance liquid chromatography was carried out using a
Gilson 303 pump (with manometric module), Dynamax 83-211-C
column 25 cm ¥ 10 mm, 8 m silica, detection with a Gilson 131
refractive index detector and Gilson 115 UV detector at 254 nm.
Chromatography refers to flash chromatography and was carried
out using Merck silica 60H (40–60 m, 230–300 mesh) or May and
Baker Sorbsil C60 silica gel (40–60 m) as the stationary phase.
Petrol refers to light petroleum which distils between 40 ◦C and
60 ◦C. Tin(IV) chloride was dried with phosphorus pentoxide and
distilled. Ether refers to diethyl ether. Brine refers to saturated
aqueous sodium chloride. All solvents were dried and distilled
before use.
General procedure for the preparation of O-acetylmandelates
2-Acetoxy-2-phenylacetic acid (0.30 mmol), DCC (0.30 mmol)
and 4-N,N-dimethylaminopyridine (0.005 mmol) were added
to the alcohol (0.10 mmol) in DCM (2 ml) and the mixture
stirred at room temperature for 15 h. DCM (15 ml) and water
(15 ml) were added and the organic phase washed with dilute
aqueous hydrogen chloride (3.5 M, 10 ml), saturated aqueous
sodium hydrogen carbonate (10 ml) and brine (10 ml), then
dried (MgSO4). Concentration under reduced pressure left a solid
which was absorbed onto silica. Chromatography gave the O-
acetylmandelate as a colourless oil.
O-[(R)-5-Benzyloxy-4-methylpent-2-enyl]-S-methyl
dithiocarbonate 4
Alcohol 3 [(E) : (Z) = 80 : 20; 3.39 g, 16.46 mmol) in benzene
(16 ml) was added to sodium hydride (723 mg; 60% in mineral
oil, 18.08 mmol) in benzene (16 ml) at 5 ◦C. After 1 h at room
temperature, carbon disulfide (5.00 g, 65.76 mmol) was added at
5
◦C and the mixture was stirred at room temperature for 3 h.
Methyl iodide (9.34 g, 65.76 mmol) was added and the mixture
stirred for 15 h then filtered through celite washing the filter-cake
with DCM (120 ml). The organic extracts were washed with brine
(80 ml), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using petrol : ether (15 : 1) as eluent
gave the title compound 4 (3.72 g, 76%) as a yellow oil, a 4 : 1
mixture of (E)- and (Z)-isomers, [a]D -1.9 (c = 0.49) (Found: M+ +
H, 297.0986. C15H21O2S2 requires M, 297.0983); nmax/cm- 1 2856,
1453, 1217, 1060, 970 and 737; dH (300 MHz, C6D6) 0.90 (0.6 H,
d, J 7, 4-CH3), 0.98 (2.4 H, d, J 7, 4-CH3), 2.21 (0.6 H, s, SCH3),
2.22 (2.4 H, s, SCH3), 2.39 (0.8 H, m, 4-H), 2.74 (0.2 H, m, 4-H),
Alcohol 3 was prepared as described in the literature.5 Its e.e.
was estimated by ozonolysis with a reductive work-up to give (R)-
3-benzyloxy-2-methylpropanol shown to have an e.e. of >85% by
Mosher’s derivatisation.
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3.07–3.21 (2 H, m, 5-H2), 4.33 (0.4 H, s, PhCH2), 4.34 (1.6 H, s,
PhCH2), 4.98 (1.6 H, d, J 5.5, 1-H2), 5.18 and 5.26 (each 0.2 H, dd,
J 14, 7, 1-H), 5.43 (0.2 H, t, J 11.5, 3-H), 5.52–5.69 (1.8 H, m, 2-H
and 3-H) and 7.17–7.36 (5 H, m, ArH); dC (75 MHz, C6D6) 16.4,
17.3, 18.6, 33.1, 36.8, 69.8, 72.9, 74.3, 74.6, 122.5, 122.7, 127.7,
128.3, 139.0, 140.0 and 215.8; m/z (CI, NH3) 314 (M+ + 18, 33%),
297 (M+ + 1, 82) and 189 (100).
OH), 4.56 (2 H, s, PhCH2), 4.68 (1 H, dd, J 8, 3.5, 1-H), 5.36 (1
H, t, J 10, 4-H), 5.58 (1 H, td, J 10, 6, 3-H) and 7.30–7.40 (10
H, m, ArH); minor epimer 8, 0.95 (3 H, d, J 7.5, 5-CH3), 4.50 (2
H, s, PhCH2); dC (75 MHz, CDCl3) 17.4, 32.5, 38.7, 73.2, 73.5,
74.9, 125.9, 126.4, 127.4, 127.9, 128.1, 128.5, 128.6, 136.9, 138.2
and 145.0; m/z (CI, NH3) 314 (M+ + 18, 36%), 296 (M+, 10) and
279 (M+ - 17, 100).
S-[(3RS,4S)-5-Benzyloxy-4-methylpent-1-en-3-yl]-S-methyl
(1S,5R,3Z)-1-[(R)-2-Acetoxy-2-phenylacetoxy]-6-benzyloxy-5-
dithiocarbonate 5
methyl-1-phenylhex-3-ene 9
The xanthate 4 (3.72 g, 12.57 mmol) was heated under reflux in
toluene (150 ml) for 15 h. Concentration under reduced pressure
gave the title compound 5 (3.72 g, 100%) as a yellow oil, a 1 : 1
mixture of epimers, [a]D +1.5 (c = 0.52) (Found: M+, 296.0909.
C15H20O2S2 requires M, 296.0905); nmax/cm- 1 2856, 1647, 1454,
1101, 924, 870 and 737; dH (300 MHz, CDCl3) 0.98 (3 H, d, J 7,
4-CH3), 2.18 (1 H, m, 4-H), 2.42 (1.5 H, s, SCH3), 2.43 (1.5 H, s,
SCH3), 3.29–3.46 (2 H, m, 5-H2), 4.44–4.52 (3 H, m, PhCH2 and
3-H), 5.11–5.33 (2 H, m, 1-H2), 5.80 (1 H, m, 2-H), 7.27–7.37 (5
H, m, ArH); dC (75 MHz, CDCl3) 13.2, 13.3, 14.3, 14.5, 37.6, 37.8,
51.2, 51.5, 72.7, 72.7, 73.2, 73.4, 117.3, 118.2, 127.7, 127.8, 128.5,
134.8, 136.3, 138.6, 188.8 and 188.9; m/z (CI, NH3) 314 (M+ + 18,
5%), 297 (M+ + 1, 24) and 91 (100).
Following the general procedure, the alcohol 7 (25 mg,
0.084 mmol) and (R)-2-acetoxy-2-phenylacetic acid, after chro-
matography using petrol : ether (3 : 1) as eluent, gave the title
compound 9 (33 mg, 83%) as a colourless oil, [a]D -95 (c = 0.37)
(Found: M+ + NH4, 490.2597. C30H36NO5 requires M, 490.2593);
n
max/cm-1 2924, 1744, 1453, 1371, 1229, 1206, 1173, 1056 and 735;
dH (300 MHz, CDCl3) 0.78 (3 H, d, J 7, 5-CH3), 2.13 (3 H, s,
O2CCH3), 2.42–2.68 (3 H, m, 5-H and 2-H2), 3.12 (2 H, d, J 8,
6-H2), 4.43 (2 H, s, PhCH2), 5.03 (1 H, dt, J 10.5, 7, 3-H), 5.12
(1 H, dd, J 10.5, 9.5, 4-H), 5.75 (1 H, t, J 7, 1-H), 5.95 (1 H, s,
2¢-H) and 7.20–7.50 (15 H, m, ArH); m/z (CI, NH3) 490 (M+ +
18, 100%), 296 (17) and 279 (42).
(1S,5R,3Z)-1-[(S)-2-Acetoxy-2-phenylacetoxy]-6-benzyloxy-5-
(R)-5-Benzyloxy-4-methylpent-2-enyl(tributyl)stannane 6
methyl-1-phenylhex-3-ene 10
Tributyltin hydride (4.80 g, 16.49 mmol) and azobis-iso-
butyronitrile (135 mg, 0.825 mmol) were added to a degassed
solution of the dithiocarbonate 5 (3.72 g, 12.57 mmol) in benzene
(125 ml) and the solution was heated under reflux for 2.5 h.
After concentration under reduced pressure, chromatography of
the residue using petrol : ether (50 : 1 + 1% triethylamine) as eluent
gave the title compound 6 (5.18 g, 86%) as a colourless oil, a 4 : 1
mixture of (E)- and (Z)-isomers), [a]D -6.3 (c = 0.79); (Found: M+
- C4H9, 423.1723. C21H35O120Sn requires M, 423.1710; nmax/cm-1
2956, 2925, 1455, 1095, 962 and 734; dH (300 MHz, CDCl3) 0.78–
0.98 (15 H, m, 3 ¥ SnCH2CH2CH2CH3), 1.03 (3 H, m, 4-CH3),
1.22–1.75 (14 H, m, 3 ¥ SnCH2CH2CH2CH3 and 1-H2), 2.48 (0.8
H, m, 4-H), 2.78 (0.2 H, m, 4-H), 3.24 (1 H, dd, J 8, 6, 5-H), 3.46
(1 H, m, 5-H¢), 4.46–4.57 (2 H, m, PhCH2), 4.89 (0.2 H, dd, J 10.5,
9.5, 3-H), 5.16 (0.8 H, dd, J 15, 7, 3-H), 5.53–5.67 (1 H, m, 2-
H) and 7.25–7.38 (5 H, m, ArH); dC (75 MHz, CDCl3) (E)-isomer
9.3, 13.9, 14.5, 17.9, 27.5, 29.3, 37.2, 73.1, 76.2, 127.6, 127.7, 128.1,
128.5, 129.3 and 139.0; m/z (EI) 423 (M+ - 57, 54%), 291 (33) and
91 (100).
Following the general procedure, the alcohol 7 (25 mg,
0.084 mmol) and (S)-2-acetoxy-2-phenylacetic acid, after chro-
matography using petrol : ether (3 : 1) as eluent, gave the title
compound 10 (35 mg, 88%) as a colourless oil; [a]D -1.5 (c = 0.48);
(Found: M+ + NH4, 490.2581. C30H36NO5 requires M, 490.2593);
n
max/cm-1 2854, 1745, 1454, 1372, 1232, 1207, 1175, 1058 and 738;
dH (300 MHz, CDCl3) 0.83 (3 H, d, J 7, 5-CH3), 2.19 (3 H, s,
O2CCH3), 2.49–2.73 (3 H, m, 5-H and 2-H2), 3.15–3.28 (2 H, m,
6-H2), 4.48 (2 H, s, PhCH2), 5.22–5.36 (2 H, m, 3-H and 4-H),
5.73 (1 H, t, J 7, 1-H), 5.99 (1 H, s, 2¢-H) and 6.90–7.40 (15 H,
m, ArH); m/z (CI, NH3) 490 (M+ + 18, 100%), 296 (17) and
279 (39).
(1S,5R,3Z)-1-Acetoxy-6-benzyloxy-5-methyl-1-phenylhex-3-ene
11
Triethylamine (182 mg, 1.802 mmol), 4-N,N-dimethylamino-
pyridine (4 mg, 0.033 mmol) and acetic anhydride (65 mg,
0.637 mmol) were added to the alcohol 7 (103 mg, 0.348 mmol) in
DCM (2 ml) and the solution stirred for 50 h. DCM (20 ml) and
water (20 ml) were added and the organic phase was washed with
dilute aqueous hydrogen chloride (3.5 M, 15 ml) and brine (15 ml)
then dried (MgSO4). Concentration under reduced pressure and
chromatography of the residue using petrol : ether (3 : 1) as eluent,
gave the title compound 11 (105 mg, 89%) as a colourless oil, [a]D
-68 (c = 0.50); (Found: M+ + NH4, 356.2227. C22H30NO3 requires
M, 356.2226; nmax/cm-1 2854, 1744, 1372, 1234, 1092, 1028 and
738; dH (300 MHz, CDCl3) 0.86 (3 H, d, J 7, 5-CH3), 2.05 (3
H, s, O2CCH3), 2.52–2.78 (3 H, m, 5-H and 2-H2), 3.18–3.29 (2
H, m, 6-H2), 4.48 (2 H, s, PhCH2), 5.23–5.36 (2 H, m, 3-H and
4-H), 5.76 (1 H, t, J 7, 1-H) and 7.25–7.40 (10 H, m, ArH); dC
(75 MHz, CDCl3) 17.7, 21.4, 32.7, 34.8, 73.1, 75.2, 75.7, 124.3,
126.8, 127.6, 127.7, 128.1, 128.5, 128.5, 135.8, 138.8, 140.4 and
(1S,5R,3Z)-6-Benzyloxy-5-methyl-1-phenylhex-3-en-1-ol 7
Following the general procedure, stannane
6 (500 mg,
1.044 mmol), tin(IV) chloride in DCM (1.044 M, 1.00 ml,
1.044 mmol) and benzaldehyde in DCM (4.16 M, 250 ml,
1.044 mmol), with chromatography using petrol : ether (3 : 1) as
eluent, gave the title compound 7 (257 mg, 83%) as a colourless
oil, a 97 : 3 mixture of epimers, [a]D -88 (c = 0.36); (Found: M+ +
NH4, 314.2108. C20H28NO2 requires M, 314.2120); nmax/cm-1 3422,
2958, 2926, 1454, 1090, 1029, 913, 877, 740 and 700; dH (300 MHz,
CDCl3) major epimer 7, 0.91 (3 H, d, J 7.5, 5-CH3), 2.39 (1 H, m,
2-H), 2.60 (1 H, dt, J 13, 9.5, 2-H¢), 2.88 (1 H, m, 5-H), 3.16 (1
H, t, J 8.5, 6-H), 3.35 (1 H, dd, J 8.5, 5.5, 6-H¢), 3.42 (1 H, br s,
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170.4; m/z (CI, NH3) 356 (M+ + 18, 37%), 296 (25), 279 (75) and
85 (100).
O-[(5R,2E)-5-tert-Butyldimethylsilyloxyhex-2-en-1-yl] S-methyl
dithiocarbonate 70
Ozone was bubbled through a solution of acetate 11 (103 mg,
0.308 mmol) in chloroform (10 ml) at -60 ◦C for 30 min. The
solution was purged with oxygen for 10 min, dimethyl sulfide
(191 mg, 3.08 mmol) was added and the solution was allowed
to warm to room temperature. Following concentration under
reduced pressure, the residual oil was dissolved in DCM (5 ml)
and added dropwise to a suspension of sodium borohydride
(100 mg, 2.63 mmol) in methanol (5 ml) at 0 ◦C. After 3 h at
room temperatu◦re, dilute aqueous hydrogen chloride (1 M, 5 ml)
was added at 0 C. Upon warming to room temperature, DCM
(25 ml) and water (25 ml) were added, and the aqueous phase was
extracted with DCM (25 ml). The organic extracts were washed
with brine (30 ml), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using petrol : ether (1 : 1)
as eluent gave a mixture of 3-benzyloxy-2-methylpropanol 16 and
(S)-3-acetoxy-1-phenylpropan-1-ol (S)-15 (2 : 1, 42 mg), and (S)-3-
acetoxy-3-phenylpropan-1-ol (S)-14 (17 mg, 29%), as a colourless
oil, [a]D -79 {c = 0.61; lit.1a for (R)-14, [a]D +79.2} (Found: M+ +
NH4, 212.1294. C11H18NO3 requires M, 212.1287); nmax/cm-1 3415,
2956, 1736, 1374, 1240, 1048 and 760; dH (300 Mhz, CDCl3) 1.98–
2.18 (5 H, m, 2-H2 and O2CCH3), 3.65 (2 H, dd, J 7, 5 Hz, 1-H2),
5.96 (1 H, dd, J 9, 5, 3-H) and 7.25–7.40 (5 H, m, ArH); dC
(75 MHz, CDCl3) 21.4, 39.7, 59.0, 73.4, 126.6, 128.3, 128.8, 140.4
and 171.1; m/z (CI, NH3) 212 (M+ + 18, 100%), 152 (95) and 134
(98).
Allylic alcohol 69 (2.98 g, 12.96 mmol) in benzene (15 ml) was
added to sodium hydride (571 mg, a 60% dispersion in mineral
oil, 14.27 mmol) in benzene (12.5 ml) at room temperature. After
2 h at 40 ◦C, carbon disulfide (3.94 g, 51.84 mmol) was added at
5
◦C and the mixture was stirred at room temperature for 3 h.
Methyl iodide (7.37 g, 51.90 mmol) was added at 5 ◦C and the
mixture stirred for 15 h at room temperature. The mixture was
filtered through celite and the filtercake was washed with DCM
(100 ml). The organic extracts were washed with brine (75 ml),
dried (MgSO4) and concentrated under reduced pressure to yield
the title compound 70 (3.82 g, 92%) as a yellow oil, [a]D -4.7
(c = 0.80) (Found: M+ + H, 321.1389. C14H29O2S2Si2 requires M,
321.1378; nmax/cm-1 2929, 1254, 1217, 1185, 1059, 836 and 775; dH
(300 MHz, C6D6) 0.07 [6 H, s, Si(CH3)2], 1.04 [9 H, s, SiC(CH3)3],
1.07 (3 H, d, J 6, 6-H3), 1.97–2.18 (2 H, m, 4-H2), 2.22 (3 H, s,
SCH3), 3.68 (1 H, m, 5-H), 5.02 (2 H, d, J 6.5, 1-H2) and 5.56 and
5.72 (each 1 H, dt, J 15.5, 6.5, 2-H or 3-H); dC (75 MHz, C6D6)
-4.6, -4.4, 18.2, 18.8, 23.6, 26.0, 42.8, 68.2, 74.2, 125.3, 134.5 and
216.0; m/z (CI, NH3) 321 (M+ + 1, 63%), 189 (97), 159 (100) and
132 (84).
S-[(3RS,5R)-5-tert-Butyldimethylsilyloxyhex-1-en-3-yl] S¢-methyl
dithiocarbonate 71
Xanthate 70 (3.82 g, 11.93 mmol) was heated under reflux in
toluene (120 ml) for 15 h. Concentration under reduced pressure
gave the title compound 71 (3.82 g, 100%) as a yellow oil, a 1 : 1
mixture of epimers (Found: M+ + H, 321.1376. C14H29O2S2Si2
requires M, 321.1378); nmax/cm-1 2930, 1649, 1255, 1047, 865, 836
and 775; dH (300 MHz, CDCl3) 0.05 and 0.06 (each 3 H, s, SiCH3),
0.89 and 0.91 [each 4.5 H, s, SiC(CH3)3], 1.16 (3 H, d, J 6, 6-H3),
1.64–1.88 (2 H, m, 4-H2), 2.41 and 2.42 (each 1.5 H, s, SCH3), 3.89
(1 H, m, 5-H), 4.29 (1 H, m, 3-H), 5.06–5.32 (2 H, m, 1-H2) and
5.80 (1 H, m, 2-H); dC (75 MHz, CDCl3) -4.8, -4.6, -4.2, -4.0,
12.9, 13.0, 18.0, 23.8, 24.0, 25.9, 25.9, 29.7, 43.2, 43.8, 45.1, 45.8,
65.7, 66.0, 115.9, 116.9, 137.4, 138.0, 188.5 and 188.6; m/z (CI,
NH3) 321 (M+ + 1, 26%) and 189 (100).
(1S,5R,3Z)-6-Benzyloxy-1-[(R)-2-methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-5-methyl-1-phenylhex-3-ene 12
Following the general procedure, alcohol 7 (31 mg, 0.105 mmol)
and (S)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride
gave the title compound 12 (46 mg, 86%) as a colourless oil, [a]D
-14 (c = 0.48) (Found: M+ + NH4, 530.2498. C30H35F3NO4 requires
M, 530.2518); nmax/cm-1 2928, 2851, 1749, 1454, 1272, 1170, 1017
and 762; dH (300 MHz, CDCl3) 0.84 (3 H, d, J 7, 5-CH3), 2.57–
2.83 (3 H, m, 5-H and 2-H2), 3.21 (2 H, d, J 7.5, 6-H2), 3.53 (3
H, s, OCH3), 4.46 (2 H, s, PhCH2), 5.30–5.37 (2 H, m, 3-H and
4-H), 5.91 (1 H, t, J 7, 1-H) and 7.20–7.45 (15 H, m, ArH); dF
(470 MHz, CDCl3) -73.0, -73.2, ratio 9 : 91; m/z (CI, NH3) 530
(M+ + 18, 92%), 279 (87), 189 (69) and 85 (100).
(R)-5-tert-Butyldimethylsilyloxyhex-2-enyl(tributyl)stannane 72
Tributyltin hydride (2.27 g, 7.81 mmol) and a-azo-bis-iso-
butyronitrile (51 mg, 0.311 mmol) were added to a degassed
solution of the dithiocarbonate 71 (2.0 g, 6.25 mmol) in benzene
(85 ml) and the solution was heated to reflux for 3.5 h. Following
concentration under reduced pressure, chromatography of the
residue using petrol (with 2% triethylamine) as eluent afforded the
title compound 72 (2.66 g, 85%) as a colourless oil, a 2 : 1 mixture
of (E)- and (Z)-isomers, [a]D +2.3 (c = 1.16) (Found: M+ - C4H9,
447.2109. C20H43OSi120Sn requires M, 447.2104); nmax/cm-1 2928,
1463, 1376, 1254, 1129, 1090, 1004, 836 and 775; dH (300 MHz,
CDCl3) 0.05 and 0.07 (each 3 H, s, SiCH3), 0.84–0.94 [24 H, m, 3 ¥
SnCH2CH2CH2CH3 and SiC(CH3)3], 1.11 (2 H, d, J 6, 6-H3), 1.13
(1 H, d, J 6, 6-H3), 1.24–1.74 (14 H, m, 3 ¥ SnCH2CH2CH2CH3
and 1-H2), 1.98–2.23 (2 H, m, 4-H2), 3.73 (0.66 H, m, 5-H), 3.81
(0.34 H, m, 5-H), 5.08 (0.33 H, dt, J 10.5, 7, 2-H), 5.18 (0.67 H, dt,
J 15, 7, 2-H) and 5.57 (1 H, m, 3-H); dC (75 MHz, CDCl3) -4.6,
-4.5, 9.2, 9.4, 10.7, 13.7, 14.4, 18.2, 23.2, 23.5, 25.9, 27.3, 29.1,
(1S,5R,3Z)-6-Benzyloxy-1-[(S)-2-methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-5-methyl-1-phenylhex-3-ene 13
Following the general procedure, alcohol 7 (26 mg, 0.088 mmol)
and (R)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride,
after chromatography using petrol : ether (3 : 1) as eluent, gave the
title compound 13 (23 mg, 51%) as a colourless oil, [a]D -70 (c =
0.83) (Found: M+ + NH4, 530.2528. C30H35F3NO4 requires M,
530.2518); nmax/cm-1 2851, 1748, 1454, 1271, 1170, 1121, 1018 and
718; dH (300 MHz, CDCl3) 0.83 (3 H, d, J 7, 5-CH3), 2.56–2.78
(3 H, m, 5-H and 2-H2), 3.16 (2 H, d, J 6.5, 6-H2), 3.46 (3 H, s,
OCH3), 4.46 (2 H, s, PhCH2), 5.16–5.25 (2 H, m, 3-H and 4-H),
5.98 (1 H, t, J 7, 1-H) and 7.30–7.50 (15 H, m, ArH); dF (470 MHz,
CDCl3) -73.0, -73.2, ratio 95 : 5; m/z (CI, NH3) 530 (M+ + 18,
55%) and 279 (100).
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37.4, 43.3, 69.0, 69.4, 120.5, 122.0, 129.7 and 131.5; m/z (EI) 447
(M+ - 57, 86%), 445 (M+ - 57, 70) and 291 (100).
The organic phase was washed with brine (20 ml), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using petrol : ether (5 : 1 + 1% triethylamine) as the eluent,
gave the title compound 75 (83 mg, 83%) as a colourless oil,
[a]D -3.7 (c = 0.86) (Found: M+ - C4H9, 335.1393. C14H31O120Sn
requires M, 335.1396); nmax/cm-1 3339, 2925, 1462, 1376 and
1072; dH (300 MHz, CDCl3) 0.74–0.97 (17 H, m, 1-H2 and 3 ¥
SnCH2CH2CH2CH3), 1.22 (3 H, d, J 6, 6-H3), 1.25–1.65 (18 H,
m, 2-H2, 3-H2, 4-H2 and 3 ¥ SnCH2CH2CH2CH3) and 3.83 (1 H,
m, 5-H); dC (75 MHz, CDCl3) 8.8, 9.0, 13.7, 23.5, 27.1, 27.4, 29.3,
30.5, 39.0 and 68.2; m/z (EI) 335 (M+ - 57, 100%), 333 (M+ - 57,
80) and 177 (74).
(R)-5-Hydroxyhex-2-enyl(tributyl)stannane 73
Tetrabutylammonium fluoride in THF (1 M, 10.4 ml, 10.4 mmol)
was added to the silyl ether 72 (3.39 g, 6.74 mmol) in THF (10 ml)
and was stirred at room temperature for 15 h. Water (20 ml) was
added and the mixture was stirred for a further 1 h. The mixture
was extracted with ether (4 ¥ 20 ml) and the organic extracts
were washed with brine (75 ml), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
petrol : ether (10 : 1 + 1% triethylamine) as solvent, gave the title
compound 73 (2.31 g, 88%) as a colourless oil, a 2 : 1 mixture of
(E)- and (Z)-isomers), [a]D +2.3 (c = 0.70) (Found: M+ - C4H9,
333.1236. C14H29O120Sn requires M, 333.1239); nmax/cm-1 3351,
2925, 1463, 1376, 1073 and 961; dH (300 Mz, CDCl3) 0.76–0.95
(15 H, m, 3 ¥ SnCH2CH2CH2CH3), 1.18 (2 H, d, J 6.5, 6-H3), 1.22
(1 H, d, J 6, 6-H3), 1.25–1.87 (14 H, m, 3 ¥ SnCH2CH2CH2CH3
and 2-H2), 2.00–2.26 (2 H, m, 4-H2), 3.72 (0.7 H, m, 5-H), 3.81 (0.3
H, m, 5-H), 5.16 and 5.69 (each 1 H, m, 2-H or 3-H); dC (75 MHz,
CDCl3) 9.2, 9.4, 10.8, 13.7, 14.5, 22.5, 22.8, 27.3, 29.1, 36.9, 42.8,
67.5, 67.9, 119.2, 120.8, 132.0 and 133.8; m/z (EI) 333 (M+ - 57,
1%), 331 M+ - 57, 1), (291 (9), 269 (17), 135 (43) and 84 (100).
(R)-5-[(R)-2-Methoxy-2-phenyl-3,3,3-trifluoropropanonyl-
oxy]hexyl(tributyl)stannane 76
Following the general procedure, alcohol 75 (14 mg, 0.036 mmol)
and (S)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride af-
forded the title compound 76 (22 mg, 100%) as a colourless oil, [a]D
+14.5 (c = 0.94) (Found: M+ - C4H9, 551.1794. C24H38F3O3120Sn
requires M, 551.1794); nmax/cm-1 2925, 1746, 1454, 1270, 1170,
1123, 1020 and 716; dH (500 MHz, C6D6) 0.86–1.10 (15 H, m, 3 ¥
SnCH2CH2CH2CH3), 1.12 (3 H, d, J 6, 6-H3), 1.30–1.76 (20 H,
m, 3 ¥ SnCH2CH2CH2CH3 and 1-H2, 2-H2, 3-H2 and 4-H2), 3.57
(3 H, s, OCH3), 5.19 (1 H, m, 5-H), 7.13–7.24 (3 H, m, ArH) and
7.80–7.84 (2 H, m, ArH); dF (470 MHz, C6D6) -73.0; m/z (EI) 551
(M+ - 57, 21%), 549 (M+ - 57, 15) and 317 (100).
(R)-5-Methoxyhex-2-enyl(tributyl)stannane 74
Hydroxyalkenylstannane 73 (516 mg, 1.326 mmol) in THF (5 ml)
was added to a suspension of sodium hydride (64 mg of a
60% dispersion in mineral oil, 1.60 mmol) in THF (1 ml) at
room temperature. After 2 h at 35 ◦C, methyl iodide (941 mg,
6.630 mmol) was added at room temperature and the suspension
was stirred for 15 h. Water (5 ml) was added and the mixture
was extracted with ether (4 ¥ 15 ml). The organic extracts were
washed with brine (50 ml), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
petrol : ether (40 : 1 + 1% triethylamine) gave the title compound
74 (452 mg, 85%) as a colourless oil, a 2 : 1 mixture of the (E)- and
(Z)-isomers, [a]D +7.3 (c = 1.90) (Found: M+ - C4H9, 347.1398.
C15H31O120Sn requires M, 347.1397); nmax/cm-1 2925, 1463, 1376,
1129, 1099 and 960; dH (300 MHz, CDCl3) 0.75–0.96 (15 H, m,
3 ¥ SnCH2CH2CH2CH3), 1.11 (2 H, d, J 6, 6-H3), 1.14 (1 H, d, J
6, 6-H3), 1.22–1.84 (14 H, m, 3 ¥ SnCH2CH2CH2CH3 and 1-H2),
1.98–2.35 (2 H, m, 4-H2), 3.25 (1 H, m, 5-H), 3.31 (2 H, s, OCH3),
3.33 (1 H, s, OCH3), 5.08 (0.34 H, dt, J 10.5, 7, 2-H), 5.18 (0.66 H,
dt, J 15, 7.5, 2-H) and 5.60 (1 H, m, 3-H); dC (75 MHz, CDCl3)
9.2, 9.4, 10.7, 13.7, 14.4, 18.8, 19.1, 27.3, 29.1, 33.6, 39.4, 55.9,
56.0, 77.4, 119.7, 121.3, 130.2 and 131.8; m/z (EI) 347 (M+ - 57,
13%), 345 (M+ - 57, 9), 291 (20), 269 (11) and 59 (100).
(R)-5-[(S)-2-Methoxy-2-phenyl-3,3,3-trifluoropropionyloxy]-
hexyl(tributyl)stannane 77
Following the general procedure, alcohol 75 (37 mg, 0.095 mmol)
and (R)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride af-
forded the title compound 77 (40 mg, 70%) as a colourless oil, [a]D
-36.5 (c = 1.62) (Found: M+ - C4H9, 551.1788. C24H38F3O3120Sn
requires M, 551.1794); nmax/cm-1 2925, 1746, 1454, 1270, 1169,
1123, 1081, 1021 and 715; dH (500 MHz, C6D6) 0.86–1.08 (15 H,
m, 3 ¥ SnCH2CH2CH2CH3), 1.16 (3 H, d, J 6, 6-H3), 1.20 - 1.75
(20 H, m, 3 ¥ SnCH2CH2CH2CH3 and 1-H2, 2-H2, 3-H2 and 4-
H2), 3.57 (3 H, s, OCH3), 5.20 (1 H, m, 5-H), 7.14–7.23 (3 H, m,
ArH) and 7.80–7.84 (2 H, m, ArH); dF (470 MHz, C6D6) -72.9;
m/z (CI, NH3) 551 (M+ - 57, 7%), 549 (M+ - 57, 5), 308 (56) and
30 (100).
(1R,6R,3Z)-6-Methoxy-1-phenylhept-3-en-1-ol 78
Following the general procedure, stannane 74 (450 mg,
1.12 mmol), tin(IV) bromide (1.044 M in DCM, 1.07 ml,
1.12 mmol) and benzaldehyde (321 ml, 1.12 mmol), after chro-
matography using petrol : ether (2 : 1) as eluent, gave the title
compound 78 (193 mg, 78%) as a colourless oil, a 91 : 9 mixture of
epimers, [a]D +95 (c = 0.90) (Found: M+ - OH, 203.1434. C14H18O
requires M, 203.1436); nmax/cm-1 3417, 2972, 1493, 1453, 1135,
1086, 1054, 760 and 701; dH (300 MHz, CDCl3) 1.16 (3 H, d, J 6,
7-H3), 2.12 (1 H, dt, J 14, 5, 2- or 5-H), 2.30–2.50 (2 H, m, 2 ¥ 2-
or 5-H), 2.58 (1 H, m, 2- or 5-H), 3.15 (1 H, br s, OH), 3.25–3.40
(4 H, m, 6-H and OCH3), 4.71 (1 H, dd, J 8.5, 4.5, 1-H), 5.50–5.66
(2 H, m, 3-H and 4-H) and 7.23–7.39 (5 H, m, ArH); dC (75 MHz,
CDCl3) major epimer 78 18.9, 34.5, 37.8, 56.1, 73.5, 76.5, 125.8,
127.3, 127.4, 128.3, 129.3 and 144.6; minor epimer 81 18.6, 34.0
(R)-5-Hydroxyhexyl(tributyl)stannane 75
Toluene 4-sulfonyl hydrazide (239 mg, 1.28 mmol) and then
sodium acetate (105 mg, 1.28 mmol) were added to the allylstan-
nane 73 (100 mg, 0.257 mmol) in ethanol (10 ml) and the solution
was heated under reflux. After 2 h, further portions of toluene
4-sulfonyl hydrazide (239 mg, 1.28 mmol) and sodium acetate
(105 mg, 1.28 mmol) were added and the solution was heated
under reflux for a further 2 h. Following concentration under
reduced pressure, hexane (25 ml) and water (25 ml) were added.
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and 37.3; m/z (CI, NH3) 238 (M+ + 18, 1%), 220 (M+, 9), 203 (M+
- 17, 96), 171 (98), 121 (66) and 59 (100).
organic extracts were washed with brine (30 ml), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using petrol : ether (2 : 1 to 1 : 2) as eluent gave (R)-1-
phenyl-3-acetoxypropan-1-ol (R)-15 (11 mg, 15%) as a colourless
oil, [a]D +15 (c = 0.49) (Found: M+, 194.0943. C11H14O3 requires
M, 194.0943); nmax/cm-1 3438, 2957, 1738, 1368, 1243, 1041 and
702; dH (300 MHz, CDCl3) 2.01–2.45 (6 H, m, O2CCH3, 2-H2 and
OH), 4.16 (1 H, dt, J 11.5, 5.5, 3-H), 4.35 (1 H, ddd, J 11.5, 7.5, 5.5,
3-H¢), 4.83 (1 H, dd, J 8, 5.5, 1-H) and 7.30–7.42 (5 H, m, ArH); dC
(75 MHz, CDCl3) 21.0, 38.0, 61.6, 71.3, 125.8, 127.8, 128.6, 143.9
and 171.3; m/z (CI, NH3) 212 (M+ + 18, 4%), 193 (M+ - 1, 7) and
177 (M+ - 17, 100). The second fraction contained (R)-3-acetoxy-
3-phenylpropan-1-ol (R)-14 (43 mg, 58%) as a colourless oil, [a]D
+69 (c = 1.35; lit.1a,9 +79.2), all other data as for the (S)-enantiomer
(S)-14 prepared earlier.
(1R,6R,3Z)-6-Methoxy-1-(4-nitrobenzoyloxy)-1-phenylhept-3-ene
79
Triethylamine (27 mg, 0.27 mmol), 4-N,N-dimethylaminopyridine
(2 mg, 0.016 mmol) and 4-nitrobenzoyl chloride (59 mg,
0.318 mmol) were added to the alcohol 78 (23 mg, 0.105 mmol)
in DCM (2 ml) and the mixture stirred at room temperature for
72 h. Ether (20 ml) and water (20 ml) were added, and the organic
phase was washed with aqueous hydrogen chloride (3.5 M, 15 ml)
and brine (15 ml) then dried (MgSO4). After concentration under
reduced pressure, chromatography of the residue using petrol ether
(4 : 1) as eluent gave the title compound 79 (34 mg, 88%) as a
colourless oil, [a]D -18 (c = 1.58 (Found: M+ + NH4, 387.1914.
C21H27N2O5 requires M, 387.1919); nmax/cm-1 2972, 1725, 1607,
1529, 1345, 1273, 1102 and 720; dH (300 MHz, CDCl3) 1.11 (3 H,
d, J 6 7-H3), 2.16 and 2.29 (each 1 H, dt, J 14.5, 7, 5-H), 2.75 and
2.92 (each 1 H, dt, J 14.5, 7, 2-H), 3.28 (1 H, m, 6-H), 3.33 (3
H, s, OCH3), 5.47–5.62 (2 H, m, 3-H and 4-H), 6.06 (1 H, t, J 7,
1-H), 7.31–7.49 (5 H, m, ArH) and 8.23–8.36 (4 H, m, ArH); dC
(75 MHz, CDCl3), 18.9, 34.1, 34.5, 56.1, 76.4, 77.3, 123.5, 125.2,
126.6, 128.3, 128.6, 129.4, 130.8, 135.8, 139.6, 150.6 and 163.9;
m/z (CI, NH3) 387 (M+ + 18, 8%), 203 (100) and 171 (56).
(1S,6R,3Z)-6-Methoxy-1-phenylhept-3-en-1-ol 81
Sodium hydroxide (57 mg, 1.43 mmol) was added to the 4-
nitrophenyl ester 86 (80 mg, 0.216 mmol) in methanol (6 ml). After
2 h at room temperature water (15 ml) was added and the mixture
extracted with ether (2 ¥ 20 ml). The organic extracts were washed
with brine (30 ml), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using petrol : ether (2 : 1)
as eluent gave the title compound 81 (40 mg, 84%) as a colourless
oil, [a]D -72 (c = 1.78) (Found: M+, 220.1461. C14H20O2 requires
M, 220.1463); nmax/cm-1 3422, 3126, 2972, 1494, 1453, 1378, 1199,
1135, 1087, 1052, 760 and 702; dH (300 MHz, CDCl3) 1.18 (3 H,
d, J 6.5, 7-H3), 2.28 (2 H, t, J 6.5, 5-H2), 2.58 (2 H, t, J 6.5, 2-H2),
3.09 (1 H, br s, OH), 3.31–3.42 (4 H, m, 6-H and OCH3), 4.78 (1
H, t, J 6.5, 1-H), 5.53 (1 H, dt, J 11, 7, 3-H), 5.64 (1 H, dt, J 11,
7, 4-H) and 7.26–7.42 (5 H, m, ArH); dC (75 MHz, CDCl3) major
epimer 81 18.6, 34.0, 37.3, 56.1, 73.4, 76.4, 125.8, 127.1, 127.3,
128.3, 128.8 and 144.5; minor epimer 78 18.9, 34.5 and 37.8; m/z
(CI, NH3) 238 (M+ + 18, 38%), 220 (M+, 33) and 203 (100).
(1R,6R,3Z)-1-Acetoxy-6-methoxy-1-phenylhept-3-ene 80
Triethylamine (402 mg, 3.98 mmol), 4-N,N-dimethyl-
aminopyridine (5 mg, 0.041 mmol) and acetic anhydride
(162 mg, 1.59 mmol) were added to the alcohol 78 (175 mg,
0.795 mmol) in DCM (4 ml) and the mixture stirred at room
temperature for 15 h. DCM (35 ml) and water (35 ml) were added,
and the organic phase washed with aqueous hydrogen chloride
(3.5 M, 25 ml), saturated aqueous sodium hydrogen carbonate
(25 ml) and brine (15 ml) then dried (MgSO4). After concentration
under reduced pressure, chromatography of the residue using
petrol : ether (3 : 1) as eluent gave the title compound 80 (192 mg,
92%) as a colourless oil, [a]D +34 (c = 0.7); Found: M+ + NH4,
280.1917. C16H26NO3 requires M, 280.1913); nmax/cm-1 2972,
1741, 1373, 1237, 1094, 1024 and 700; dH (300 MHz, C6D6) 1.07
(3 H, d, J 6, 7-H3), 1.74 (3 H, s, O2CCH3), 2.12, 2.31, 2.56 and
2.76 (each 1 H, dt, J 14, 7, 2-H or 5-H), 3.12 (1 H, m, 6-H), 3.16
(3 H, s, OCH3), 5.50 and 5.63 (each 1 H, m, 3- or 4-H), 6.02 (1 H,
t, J 7, 1-H), and 7.10–7.37 (5 H, m, ArH); dC (75 MHz, C6D6)
19.1, 20.7, 34.4, 34.8, 55.8, 75.5, 76.6, 125.9, 127.0, 128.6, 129.3,
140.9 and 169.4; m/z (CI, NH3) 280 M+ + 18, 50%), 220 (71), 203
(100) and 171 (100).
Ozone was bubbled through a solution of the acetoxyalkene
80 (100 mg, 0.382 mmol) in chloroform (5 ml) at -78 ◦C for
15 min. The solution was purged with oxygen for 10 min, then
dimethyl sulfide (170 mg, 2.73 mmol) was added and the mixture
allowed to warm to room temperature. After concentration under
reduced pressure, the residual oil was dissolved in DCM (2 ml),
and methanol (2 ml) and sodium borohydride (100 mg, 2.63 mmol)
were added at 0 ◦C. After 1.5 h at room temperature aqueous
hydrogen chloride (1 M, 4 ml) was added at 0 ◦C. After warming
to room temperature DCM (25 ml) and water (25 ml) were added,
and the aqueous phase was extracted with DCM (25 ml). The
(1R,6R,3Z)-6-Methoxy-1-[(R)-2-methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-1-phenylhept-3-ene 82
Following the general procedure, alcohol 78 (16 mg, 0.072 mmol)
and (S)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride af-
forded the title compound 82 (31 mg, 97%) as a colourless oil, [a]D
+52 (c = 1.35) (Found: M+ + NH4, 454.2201. C24H31F3NO4 requires
M, 454.2205); nmax/cm-1 2967, 1748, 1261, 1170, 1095, 1018, 801
and 700; dH (300 MHz, CDCl3) 1.08 (3 H, d, J 6, 7-H3), 2.05 and
2.17 (each 1 H, dt, J 14.5, 7, 5-H), 2.62 and 2.76 (each 1 H, dt,
J 14.5, 7, 2-H), 3.22 (1 H, m, 6-H), 3.31 and 3.49 (each 3 H, s,
OCH3), 5.36 (1 H, m, 3- or 4-H), 5.49 (1 H, dt, J 10.5, 7, 3- or
4-H), 6.02 (1 H, dd, J 7, 6.5, 1-H) and 7.31–7.48 (10 H, m, ArH);
dF (470 MHz, CDCl3) -73.0, -73.1, ratio 91 : 9; m/z (CI, NH3) 454
(M+ + 18, 8%), 203 (100) and 171 (62).
(1R,6R,3Z)-6-Methoxy-1-[(S)-2-methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-1-phenylhept-3-ene 83
Following the general procedure, alcohol 78 (15 mg, 0.068 mmol)
and (R)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoyl chloride af-
forded the title compound 83 (23 mg, 78%) as a colourless oil,
[a]D -4.9 (c = 0.93) (Found: M+ + NH4, 454.2210. C24H31F3NO4
requires M, 454.2205); nmax/cm-1 2972, 1749, 1272, 1170, 1124,
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1017, 995, 719 and 699; dH (300 MHz, CDCl3) 1.09 (3 H, d, J 6,
7-H3), 2.11 and 2.23 (each 1 H, dt, J 14.5, 7, 5-H), 2.64 and 2.82
(each 1 H, dt, J 14.5, 7, 2-H), 3.27 (1 H, m, 6-H), 3.32 and 3.58
(each 3 H, s, OCH3), 5.48 (1 H, m, 3- or 4-H), 5.58 (1 H, dt, J
10.5, 7, 3- or 4-H), 5.96 (1 H, dd, J 7.5, 6.5, 1-H) and 7.23–7.47
(10 H, m, ArH); dF (470 MHz, CDCl3) -73.0, -73.2, ratio 10 : 90;
m/z (CI, NH3) 454 (M+ + 18, 19%), 220 (18) and 203 (100).
126.5, 128.3, 128.6, 129.3, 130.8, 135.8, 139.6, 150.6 and 163.9;
m/z (CI, NH3) 387 (M+ + 18, 10%), 203 (100) and 171 (44).
N-Methyl-2-(prop-2-enylthio)imidazole 133
Allyl bromide (10 g, 82.64 mmol) was added dropwise to 2-
mercapto-1-methylimidazole (4.71 g, 41.32 mmol) and potassium
carbonate (5.70 g, 41.32 mmol) in acetone (100 ml) and the mixture
stirred for 3 h. Water (50 ml) was added and the stirring continued
for a further 30 min. The mixture was extracted with ether
and the organic extracts washed with brine and dried (MgSO4).
Following concentration under reduced distillation of the residue
at 160 ◦C, 2 mm Hg, gave the title compound 133 (5.3 g, 83%) as a
yellow oil (Found: M+, 154.0565. C7H10N2S requires M, 154.0565);
(1R,6R,3Z)-1-[(R)-2-Acetoxy-2-phenylacetoxy]-6-methoxy-1-
phenylhept-3-ene 84
Following the general procedure, alcohol 78 (9 mg, 0.041 mmol)
and (R)-2-acetoxy-2-phenylacetic acid, after chromatography us-
ing petrol : ether (2 : 1) as eluent, gave the title compound 84
(13 mg, 80%) as a colourless oil, [a]D -31 (c = 0.53) (Found: M+ +
NH4, 414.2265. C24H32NO5 requires M, 414.2281); nmax/cm-1 2931,
1747, 1373, 1232, 1208, 1175, 1089, 1056 and 699; dH (300 MHz,
CDCl3) 1.08 (3 H, d, J 6, 7-H3), 2.07 (1 H, m, 5-H), 2.17 –2.30 (4
H, m, 5-H¢ and O2CCH3), 2.57 and 2.69 (each 1 H, dt, J 14.5, 7,
2-H), 3.24 (1 h, m, 6-H), 3.32 (3 H, s, OCH3), 5.43 (1 H, m, 3- or
4-H), 5.54 (1 H, dt, J 10.5, 7, 3- or 4-H), 5.77 (1 H, t, J 7, 1-H),
6.02 (1 H, s, 2¢-H) and 6.98–7.55 (10 H, m, ArH); m/z (CI, NH3)
414 (M+ + 18, 4%), 341 (17), 203 (100), 171 (76) and 59 (88).
n
max/cm-1 3375, 1459, 1413, 1280, 1125, 920, 734 and 688; dH
(300 MHz, CDCl3) 3.60 (5 H, m, NCH3, CH2S), 5.00 (2 H, m,
3¢-H2), 5.90 (1 H, ddt, J 17, 10, 7, 2¢-H), 6.90 (1 H, d, J 1, ArH)
and 7.05 (1 H, d, J 1, ArH); dC (75 MHz, CDCl3) 33.4, 37.8, 118.0,
122.4, 129.4, 133.6 and 140.8; m/z (EI) 154 (M+, 100%).
(S)-3-tert-Butyldimethylsilyloxy-1-iodo-2-methylpropane 135
Methanesulfonyl chloride (12.0 ml, 155.3 mmol) was added
dropwise to the alcohol 134 (26.4 g, 129.4 mmol) and triethylamine
(36 ml, 259 mmol) in DCM (200 ml) at -20 ◦C. The mixture
was allowed to warm to ambient temperature over 1 h and was
then washed with sodium hydroxide (10% w/v) and water then
dried (MgSO4). Concentration under reduced pressure gave the
corresponding mesylate (36.6 g, 100%) as a colourless oil, [a]D
+4.1 (c = 6) (Found: M+ + H, 283.1401. C11H27O4SSi requires M,
283.1399); nmax/cm-1 2956, 1473, 1358, 1255, 1177, 1094, 1044,
966, 839 and 779; m/z (CI, NH3) 300 (M+ + NH4, 8%), 283 (M+ +
1, 100) and 264 (60).
(1R,6R,3Z)-1-[(S)-2-Acetoxy-2-phenylacetoxy]-6-methoxy-1-
phenylhept-3-ene 85
Following the general procedure, alcohol 78 (12 mg, 0.055 mmol)
and (S)-2-acetoxy-2-phenylacetic acid, after chromatography us-
ing petrol : ether (4 : 1) as eluent, gave the title compound 85
(19 mg, 87%) as a colourless oil, [a]D +75 (c = 0.90) (Found: M+ +
NH4, 414.2287. C24H32NO5 requires M, 414.2281); nmax/cm-1 2972,
1747, 1373, 1232, 1176, 1089, 1056 and 699; dH (300 MHz, CDCl3)
1.04 (3 H, d, J 6, 7-H3), 1.92–2.14 (2 H, m, 5-H2), 2.21 (3 H, s,
O2CCH3), 2.42–2.63 (2 H, m, 2-H2), 3.18 (1 H, m, 6-H), 3.24 (3
H, s, OCH3), 5.17 (1 H, m, 3- or 4-H), 5.36 (1 H, dt, J 11, 7.5, 3- or
4-H), 5.79 (1 H, t, J 6.5, 1-H), 6.03 (1 H, s, 2¢-H) and 7.18–7.55 (10
H, m, ArH); m/z (CI, NH3) 414 (M+ + 18, 28%) and 203 (100).
The mesylate (36.49 g, 129.4 mmol) and sodium iodide (58.2 g,
388.2 mmol) in acetone (500 ml) was heated under reflux for 18 h.
Following concentration under reduced pressure, the residue was
diluted with ethyl acetate and the solution washed with aqueous
sodium thiosulfate (5% w/v) and brine then dried (MgSO4).
Concentration under reduced pressure and chromatography of the
residue using petrol : ether (3 : 1) as eluent gave the title compound
135 (28.46 g, 70%) as a colourless oil, [a]D +5.6 (c = 7.2, CH2Cl2)
(Found: M+ + H, 315.0643. C10H24IOSi requires M, 315.0641);
(1S,6R,3Z)-6-Methoxy-1-(4-nitrobenzoyloxy)-1-phenylhept-3-ene
86
n
max/cm-1 2956, 2929, 2857, 1471, 1257, 1196, 1103, 839 and 777;
Diethyl azodicarboxylate (94 mg, 0.540 mmol) was added to a
suspension of the alcohol 78 (79 mg, 0.359 mmol), triphenylphos-
phine (141 mg, 0.538 mmol) and 4-nitrobenzoic acid (90 mg,
0.539 mmol) in toluene (3 ml) at -35 ◦C and the mixture was
allowed to warm to room temperature. After 1.75 h, ether (25 ml)
and water (25 ml) were added. The organic phase was washed with
brine (20 ml), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using petrol : ether (6 : 1)
as eluent gave the title compound 86 (106 mg, 80%) as a colourless
oil, [a]D +35.5 (c = 0.76) (Found: M+ + NH4, 387.1917. C21H27N2O5
requires M, 387.1919); nmax/cm-1 2972, 1726, 1607, 1529, 1345,
1273, 1102, 720 and 700; dH (300 MHz, CDCl3) 1.12 (3 H, d, J 6
7-H3), 2.16 (1 H, dt, J 14, 7, 5-H), 2.30 (1 H, dt, J 14.5, 6, 5-H),
2.75 and 2.92 (each 1 H, dt, J 14.5, 7, 2-H), 3.28 (1 H, m, 6-H), 3.32
(3 H, s, OCH3), 5.45–5.63 (2 H, m, 3-H and 4-H), 6.08 (1 H, t, J 7,
1-H), 7.32–7.48 (5 H, m, ArH) and 8.24–8.35 (4 H, m, ArH); dC
(75 MHz, CDCl3), 18.9, 34.1, 34.5, 56.1, 76.4, 77.3, 123.5, 125.3,
dH (300 MHz, CDCl3) 0.10 (6 H, s, 2 ¥ CH3Si), 0.92 [9 H, s,
SiC(CH3)3], 0.98 (3 H, d, J 7, 2-CH3), 1.65 (1 H, m, 2-H), 3.30 (2
H, m, 1-H2), 3.42 (1 H, dd, J 10, 7, 3-H) and 3.55 (1 H, dd, J 10,
5, 3-H¢); m/z (CI, NH3) 315 (M+ + 1, 100%).
(5R)-6-tert-Butyldimethylsilyloxy-3-(N-methyl-2-imidazol-2-
ylthio)-5-methylhex-1-ene 136
Butyllithium in hexanes (1.6 M, 22 ml, 34.98 mmol) was added
to the propenyl sulfide 133 (4.90 g, 31.8 mmol) and hexam-
ethylphosphoric triamide (11.4 ml, 63.6 mmol) in THF (150 ml)
at -78 ◦C and the mixture stirred for 30 min. The iodide 133 (10 g,
31.8 mmol) in THF (50 ml) was added and the mixture stirred at
-78 ◦C for 2.5 h. Saturated aqueous ammonium chloride (50 ml)
was added and the reaction warmed to ambient temperature
then diluted with ether and washed with water and brine then
dried (MgSO4). After concentration under reduced pressure,
3914 | Org. Biomol. Chem., 2011, 9, 3896–3919
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chromatography of the residue using petrol : ethyl acetate (3 : 1)
gave the title compound 136 (4.51 g, 42%) as a colourless oil, [a]D
+0.4 (c = 5.6) (Found: M+, 340.2009. C17H32N2OSSi requires M,
340.2005); nmax/cm-1 2955, 2930, 1460, 1280, 1254, 1094, 838 and
776; dH (300 MHz, CDCl3) 0.05 (6 H, s, 2 ¥ CH3Si), 0.90 [9 H, s,
SiC(CH3)3], 0.96 (3 H, d, J 7, 5-CH3), 1.45 (1 H, m, 5-H), 1.85 (2
H, m, 4-H2), 3.44 (2 H, m, 6-H2), 3.68 (3 H, s, NCH3), 3.90 (1 H,
m, 3-H), 4.85 (2 H, m, 1-H2), 5.72 (1 H, m, 2-H), 6.90 (1 H, d, J 1,
ArH) and 7.10 (1 H, d, J 1, ArH); dC (75 MHz, CDCl3) -5.4, -5.3,
16.0, 17.1, 18.3, 25.9, 33.6, 33.7, 33.8, 37.3, 37.7, 51.9, 51.9, 67.6,
68.1, 115.6, 116.2, 122.6, 129.7, 138.6, 139.6, 139.9 and 140.0; m/z
(EI) 340 (M+, 5%), 95 (100); m/z (CI, NH3) 341 (M+ + 1, 100%).
1.88 and 2.18 (each 1 H, dt, J 13, 7, 5-H), 2.35 (1 H, dt, J 15, 4,
2-H), 2.58 (1 H, dt, J 14, 8, 2-H¢), 2.67 and 3.06 (each 1 H, br s,
OH), 3.36 (1 H, dd, J 12, 4.5, 7-H), 3.46 (1 H, dd, J 11, 6, 7-H¢),
4.65 (1 H, dd, J 9, 4, 1-H), 5.40–5.55 (2 H, m, 3-H and 4-H) and
7.22–7.32 (5 H, m, ArH); minor 1,6-syn-epimer 142 2.05 (2 H, t,
J 7, 5-H2) and 4.69 (1 H, dd, J 8,5, 1-H); dC (75 MHz, CDCl3)
17.0, 31.0, 35.7, 37.4, 66.8, 73.8, 125.8, 126.4, 127.5, 128.4, 131.3
and 144.4; m/z (CI/NH3) 238 (M+ + 18, 5%), 221 (M+ + 1, 6), 220
(M+, 22) and 203 (M+ - 17, 100).
(1S,6R,3Z)-6-Methyl-1-phenylhept-3-ene-1,7-diol 142
TBAF in THF (1 M, 134 ml, 0.134 mmol) was added to the silyl
ether 148 (30 mg, 0.09 mmol) in THF (1 ml) and the solution
stirred for 18 h. After concentration under reduced pressure,
chromatography of the residue using ether : petrol (2 : 1) as eluent,
gave the title compound 142 (17 mg, 88%) as a colourless oil, [a]D
-48 (c = 1.7) (Found: M+ + NH4, 238.1809. C14H24NO2 requires
M, 238.1807); nmax/cm-1 3333, 2960, 1454, 1261, 1030, 799, 759
and 700; dH (500 MHz, CDCl3) 0.88 (3 H, d, J 7, 6-CH3), 1.68 (1
H, oct, J 7, 6-H), 2.05 (2 H, t, J 7, 5-H2), 2.46 (1 H, dt, J 13.5, 5.5,
2-H), 2.75 (1 H, dt, J 13.5, 7, 2-H¢), 3.40 (2 H, m, 7-H2), 4.71 (1 H,
dd, J 8, 4.5, 1-H), 5.40–5.60 (2 H, m, 3-H and 4-H) and 7.20–7.35
(5 H, m, ArH); dC (75 MHz, CDCl3) 16.4, 30.6, 35.6, 37.1, 67.0,
73.8, 125.8, 126.3, 127.5, 128.4, 130.7 and 144.2; m/z (CI, NH3)
238 (M+ + 18, 18%), 221 (M+ + 1, 27), 220 (M+, 100) and 203 (M+
- 17, 98).
(5R)-6-tert-Butyldimethylsilyloxy-5-methylhex-2-
enyl(tributyl)stannane 137
A solution of the hex-2-en-3-yl sulfide 136 (3.42 g, 10.05 mmol),
tributyltin hydride (5.4 ml, 20.1 mmol) and azobis-iso-
butyronitrile (150 mg, 5% w/w) in degassed benzene (100 ml) was
heated under reflux for 18 h. After concentration under reduced
pressure, chromatography of the residue using petrol containing
0.5% triethylamine as eluent gave the title compound 137 (4.11 g,
79%) as a colourless oil, [a]D +0.9 (c = 3.7, CH2Cl2) (Found: M+ -
C4H9, 461.2262. C21H45OSi120Sn requires M, 461.2262); nmax/cm-1
2956, 2928, 2856, 1463, 1255, 1094, 838 and 775; dH (300 MHz,
CDCl3) 0.10 (6 H, s, 2 ¥ CH3Si), 0.80–1.00 [27 H, m, 5-CH3,
SiC(CH3)3, 3 ¥ SnCH2CH2CH2CH3), 1.30–1.80 (16 H, m, 5-H,
1-H2, 4-H, 3 ¥ SnCH2CH2CH2CH3), 2.12 (1 H, m, 4-H¢), 3.45 (2
H, m, 6-H2) 5.20 (1 H, m, 3-H) and 5.52 (1 H, m, 2-H); m/z (EI)
461 (M+ - 57, 37%), 459 (M+ - 57, 30%), 291 (40), 289 (30) and
75 (100).
(1R,6R,3Z)-7-tert-Butyldimethylsilyloxy-6-methyl-1-phenylhept-
3-en-1-ol 143
tert-Butyldimethylsilyl chloride (101 mg, 0.673 mmol) was added
to the alcohol 141 (148 mg, 0.673 mmol), triethylamine (103 ml,
0.74 mmol) and 4-N,N-dimethylaminopyridine (5 mg) in DCM
(3 ml). The mixture was stirred for 18 h, diluted with DCM
and washed with water and brine then dried (MgSO4). After
concentration under reduced pressure, chromatography of the
residue using petrol : ether (5 : 1) as eluent, gave the title compound
143 (176 mg, 92%) as a colourless oil, [a]D +32 (c = 2.0)
(Found: M+ + H, 335.2374. C20H35O2Si requires M, 335.2406);
(5R)-6-Hydroxy-5-methylhex-2-enyl(tributyl)stannane 138
Tetrabutylammonium fluoride in THF (1 M, 15.9 ml, 15.9 mmol)
was added to the stannane 137 (4.11 g, 7.93 mmol) in THF
(16 ml) and the solution stirred for 18 h. After concentration
under reduced pressure, chromatography of the residue using
petrol : ether (5 : 1 containing 1% triethylamine) gave the title
compound 138 (2.54 g, 79%) as a colourless oil, a 2 : 1 mixture of
(E)- and (Z)-isomers (Found: M+ - C4H9, 347.1400. C15H31O120Sn
requires M, 347.1397); nmax/cm-1 3334, 2956, 2925, 1462, 1377,
1038, 960 and 874; dH (300 MHz, CDCl3) 0.85–1.00 (18 H, m,
5-CH3, 3 ¥ SnCH2CH2CH2CH3), 1.30–1.65 (13 H, m, 5-H, 3 ¥
SnCH2CH2CH2CH3), 1.72 (2 H, d, J 8.5, 1-H2), 1.80–2.15 (2 H,
m, 4-H2), 3.50 (2 H, m, 6-H2), 5.15 (0.33 H, m, 2-H), 5.25 (0.67 H,
dt, J 15, 7.5, 2-H) and 5.60 (1 H, m, 3-H); m/z (EI) 347 (M+ - 57,
36%) 345 (M+ - 57, 30), 291 (55), 289 (40) and 177 (100).
n
max/cm-1 3358, 2955, 2929, 1471, 1389, 1255, 1091, 837, 776 and
700; dH (300 MHz, CDCl3) 0.10 (6 H, s, 2 ¥ CH3Si), 0.87 (3 H, d,
J 6.5, 6-CH3), 0.94 [9 H, s, (CH3)3CSi], 1.67 (1 H, m, 6-H), 1.90 (1
H, dt, J 14, 7, 5-H), 2.15 (1 H, d, J 3, OH), 2.20 (1 H, m, 5-H¢),
2.55 (2 H, m, 2-H2), 3.45 (2 H, m, 7-H2), 4.75 (1 H, m, 1-H), 5.55
(2 H, m, 3-H and 4-H) and 7.30–7.45 (5 H, m, ArH); dC (75 MHz,
CDCl3) -5.3, 16.5, 18.4, 26.0, 31.0, 36.3, 37.4, 67.9, 73.9, 125.7,
125.9, 127.5, 128.4, 131.9 and 144.2; m/z (CI, NH3) 335 (M+ + 1,
5%), 334 (M+, 2) and 317 (M+ - 17, 100).
(1R,6R,3Z)-6-Methyl-1-phenylhept-3-ene-1,7-diol 141
(1R,6R,3Z)-1-[(R)-2-Acetoxy-2-phenylacetoxy]-7-tert-butyldi-
methylsilyloxy-6-methyl-1-phenylhept-3-ene 144
Following the general procedure, tin(IV) bromide (1 M in DCM,
230 ml, 0.23 mmol), stannane 138 (92 mg, 0.23 mmol) in DCM
(2 ml) and benzaldehyde in DCM (3 M, 76 ml, 0.23 mmol), after
chromatography using ether : petrol (2 : 1 + 1% triethylamine) as
eluent, gave the title compound 141 (42 mg, 84%) as a colourless
oil, a 93 : 7 mixture of epimers, [a]D +60 (c = 3.2) (Found: M+ +
NH4, 238.1809. C14H24NO2 requires M, 238.1807); nmax/cm-1 3346,
2955, 1494, 1454, 1035, 876, 759 and 701; dH (500 MHz, CDCl3)
major epimer 141 0.87 (3 H, d, J 7, 6-CH3), 1.63 (1 H, m, 6-H),
Following the general procedure, alcohol 143 (27 mg, 0.081 mmol),
after chromatography using petrol : ether (5 : 1) as eluent, gave the
title compound 144 (37 mg, 90%) as a colourless oil, [a]D -18
(c = 3.7) (Found: M+ + NH4, 528.3135. C30H46NO5Si requires M,
528.3145); nmax/cm-1 2955, 2929, 1751, 1372, 1207, 1175, 1085,
1059, 838, 776 and 698; dH (300 MHz, CDCl3) 0.05 (6 H, s, 2 ¥
CH3Si), 0.83 (3 H, d, J 7, 6-CH3), 0.92 [9 H, s, SiC(CH3)3], 1.60
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(1 H, m, 6-H), 1.78 (1 H, dt, J 14.5, 7.5, 5-H), 2.10 (1 H, dt, J 13,
7, 5-H¢), 2.22 (3 H, s, CH3CO2), 2.60 (2 H, m, 2-H2), 3.40 (2 H, dd,
J 6, 1.5, 7-H2), 5.45 (2 H, m, 3-H and 4-H), 5.76 (1 H, t, J 7, 1-H),
6.01 (1 H, s, 2¢-H) and 6.95–7.45 (10 H, m, ArH); dC (75 MHz,
CDCl3) -5.3, 16.4, 18.3, 20.7, 25.9, 30.8, 34.3, 36.2, 67.8, 74.5,
77.2, 124.3, 126.1, 127.7, 127.8, 127.9, 128.7, 129.2, 131.5, 133.7,
139.5, 167.9 and 170.3; m/z (CI, NH3) 528 (M+ + 18, 5%) and 317
(100).
2917, 1737, 1245, 1037 and 756; dH (300 MHz, CDCl3) 1.02 (3 H,
d, J 7, 3-CH3), 1.40–1.75 (3 H, m, OH, 2-H2), 2.00 (1 H, oct, J 7,
3-H), 2.10 (3 H, s, CH3CO2), 3.75 (2 H, m, 1-H2) and 3.97 (2 H,
m, 4-H2); m/z (CI/NH3) 164 (M+ + 18, 100%) and 147 (M+ + 1,
25).
(1S,6R,3Z)-7-tert-Butyldimethylsilyloxy-6-methyl-1-phenylhept-
3-en-1-ol 148
Following the procedure outlined for the synthesis of 4-
nitrobenzoate 86, alcohol 143 (98 mg, 0.293 mmol), after chro-
matography using petrol : ether (30 : 1) as eluent, gave the inverted
4-nitrobenzoate 147 (97 mg, 69%) as a colourless oil, [a]D +19.5
(c = 1.7); nmax/cm-1 2955, 1728, 1530, 1344, 1272, 1102, 838, 777
and 720; dH (300 MHz, CDCl3) 0.05 (6 H, s, 2 ¥ CH3Si), 0.86 (3 H,
d, J 7, 6-CH3), 0.92 [9 H, s, (CH3)3CSi], 1.60 (1 H, m, 6-H), 1.86
and 2.20 (each 1 H, dd, J 14, 7, 5-H), 2.72 and 2.90 (each 1 H, dt, J
15, 7.5, 2-H), 3.41 (2 H, d, J 6, 7-H2), 5.50 (2 H, m, 3-H and 4-H),
6.06 (1 H, t, J 7, 1-H), 7.30–7.50 (5 H, m, ArH) and 8.30 (4 H, m,
ArH); dC (75 MHz, CDCl3) -5.3, 16.5, 18.3, 25.9, 30.9, 34.4, 36.2,
67.6, 123.5, 124.4, 126.6, 128.3, 128.6, 130.8, 131.9, 135.9, 139.6,
150.6 and 163.9.
(1R,6R,3Z)-1-[(S)-2-Acetoxy-2-phenylacetoxy]-7-tert-butyldi-
methylsilyloxy-6-methyl-1-phenylhept-3-ene 145
Following the general procedure, alcohol 141 (27 mg, 0.081 mmol),
after chromatography using petrol : ether (5 : 1) as eluent, gave the
title compound 145 (33 mg, 80%) as a colourless oil, [a]D +54
(c = 3.3) (Found: M+ + NH4, 528.3113. C30H46NO5Si requires M,
528.3145); nmax/cm-1 2956, 1748, 1373, 1232, 1176, 1084, 1060,
838, 758 and 698; dH (300 MHz, CDCl3) 0.05 (6 H, s, 2 ¥ CH3Si),
0.78 (3 H, d, J 6.5, 6-CH3), 0.93 [9 H, s, SiC(CH3)3], 1.55 (1 H, oct,
J 6.5, 6-H), 1.70 and 1.95 (each 1 H, dt, J 14, 6.5, 5-H), 2.20 (3
H, s, CH3CO2), 2.55 (2 H, m, 2-H2), 3.36 (2 H, d, J 6, 7-H2), 5.10
and 5.35 (each 1 H, m, 3-H or 4-H), 5.80 (1 H, t, J 6.5, 1-H), 6.05
(1 H, s, 2¢-H) and 7.30–7.55 (10 H, m, ArH); dC (75 MHz, CDCl3)
-5.3, 16.4, 18.3, 20.7, 26.0, 29.7, 30.7, 34.1, 36.1, 67.7, 74.6, 124.2,
126.3, 127.7, 128.0, 128.4, 128.7, 129.2, 131.3, 134.0, 139.5, 168.2
and 170.2; m/z (CI, NH3) 528 (M+ + 18, 8%) and 317 (100).
Following the procedure outlined for the synthesis of alcohol 81,
nitrobenzoate 147 (75 mg, 0.157 mmol) gave the title compound
148 (38 mg, 73%) as a colourless oil, [a]D -16 (c = 3.7)
(Found: M+ + H, 335.2404. C20H35O2Si requires M, 335.2406);
n
max/cm-1 3385, 2955, 2929, 1471, 1255, 1091, 837, 776 and 700;
dH (300 MHz, CDCl3) 0.05 (6 H, s, 2 ¥ CH3Si), 0.90 (3 H, d, J 7,
6-CH3), 0.94 [9 H, s, (CH3)3CSi], 1.68 (1 H, oct, J 6.5, 6-H), 1.90
(1 H, dt, J 15, 7.5, 5-H), 2.20 (2 H, m, 5-H¢ and OH), 2.55 (2 H,
m, 2-H2), 3.45 (2 H, m, 7-H2), 4.75 (1 H, dd, J 7.5, 5.5, 1-H), 5.55
(2 H, m, 3-H and 4-H) and 7.30–7.45 (5 H, m, ArH); dC (75 MHz,
CDCl3) -5.3, 16.5, 18.4, 26.0, 30.9, 36.3, 37.4, 67.8, 73.9, 125.8,
125.9, 127.5, 128.4, 131.8 and 144.2; m/z (CI, NH3) 335 (M+ + 1,
8%), 334 (M+, 2) and 317 (M+ - 17, 100).
(1R,6R,3Z)-1,7-diacetoxy-6-methyl-1-phenylhept-3-ene 146
Acetic anhydride (195 ml, 2.07 mmol) was added to the diol 141
(114 mg, 0.52 mmol), triethylamine (72 ml, 5.2 mmol) and 4-
N,N-dimethylaminopyridine (10 mg) in DCM (5 ml) and the
solution stirred for 18 h. Water was added, the aqueous phase
was extracted with DCM and the organic extracts were washed
with brine and dried (MgSO4). After concentration under reduced
pressure, chromatography using petrol : ether (4 : 1) as eluent gave
the title compound 146 (141 mg, 90%) as a colourless oil, [a]D
+27 (c = 3.4); (Found: M+ + NH4, 322.2032. C18H28NO4 requires
M, 322.2018); nmax/cm-1 2962, 1739, 1373, 1237, 1035 and 701; dH
(300 MHz, CDCl3) 0.90 (3 H, d, J 7, 6-CH3), 1.85 (2 H, m, 5-H2),
2.07 and 2.11 (each 3 H, s, CH3CO2), 2.12 (1 H, m, 6-H), 2.55 and
2.70 (each 1 H, dt, J 14.5, 7.5, 2-H), 3.87 and 3.94 (each 1 H, dd,
J 11, 6, 7-H), 5.35–5.55 (2 H, m, 3-H and 4-H), 5.79 (1 H, t, J
7, 1-H) and 7.30–7.40 (5 H, m, ArH); dC (75 MHz, CDCl3) 16.6,
21.0, 21.3, 31.0, 32.9, 34.4, 68.7, 75.5, 125.6, 126.5, 128.0, 128.4,
130.2, 140.2, 170.3 and 171.2; m/z (CI, NH3) 322 (M+ + 18, 18%)
and 245 (100).
Following the procedure outlined for the ozonolysis of ac-
etate 11, bis-acetate 146 (106 mg, 0.349 mmol), after chro-
matography using petrol : ether (5 : 2) as eluent, gave (R)-3-
acetoxy-1-phenylpropan-1-ol (R)-15 (11 mg, 16%) as a colour-
less oil, [a]D +31 (c = 1), and a mixture of (R)-3-acetoxy-3-
phenylpropan-1-ol (R)-14 and (R)-4-acetoxy-3-methylbutan-1-ol,
which were separated by reverse phase semi-preparative HPLC
using acetonitrile : water (1 : 1, flow rate 15 ml min-1) as eluent to
give (R)-3-acetoxy-3-phenylpropan-1-ol (R)-141a (23 mg, 34%) as a
colourless oil, [a]D +73 (c = 2), and (R)-4-acetoxy-3-methylbutan-
1-ol (5 mg, 10%) as a colourless oil, [a]D -3.5 (c = 0.5) (Found: M+ +
NH4, 164.1285. C7H18NO3 requires M, 164.1287); nmax/cm-1 3410,
(3RS,6R)-6-tert-Butyldimethylsilyloxy-3-(N-methylimidazol-2-
ylthio)hept-1-ene 161
Butyllithium in hexanes (1.6 M, 19.6 ml, 31.36 mmol) was
added to the propenyl sulfide 133 (4.43 g, 28.77 mmol) in THF
(150 ml) at -78 ◦C. After 20 min, the 3-tert-butyldimethylsilyloxy-
1-iodobutane 160 (9.04 g, 28.79 mmol) in THF (50 ml) was
added and the solution maintained at -78 ◦C for 2.5 h. Saturated
aqueous ammonium chloride (20 ml) was added and the mixture
was allowed to warm to room temperature. Water (150 ml) and
ether (200 ml) were added, the aqueous phase was extracted
with ether (100 ml) and the organic extracts were washed with
brine (250 ml), dried (MgSO4) and concentrated under reduced
pressure. Chromatography using petrol : ether (1 : 3) as eluent
afforded the title compound 161 (8.09 g, 83%) as a colourless
oil, a mixture of epimers, [a]D +0.6 (c = 0.86) (Found: M+ + H,
341.2080. C17H33N2OSSi requires M, 341.2083); nmax/cm-1 2955,
2930, 2857, 1458, 1255, 1131, 1078, 1047, 1005, 916, 836 and 775;
dH (300 MHz, CDCl3) 0.05 (1.5 H, s, SiCH3), 0.07 (4.5 H, s, 3 ¥
SiCH3), 0.90 [9 H, s, SiC(CH3)3], 1.14 (3 H, d, J 6, 7-H3), 1.45–1.90
(4 H, m, 4-H2 and 5-H2), 3.69 (3 H, s, NCH3), 3.82 (2 H, m, 3-H
and 6-H), 4.91 (2 H, m, 1-H2), 5.76 (1 H, m, 2-H) and 6.95 and
7.11 (each 1 H, s, ArH); dC (75 MHz, CDCl3) -4.7, -4.4, 18.1,
3916 | Org. Biomol. Chem., 2011, 9, 3896–3919
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23.7, 23.9, 25.9, 30.3, 30.3, 33.8, 37.0, 37.1, 53.8, 53.8, 68.1, 68.2,
116.3, 122.6, 129.6, 138.7 and 140.1; m/z (CI, NH3) 341 (M+ + 1,
100%), 301 (14) and 115 (42).
4.72 (1 H, t, J 6, 1-H), 5.35 and 5.51 (each 1 H, dt, J 10.5, 7, 3-H
or 4-H) and 7.24–7.32 (5 H, m, ArH); dC (75 MHz, CDCl3) major
epimer 164 23.6, 23.9, 37.1, 38.6, 67.5, 73.7, 125.1, 125.9, 127.4,
128.4, 133.0 and 144.1; minor 1,7-anti-epimer 37.4 and 38.4; m/z
(CI, NH3) 221 (M+ + 1, 35%), 204 (100) and 186 (85).
(R)-6-tert-Butyldimethylsilyloxyhept-2-enyl(tributyl)stannane 162
Tributyltin hydride (13.85 g, 47.59 mmol) and azo-bis-iso-
butyronitrile (390 mg, 2.38 mmol) were added to a degassed
solution of the alkenyl sulfide 161 (8.09 g, 23.79 mmol) in benzene
(240 ml) and the solution heated under reflux for 1.5 h. After
concentration under reduced pressure, chromatography of the
residue using petrol (+ 1% triethylamine) as eluent gave the title
compound 162 (11.27 g, 92%) as a colourless oil, a 2 : 1 mixture
of (E)- and (Z)-isomers, [a]D -7.1 (c = 1.19) (Found: M+ - C4H9,
461.2259. C21H45OSi120Sn requires M, 461.2262; nmax/cm-1 2957,
2928, 2856, 1463, 1254, 1133, 1083, 1035, 960, 836 and 774; dH
(300 MHz, CDCl3) 0.06 (6 H, s, 2 ¥ SiCH3), 0.82–0.97 [24 H, m,
3 ¥ SnCH2CH2CH2CH3 and SiC(CH3)3], 1.16 (2 H, d, J 6.5, 7-H3),
1.18 (1 H, d, J 6, 7-H3), 1.25–1.80 (16 H, m, 1-H2, 5-H2 and 3 ¥
SnCH2CH2CH2CH3), 2.02 (2 H, m, 4-H2), 3.81 (1 H, m, 6-H) and
4.95–5.65 (2 H, m, 2-H and 3-H); dC (75 MHz, CDCl3) -4.7, -4.3,
9.1, 9.3, 10.5, 11.2, 13.8, 14.1, 18.2, 23.5, 23.8, 25.9, 27.4, 29.0,
29.2, 39.2, 40.3, 68.3, 68.5, 124.0, 125.2, 128.3 and 129.1; m/z (CI,
NH3) 461 (M+ - 57, 32%), 459 (M+ - 57, 28), 308 (100) and 306
(65).
(1R,7R,3Z)-1-Phenyloct-3-ene-1,7-diol 165
TBAF in THF (1 M, 0.74 ml, 0.74 mmol) was added to the silyl
ether 171 (82 mg, 0.246 mmol) in THF (0.3 ml) and the solution
stirred at room temperature for 72 h. Water (2 ml) was added and
the mixture stirred for 1 h, then extracted with ether (4 ¥ 5 ml). The
organic extracts were washed with brine (10 ml), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using petrol : ethyl acetate (1 : 1) as eluent gave the
title compound 165 (52 mg, 96%) as a colourless oil, [a]D +58
(c = 2.22) (Found: M+, 220.1462. C14H20O2 requires M, 220.1463);
n
max/cm-1 3358, 2965, 2924, 1453, 1130, 1081, 1054, 759 and 700;
dH (500 MHz, CDCl3) 1.11 (3 H, d, J 6.5, 8-H3), 1.41 (2 H, m,
6-H2), 2.00 and 2.24 (each 1 H, m, 2- or 5-H), 2.34 (1 H, dt, J 14,
5, 2- or 5-H), 2.58 (1 H, dt, J 14, 8, 2- or 5-H), 2.82 (2 H, br s, 2 ¥
OH), 3.72 (1 H, m, 7-H), 4.63 (1 H, dd, J 8.5, 4, 1-H), 5.44 (2 H, m,
3-H and 4-H) and 7.21–7.34 (5 H, m, ArH); dC (75 MHz, CDCl3)
major 1,6-anti-epimer 165 23.5, 37.4, 38.3, 66.6, 73.7, 125.6, 125.7,
127.4, 128.2, 132.3 and 144.3; minor 1,7-syn-epimer 164 23.6, 37.1
and 38.6; m/z (CI, NH3) 238 (M+ + 18, 12%), 220 (M+, 38), 203
(M+ - 17, 100) and 185 (87).
(R)-6-Hydroxyhept-2-enyl(tributyl)stannane 163
TBAF in THF (1 M, 10.3 ml, 10.30 mmol) was added to the
silyl ether 162 (1.77 g, 3.42 mmol) and the solution stirred at
room temperature for 50 h. Water (10 ml) was added, the mixture
was stirred for 1 h, then extracted with ether (4 ¥ 15 ml). The
organic extracts were washed with brine (50 ml), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using petrol : ether (2 : 1 + 1% triethylamine) as eluent gave
the title compound 163 (1.10 g, 80%) as a colourless oil, a 2 : 1
mixture of (E)- and (Z)-isomers, [a]D -3.4 (c = 1.08) (Found: M+
- C4H9, 347.1397. C15H31O120Sn requires M, 347.1397); nmax/cm-1
3331, 2957, 2925, 2872, 1463, 1376, 1075 and 960; dH (300 Mz,
CDCl3) 0.85–1.00 (15 H, m, 3 ¥ SnCH2CH2CH2CH3), 1.21 (2 H,
d, J 6, 7-H3), 1.24 (1 H, d, J 6, 7-H3), 1.26–1.80 (16 H, m, 3 ¥
SnCH2CH2CH2CH3, 1-H2 and 4-H2), 2.10 (2 H, m, 5-H2), 3.85 (1
H, m, 6-H), 5.11 (0.33 H, dt, J 10.5, 7, 2- or 3-H), 5.25 (0.67 H,
dt, J 15, 7, 2- or 3-H) and 5.60 (1 H, m, 2- or 3-H); dC (75 MHz,
CDCl3) 9.1, 9.4, 10.5, 11.2, 13.8, 14.2, 23.4, 27.4, 29.2, 39.2, 39.6,
67.9, 68.2, 123.5, 124.9, 129.1 and 129.9; m/z (EI) 347 (M+ - 57,
72%), 345 (M+ - 57, 55), 291 (39), 289 (40) and 233 (15).
(1S,7R,3Z)-7-tert-Butyldimethylsilyloxy-1-phenyloct-3-en-1-ol
166, (2R,8S,5Z)-8-tert-butyldimethylsilyloxy-8-phenyloct-
5-en-2-ol 167 and (1S,7R,3Z)-1,7-bis-(tert-butyldimethylsilyloxy)-
1-phenyloct-3-ene 168
Imidazole (78 mg, 1.15 mmol) and tert-butyldimethylsilyl chloride
(173 mg, 1.15 mmol) were added to the diol 164 (230 mg,
1.045 mmol) in N,N-dimethylformamide (1 ml) and the mixture
stirred at room temperature for 15 h. Water (2 ml) was added
and the mixture extracted with ether (4 ¥ 10 ml). The organic
extracts were washed with brine (30 ml), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using petrol : ether (7 : 1 to 1 : 3) as eluent afforded the
title compound 168 (72 mg, 15%) as a colourless oil, [a]D -25
(c = 1.12) (Found: M+ - H, 447.3117. C26H47O2Si2 requires M,
447.3115); nmax/cm-1 2957, 2929, 2858, 1472, 1382, 1255, 1137,
1091, 836 and 775; dH (300 MHz, CDCl3) -0.07, 0.07, 0.08 and
0.09 (each 3 H, s, SiCH3), 0.92 and 0.93 [each 9 H, s, SiC(CH3)3],
1.13 (3 H, d, J 6, 8-H3), 1.25–1.55 (2 H, m, 6-H2), 1.85–2.18 and
2.45 (each 2 H, m, 2-H2 or 5-H2), 3.78 (1 H, m, 7-H), 4.70 (1
H, t, J 6, 1-H), 5.44 (2 H, m, 3-H and 4-H) and 7.21–7.36 (5
H, m, ArH); dC (75 MHz, CDCl3) -4.9, -4.7, -4.3, 18.2, 18.3,
23.7, 23.8, 25.9, 25.9, 38.9, 39.6, 68.3, 75.1, 125.7, 126.0, 126.7,
127.9, 131.5 and 145.3; m/z (FAB, Xe) 447 (M+ - 1, 1%), 433
(2), 315 (6) and 221 (100). The second fraction contained the
title compound 166 (219 mg, 63%) as a colourless oil, [a]D -61
(c = 0.88) (Found: M+ - OH, 317.2295. C20H33OSi requires M,
317.2301); nmax/cm-1 3365, 2957, 2929, 2857, 1255, 1137, 1091,
1051, 1005, 836, 775 and 700; dH (500 MHz, CDCl3) 0.09 (6 H, s,
2 ¥ SiCH3), 0.94 [9 H, s, SiC(CH3)3], 1.15 (3 H, d, J 6, 8-H3), 1.43
(2 H, m, 6-H2), 1.95–2.25 (2 H, m, 2- or 5-H2), 1.98 (1 H, d, J 2.5,
(1S,7R,3Z)-1-Phenyloct-3-ene-1,7-diol 164
Following the general procedure, stannane 163 (500 mg,
1.24 mmol), tin(IV) bromide (545 mg, 1.24 mmol) in DCM (1 ml)
and benzaldehyde (132 mg, 1.24 mmol) in DCM (0.5 ml), after
chromatography using petrol : ether (1 : 2 + 1% triethylamine) as
eluent gave the title compound 164 (196 mg, 72%) as a colourless
oil, a 92 : 8 mixture of epimers, [a]D -71 (c = 0.82) (Found: M+,
220.1456. C14H20O2 requires M, 220.1463); nmax/cm-1 3348, 2965,
2925, 1453, 1129, 1081, 1053, 759 and 701; dH (500 MHz, CDCl3)
1.12 (3 H, d, J 6, 8-H3), 1.41 (2 H, m, 6-H2), 2.10 (4 H, m, 2- or
5-H2 and 2 ¥ OH), 2.51 (2 H, t, J 7, 2- or 5-H2), 3.73 (1 H, m, 7-H),
This journal is
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Org. Biomol. Chem., 2011, 9, 3896–3919 | 3917
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OH), 2.57 (2 H, m, 2- or 5-H2), 3.82 (1 H, m, 7-H), 4.74 (1 H,
ddd, J 7.5, 5.5, 2.5, 1-H), 5.43 and 5.60 (each 1 H, m, 3-H or 4-H)
and 7.28–7.44 (5 H, m, ArH); dC (75 MHz, CDCl3) -4.7, -4.3,
18.2, 23.7, 23.8, 25.9, 37.3, 39.5, 68.3, 73.9, 124.7, 125.9, 127.5,
128.4, 133.4 and 144.1; m/z (CI, NH3) 317 (M+ - 17, 78%), 221
(70), 185 (100) and 143 (75). The third fraction contained the title
compound 167 (18 mg, 5%) as a colourless oil, [a]D -29 (c = 0.52)
(Found: M+ - OH, 317.2310. C20H33OSi requires M, 317.2301);
oil, [a]D -72 (c = 0.92)1a with spectroscopic data identical to those
of a sample prepared earlier.
(1R,7R,3Z)-7-tert-Butyldimethylsilyloxy-1-phenyloct-3-en-1-yl
4-nitrobenzoate 170
Diethyl azodicarboxylate (149 mg, 0.856 mmol) was added to a
suspension of alcohol 166 (190 mg, 0.569 mmol), triphenylphos-
phine (223 mg, 0.853 mmol) and 4-nitrobenzoic acid (142 mg,
n
max/cm-1 3333, 2957, 2929, 2857, 1255, 1088, 1070, 836, 777 and
◦
0.853 mmol) in toluene (4.5 ml) at -35 C and the mixture was
700; dH (300 MHz, CDCl3) -0.08 and 0.06 (each 3 H, s, SiCH3),
0.93 [9 H, s, SiC(CH3)3], 1.18 (3 H, d, J 6, 8-H3), 1.28 (1 H, d, J
5, OH), 1.40 (2 H, m, 6-H2), 2.04 and 2.49 (each 2 H, m, 2-H2 or
5-H2), 3.73 (1 H, m, 7-H), 4.71 (1 H, t, J 6, 1-H), 5.46 (2 H, m, 3-H
and 4-H) and 7.20–7.35 (5 H, m, ArH); dC (75 MHz, CDCl3) -4.9,
-4.7, 18.3, 23.5, 23.7, 25.9, 38.9, 67.7, 75.0, 126.0, 126.2, 126.9,
127.9, 131.1 and 145.3; m/z (CI, NH3) 335 (M+ + 1, 1%), 317 (M+
- 17, 8), 220 (75), 203 (85), 185 (60) and 102 (100). The fourth
fraction contained recovered starting material 164 (33 mg, 14%).
allowed to warm to room temperature. After 2 h, ether (30 ml)
and water (30 ml) were added and the organic phase was washed
with brine (30 ml) and dried (MgSO4). Concentration under
reduced pressure gave a solid which was absorbed onto silica.
Chromatography using petrol : ether (10 : 1) as eluent afforded the
title compound 170 (203 mg, 74%) as a colourless oil, [a]D -30
(c = 1.39) (Found: M+ - H, 482.2370. C27H36NO5Si requires M,
482.2363); nmax/cm-1 2929, 2856, 1727, 1608, 1530, 1344, 1272,
1102, 837, 775 and 720; dH (300 MHz, CDCl3) 0.08 and 0.09 (each
3 H, s, SiCH3), 0.92 [9 H, s, SiC(CH3)3], 1.13 (3 H, d, J 6, 8-H3),
1.40 (2 H, m, 6-H2), 1.90–2.25 (2 H, m, 2- or 5-H2), 2.74 and 2.90
(each 1 H, dt, J 14.5, 7, 2- or 5-H), 3.79 (1 H, m, 7-H), 5.39 and
5.55 (each 1 H, dt, J 10.5, 7.5, 3-H or 4-H), 6.07 (1 H, t, J 7,
1-H), 7.30–7.50 (5 H, m, ArH) and 8.22–8.37 (4 H, m, ArH); dC
(75 MHz, CDCl3), -4.7, -4.3, 18.1, 23.8, 25.9, 34.3, 39.4, 68.2,
77.4, 123.3, 123.6, 126.6, 128.3, 128.6, 130.8, 133.4, 135.9, 139.6,
150.6 and 163.9; m/z (FAB, Xe) 482 (M+ - 1, 2%), 317 (26), 221
(100), 185 (64), 143 (84), 129 (83) and 115 (80).
(1S,7R,3Z)-1,7-Diacetoxy-1-phenyloct-3-ene 169
Triethylamine (500 mg, 4.95 mmol), 4-N,N-dimethyl-
aminopyridine (6 mg, 0.049 mmol) and acetic anhydride
(202 mg, 1.98 mmol) were added to the diol 164 (109 mg,
0.495 mmol) in DCM (3 ml) and the solution stirred at room
temperature for 15 h. DCM (35 ml) and water (35 ml) were added,
and the organic phase washed with aqueous hydrogen chloride
(3.5 M, 25 ml), saturated aqueous sodium hydrogen carbonate
(25 ml) and brine (15 ml) then dried (MgSO4). After concentration
under reduced pressure, chromatography of the residue using
petrol : ether (3 : 1) as eluent gave the title compound 169 (145 mg,
96%) as a colourless oil, [a]D -39 (c = 1.10) (Found M+ + NH4,
322.2021. C18H28NO4 requires M, 332.2018); nmax/cm-1 2937,
1736, 1373, 1238, 1024 and 701; dH (300 MHz, CDCl3) 1.22 (3 H,
d, J 6.5, 8-H3), 1.33–1.68 (2 H, m, 6-H2), 2.01 (2 H, m, 2- or 5-H2),
2.05 and 2.10 (each 3 H, s, CH3CO2), 2.54 and 2.68 (each 1 H, dt,
J 14.5, 7, 2- or 5-H), 4.87 (1 H, m, 7-H), 5.36 and 5.47 (each 1 H,
dt, J 10.5, 7, 3-H or 4-H), 5.77 (1 H, t, J 6.5, 1-H) and 7.28–7.40
(5 H, m, ArH); dC (75 MHz, CDCl3) 19.9, 21.3, 21.4, 23.4, 34.3,
35.6, 70.5, 75.5, 124.5, 126.6, 127.9, 128.4, 131.9, 140.2, 170.2 and
170.7; m/z (CI, NH3) 322 M+ + 18, 1%), 245 (26) and 185 (100).
Ozone was bubbled through a solution of the alkene 169
(107 mg, 0.352 mmol) in DCM (5 ml) at -78 ◦C for 15 min. The
solution was purged with oxygen for 10 min, then dimethyl sulfide
(200 mg, 3.23 mmol) was added and the solution allowed to warm
to room temperature. After concentration under reduced pressure,
the residue was dissolved in DCM (2 ml) and methanol (2 ml) and
sodium borohydride (82 mg, 2.16 mmol) were added at 0 ◦C. After
15 min at room temperature, aqueous hydrogen chloride (1 M,
2 ml) was added at 0 ◦C. After warming to room temperature DCM
(25 ml) and water (25 ml) were added, and the aqueous phase was
extracted with DCM (25 ml). The organic extracts were washed
with brine (30 ml), dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using petrol : ether (2 : 1)
gave (S)-3-acetoxy-1-phenylpropan-1-ol (S)-15 (9 mg, 13%) as a
colourless oil, [a]D -25 (c = 0.73) and a 3 : 1 mixture of (S)-3-
acetoxy-3-phenylpropan-1-ol (S)-14 and (R)-4-acetoxypent-1-ol
(58 mg). HPLC of this mixture allowed the isolation of (S)-3-
acetoxy-3-phenylpropan-1-ol (S)-14 (18 mg, 27%) as a colourless
(1R,7R,3Z)-7-tert-Butyldimethylsilyloxy-1-phenyloct-3-en-1-ol
171
Sodium hydroxide (101 mg, 2.53 mmol) was added to the ester
170 (175 mg, 0.362 mmol) in methanol (10 ml) and, after 2 h
at room temperature, water (15 ml) was added. The mixture
was extracted with ether (2 ¥ 20 ml) and the organic extracts
were washed with brine (30 ml), dried (MgSO4) and concentrated
under reduced pressure to afford the title compound 171 (112 mg,
93%) as a colourless oil, [a]D +15 (c = 0.98) (Found: M+ - OH,
317.2305. C20H33OSi requires M, 317.2301); nmax/cm-1 3359, 2957,
2929, 2857, 1255, 1137, 1091, 1051, 1001, 836, 775 and 700;
dH (300 MHz, CDCl3) 0.11 (6 H, s, 2 ¥ Si(CH3), 0.95 [9 H, s,
SiC(CH3)3], 1.16 (3 H, d, J 6, 8-H3), 1.45 (2 H, m, 6-H2), 1.90–2.25
(3 H, m, 2- or 5-H2 and OH), 2.55 (2 H, m, 2- or 5-H2), 3.82 (1
H, m, 7-H), 4.75 (1 H, dd, J 7.5, 5.5, 1-H), 5.43 and 5.61 (each
1 H, m, 3-H or 4-H) and 7.26–7.42 (5 H, m, ArH); dC (75 MHz,
CDCl3) -4.7, -4.3, 18.2, 23.7, 23.8, 25.9, 37.4, 39.5, 68.3, 74.0,
124.8, 125.9, 127.5, 128.4, 133.5 and 144.1; m/z (CI, NH3) 317
(M+ - 17, 100%), 221 (51) and 185 (68).
(1S,7R,3Z)-1-[(R)-2-Acetoxy-2-phenylacetoxy]-7-tert-butyldi-
methylsilyloxy-1-phenyloct-3-ene 172
Following the general procedure, alcohol 166 (25 mg, 0.075 mmol)
and (R)-2-acetoxy-2-phenylacetic acid, after chromatography us-
ing petrol : ether (4 : 1) as eluent, gave the title compound 172
(30 mg, 78%) as a colourless oil, [a]D -61 (c = 1.36) (Found: M+ +
NH4, 528.3142. C30H46NO5Si requires M, 528.3145); nmax/cm-1
2929, 1750, 1373, 1231, 1208, 1174, 1138, 1084, 1058, 1003, 836,
775 and 698; dH (300 MHz, CDCl3) 0.06 and 0.08 (each 3 H, s,
3918 | Org. Biomol. Chem., 2011, 9, 3896–3919
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SiCH3), 0.92 [9 H, s, SiC(CH3)3], 1.10 (3 H, d, J 6, 8-H3), 1.17–
1.44 (2 H, m, 6-H2), 1.73–2.01 (2 H, m, 2- or 5-H2), 2.21 (3 H, s,
CH3CO2), 2.42–2.65 (2 H, m, 2- or 5-H2), 3.73 (1 H, m, 7-H), 5.06
and 5.33 (each 1 H, m, 3-H or 4-H), 5.80 (1 H, t, J 7, 1-H), 6.03
(1 H, s, 2¢-H) and 7.30–7.56 (10 H, m, ArH); m/z (CI, NH3) 528
(M+ + 18, 28%), 384 (25) and 317 (100).
5 H. Nagaoka and Y. Kishi, Tetrahedron, 1981, 37, 3873.
6 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 13, 3769.
7 The relative chemical shifts of (R)- and (S)-O-acetylmandelates is
a reliable method of establishing the absolute configuration of a
secondary alcohol: see reference 8.
8 B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal, J. M. Balkovec,
J. L. Baldwin, M. E. Christy, G. S. Ponticello, S. L. Varga and J. P.
Springer, J. Org. Chem., 1986, 51, 2370.
9 The absolute configuration of 3-acetoxy-3-phenylpropan-1-ol was
established by correlation with the known 3-tert-butyldimethylsilyloxy-
1-phenylpropan-1-ol; see reference 10.
(1S,7R,3Z)-1-[(S)-2-Acetoxy-2-phenylacetoxy]-7-tert-butyldi-
methylsilyloxy-1-phenyloct-3-ene 173
10 T. Mukaiyama, K. Tominori and T. Oriyama, Chem. Lett., 1985, 1359.
11 The work in this paper is concerned with remote diastereoselectivity in
reactions of allylstannanes and aldehydes. From this point of view, the
optical purities of the allylstannanes are of no consequence. However,
the optical purities of the starting materials and products are important
when the stereoselectivity is being established either by ozonolysis or
by the use of acetyl mandelates.
Following the general procedure, alcohol 166 (26 mg, 0.078 mmol)
and (S)-2-acetoxy-2-phenylacetic acid, after chromatography us-
ing petrol : ether (4 : 1) as eluent, gave the title compound 173
(33 mg, 83%) as a colourless oil, [a]D +11.5 (c = 1.38) (Found: M+ +
NH4, 528.3142. C30H46NO5Si requires M, 528.3145); nmax/cm-1
2929, 1750, 1373, 1232, 1207, 1175, 1138, 1084, 1058, 836, 775 and
698; dH (300 MHz, CDCl3) 0.07 and 0.09 (each 3 H, s, SiCH3),
0.92 [9 H, s, SiC(CH3)3], 1.13 (3 H, d, J 6, 8-H3), 1.24–1.51 (2 H,
m, 6-H2), 1.81–2.15 (2 H, m, 2- or 5-H2), 2.22 (3 H, s, CH3CO2),
2.57 and 2.68 (each 1 H, dt, J 14.5, 7, 2- or 5-H), 3.77 (1 H, m,
7-H), 5.33 and 5.51 (each 1 H, m, 3-H or 4-H), 5.88 (1 H, t, J 7,
1-H), 6.05 (1 H, s, 2¢-H) and 6.99–7.46 (10 H, m, ArH); m/z (CI,
NH3) 528 (M+ + 18, 100%), 414 (28) and 317 (73).
12 O. Mitsunobu, Synthesis, 1981, 1.
13 G. E. Keck and J. A. Murry, J. Org. Chem., 1991, 56, 6606.
14 A. Furstner, T. Gaster and J. Rust, Synlett, 1999, (1), 29.
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24 E.-M. Moffatt and E. J. Thomas, Tetrahedron, 1999, 55, 3723.
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Acknowledgements
We thank Dr E. K. Dorling for her work on the 7-hydroxy-
7-phenylhept-2-enylstannane 225, the EPSRC for studentships
(to J. S. C., S. McC. and S. J. S.) and the Institute for the Promotion
of Teaching Science and Technology (Thailand) for a studentship
(to A. T.).
Notes and references
26 C. T. Brain and E. J. Thomas, Tetrahedron Lett., 1997, 38, 2387.
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4 For preliminary communications on the work reported in this paper see:
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28 S. Donnelly, M. Fielding and E. J. Thomas, Tetrahedron Lett., 2004,
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29 S. J. Stanway and E. J. Thomas, Synlett, 1995, 214.
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34 Note that according to the sequence rules, (R)-Mosher’s acid and hence
(R)-esters correspond to the (S)-Mosher’s acid chloride.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3896–3919 | 3919
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