Applications of remote stereocontrol using allylstannanes: An approach to the stereoselective synthesis of aliphatic polyols

Article abstract of DOI:10.1016/j.tet.2010.10.045

(4R,2E)-4-Benzyloxy-octa-2,7-dienyl(tributyl)stannane was transmetalated by tin(IV) chloride to generate an allyltin trichloride, which reacted with aldehydes to give (3Z)-1,5-syn-5-benzyloxynona-3,8-dien-1-ols with useful 1,5-stereocontrol. O-Benzylation, hydroboration and oxidation of the terminal double-bond of the product from 2-methylpropanal gave (5R,9S,6Z)-5,9- dibenzyloxy-10-methylundec-6-enal. Further reactions with 4-alkoxyalk-2- enylstannanes proceeded with useful 1,5-stereocontrol to give open-chain products with hydroxy or benzyloxy substituents stereoselectively disposed at remote positions along the chain.

Full text of DOI:10.1016/j.tet.2010.10.045

Tetrahedron 67 (2011) 257e266
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Applications of remote stereocontrol using allylstannanes: an approach
to the stereoselective synthesis of aliphatic polyols
*
Alan H. McNeill, Eric J. Thomas
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2010
Received in revised form 24 September 2010
Accepted 18 October 2010
Available online 22 November 2010
(4R,2E)-4-Benzyloxy-octa-2,7-dienyl(tributyl)stannane was transmetalated by tin(IV) chloride to generate
an allyltin trichloride, which reacted with aldehydes to give (3Z)-1,5-syn-5-benzyloxynona-3,8-dien-1-ols
withuseful1,5-stereocontrol. O-Benzylation,hydroborationandoxidationoftheterminaldouble-bondof the
product from 2-methylpropanal gave (5R,9S,6Z)-5,9-dibenzyloxy-10-methylundec-6-enal. Further reactions
with 4-alkoxyalk-2-enylstannanes proceededwith useful 1,5-stereocontrolto give open-chainproducts with
hydroxy or benzyloxy substituents stereoselectively disposed at remote positions along the chain.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Allylstannanes
Remote stereocontrol
Aliphatic compounds
Polyols
Homoallylic alcohols
1. Introduction
with methoxycarbonylmethylene(triphenyl)phosphorane to give
the separable (2E)- and (2Z)-esters 4, ratio ca. 88:12. Reduction of
Reaction of the (4S)-4-benzyloxypent-2-enylstannane 1 with tin
(IV) chloride generates an allyltin trichloride, which reacts with al-
dehydes to give (Z)-5-benzyloxyhex-3-en-1-ols with useful levels of
stereocontrol in favourof the 1,5-syn-isomers 2.1,2 With chiral 2- and
3-alkoxyaldehydes, the 1,5-syn-stereoselectivity introduced by the
allylstannane determines the configuration of the newly introduced
hydroxyl bearing stereogenic centre, not the chirality of the alde-
hyde.1,3 We here report the application of this chemistry using the
the (2E)-isomer using DIBAL-H gave the (2E)-alcohol 5, which was
converted into the xanthate 6. Heating the allylic xanthate initiated
a [3.3]-sigmatropic rearrangement, which gave a mixture of the
diastereoisomeric dithiocarbonates 7, ratio ca. 4:1. These were not
i, ii
MeO2C
HO
OBn
OBn
(4R,2E)-4-benzyloxy-octa-2,7-dienylstannane
8 for the stereo-
4 [(2E) : (2Z) = 88 : 12]
3
selective synthesis of aliphatic compounds with severalhydroxyand
iii
benzyloxy substituents 1,5-disposed along the open-chain.4
SC(O)SMe
i. SnCl4, -78 oC, 5 min.
ii RCHO, -78 oC, 1 h
Me
OBn
OH
v
Bu3Sn
PO
Me
OBn
R
OBn
OBn
5 P = H
6 P = OC(S)SMe
1
2
7
iv
vi
2. Results and discussion
Bu3Sn
The octadienylstannane 8 was prepared as outlined in Scheme 1.
Swern oxidation of (R)-2-benzyloxyhex-5-en-1-ol (3) (>90% ee,
Mosher’s), available by reduction of the corresponding benzylidene
acetal5 using DIBAL-H, gave an aldehyde, which was condensed
OBn
8
Scheme 1. Synthesis of the octadienylstannane 8. Reagents and conditions: (i) DMSO,
(COCl)2, DCM, ꢀ60 ꢁC, 15 min, then Et3N, ꢀ60 ꢁC (99%); (ii) MeO2CCH.PPh3, DCM, 20 ꢁC,
12 h (96%); (iii) DIBAL-H, ꢀ78 ꢁC, 2 h (81%); (iv) NaH, benzene, CS2, 20 ꢁC, 3 h, then
MeI, 20 ꢁC, 12 h (95%); (v) toluene, heat, 20 h (98%); (vi) Bu3SnH, AIBN, benzene, heat
under reflux, 3.5 h (82%).
* Corresponding author. Tel.: þ44 161 275 4614; fax: þ44 161 275 4939; e-mail
address: e.j.thomas@manchester.ac.uk (E.J. Thomas).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.045

258
A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
separated, instead reaction of the mixture with tributyltin hydride
under free radical conditions1 gave the allylstannane 8 pre-
dominantly as its (E)-isomer.
Reactions of the stannane 8 with benzaldehyde and 2-methyl-
propanal mediated by tin(IV) chloride were carried out at ꢀ78 ꢁC
and gave the (3Z)-1,5-syn-5-benzyloxyalk-3-enols 9 (66%) and 10
(75%) containing ca. 2% and <5% of the corresponding (3Z)-1,5-anti-
epimers, respectively, see Scheme 2.
To incorporate the 1,5-syn-alcohol 10 into a stereoselective
synthesis of an aliphatic tetrol, it was protected as its benzyl ether
17, which was hydroborated using 9-borabicyclononane (9-BBN) to
give the primary alcohol 18 after oxidation of the intermediate
trialkylborane, see Scheme 3. This hydroboration was difficult to
drive to completion but the use of the less hindered borane in
tetrahydrofuran gave a mixture of products. Following oxidation of
the alcohol, the tin(IV) chloride mediated reaction of the resulting
aldehyde 19 with stannane 1 gave the 1,5-syn- and anti-products 20
and 24 in a combined yield of 76%. A sample of this mixture was
oxidized to give ketone 23, which was reduced using sodium bo-
rohydride to give a mixture of the alcohols 20 and 24 in a 1:1 ratio.
These epimers could not be separated and were again very
difficult to distinguish by 1H NMR although one of the diaster-
eotopic benzylic hydrogens gave doublets with slightly different
OH
i
8
R
OBn
9 R = Ph
i
10 R = Pr
chemical shifts, at
d 4.35 and 4.37, for the two epimers. Integration
of these peaks indicated that less than 5% of the 1,5-anti-alcohol 24
was present in the mixture of products from the reaction of allyl-
stannane 1 with aldehyde 19 and so the stereoselectivity of this
reaction was judged to be >95:5. Some doubling of peaks was seen
in the 13C NMR spectrum of the 1:1 mixture of alcohols 20 and 24,
but in the 13C NMR spectrum of the product from the allylstannane
reaction, only alcohol 20 could be detected with peaks due to al-
cohol 24, or indeed from any other isomer, e.g., one derived from
the small amount of 1,5-anti-product 12 carried through from the
first allylstannane reaction or due to the allylstannanes being less
than 100% optically pure, not being distinguished from the baseline.
As a final check of stereochemical integrity, the product 20 pre-
pared from the reaction of allylstannane 1 with aldehyde 19, was
converted into its (R)- and (S)-Mosher’s derivatives 21 and 22. For
both of these, minor components accounted for less than 10% of the
product mixture according to their 19F NMR spectra.
i
ii
(R = Pr)
O
Me
Me
OBn
11
iii
OH
10
+
Me
Me
OBn
12
Scheme 2. Reactions of stannane 8 with simple aldehydes. Reagents and conditions:
(i) 8, SnCl4, ꢀ78 ꢁC, 5 min add aldehyde, ꢀ78 ꢁC, 1 h (9, 66%, 1,5-syn/1,5-anti¼98:2; 10,
75%, 1,5-syn/1,5-anti¼>95:<5); (ii), DMSO, (COCl)2, ꢀ60 ꢁC, 15 min, then iPr2NEt (84%);
(iii) NaBH4, EtOH, H2O, 20 ꢁC, 20 h (74%; 10/12¼50:50).
Hydrogenationof thealkenyl benzyl ether20using10%palladium
on charcoal gave a good yield of the 2,6,10,14-anti,syn,anti-tetrol 25
although the use of 5% palladium on charcoal was accompanied by
competing hydrogenolysis of the allylic alkoxy groups and gave diol
26, characterised as its di-acetate 27, as the major product.
Structures were initially assigned to the major products 9 and 10
by analogy with the corresponding reactions of stannane 1.1 In their
1H NMR spectra, the vicinal vinylic coupling constants across the
internal double-bonds were 11 Hz, so confirming the assigned cis-
stereochemistry.
To confirm the structure of the minor (<5%) product from the
reaction of stannane 8 with 2-methylpropanal, the mixture of
products from this reaction was oxidised to ketone 11. Reduction
using sodium borohydride then gave a 50:50 mixture of the 1,5-
syn- and anti-epimers 10 and 12, which were separated by HPLC.
These were extremely difficult to distinguish spectroscopically but
one of the diastereotopic benzylic hydrogens was observed at
OR
OR
Me
Me
Me
26 R = H
27 R = Ac
To take this chemistry further, the aldehyde 19 was reacted with
the allyltin trichloride generated from the stannane 8 to prepare
the 1,5-syn-alcohol 28, see Scheme 4. The structure shown was
initially assigned to the major product from this reaction by analogy
with earlier work. To check the 1,5-stereoselectivity, alcohol 28 was
oxidized to give ketone 32, which was reduced using sodium bo-
rohydride to give a 1:1 mixture of epimeric alcohols 28 and 33.
These could not be separated but again were distinguished using 1H
NMR due to a difference in the chemical shift of one of the dia-
d
4.37 for epimer 10 and at d 4.35 for epimer 12. Integration of
these peaks in the 1H NMR spectrum of the product from the
reaction of allystannane 8 with 2-methylpropanal, confirmed that
the 1,5-syn/anti-stereoselectivity had been better than 95:5. Fi-
nally, the configurations shown for the major products 9 and 10 at
their hydroxyl bearing stereogenic centres were confirmed by the
relative chemical shifts of their (R)- and (S)-O-acetylmandelates
13e16.6,7
stereotopic benzylic protons, which was observed at
d 4.54 for al-
cohol 28 and at
d
4.55 for its epimer 33. Examination of the 1H NMR
O
spectra of the product 28 obtained from the allylstannane reaction
between aldehyde 19 and stannane 8 confirned that only ca. 5% of
epimer 33 was present in the product mixture. This stereo-
selectivity was consistent with the 19F NMR spectra of the Mosher’s
derivatives 29 and 30, which indicated 92:4:4 and 93:5:2 ratios of
products, respectively, and with the 13C NMR spectrum of the
allylstannane product 28 in which minor products were not dis-
tinguished from the baseline.
Ph
O
AcO
R
OBn
13 R = Ph, (S)-O-acetylmandelate; 14 R = Ph, (R)-O-acetylmandelate
15 R = Pr, (S)-O-acetylmandelate; 16 R = Pr, (R)-O-acetylmandelate
i
i

A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
259
OBn
OBn
OBn
Me
OH
Me
Me
i
iii
ii
CHO
OBn
10
Me
OBn
Me
OBn
OBn
Me
OBn
17
19
18
iv
OBn
OBn
v
Me
Me
Me
Me
Me
OBn
O
Me
OBn
20 R = H
OR
23
21 R = (S)-Ph(MeO)CF3C.CO
22 R = (R)-Ph(MeO)CF3C.CO
vi
vii
OBn
OBn
Me
OH
OH
OH
OH
Me
Me
20
+
Me
Me
OBn
OH
Me
24
25
n
Scheme 3. Synthesis of (2S,6R,10R,14S)-15-methylhexadeca-2,6,10,14-tetrol 25 Reagents and conditions: (i) NaH, DMF, 20 ꢁC, 1 h, BnBr, Bu4NI, THF, 20 ꢁC, 12 h (86%); (ii) 9-BBN,
THF, 20 ꢁC, 2 h, then H2O2, NaOH, 20 ꢁC, 12 h (64% allowing for recovered starting material); (iii) DMSO, (COCl)2, ꢀ60 ꢁC, then Et3N (95%); (iv) 1-SnCl4, ꢀ78 ꢁC, 1 h (76%); (v) DMSO,
i
(COCl)2, ꢀ60 ꢁC, Pr2NEt (74%); (vi) NaBH4, EtOH, H2O, 20 ꢁC, 3 h (95%; 20/22¼50:50); (vii) 10% Pd/C, MeOH, H2, 20 ꢁC, 3 h (88%).
OBn
OBn
OBn
OBn
OBn
Me
Me
v
i
OH
19
Me
Me
OBn
OBn
OBn
Me
OBn
28 R = H
29 R = (S)-Ph(MeO)CF3C.CO
30 R = (R)-Ph(MeO)CF3C.CO
31 R = Bn
OR
34
vi
ii
OBn
Me
CHO
iii
OBn
OBn
OBn
OBn
OBn
35
Me
Me
vii
Me
Me
OBn
OBn
O
OBn
OH
32
Me
Me
OBn
iv
Me
OBn
OBn
OBn
36
+
28
OH
33
Scheme 4. Further stereoselective syntheses of derivatives of aliphatic polyols Reagents and conditions: (i) 8-SnCl4, ꢀ78 ꢁC, 1 h (72%); (ii) NaH, DMF, 0 ꢁC, 1 h then BnBr, 20 ꢁC, 12 h
nBu4NI (68% allowing for recovered starting material); (iii) DMSO, (COCl)2, ꢀ60 ꢁC, iPr2NEt (85%); (iv) NaBH4, EtOH, H2O, 20 ꢁC, 3 h (92%); (v) 9-BBN, THF, 20 ꢁC, 2 h then H2O2, NaOH,
20 ꢁC, 12 h (40%); (vi) DMSO, (COCl)2, ꢀ60 ꢁC then Et3N (72%); (vii) 1-SnCl4, ꢀ78 ꢁC, 1 h (67%).
Following protection of the alcohol 28 as its benzyl ether 31,
preliminary studies were carried out on further chain extension
reactions using allylstannanes. In this work, some of the re-
actions, notably the hydroboration, were difficult to drive to
completion perhaps because of the long aliphatic chains present
in the intermediates. Nevertheless, hydroboration using 9-BBN
with oxidation of the organoborane gave the alcohol 34, which
was further oxidised to give aldehyde 35. The reaction of this
aldehyde with the allyltin trichloride prepared from the stannane
1 gave a major product, which was identified as the long-chain
(Z)-syn-1,5-alcohol 36 by analogy with other tin(IV) chloride
mediated reactions of allylstannane 1 with aldehydes.1 In this
case, the product was not taken through to its epimeric alcohol.
However, the 1H and 13C NMR spectra were very clean and were
consistent with the allylstannane reaction having been highly
stereoselective.
3. Summary and conclusions
This work shows that tin(IV) chloride mediated reactions of 4-alk-
oxy-substituted allylstannanes with aldehydes known to proceed with
syn-1,5-stereoselectivity, even with chiral aldehydes, can be used to
prepare open-chain compounds with several hydroxy and benzyloxy
substituents at remote positions along aliphatic chains with useful
levels of 1,5-stereocontrol. In the present work, the dienyl stannane 8
was useful in that hydroborationeoxidation of the terminal double
bond in the products gave aldehydes which could be taken further to
provide for additional stereoselective chain extension.
The examples in this paper are only illustrative; the use of enan-
tiomeric 4-alkoxy-alk-2-enylstannanes or 4-alkoxy-alk-2,u-dienyl-
stannanes with different chain lengths could be used to provide
access to open-chain compounds with a variety of hydroxy and alk-
oxy substituents at different positions along aliphatic chains.

260
A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
In these studies care was taken to use allylstannanes, which were
aqueous sodium hydrogen carbonate and CH2Cl2 were added. The
mixture was allowed to warm to room temperature and the organic
phase was washed with water and brine then dried (MgSO4). After
concentration under reduced pressure, chromatography, typically
using ether/petroleum (1:3) as eluant, gave the product.
as optically pure as possible, >90% ee for both stannanes 1 and 8.
Nevertheless, minor products were expected to accumulate during
the second and third iterations of reactions of the aldehydes with
allylstannanes because neither the starting materials nor the allyl-
stannanes were 100% optically pure and because minor (Z)-1,5-anti-
epimers, i.e., alcohols 12 and 33, which typically accounted for 2e5%
of the product mixtures from the corresponding reactions with al-
dehydes, could not be separated from the major syn-1,5-products 10
and 28. Indeed, the 19F NMR spectra of the Mosher’s derivatives 29
and 30 indicated that the major diastereoisomeric alcohol 28
accounted for 92% of the product fromthe reaction of allylstannane 8
with aldehyde 19 with two other products each being present at the
2e4% level. For this reason, the alcohol 36, the product of three it-
erations of the allylstannane chemistry, may contain ca. 10% of ac-
cumulated minor isomers, although these were not apparent from
its 1H and 13C NMR spectra and may have been reduced by peak
shaving during chromatography.8 Nevertheless, as the (Z)-1,5-syn/
(Z)-1,5-anti-diastereoselectivity is typically 95e98:5e2, even for
reactions of the 5-benzyloxyundecenal 19, this chemistry does
provide useful procedures for the stereoselective preparation of
open-chain compounds with remote functionality, which would be
difficult to access by other means.
4.3. General procedure for the preparation of O-
acetylmandelates
(R)- or (S)-O-Acetylmandelic acid (2 mol equiv) and DMAP
(2 mg) were added to the alcohol in CH2Cl2 at 0 ꢁC followed by
dicyclohexylcarbodi-imide (2 mol equiv) in CH2Cl2. After 5 min, the
cooling bath was removed and the suspension stirred for 24 h at
room temperature. Following filtration, the filtercake was washed
with hexane (ꢂ3) and the organic extracts were washed with
aqueous hydrogen chloride (1 N), saturated sodium hydrogen car-
bonate, then dried (MgSO4) and concentrated under reduced
pressure. Chromatography, using ether/petroleum (1:2) as eluant,
gave the O-acetyl mandelate.
4.4. General procedure for the preparation of Mosher’s esters
(R)- or (S)-2-Methoxy-2-phenyl-3,3,3-trifluoropropanoyl chlo-
ride (1.2 mol equiv) was added to the alcohol and pyridine (2 mol
equiv) in carbon tetrachloride and the mixture stirred for 12 h at
room temperature. 3-Dimethylaminopropylamine (1.5 mol equiv)
was added and the mixture diluted with ether. The organic extracts
were washed with aqueous hydrogen chloride (1 N), saturated
aqueous sodium bicarbonate and brine, then dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue, using ether/petroleum (1:3) as eluant, gave the Mosher’s
ester.
More recent studies have shown that transmetalation of
alkoxyalk-2-ylgermanium compounds with tin(IV) bromide, pro-
vides highly stereoselective access to allyltin tribromides giving
even better overall 1,5-stereocontrol in reactions with alde-
hydes.9,10 These reagents should also be useful for the preparation
of compounds with functionality dispersed at remote positions
along aliphatic chains as discussed here.
4. Experimental
4.1. General procedures
4.5. Methyl (4R,2E)- and (4R,2Z)-4-benzyloxy-octa-2,7-
dienoate 4
All non-aqueous reactions were performed under an atmo-
sphere of argon. 1H NMR spectra were recorded on Varian Unity-
500 (500 MHz), Bruker AC-300 or Varian XL-300 (300 MHz)
spectrometers at 300 MHz in CDCl3 unless otherwise stated. 13C
NMR spectra were recorded on a Bruker AC-300 at 75 MHz in CDCl3
and 19F spectra were recorded on a Varian Unity-500 spectrometer
at 470 MHz. IR spectra were recorded on a Perkin Elmer 1710FT
spectrometer and mass spectra were recorded on a Kratos MS25
mass spectometer coupled to a DS55 data system. Typical isotope
patterns were observed for compounds containing tin with peaks
due to 118Sn and 120Sn reported. Melting points were determined
on a Kofler Block apparatus and optical rotations were recorded on
a Optical Activity AA100 polarimeter at 25 ꢁC.
DMSO (5.01 g, 0.068 mol) in CH2Cl2 (25 ml) was added to oxalyl
chloride (4.42 g, 0.034 mol) in CH2Cl2 (50 ml) at ꢀ60 ꢁC. After 5 min,
the alcohol 3 (6.50 g, 0.031 mol) in CH2Cl2 (50 ml) was added and
the mixture stirred for 15 min. Triethylamine (15.96 g, 0.155 mol)
was then added and the mixture was stirred for 5 min at ꢀ60 ꢁC
before being allowed to warm to room temperature. Water (60 ml)
was added and the organic layer was washed with brine (60 ml),
dried (MgSO4) and concentrated under reduced pressure to give
(R)-2-benzyloxyhex-5-enal (6.40 g, 99%) as a pale yellow oil.
Chromatography of a small sample using EtOAc/petroleum (1:9) as
eluant gave (R)-2-benzyloxyhex-5-enal as a colourless oil, [
a
]
D þ42
(c 1, CHCl3) (found: MþþNH4, 222.1486. C13H20NO2 requires M,
222.1494); nmax (film) 2922, 1733, 1455, 1105, 914, 739 and 698
Chromatography refers to flash chromatography using either
Merck silica gel 60H (40e63 m, 230e300 mesh) or May and Baker
Sorbsil C60 silica gel (40e60 m) as the stationary phase.
cmꢀ1
; dH 1.79 (2H, m, 3-H2), 2.20 (2H, m, 4-H2), 3.80 (1H, td, J 6.5, 2
Hz, 2-H), 4.55 and 4.68 (each 1H, d, J 12 Hz, CHHPh), 4.98e5.07 (2H,
m, 6-H2), 5.78 (1H, ddt, J 17, 10, 6.5 Hz, 5-H), 7.30 (5H, m, ArH) and
9.68 (1H, d, J 2 Hz, 1-H); dC 29.0, 29.5, 72.8, 83.0, 116.0, 128.2, 128.3,
128.7, 137.4, 137.5 and 204.0; m/z (C.I./NH3) 222 (Mþþ18, 100%) and
205 (Mþþ1, 2).
Petroleum refers to light petroleum, bp 40e60 ꢁC, distilled be-
fore use, and ether to diethyl ether. Solvents were dried using
conventional procedures. Tin(IV) chloride and acetic anhydride
were dried over and distilled from phosphorous pentoxide (P2O5).
Brine refers to saturated aqueous sodium chloride. n-Butyllithium
was in hexane and was titrated against 2,5-dimethoxybenzyl al-
cohol before use.
(R)-2-Benzyloxyhex-5-enal (6.40 g, 0.031 mol) in CH2Cl2 (50 ml)
was added to methoxycarbonylmethylene(triphenyl)-phosphorane
(11.0 g, 0.034 mol), in CH2Cl2 (60 ml) for 15 min at 20 ꢁC. After 12 h
at 20 ꢁC, water (50 ml) was added and the organic layer dried
(MgSO4) and concentrated under reduced pressure. Chromatogra-
phy with preabsorbtion onto the silica, using ether/petroleum (1:9)
as eluant, gave the (Z)-isomer of the title compound 4 (863 mg, 11%)
4.2. General procedure for tin(IV)chloride mediated reactions
of aldehydes with 4-alkoxystannanes
Tin(IV) chloride (1 mol equiv) in CH2Cl2 cooled to ꢀ78 ꢁC was
added dropwise via a syringe to the 4-alkoxyalkenylstannane in
CH2Cl2 at ꢀ78 ꢁC. After 5 min, the aldehyde in CH2Cl2, cooled to ꢀ78
ꢁC was added and the mixture stirred for 1 h at ꢀ78 ꢁC before
as a colourless oil, [
a
]
ꢀ6.4 (c 1, CHCl3) (found: MþþH, 261.1497.
D
C16H21O3 requires M, 261.1491); nmax (film) 2950, 1724, 1641, 1455,
1206, 1094, 1029, 914, 825, 736 and 698 cmꢀ1
5-H2), 2.21 (2H, m, 6-H2), 3.72 (3H, s, OMe), 4.43 and 4.53 (each
; dH 1.58e1.86 (2H, m,

A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
261
1H, d, J 12 Hz, CHHPh), 4.95e5.10 (3H, m, 4-H and 8-H2), 5.84 (1H,
ddt, J 17, 10, 6.5 Hz, 7-H), 5.92 (1H, dd, J 12, 1 Hz, 2-H), 6.21 (1H, dd, J
12, 9 Hz, 3-H) and 7.32 (5H, m, ArH); dC 29.7, 34.3, 51.5, 71.6, 74.8,
114.9, 121.0, 127.7, 128.0, 128.5, 138.4, 138.6, 151.5 and 166.4; m/z
(C.I./NH3) 261 (Mþþ1, 100%); followed by the (E)-isomer of the title
a
4:1 mixture of diastereoisomers (found: MþþH, 323.1139.
C17H23O2S2 requires M, 323.1139); nmax (film) 2929, 1646, 1095,
920, 867 and 697 cmꢀ1
; dH (major diastereoisomer) 1.51e1.79 (2H,
m, 5-H2), 2.15 (2H, m, 6-H2), 2.42 (3H, s, SMe), 3.65 (1H, m, 4-H),
4.55 (1H, d, J 12 Hz, CHHPh), 4.56 (1H, dd, J 12, 3.5 Hz, 3-H), 4.64
(1H, d, J 12 Hz, CHHPh), 4.94e5.06 (2H, m, 8-H2), 5.21 (1H, d, J 10
Hz, 1-H), 5.34 (1H, d, J 17 Hz, 1-H0), 5.78 (1H, ddt, J 17, 10, 6.5 Hz, 7-
H), 5.91 (1H, ddd, J 17, 10.5, 9 Hz, 2-H) and 7.31 (5H, m, ArH); dH
(distinctive peaks due to the minor diastereoisomer) 2.42 (3H, s,
SMe), 5.19 (1H, d, J 10 Hz, 1-H) and 5.32 (1H, d, J 17 Hz, 1-H0); dC
(major diastereoisomer) 13.3, 30.0, 31.7, 52.3, 72.7, 80.6, 115.4,
119.0, 127.9, 128.0, 128.5, 133.8, 138.0, 138.3 and 189.4; dC (dis-
tinctive peaks due to the minor diastereoisomer) 31.0, 51.0, 72.3,
115.3, 118.3, 134.3 and 138.1; m/z (C.I./NH3) 340 (Mþþ18, 16%) and
323 (Mþþ1, 100).
compound 4 (6.91 g, 85%) as a colourless oil; [
a]
þ42 (c 1, CHCl3)
D
(found: MþþNH4, 278.1752. C16H24NO3 requires M, 278.1756); nmax
(film) 2948, 1726, 1659, 1436, 1273, 1168, 1096, 915, 736 and 698
cmꢀ1
; dH 1.59e1.82 (2H, m, 5-H2), 2.17 (2H, m, 6-H2), 3.77 (3H, s,
OMe), 3.99 (1H, m, 4-H), 4.38 and 4.59 (each 1H, d, J 12 Hz, CHHPh),
4.93e5.03 (2H, m, 8-H2), 5.78 (1H, ddt, J 17, 10, 6.5 Hz, 7-H), 6.05
(1H, dd, J 16, 1 Hz, 2-H), 6.89 (1H, dd, J 16, 6.5 Hz, 3-H) and 7.32 (5H,
m, ArH); dC 29.4, 34.2, 51.6, 71.2, 77.5, 115.3, 121.9, 127.8,127.9, 128.6,
137.9, 138.2, 148.6 and 166.6; m/z (C.I./NH3) 278 (Mþþ18, 100%).
4.6. (4R,2E)-4-Benzyloxyocta-2,7-dien-1-ol 5
4.9. (4R,2E)-4-Benzyloxyocta-2,7-dien-1-yl(tributyl)stannane 8
DIBAL-H (1.0 M in hexane, 65.7 ml, 0.066 mol) was added for 50
min to the (2E)-isomer of the ester 4 (7.77 g, 0.03 mol) in CH2Cl2 (90
ml) at ꢀ78 ꢁC. After 2 h at ꢀ78 ꢁC, water (16.6 ml) was added and
the mixture allowed to warm to room temperature then filtered
through Celite and triturated with ether (2ꢂ30 ml). The ethereal
extracts were dried (MgSO4) and concentrated under reduced
pressure. Chromatography of the residue using ether/petroleum
(1:1) as the eluant gave the title compound 5 (5.60 g, 81%) as a col-
Tributyltin hydride (7.82 g, 0.026 mol) and AIBN (10 mg) in
benzene (15 ml) were added dropwise via a syringe to a degassed
solution of the dithiocarbonate 7 (7.21 g, 0.022 mol) in benzene
(75 ml). The mixture was heated under reflux for 3.5 h, allowed to
cool to room temperature and concentrated under reduced
pressure. Chromatography of the residue using triethylamine/
ether/petroleum (1:2:97) as the eluant gave the title compound 8
ourless oil, [
a]
þ35 (c 1, CHCl3) (found: MþþNH4, 250.1811.
(9.24 g, 82%) as a colourless oil, [
a
]
þ29 (c 1, CHCl3) (found:
D
D
C15H24NO2 requires M, 250.1807); nmax (film) 3377, 2862,1641,1455,
MþꢀC4H9, 449.1875. C23H37O120Sn requires M, 449.1866); nmax
1089, 1071, 996, 975, 912, 736 and 698 cmꢀ1
; dH 1.57 (1H, br s, OH),
(film) 2956, 2926, 1641, 1070, 1454, 1029, 963, 909, 731 and 696
1.59 and 1.77 (each 1H, m, 5-H), 2.14 (2H, m, 6-H2), 3.81 (1H, q, J 4
Hz, 4-H), 4.19 (2H, dd, J 5, 1 Hz, 1-H2), 4.37 and 4.58 (each 1H, d, J 12
Hz, CHHPh), 4.91e5.04 (2H, m, 8-H2), 5.62 (1H, dd, J 16, 8 Hz, 3-H),
5.73e5.88 (2H, m, 7-H and 2-H) and 7.32 (5H, m, ArH); dC 29.8, 35.0,
63.1, 70.4, 79.0, 115.0, 127.6, 127.9, 128.5, 132.2, 132.3, 138.5 and
138.9; m/z (C.I./NH3) 250 (Mþþ18, 100%) and 233 (Mþþ1, 5).
cmꢀ1
;
dH 0.90 (9H, t,
J
7
Hz, 3ꢂCH3), 1.25e1.60 (18H, m,
3ꢂCH2CH2CH2), 1.75 (2H, m, 5-H2), 1.77 (2H, d, J 8.5 Hz, 1-H2), 2.11
(2H, m, 6-H2), 3.65 (1H, q, J 8 Hz, 4-H), 4.30 and 4.56 (each 1H, d, J
12 Hz, CHHPh), 4.90e5.02 (2H, m, 8-H2), 5.15 (1H, dd, J 15, 8.5 Hz,
3-H), 5.71e5.86 (2H, m, 2-H, 7-H) and 7.31 (5H, m, ArH); dC 9.3,
13.7, 14.3, 27.4 (JCeSn 60), 29.2 (JCeSn 25), 29.9, 35.5, 69.5, 80.0,
114.4, 126.0, 127.3, 127.7, 128.3, 134.1, 138.7 and 138.2; dSn ꢀ14.7;
m/z (C.I./NH3) 449 [M (120Sn)þꢀ57, 4%], 447 [M (118Sn)þꢀ57, 4],
308 (100) and 306 (90).
4.7. S-Methyl O-(4R,2E)-4-benzyloxyocta-2,7-dien-1-yl dithio-
carbonate 6
The (2E)-alcohol 5 (5.60 g, 0.024 mol) in benzene (30 ml) was
added for 20 min to sodium hydride (60% in mineral oil, 966 mg,
0.024 mol) in benzene (60 ml) at 0 ꢁC. The reaction mixture was
stirred for 1 h at 20 ꢁC then cooled to 0 ꢁC and carbon disulphide
(7.34 g, 0.096 mol) was added. The resulting suspension was stirred
for 3 h at 20 ꢁC, cooled to 0 ꢁC and methyl iodide (13.71 g, 0.096
mol) was added. The mixture was then stirred for 12 h at 20 ꢁC,
filtered through Celite and the solids triturated with CH2Cl2 (2ꢂ80
ml). The filtrate was washed with brine (40 ml), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ether/petroleum (1:9) as eluant gave the title com-
4.10. (1S,5R,3Z)-5-Benzyloxy-1-phenylnona-3,8-dien-1-ol 9
Following the general procedure, tin(IV) chloride (51 mg,
0.198 mmol) in CH2Cl2 (230
mmol) in CH2Cl2 (3 ml) and benzaldehyde (21 mg, 0.198 mmol)
in CH2Cl2 (50 l), after chromatography using ether/petroleum
ml), the stannane 8 (100 mg, 0.198
m
(1:3) as eluant, gave the title compound 9 (42 mg, 66%) as a col-
ourless oil, [
a
]
ꢀ15.2 (c 1, CHCl3) (found: MþþNH4, 340.2283.
D
C22H30NO2 requires M, 340.2276); nmax (film) 3418, 2922, 1055,
912, 736 and 699 cmꢀ1
; dH 1.35 (1H, ddt, J 13, 9.5, 6 Hz, 6-H), 1.70
(1H, m, 6-H0), 2.08 (3H, m, 7-H2 and OH), 2.40e2.62 (2H, m, 2-
H2), 4.09 (1H, m, 5-H), 4.31 and 4.51 (each 1H, d, J 12 Hz, CHHPh),
4.72 (1H, dd, J 8, 6 Hz, 1-H), 4.91e5.01 (2H, m, 9-H2), 5.49 (1H, dd,
J 11, 9 Hz, 4-H), 5.68 (1H, dt, J 11, 7 Hz, 3-H), 5.77 (1H, ddt, J 17, 10,
6.5 Hz, 8-H) and 7.31(10H, m, ArH); dC 29.7, 34.7, 38.0, 70.0, 73.8,
74.1, 114.8, 126.0, 127.6, 127.8, 128.0, 128.5, 128.6, 128.7, 134.0,
138.5, 139.0 and 144.1; m/z (C.I./NH3) 340 (Mþþ18, 44%), 323
(Mþþ1, 11) and 197 (100).
pound 6 (7.34 g, 95%) as a pale yellow oil, [
a
]
þ25.6 (c 1, CHCl3)
D
(found: MþþH, 323.1148. C17H23O2S2 requires M, 323.1139); nmax
(film) 2922, 1641, 1212, 1060, 970, 912, 736 and 698 cmꢀ1
; dH 1.51
and 1.77 (each 1H, m, 5-H), 2.14 (2H, m, 6-H2), 2.58 (3H, s, SMe), 3.83
(1H, q, J 6 Hz, 4-H), 4.37 and 4.58 (each 1H, d, J 12 Hz, CHHPh),
4.93e5.04 (2H, m, 8-H2), 5.14 (2H, d, J 5.5 Hz, 1-H2), 5.80 (3H, m, 2-
H, 3-H, 7-H) and 7.32 (5H, m, ArH); dC 19.3, 29.7, 34.8, 70.6, 73.3,
78.6, 115.1, 125.6, 127.2, 128.0, 128.6, 136.9, 138.3, 138.7 and 215.8;
m/z (C.I./NH3) 323 (Mþþ1, 12%) and 91 (100).
4.11. (3S,7R,5Z)-7-Benzyloxy-2-methylundeca-5,10-dien-3-ol 10
4.8. S-(3RS,4R)-3-(4-Benzyloxyocta-1,7-dien-3-yl) S-methyl
dithiocarbonate 7
Following the general procedure, tin(IV) chloride (1.03 g, 3.96
mmol) in CH2Cl2 (4.60 ml), the stannane 8 (2.0 g, 3.96 mmol) in
CH2Cl2 (25 ml) and 2-methylpropanal (286 mg, 3.96 mmol) in
The xanthate 6 (7.34 g, 0.023 mol) heated under reflux in tol-
uene (80 ml) for 20 h. After concentration under reduced pressure,
chromatography of the residue using ether/petroleum (1:9) as
eluant afforded the title compound 7 (7.21 g, 98%) as a yellow oil,
CH2Cl2 (200 ml), after chromatography using ether/petroleum (1:3)
as eluant, gave the title compound 10 (857 mg, 75%) as a colourless
oil, [
a
]
þ14.0 (c 1, CHCl3) (found: MþþH, 289.2179. C19H29O2 re-
D
quires M, 289.2167); nmax (film) 3415, 2959, 1661, 1068, 912, 872,

262
A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
735 and 698 cmꢀ1
;
dH 0.92 (6H, d, J 7 Hz, 1-H3 and 2-Me), 1.48e1.88
4.22 and 4.48 (each 1H, d, J 12 Hz, CHHPh), 4.90e5.01 (2H, m, 1-H2),
5.44 (1H, t, J 10 Hz, 6-H), 5.59 (1H, dt, J 11, 9 Hz, 7-H), 5.72 (1H, ddt, J
17, 10, 6.5 Hz, 2-H), 5.79 (1H, t, J 6.5 Hz, 9-H), 6.00 (1H, s, 20-H) and
6.95e7.50 (15H, m, ArH); m/z (C.I./NH3) 516 (Mþþ18, 16%) and 197
(100).
(4H, m, 2-H, 8-H2 and OH), 2.09e2.21 (4H, m, 4-H2 and 9-H2), 3.40
(1H, q, J 6 Hz, 3-H), 4.15 (1H, m, 7-H), 4.38 and 4.59 (each 1H, d, J 12
Hz, CHHPh), 4.92e5.05 (2H, m, 11-H2), 5.52 (1H, dd, J 11, 9 Hz, 6-H),
5.71 (1H, dt, J 11, 7 Hz, 5-H), 5.80 (1H, ddt, J 17, 10, 6.5 Hz, 10-H) and
7.32 (5H, m, ArH); dC 17.5, 18.9, 29.7, 32.8, 33.5, 34.9, 70.2, 73.7, 76.5,
114.9, 127.6, 128.0, 128.5, 130.0, 133.8, 138.6 and 138.9; m/z (C.I./
NH3) 289 (Mþþ1, 3%) and 181 (100).
4.15. (5R,9S,6Z)-9-[(R)-2-Acetoxy-2-phenylacetoxy]-5-benzyl-
oxy-9-phenylnona-1,6-diene 14
4.12. (7R,5Z)-7-Benzyloxy-2-methylundeca-5,10-dien-3-one 11
Following the general procedure, (R)-O-acetylmandelic acid and
alcohol 9 (26 mg) gave the title compound 14 (31 mg, 78%) as
a colourless oil (found: MþþNH4, 516.2748, C32H38NO5 requires M,
DMSO (36 mg, 0.458 mmol) in CH2Cl2 (500
oxalyl chloride (29 mg, 0.229 mol) in CH2Cl2 (500
After 5 min, the alcohol 10 (60 mg, 0.208 mmol) in CH2Cl2 (500
ml) was added to
m
l) at ꢀ60 ꢁC.
516.2750); nmax (film) 1746, 1232, 1207, 915, 738 and 698 cmꢀ1
; dH
1.24 and 1.61 (each 1H, m, 4-H), 2.00 (2H, m, 3-H2), 2.19 (3H, s,
MeCO), 2.45 and 2.54 (each 1H, dt, J 15, 6 Hz, 8-H), 3.89 (1H, m, 5-H),
4.11 and 4.37 (each 1H, d, J 12 Hz, CHHPh), 4.89e4.99 (2H, m, 1-H2),
5.28 (2H, m, 6-H, 7-H), 5.72 (1H, ddt, J 17,10, 6.5 Hz, 2-H), 5.79 (1H, t,
J 6.5 Hz, 9-H), 6.00 (1H, s, 20-H) and 7.20e7.55 (15H, m, ArH); dC
20.7, 29.5, 34.5, 34.6, 69.9, 73.4, 74.5, 76.7, 114.7, 126.3, 126.8, 127.5,
127.7, 127.8, 127.9, 128.3, 128.5, 128.8, 129.3, 133.9, 135.3, 138.3,
138.7, 139.0, 168.1 and 170.2; m/z (C.I/NH 3) 516 (Mþþ18, 19%) and
197 (100).
m
l) was added and the mixture stirred for 15 min. N,N-Di-iso-
propylethylamine (134 mg, 1.04 mmol) was added and the
mixture was stirred for 5 min at ꢀ60 ꢁC then allowed to warm
to room temperature. Water (800
ml) was added and the or-
ganic layer washed with brine (800
ml), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using ether/petroleum (1:3) as eluant, gave the title
compound 11 (50 mg, 84%) as a pale yellow oil, [
CHCl3); nmax (film) 2972, 1715, 1641, 1466, 1455, 1092, 1069, 913,
736 and 699 cmꢀ1
dH (C6D6) 0.9 and 0.94 (each 3H, d, J 7 Hz, 1-
a
]
þ25 (c 1,
D
;
4.16. (5R,9S,6Z)-9-[(S)-2-Acetoxy-2-phenylacetoxy]-5-benzyl-
H3 or 2-Me), 1.66 and 1.91 (each 1H, m, 8-H), 2.22 (3H, m, 2-H
and 9-H2), 2.92 (2H, m, 4-H2), 4.08 (1H, m, 7-H), 4.37 and 4.65
(each 1H, d, J 12 Hz, CHHPh), 5.00e5.12 (2H, m, 11-H2), 5.55
(1H, ddt, J 11, 9, 2 Hz, 6-H), 5.85 (1H, ddt, J 17, 10, 6.5 Hz, 10-H),
5.91 (1H, dt, J 11, 7 Hz, 5-H) and 7.13e7.40 (5H, m, ArH); dC
(C6D6) 18.2, 29.9, 35.2, 39.2, 40.6, 69.9, 73.6, 114.9, 125.5, 127.5,
127.9, 128.5, 133.7, 138.7, 139.5 and 209.5; m/z (C.I./NH3) 304
(Mþþ18, 4%) and 52 (100).
oxy-10-methylundeca-1,6-diene 15
Following the general procedure, (S)-O-acetylmandelic acid and
alcohol 10 (19 mg) gave the title compound 15 (27 mg, 88%) as
a colourless oil (found: MþþNH4, 482.2894. C29H40NO5 requires M,
482.2906); nmax (film) 2966, 1746, 1372, 1233, 1210, 1179, 1059, 995,
915, 737 and 698 cmꢀ1
; dH 0.63 and 0.65 (each 3H, d, J 7 Hz,11-H3 or
10-Me), 1.53 (1H, m, 10-H), 1.76 (2H, m, 4-H2), 2.14 (2H, m, 3-H2),
2.20 (3H, s, MeCO), 2.33 (2H, m, 8-H2), 4.11 (1H, m, 5-H), 4.35 and
4.60 (each 1H, d, J 12 Hz, CHHPh), 4.80 (1H, dt, J 8, 5 Hz, 9-H),
4.91e5.03 (2H, m, 1-H2), 5.47 (1H, dd, J 11, 9 Hz, 6-H), 5.60 (1H, dt, J
11, 7 Hz, 7-H), 5.80 (1H, ddt, J 17, 10, 6.5 Hz, 2-H), 5.91 (1H, s, 20-H)
and 7.25e7.49 (10H, m, ArH); dC 16.8,18.4, 20.7, 29.5, 29.7, 31.0, 34.8,
70.0, 73.5, 74.7, 80.0, 114.7, 127.5, 127.7, 128.0, 128.1, 128.3, 128.7,
129.2, 133.3, 134.1, 138.4, 138.9, 168.7 and 170.2; m/z (FAB) 482
(Mþþ18, 0.3%), 465 (Mþþ1, 0.7) and 163 (100).
4.13. (3R,7R,5Z)- and (3S,7R,5Z)-7-Benzyloxy-2-methylun-
deca-5,10-dien-3-ols 12 and 10
Sodium borohydride (1.8 mg, 0.045 mmol) in aqueous ethanol
(1 ml) was added dropwise to the ketone 11 (27 mg, 0.09 mmol) in
CH2Cl2 (1 ml) at 0 ꢁC. After 20 h at 20 ꢁC aqueous citric acid (5%, 500
ml) was added and the organic layer was separated, dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
residue using ether/petroleum (1:3) as eluant gave the title com-
pounds 10 and 12 (20 mg, 74%) as a colourless oil, a 1:1 mixture;
nmax (film) 3454, 2959, 1640, 1068, 912, 735 and 698 cmꢀ1; m/z (C.I./
NH3) 306 (Mþþ18, 9%), 289 (Mþþ1, 8) and 181 (100). Following
separation by HPLC, the less polar isomer was identified as the title
compound 12; dH 0.91 and 0.92 (each 3H, dd, J 7 Hz, 1-H3 or 2-Me),
1.44 (1H, br s, OH), 1.57 (1H, m, 2-H), 1.68 and 1.80 (each 1H, m, 8-
H), 2.09e2.29 (4H, m, 4-H2 and 9-H2), 3.39 (1H, m, 3-H), 4.15 (1H, m,
7-H), 4.35 and 4.58 (each 1H, d, J 12 Hz, CHHPh), 4.92e5.06 (2H, m,
11-H2), 5.51 (1H, dd, J 11, 9 Hz, 6-H), 5.73 (1H, dt, J 11, 7 Hz, 5-H),
4.17. (5R,9S,6Z)-9-[(R)-2-Acetoxy-2-phenylacetoxy]-5-benzyl-
oxy-10-methylundeca-1,6-diene 16
Following the general procedure, (R)-O-acetylmandelic acid
and alcohol 10 (16 mg) gave the title compound 16 (23 mg, 89%)
as a colourless oil (found: MþþNH4, 482.2885. C29H40NO5 re-
quires M, 482.2906); nmax (film) 2965, 1746, 1640, 1372, 1233,
1210, 1179, 1058, 915, 737 and 697 cmꢀ1
; dH 0.90 (6H, d, J 7 Hz,
11-H3, 10-Me), 1.43 (1H, m, 10-H), 1.70 and 1.85 (each 1H, m, 4-H),
2.05 (2H, m, 3-H2), 2.13 (2H, t, J 6 Hz, 8-H2), 2.20 (3H, s, MeCO),
3.94 (1H, q, J 7 Hz, 5-H), 4.11 and 4.40 (each 1H, d, J 12 Hz,
CHHPh), 4.79 (1H, q, J 6 Hz, 9-H), 4.90e5.00 (2H, m, 1-H2), 5.18
(2H, m, 6-H, 7-H), 5.77 (1H, ddt, J 17, 10, 6.5 Hz, 2-H), 5.90 (1H, s,
20-H) and 7.23e7.49 (10H, m, ArH); dC 17.4, 18.5, 20.7, 29.3, 29.5,
31.3, 34.6, 69.7, 73.1, 74.8, 79.7, 114.7, 127.5, 127.7, 127.8, 127.9,
128.3, 128.8, 129.3, 133.0, 133.9, 138.3, 138.8, 168.7 and 170.3; m/z
(C.I./NH3) 482 (Mþþ18, 100%).
5.81 (1H, ddt, J 17, 10, 6.5 Hz, 10-H) and 7.32 (5H, m, ArH);
d 17.3,
18.8, 29.6, 32.7, 33.2, 34.7, 69.9, 73.5, 76.2, 114.7, 127.5, 127.8, 128.3,
129.7, 133.4, 138.4 and 138.8. The more polar compound had
spectroscopic data identical to those of alcohol 10 prepared
previously.
4.14. (5R,9S,6Z)-9-[(S)-2-Acetoxy-2-phenylacetoxy]-5-benzyl-
oxy-9-phenylnona-1,6-diene 13
4.18. (5R,9S,6Z)-5,9-Dibenzyloxy-10-methylundeca-1,6-diene17
Following the general procedure, (S)-O-acetylmandelic acid and
alcohol 9 (37 mg) gave the title compound 13 (40 mg, 70%) as
a colourless oil (found: MþþNH4, 516.2746. C32H38NO5 requires M,
The alcohol 10 (980 mg, 3.40 mmol) in DMF (2 ml) was added
dropwise to a suspension of sodium hydride (60% in mineral oil;
163 mg, 4.08 mmol) in DMF (4 ml) at 0 ꢁC. The mixture was
stirred for 1 h at 20 ꢁC, then cooled to 0 ꢁC and benzyl bromide
(640 mg, 374 mmol) and tetrabutylammonium iodide (10 mg,
516.2750); nmax (film) 1746, 1232, 1207, 915, 738 and 698 cmꢀ1
; dH
1.29 and 1.65 (each 1H, m, 4-H), 2.00 (2H, m, 3-H2), 2.19 (3H, s,
MeCO), 2.53 and 2.69 (each 1H, m, 8-H), 3.98 (1 h, q, J 7 Hz, 5-H),

A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
263
0.027 mmol) in THF (1 ml) were added. The mixture was stirred
4.21. (2S,6S,10R,14S,3Z,11Z)-15-Methyl-2,10,14-tribenzyloxy-
for 12 h at 20 ꢁC then partitioned between ether (20 ml) and
water (20 ml). The ethereal layer was washed with water (15 ml),
dried (MgSO4), and concentrated under reduced pressure. Chro-
matography of the residue using ether/petroleum (1:9) as the
eluant gave the title compound 17 (1.10 g, 86%) as a pale yellow oil,
hexadeca-3,11-dien-6-ol 20
Following the general procedure, tin(IV) chloride (48 mg, 0.183
mmol) in CH2Cl2 (214 l), stannane 1 (85 mg, 0.183 mmol) in CH2Cl2
(2 ml) and the aldehyde 19 (72 mg, 0.183 mmol) in CH2Cl2 (100 l)
after chromatography using ether/petroleum (1:3) as the eluant
m
m
[
a
]
þ20 (c 1, CHCl3) (found: MþþNH4, 396.2885. C26H38NO2 re-
D
quires M, 396.2902); nmax (film) 2960, 1641, 1454, 1093, 1070,
gave the title compound 20 (79 mg, 76%) as a colourless oil, [
a]
D þ17
1029, 912, 734 and 697 cmꢀ1
;
dH 0.93 (6H, d, J 6.5 Hz, 11-H3, 10-
(c 1, CHCl3) (found: MþþH, 571.3799. C38H51O4 requires M,
Me), 1.52 (1H, m, 10-H), 1.77 and 1.91 (each 1H, m, 4-H), 2.12 (1H,
m, 3-H2), 2.25 (1H, m, 8-H2), 3.20 (1H, dt, J 7, 5 Hz, 9-H), 4.13 (1H,
m, 5-H), 4.31, 4.52, 4.53 and 4.55 (each 1H, d, J 12 Hz, CHHPh),
4.91e5.02 (2H, m, 1-H2), 5.42 (1H, dd, J 11, 9 Hz, 6-H), 5.74 (1H, dt,
J 11, 7 Hz, 7-H), 5.81 (1H, ddt, J 17, 10, 6.5 Hz, 2-H) and 7.31 (10H,
m, ArH); dC 18.3, 18.5, 29.3, 29.8, 31.1, 35.1, 70.1, 72.1, 73.7, 84.3,
114.8, 127.5, 127.6, 127.8, 127.9, 128.4, 128.6, 130.4, 132.4, 138.5,
138.7 and 139.1; m/z (C.I./NH3) 396 (Mþþ18, 41%), 106 (99) and 32
(100).
571.3787); nmax (film) 3461, 2930, 1454, 1070, 735 and 698 cmꢀ1
; dH
(500 MHz) 0.91(6H, d, J 6.5 Hz,16-H3, 15-Me), 1.25 (3H, d, J 6.5 Hz,1-
H3),1.31e1.68 (6H, m, 3ꢂCH2),1.72 (1H, br s, OH),1.90 (1H, m, 15-H),
2.14e2.32 (4H, m, 5-H2, 13-H2), 3.19 (1H, dt, J 7, 5 Hz, 14-H), 3.58
(1H, m, 6-H), 4.11 (1H, dt, J 9, 6.5 Hz, 10-H), 4.28 (1H, m, 2-H), 4.30,
4.38, 4.49, 4.52, 4.53 and 4.54 (each 1H, d, J 12 Hz, CHHPh), 5.41 (1H,
dd, J 11, 9 Hz, 11-H), 5.51e5.61 (2H, m, 3-H, 4-H), 5.73 (1H, dt, J 11, 7
Hz, 12-H) and 7.22e7.34 (15H, m, ArH); dC 18.2, 18.4, 21.3, 21.6, 29.1,
30.9, 35.7, 35.8, 37.0, 69.8, 70.0, 70.3, 71.3, 72.0, 74.0, 84.1, 127.4(2),
127.5, 127.6, 127.7, 127.8, 128.0(2), 128.3, 128.4, 130.2, 132.3, 135.1,
138.8 and 139.0; m/z (FAB) 571 (Mþþ1, 2%) and 91 (100).
4.19. (5R,9S,6Z)-5,9-Dibenzyloxy-10-methylundec-6-en-1-ol 18
4.22. (2S,6S,10R,14S,3Z,11Z)-6-[(S)-2-Methoxy-2-phenyl 3,3,3-
trifluoropropanoyloxy]-15-methyl-2,10,14-tribenzyloxy-
hexadeca-3,11-diene 21
9-Borabicyclononane (0.5 M in THF; 1.06 ml, 0.529 mmol)
was added for 10 min to the diene 17 (200 mg, 0.529 mmol) in
THF (2 ml) at 0 ꢁC. After 2 h at 20 ꢁC, the mixture was cooled to
0
ꢁC and aqueous sodium hydroxide (21 mg, 0.529 mmol) and
Following the general procedure, the alcohol 20 (18 mg) gave
the title compound 21 (24 mg, 96%) as a colourless oil, nmax (film)
aqueous hydrogen peroxide (30%; 60 mg, 0.529 mmol) and
water (1.5 ml) were added dropwise. The mixture was stirred
for 12 h at 20 ꢁC, then partitioned between ether (10 ml) and
water (10 ml). The organic layer was washed with water (10 ml),
dried (MgSO4) and concentrated under reduced pressure.
Chromatography using ether/petroleum (1:10 to 1:1) as eluant,
gave the title compound 18 (77 mg, 64% allowing for 86 mg re-
2957, 1745, 1454, 1271, 1169, 1071, 1027, 735, 717 and 698 cmꢀ1
; dH
0.93 (6H, d, J 6.5 Hz, 16-H3, 15-Me), 1.24 (3H, d, J 6.5 Hz, 1-H3),
1.35e1.65 (6H, m, 3ꢂCH2), 1.90 (1H, m, 15-H), 2.14e2.49 (4H, m, 5-
H2, 13-H2), 3.20 (1H, dt, J 7, 5 Hz, 14-H), 3.52 (3H, s, OMe), 4.06 (1H,
m, 10-H), 4.22 (1H, m, 2-H), 4.28, 4.33, 4.50, 4.52, 4.53 and 4.54
(each 1H, d, J 12 Hz, CHHPh), 5.10 (1H, m, 6-H), 5.37 (1H, dd, J 11, 9
Hz, 11-H), 5.51 (2H, m, 3-H, 12-H), 5.71 (1H, dt, J 11, 7 Hz, 4-H) and
7.23e7.55 (20H, m, ArH); dC 18.1, 18.3, 20.9, 21.3, 29.1, 30.9, 31.9,
33.3, 35.4, 55.4, 69.8, 69.9, 70.1, 72.0, 73.8, 76.7, 84.1, 126.2, 127.3,
127.4,127.5,127.6,127.7,128.3,128.4,129.6,130.3,132.1,132.3,135.4,
138.7, 138.9, 139.0 and 166.3; dF ꢀ72.82 and ꢀ72.84, ratio 10:1; m/z
(C.I./NH3) 805 (Mþþ19, 3%), 231 (40) and 108 (100).
covered starting material) as a colourless oil, [
a
]
þ42.4 (c 1,
D
CHCl3) (found: MþþH, 397.2749. C26H37O3 requires M,
397.2743); nmax (film) 3409, 2933, 1454, 1068, 734 and 697
cmꢀ1
; dH 0.94 (6H, d, J 7 Hz, 11-H3, 10-Me), 1.35e1.72 (7H, m,
3ꢂCH2 and OH), 1.91 (1H, m, 10-H), 2.29 (2H, m, CH2), 3.20 (1H,
m, 9-H), 3.60 (2H, t, J 6.5 Hz, 1-H2), 4.13 (1H, m, 5-H), 4.34, 4.51,
4.56 and 4.57 (each 1H, d, J 12 Hz, CHHPh), 5.44 (1H, t, J 10 Hz,
6-H), 5.75 (1H, dt, J 11, 7 Hz, 7-H) and 7.31 (10H, m, ArH); dC 18.3,
18.4, 21.8, 29.2, 31.0, 32.8, 35.6, 62.8, 70.0, 72.1, 74.2, 84.2, 127.5,
127.6, 127.7, 128.0, 128.4, 130.3, 132.5 and 139.1; m/z (FAB) 397
(Mþþ1, 4%) and 91 (100).
4.23. (2S,6S,10R,14S,3Z,11Z)-6-[(R)-2-Methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-15-methyl-2,1014-tribenzyloxy-
hexadeca-3,11-diene 22
Following the general procedure, the alcohol 20 (21 mg) gave the
title compound 22 (26 mg, 90%) as a colourless oil (found:
MþꢀC7H7O, 679.3608. C41H50F3O5 requires M, 679.3610); nmax
4.20. (5R,9S,6Z)-5,9-Dibenzyloxy-10-methylundec-6-enal 19
DMSO (41 mg, 0.53 mmol) in CH2Cl2 (200
oxalyl chloride (38 mg, 0.26 mmol) in CH2Cl2 (200
After 5 min, alcohol 18 (95 mg, 0.24 mmol) in CH2Cl2 (200 ml) was
m
l) was added to
m
(film) 2957, 1744, 1454, 1260, 1169, 1071, 1027, 735 and 698 cmꢀ1
; dH
l) at ꢀ60 ꢁC.
0.93 (6H, d, J 6.5 Hz, 16-H3, 15-Me), 1.21 (3H, d, J 6.5 Hz, 1-CH3),
1.29e1.66 (6H, m, 3ꢂCH2), 1.90 (1H, m, 15-H), 2.15e2.40 (4H, m, 5-
H2, 13-H2), 3.20 (1H, m, 14-H), 3.52 (3H, s, OMe), 4.09 (1H, m, 10-H),
4.16 (1H, m, 2-H), 4.23, 4.28 and 4.44 (each 1H, d, J 12 Hz, CHHPh),
4.52 (2H, s, CH2Ph), 4.53 (1H, d, J 12 Hz, CHHPh), 5.10 (1H, m, 6-H),
5.40 (3H, m, 3-H, 4-H, 11-H), 5.71 (1H, dt, J 11, 7 Hz, 12-H) and
7.24e7.54 (20H, m, ArH); dC 18.1, 18.3, 21.3, 29.1, 30.9, 31.8, 33.5,
35.5, 55.5, 69.8, 70.0, 72.0, 73.8, 84.1, 126.0, 127.4, 127.6, 127.7, 127.8,
128.3, 128.4, 129.6, 130.4, 132.1, 132.3, 135.2, 138.7, 138.9, 139.0 and
166.3; dF ꢀ72.82 and ꢀ72.88, ratio 1:10; m/z (FAB) 679 (MþꢀC7H7O,
3%), 189 (75) and 91 (100).
added and the mixture stirred for 15 min before triethylamine (121
mg, 1.2 mmol) was added. The mixture was stirred for 5 min at
ꢀ60 ꢁC and allowed to warm to room temperature. Water (2 ml)
was added and the layers separated. The organic layer was washed
with brine (2 ml), dried (MgSO4) and concentrated under reduced
pressure to give the aldehyde 19 (85 mg, 95%) as a pale yellow oil.
Chromatography of a sample using EtOAc/petroleum (1:9) as elu-
ant gave the title compound 19 [
a]
þ48 (c 1, CHCl3); nmax (film)
D
2958, 1724, 1454, 1069, 1028, 735 and 698 cmꢀ1
;
dH 0.92 (6H, d, J
6.5 Hz, 11-H3, 10-Me), 1.41e1.79 (4H, m, 2ꢂCH2), 1.90 (1H, m, 10-H),
2.26 (2H, m, 8-H2), 2.40 (2H, m, 2-H2), 3.20 (1H, dt, J 7, 5 Hz, 9-H),
4.11 (1H, dt, J 9, 5.5 Hz, 5-H), 4.30 (1H, d, J 12 Hz, CHHPh), 4.52 (2H,
s, CH2Ph), 4.55 (1H, d, J 12 Hz, CHHPh), 5.41(1H, dd, J 11, 9 Hz, 6-H),
5.75 (1H, dt, J 11, 7 Hz, 7-H), 7.25e7.35 (10H, m, ArH) and 9.72 (1H,
t, J 2 Hz, 1-H); m/z (C.I./NH3) 412 (Mþþ18, 4%), 163 (95) and
91 (100).
4.24. (2S,10R,14S,3Z,11Z)-15-Methyl-2,10,14-tribenzyloxy-
hexadeca-3,11-dien-6-one 23
DMSO (18 mg, 0.22 mmol) in CH2Cl2 (200
oxalyl chloride (16 mg, 0.12 mol) in CH2Cl2 (200
5 min, the alcohol 20 (58 mg, 0.10 mmol) in CH2Cl2 (200 ml) was
ml) was added to
m
l) at ꢀ60 ꢁC. After

264
A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
added and the mixture stirred for 15 min. N,N-Di-isopropylethyl-
amine (66 mg, 0.51 mmol) was added and the mixture stirred for 5
min at ꢀ60 ꢁC then allowed to warm to room temperature. Water
suspension stirred vigorously for 6 h under an atmosphere of hy-
drogen then filtered through Celite and the filtercake washed with
CH2Cl2 (10 ml). The filtrate was concentrated under reduced pres-
sure and chromatography using ether as eluant gave the title
(800
ml) was added and the layers were separated. The organic layer
was washed with brine (800
m
l), dried (MgSO4) and concentrated
compound 26 (20 mg, 70%) as a white waxy solid, mp 44 ꢁC, [
a]
D
under reduced pressure. Chromatography of the residue using
ꢀ6.4 (c 1, CHCl3) (found: MþþNH4, 290.3040. C17H40NO2 requires
ether/petroleum (1:3) as eluant gave the title compound 23 (43 mg,
M, 290.3059); nmax (film) 3328, 2925, 1467 and 1131 cmꢀ1
; dH 0.90
74%) as a pale yellow oil, [
a
]
þ21 (c 1, CHCl3) (found: MþþH,
(9H, m, 1-H3, 16-H3, 2-Me), 1.25e1.49 (22H, m, 11ꢂCH2), 1.64 (1H, m,
2-H) and 3.35 and 3.58 (each 1H, m, CHOH); dC 14.0, 17.1, 18.9, 22.6,
25.3, 25.6, 26.0, 29.6, 29.7, 31.9, 33.5, 34.2, 37.5, 72.0 and 76.7; m/z
(C.I./NH3) 290 (Mþþ18, 20%), 273 (Mþþ1, 50) and 237 (100).
D
569.3621. C38H49O4 requires M, 569.3631); nmax (film) 2960, 1718,
1454, 1070, 1024, 736 and 698 cmꢀ1
; dH (500 MHz; C6D6) 1.01 (3H,
d, J 6 Hz, 16-H3), 1.03 (3H, d, J 6 Hz, 15-Me), 1.34 (3H, d, J 6 Hz, 1-H3),
1.61 (1H, m, CHH), 1.76e1.86 (3H, m, CHH, CH2), 1.91 (1H, m, 15-H),
2.08 (2H, m, 7-H2), 2.27 and 2.41 (each 1H, m, 13-H), 2.80 (1H, ddd, J
17, 7, 2 Hz, 5-H), 2.84 (1H, ddd, J 17, 7, 1, Hz, 5-H0), 3.17 (1H, dt, J 6, 4
Hz,14-H), 4.17 (1H, m,10-H), 4.29 (1H, m, 2-H), 4.38, 4.44, 4.45, 4.51,
4.61 and 4.74 (each 1H, d, J 12 Hz, CHHPh), 5.61 and 5.81 (each 2H,
m, vinylic H) and 7.17e7.48 (15H, m, ArH); dC (C6D6) 18.1, 18.5, 20.1,
21.5, 29.5, 31.2, 35.6, 41.4, 42.2, 69.9, 70.0, 70.4, 72.1, 74.3, 84.2,124.1,
127.5(2), 127.7(2), 127.9, 128.3, 128.4, 128.5, 130.5, 132.8, 135.3,
139.6, 139.8 and 205.8; m/z (FAB) 591 (Mþþ23, 0.5%), 569 (Mþþ1,
2), 353 (50) and 91 (100).
4.28. (3S,11R)-3,11-Diacetoxy-2-methylhexadecane 27
Acetic anhydride (11 mg, 0.10 mmol), triethylamine (26 mg, 0.26
mmol) and DMAP (3 mg, 0.025 mmol) were added to the alcohol 20
(14 mg, 0.05 mmol) in CH2Cl2 (400 m
l) at 0 ꢁC. The mixture was
stirred for 4 h at 20 ꢁC then poured into water (2 ml) and extracted
with CH2Cl2 (2ꢂ4 ml). The organic extracts were washed with
aqueous hydrogen chloride (1 N, 2ꢂ3 ml), water (4 ml) and brine (4
ml), then dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ether/petroleum (1:3) as el-
uant, gave the title compound 27 (16 mg, 87%) as a colourless oil,
4.25. (2S,6RS,10R,14S,3Z,11Z)-15-Methyl-2,10,14-tribenzyl-
oxyhexadeca-3,11-dien-6-ols 20 and 24
[a
]
D ꢀ4 (c 1, CHCl3) (found: MþþH, 357.3013. C21H41O4 requires M,
357.3005); nmax (film) 2932, 1737, 1373, 1244 and 1021 cmꢀ1
; dH
Sodium borohydride (3 mg, 0.07 mmol) in aqueous ethanol (1
0.92 (9H, m, 1-H3, 16-H3, 2-Me), 1.25e1.58 (22H, m, 11ꢂCH2), 1.84
(1H, m, 2-H), 2.07 and 2.09 (each 3H, s, MeCO), 4.76 (1H, q, J 6 Hz, 3-
H) and 4.89 (1H, pent, J 6 Hz,11-H); dC 14.0,17.6,18.6, 21.1, 21.3, 22.5,
25.0, 25.3, 25.5, 29.4, 29.5(2), 31.1, 31.4, 31.7, 34.0, 34.1, 74.4, 78.5,
170.9 and 171.0; m/z (FAB) 357 (Mþþ1, 17%), 237 (50) and 43 (100).
ml) was added to the ketone 23 (40 mg, 0.07 mmol) in CH2Cl2 (1 ml)
at 0 ꢁC. After 3 h at 20 ꢁC, aqueous citric acid (5%, 500
ml) was added
and the organic layer was separated, dried (MgSO4) and concen-
trated under reduced pressure. Chromatography using ether/pe-
troleum (1:3) as the eluant gave the title compounds 20 and 24 (38
mg, 95%) as a colourless oil, a 1:1 mixture of epimers; nmax (film)
4.29. (5R,9R,13R,17S,6Z,14Z)-18-Methyl-5,13,17-tribenzyl-
oxynonadeca-1,6,14-trien-9-ol 28
3452, 2928, 1454, 1070, 1028, 735 and 697 cmꢀ1
;
dH (500 MHz) 0.90
(6H, d, J 6.5 Hz,16-H3, 15-Me),1.25 and 1.26 (each 1.5H, d, J 6.5 Hz,1-
H3), 1.36e1.70 (7H, m, 3ꢂCH2 and OH), 1.90 (1H, m,15-H), 2.15e2.32
(4H, m, 5-H2, 13-H2), 3.18 (1H, dt, J 7, 5 Hz, 14-H), 3.56 (1H, m, 6-H),
4.11 (1H, m, 10-H), 4.28 (1H, m, 2-H), 4.30 (1H, d, J 12 Hz, CHHPh),
4.35 and 4.37 (each 0.5H, d, J 12 Hz, CHHPh), 4.49 (1H, d, J 12 Hz,
CHHPh), 4.51e4.56 (3H, m, 3ꢂCHHPh), 5.41 (1H, t, J 10 Hz, 11-H),
5.51e5.63 (2H, m, 3-H, 4-H), 5.73 (1H, m, 12-H) and 7.23e7.34 (15H,
m, ArH); dC (additional peaks assigned to epimer 24) 21.5, 21.7, 35.9,
36.9, 69.9, 71.1, 74.1, 132.4, and 135.0; m/z (FAB) 571 (Mþþ1, 4%) and
91 (100).
Following the general procedure, tin(IV) chloride (154 mg, 0.59
mmol) in CH2Cl2 (690
CH2Cl2 (8 ml) and the aldehyde 19 (253 mg, 0.59 mmol) in CH2Cl2
(150 l), after chromatography using ether/petroleum (1:3) as el-
ml), the stannane 8 (299 mg, 0.59 mmol) in
m
uant, gave the title compound 28 (261 mg, 72%) as a colourless oil,
[a
]
þ26 (c 1, CHCl3) (found: MþþH, 611.4104. C41H55O4 requires
D
M, 611.4100); nmax (film) 3456, 2932, 1641, 1497, 1455, 1206, 1070,
1029, 912, 736 and 698 cmꢀ1
; dH (500 MHz) 0.91 (6H, d, J 7 Hz, 19-
H3, 18-Me), 1.36e1.80 (9H, m, 4ꢂCH2 and OH), 1.89 (1H, m, 18-H),
2.09e2.32 (6H, m, 3-H2, 8-H2, 16-H2), 3.18 (1H, dt, J 7, 5 Hz, 17-H),
3.59 (1H, m, 9-H), 4.11 (2H, m, 5-H, 13-H), 4.29, 4.34, 4.49, 4.51,
4.53 and 4.54 (each 1H, d, J 12 Hz, CHHPh), 4.91e5.00 (2H, m, 1-
H2), 5.40 and 5.49 (each 1H, dd, J 11, 9 Hz, 6-H or 14-H), 5.64 and
5.72 (each 1H, dt, J 11, 7 Hz, 7-H or 15-H), 5.78 (1H, ddt, J 17, 10, 6.5
Hz, 2-H) and 7.22e7.32 (15H, m, ArH); dC 18.2, 18.3, 21.7, 29.1, 29.6,
30.9, 34.8, 35.7, 36.0, 37.0, 69.9, 70.1, 71.3, 72.0, 73.7, 74.1, 84.1,
114.7, 127.3, 127.4, 127.5, 127.6, 127.8, 128.2, 128.3, 129.1, 130.2,
132.4, 133.8, 138.4, 138.8, 138.9 and 139.0; m/z (FAB) 611 (Mþþ1,
2%) and 91 (100).
4.26. (2S,6R,10R,14S)-15-Methylhexadeca-2,6,1014-tetrol 25
Palladium on charcoal (10%; 15 mg, 0.014 mmol Pd) was added
to the alcohol 20 (15 mg, 0.026 mmol) in methanol (1 ml) and the
suspension stirred vigorously for 6 h under an atmosphere of hy-
drogen then filtered through Celite, which was washed with CH2Cl2
(8 ml). The filtrate was concentrated under reduced pressure and
chromatography of the residue using methanol/EtOAc (1:20) as
eluant gave the title compound 25 (7 mg, 88%) as a white waxy solid,
mp 85e87 ꢁC, [
a]
ꢀ8.4 (c 1, CHCl3) (found: MþþH, 305.2703.
D
C17H37O4 requires M, 305.2692); nmax (film) 3331, 2927, 1462 and
4.30. (5R,9R,13R,17S,6Z,14Z)-9-[(S)-2-Methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-18-methyl-5,13,17-tribenzyloxy-
nonadeca-1,6,14-triene 29
1034 cmꢀ1
; dH (500 MHz) 0.885 and 0.892 (each 3H, d, J 6.5 Hz, 16-
H3 or 15-Me), 1.17 (3H, d, J 6.5, 1-H3), 1.36e1.52 (18H, m, 9ꢂCH2),
1.63 (1H, m, 15-H), 1.75 (4H, br s, 4ꢂOH), 3.34 (1H, m, CHOH), 3.61
(2H, m, 2ꢂCHOH) and 3.79 (1H, m, CHOH); dC 17.2, 18.8, 21.6, 21.8,
22.1, 23.6, 33.7, 33.8, 37.2, 37.3, 37.4, 39.1, 67.9, 71.6 and 77.2; m/z
(FAB) 327 (Mþþ23, 2%) and 305 (Mþþ1, 100).
Following the general procedure, the alcohol 28 (16 mg) gave the
title compound 29 (20 mg, 93%) as a colourless oil; nmax (film) 2930,
1744, 1497, 1454, 1260, 1169, 1070, 995, 915, 735 and 698 cmꢀ1
; dH
(500 MHz) 0.89 and 0.90 (each 3H, d, J 6.5 Hz, 19-H3 or 18-Me),
1.35e1.65 (7H, m, 3ꢂCH2, CHH), 1.72 (1H, m, CHH), 1.88 (1H, m, 18-
H), 2.00e2.36 (6H, m, 3-H2, 8-H2, 16-H2), 3.16 (1H, dt, J 7, 5 Hz, 17-H),
3.50 (3H, s, OMe), 3.99 and 4.05 (each 1H, m, 5-H or 13-H), 4.16, 4.27,
4.42, 4.48, 4.50 and 4.51 (each 1H, d, J 12 Hz, CHHPh), 4.91 (1H, d, J
4.27. (3S,11R)-2-Methylhexadeca-3,11-diol 26
Palladium on charcoal (5%; 30 mg, 0.014 mmol Pd) was added to
the alcohol 20 (60 mg, 0.105 mmol) in methanol (2 ml) and the

A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
265
10.5 Hz, 1-H), 4.96 (1H, dd, J 17, 1.5 Hz, 1-H0), 5.07 (1H, m, 9-H), 5.37
(3H, m, vinylic H), 5.70 (1H, dt, J 11, 7 Hz, vinylic H), 5.75 (1H, ddt, J
17, 10.5, 7 Hz, 2-H) and 7.20e7.51 (20H, m, ArH); dC 18.1, 18.3, 21.3,
29.1, 29.5, 29.7, 30.9, 32.0, 33.6, 34.7, 35.5, 55.5, 69.8, 69.9, 72.0, 73.4,
73.7, 73.8, 76.7, 84.0, 114.8, 127.1, 127.4, 127.5, 127.6, 127.7, 128.2,
128.3, 128.4, 129.6, 130.4, 132.1, 132.3, 133.9, 138.3, 138.7, 138.8, 138.9
and 166.3; dF ꢀ72.79, ꢀ72.82 and ꢀ72.84, ratio 93:5:2; m/z (FAB)
839 (Mþþ23, 1%) and 189 (100).
petroleum (1:3) as eluant gave the title compounds 28 and 33 (34 mg,
92%) as a colourless oil, a 1:1 mixture of epimers; nmax (film) 3450,
2932, 1641, 1454, 1093, 1069, 1029, 912, 735 and 698 cmꢀ1
; dH (500
MHz) 0.91 (6H, d, J 7 Hz,19-H3,18-Me),1.36e1.80 (9H, m, 4ꢂCH2, OH),
1.89 (1H, m,18-H), 2.06e2.32 (6H, m, 3-H2, 8-H2,16-H2), 3.18 (1H, dt, J
7, 5 Hz, 17-H), 3.59 (1H, m, 9-H), 4.11 (2H, m, 5-H, 13-H), 4.29, 4.34,
4.49, 4.51 and 4.53 (each 1H, d, J 12 Hz, CHHPh), 4.54 and 4.55 (each
0.5H, d, J 12 Hz, CHHPh), 4.91e5.01 (2H, m, 1-H2), 5.40 (1H, dd, J 11, 9
Hz, vinylic H), 5.49, 5.64 and 5.72 (each 1H, m, vinylic H), 5.78 (1H, m,
2-H) and 7.22e7.32 (15H, m, ArH); dC (additional peaks assigned to
epimer 33) 21.6, 34.9, 36.9, 69.8, 70.0, 71.2, 73.6, 74.0, 129.2, 130.3,
132.3, 133.7 and 138.5; m/z (FAB) 623 (Mþþ23, 2%), 611 (Mþþ1, 9),
395 (90), 287 (85) and 91 (100).
4.31. (5R,9R,13R,17S,6Z,14Z)-9-[(R)-2-Methoxy-2-phenyl-3,3,3-
trifluoropropanoyloxy]-18-methyl-5,13,17-tribenzyloxy-
nonadeca-1,6,14-triene 30
Following the general procedure, the alcohol 28 (16 mg) gave
the title compound 30 (22 mg, 86%) as a colourless oil; nmax (film)
4.34. (5R,9R,13R,17S,6Z,14Z)-18-Methyl-5,9,13,17-tetra-
benzyloxynonadeca-1,6,14-triene 31
2928, 1745, 1453, 1271, 1169, 1070, 1027, 916, 735 and 697 cmꢀ1
;
dH
(500 MHz) 0.89 and 0.90 (each 3H, d, J 6.5 Hz, 19-H3 or 18-Me),
1.28 (2H, m, CH2), 1.44e1.62 (5H, m, 2ꢂCH2, CHHe), 1.74 (1H, m,
CHH), 1.87 (1H, m, 18-H), 2.04e2.90 (6H, m, 3-H2, 8-H2, 16-H2), 3.16
(1H, dt, J 7, 5 Hz, 17-H), 3.50 (3H, s, OMe), 3.99 and 4.04 (each 1H,
m, 5-H or 13-H), 4.25 (2H, d, J 12 Hz, 2ꢂCHHPh), 4.49 (4H, m,
CH2Ph and 2ꢂCHHPh), 4.91 (1H, d, J 10 Hz, 1-H), 4.96 (1H, dd, J 17,
1.5 Hz, 1-H0), 5.08 (1H, m, 9-H), 5.34 and 5.46 (each 1H, dd, J 11, 9
Hz, 6-H or 14-H), 5.52 and 5.68 (each 1H, dt, J 11, 7 Hz, 7-H or 15-
H), 5.75 (1H, ddt, J 17, 10, 6.5 Hz, 2-H) and 7.20e7.50 (20H, m,
ArH); dC 18.1, 18.3, 21.0, 29.1, 29.5, 30.9, 32.1, 33.5, 34.7, 35.5, 55.5,
69.8, 70.0, 72.0, 73.4, 73.8, 76.7, 84.1, 114.8, 127.3, 127.4, 127.5, 127.6,
127.7, 128.3, 128.4, 129.6, 130.3, 132.1, 132.4, 138.3, 138.7, 138.9,
139.0 and 166.3; dF ꢀ72.81, ꢀ72.84 and ꢀ72.90, ratio 4:92:4;m/z
(FAB) 839 (Mþþ23, 1%) and 189 (100).
The alcohol 28 (115 mg, 0.186 mmol) in DMF (1 ml) was added to
sodium hydride (60% in mineral oil; 9 mg, 0.22 mmol), in DMF (1.5
ml) at 0 ꢁC. The mixture was stirred for 1 h at 20 ꢁC, cooled to 0 ꢁC
and benzyl bromide (35 mg, 0.21 mmol) and tetrabutylammonium
iodide (5 mg, 0.014 mmol) in THF (400 ml) were added. The mixture
was stirred for 12 h at 20 ꢁC, then partitioned between ether (10 ml)
and water (10 ml). The ethereal layer was washed with water (10
ml), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ether/petroleum (1:9) as el-
uant gave the title compound 31 (56 mg, 68% allowing for 43 mg
recovered starting material) as a pale yellow oil, [
a]
þ23 (c 1,
D
CHCl3); nmax (film) 2933, 1454, 1093, 1069, 1029, 735 and 697 cmꢀ1
;
dH (500 MHz) 0.93 (6H, d, J 6.5 Hz, 19-H3, 18-Me), 1.41e1.58 (6H, m,
3ꢂCH2), 1.64e1.81 (2H, m, CH2), 1.91 (1H, m, 18-H), 2.07e2.39 (6H,
m, 3-H2, 8-H2, 16-H2), 3.20 (1H, dt, J 7, 5 Hz, 17-H), 3.41 (1H, m, 9-H),
4.12 (2H, m, 5-H, 13-H), 4.31, 4.32 and 4.47 (each 1H, d, J 12 Hz,
CHHPh), 4.50e4.57 (5H, m, 5ꢂCHHPh), 4.95 (1H, dd, J 10, 1.5 Hz, 1-
H), 5.00 (1H, dd, J 17, 1.5 Hz, 1-H0), 5.43 and 5.72 (each 2H, m, vinylic
H), 5.80 (1H, ddt, J 17, 10, 6.5 Hz, 2-H) and 7.23e7.35 (20H, m, ArH);
dC 18.2, 18.4, 21.5, 29.2, 29.7, 31.0, 32.4, 34.2, 34.9, 35.9, 69.9, 70.0,
71.2, 72.0, 73.8, 74.2, 78.7, 84.1, 114.7, 127.3, 127.4, 127.5, 127.6, 127.7,
127.8, 128.3, 128.4, 129.4, 130.2, 132.4, 132.5, 132.7, 138.5, 138.6,
139.0 and 139.1; m/z (FAB) 701 (Mþþ1, 2.5%) and 163 (100).
4.32. (5R,13R,17S,6Z,14Z)-18-methyl-5,13,17-tribenzyloxy-
nonadeca-1,6,14-trien-9-one 32
DMSO (13 mg, 0.15 mmol) in CH2Cl2 (200
oxalyl chloride (11 mg, 0.089 mmol) in CH2Cl2 (200
After 5 min, the alcohol 28 (45 mg, 0.074 mmol) in CH2Cl2 (200 ml)
ml) was added to
m
l) at ꢀ60 ꢁC.
was added and the mixture was stirred for 15 min. N,N-Di-iso-
propylethylamine (48 mg, 0.37 mmol) was added and the mixture
stirred for 5 min at ꢀ60 ꢁC then allowed to warm to room tem-
perature. Water (800
with brine (800
ml) was added and the organic layer washed
l), dried (MgSO4) and concentrated under re-
m
4.35. (5R,9R,13R,17S,6Z,14Z)-18-Methyl-5,9,13,17-tetra-
duced pressure. Chromatography of the residue using ether/pe-
benzyloxynonadeca-6,14-dien-1-ol 34
troleum (1:3) as the eluant gave the title compound 32 (38 mg,
85%) as a pale yellow oil, [
a
]
þ33 (c 1, CHCl3); nmax (film) 2931,
9-Borabicyclononane (0.5 M in THF; 680 ml, 0.34 mmol) was
D
1718, 1641, 1454, 1093, 1069, 912, 736 and 698 cmꢀ1
;
dH (C6D6)
added for 10 min to the triene 31 (237 mg, 0.34 mmol) in THF (1
ml) at 0 ꢁC. After 2 h at 20 ꢁC, the mixture was cooled to 0 ꢁC and
aqueous sodium hydroxide (14 mg, 0.34 mmol) and aqueous hy-
0.98 and 1.00 (each 3H, d, J 6 Hz, 19-H3 or 18-Me), 1.55e1.95 (7H,
m, 18-H, 3ꢂCH2), 2.05e2.45 (6H, m, 3-H2, 10-H2, 16-H2), 2.86 (2H,
m, 8-H2), 3.15 (1H, dt, J 7, 5 Hz, 17-H), 4.07 (1H, m, CHOBn), 4.28
(1H, dt, J 9, 6 Hz, CHOBn), 4.35, 4.42, 4.43, 4.50, 4.62 and 4.71 (each
1H, d, J 12 Hz, CHHPh), 5.04 (1H, d, J 11 Hz, 1-H), 5.10 (1H, dd, J 17,
1.5 Hz, 1-H0), 5.55 (2H, m, 2ꢂvinylic H), 5.82 (3H, m, 2ꢂvinylic H,
2-H) and 7.12e7.45 (15H, m, ArH); dC (C6D6) 18.1, 18.5, 20.1, 29.4,
29.9, 31.2, 35.2, 35.6, 41.6, 42.3, 69.9, 70.0, 72.1, 73.7, 74.3, 84.2,
114.9, 125.2, 127.5, 127.6, 127.9, 128.4, 130.5, 132.8, 133.9, 138.7,
139.5, 139.6, 139.7 and 205.9; m/z (FAB) 631 (Mþþ23, 0.5%), 287
(35) and 91 (90).
drogen peroxide (30%; 12 mg, 0.34 mmol) in water (800 ml) was
added dropwise. The mixture was stirred for 12 h at 20 ꢁC and
partitioned between ether (10 ml) and water (10 ml). The organic
layer was washed with water (10 ml), dried (MgSO4) and con-
centrated under reduced pressure. Chromatography of the residue
using ether/petroleum (1:10 to 1:1) as eluant gave the title com-
pound 34 (59 mg, 40% allowing for 91 mg recovered starting
material) as a colourless oil, [
a
]
þ12 (c 1, CHCl3) (found: MþþH,
D
719.4658. C48H63O5 requires M, 719.4676); nmax (film) 3451, 3030,
2933, 1454, 1093, 1069, 1028, 735 and 697 cmꢀ1
; dH (500 MHz)
4.33. (5R,9RS,13R,17S,6Z,14Z)-18-Methyl-5,13,17-tribenzyl-
oxynonadeca-1,6,14-trien-9-ols 28 and 33
0.85 (6H, d, J 6.5 Hz, 19-H3, 18-Me), 1.30e1.64 (12H, m, 6ꢂCH2),
1.83 (1H, m, 18-H), 2.10e2.30 (4H, m, 8-H2, 16-H2), 3.12 (1H, dt, J 7,
5 Hz, 17-H), 3.34 (1H, m, 9-H), 3.50 (2H, t, J 6.5 Hz, 1-H2), 4.04 (2H,
m, 5-H, 13-H), 4.23, 4.24 and 4.39 (each 1H, d, J 12 Hz, CHHPh),
4.42e4.49 (5H, m, 5ꢂCHHPh), 5.35 (2H, m, 6-H, 14-H), 5.62 and
5.66 (each 1H, dt, J 11, 7 Hz, 7-H or 15-H) and 7.16e7.27 (20H, m,
ArH); dC 18.1, 18.4, 21.5, 21.7, 29.2, 31.0, 32.4, 32.7, 34.2, 35.5, 35.9,
62.8, 69.9, 70.0, 71.2, 72.0, 74.2, 74.3, 78.8, 84.1, 127.3, 127.4, 127.5,
Sodium borohydride (2 mg, 0.06 mmol) in aqueous ethanol (1 ml)
was added to the ketone 32 (37 mg, 0.06 mmol) in CH2Cl2 (1 ml) at
0 ꢁC. After 3 h at 20 ꢁC, aqueous citric acid (5%, 500
ml) was added and
the organic layer was separated, dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using ether/

266
A.H. McNeill, E.J. Thomas / Tetrahedron 67 (2011) 257e266
127.6, 127.7, 127.8, 128.2, 128.3, 129.3, 130.2, 132.4, 132.8, 138.8 and
(40 ml), after chromatography using ether/petroleum (1:3) as elu-
139.0; m/z (FAB) 719 (Mþþ1, 3%), 503 (20) and 91 (100).
ant, gave the title compound 36 (25 mg, 67%) as a colourless oil, [a]
D
þ22 (c 1, CHCl3) (found: Mþ, 892.5693. C60H76O6, requires M,
892.5720); nmax (film) 3464, 2931, 1454, 1093, 1070, 1028, 735 and
4.36. (5R,9R,13R,17S,6Z,14Z)-18-Methyl-5,9,13,17-tetra-
benzyloxynonadeca-6,14-dienal 35
697 cmꢀ1
; dH (500 MHz) 0.89 (6H, d, J 7 Hz, 24-H3, 23-Me), 1.24 (3H,
d, J 6.5 Hz, 1-H3), 1.32e1.70 (13H, m, 6ꢂCH2, OH), 1.87 (1H, m, 23-H),
2.13 (2H, m, CH2), 2.14e2.35 (4H, m, 2ꢂCH2), 3.17 (1H, dt, J 7, 5 Hz,
22-H), 3.39 (1H, m, 6-H), 3.55 (1H, m, 14-H), 4.09 (2H, m,
2ꢂCHOBn), 4.26 (1H, m, CHOBn), 4.28, 4.29, 4.36, 4.44, 4.47, 4.49,
4.50, 4.51, 4.52 and 4.53 (each 1H, d, J 12 Hz, CHHPh), 5.40 (2H, m,
vinylic H), 5.53 (2H, m, vinylic H), 5.66 and 5.70 (each 1H, dt, J 11, 7
Hz, vinylic H) and 7.20e7.32 (25H, m, ArH); dC 18.1, 18.4, 21.3, 21.5,
21.6, 29.2, 31.0, 32.4, 34.2, 35.6, 35.8, 35.9, 37.0, 69.9, 70.3, 71.2, 72.0,
74.2, 78.7, 84.1, 127.4, 127.6, 127.7, 127.8, 128.1, 128.2, 128.3, 129.3,
130.2, 132.4, 132.8, 135.1, 138.8 and 139.0; m/z (FAB) 893 (Mþþ1,
0.2%) and 91 (100).
DMSO (15 mg, 0.19 mmol) in CH2Cl2 (200
chloride (13 mg, 0.10 mmol) in CH2Cl2 (200
min, the alcohol 34 (61 mg, 0.085 mmol) in CH2Cl2 (200 ml) was
ml) was added to oxalyl
m
l) at ꢀ60 ꢁC. After 5
added and the mixture was stirred for 15 min. Triethylamine (43
mg, 0.425 mmol) was added and the mixture was stirred for 5 min
at ꢀ60 ꢁC then allowed to warm to room temperature. Water (2 ml)
was added and the layers were separated. The organic layer was
washed with brine (2 ml), dried (MgSO4) and concentrated under
reduced pressure to give aldehyde 35 (35 mg, 72%) as a pale yellow
oil. Chromatography of a sample using EtOAc/petroleum (1:9) as
the eluant gave the title compound 35 as a colourless oil, [a]D þ26 (c
1, CHCl3) (found: MþþH, 717.4556. C48H61O5 requires M, 717.4519);
Acknowledgements
nmax (film) 2932, 1724, 1454, 1093, 1069, 1028, 735 and 697 cmꢀ1
; dH
1.00 and 1.02 (each 3H, d, J 6.5 Hz, 19-H3 or 18-Me), 1.55e1.76 (10H,
m, 5ꢂCH2), 1.92 (3H, m,18-H, 2-H2), 2.28 and 2.42 (each 2H, m, 8-H2
or 16-H2), 3.17 (1H, dt, J 7, 5 Hz, 17-H), 3.41 (1H, m, 9-H), 4.20 and
4.34 (each 1H, m, 5-H or 13-H), 4.40, 4.43, 4.47, 4.48, 4.50, 4.52, 4.71
and 4.77 (each 1H, d, J 12 Hz, CHHPh), 5.55 and 5.64 (each 1H, dd, J
11, 9 Hz, 6-H or 14-H), 5.76 and 5.81 (each 1H, dt, J 11, 7 Hz, 7-H or
15-H), 7.16e7.50 (20H, m, ArH) and 9.38 (1H, t, J 1 Hz, 1-H); m/z
(FAB) 717 (Mþþ1, 2%), 181 (65) and 91 (100).
We thank the EPSRC for a studentship (to A.H.McN).
References and notes
1. MacNeill, A. H.; Thomas, E. J. Synthesis 1994, 322.
2. Thomas, E. J. J. Chem. Soc., Chem. Commun. 1997, 411.
3. McNeill, A. H.; Thomas, E. J. Tetrahedron Lett. 1992, 33, 1369.
4. For a preliminary communication of part of this work see: McNeill, A. H.;
Thomas, E. J. Tetrahedron Lett. 1993, 34, 1669.
5. Wu, Z.; Mootoo, D. R.; Fraser-Reid, B. Tetrahedron Lett. 1988, 29, 6549.
6. . 5-H, 6-H, 7-H, 8-H2 and CH2Ph were more shielded for the (R)-acetyl mandelates
14 and 16 than for the (S)-epimers 13 and 15. 11eH3 and 10-CH3 were more
shielded for the (S)-acetyl mandelate 15 than for the (R)-epimer 16; see Ref. 7.
7. Trost, B. M.;Belletire, J.L.; Godleski, S.; McDougal, P. G.; Balkovec, J.M.; Baldwin,J. L.;
Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem.1986, 51, 2370.
8. Dorling, E. K.; Thomas, E. J. Tetrahedron Lett. 1999, 40, 471.
9. Casteno, P.; Thomas, E. J.; Weston, A. Tetrahedron Lett. 2007, 48, 337.
10. Thomas, E. J. Chem. Rec. 2007, 7, 115.
4.37. (2S,6S,10R,14R,18R,22S,3Z,11Z,19Z)-23-Methyl-
2,10,14,18,22-pentabenzyloxytetracosa-3,11,19-trien-6-ol 36
Following the general procedure, tin(IV) chloride (11 mg, 0.042
mmol) in CH2Cl2 (490
ml), the stannane 1 (20 mg, 0.042 mmol) in
CH2Cl2 (2 ml) and the aldehyde 35 (30 mg, 0.042 mmol) in CH2Cl2