1,5-Stereocontrol in reactions of 5-benzyloxy-4-methylpent-2-enyl bromides with aldehydes mediated by Bi(0): Synthesis of aliphatic compounds with 1,5-syn-related methyl groups

Article abstract of DOI:10.1016/j.tetlet.2004.07.035

Treatment of the 5-benzyloxy-4-methylpent-2-enyl bromide 6 with the low valent bismuth species formed by reduction of bismuth(III) iodide with zinc powder generates an intermediate, which reacts with aldehydes with useful levels of 1,5-stereocontrol in favour of the 1,5-anti-(E)-isomers 4. These products were used to prepared aliphatic compounds with 1,5-syn-related methyl groups.

Full text of DOI:10.1016/j.tetlet.2004.07.035

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6779–6782
1,5-Stereocontrol in reactions of
5-benzyloxy-4-methylpent-2-enyl bromides with aldehydes
mediated by Bi(0):synthesis of aliphatic compounds with
1,5-syn-related methyl groups
b
Sam Donnelly,a Eric J. Thomasa, and Mark Fielding
*
aDepartment of Chemistry, The University of Manchester, Manchester M13 9PL, UK
bAstraZeneca, Hurdsfield Industrial Estate, Macclesfield, Cheshire SK10 2NA, UK
Received 2 July 2004; accepted 8 July 2004
Available online 29 July 2004
Abstract—Treatment of the 5-benzyloxy-4-methylpent-2-enyl bromide 6 with the low valent bismuth species formed by reduction of
bismuth(III) iodide with zinc powder generates an intermediate, which reacts with aldehydes with useful levels of 1,5-stereocontrol in
favour of the 1,5-anti-(E)-isomers 4. These products were used to prepared aliphatic compounds with 1,5-syn-related methyl groups.
Ó 2004 Elsevier Ltd. All rights reserved.
Allylstannanes with heteroatom substituents at the 4-, 5-
and 6-positions are transmetallated by tin(IV) halides to
give intermediates, which react with aldehydes with
effective 1,5-, 1,6- and 1,7-stereocontrol.1 For example,
the 5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane
1 reacts with tin(IV) chloride to give the allyltin trichlor-
ide 2, which gives the 1,5-anti-(Z)-products 3 on reaction
with aldehydes. Recently, it has been found that comple-
mentary results are obtained if the transmetallation is
carried out using bismuth(III) iodide. Thus addition of
the stannane 1 to a suspension of bismuth(III) iodide
and an aldehyde in a mixed solvent of acetonitrile and
dichloromethane gave the 1,5-anti-(E)-isomers 4 perhaps
via the allylbismuth diiodide 5.2
It would be of interest if these reactions could be carried
out by a procedure, which did not use allylstannanes as
starting materials.3 We now report that pent-2-enyl bro-
mides analogous to the stannane 1 react with the low
valent bismuth species generated by treatment of
bismuth(III) iodide with zinc powder to give intermedi-
ates, which give the 1,5-anti-(E)-products on reaction
with aldehydes. These products were used to prepare ali-
phatic compounds with 1,5-syn-related methyl groups.
Cl3Sn
OBn
SnCl4
Bu3Sn
OBn
-78 oC
Me
r.t.
Me
1
2
BiI3
-78 oC
RCHO
OH
RCHO
OH
Me
It has been reported that reduction of bismuth(III)
halides with powdered zinc, iron or aluminium generates
bismuth(0), which promotes the reaction of allylic bro-
mides and iodides with aldehydes to give homoallylic
OBn
R
OBn
R
Me
4
3
I2Bi
OBn
1,5-anti : 1,5-syn
1,5-anti : 1,5-syn
alcohols.4 Following the published procedure,
a
= 93 : 7
= 96 : 4
suspension of powdered zinc and a solution of bis-
muth(III) iodide in tetrahydrofuran was stirred at room
temperature for 1h. Benzaldehyde and the (4R)-5-benz-
yloxy-4-methylpent-2-enyl bromide 65,6 were then added
and the mixture heated under reflux for a further 2h.
After cooling, filtration and chromatography on silica
Me
5
*
Corresponding author. Tel.: +44-0161-2754609; fax: +44-0161-
2754622; e-mail: tetlet@man.ac.uk
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.035

6780
S. Donnelly et al. / Tetrahedron Letters 45 (2004) 6779–6782
gel gave a good yield of the 1,5-anti-(E)-alcohol 4a
inseparable from its 1,5-syn-(E)-diastereoisomer 7a,
ratio 96:4(83%). A small amount, ca. 5%, of the less
polar 1,5-anti-(Z)-diastereoisomer 3a was also obtained
(Scheme 1).
the similarity, in particular the regioselectivity, of the
products from the bismuth(III) iodide promoted reac-
tions of the allylstannane 1 and the bismuth(0) induced
reactions of the pentenyl bromide 6, suggests that anal-
ogous intermediates are involved. The allyl bismuth
intermediates must therefore be undergoing 1,3-migra-
tion prior to reaction with the aldehyde.
Structures were assigned to the products 3a, 4a and 7a by
comparison with authentic samples.2 The absolute con-
figuration of the hydroxyl group in the major 1,5-anti-
The direct, oxidative insertion of bismuth(0) into the C–
Br bond of the pentenyl bromide should not give an
intermediate allylbismuth dihalide directly, but dispro-
portionation reactions are possible. Therefore, it may
be that an allylbismuth dihalide, for example, 8 (X = I,
Br), reminiscent of that proposed for the bismuth(III)
iodide promoted reaction of the allylstannane 1,2 is in-
volved, and reacts with the aldehyde via a six-membered
cyclic transition state, for example, 9, in which the group
next to the bismuth has adopted the equatorial position
so leading to the formation of the (E)-double-bond. This
contrasts with the reactions of the allyltin trichlorides,
for example, 2, formed by transmetallation of allyl-
stannanes by tin(IV) halides. In these cases, (Z)-dou-
ble-bond formation is preferred.1
1
(E)-isomer 4a was confirmed by comparison of the H
NMR spectra of its (R)- and (S)-O-acetyl mandelates.7
Analogous bismuth(0) mediated reactions of the pentenyl
bromide 6 with a range of aldehydes were investigated. In
all cases useful stereoselectivity in favour of the 1,5-anti-
(E)-stereoisomers 4 was obtained, see Table 1.8
Mechanistic details of these reactions are not clear. Both
the zinc powder and the bismuth(III) iodide are required
since if either were omitted, no reaction took place. Of
interest is the use of very different reaction conditions
for the bismuth mediated reactions from those used
for the tin(IV) halide promoted reactions of the allyl-
stannanes. In the latter reactions, which are carried
out at À78°C, it is necessary to effect transmetallation
of the allylstannane before addition of the aldehyde to
avoid the formation of regioisomers via Lewis acid cat-
alysed reactions of the aldehyde with the allylstannane.1
However, in the reactions involving transmetallation of
the allylstannane 1 with bismuth(III) iodide, or in the
bismuth(0) induced reactions of the pentenyl bromide
6, the allylic reagent and the aldehyde were added simul-
taneously to the bismuth reagent. Prior formation of the
reactive allyl metal species is not required. Moreover,
X
X2Bi
OBn
O
Me
H
:
R
Bi
7
BnO
H
Me
X
H
8
9
Notwithstanding the mechanistic dichotomy, the use of
the pentenyl bromide 6 rather than the allylstannane 1 in
OH
Me
OBn
OBn
Ph
Ph
Bi(0)[ex. BiI3, Zn(0)]
4a
PhCHO
Br
OBn
Me
+
OH
Me
83%
4a : 7a = 96 : 4
6
(+ ca. 5% 3a)
7a
Scheme 1. Bismuth(0) mediated reaction between bromide 6 and benzaldehyde.
Table 1. Bi(0) mediated reactions between aldehydes and the pent-2-enyl bromide 6
OH
Me
OH
Me
Bi(O), 6
OBn
OBn
+
RCHO
Ph
R
7
1,5-syn (E)
4 1,5-anti (E)
Aldehyde (R)
Major producta
Yield (%)b
1,5-anti:1,5-syn
Ph
n-Pr
4a
4b
4c
4d
4e
4f
83
92
82
86
66
63
96:4
93:7
95:5
93:7
95:5
95:5
i-Pr
MeCH@CH
TBSOCH2
TBSOCH2CH2
a In addition to the mixture of anti- and syn-(E)-products 4 and 7, approximately 5% of less polar (Z)-products were also isolated.
b Yield corresponds to the mixture of 4 + 7.

S. Donnelly et al. / Tetrahedron Letters 45 (2004) 6779–6782
6781
these stereoselective reactions with aldehydes is of inter-
est since separation problems associated with the
removal of the organotin side-products are avoided.
verted into the syn-2,6-dimethylheptane 13 using a Bar-
ton procedure. For comparison a mixture of 13 and its
2,6-anti-diastereoisomer was also prepared by this route
using the racemic 2-methyl-3-tert-butyldimethylsilyloxy-
propanal. Comparison by GLC of the syn-2,6-dimethyl-
heptane 13 with the sample prepared from the aldehyde
16 confirmed the assigned syn-stereochemistry. Compari-
son with the mixture of diastereoisomers prepared
using the racemic aldehyde confirmed that the 1,5-
syn:1,5-anti ratio in the sample of the dimethylheptane
13 prepared from the alcohol 4e was ca. 94:6. This also
confirmed the 1,5-anti-configuration assigned to the
alcohol 4e.
To show an application of this chemistry in synthesis,
compounds with 1,5-syn-methyl bearing stereogenic cen-
tres were identified as interesting targets. Such fragments
are found in a range of natural products including terp-
enoids and lipids, for example, 10, found in the mem-
branes of Archaea bacteria.9 Since methylcuprates are
known to react with alkyl toluene p-sulfonates with
inversion of configuration,10 the 1,5-anti-(E)-products
from the pentenyl bromide––aldehyde reactions would
appear to be suitable precursors for syn-1,5-dimethyl
compounds.
Finally, the syn-2,6-dimethylheptane 13 was incorpo-
rated into a synthesis of the all syn-2,6,10,14-tetrameth-
yl-15-tert-butyldimethylsilyloxypentadecan-1-ol 25 an
advanced precursor for a synthesis of the membrane
lipid 10, see Scheme 4.
Me
Me
Me
Me
Me
Me
Me
Me
OH
O
O
Selective deprotection of the syn-2,6-dimethylheptane-
1,7-diol derivative 13 gave the alcohols 19 and 21, which
were converted into the corresponding iodides 20 and 22.
Alkylation of dithiane, first with the iodide 20 and then
with 22, gave the bis-alkylated dithiane 24, which on
treatment with Raney nickel gave the monoprotected
all syn-2,6,10,14-tetramethylpentadecane-1,15-diol deri-
vative 25. The structure of 25 was consistent with its
spectroscopic data with the configuration being assigned
on the basis of its synthesis from the syn-dimethylheptane
10
To avoid competing rearrangements of the homoallylic
toluene p-sulfonate, the 1,5-anti-(E)-product 4e was
reduced using diimide to give the saturated alcohol 11,
which was converted into its toluene p-sulfonate 12.
Reaction of this with a higher order cuprate prepared
from methyllithium and copper(I) cyanide10 in toluene
as solvent gave the required syn-2,6-dimethylheptane-
1,7-diol derivative 13 in a 73% yield, Scheme 2, together
with a small amount of an elimination product, which
was conveniently removed by oxidation of the mixture
of crude products using osmium tetraoxide.
Me
OR
i
4e
BnO
OTBS
11 R = H
12 R = Ts
ii
To check the syn-stereochemistry assigned to the di-
methylheptane 13, an authentic sample was made
by an established route, see Scheme 3.11 The ketophos-
phonate 15 was prepared from methyl (2S)-3-ben-
zyloxy-2-methylpropanoate 14 and condensed with
(2R)-2-methyl-3-tert-butyldimethylsilyloxypropanal 16
to give the enone 17. This was reduced using an excess
of sodium borohydride to give the saturated alcohol
18 as a mixture of diastereoisomers, which was con-
iii
Me
Me
BnO
OTBS
13
Scheme 2. Reagents and conditions: (i) TsNHNH2, NaOAc (92%); (ii)
TsCl, DMAP (90%); (iii) 2equiv MeLi, CuCN, toluene, 0°C, 5h, then
OsO4 (cat.), NMO (73%).
Me
Me
i
BnO
BnO
CO2Me
P(OMe)2
O
O
O
14
15
17
ii
Me
iv
Me
Me
Me
BnO
OTBS
iii
BnO
OTBS
X
18 X = OH
13 X = H
Scheme 3. Reagents and conditions: (i) BuLi, MeP(O)(OMe)2 (88%); (ii) Ba(OH)2, (2R)-TBSOCH2CHMeÆCHO 16 (84%); (iii) NaBH4 (70%); (iv) a.
PhOC(S)Cl (82%), b. Bu3SnH, AIBN (90%).

6782
S. Donnelly et al. / Tetrahedron Letters 45 (2004) 6779–6782
References and notes
Me
Me
i
13
X
ii
OTBS
1. Thomas, E. J. J. Chem. Soc., Chem. Commun. 1997, 411.
2. Donnelly, S.; Thomas, E. J.; Arnott, E. A. Chem.
Commun. 2003, 1460.
iii
19 X = OH
20 X = I
Me
Me
3. Recently a procedure for 1,6-stereocontrol in indium
mediated reactions of 5-hydroxypropargyllic bromides
and aldehydes was disclosed, see: Miao, W.; Lu, W.;
Chan, T. H. J. Am. Chem. Soc. 2003, 125, 2412.
4. Wada, M.; Ohki, H.; Akiba, K.-Y. Bull. Chem. Soc. Jpn.
1990, 63, 1738.
iv
BnO
ii
X
S
Me
Me
21 X = OH
22 X = I
OTBS
S
5. The bromide 6 was prepared from the corresponding
alcohol (Ref. 6) using CBr4, Ph3P.
23
6. Carey, J. S.; Thomas, E. J. Synlett 1992, 585.
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.
v
Me
Me
Me
Me
Me
Me
S
S
BnO
HO
OTBS
OTBS
8. Representative procedure for the bismuth(0) mediated
reaction between bromide 6 and an aldehyde: activated zinc
powder (31mg, 0.476mmol) was suspended in a solution
of bismuth(III) iodide (248mg, 0.42mmol) in tetra-
hydrofuran (1.5cm3) and the mixture stirred at room
temperature for 1h during which time the grey suspension
turned black. A solution of the pentenyl bromide 6 (75mg,
0.28mmol) in tetrahydrofuran (0.5cm3) and benzaldehyde
(29lL, 0.28mmol) were added and the resulting mixture
heated under reflux for 2h. After cooling and concentra-
tion under reduced pressure, the residue was subjected
to flash chromatography on silica being eluted with
light petroleum–ether (4:1) to give a mixture of the
alcohols 4a and 7a (69mg, 83%) as a colourless oil (found:
[M = NH4]+, 314.2118. C20H28NO2 requires M, 314.2120);
24
25
vi
Me
Me
Scheme 4. Reagents and conditions: (i) H2, Pd/C (98%); (ii) I2, PPh3,
imid (20, 96%:22, 94%); (iii) TBAF (98%); (iv) n-BuLi, dithiane (86%);
(v) n-BuLi, 22 (78%); (vi) Raney Ni (94%).
13. Since 13 contains about 5% of its anti-diastereoiso-
mer, 25 must contain about 10% of minor diastereoiso-
mers, but these could not be separated and were not
detected by NMR.
t
max/cmÀ1 3424, 3029, 2857, 1494, 1453, 1361, 1201, 1091,
92 and 737; dH (CDCl3, 300MHz): 1,5-anti-(E)-isomer 4a
1.14(3H, d, J 7, 5-CH3), 2.55 (3H, m, 2-H2 and 5-H), 3.34
(2H, m, 6-H2), 4.55 (2H, s, PhCH2O), 4.70 (1H, dd, J 8
and 5, 1-H), 5.54(2H, m, 3-H and 4-H) and 7.36 (10H, m,
ArH); for the 1,5-syn-(E)-isomer 7a 1.15 (3H, d, J 7, 5-
CH3); dC 17.1, 32.3, 38.5, 73.0, 73.2, 74.6, 125.6, 127.1,
127.6, 127.8, 128.2, 128.5, 136.7 and 144.7;
m/z (CI) 314([M+NH 4]+, 22%), 296 (M+, 50), 279 (74),
261 (24) and 173 (38).
This work has reported a ꢀtin-freeꢁ procedure for
1,5-stereocontrol in reactions between an allylmetal
derivative and aldehydes, together with a stereoselective
synthesis of open-chain compounds with syn-related 1,5-
dimethyl substituents.
9. (a) Montenegro, E.; Gabler, B.; Paradies, G.; Seemann,
M.; Helmchem, G. Angew. Chem., Int. Ed. 2003, 42, 2419;
(b) Eguchi, T.; Ibaragi, K.; Kakinuma, K. J. Org. Chem.
1998, 63, 2689.
Acknowledgements
10. Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.
Tetrahedron 1984, 40, 5005.
11. Mulzer, J.; Berger, M. Tetrahedron Lett. 1998, 39, 803.
We thank AstraZeneca for a studentship (to S.D.) and
Somhairle MacCormick for preparing the enone 17.