Studies towards total synthesis of antillatoxin: Indium-mediated allylation reaction of carbonyl compounds with secondary allylic bromide in aqueos media

Article abstract of DOI:10.1055/s-2002-35606

We have established a new reaction condition for the indium-mediated allylation of an unreactive secondary allylic bromide with aldehydes in aqueous media to afford the corresponding homoallylic alcohols in high yields and syn diastereoselectivity. Furthe

Full text of DOI:10.1055/s-2002-35606

LETTER
2119
Studies Towards Total Synthesis of Antillatoxin: Indium-mediated Allylation
Reaction of Carbonyl Compounds with Secondary Allylic Bromide in Aqueous
Media
Studies
Toward
e
s
T
otal
S
yn
c
thesis of
A
k
ntillatoxin -Peng Loh,* Hong-Yan Song
National University of Singapore, Department of Chemistry, 3 Science Drive 3, Singapore 117543, Singapore
Fax +6567791691; E-mail: chmlohtp@nus.edu.sg
Received 30 August 2002
that the homoallylic alcohol 2 can be obtained from the
metal-mediated allylation of aldehyde 3 with secondary
allylic bromide 4 in water (Scheme 1).
Abstract: We have established a new reaction condition for the
indium-mediated allylation of an unreactive secondary allylic
bromide with aldehydes in aqueous media to afford the correspond-
ing homoallylic alcohols in high yields and syn diastereoselectivity.
Furthermore, it has provided an easy entry to the key intermediate
for the total synthesis of antillatoxin under mild and environment
profitable conditions.
Allylic bromide 4 was synthesized in seven steps from the
known methyl 2-(hydroxyethyl)prop-2-enoate 55 as out-
lined in Scheme 2. Protection of the hydroxyl group with
TBDPS, followed by reduction of the ester group afforded
alcohol 7 in 75% yield. Subsequently, alcohol 7 was bro-
minated with NBS and PPh3 to afford the allylic bromide
8 in 95% yield. Synthesis of 9 was accomplished by using
an indium-mediated one-carbon elongation with formal-
dehyde in water (90%). Selective silyl protection of the al-
cohol 10, followed by bromination of the secondary
alcohol 11 furnished the distinct allylic bromide 4 in 80%
isolated yield.
Key words: antillatoxin, homoallylic alcohols, indium, allylation
reaction, aqueous media
Indium-mediated allylation has gained widespread popu-
larity because of the possibility of carrying out the reac-
tion in water.1,2 In our group, we have been interested in
applying this reaction to sophisticated chemical synthe-
sis.3 However, in this course, we were frequently frustrat-
ed by the limitations of existing methods, especially when
more complex allylic bromides and carbonyl compounds
were used in the allylation. In this paper, we developed
new conditions for the indium-mediated allylation of a
secondary allylic bromide and applied it to the total syn-
thesis of antillatoxin (1).4
The advanced homoallylic alcohol 2 could be potentially
obtained from the indium-mediated allylation of aldehyde
3 with allylic bromide 4. Although indium has been suc-
cessfully applied for organic reactions in water, no suc-
cessful indium-mediated coupling of allylic bromide 4
with aldehydes in aqueous media has been reported so far.
Therefore, the reactivities and selectivities of the indium-
mediated allylation of this allylic bromide 4 with different
aldehydes were carried out to test the scope and limita-
tions of the reaction (Table 1). This secondary allylic
As part of our studies towards the total synthesis of antil-
latoxin (1), we are interested in the synthesis of the ad-
vanced intermediate, homoallylic alcohol 2. We envisage
CH3
N
O
CH3 CH3 CH3
CH3
CH3
N
O
CH3 CH3 CH3
CH3
O
5
4
H3C
N
H3C
N
COOH
HO 5
4
CH3
H
CH3
H
+
O
O
H
H
CH3
H3C
RO
N
H3C
N
CH3
R'
O
O
H3C
CH3
1 antillatoxin
CH3 CH3 CH3
CH3
CH3
HO 5
4
CH3 CH3 CH3
CH3
CH3
OTBDPS
O
+
TBDPSO
CH3
Br
H
4
2
3
Scheme 1 Retrosynthetic analysis of antillatoxin.
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2119,2121,ftx,en;U07502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2120
T.-P. Loh, H.-Y. Song
LETTER
Table 1 The Allylation of Bromide 4 with Various Aldehydesa
b)
H3C
X
H3C
H3C
OMe
d)
OH
OH
75%
2 steps
O
4, In, La(OTf)3
OTBDPS 90%
OTBDPS
OR
O
R
OTBDPS
R
H
5 R=H
6 R=TBDPS
7 X=OH
8 X=Br
95%
THF-H2O, rt, 12 h
a)
c)
CH3
9
13
12
Entry
Aldehyde
Yield (%)b
Selectivity
(syn:anti)c
H3C
c)
e) H3C
X
OTBDPS
1
2
3
4
73
78
75
67
77:23
80%
2 steps
CHO
Br
100%
OH
10 X=OH
11 X=OTBDPS
f)
4
70:30
62:38
65:35
CHO
Scheme 2 Synthesis of bromide 4. Reagents and conditions: a) TB-
DPSCl, imidazol, DMF, r.t., 10 h; b) DIBALH, CH2Cl2, 0 ºC, 0.5 h;
c) NBS, PPh3, CH2Cl2, –78 ºC, 0.5 h; d) HCHO, In, THF–H2O, r.t., 12
h; e) TBAF, THF, r.t., 0.5 h; f) TBDPSCl, imidazole, DMF–CH2Cl2,
r.t. 2 h. TBDPSCl = tert-butyl diphenyl silyl chloride; NBS = N-bro-
mosuccinimide; DIBALH = diisobutylaluminum hydride; TBAF =
tetrabutyl ammonium fluoride.
CHO
CHO
N
5
CH3(CH2)7CHO
54
72:28
bromide 4 was unreactive when classical indium-mediat-
ed allylation reaction conditions were employed. Fortu-
nately, this reaction proceeded smoothly in the presence
of La(OTf)3 to afford the products in good yields with
high syn selectivities.6 It is important to note that no reac-
tion was observed in the absence of La(OTf)3. In contrast
to reactions with primary allylic bromides, the indium-
mediated allylation of this secondary bromide afforded
only the -adduct. Although the real reason is unknown,
a All reactions were done on 1 mmol scale; reactions were carried out
with aldehyde (1 equiv), Indium (2 equiv), allylic bromide 4 (1 equiv)
and La(OTf)3 (1 equiv) in THF–H2O (1:1) (20 mL) at r.t. for 12 h.;
b Based on separated product by flash column chromatography.
c Determined by 1H NMR and 13C NMR.
we believe that this is most probably due to the 1,3 allylic With the success of the reactions with various aldehydes,
shift of the corresponding allylic indium species to afford we embarked on the synthesis of the advanced homoallyl-
predominantly the primary allylic indium species and ic alcohol 2 which was required for the total synthesis of
therefore the overall -selectivity (Scheme 3).
antillatoxin. Therefore, the indium-mediated allylation of
allylic bromide 4 with aldehyde 37 was carried out using
the optimized reaction conditions (Scheme 4). To our de-
light, the desired homoallylic alcohol 2 was obtained in
75% yield albeit with moderate selectivity. The two dia-
stereomers can be easily separated by flash column chro-
matography.
In
H3C
OTBDPS
H3C
OTBDPS
In
Scheme 3
In, La(OTf)3,
THF-H2O, rt., 12 h
CH3 CH3 CH3
CH3
CH3
Br
O
H
+
OTBDPS
75%
CH3
4
3
CH3 CH3 CH3
CH3
CH3 CH3 CH3
CH3
CH3
HO
5
HO
5
CH3
+
TBDPSO
TBDPSO
CH3
4
CH3
4
2b
2a
2a:2b = 72:28
Scheme 4 Synthesis of homoallylic alcohol 2.
Synlett 2002, No. 12, 2119–2121 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Studies Towards Total Synthesis of Antillatoxin
2121
CH3 CH3 CH3
CH3 CH3 CH3
CH3
CH3 CH3 CH3
CH3
CH3
CH3
TBDPSO
HO
TBDPSO
HO
a), b)
c), d)
*
*
*
*
*
CH3
CH3
HO
72%
2 Steps
76%
MeOOC
*
CH3
CH3
CH3
2 Steps
syn (±)-14
(±)-15
(±)-16
a)
90%
CH3 CH3 CH3
CH3 CH3 CH3
CH3
CH3
CH3
TBDPSO
HO
*
*
5
a)
CH3
TBDPSO
TBDPSO
85%
CH3
CH3
4
(±)-17
major isomer of 2
Scheme 5 Reagents and conditions: a) TBDPSCl, imidazol, DMF, r.t., 16 h; b) DIBALH, CH2Cl2, 0 ºC, 0.5 h; c) NBS, PPh3, CH2Cl2,
–78 ºC, 0.5 h; d) HCHO, In, THF–H2O, r.t., 12 h.
The syn relative stereoselectivity of homoallylic alcohol 2
was confirmed by comparing its derivative with that from
the known syn ( )-14, as described in Scheme 5. In our
previous work, we have synthesized the syn configuration
product ( )-14,7 possessing two stereogenic centers in the
target molecule. Protecting the alcohol group of ( )-14
with silyl group followed by reduction of ester group gave
the primary alcohol ( )-15. Bromination of ( )-15 fol-
lowed by one carbon elongation and silylation of the alco-
hol ( )-16 with TBDPS provided compound ( )-17. On
the other hand, silylation of the major isomer of 2 also
provided compound ( )-17. Comparing the spectroscopic
data and TLC confirmed that the major isomer of homo-
allylic alcohol 2 was of syn configuration.
References
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In summary, we have established a new reaction condition
for the indium-mediated allylation of an unreactive sec-
ondary allylic bromide with aldehydes in aqueous media.
This reaction proceeded smoothly with a wide variety of
aldehydes, which afforded the corresponding homoallylic
alcohols in high yields. In all these cases, moderate syn se-
lectivity was observed. Furthermore, it has provided an
easy entry to the advanced intermediate for the total syn-
thesis of antillatoxin.
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Acknowledgment
This research was supported by the grants from the National Uni-
versity of Singapore.
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Synlett 2002, No. 12, 2119–2121 ISSN 0936-5214 © Thieme Stuttgart · New York