Indium-mediated allylation of carbonyl compounds with an allylic bromide in aqueous media: Anomalous syn-diastereoselectivity regardless of allylic bromide geometry

Article abstract of DOI:10.1016/S0040-4039(02)02773-9

Anomalous syn-diastereoselectivity of indium-mediated coupling of aldehydes with bromides Z-3b and E-3b is reported. The reaction afforded high syn selectivity regardless of the allylic bromide geometry. Preliminary studies on the enantioselective indium-mediated allylation were attempted and found to give the desired products in moderate yield with high syn selectivity and enantioselectivity.

Full text of DOI:10.1016/S0040-4039(02)02773-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 911–914
Indium-mediated allylation of carbonyl compounds with an allylic
bromide in aqueous media: anomalous syn-diastereoselectivity
regardless of allylic bromide geometry
Teck-Peng Loh,a,* Zheng Yin,† Hong-Yan Song and Kee-Leng Tan
aDepartment of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Received 26 September 2002; revised 27 November 2002; accepted 6 December 2002
Abstract—Anomalous syn-diastereoselectivity of indium-mediated coupling of aldehydes with bromides Z-3b and E-3b is
reported. The reaction afforded high syn selectivity regardless of the allylic bromide geometry. Preliminary studies on the
enantioselective indium-mediated allylation were attempted and found to give the desired products in moderate yield with high syn
selectivity and enantioselectivity. © 2003 Elsevier Science Ltd. All rights reserved.
Indium-promoted allylation of carbonyl compounds
has proved to be one of the most useful methods for the
preparation of synthetically useful homoallylic alco-
hols.1 Furthermore, the possibility of carrying out this
reaction in aqueous media has made this reaction a
potentially useful tool for the construction of complex
molecules. Our group has been interested in applying
this reaction to sophisticated chemical synthesis. How-
ever, during this work, we were frequently frustrated by
the limitation of existing methods and the lack of
stereochemical studies, although recent contributions
from Chan, Li, Whitesides,2 Paquette, our group and
others have expanded further the scope of this reac-
tion.3 In this paper, we report anomalous syn-
diastereoselectivity of the indium-mediated allylation
reaction regardless of the allylic bromide geometry and
its application to the total synthesis of antillatoxin 1.4
As part of our studies towards the total synthesis of
antillatoxin 1, we are interested in the synthesis of a key
intermediate, the advanced homoallylic alcohol 2, hav-
ing the anti-configuration at C4 and C5 via an indium-
mediated allylation strategy (Scheme 1). Since a cyclic
or Zimmerman–Traxler5 transition state model has been
Scheme 1. Retrosynthetic analysis.
* Corresponding author. Tel.: 65-68747851; fax: 65-67791691; e-mail: chmlohtp@nus.edu.sg
† Current address: S*Bio Pte Ltd, 1 Science Park Road, c05-09 The Capricorn, Singapore Science Park II, Singapore 117528
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02773-9

912
T.-P. Loh et al. / Tetrahedron Letters 44 (2003) 911–914
Table 1. Indium-mediated allylation reactions using the
allylic bromides Z-3b and E-3b with various aldehydesa
proposed to explain characteristic diastereoselectivity,
we envisaged that the E-allylic bromide 3b would
afford the anti-product while the Z-allylic bromide 3b
should give the syn-product.
Synthesis of the prequisite E- and Z- allylic bromides
3b is shown in Scheme 2. Synthesis of Z-3a was accom-
plished by DIBAL-H reduction of methyl (Z)-2-(bro-
momethyl)-2-butenate 5, which was prepared according
to a literature procedure.6 Treatment of Z-3a with
TBDPS-Cl in the presence of imidazole afforded the
desired allylic bromide Z-3b in 92% yield. The allylic
bromide E-3b was also synthesized starting from 5.
Exposure of 5 to excess sodium acetate in refluxing
methanol followed by the addition of one equivalent of
K2CO3 to affect acetate cleavage produced the
butenoate 6 in 82% yield.7 Protection of the hydroxy
group of 6 with TBDPS followed by DIBAL-H reduc-
tion gave the butenol 7. Bromination of the butenol 7
with NBS in the presence of PPh3 provided the desired
allylic bromide E-3b in 90% yield.
Before embarking on the reaction with the complex
aldehyde 48 for the antillatoxin synthesis, we carried
out model studies using these bromides (E-3b and
Z-3b) with various carbonyl compounds. The results
are shown in Table 1. In all cases, the reactions were
carried out in THF-H2O (1:1) with indium in the
presence of an external Lewis acid and afforded the
corresponding homoallylic alcohols in moderate yields.
Contrary to our expectation, the syn products were
obtained as the major products regardless of the allylic
bromide geometry. Especially noteworthy is the fact
that in the absence of lanthanide triflate, no allylation
was observed. Of mechanistic interest is that the excess
of the bromides could be recovered without isomeriza-
tion of the double bond.
Based on the fact that this reaction does not work in
the absence of La(OTf)3, and the configurations of the
recovered allylic bromides remain the same, we propose
that an open-chain anti-periplanar transition state may
be playing a role (Fig. 1). Allylic indium generated
Figure 1. Proposed mechanism.
using allylic bromide and indium powder in aqueous
media has been shown to exist as an indium(I) species.
This has been reported by Chan and co-workers.9
Using the optimized conditions, we proceeded to inves-
tigate the indium-promoted allylation of bromides Z-3b
and E-3b with the aldehyde 4 (Scheme 3). As before,
the desired products were obtained in good yields with
the syn product as the major product, irrespective of
which allylic bromide was employed and the pure syn
isomer was easily obtained by flash column
chromatography.
Scheme 2. Reagents and conditions: (i) DIBAL-H, CH2Cl2,
0°C, 1 h; (ii) TBDPS-Cl, imidazole, DMF, rt., 10 h; (iii)
NaOAc, MeOH, reflux, 3.5 h; K2CO3; (iv) NBS, PPh3,
CH2Cl2, −78°C, 0.5 h. DIBAL-H=diisobutylaluminum
hydride; TBDPSCl=tert-butyl diphenyl silyl chloride; NBS=
N-bromosuccinimide.
Preliminary studies on the enantioselective indium-
mediated allylation using a method established in our
group were attempted (Scheme 4).10 11 No reaction was

T.-P. Loh et al. / Tetrahedron Letters 44 (2003) 911–914
913
Acknowledgements
This research was supported by grants from the
National University of Singapore.
References
1. For the pioneering work on the indium-mediated allyla-
tion reaction of carbonyl compounds: (a) Li, C. J. Chem.
Rev. 1993, 93, 2023; (b) Chan, T. H.; Li, C. J.; Lee, M.
C.; Wei, Z. Y. Can. J. Chem. 1994, 72, 1181; (c) Cintas,
P. Synlett. 1995, 1087; (d) Chan, T. H.; Lee, M. C. J.
Org. Chem. 1995, 60, 4228; (e) Chan, T. H.; Yang, Y. J.
Am. Chem. Soc. 1999, 121, 3228; (f) Araki, S.; Ito, H. J.
Org. Chem. 1988, 53, 1831; (g) Paquette, L. A.; Lobben,
P. C. J. Am. Chem. Soc. 1996, 118, 1917; (h) Paquette, L.
A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931; (i)
Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1997, 62,
2318; (j) Paquette, L. A.; Mitzel, T. M. J. Org. Chem.
1997, 62, 4293; (k) Isaac, M. B.; Paquette, L. A. J. Org.
Chem. 1997, 62, 5333; (l) Hirashita, T.; Kamei, T. J. Org.
Chem. 1999, 64, 172; (m) Paquette, L. A.; Rothhaar, R.
R. J. Org. Chem. 1999, 64, 217.
Scheme 3.
2. (a) Gordon, D. M.; Whitesides, G. M. J. Org. Chem.
1993, 58, 7937; (b) Choi, S. K.; Lee, S.; Whiteside, G. M.
J. Org. Chem. 1996, 61, 8739.
3. Lanthanide triflate has been shown to increase the rate
and selectivity of the indium-mediated allylation reaction
of carbonyl compounds: (a) Wang, R. B.; Lim, B. K.,
Sim K. Y.; Loh, T. P. Tetrahedron: Asymmetry 1995, 6,
1825; (b) Ho, D. S.-C.; Sim, K. Y.; Loh, T. P. Synlett.
1996, 3, 263; (c) Loh, T. P.; Wang, R. B.; Tan, K. L.;
Sim, K. Y. Main Group Metal Chemistry, 1997, 20, 237;
(d) Loh, T. P.; Cao, G. Q.; Pei, J. Tetrahedron Lett. 1998,
39, 1453.
4. (a) Orjala, J.; Nagle, G. D.; Hsu, L. V.; Gervick, W. H.
J. Am. Chem. Soc. 1995, 117, 8281–8282; (b) Yokokawa,
F.; Shioiri, T. J. Org. Chem. 1998, 63, 8638; (c)
Yokokawa, F.; Fujiwara, H.; Shioiri, T. Tetrahedron
Lett. 1999, 40, 1915; (d) White, J. D.; Hanselmann, R.;
Wardrop, D. J. Am. Chem. Soc. 1999, 121, 1106; (e)
Yokokawa, F.; Fujiwara, H.; Shioiri, T. Tetrahedron
2000, 56, 1759.
5. (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc.
1957, 79, 1920; (b) Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic: New York,
1983; Vol. 3.
Scheme 4.
observed with Z-3b. However, the reaction proceeded
with Z-3a to afford the product in moderate yield with
high syn selectivity (syn:anti=99:1) and enantioselectiv-
ity (85% ee).
In conclusion, anomalous syn diastereoselectivity in the
Lewis-acid promoted indium-mediated coupling of
aldehydes with allylic bromides Z-3b and E-3b was
observed. The reaction proceeded smoothly with a vari-
ety of aldehydes and afforded high syn selectivity
regardless of the allylic bromide geometry. The experi-
mental protocol is simple without the need of strictly
anhydrous conditions. In addition, preliminary studies
on the enantioselective indium-mediated allylation were
attempted providing the product in moderate yield with
high syn selectivity and enantioselectivity. Furthermore,
this has provided a novel and efficient method under
very mild conditions to a key intermediate for the total
synthesis of antillatoxin.
6. Brown, J. M.; Evans, P. L. Organic Syntheses 1990, 68,
64.
7. Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58,
2151.
8. Loh, T. P.; Cao, G. Q.; Pei, J. Tetrahedron Lett. 1998, 39,
1457–1460.
9. Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121,
3228–3229.
10. Loh, T. P.; Zhou, J. R.; Yin, Z. Org. Lett. 1999, 1,
1855–1857.
11. Typical experimental procedure: To a 50 mL round-bot-
tom flask containing an egg-shaped stirring bar were
added (−)-cinchonidine (0.5 mmol) and indium powder
(0.5 mmol, 57 mg). The solids were azeotropically dried

914
T.-P. Loh et al. / Tetrahedron Letters 44 (2003) 911–914
twice with 3 mL of dry THF and then treated with 3 mL
of dry THF and allylic bromide (1.5 mmol). The mixture
was stirred vigorously until it turned into a clear solution,
to which was added dropwise 1 mL of dry hexane. The
resulting clear solution was cooled to −78°C, followed by
introduction of the aldehyde (0.25 mmol) dropwise. The
reaction mixture was stirred at −78°C for 2 h, then
allowed to warm to room temperature, and finally
quenched with 10 mL of dilute HCl solution. The
aqueous layer was extracted with hexane (10 mL×3). The
combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, concentrated under vacuum,
and purified by flash column chromatography to afford
the homoallylic alcohol.