A novel one-step method for the reductive allylation of esters and the first total synthesis of (±)-erythrococcamide B

Article abstract of DOI:10.1016/j.tetlet.2010.10.159

A novel and convenient one-step method for the reductive allylation of aliphatic and alicyclic esters using InBr₃ as a catalyst is reported. This methodology has also been applied in the first total synthesis of (±)-erythrococcamide B.

Full text of DOI:10.1016/j.tetlet.2010.10.159

Tetrahedron Letters 51 (2010) 6942–6944
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel one-step method for the reductive allylation of esters and the first
total synthesis of ( )-erythrococcamide B
⇑
Roman Lagoutte, James A. Wilkinson
Centre for Drug Design, Biochemistry and Cancer Research, Cockcroft Building, University of Salford, Salford M5 4WT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and convenient one-step method for the reductive allylation of aliphatic and alicyclic esters using
InBr3 as a catalyst is reported. This methodology has also been applied in the first total synthesis of ( )-
erythrococcamide B.
Received 20 August 2010
Revised 18 October 2010
Accepted 29 October 2010
Available online 4 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Reductive allylation
Indium(III) bromide
Erythrococcamide B
Indium(III) halides have recently been the subject of numerous
studies leading to the development of novel methods. While the
applications of dihaloindium hydrides have been reviewed,1 newer
methods have emerged, such as the preparation of alkynyl and al-
lyl ketones from acyl chlorides,2 propargyl alcohols and amines
from aldehydes and N,O- or N,S-acetals,3 synthesis of indoles and
quinolines from 2-ethynylanilines,4 cross-coupling of alcohols5 or
trimethylsilyl ethers6 with allylsilanes, hydroarylation of arenes
with styrenes,7 reductive amination of carbonyl compounds8 and
one-step reduction of esters to ethers9 and amides to amines.10
We were interested in the synthesis of 6-oxygenated 2-allyl
chromans as precursors to novel heparin mimics.11,12 While reac-
tion of lactone 1 (Scheme 1) with allyl magnesium bromide gave
only a mixture of starting material and a bis-allylated tertiary alco-
hol, reduction of 1 to lactol 2 using DIBAL-H, followed by allyl Grig-
nard addition to form the secondary alcohol 3 and Mitsunobu
cyclisation was successful. We wished to investigate shorter routes
to this type of structure. In the one-step reduction of esters to
ethers9 with InBr3/Et3SiH it was felt that the reduction may pro-
ceed via an oxonium intermediate and that this could be inter-
cepted by allyltrimethylsilane. Herein we report
a one-step
method for the reductive allylation of a range of esters.
Initially, reduction of 3,4-dihydrocoumarin (5) to the unsubsti-
tuted chroman 7 was attempted using Sakai’s conditions (Table 1,
entries 1–3). Reduction only occurred successfully when the reac-
tion mixture containing triethylsilane and 5 in toluene was heated
to 70 °C, before addition of InBr3 (0.1 equiv). Toluene was found to
be superior to chloroform for the overall yield of the transforma-
tion and was preferred since it has a higher boiling point and addi-
tion of the catalyst led to a quite exothermic reaction.
Having established conditions for the reduction, reductive ally-
lation was attempted using an excess of allyltrimethylsilane. We
Et SiH, AllTMS, InBr (10%),
3
3
O
O
O
PhMe, 70 °C, 2 h
TBSO
TBSO
4
1
DIBAL-H, PhMe,
DIAD, Ph3P
THF, rt, 12 h, 89%
-78
°C, 6 h, 78%
OH
O
OH
AllMgBr (2 equiv),
Et2O, 0
°C, 12 h, 92%
TBSO
TBSO
2
3
OH
Scheme 1.
⇑
Corresponding author. Tel.: +44 161 295 4046; fax: +44 161 295 5111.
E-mail address: J.A.Wilkinson@salford.ac.uk (J.A. Wilkinson).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.159

R. Lagoutte, J. A. Wilkinson / Tetrahedron Letters 51 (2010) 6942–6944
6943
Table 1
Optimisation of the conditions for the reductive allylation
O
O
OTES
O
O
O
OTES
Conditions
5
6
8
9
7
OTMS
Entry
Additives (equiv)
Triethylsilane
Solvent
Ratioa
Yieldb(%)
InBr3
AllTMS
5
6
7
8
9
1
2
3
0.05
0.1
0.1
4
4
4
—
—
—
CHCl3
CHCl3
PhMe
1
—
—
4
1
—
2
2.3
1
—
—
—
—
—
—
nd
63
93
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
1.5
1.1
1.1
1.1
1.1
2.5
2.5
2.5
2
PhMe
CHCl3
PhMe
PhMe
PhMe
—
—
—
—
—
4
1
14
2
1
1
4.3
—
1
—
—
—
nd
—
—
—
2.8
—
—
—
1
66
79
83c
nd
1
9
10
11
—
0.1
0.1
1
—
1
2
2
—
PhMe
PhMe
PhMe
1
1
6.8
—
—
4
—
—
1
—
—
—
—
—
nd
nd
nd
a
b
c
Ratios determined by 1H NMR spectroscopy of the crude mixture.
Isolated yields, nd = not determined.
Reaction on a 50 mmol scale.
were pleased to observe the presence of the desired product 8
along with silylated lactol 6 and chroman 7 (entry 4). When the
amount of triethylsilane introduced was decreased from 1.5 to
1.1 equiv (entries 5 and 6), the reductive allylation product was ob-
tained exclusively. Toluene appeared again to be superior to chlo-
roform (entries 5 and 6). A slight decrease in the excess of
allyltrimethylsilane to 2 equiv did not decrease the yield (entry
7), however, with only 1 equiv, the proportion of hydroallylated
product decreased dramatically (entry 8).
For mechanistic considerations, the reaction was conducted
with either InBr3, triethylsilane or allyltrimethylsilane left out of
the mixture. While no reaction occurred in the absence of InBr3
or triethylsilane (entries 9 and 10), reduction products were
observed when no allyltrimethylsilane was added (entry 11). In
addition, hexaethyldisiloxane could be isolated quantitatively from
all reactions.
We, therefore, suggest that the reaction proceeds via (i) hydro-
indation of the ester by dibromoindium hydride (Scheme 2),
followed by (ii) replacement of the dibromoindyl by a triethylsilyl
group with regeneration of indium bromide. A complex of triethyl-
silyl bromide and indium bromide then allows (iii) elimination of
the triethylsiloxyl from A to form the oxonium species B, which
is then (iv) allylated by allyltrimethylsilane. In lower-yielding reac-
tions (e.g., entry 5), the bis O-silylated by-product 9 was obtained.
Presumably this arises from opening of the ring by elimination of
phenoxide from intermediate A, with subsequent allylation of the
aldehyde.
The reductive allylation methodology13 was then extended to a
representative range of esters (Table 2). Aliphatic and alicyclic es-
ters (entries 1, 3–5) reacted smoothly to form the desired homoal-
lylic ethers. Valeric acid (entry 2) showed no reaction at all even
after 24 h. Derivatives of dihydrocoumarin also reacted well: the
presence of a phenol (entry 8) seemed to slow down the reaction;
this was attributed to the low solubility of the substrate. The tert-
butylsilyl and methylenedioxy groups (entries 7 and 9) were stable
under the reaction conditions. Introduction of InBr3 when the mix-
ture was already at 70 °C was found necessary to avoid cleavage of
Lewis acid sensitive functionalities. For example, when InBr3 was
added before heating for the reductive allylation of methylenedi-
oxychromanone 14b, cleavage of the methylenedioxy group was
observed. When coumarin (entry 10) was subjected to the condi-
tions, conjugate reduction1 was observed exclusively, presumably
through a silyl ketene acetal, cleaved upon work-up, to form com-
pound 5, quantitatively. Reduction of aromatic esters with InBr3/
Et3SiH is known to be slow and low-yielding and reductive allyla-
tion of aromatic (entries 11–13) and heteroaromatic esters (entries
14 and 15) gave poor results. Apart from methyl anisate (entry 12)
which was hydroallylated in a rather low yield, other aromatic and
heteroaromatic esters were inert to the conditions. Despite re-
ports10 suggesting that reduction of amides is possible using
InBr3/Et3SiH, an attempt to apply the methodology to amide 21
(entry 16) was unsuccessful.
Et3SiH
InBr3
Et3SiBr
O
O
O
HInBr2
+ TMSBr
TMS
We then applied the new methodology in total synthesis. The
isobutyl amides (+)-22 and (+)-23, respectively, erythrococcamides
A and B (Fig. 1), have been extracted from Dinosperma erythrococca
and exhibited insecticidal activity.14 The absolute configuration of
the stereocentres is not known.
(iv)
(i)
O
InBr4
H
O
OInBr2
B
The synthesis (Scheme 3) started with sesamol (24), which was
converted into the methylenedioxychromanone 14b in 67% yield
using methyl acrylate in TFA. Reductive allylation proceeded
smoothly in a very good yield, followed by oxidative cleavage of
the olefin using Lemieux–Von Rudloff’s reagent15 in a 77% yield.
DCC/HOBt coupling with isobutylamine gave racemic 23 in 84%
yield, 35% overall for four steps. The properties of our material
were identical in all respects to those reported for the natural
(iii)
Et3Si-Br InBr3
OSiEt3
(Et3Si)2O
(ii)
Et3SiBr
O
A
InBr3
Scheme 2. Proposed mechanism for the reductive allylation of esters.

6944
R. Lagoutte, J. A. Wilkinson / Tetrahedron Letters 51 (2010) 6942–6944
Table 2
Reductive allylation of various substrates
Entry
Ester
Solvent, time
Producta
Yieldb(%)
1
2
10a: R1 = Me
PhMe, 2 h
PhMe, 24 h
11a: R1 = Me
11b: R1 = H
99
NR
CO2R1
O
10b: R1 = H
4
4
OR1
O
O
3
4
12a: n = 1
12b: n = 2
PhMe-d8, 2 h
PhMe, 2 h
13a: n = 1
13b: n = 2
99
99
5
12c: n = 3
PhMe, 2 h
13c: n = 3
88
R2
R3
O
O
R2
R3
O
6
7
8
9
5: R2 = R3 = H
PhMe, 2 h
PhMe, 2 h
PhMe, 24 h
PhMe, 2 h
8: R2 = R3 = H
94 (83)c
1: R2 = H, R3 = OTBS
4: R2 = H, R3 = OTBS
92 (80)c
14a: R2 = H, R3 = OH
14b: R2, R3 = OCH2O
15a: R2 = H, R3 = OH
15b: R2, R3 = OCH2O
89
89 (81)c
O
O
10
16
PhMe, 24 h
5
99
CO2Me
OMe
11
12
13
17a: R4 = H
PhMe, 24 h
PhMe, 24 h
PhMe, 24 h
18a: R4 = H
NR
25
NR
17b: R4 = 4-MeO
18b: R4 = 4-MeO
17c: R4 = 4-NO2
18c: R4 = 4-NO2
R4
R4
O
CO2Me
14
15
19
20
PhMe, 24 h
PhMe, 24 h
NR
NR
CO2Me
N
O
N
16
21
PhMe, 72 h
NR
a
b
c
All compounds were compared to literature precedents and all new compounds gave satisfactory spectral data.
Conversions determined by 1H NMR spectroscopy of the crude mixture, NR = no reaction.
Isolated yields on a multigram scale reaction.
Acknowledgements
H
N
H
N
O
O
O
O
O
O
We would like to thank EPSRC for provision of mass spectral
data and the University of Salford for a Ph.D. studentship for R.L.
O
O
(+)-22
(+)-23
Figure 1. Structures of erythrococcamides A (22) and B (23).
References and notes
OH
1. Baba, A.; Shibata, I. Chem. Rev. 2005, 5, 323–335.
O
O
O
O
O
O
O
O
O
ii
i
2. Yadav, J. S.; Reddy, B. V.; Reddy, M. S.; Parimala, G. Synthesis 2003, 2390–2394.
3. Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara, T. Tetrahedron 2005, 61, 9298–
9304.
4. Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J. Org. Chem. 2008, 73,
4160–4165.
24
14b
iv
15b
H
N
O
O
O
O
O
CO2H
iii
5. Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71, 8516–8522.
6. Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2007, 72, 8588–8590.
7. Sun, G.; Sun, H.; Wang, Z.; Zhou, M.-M. Synlett 2008, 1096–1100.
8. Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008, 73, 8829–8837.
9. Sakai, N.; Moriya, T.; Konakahara, T. J. Org. Chem. 2007, 72, 5920–5922.
10. Sakai, N.; Fujii, K.; Konakahara, T. Tetrahedron Lett. 2008, 49, 6873–6875.
11. Raiber, E.-A.; Wilkinson, J. A.; Manetti, F.; Botta, M.; Deakin, J.; Gallagher, J.;
Lyon, M.; Ducki, S. W. Bioorg. Med. Chem. Lett. 2007, 17, 6321–6325.
12. Wilkinson, J. A.; Raiber, E.-A.; Ducki, S. Tetrahedron 2008, 64, 6329–6333.
13. General procedure for the reductive allylation of esters: a solution of the ester
(1 mmol, 1 equiv), triethylsilane (1.1 equiv) and allyltrimethylsilane (2 equiv)
in toluene (3 mL) was heated to 70 °C and InBr3 (0.1 equiv) was added in one
portion. The mixture was left to stir at this temperature for 2 h and then
poured into EtOAc (20 mL) containing water (0.1 mL). The solution was dried
over MgSO4, filtered through a pad of silica gel and concentrated, leading to a
mixture of hexaethydisiloxane and the homoallylic ether, which could be
purified by flash column chromatography, first using petroleum ether to elute
the hexaethydisiloxane by-product and then a mixture EtOAc and petroleum
ether, typically 1:6.
O
O
25
( )-23
Scheme 3. Total synthesis of erythrococcamide B. Reagents and conditions: (i)
methyl acrylate (3 equiv), TFA, 70 °C, 6 h, 67%; (ii) InBr3 (0.1 equiv), Et3SiH
(1.1 equiv), allyl-TMS (2.0 equiv), PhMe, 70 °C, 2 h, 81%; (iii) KMnO4 (0.2 equiv),
NaIO4 (6.0 equiv), K2CO3 (1.5 equiv), tBuOH/water 1:1, rt, 3 h, 77%; (iv) DCC
(1.1 equiv), HOBt (1.1 equiv), isobutylamine (1.5 equiv), CH2Cl2, 0 °C to rt, 12 h, 84%.
product, except for optical rotation.14 This represents the first total
synthesis of this natural product, which also confirms the proposed
structure.
We have reported an efficient method for the one-step reduc-
tive allylation of esters, allowing rapid access to aliphatic and ali-
cyclic homoallylic ethers. Studies are underway for the
development of an enantioselective version of this reaction using
Leighton’s reagent.16 We are also investigating the use of silyl
ketene acetals and propargyl, allenyl and alkynyl silanes as
nucleophiles.
14. Latif, Z.; Hartley, T. G.; Rice, M. J.; Waigh, R. D.; Waterman, P. G. J. Nat. Prod.
1998, 61, 614–619.
15. Lemieux, R. U.; von Rudloff, E. Can. J. Chem. 1955, 33, 1701–1709.
16. Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596–
9597.