Synthesis of ω-hydroxy ketones from ω-benzyloxy weinreb amides by using a chemoselective nucleophilic addition/ birch reduction process

Article abstract of DOI:10.1021/ol049434f

A chemoselective nucleophilic addition/Birch reduction process applied to ω-benzyloxy Weinreb amides led to ω-hydroxy ketones in good yields.

Full text of DOI:10.1021/ol049434f

ORGANIC
LETTERS
2
004
Vol. 6, No. 13
145-2147
Synthesis of ω-Hydroxy Ketones from
ω-Benzyloxy Weinreb Amides by Using
a Chemoselective Nucleophilic Addition/
Birch Reduction Process
2
Catherine Taillier, V e´ ronique Bellosta, Christophe Meyer, and Janine Cossy*
Laboratoire de Chimie Organique, associ e´ au CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received March 26, 2004
ABSTRACT
A chemoselective nucleophilic addition/Birch reduction process applied to ω-benzyloxy Weinreb amides led to ω-hydroxy ketones in good
yields.
Weinreb amides have emerged as highly effective acylating
agents for a wide range of nucleophiles. Even with a large
converted into aldehydes when treated with aluminum or
boron hydrides.
1
1
excess of the organometallic reagent, such amides lead to
ketones exclusively due to the exceptional stability of the
tetrahedral intermediate I (Scheme 1) that is generated in
The high stability of the tetrahedral intermediate I can also
allow additional functionalization at other remote sites within
2
a molecule.
To avoid several protection-deprotection steps in multi-
step syntheses of highly functionalized compounds, efficient
and chemoselective reactions have to be devised and/or latent
protecting groups have to be found. Herein, we would like
to report that intermediates of type II can serve as a latent
carbonyl protecting group for the preparation of ω-hydroxy
ketones from functionalized ω-hydroxy-protected Weinreb
amides when a combined nucleophilic addition/Birch reduc-
tion process is used (Scheme 2).
Scheme 1. Nucleophilic Addition to Weinreb Amides
situ. No over addition occurs due to chelation of the metal
ion between the resulting alkoxide and the oxygen atom of
the N-methoxy group, which prevents premature release of
the ketone functionality or formation of an iminium inter-
mediate until an acidic work-up has been performed. This
remarkable behavior of Weinreb amides allows them to be
Initially, the feasibility of the idea was investigated on
the δ-benzyloxy Weinreb amide 1 using n-BuLi as a nucleo-
phile. Addition of n-BuLi (5 equiv) in THF at -78 °C to
compound 1 led to the lithiated tetrahedral intermediate of
3
type II, which was added to a solution of lithium in liquid
(
2) (a) Evans, D. E.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
(
1) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
110, 2506-2526. (b) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S.
W. J. Org. Chem. 1990, 55, 6260-6268. (c) Evans, D. E.; Polniaszek, R.
P.; DeVries, K. M.; Guinn, D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991,
113, 7613-7630. (d) Bergman, R.; Hansson, T.; Sterner, O.; Wickberg, B.
Chem. Commun. 1990, 865-867. (e) Bray, B. L.; Mathies, P. H.; Naef, R.;
Solas, D. R.; Tidwell, T. T.; Artis, D. R.; Muchowski, J. M. J. Org. Chem.
1990, 55, 6317-6328.
3
818. (b) O’Neill, B. T. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Schreiber, S. L., Eds.; Pergamon Press: Oxford, 1991;
Vol. 1, pp 399-407. (c) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15-
4
5
3
0. (d) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339, 517-
24. (e) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000,
42, 340-347.
1
0.1021/ol049434f CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/25/2004

Scheme 2. Nucleophilic Addition/Birch Reduction Process
Scheme 3. Reactivity of Benzylated Weinreb Amide 1 under
Birch Reduction Conditions
underwent simultaneous O-debenzylation and N-demethoxy-
lation, as previously reported for N-alkoxyamides.4
To explore the scope of the nucleophilic addition/Birch
reduction process, the influence of the substitution pattern
present in the starting substrates was first examined. In a
systematic study, only n-BuLi was used as a nucleophile.
When the primary benzyloxy amide 7 was subjected to the
nucleophilic addition/Birch reduction process under opti-
mized conditions, the hydroxy ketone 13 was isolated in 72%
yield (Table 2, entry 1). In addition to 1, the secondary
benzyloxy amides 8 and 9 were converted to the correspond-
ammonia [Li (excess), NH (l)] at -78 °C. After 5 min, the
reaction was quenched with solid ammonium chloride and
the hydroxy ketone 2 was isolated in 78% yield (Table 1,
3
entry 1). The addition of t-BuOH (20 equiv) to the Li, NH
3
(l)
solution, which is usually recommended for efficient cleavage
4a
of benzyloxy groups, slightly improved the yield of hydroxy
ketone 2; this compound being isolated in 85% yield (Table
1, entry 2).
Table 2. Consecutive Addition of Nucleophiles/Birch
Table 1. Addition of Various Nucleophiles/Birch Reduction
Reduction Process
entry
nucleophile
additive
R
product
yield (%)
1
2
3
4
5
a
n-BuLi
n-BuLi
EtMgBr
AllyMgBr
(i-Bu)2AlH
Bu
Bu
Et
allyl
H
2
2
3
4
5
78
85
58
85
70
t-BuOH
t-BuOH
t-BuOH
t-BuOH
a
b
c
Conversion of the starting amide 1 was completed by warming to
b
0
°C (alkylation step). 4 partially cyclized to the corresponding lactols.
c
5
cyclized to the corresponding lactols.
Likewise, the addition of ethylmagnesium bromide and
allylmagnesium bromide to 1 led to magnesium intermediates
of type II, which were added to Li, NH (l) solutions in the
3
presence of t-BuOH to afford the corresponding δ-hydroxy
ketones 3 (58% yield) and 4 (85% yield) respectively (Table
1
, entries 3 and 4). Significantly, reaction of 1 with Dibal-H
and the subsequent addition of the reaction mixture to a
solution of Li, NH (l) in the presence of t-BuOH provided
3
the δ-hydroxy aldehyde 5 as a diastereomeric mixture of
lactols (2:1 ratio) in 70% yield (Table 1, entry 5).
It is worth noting that the selective debenzylation of 1
was also tested [Li, NH
the secondary hydroxy amide 6 was isolated in 95% yield
Scheme 3). No selectivity was observed as the amide 1
3
(l), -78 °C, 5 min]. However, only
(
(3) Complete conversion of the starting amide was ascertained by TLC
after aqueous workup of an aliquot.
(
4) (a) Shirai, F.; Nakai, T. Tetrahedron Lett. 1988, 29, 6461-6464. (b)
Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.; Sakai, S.-I.
Tetrahedron 1989, 45, 1327-1336. (c) Banfi, L.; Cascio, G.; Guanti, G.;
Manghisi, E.; Narisano, E.; Riva, R. Tetrahedron 1994, 41, 11967-11982.
a
Debenzylation step carried out without t-BuOH. b PMB ) p-MeO-
C6H4-CH2. c Tr ) Ph3C.
(
d) Yus, M.; Radivoy, G.; Alonso, F. Synthesis 2001, 914-918.
2146
Org. Lett., Vol. 6, No. 13, 2004

ing R- and â-hydroxy ketones 14 and 15 in satisfactory yields
58-59%) (Table 2, entries 2 and 3), which demonstrated
(
Scheme 4. Consecutive Alkylation/Birch Reduction Process of
that the relative position of the benzyl ether and the amide
function has no bearing on the success of the alkylation/
debenzylation process. In the case of compound 10 with its
tertiary O-benzyl ether, the expected hydroxy ketone 16 was
isolated in poor yield (16%), and the diol 17 was obtained
in 51% yield. However, when the Birch reduction step was
carried out without t-BuOH, the yield of 16 was raised to
an Acetylenic Weinreb Amide
92% (Table 2, entries 4 and 5).
We have also shown that p-methoxybenzyl and trityl ethers
In conclusion, we have shown that the stable tetrahedral
intermediate II that results from the addition of an organo-
metallic reagent to a Weinreb amide can efficiently serve as
a latent carbonyl protecting group and enable a subsequent
chemoselective deprotection of various protecting groups
(Bn, PMB, Tr) via the Birch reduction. This general and
reliable protocol provides direct access to various hydroxy
ketones in good yields from Weinreb amides. Application
of this methodology to the synthesis of natural products such
as (+)-zoapatanol is reported in the following paper.
can be reduced using the same process. Indeed, treatment
of amides 11 and 12 under the optimized conditions
proceeded smoothly and provided the expected hydroxy
ketones 2 and 13 in 74 and 70% yields, respectively (Table
, entries 6 and 7).
The aforementioned nucleophilic addition/Birch reduction
process is very chemoselective as alkynes are not reduced.
When the acetylenic amide 18 was treated with n-BuLi in
THF at -78 °C and the resulting tetrahedral intermediate of
2
type II was added to a solution of Li, NH
of t-BuOH (-78 °C, 5 min), the acetylenic hydroxy ketone
9 was isolated in 58% yield (Scheme 4). Under these
3
(l) in the presence
Acknowledgment. C.T. thanks the MRES for a grant.
1
specific conditions, no trace of alkene was detected by GC/
MS or H NMR spectral analysis of the crude reaction
mixture. By way of contrast, when the reduction step was
carried out at -33 °C with extended reaction times, a partial
reduction of the alkyne and an over-reduction of the ketone
to the corresponding alcohol were observed.
Supporting Information Available: General experimen-
tal procedure and characterization data of the described
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
OL049434F
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