Communications
Table 1: Scope of the reaction in terms of the Reformatsky reagent and
with only trace quantities of 8 [Scheme 2, Eq. (3)]. The impact
terminal electrophile.[a,b]
of the countercation on the facility of the Brook rearrange-
ment remains a point of interest and development.[9] The
present example appears to involve an equilibrating mixture
À
À
of C Si and O Si isomers: The warming of a solution of the
unrearranged zinc aldolate to room temperature in the
absence of a ketone electrophile resulted in a complex
mixture that contained both the hydroxysilane 8 and the
product derived from protonation of the enolate 3 in similar
amounts.
Product
Yield
[%]
d.r.
Product
Yield
[%]
d.r.
52
67
46
11:1
40
57
53
12:1
Subsequent experiments were directed at improving the
diastereoselectivity of the reaction. The use of the acetate-
derived Reformatsky reagent 1a in conjunction with aceto-
phenone led to modest diastereoselectivity [d.r. 3:1;
Scheme 2, Eq. (4)]; however, when the propionate reagent
1b was used to initiate the reaction, the desired lactone
product was obtained in 67% yield with d.r. > 25:1 [9b/all
other diastereomers; Scheme 2, Eq. (5)]. Similar results were
obtained with the Reformatsky reagent derived from ethyl
2-bromobutyrate [Scheme 2, Eq. (6)], but the use of the
analogous isovalerate led to a low yield and complex
diastereomer mixtures.[10] The results with 1b and 1c were
somewhat unexpected, as diastereoselectivities in Reformat-
sky reactions with simple ketones are generally modest.[11]
The use of other alkyl esters or other silyl groups in the silyl
glyoxylate reagent generally led to lower yields and/or
diastereoselectivities.[12]
An examination of a variety of alkyl aryl ketones revealed
favorable results within this subset of electrophile (Table 1).
The yields of the isolated products ranged from 40 to 73%
with diastereomer ratios from 7.5:1 to > 25:1. Surprisingly
high selectivity was also observed in the formation of 10 f with
benzoylthiophene. In contrast, the equivalent reaction with
benzaldehyde provided the product 10m with only 3:1
diastereoselectivity.
>25:1
>25:1
30:1
>25:1
73
70
41
7.5:1
18:1
9.5:1
40
>25:1
68
63
3:1
1.6:1
71
–
In cases in which modest yields were observed, the
quenched glycolate enolate 3 comprised the majority of the
mass balance; intermolecular proton transfer is a likely
pathway with certain ketone electrophiles.[10] The highly
substituted g-butyrolactones were purified conveniently in
most cases through selective crystallization from pentane
after column chromatography to afford the products as single
diastereomers.[12]
The high diastereoselectivity observed in the formation of
isobenzofuranone 10q (terminating electrophile: methyl
2-acetylbenzoate), which must result from lactonization via
a different transition state, suggests that selective lactoniza-
tion by one of a mixture of equilibrating stereoisomeric
aldolates is probably not responsible for the remarkable
diastereoselectivity. The alkyl group R1 (R1 = Me in
Scheme 3) in the substituted Reformatsky reagents is thus a
likely determinant of the facial selectivity in the second
Reformatsky reaction. In the present case, the ethyl ester
could conceivably enforce the illustrated boat/twist-boat
transition state[11a] through chelation. This type of organized
structure, 11, provides a plausible rationalization for the high
enolate facial selectivity insofar as an approach of the ketone
syn to the hydrogen atom a to the ester group should be
preferred.[13] The model shown in Scheme 3 further supposes
48
44
>25:1
>25:1
68
51
1.2:1
20:1
[a] Reagents: enolate (1.5 equiv), ketone (3.0 equiv), 2 (1.0 equiv), [2]0 =
0.05m in Et2O. [b] See the Supporting Information for detailed
procedures. Stereostructures were determined through NOESY experi-
ments.
a pseudoequatorial orientation of the aryl group and an E
enolate geometry (as in 12°); however, it would be premature
to discount alternative models (including those involving
other structures of the organometallic intermediate) in the
absence of more-complete experimental data.
The transformations shown in Scheme 4 further highlight
the synthetic utility of this methodology. Alkylation occurred
faster than dehydrohalogenation when 10h was heated with
DBU and resulted in the formation of the bicyclic lactone 13,
which contains three contiguous fully substituted stereogenic
centers. A zinc-insertion/elimination reaction of bromolac-
tone 10g provided the g,d-unsaturated acid 14, which can be
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Angew. Chem. Int. Ed. 2009, 48, 3689 –3691