Angewandte
Communications
Chemie
[
5]
THF provides 4-nitro-2-butanone (3) in 82% yield. When
we employed this method to prepare 3 we did successfully
obtain the desired product, but it was contaminated with 4-
acetoxy-2-butanone as a by-product (ca. 4:1 ratio, respec-
tively) and the mixture proved challenging to separate. We
found that this problem was obviated by substituting pyridi-
nium trifluoroacetate for acetic acid. Thus, in one larger-scale
experiment, solid pyridinium trifluoroacetate (173 g,
(100 mL) were added to the suspension. Further stirring for
24 h at 238C led to additional precipitation of product 6,
presumably due to acid-catalyzed conversion of the soluble b-
anomer in the mother liquor to the less soluble a-anomer.
Filtration of the reaction suspension through a sintered glass
funnel (medium porosity) afforded the first crop of 6 in pure
form as a white powder (20.1 g, 45%, m.p. 178–1808C). A
second crop of 6 was obtained by extracting the filtrate with
ethyl acetate, concentration of the extracts, and trituration of
the residue with ether (2.2 g, 5%, m.p. 178–1808C, see
Supporting Information for details). Chiral HPLC analysis
established that both crops of the product were of > 97% ee,
which is substantially higher than the ee of the starting nitro
alcohol 5. Although further purification of 6 is unnecessary, if
desired, it can be recrystallized from hot n-butanol (75%
recovery, m.p. 185–1878C). X-ray crystallographic analysis of
crystals obtained from n-butanol confirmed that the stereo-
chemistry of the nitro sugar was fully homologous with d-
desosamine and further revealed that the anomeric config-
8
98 mmol, 1.10 equiv) was added portionwise over 10 min to
a stirred heterogeneous mixture of methyl vinyl ketone
68.1 mL, 816 mmol, 1 equiv) and sodium nitrite (61.9 g,
98 mmol, 1.10 equiv) in THF (408 mL) at 08C. Upon
completion of addition, the mixture was allowed to warm to
38C over 1 h. After 17 h, a second portion of sodium nitrite
11.3 g, 164 mmol, 0.200 equiv) and pyridinium trifluoroace-
tate (31.5 g, 164 mmol, 0.200 equiv) was added at 238C and
the mixture was further stirred for 3 h. 4-Nitro-2-butanone (3)
was obtained in a high state of purity in 78% yield (74.2 g)
after extractive isolation (ether-hydrochloric acid) and filtra-
tion of the crude product through a pad of silica gel (see
Supporting Information for details). While it has been
reported that 3 can be purified by distillation, we do not
recommend this, as we have observed that more often than
not attempted distillation leads to decomposition (browning)
with bumping, perhaps due to retro-Michael addition to form
nitrous acid and methyl vinyl ketone. Because 3 is formed in
a high state of purity by our modified method, we find that no
further purification is necessary. Enantioselective reduction
of 3 was achieved by slow addition over 1 h of a solution of the
(
8
2
(
1
uration was a ( H NMR analysis of a solution of 6 in
deuterated methanol showed it to exist as a 15:1 mixture of a-
and b-anomers, respectively). The cyclization reaction can
also be performed with 40 wt % aqueous glyoxal solution
(1.05 equiv) and sodium carbonate (5 mol%) in 3:1 dichloro-
methane:water, but proceeds in lower yield (41%, entry 2,
Table 1). Completion of the synthesis was achieved in one
final operation wherein nitro reduction and reductive amina-
tion were conducted sequentially. Thus, a suspension of 6
(15.0 g, 85.0 mmol, 1 equiv) and palladium hydroxide on
carbon (20 wt %, 6.0 g) in 9:1 methanol:acetic acid (420 mL)
“
crude” ketone 3 (46.0 g, 393 mmol, 1 equiv) in THF
(
100 mL) to a stirred mixture of a solution of the Corey–
was stirred under H (1 atm) at 238C. Aqueous formaldehyde
2
[6]
Bakshi–Shibata oxazaborolidine catalyst 4 in toluene (1.0m,
9 mL, 79 mmol, 20 mol%), a solution of borane-tetrahydro-
(37 wt %, 15.8 mL, 2.50 equiv) was added after 7–8 h, when
TLC analysis indicated that full consumption of nitro sugar 6
had occurred, and the mixture was stirred under hydrogen for
an additional 12 h. Filtration of the reaction suspension
through Celite, concentration of the filtrate and neutraliza-
tion of the ammonium acetate salt with Amberlyst A26 resin
afforded d-desosamine (1) as a yellow oil in 94% yield
(13.9 g, 94% yield, 1:1.6 a:b). The yield of the 4-step sequence
from methyl vinyl ketone is 27.5%.
7
furan complex in THF (1.0m, 275 mL, 275 mmol, 0.70 equiv),
and THF (982 mL) at À108C. Dilution of the reaction mixture
with 2n hydrochloric acid, extraction of the product with
ethyl acetate, concentration of the product extract and
distillation of the residue (1.5 mmHg, 858C) afforded the
secondary alcohol 5 in 75% yield (35.1 g) and 87% ee
[
7]
(
Mosher ester analysis). We find that the use of a substoi-
chiometric amount of borane and slow addition of the ketone
are key factors to achieve reproducibly high enantioselectiv-
ities. The amino alcohol ligand (S)-1,1-diphenylprolinol was
readily recovered by neutralization of the acidic aqueous
layer with solid sodium hydroxide, extraction with dichloro-
methane, concentration of the extracts, and recrystallization
of the residue from hot heptane (16.9 g, 84% recovery, m.p.
A remarkable feature of our synthesis of desosamine is
the efficient and operationally simple cyclization reaction that
provides the crystalline nitro sugar 6. This key cyclization
certainly involves both a Henry reaction and hemiacetaliza-
tion, though the ordering of these events is not known. We
surmise that the nitroalcohol 5 and glyoxal first form
a diastereomeric mixture of open-chain hemiacetals, which
then undergo an intramolecular Henry reaction to give the
product (as an a-anomeric mixture), but we have no direct
7
2–748C). The recovered ligand can be used to regenerate the
[
6a]
catalyst 4 in one step, as reported by Corey et al.
(see
1
Supporting Information for details).
evidence to support this. H NMR analysis of the reaction
In the key step of the sequence, an aqueous solution of
cesium carbonate (5.0m, 2.52 mL, 12.6 mmol, 0.050 equiv)
was added to a stirred heterogeneous mixture of glyoxal
trimer dihydrate (24.8 g, 118 mmol, 1.41 equiv of monomeric
glyoxal), nitro alcohol 5 (30.0 g, 252 mmol, 1 equiv) and 1:1 n-
butanol:dichloromethane (50.4 mL) at 08C. The a-d nitro
sugar 6 precipitated from the reaction mixture over the course
of 17 h at 238C. The precipitate was not isolated at this stage;
instead, 6n aqueous hydrochloric acid (6.0 mL) and ether
solution reveals that other minor diastereomers are present in
the mother liquor, but the desired product 6 is formed
preferentially and precipitates selectively from the reaction
mixture. Presumably the CÀC bond-forming (Henry) reaction
is reversible under the reaction conditions, allowing for
equilibration of diastereomers in solution; when the concen-
tration of diastereomer 6 reaches saturation, this isomer
precipitates, driving the production of the desired diastereo-
mer (6). Although the yield (50%) may be regarded as
5
24
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 523 –527