Tetrahedron Letters,Vol.27,No.49,pp 5939-5942, 1986 0040-4039

Tetrahedron
Printed
Letters,Vol.27,No.49,pp
Great
Britain
in
THE DIRECTED
5939-5942,
REDUCTION
OF EHYDROXY
David
A. Evans*
1986
KETONES
and Kevin
0040-4039/86
Pergamon
EMPLOYING
$3.00
Journals
+ .OO
Ltd.
hie@HB(OAc)S
T. Chapman
Department
of Chemistry
Harvard
University
Cambridge,
Massachusetts
02138
Abstract:
borohydride
The diastereoselective
reduction
of a range
is described.
In all cases,
the anti 1,3-dial
Chemical
valuable
such
reactions
which
in stereoselective
reactions
propagated
related
wherein
during
studies
agent
MeQNBH(OAc)3
be
actively
I-3
course
directed
We have
stereochemical
the
on the
may
synthesis.
of acyclic
Bhydroxy
ketones
diastereomer
is the principal
information
of olefin
from
hydrogenation.
hydroxyl-directed
hydride
by
recently
substrate
functionality
focused
our
attention
hydroxyl-bearing
1 In the
reduction
present
have
proven
on the
stereogenic
Letter
of acyclic
with triacetoxyproduct
(eq I).
centers
ketones
be
using
of
might
we wish to report
Bhydroxy
to
development
some
the
be
of our
reducing
(eq 1).
Me,NHB(OAc),
(1)
R
R
CH,CN I HOAc
Diastereoselection20-50
It
has
been
temperatures
or
2-heptanone.4
with
in
generated
with
in this
As a first
might
also
several
months.7
infrared
spectra
has
spectral
abbreviated
times,
several
area,
5
Since
and
hydride.
properties
objective,
description
previously
hydrolysis
freely
combustion
of the synthesis
6 The
mp 96.5
-98’
we
soluble
chose
analysis
of this
to
fully
reagent
5939
reduced
under
mild
conditions
gained
from
these
cases
fully
of choice
C, which
CHC13
consistent
suggested
is stable
been
that
we
with
aspects
which
has been
at room
indeed
the
IS
In
of these
triacyloxyborohydride
characterized
and numerous
as acetophenone
by Gribble.bb
mechanistic
characterized
reagent
verify
follows:
first
and
have
in CH2C12,
elevated
been
synthetic
acyloxyborohydrides
at
such
postulate
the
even
ketones
have
a stable,
studies.
solid,
products,9
The reagent,
in both
counterion
BubNBH(OAc)3,
simple
information
a mechanistic
to produce
reported
ketones
stereochemical
interested
hygroscopic
and
completely
Bhydroxy
The
we sought
in metal
and
NaBH(OAc)3
to reduce
reduction,
we were
a colorless,
both
fail
cyclic
NaBH(OAc)j.
be utilized
is MebNBH(OAc)3,
homogeneous
that
reaction
a hydroxyl-mediated
studies
reactions.
which
documented
In contrast,
situ
consistent
pursuing
well
or prolonged
:1
were
other
indicated
developed
temperature
only
dealing
common
structure.
for
by
their
with
a
solvents,
An
5940
Tetramethylammonium
was charged
with
The
benzene.
dropwise
was
15 min.
white
semisolid
vacua
to give
3.34
10.8 g (121
mixture
over
washed
Anal.
The
system
does
range
of
not
HOAc
MHz,
I:1 acetic
the Table,
high
levels
bearing
determined
these
keto
of
that
esters
intermediate
are
not
where
diketo
the double
below.
L&and
intermediate
hydride
delivery
course
exchange
We
bond
but is actually
good
for
the
presume
proximal
that
a-methyl
m Entry
postulate
is -not conjugated
reductions
substrate
alkoxydlacetoxy
a stronger
and
borohydride
hydride
donor
than
the
which
reactton
mira).
(Entries
from
proceeds
the
distal
undergolng
only
capable
an
it IS
related
&
enoiborohydride
reduction.
of
illustrated
affords
mtramolecular
borohydride.‘l
OH
Minor
degree
Finally,
via the transition
states
-iabile
borohydride
ligands
is not
m
hydroxyl-
In comparison,
through
as
2.3) also exhlblt
configuration.
reduction.
the parent
such
As illustrated
Me4NBH(OAc),
HOAu’MeCN
I’B
medium
acids
and an impressive
adducts
center
this
r
R
E
IH, BI-J),
A solvent
be ratlonahzed
hydroxyl
The
23.24;
Table.
Bronsred
(vlde
__-.
m either
undergoes
to the carbonyl
may
added
overmght
55.63,
m the
induction
reduction
dried
6 4.4 (br,
6 172.60,
diastereoselectlon
asymmetrlc
this
and
second,
reduction
srereocenters
that
was
3 h, and filtered.
First,
(-40” C); and
and syn aldol
10 also
distilled
acid
H, 8.39.
reasons.
anti
filter
ppm (d, 18, BH, JBH = 136 Hz).
following
actual
acetic
for
CDC13)
is illustrated
of reaction
the
MHz,
a Schlenk
300 mL of freshly
ether,
study
the
with
(300 IMHz, CDC13)
C, 45.64;
employed
both
dlstilled
6 co.71
Found
m this
levels
that
must
of these
between
substrate-bound
chosen
Illustrated
reduced.
The stereochemlcai
both
the
ester
of freshly
m facllltarmg
Interest
One
overrides
the
was
exhibit
reduction.
Included
and
stirred
C; 1H NMR
reference)
H, 8.43;
equipped
of anhydrous
temperature,
13C NNlR (75.5
temperatures
to be important
reductions
ant1
ketones
reactlon
It IS of particular
stereocenter
noteworthy
hydroxy
lower
portions
as external
C, 45.65;
flask
borohydride8
mp 96.5-98.0”
(s, YH, CFI3CO2B);
BF3 etherate
Schlenk
mL (425 mmol)
to ambient
IOO-mL
actd-acetonltrile
at the
of generality.
five
powder:
for ClOH22NOgB:
of acyclic
freeze
were
2.02
24.3
was warmed
white
CD3CN,
Calcd.
of tetramethylammonium
to 10” C, and
with
a free-flowing
(S, 12 H, (Cg3)4N),
NcMR (96.3
mmol)
cooled
The mixture
was
A 500-mL
Triacetoxyborohydride.
OH
an
5941
The diastereoselectivity
analogous
nonbonding
to explain
the high anti selectivity
Several
in transition
observed
of evidence
determining.
ketone
herein
the presumed
reduction
nicely complement
Diasteroselective
Table.
Entry
in transition
state
are relevant
arguments
to the mechanism
of either
states
TS destabilize
TA and TS.
it relative
have recently
of E-hydrosilyloxy
It is
to the
been extended
ketones.l*
of this reaction.
First
we have
acids such as HOAc or metal ions such as Na+
The same requirements
We have followed
intramolecularity
can be carried
the recently
must also be met to effect
iigand
the
ketones
reductions
of Bhydroxy
exchange
by
IlB
of these
reported
syn-selective
can be demonstrated
acid!
The selective
by the fact
reductions
reductions.13
Time (Temp)
Product
1
OH
reductions
out in acetone-acetic
Hydroxy Ketone Reductions with Me,NBH(OAc),.lo
Reactant
2
transition
state
Similar
TA.
in the reduction
the presence
and Me/+NBH(OAc)3.
Finally,
Ehydroxy
ketones.
via the chair-like
present
and have -not observed the buildup of metastable
borohydrlde Intermediates.
Based upon
we have tentatively
concluded that ligand exchange rather than hydride transfer is rate
this information
described
pieces
hydroxy
2-propanol
NMR spectroscopy
that
interactions
additional
rationalized
interactions
that MeQNBH(OAc)3 requires
or Li+ to reduce
between
1,3-diaxiai
easily
that
observed
the
is then
presumed
Ratio a
Anti:Syn
Yield, % b
5 h (-20°C)
96:4
86
ia h (-20-c)
98:2
92
18 h (-2O’C)
98:2
a4
30 min (+25’C)C0d
>98 : 2
99
0
Me
3
Me
Me
Me
69
Me
MB
a Diastereomer ratios were determined by HPLC. b Values refer to isolated yields of major isomer of z-99% purity.
c Neat acetic acid used as solvent. d NaHB(OAc)3 used as reducing agent.
Representative
solution
the
of 1 mmol
indicated
aqueous
acetonitrile
of hydroxyketone
time
sodium
at the
indicated
potassium
tartrate
dichloromethane
and
washed
times
ternperature
with
with
several
aqueous
sodium
bicarbonate.
methane,
and
combined
organic
The desired
This
Acknowledgements:
National
may
Institutes
layers
aqueous
are
be purified
research
of Health.
IS also acknowledged
and
The
by flash
has
been
Tile NIH-BRS
for providing
dried
After
it IS quenched
by the
for
sodium
the
The
30 mm.
combined
addition
with
anhydrous
are
several
sodium
chromatography
is then
aqueous
layers
extracted
diluted
layer
again
times
sulfate.
added
IS
has stirred
a
for
of 15 mL of 0.5 N
mixture
The
organic
IS back
triacetoxy-
at -40” C
acid
the reaction
bicarbonate.
layer
supported
Sirared
acetic
acetonitrile.
stirring
aqueous
dichloromethane,
products
of 5 mm01 of tetramethylammonium
4.0 mL of anhydrous
(Table),
vigorous
saturated
extracted
the
with
and
in 1.0 mL of anhydrous
saturated
trated.
To a solution
reduction procedure:
in 4.0 mL of anhydrous
borohydride
with
is back
washed
with
filtered,
with
dichloro-
and
concen-
on s111ca gel.
by the
National
Instrumentation
Grant
Scier.ce
Foundation
ana
:!IC
1-SL5-RKC17iiY-31;\ I
Program
.UblR facilities.
References and Notes
1.
For earlier
(a) Evans,
(b) Evans,
(c) Evans,
2.
Stork,
3.
Crabtree,
4.
(a) For an exceilent
review of borohydride
reductions
in acidic media
Organic
Preparation
and Procedures
Int. 1985, 11, 317-84.
(b) Grabble,
G.W.; Nutaitis,
C.F.
Tetrahedron
Lett. 1983, E, 4237.
5.
(a) Saksena,
(b) Turnbull,
6.
In the
7.
After a six-month
period the reagent
does not completely
This does not, however,
lead to a drop in reduction
yield
8.
Banus,
9.
(a) Wartik,
T.; Pearson,
R.K. J. Inorg. Nucl. Chem.
1958, z, 404-11.
(b) Marchim,
G.; Lisa, A.; Reho, F.; Liberatore,
F.; Moracci,
F.&l. J. Org. Chem.
1975, s,
3453.
(cl Oklobdzija,
Xl.; Fajdiga,
T.; Kovak, 1.; Zonno, F.; Sega, A.; Sunlit,
V. Acra Pharm.
Juposl.
1980, -30.
121; Chem. Abs. 1981,94,
121481g.
work on directed
D.A.; Llorrissey,
D.A.; .Morrissey,
D.A.; %?orrissey,
G.; Kahne,
R.H.;
above
hydrogenation
reactions
see:
“i1.U. Tetrahedron
Lett. 1984, 2. 4637.
11.11. _1. Am. Chem. Sot. 1984, G.
3866.
lI.:~l.; Dow, R.L. Tetrahedron
Lett. 1985.
D.E. J. Am. Chem.
Davis,
M.W. 3. Org.
Sot.
1983,
Chern.
1986,
l&,
1072.
2,
2655.
A.K.; !v!angiaracma,
P. Tetrahedron
Lett. 1983,
.___
<M.D.; Hatter,
G.; Ledgerwood,
D.E. Tetrahedron
studies
(Ref.
,M.D.; Bragdon,
spectral
4b, 51, the borohydride
R.W.;
and elemental
T.R.P.
3. Am.
273.
Lett, 1984,g,
never
fully
Sot.
other
than
13.
Kathawala,
F.C., Prager,
5.; Prasad,
K.; Repic, 0.; Shapiro,
,M.J.; Stabler,
Chim. .Ac:a
1986, 69. YS3-YO5 ant; references
reported
therein.
(Received
in
USA
3 SeptemBer
Chern.
1986)
Commun.
1986,
for all compounds
Anwar,
C.F.
acetic
acid.
23116.
For comparisons
of reactivity
of acyloxyalkoxy
borohydrides
see:
(a) Hirao, A.; Itsuno, S.; Owa, &$.; Nagami,
S.; Uochizuki,
H.; Zoorov,
H.H. .4.; Niakahama,
Yamazaki,
N. J. Chem. SW. Perkin I 1981, 900.
(b) Uasipuri,
D.; Sskar,
A.; Konar, S.K.; Chosh. A. Indian 3. Chem.
1982, 218, 212-5.
12.
Nutaitis,
5449.
Satisfactory
Sot.
obtained
1952,2,
C.k.;
characterized.
dissolve
in solvents
or stereoselectivity.
Chem.
were
Gribbie,
il.
.A.P.. J. Chem.
analyses
were
see:
6005.
10.
S.; Davis,
data
Cobb, Jr.,
species
2,
26(49).
--
reportea.
S.;
831-332.
R.S.;
Tidier,
L.
Helv.