Synthesis of Enantiomerically Pure β-Hydroxy Ketones via β-Keto Weinreb Amides by a Condensation/Asymmetric-Hydrogenation/Acylation Sequence

Article abstract of DOI:10.1002/ejoc.201601202

An established route to enantiomerically pure β-hydroxy ketones proceeds through the asymmetric hydrogenation of β-keto esters, an ester/amide exchange, and the use of the resulting β-hydroxy amide for the acylation of an organometallic compound. We shortened this route by showing that β-keto Weinreb amides are hydrogenated with up to 99 % ee in the presence of [Me₂NH₂]⁺{[RuCl(S)-BINAP]₂(μ-Cl)₃}^–(0.5 mol-%) at room temp./5 bar. These Weinreb amides were prepared by seemingly obvious yet unprecedented condensations of lithiated N-methoxy-N-methylacetamide with carboxylic chlorides (51–87 % yield). The resulting β-hydroxy Weinreb amides were used for the acylation of organolithium and Grignard reagents. They thus gave enantiomerically pure β-hydroxy ketones (28 examples). A selection of these compounds gave anti-1,3-diols after another C=O bond hydrogenation, or syn-1,3-diols by a Narasaka–Prasad reduction.

Full text of DOI:10.1002/ejoc.201601202

A Journal of
Accepted Article
Title: Synthesis of Enantiomerically Pure β-Hydroxyketones via β-Keto Weinreb
Amides by a Condensation / Asymmetric Hydrogenation / Acylation Sequence
Authors: Reinhard Bru¨ckner; Julian Diehl
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((For Table of Contents:)) Julian Diehl, Reinhard Brückner
Synthesis of Enantiomerically Pure β-Hydroxyketones via β-Keto
Weinreb Amides by a Condensation / Asymmetric Hydrogenation
/ Acylation Sequence
((Short Title)) Preparation and Asymmetric Hydrogenation of β-Keto Weinreb Amides
O
OLi
O
O
OH
O
OH O
R2Li or
H2,
OMe
OMe
OMe
R1
Cl
N
R1
N
R1
N
R1
R2
+
R2MgHal
cat. RuL*n
Me
Me
75% - 99% ee
Me
50% - 96%
A condensation route to β-keto Weinreb amides was developed (10 examples). They were hydrogenated in the presence of
0.5 mol-% [Me2NH2] {[RuCl(S)-BINAP]2(µ-Cl)3} at 5 bar with up to 99% ee. The resulting β-hydroxy Weinreb amides and
organolithium or Grignard compounds reacted to give enantiopure β-hydroxyketones in good yields (28 examples). The latter
provided syn-1,3-diols by Narasaka-Prasad reductions (6 examples) and anti-1,3-diols by further hydrogenation (10
examples).
Key Topic for Table of Contents: Asymmetric Hydrogenation
1
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Synthesis of Enantiomerically Pure β-Hydroxyketones via β-Keto
Weinreb Amides by a Condensation / Asymmetric Hydrogenation
/ Acylation Sequence
Dedicated to Professor Gerhard Bringmann at the occasion of his 65th birthday
Julian Diehl[a] and Reinhard Brückner*[a]
hydroxyamides become available with over 91% ee.9 Additional
Abstract: An established route to enantiomerically pure β-hy-
droxyketones proceeds via the asymmetric hydrogenation of β-
ketoesters, an ester/amide exchange, and employing the result-
ing β-hydroxyamide for the acylation of an organometallic com-
pound. We shortened this route by establishing that β-keto
Weinreb amides are hydrogenated with up to 99% ee in the
presence of 0.5 mol-% [Me2NH2] {[RuCl(S)-BINAP]2(µ-Cl)3} at
room temp. / 5 bar. These Weinreb amides were prepared by
seemingly obvious yet unprecedented condensations of lithiated
N-methoxy-N-methylacetamide with carboxylic chlorides (51-
87% yield). The resulting β-hydroxy Weinreb amides acylated
organolithium and Grignard compounds. They provided
enantiomerically pure β-hydroxyketones thereby (28 examples).
A selection thereof gave an anti-1,3-diol after another C=O-bond
β-ketoamides were hydrogenated asymmetrically by Zhang et al.
using the SunPhos-based Ru(II) catalyst 10 (Scheme 1).10 Their
conditions (20 bar H2 pressure at 70°C) were harsher than ours.
Milder conditions than in the Zhang group but more stringent
conditions than in ours – 5-6 bar H2 pressure at 65°C – allowed
the
Ru(OAc)2[(S)-tol-BINAP]-catalyzed
enantioselective
hydrogenation of a β-keto--lactam.11
At the time, our asymmetric β-ketoamide hydrogenations
included one β-keto Weinreb amide 1c (Scheme 1, top half).8
Whether the Ru(II) catalyst contained BINAP (cf. 312a,b), BIPHEP
(cf. 413a,b) or SEGPHOS (cf. 514) was inconsequential for the
yield (96%) and the enantiomeric purity (>97% ee) of the
resulting β-hydroxy Weinreb amide (2c).8 Zhang et al.
hydrogenated β-keto Weinreb amides asymmetrically, too
(Scheme 1, bottom half).10 Like us, they studied one “simple”
Weinreb amide (1a).10a Controlled by their Ru(II) catalyst 1015 it
provided the hydroxy Weinreb amide 2a with 97% ee.16 Then
they proceeded to more complex substrates, i. e., to the ester-
containing β-keto Weinreb amides 610b and 8a-e.10a,b 10-
Catalyzed hydrogenations thereof gave the ester-containing β-
hydroxy Weinreb amides 7 and 9a-e, respectively, with up to
98% ee.
Enantiomerically pure β-hydroxy Weinreb amides 2 were recog-
nized as synthetically worthwhile before they became accessible
as described above.17 This is because they acylate organo-
lithium compounds or Grignard compounds yielding enantiomeri-
cally pure β-hydroxyketones 18 (Scheme 2).18a,b The latter are
valuable precursors of enantiomerically pure 1,3-diols 19, be
they anti- or syn-configured. The β-hydroxy Weinreb amides 2,
which provided the 1,3-diols of the mentioned study,17 were
obtained from enantiomerically pure β-hydroxyesters 17.18 This
required performing an ester/ Weinreb amide exchange 172
as a preparatory step.
hydrogenation or
reduction.
a
syn-1,3-diol by
a
Narasaka-Prasad
Introduction
Three pivotal contributions of Ryōji Noyori to the field of
asymmetric catalysis appeared in the 1980s. One of them
disclosed the invention of (R)- and (S)-BINAP and the aptitude of
these ligands to exert entiofacial control in Rh-catalyzed
hydrogenations of -(acylamido)acrylic acids.1 The second
publication
described
the
Ru-catalyzed
asymmetric
hydrogenation of β-ketoesters in the presence of the same
ligands.2 The third contribution extended such Ru-catalyzed
asymmetric C=O-hydrogenations to a variety of other types of
ketones with a Lewis-basic coordination site  or β to their
carbonyl group.3 The BINAP ligands and the mentioned
hydrogenations were attributed an outstanding importance and
immense value.4 It came with little surprise that they earned their
originator his share of the 2001 Nobel Prize in Chemistry.5
Noyori´s asymmetric hydrogenations of functionalized ketones3
affected, besides representatives of other compound classes, a
single β-ketoamide, i. e., the N,N-dimethylamide of acetoacetic
acid. It was hydrogenated in the presence of 0.14 mol-% of (S)-
BINAP-complexed Ru(II) under 86 bar H2 pressure at 20-32°C in
ethanol solution for 86 h. This provided 100% of the (S)-enantio-
mer of the corresponding β-hydroxyamide with 96% ee.3 This pi-
oneering reaction did not attract many followers6 until we re-
ported that
5 bar H2 pressure suffice for Ru-catalyzed
asymmetric hydrogenations of ß-ketoamides at room temp. to go
to completion within less than a day.7 These conditions are
generalizable:8,9 0.5 Mol-% of the dinuclear Ru(II) complex
[Et2NH2] {[RuCl(S)-BINAP]2(µ-Cl)3}, ethanol as the solvent,
4 bar of H2 pressure, and reaction times of 14-36 h let β-
2
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European Journal of Organic Chemistry
10.1002/ejoc.201601202
FULL PAPER
H2 (4.0 bar),
catalyst 3 (0.5 mol-%)
or
this work:
Genêt et al.[17,18]
OLi
OR'
:
O
OLi
O
catalyst 4 (0.5 mol-%)
OMe
O
O
OH O
or
+
+
R
Cl
11
N
R
Het
13
catalyst 5 (0.5 mol-%),
O
O
Me
Pent
N
Pent
N
lithio-12
lithio-14
EtOH, room temp., 15-48 h;
1c
2c
>97% ee
([]20 = +48.0)
96-97% (ref.[8]
)
asymmetric hydrogenation of....
O
O
O
O
OMe
Ph2
Ph2
P
R1
N
R
OR'
.. .-ketoesters
Cl
Ru Cl
Cl
P
Me
[Et2NH2]
Ru
1
15
P
P
ref.[8]
and here:
5 bar H2,
BINAP[b]
... -keto Weinreb amides
ref.[17]
:
ref.[10]
:
Ph2
Ph2
10-30 bar H2,
20 bar H2,
MeO-BIPHEP[c,d]
SunPhos[a]
catalyst 3 (ref.[12]):
[Et2NH2] {[RuCl(S)-BINAP]2(µ-Cl)3}
Li
OMe
N
OH
O
OH
O
Me
Cl
Cl
OMe
R1
N
R
OR'
16
Ph2
P
Ph2
P
Cl
Me
R2Li or R2MgHal (here and ref.[18]
OH OH
MeO
OMe
OMe
2
17
[Et2NH2]
Ru
Ru Cl
Cl
MeO
P
P
)
Ph2
Ph2
Cl
Cl
OH
O
OH OH
catalyst 4 (ref.[13]):
R1
R2
R1
R2
R1
R2
[Et2NH2] {[RuCl(S)-Cl-MeO-BIPHEP]2(µ-Cl)3}
18
anti-19
syn-19
O
O
Ph2
P
Ph2
P
Cl
OH-directed reduction
O
O
O
O
OH-directed reduction
Ru
[Et2NH2]
Ru Cl
Cl
P
P
Ph2
Ph2
Scheme 2: Synthetic context and objective of this study.
O
O
catalyst 5 (ref.[14]):
[Et2NH2] {[RuCl(S)-SEGPHOS]2(µ-Cl)3}
[a]
This ligand is a constituent of the catalyst 10 (formula: Scheme 1); [b]this ligand is a
constituent of the catalyst 3 (formula: Scheme 1) and was used in ref.8. Being commercially
available [Me2NH2] {[RuCl(S)-BINAP]2(µ-Cl)3} was employed as a catalyst in the present
study, though. It contains the same anion as 3 but a modified cation; [c]this ligand is a
constituent of the catalyst 4 (formula: Scheme 1); [d]in reality,17 this hydrogenation was
performed with [Ru(R)-MeO-BIPHEP)]Br2. It incorporates the mirror image of the ligand de-
picted in Scheme 1. By consequence the β-hydroxyesters 17 and their follow-up products
are depicted here with the opposite configurations as published.17,18
H2 (20 bar),
catalyst 10 (0.5 mol-%),
O
O
OH O
O
O
N
N
THF, 70°C, 8 h;
100% conversion (ref.[10a]
)
1a
2a
97.2% ee
([]20 = +67.8)
H2 (20 bar),
catalyst 10 (0.5 mol-%),
O
O
O
O
O
O
O
O
OH
*
O
O
O
O
EtO
EtO
N
N
EtO
EtO
N
THF, 70°C, 20 h;
36% conversion (ref.[10b]
H2 (20 bar),
)
Results and Discussion
6
7
92.4% ee
Ten variations a-j of β-keto Weinreb amides 1 were prepared
from one equivalent each of a carboxylic acid chloride 11, the
lithium enolate of N-methoxy-N-methylacetamide (12), and LDA
(Table 1). The latter was added such that once the β-keto
Weinreb amide – a C,H acid – forms it would not protonate
unconsumed lithio-12 but the stronger base LDA. Enolate lithio-
12 was generated over the course of 90 min from Weinreb
amide 12 and LDA at −78°C. The acid chlorides, by which it was
acylated, gave the highest yields when they could not – or
OH
O
catalyst 10 (0.5 mol-%),
O
N
*
R
EtOH, 70°C, 15 h;
100% conversion (ref.[10a,b]
)
R
R
R
8a-e
9a-e
8, 9
R2
H
ee
O
Ph2
a
b
c
d
e
87.3%[a]
98.1%[b]
32.5%
P
O
O
Me
Cl
Ru
P
Cl
-(CH2)2-
-(CH2)3-
-(CH2)4-
Ph2
O
84.1%
catalyst 10 (ref.[15]):
[RuCl(S)-SunPhos(C6H6)] Cl
91.7%
should not
–
β-eliminate HCl and form
a
ketene.
Cyclopropylformyl chloride gave 78% yield (1f), pivaloyl
chloride 87% (1i), and benzoyl chloride 85% (1j). The
lowest yields resulted from acetyl chloride ( 51% 1a), hex-
anoyl chloride ( 56% 1c), and tert-butylacetyl chloride ( 57%
1e)
Scheme 1: Literature precedence for the asymmetric hydrogenation of the
“simple” β-keto Weinreb amides 1c8 und 1a10a and the functionalized β-keto
Weinreb amides 610b und 8a-e10a,b
.
[a] In THF; [b] H2 (30 bar), 75°C.
Table 1: β-Keto Weinreb Amide Syntheses
From now on, such an exchange can be obviated. This is be-
cause, firstly, β-hydroxy Weinreb amides 2 are broadly acces-
sible by hydrogenating β-keto Weinreb amides 1 asymmetrically.
Secondly, β-keto Weinreb amides 1 can be prepared in a
hitherto unexploited manner, namely by a C2 extension of a car-
boxylic acid chloride with the lithium enolate of N-methoxy-N-
methylacetamide. Both reactions are described in the following.
They shorten Genêt´s route to enantiomerically pure β-hydroxy-
ketones 18, 1,3-diols anti-19, and 1,3-diols syn-19 by one step
(Scheme 2). Making this possible was our objective.
O
O
O
O
OH
O
cond.
+
O
O
O
R
Cl
11a-j
N
R
N
R
N
2
2
12
keto-1a-j
enol-1a-j
11, 1
R
keto-1
:
2-H /ppm
in keto-1
2-H/ppm
OH/ppm Yield/%
2
in enol-1
in enol-
1
enol-1
a
Me
85 : 15
3.54
5.36
13.69
51
3
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European Journal of Organic Chemistry
10.1002/ejoc.201601202
FULL PAPER
exclusively in conjunction with dilithio-25 as an enolate.24 The
carbon in excess was expelled as CO2 during the workup.
Staying with carboxylic acid chlorides as the most common
acylating agent our procedure simplifies the nucleophile, too, by
employing lithio-12 (reaction e, Scheme 3) instead of dilithio-
25.24,25
b
c
d
e
f
Et
Pent
iPrCH2
tBuCH2
cPr
88 : 12
85 : 15
77 : 23
64 : 36
3.56
3.55
3.54
3.55
3.70
3.63
3.61
3.69
4.14
5.39
5.38
5.36
5.33
5.51
5.39
5.36
5.44
6.09
13.72
13.71
13.67
13.65
13.95
13.77
13.75
13.98
14.24
65
56
69
57
78
69
72
87
85
Table 2: Asymmetric β-Keto Weinreb Amide Hydrogenations (ee determined
by HPLC analysis; the full details of the particular methods are given in the
Supporting Information).
96 :
4
g
h
i
iPr
82 : 18
82 : 18
77 : 23
66 : 34
[Me2NH2] {[RuCl(S-BINAP)]2-Cl3} (0.5 mol-%)
O
O
OH
O
O
O
cHex
tBu
R
N
R
N
H2 (5 bar), EtOH, room temp.,15 h
1a-j
2a-j
1, 2
R
Yield/%
Sign of spe-
cific rotation[a]
Configuration
ee/%
j
Ph
of 2
Conditions: iPr2NH (2.2 equiv.), nBuLi (2.0 equiv., solution in hexane), THF, −78°C, 1 h; ad-
dition of 12, −78°C, 1.5 h ( lithio-12); addition of 11a-j (1.0 equiv.), −78°C, 3 h.
a
b
c
d
e
f
Me
Et
98
96
99
99
96
99
96
97
99
92
+
+
+
+
+
+
+
+
+
+
S[b]
S[c]
99.0
98.8
98.9
98.9
85.7
98.9
98.7
96.3
92.8
76.8
The 1H-NMR data of the resulting β-keto Weinreb amides 1
showed that they were 2:1 – 24:1 mixtures of the keto- and one
enol-tautomer. It is plausible that the latter possesses a Z-config-
ured C=C bond as depicted in formula enol-1 of Table 1.
Pent
S[b]
iPrCH2
S[c]
CN bond formation
CC bond formation
 [d]
 [d]
R[b]
R[b]
R[c]
tBuCH2
cPr
OLi
O
a) ref.[22]
OMe
N
R1
OH
+
+
in situ activation
Cl
Me
lithio-12
O
O
b) ref.[19]
20
OMe
H2N
R1
Cl
+
g
h
i
iPr
Me
O
OLi
21
22-HCl
c) ref.[23]
OMe
R1
N
N
cHex
tBu
Cl
OMe
Me
N
H2N
Me
22-HCl
+
23
lithio-12
d) ref.[20]
OLi
O
O
O
j
Ph
R[b]
e)
O
O
OMe
OMe
+
R1
Cl
R1
N
N
ref.[24]
f) ref.[21]
OMe
R1
O
O
[a]
[b]
Me
OLi
dilithio-25
Me
At 589 nm (D-line of Na vapor).−
The sign (and magnitude) of our specific rotation
1
O
HN
Me
allowed to assign this configuration in conjunction with respective references value from the
following sources: ref.10 for 2a26, ref. for 2c, ref.18b for 2g, ref.27 for 2h, and ref.18b for 2j.− [c]
This configurational assignment was made after conversion into a β-hydroxyketone (Table
3) whose the 3D structure could be inferred from comparing its specific rotation to a
reference value, which the literature gave for specimens of the same β-hydroxyketones
there obtained: ref.28 for 32 (which we prepared from 2b), ref.29 for 40 (which we prepared
from 2d), and ref.30 for 52 (which we prepared from 2i).−
+
+
24
11
22
OH
O
O
O
O
OLi
g) ref.[21]
this work
OMe
R1
HN
+
OMe
R1
Cl
N
Me
22
[d]
Me
No specific rotation value
26
11
lithio-12
available in the literature.
Scheme 3: Established strategies for making β-keto Weinreb amides (a-g) vs.
The β-keto Weinreb amides 1a-j were hydrogenated at ambient
our own synthesis (bottom right).
temperature under an H2 atmosphere of 5 bar in ethanol solution

in the presence of 0.5 mol-% of Me2NH2 {[RuCl(S)-BINAP]2(µ-
A survey of literature syntheses of β-keto Weinreb amides 1 re-
vealed two preferred strategies (Scheme 3): forming a C−N
bond between a β-ketocarboxylic acid derivative and either
N-methoxy-N-methylamine (22) or its hydrochloride (22-HCl; re-
actions b,19 d,20 f,21 and g21) or forming a C−C bond between an
acylating agent and a Weinreb amide enolate derived from
acetic acid ( lithio-12) or monolithium malonate ( dilithio-25;
reactions a,22 c,23 and e24). Such C−N bond forming routes to β-
keto Weinreb amides engaged three β-ketocarboxylic acid
derivatives: a β-keto acid chloride (R1 = Me) 21,19 dioxinones
(24)20,21 or a C-acylated Meldrum’s acid (R1 = Ph) (26; the extra
carbon is lost as CO2 during the workup).21 C−C bond forming
routes to β-keto Weinreb amides employed an in-situ activated
carboxylic acid 20,22 imidazolides 2323 or carboxylic acid
chlorides 1124 as acylating agents. The latter were used
Cl)3} (Table 2). After routinely admitted durations of 15 h the β-
hydroxy Weinreb amides 2a-j were the only recognizable com-
pounds. With yields of 96-99%, the enantiomeric purity of the 6
top products amounted to 99% ee. This outcome resembles that
of asymmetric hydrogenations of analogously substituted β-ke-
toesters.2 Our other β-hydroxy Weinreb amides resulted with 96,
93, 86, and 77% ee. The last value is low and therefore
remindful of the dissatisfactory ee-values of equally BINAP-
controlled asymmetric hydrogenations of the analogously
phenylated ethyl (85% ee2) or methyl ester (90% ee31).
We assigned the absolute configuration of eight of the ten β-hy-
droxy Weinreb amides of Table 2 by comparing their specific ro-
tation
–
or the specific rotation of
a β-hydroxyketone
subsequently prepared therefrom (Table 3) – with a reference
value from the literature. The geometry was always the same
4
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European Journal of Organic Chemistry
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FULL PAPER
even if the CIP stereodescriptor varied. This justifies assuming
that the two remaining Weinreb amides of Table 2 posses the
analogous 3D structures. This would mean that the rule
“hydrogenations catalyzed by Ru complexes of S-BINAP
establish hashed COH bonds – provided the product is oriented
as 2 – ” applies not only to such hydrogenations of β-ketoesters2
and β-keto amides7b but to β-keto Weinreb amides as well.
25
26
27
28
cHEXLi
MeMgI
PhMgBr
nBuLi
C
A
B
+
+
+
+
51
52
53
54
74
88
90
88
2i
[a] Method A: RMgX (2.5 equiv., in Et2O), Et2O, 0°C, 1 h; room temp.; 1 - 15 h.− Method B:
nBuli (3.0 equiv., in hexane), THF, −78°C, 3 h; room temp., 0 – 3 h.− Method C: Di-tert-
butylbiphenyl (0.35 mol-% of R2Cl), lithium (6.4 equiv.), THF, 0°C, 4 h; R2Cl (3.2 equiv.),
−78°C, 15 h; addition of 2, −78°C, 1.5 h.− Method D: tBuli (3.0 equiv., in pentane), THF,
−78°C, 3 h; room temp., 3 h.− [b] at 589 nm (D-line of Na vapor).
Table 3: β-Hydroxyketone Syntheses
R2M
OH
O
OH
O
O
R1
N
R1
R2
method A, B, C or D
2a-d, f-i
27-54
Eight of the ten β-hydroxy Weinreb amides 2a-j from the asym-
metric hydrogenations of Table 2 exhibited ee values ≥92%.
They were used to acylate representative Grignard reagents
(MeMgI, PhMgBr) and organolithium compounds (nBuLi, iPrLi,
cHexLi, tBuLi). This made available a total of 28 enantiomerically
pure β-hydroxyketones 27-54 in 77% average yield (highest
yield 96%, lowest yield 50%; Table 3). Attaining these
compounds accomplished our goal of making such compounds
available based on catalytic asymmetric hydrogenations of β-
keto Weinreb amides 1 and more directly than via the β-
ketoester (15) hydrogenation route of Genêt et al.17,18 (Scheme
2).
En-
try
Substrate
R2M
Meth- Sign of spe- Pro- Yield/%
od[a]
duct
cific rotation[b]
1
MeMgI
PhMgBr
nBuLi
+
27
62
70
68
73
50
58
82
77
96
79
73
84
73
74
81
84
74
92
78
81
66
90
91
65
A
2
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
OH
O
O
Me
N
3
B
C
D
2a
4
iPrLi
5
tBuLi
6
MeMgI
PhMgBr
nBuLi
Table 4: Syn-1,3-diol Syntheses.
A
B
A
B
A
B
A
B
A
7
OH
O
OH OH
Et2BOMe (1.1 equiv.), THF/MeOH (4:1), -78°C, 15 min;
R1
R2
R1
R2
1
3
2b
NaBH4 (1.1-fold molar amount), -78°C, 3 h
8
28-29, 34, 41, 44-45
syn-55-60
syn-reduction
9
MeMgI
PhMgBr
nBuLi
Sub- R1 R2
strate
Diol
Syn:anti

C-1/ppm Sign of spe- Yield/%
[a]
C-3/ppm
cific rota-
tion[b]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2c
2d
69.3
73.3
29
Me nBu syn-55 100:0
Me Ph syn-56 100:0
Et nBu syn-57 100:0
cPr Me syn-58 100:0
+
91
MeMgI
PhMgBr
nBuLi
69.0
75.5
28
34
41
44
45
+
+
+
+
+
93
99
96
93
79
73.3
74.7
MeMgI
PhMgBr
nBuLi
78.0
68.8
2f
78.1
69.5
iPr Me syn-59
95:5
MeMgI
PhMgBr
nBuLi
77.8
75.8
iPr Ph syn-60 100:0
[a]The syn:anti ratios are the integral ratios over appropriate 1H-NMR resonances of the puri-
fied materials; their compositions might vary relative to the composition of the respective
crude product; [b] at 589 nm (D-line of Na vapor).
B
C
2g
iPrLi
Enantiomerically pure β-hydroxyketones akin to our specimens
of 27-54 (Table 3) can be processed to sterically homogenous
1,3-diols. This relies on reductants, which exhibit a high facial
selectivity because intermittently they bind to the OH group of
the substrate. Preparing syn-1,3-diols in such a manner the
method of choice is the Narasaka-Prasad reduction.32 We
applied it to six β-hydroxyketones from our stock successfully
MeMgI
PhMgBr
nBuLi
A
B
2h
5
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601202
FULL PAPER
(Table 4). The 1,3-diols 55-58 and 60 resulted uniquely with a
were isolable with perfect diastereomeric purities. If traces of the
syn-diastereomer were accompanying initially they were readily
removed by flash chromatography on silica gel.36 If the β-
hydroxyketone bore a phenyl group (R2) like in 28, 45 or 49 the
amount of syn-diastereomer increased and, annyingly, could not
be removed. This implies that phenyl-substituted ketones are
syn-configuration and the 1,3-diol 59 with
a
95:5
preponderance.33
The conversion of β-hydroxyketones into anti-1,3-diols has been
achieved mostly by the Evans(-Saksena) reduction.34 However,
diastereocontrol there is less efficient than in Narasaka-Prasad
reductions. According to Genêt et al. OH-directed Ru-catalyzed
C=O hydrogenations constitute an excellent alternative for such
anti-reductions.18a,b They turn β-hydroxyketones into anti-1,3-di-
ols with ds up to 99:1 even if the metal usually was complexed
with an achiral phosphane, namely PPh3.35
awkward
substrates
for
the
Ru-BINAP-catalyzed
hydrogenation.37
The result of Tables 4-5 makes our asymmetric hydrogenation
route to enantiomerically pure β-hydroxyketones (Tables 1-3)
part of efficient 4-step syntheses of enantiomerically pure
1,3-diols of any absolute or relative configuration. 1,3-Diol motifs
abound natural products – particularly, if they are polyketide-
based, but not only then.38 Methods for synthesizing 1,3-diols
stereoselectively are of great importance, accordingly.39,40
Table 5: Anti-1,3-diol Syntheses.
[Me2NH2] {[RuCl(S-BINAP)]2-Cl3} (0.5 - 1.0 mol-%)
OH
O
OH OH
R1
R2
R1
R2
1
3
H2 (5 bar), EtOH, room temp., 36 h
28-29, 34, 44-45, 47-49, 51
anti-55-57, 59-64
anti-reduction
Experimental Section
Sub-
strate
R1
R2
Diol
Anti:syn

C-1/ppm Sign of spe- Yield
[a]
General Working Technique and Analytic Techniques
/%
C-3/ppm
cific rota-
tion[b]
Working technique: All reactions, which did not require the presence of
water were carried out under an atmosphere of dry N2. Reaction flasks
were dried in an oven (65°C) and under reduced pressure with a heat
gun prior to use. Liquids were added with syringe and via cannula
through a rubber septum. Solids were added in a countercurrent of dry
N2. Reactions, which required or allowed the presence of water were
carried out in laboratory atmosphere. Solvents: Prior to use, diethyl
ether (Et2O) was distilled over sodium/potassium alloy, tetrahydrofuran
(THF) over potassium, dichloromethane (CH2Cl2), and triethyl amine
(NEt3) as well as diisopropyl amin (iPr2NH) over CaH2 under an atmos-
phere of dry N2. Other solvents, which were obtained commercially as
"dry" or "extra dry" solvents, were used without further purification.
29
28
Me
Me
nBu anti-55 100:0
65.7
69.6
+
82
99
Ph
anti-56
94:6
65.6
72.0
+
34
44
45
47
48
49
Et
iPr
nBu anti-57 100:0
69.6
71.0
+
+
+
+
+
+
95
88
Me
Ph
iPr
Me
Ph
anti-59 100:0
anti-60 85:15
anti-61 100:0
anti-62 100:0
anti-63 86:14
74.1
65.8
Cyclohexane (c-C6H12
column chromatography were distilled prior to use using
)
and ethyl acetate (EtOAc), for workup and
rotary
a
iPr
74.0
72.0
99
evaporator to remove high boiling fractions. Dichloromethane (CH2Cl2),
and tert-butyl methyl ether (TBME) for workup were obtained as p. a.
grade solvents and used without further purification. Organolithium
compounds and Grignard reagents were stored in a freezer in Schlenk
flasks with PTFE screw caps and PTFE valves. Prior to use,
organolithium compounds and Grignard reagents were titrated using
salicylaldehyde phenylhydrazone.41 Chromatography: Thin layer chro-
matography (TLC) on Merck silica plates with glass as supporting
material (TLC Silica gel 60 F254) was used to monitor reactions and
assess purification procedures. If possible, chromatograms were marked
in UV light at 254 nm and subsequently stained using permanganate
stain (2 g KMnO4, 4 g NaHCO3, 100 mL H2O) or vanillin stain (4.5 g
vanillin, 75 mL EtOH, 4 mL conc. H2SO4). Macherey-Nagel & Co silica
gel 60® (230-400 mesh) was used for flash column chromatography.36
Chromatography conditions are documented at the respective
experiment in the following manner: (d  h cm, solv1:solv2, a:b - c:d),
which means: a column with the inner diameter d cm was packed with
h cm silica gel. The product was eluted with the solvents solv1 and solv2
in the ratio a:b. HPLC: Determinations of the enantiomeric excess (ee)
were conducted by A. Schuschkowski using a Merck Hitachi LaChrom L
7100; further details: cf. individual experimental descriptions. NMR
spectroscopy: NMR spectra were recorded by Dr. M. Keller, F.
Reinbold, and M. Schonhard on a Bruker Avance 400 spectrometer [1H
(400 MHz), 13C (100 MHz), DQF-COSY, and edHSQC ("C,H-COSY")],
and a Bruker Avance III HD 500 spectrometer [1H (500 MHz), 13C
(126 MHz), DQF-COSY, and edHSQC ("C,H-COSY")] or on an
automated Varian Mercury VX 300 spectrometer [1H (300 MHz)] or an
automated Bruker Avance III HD 300 spectrometer [1H (300 MHz)].
Spectra were referenced internally by the 1H- and 13C-NMR signals of the
solvent [CDCl3: 7.26 ppm (1H) and 77.16 ppm (13C)]. 1H-NMR data are
reported as follows: chemical shift ( in ppm), multiplicity (s for singlet; d
for doublet; t for triplet; m for multiplet; mc for symmetrical multiplet; br for
iPr
74.4
74.4
93
cHex
cHex
73.5
65.8
95
73.5
72.0
88[c]
51
cHex cHex anti-64 100:0
73.8
73.8
+
93
[a] The anti:syn ratios are the integral ratios over appropriate 1H-NMR resonances of the pu-
rified materials; their compositions might vary relative to the composition of the respective
crude product;[b] at 589 nm (D-line of Na vapor); [c]72 h.
We adopted the last-mentioned method for hydrogenating nine
β-hydroxyketones from the stock of Table 3 anti-selectively
(Table 5). For being on the safe side35 we performed these
reactions in the presence of (S)-configured BINAP. This ligand

was administered as part of our ruthenium source, Me2NH2
{[RuCl(S)-BINAP]2(µ-Cl)3}. We assumed that this BINAP
enantiomer and whatever enantiomerically pure hydroxyketone
from Table 3 we combined led to a matched pair. In this regard
our choice of (S)-BINAP was in line with the (scarce) literature
precedence.17 However, we did not corroborate our assertion
experimentally. We simply found the following: The desired anti-
1,3-diols anti-55, anti-57, anti-59, anti-61, anti-62 and anti-64
6
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601202
FULL PAPER
broad signal), coupling constant(s) (Hz; 3J couplings unless otherwise
noted), integral, and specific assignment. For AB signals the high-field
part is named A and the low-field part B. 13C-NMR data are reported in
terms of chemical shift and assignment. The atom numbering used for
NMR assignments follows the IUPAC nomenclature. High resolution
mass spectra were recorded by Dr. J. Wörth and C. Warth on a Thermo
Exactive mass spectrometer equipped with an orbitrap analyzer.
Ionization methods: Electron spray ionization (ESI; spray voltage: 4-5 kV)
or atmospheric pressure chemical ionization (APCI; spray current: 5 µA).
Elemental analyses were obtained by A. Siegel on an Elementar Vario
El CHNS analyzer. IR spectra were recorded on a Perkin Elmer
Spectrum 65 FT-IR spectrometer for a film of the substance on a NaCl
plate. Optical rotations were measured on a Perkin-Elmer polarimeter
c-C6H12:EtOAc = 4:1). This furnished the title compound 1i (3.16 g, 87%)
as an orange oil.
1H NMR (400.1 MHz, CDCl3):  = 1.17 [s, 9H, 4-(CH3)3, (enol-1i)], 1.18
[s, 9H, 4-(CH3)3, (1i)], 3.20 [s, 3H, NCH3, (enol-1i)], 3.21 [s, 3H, NCH3,
(1i)], 3.65 [s, 3H, OCH3, (1i)], 3.69 [s, 2H, 2-H2, (1i)], 3.70 [s, 3H, OCH3,
(enol-1i)], 5.44 [s, 1H, 2-H, (enol-1i)], 13.98 [s, 1H, 3-OH, (enol-1i)] ppm.
13C NMR (100.6 MHz, CDCl3):  = 26.41 [4-(CH3)3, (1i)], 27.77 [4-(CH3)3,
(enol-1i)], 32.09 [NCH3, (enol-1i)], 32.23 [NCH3, (1i)], 36.95 [C-4, (enol-
1i)], 42.79 [C-2, (1i)], 44.75 [C-4, (1i)], 61.33 [OCH3, (1i)], 61.36 [OCH3,
(enol-1i)], 82.32 [C-2, (enol-1i)], 186.09 [C-1, (1i)], 209.13 [C-3, (1i)]
ppm.
IR (film): = 2970, 2940, 1710, 1665, 1620, 1480, 1465, 1445, 1385,
1370, 1220, 1065, 770 cm−1
.
341 at 589 nm (Na lamp). []20 was calculated as follows: []20 = (exp.
100)/(c × d), where λ [nm] is the wavelength, exp. [°] the experimental re-
sult, c [g/100 mL] the concentration, and d [dm] the length of the optical
cell. []20 is given as the arithmetic mean of five measurements.
×
Combustion analysis: found: C: 57.73%, H: 9.16%, N: 7.39%;
calculated for C9H17NO3: C: 57.73%, H: 9.15%, N: 7.48%.
HRMS (pos. APCI): M+H+, found m/z = 188.12870, i.e.,  = +0.2 ppm
versus what C9H18NO3 requires (188.12867).
N-Methoxy-N-methylacetamide (12) was prepared following the
description of KERR et al.42 NEt3 (23.1 mL, 16.8 g, 166 mmol, 2.0 equiv)
Representative Procedures45 for Asymmetric Hydrogenations, Acyl-
ations, syn- and anti-Reductions [all exemplarily for the Follow-up
Products of N-Methoxy-N-methyl-3-oxobutanamide (1a), the Simplest β-
Keto Weinreb Amide of this Study]:
was added to
a
stirred solution of N,O-dimethylhydroxylamine
hydrochloride (22-HCl, 8.05 g, 82.8 mmol, 1.0 equiv) in CH2Cl2 (200 ml)
at 0°C. Acetyl chloride (11a, 5.91 mL, 6.50 g, 82.8 mmol) was added
dropwise at 0°C. The resulting mixture was stirred for 17 h at ambient
temp. The reaction was quenched with satd. aq. NaHCO3 (130 mL). The
aq. layer was separated and extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were washed with aq. HCl (1M, 50 mL) and
brine (50 mL) and dried over Na2SO4. Removing the solvent under
reduced pressure and purifying the residue by distillation (bp. 65°C,
50 mbar) furnished the title compound 12 (7.09 g, 83%, ref.42 98%43) as a
colorless liquid.
(S)-3-Hydroxy-N-methoxy-N-methylbutanamide (S-2a):
[Me2NH2]
{[RuCl(S)-BINAP]2(µ-Cl)3} (4.0 mg, 2.4 μmol, 0.5 mol-%) was weighed
in an autoclave. The autoclave was evacuated and flushed with nitrogen.
A solution of the Weinreb amid 1a (78 mg, 0.54 mmol) in degassed EtOH
(6 mL) was added. The resulting mixture was stirred under H2 pressure
(5.0 bar) at ambient temp. for 15 h. The solvent was removed under re-
duced pressure and the residue was purified by flash chromatography on
silica gel36 (1 × 12 cm, c-C6H12:EtOAc = 1:2). This furnished the title com-
pound S-2a (79 mg, 98%, 99.0% ee46) as a brown liquid.
1H NMR (300.1 MHz, CDCl3):  = 2.12 (s, 3H, 2-H3), 3.18 (s, 3H, NCH3),
3.69 (s, 3H, OCH3) ppm. These data are consistent with those reported in
the literature.42
1H NMR (300.1 MHz, CDCl3):  = 1.24 (d, J4,3 = 6.3 Hz, 3H, 4-H3), AB
signal [A = 2.44 and B = 2.65 (2JAB = 17.1 Hz, part A additionally split by
J2A,3 = 9.3 Hz, 2H, 2-H2)], 3.19 (s, 3H, NCH3), 3.69 (s, 3H, OCH3), 3.82
(br. s, 1H, OH), 4.21 (mc, 1H, 3-H) ppm. These data are consistent with
Preparation of N-Methoxy-N-methyl-3-oxobutanamide (1a), i. e., the
Simplest β-Keto Weinreb Amide of this Study: At −78°C n-BuLi
(16.5 mL, 2.34 M solution in n-hexane, 38.8 mmol, 2.0 equiv) was added
to a solution of iPr2NH (6.00 mL, 4.32 g, 42.7 mmol, 2.2 equiv) in THF
(60 mL). After stirring for 1 h N-Methoxy-N-methylacetamide 12 (2.00 g,
19.4 mmol) in THF (20 mL) was added slowly. The resulting mixture was
stirred at −78°C for 1.5 h. Acetyl chloride (11a, 1.38 mL, 1.52 g,
19.4 mmol, 1.0 equiv) was added. After stirring at −78°C for 30 min the
reaction was quenched with aq. HCl (1M, 80 mL), and the organic layer
was separated. The aq. layer was extracted with EtOAc (3 × 80 mL). The
combined organic extracts were dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel36 (4 × 15 cm, c-C6H12:EtOAc = 3:1). This
furnished the title compound 1a (1.43 g, 51%44) as an orange oil.
1H NMR (300.1 MHz, CDCl3):  = 1.94 [s, 3H, 4-H3, (enol-1a)], 2.22 [s,
3H, 4-H3, (1a)], 3.15 [s, 3H, NCH3, (enol-1a)], 3.18 [s, 3H, NCH3, (1a)],
3.54 [s, 2H, 2-H2, (1a)], 3.646 [s, 3H, OCH3, (1a)] superimposed by 3.650
[s, 3H, OCH3, (enol-1a)], 5.36 [s, 1H, 2-H, (enol-1a)], 13.69 [s, 1H, 3-OH,
(enol-1a)] ppm. These data are consistent with those reported in the liter-
ature.10
those reported in the literature.47
= +61.0 (c = 1.42, CHCl3)
(S)-4-Hydroxypentan-2-one (S-27), i. e. Example for Method A (Table
3): A solution of the Weinreb amide S-2a (474 mg, 3.22 mmol) in Et2O
(13 mL) was treated with MeMgI (1.47 M solution in Et2O, 5.48 mL,
8.05 mmol, 2.5 eq) at 0°C and stirred for 1 h at 0°C. The mixture was
stirred for another 2 h at ambient temperature. Satd. aq. NH4Cl (30 mL)
was added, the layers were separated, and the aq. layer was extracted
with tBuOMe (3 × 30 mL). The aq. layer was acidified with aq. HCl (1 M)
and again extracted with tBuOMe (3 × 30 mL). The combined organic
extracts were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel36 (3 × 16 cm, C6H12:EtOAc = 1:1). This furnished the title compound
S-27 (204 mg, 62%) as a colorless liquid.
1H NMR (400.1 MHz, CDCl3):  = 1.19 (d, J5,4 = 6.3 Hz, 3H, 5-H2), 2.17
(s, 3H, 1-H3), AB signal [A = 2.54 and B = 2.63 (2JAB = 17.8 Hz, part A
additionally split by J3A,4 = 3.4 Hz, part
B
additionally split by
J3B,4 = 8.7 Hz, 2H, 3-H2)], 3.01 (br. s, 1H, 4-OH), 4.22 (mc, 1H, 4-H) ppm.
These data are consistent with those reported in the literature.48
Preparation of N-Methoxy-N,4,4-trimethyl-3-oxopentanamide (1i), i.
e., the Highest-Yielding β-Keto Weinreb Amide of this Study: At
−78°C n-BuLi (16.6 mL, 2.34 M solution in n-hexane, 38.8 mmol,
= +67.7(c = 1.06, CHCl3)
(S)-3-Hydroxy-1-phenylbutan-1-one (S-28), i. e. Example for Method
A (Table 3): A solution of the Weinreb amide S-2a (510 mg, 3.47 mmol)
in Et2O (15 mL) was treated with PhMgBr (1.54 M solution in Et2O,
5.63 mL, 8.66 mmol, 2.5 eq) at 0°C and stirred for 1 h at 0°C. Thereafter
the mixture was stirred for another 1 h at ambient temperature. Satd. aq.
NH4Cl (35 mL) was added, the layers were separated, and the aq. layer
was extracted with tBuOMe (3 × 35 mL). The combined organic extracts
were dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel36 (3 × 18 cm,
C6H12:EtOAc = 10:1). This furnished the title compound S-28 (399 mg,
70%) as a colorless liquid.
2.0 equiv) was added to
a solution of iPr2NH (6.00 mL, 4.32 g,
42.7 mmol, 2.2 equiv) in THF (60 mL). After stirring for 1 h N-Methoxy-N-
methylacetamide (12) (2.01 g, 19.4 mmol) in THF (20 mL) was added
slowly. The resulting mixture was stirred at −78°C for 1.5 h. Pivaloyl
chloride (11i, 2.39 mL, 2.34 g, 19.4 mmol, 1.0 equiv) was added. After
stirring at −78°C for 1 h the reaction was quenched with aq. HCl (1 M,
80 mL). The organic layer was separated. The aq. layer was extracted
with EtOAc (3 × 80 mL). The combined organic extracts were dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel36 (4 × 14 cm,
7
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601202
FULL PAPER
1H NMR (300.1 MHz, CDCl3):  = 1.31 (d, J4,3 = 6.3 Hz, 3H, 4-H3), AB
signal [A = 3.05 and B = 3.17 (2JAB = 17.7 Hz, part A additionally split by
J2A,3 = 3.0 Hz, part B additionally split by J2B,3 = 8.8 Hz, 2H, 2-H2)], 3.28
(br. s, 1H, 3-OH), 4.41 (mc, 1H, 3-H), 7.45-7.62 (m, 3H, 3 × Ar-H), 7.94-
7.97 (m, 2H, 2 × Ar-H) ppm. These data are consistent with those
(2S,4R)-Octane-2,4-diol (syn-55): A solution of the β-hydroxy ketone
S-29 (346 mg, 2.40 mmol) in THF/MeOH (4:1, 20 mL) was treated with
Et2BOMe (1 M solution in THF, 2.64 mL, 2.64 mmol, 1.10 equiv.) at
−78°C and stirred for 20 min at this temperature. NaBH4 (100 mg,
2.64 mmol, 1.10 equiv.) was added. The resulting mixture was stirred for
3 h at 0°C. MeOH (10 mL), aq. NaOH (1 M, 5.9 mL), and aq. H2O2 (30%,
2.9 mL) were added. The resulting mixture was stirred for 15 h at
ambient temperature. The reaction mixture was concentrated. The
residue was dissolved in a mixture of CH2Cl2 (15 mL) and brine (15 mL).
The layers were separated. The aq. layer was extracted with CH2Cl2
(5 × 30 mL). The combined organic extracts were washed with satd. aq.
Na2SO3 (30 mL), dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel36 (3 × 15 cm, C6H12:EtOAc = 9:1). This furnished the title compound
syn-55 (321 mg, 91%) as a colorless liquid.
reported in the literature.49
= +76.1 (c = 1.88, CHCl3)
(S)-2-Hydroxyoctan-4-one (S-29), i. e. Example for Method B (Table
3): A solution of the Weinreb amide S-2a (323 mg, 2.20 mmol) in THF
(10 mL) was treated with nBuLi (2.36 M solution in hexane, 2.79 mL,
6.59 mmol, 3.0 eq) at −78°C and stirred for 3 h at −78°C. Satd. aq. NH4Cl
(10 mL) was added, the layers were separated, and the aq. layer was ex-
tracted with EtOAC (3 × 20 mL). The combined organic extracts were
washed with brine (20 mL), dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel36 (3 × 16 cm, C6H12:EtOAc = 4:1). This furnished the title com-
pound S-29 (216 mg, 68%) as a colorless liquid.
1H NMR (400.1 MHz, CDCl3):  = 0.91 (t, J8,7 = 7.1 Hz, 3H, 8-H3), 1.21
(d, J1,2 = 6.3 Hz, 3H, 1-H3), 1.25-1.61 (m, 8H, 3-H2, 5-H2, 6-H2, 7-H2),
3.01 (br. s, 2H, 2-OH, 4-OH), 3.82-3.88 (m, 1H, 4-H), 4.01-4.09 (m, 1H,
2-H) ppm.
1H NMR (300.1 MHz, CDCl3):  = 0.91 (t, J8,7 = 7.3 Hz, 3H, 8-H3), 1.19
(d, J1,2 = 6.3 Hz, 3H, 1-H3), 1.32 (mc, 2H, 7-H2), 1.56 (mc, 2H, 6-H2), 2.41
13C NMR (100.6 MHz, CDCl3):  = 14.16 (C-8), 22.83 (C-7), 24.39 (C-1),
27.65 (C-6), 38.14 (C-5), 44.91 (C-3), 69.33 (C-2), 73.27 (C-4) ppm.
(t, J5,6 = 7.5 Hz, 2H, 5-H2), AB signal [A = 2.50 and
B = 2.59
These data are consistent with those reported in the literature.53
(2JAB = 17.6 Hz, part
A
additionally split by J3A,2 = 3.2 Hz, part
B
= +6.5(c = 1.08, CHCl3)
additionally split by J3B,2 = 8.7 Hz, 2H, 3-H2)], 3.09 (br. s, 1H, 2-OH), 4.21
(mc, 1H, 2-H) ppm. These data are consistent with those reported in the
literature.50
(1S,3S)-1-Phenylbutane-1,3-diol (syn-56): A solution of the β-hydroxy
ketone S-28 (316 mg, 1.92 mmol) in THF/MeOH (4:1, 18 mL) was treated
with Et2BOMe (1 M solution in THF, 2.12 mL, 2.12 mmol, 1.10 equiv.) at
−78°C and stirred for 20 min at this temperature. NaBH4 (80.0 mg,
2.64 mmol, 1.10 equiv.) was added. The resulting mixture was stirred for
3 h at 0°C. MeOH (8 mL), aq. NaOH (1 M, 4.8 mL), and aq. H2O2 (30%,
2.4 mL) were added. The resulting mixture was stirred for 15 h at
ambient temperature. The mixture was concentrated. The residue was
dissolved in a mixture of CH2Cl2 (15 mL) and brine (15 mL). The layers
were separated and the aq. layer was extracted with CH2Cl2 (5 × 30 mL).
The combined organic extracts were washed with satd. aq. Na2SO3
(30 mL), dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel36
(3 × 18 cm, C6H12:EtOAc = 2:1). This furnished the title compound syn-56
(297 mg, 93%) as a colorless liquid.
= +53.5 (c = 1.17, CHCl3)
(S)-5-Hydroxy-2-methylhexan-3-one (S-30), i. e. Example for Method
C (Table 3): A solution of 4,4’-di-tert-butylbiphenyl (0.91 g, 3.4 mmol,
contains 0.35 mol-% of 2-chloropropane) in THF (40 mL) was treated
with small pieces of lithium (134 mg, 19.3 mmol, 6.3 equiv.) at 0°C. The
mixture was stirred at 0°C for 4 h. The mixture was cooled to −78°C,
2-chloropropane (0.89 mL, 0.77 g, 9.8 mmol, 3.2 equiv) was added, and
the mixture was stirred at −78 C for 15 h. A solution of the Weinreb
amide S-2a (450 mg, 3.06 mmol) in THF (10 mL) was added by means of
a syringe pump over a period of 90 min. The mixture was stirred for
another 8 h and then treated with satd. aq. NH4Cl (35 mL). The layers
were separated and the aq. layer was extracted with EtOAC (3 × 30 mL).
The combined organic extracts were dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel36 (3 × 18 cm, C6H12:EtOAc = 5:1). This
furnished the title compound S-30 (291 mg, 73%) as a colorless liquid.
1H NMR (300.1 MHz, CDCl3):  = 1.10 (d, J2-Me,2 = 7.0 Hz, 3H, 2-CH3),
1.11 (d, J2-Me,2 = 7.0 Hz, 3H, 2-CH3), 1.19 (d, J6,5 = 6.4 Hz, 3H, 6-H3), AB
signal [A = 2.54 and B = 2.64 (2JAB = 17.7 Hz, part A additionally split by
J4A,5 = 3.0 Hz, part B additionally split by J4B,5 = 8.7 Hz, 2H, 4-H2)] super-
imposed by 2.58 (qq, 2 × J2,2-Me = 6.9 Hz, 1H, 2-H), 3.21 (br. s, 1H,
5-OH), 4.20 (mc, 1H, 5-H) ppm. These data are consistent with those
1H NMR (400.1 MHz, CDCl3):  = 1.23 (d, J4,3 = 6.2 Hz, 3H, 4-H3), AB
signal [A = 1.76 and B = 1.86 (2JAB = 14.6 Hz, part A additionally split by
J2A,1 = 9.8 Hz, J2A,3 = 9.8 Hz, part B additionally split by J2B,1 = 3.1 Hz,
J2B,3 = 2.5 Hz, 2H, 2-H2)], 3.04 (br. s, 1H, 3-OH)*, 3.22 (br. s, 1H, 1-OH)*,
4.10-4.18 (m, 1H, 3-H), 4.93 (dd, J1,2A = 10.1 Hz, J1,2B = 3.2 Hz, 1H, 1-H),
7.25-7.38 (m, 5H, 5 × Ar-H) ppm; *assignments interchangeable
13C NMR (100.6 MHz, CDCl3):  = 24.29 (C-4), 47.30 (C-2), 68.99 (C-3),
75.50 (C-1), 125.80 (2 × Co), 127.79 (Cp), 128.68 (2 × Cm), 144.62 (Cipso
)
ppm. These data are consistent with those reported in the literature.54
reported in the literature.51
= +56.8 (c = 1.46, CHCl3)
= +64.8 (c = 1.51, CHCl3)
(2S,4S)-Octane-2,4-diol (anti-55): [Me2NH2] {[RuCl(S)-BINAP]2(µ-
Cl)3} (27 mg, 16 μmol, 0.5 mol-%) was weighed in an autoclave. The
autoclave was evacuated and flushed with nitrogen. A solution of the β-
hydroxy ketone S-29 (465 mg, 3.22 mmol) in degassed EtOH (32 mL)
was added. The resulting mixture was stirred under H2 pressure (5.0 bar)
at ambient temp. for 36 h. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography on silica
gel36 (3 × 16 cm, C6H12:EtOAc = 5:1). This furnished the title compound
anti-55 (385 mg, 82%) as a brown liquid.
(S)-5-Hydroxy-2,2-dimethylhexan-3-one (S-31), i. e. Example for
Method D (Table 3): A solution of the Weinreb amide S-2a (267 mg,
1.81 mmol) in THF (10 mL) was treated with tBuLi (1.43 M solution in
pentane, 3.79 mL, 5.41 mmol, 3.0 eq) at −78°C, stirred for 3 h at −78°C
and for another 3 h at 0°C. Satd. aq. NH4Cl (10 mL) was added, the
layers were separated, and the aq. layer was extracted with tBuOMe
(3 × 20 mL). The combined organic extracts were washed with brine
(15 mL), dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel36
(3 × 16 cm, C6H12:EtOAc = 4:1). This furnished the title compound S-31
(131 mg, 50%) as a colorless liquid.
1H NMR (400.1 MHz, CDCl3):  = 0.91 (t, J8,7 = 7.1 Hz, 3H, 8-H3), 1.24
(d, J1,2 = 6.3 Hz, 3H, 1-H3), 1.25-1.57 (m, 6H, 5-H2, 6-H2, 7-H2), 1.60 (mc,
2H, 3-H2), 2.60 (br. s, 2H, 2-OH, 4-OH), 3.91-3.97 (m, 1H, 4-H), 4.71-
4.20 (m, 1H, 2-H) ppm.
1H NMR (300.1 MHz, CDCl3):  = 1.14 (s, 9H, 2-(CH3)3), 1.20 (d,
13C NMR (100.6 MHz, CDCl3):  = 14.17 (C-8), 22.84 (C-7), 23.71 (C-1),
28.10 (C-6), 37.30 (C-5), 44.21 (C-3), 65.70 (C-2), 69.58 (C-4) ppm.
J6,5 = 6.3 Hz, 3H, 6-H3), AB signal [A = 2.54 and
B = 2.69
(2JAB = 17.9 Hz, part
A
additionally split by J4A,5 = 2.8 Hz, part
B
These data are consistent with those reported in the literature.29
additionally split by J4B,5 = 8.9 Hz, 2H, 4-H2)], 3.34 (br. s, 1H, 5-OH), 4.18
(dqd, J5,4B = 9.0 Hz, J5,6 = 6.3 Hz, J5,4A = 2.7 Hz, 1H, 5-H) ppm. These
= +17.0 (c = 1.52, CHCl3)
data are consistent with those reported in the literature.52
= +65.0 (c = 1.63, CHCl3)
8
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European Journal of Organic Chemistry
10.1002/ejoc.201601202
FULL PAPER
(1R,3S)-1-Phenylbutane-1,3-diol (anti-56):
[Me2NH2]
{[RuCl(S)-
BINAP]2(µ-Cl)3} (18 mg, 11 μmol, 0.5 mol-%) was weighed in an auto-
clave. The autoclave was evacuated and flushed with nitrogen. A solution
of the β-hydroxy ketone S-28 (346 mg, 2.11 mmol) in degassed EtOH
(20 mL) was added. The resulting mixture was stirred under H2-pressure
(5.0 bar) at ambient temp. for 36 h. The solvent was removed under re-
duced pressure. The residue was purified by flash chromatography on
silica gel36 (3 × 18 cm, C6H12:EtOAc = 3:1). This furnished the title
compound anti-56 (347 mg, 99%, anti:syn 94:6 ) as a brown liquid.
1H NMR (400.1 MHz, CDCl3):  = 1.24 (d, J4,3 = 6.3 Hz, 3H, 4-H3), AB
signal [A = 1.86 and B = 1.92 (2JAB = 14.5 Hz, part A additionally split by
J2A,1 = 7.7 Hz, J2A,3 = 3.3 Hz, part B additionally split by J2B,3 = 8.1 Hz,
J2B,1 = 3.8 Hz, 2H, 2-H2)], 2.36 (br. s, 1H, 3-OH)*, 2.99 (br. s, 1H, 1-OH)*,
4.07 (mc, 1H, 3-H), 5.05 (dd, J1,2A = 7.7 Hz, J1,2B = 3.8 Hz, 1H, 1-H), 7.25-
7.39 (m, 5H, 5 × Ar-H) ppm; *assignments interchangeable
11
12
N. A. Magnus, B. A. Astleford, D. L. T. Laird, T. D. Maloney, A. D.
McFarland, J. R. Rizzo, J. C. Ruble, G. A. Stephenson, J. P. Wepsiec J.
Org. Chem. 2013, 78, 5768-5774.
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13C NMR (100.6 MHz, CDCl3):  = 23.78 (C-4), 46.30 (C-2), 65.60 (C-3),
71.99 (C-1), 125.72 (2 × Co), 127.51 (Cp), 128.61 (2 × Cm), 144.61 (Cipso
)
Ref. 10a assigned the absolute configuration of the β-hydroxy Weinreb
ppm. These NMR data are consistent with those reported in the
amide 2a by comparing (the sign of) its specific rotation with
a
literature.55
published value.
= +17.9 (c = 1.48, CHCl3)
17
18
O. Labeeuw, J.-B. Bourg, P. Phansavath, J.-P. Genêt, Arkivoc 2007,
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Acknowledgment
19
20
P. Dübon, M. Schelwies, G. Helmchen, Chem. Eur. J. 2008, 14, 6722-
6733.
Support of this work by the DFG (IRTG 1038 “Catalysts and Catalytic Re-
actions for Organic Synthesis”) is gratefully acknowledged.
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Keywords: asymmetric hydrogenation, β-keto Weinreb amides,
β-hydroxy Weinreb amides, β-hydroxyketones, anti-1,3-diols,
syn-1,3-diols
21
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26
27
28
4
Reviews: a) M. Kitamura, R. Noyori, “Hydrogenation and Transfer
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Weidmann and Hoffmann assigned the syn- vs. anti-configuration in
pairs of 1,3-diols by comparing the sums of the 13C-NMR shifts of the
OH-bearing C atoms, which each diasteromer exhibits. The correlation,
which they established is (C1syn + C3syn) > (C1anti + C3anti): R. W.
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pected) syn-selectivity of our Narasaka-Prasad reductions is corrobo-
rated by this correlation: 142.6 ppm (syn-55) > 135.3 ppm (anti-55);
8
S. Kamptmann, Diplomarbeit (Diploma Thesis), Universität Freiburg
2007, p. 45.
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H. Zhu, Dissertation, Universität Freiburg 2014, pp. 259-260.
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144.5 ppm
(syn-56) > 137.6 ppm
(anti-56);
148.0 ppm
(syn-
57) > 140.6 ppm (anti-57); 147.6 ppm (syn-59) > 139.9 ppm (anti-59);
153.6 ppm (syn-60) > 146.0 ppm (anti-60).
9
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European Journal of Organic Chemistry
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FULL PAPER
34
51
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52
53
54
55
Obviously, substrate control of diastereoselectivity suffices for
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selectivities based on Ru-catalysis. Noyori (using BINAP)3 and later
Genêt (using MeO-BIPHEP)17 showed that addition of enantiomerically
pure phosphanes instead of PPh3 increases such anti-selectivities
moderately as a result of double stereodifferentiation. Genêt et al.
chose the matched enantiomer of the MeO-BIPHEP ligand instead of
PPh3 to ensure that substrate and catalyst control of diastereoselectivity
re-enforce each other. Employing (R)-MeO-BIPHEP in that regard, the
anti-selectivity of the hydrogenation of (S)-5-(benzyloxy)-4-
hydroxypentan-2-one increased from 97:318b to >99:1.17,.
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W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923-2925.
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Genêt et al. found that SYNPHOS is apt for hydrogenating this
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hydrogenatiing (S)-3-hydroxy-4-methyl-1-phenylpentan-1-one.
38
Selection of reviews on natural products containing – inter alia – 1,3-
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Reviews on the stereoselective synthesis of 1,3-diols, 1,3,5-triols, etc.:
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43
Crude product; no purification with distillation.
44
We also synthesized 1a in a higher yield following the description of
Koert et al.20
45
The syntheses and analytical data of the compounds 1b-h,j, 2b-j, 32-53
and 57-63 are located in the Supporting Information.
46
99.0% ee determined by HPLC on a chiral stationary phase (Chiralcel
OD-3 column, n-heptane/2-propanole 98:2, 1.0 mL/min, 22°C, UV
detection at 220 nm); tr(R-enantiomer) = 13.99 min, tr(S-enantiomer) = 16.76 min.
47
F. Cohen, L. E. Overman, J. Am. Chem. Soc. 2006, 128, 2594-2603.
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10
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