Asymmetric dihydroxylation of esters and amides of methacrylic, tiglic, and angelic acid: No exception to the sharpless mnemonic!

Article abstract of DOI:10.1002/ejoc.201403622

Literature findings on the facial selectivity of the Sharpless asymmetric dihydroxylation (SAD) of isobutyl angelate are contradictory and partly in conflict with the Sharpless mnemonic. We systematically screened the SAD of esters and amides of angelic, tiglic, and methacrylic acid. Enantiocontrol arose in 14 of the 15 reactions, culminating at 99 % ee for the Weinreb amide of tiglic acid. The absolute configurations of all the nonracemic products were established by (stereo)chemical correlations. Without exception, they conform to the Sharpless mnemonic.

Full text of DOI:10.1002/ejoc.201403622

Job/Unit: O43622
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FULL PAPER
DOI: 10.1002/ejoc.201403622
Asymmetric Dihydroxylation of Esters and Amides of Methacrylic, Tiglic, and
Angelic Acid: No Exception to the Sharpless Mnemonic!
[a]
[a]
Fabian Weber and Reinhard Brückner*
Keywords: Asymmetric catalysis / Configuration determination / Dihydroxylation / 1,2-Diols / Enantioselectivity / Oxid-
ation
Literature findings on the facial selectivity of the Sharpless
asymmetric dihydroxylation (SAD) of isobutyl angelate are
trol arose in 14 of the 15 reactions, culminating at 99% ee
for the Weinreb amide of tiglic acid. The absolute configura-
contradictory and partly in conflict with the Sharpless mne- tions of all the nonracemic products were established by
monic. We systematically screened the SAD of esters and (stereo)chemical correlations. Without exception, they con-
amides of angelic, tiglic, and methacrylic acid. Enantiocon- form to the Sharpless mnemonic.
Introduction
in one instance contradictory, and in part in conflict with
[
11–19]
the Sharpless mnemonic (Scheme 1, see below).
investigation unravels the steric course of the SAD of esters
This
The Sharpless asymmetric dihydroxylation (SAD) of ole-
fins[1] is a major asset for accessing enantiomerically pure
[
20]
[21]
and amides of methacrylic acid,
tiglic acid,
gelicacid unambiguously(seebelow);enantiomericallypure
in most cases) or enriched (occasionally) 1,2-diols
obtained from such substrates were used in the construction
and an-
1,2-diols, enantiomerically pure functionalized 1,2-diols,
[
22]
[
2–4]
and enantiomerically pure follow-up products thereof.
(
The number of applications of the SAD reaction in synthe-
sis is impressive, which underlines that this transformation
is rightfully considered an extremely reliable, and hence
[
20k,21b,21c]
of complex natural products,
represented drug
[
20h,20j]
candidates,
served as building blocks for pept-
[
3]
prize-worthy, tool in asymmetric synthesis in general.
An appealing feature of SADs is that the absolute config-
urations of the resulting diols are easily predicted by the so-
called “Sharpless mnemonic”.[5] Assignments based there-
upon were corroborated by independent evidence in many
instances. Therefore, more often than not, the mnemonic
has assumed a further-going role: It is used for “deriving”
the configuration of a SAD product. Whether so much con-
fidence is warranted must be gauged against the number of
exceptions to the predictions. In essence, we are unaware of
[
20a,20c,20e–20g,21a,22b]
ides
diverse products.
or became the progenitor of other
Our central finding was
[
20b,20d,20i,21d,22a,22c]
that angelate SADs proceed in full accordance with the
Sharpless mnemonic.
any such exception at all, exempting, of course, the SADs Figure 1. Methacrylates 1, tiglates 2, and angelates 3, and their
[
6]
[7]
respective amides, the substrates used for SADs in this investigation
and in many earlier studies.[
of geminally disubstituted, cis-disubstituted, and tetra-
20–22]
substituted C=C bonds;[8] these all provide disproportion-
ately little orientational bias if scrutinized by the mne-
monic. A few SADs that engaged trisubstituted C=C bonds
in certain enynes were once associated with counter-mne-
The first SAD of an alkyl angelate was executed in the
context of the synthesis of “what should have been (2S,3R)-
[11]
α-methylthreonine”
[(2S,3R)-6]: Dihydroxylating iso-
[9]
monic facial selectivities, however, these assignments have
1
butyl angelate (3b) with Sharpless’ AD-mix β gave the diol
been corrected recently.[
10]
[11]
(
R,R)-7b (60% ee;
Scheme 1, line 2). Six steps down the
To the best of our knowledge, the trisubstituted C=C
bond of angelic acid esters 3 (Figure 1), and derivatives
thereof, is the only SAD site at which, according to the
literature, configurational control was incongruent, at least
road they achieved α-methylthreonine (6), but were sur-
prised to find that its specific rotation “was of the opposite
[11]
sign from the literature value”. The latter stemmed from
a specimen of (2S,3R)-6, the precursor (5) of which had
[
23]
been analyzed by X-ray diffraction
(Scheme 1, line 1).
[
a] Institut für Organische Chemie, Albert-Ludwigs-Universität,
Albertstraße 21, 79104 Freiburg, Germany
Later, the outcome of the SAD of isobutyl angelate (3b)
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
http//www.brueckner.uni-freiburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403622.
was re-interpreted and the configurational assignment of
[
11]
the earlier study
altered from (2S,3R)-6 to (2R,3S)-6
[
12]
(Scheme 1, line 3). Based on force field calculations and
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F. Weber, R. Brückner
FULL PAPER
a genetic algorithm for searching transition structures
reasons were forwarded as to why this particular SAD
would comply with a transition state (“Chapleur transition
[
12]
state” ) that is at odds with the Sharpless mnemonic. In
contrast, we felt that additional experiments should be per-
formed before one dismantles an otherwise utterly reliable
predictive tool like the Sharpless mnemonic.
The absolute configurations of the major diol enantio-
mers obtained by the SAD of other esters of angelic
[
13–15]
acid
substituted angelic acids (Scheme 1, lines 7–10) were also
(Scheme 1, lines 4–6) and by the SAD of esters of
[13]
published. The configurations of diol (R,R)-9 (line 4), di-
ols (R,R)-14a and (R,R)-14b (line 7),
line 9),
[
16]
diol (R,R)-18
[
18]
[19]
(
and diol (S,S)-20 (line 10)
were not estab-
lished experimentally but “simply” drawn such that they do
lines 4, 7, and 9) or do not (line 10) comply with the
Sharpless mnemonic. In contrast, the absolute configura-
(
[
14]
tions of diols (R,R)-11a and (R,R)-11b (line 5),
diol
were
[
15]
[17]
(
R,R)-7a (line 6),
proven by chemical correlations
sis of the product obtained after a further 10 synthetic
and diol (R,R)-16 (line 8)
[
14a]
and by an X-ray analy-
[
14b]
steps,
an X-ray analysis of the underlying dihydroxy-
[
15]
carboxylic acid (R,R)-12 as an enzyme complex, and by
correlating the diol (R,R)-16 chemically with a molecule,
the absolute configuration of which is known from X-ray
[
17]
crystallography, respectively.
In the context of a natural product synthesis project,[24]
we considered enantiomerically enriched diols like diol 7 as
a building block. For type-7 diols emerging from the SAD
of derivatives of angelic acid (3; Figure 1), a literature sur-
vey revealed that we would face variable enantiomeric ex-
cesses (60–99% ee) and that there was no consensus about
[
19]
the stereochemical outcome (Scheme 1 ). This led us to
diverge from the target-oriented work to study the SAD
reactions of angelic acid derivatives in some depth. We also
scrutinized their E isomers likewise, that is, tiglic acid deriv-
atives (2; Figure 1), and certain “nor-compounds”, namely
methacrylic acid derivatives (1; Figure 1). This approach
was chosen to gather insights firstly into effects of the
double bond configuration and secondly into the role of the
methyl group at C-3.
In more detail, our study comprised the SAD reactions
of isobutyl esters 1b–3b (Figure 1). This was done mainly
in order to re-investigate the SAD of isobutyl angelate (3b),
for which Scheme 1 juxtaposes conflicting literature results
[
11]
[12]
(lines 2
and 3 ). Methyl esters 1a–3a (Figure 1) were
included in our study because of their commercial availabil-
ity and PMB esters 1c–3c (Scheme 2) because they re-
semble, to some extent, PMBz-protected allyl alcohol 21.
The latter shows exceptional selectivity in the SAD reaction
[
25]
(e.g., Scheme 2, top),
which may be attributed to the
Scheme 1. Literature findings and/or claims concerning the SAD of
alkyl angelates 3 and substituted alkyl angelates. The emphasis is on the strong interactions of the PMBz group with the methoxy-
contradictions and/or doubts that are contained therein or evoked
thereby. Dihydroxylations that gave products for which the configura-
tional assignments must be reversed in the light of results of this study
[26]
quinoline moiety of the ligand, or, speaking in terms of
the Sharpless mnemonic, a strong prevalence for the PMBz
are depicted on a light-grey background. [a] This SAD was performed group to lie in the SW corner. Weinreb amides (d) were of
1
with AD-mix α and led to the mirror-image of the diol depicted in this
interest because of the exceptional selectivity observed in
scheme. For the sake of easier comparison with the facial selectivity of
the dihydroxylation of the Weinreb amide of methacrylic
AD-mix β-mediated SADs, the genuine result is replaced by the outcome
1
[27,28]
(
fictitious, yet predictable) of the corresponding SAD with AD-mix β .
acid (1d).
Pyrrolidine-derived amides (e; not depicted
2
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Asymmetric Dihydroxylation
in Scheme 2) complement our spectrum of esters/amides ation). We attempted to activate angelic acid (28) as an acid
and allowed us to verify whether Weinreb amides behave as chloride and treated the latter with nucleophile/base pairs,
ordinary amides under SAD conditions.
which had served well in the methacrylic and tiglic acid
series, but we could not suppress the systems’ tendency to
undergo EǞZ isomerizations. We circumvented this obsta-
cle as follows: PMB angelate (3c) was obtained in 90% yield
by combining angelic acid as a nucleophile with PMB-Cl as
an electrophile. The amides 3d (76%) and 3e (70%) were
derived from the magnesium salts of the underlying amines
and their acylation with methyl angelate (3a).
Scheme 2. Results of SAD reactions from the literature, which led
us to include PMB esters and Weinreb amides in our study.
Top: SAD of allylic 4-methoxybenzoates (e.g., 21) display consider-
ably more enantiocontrol than if the acyl group was different.[
Our PMB esters 1c–3c exhibit the same distance between the meth-
oxyphenyl group and the C=C bond as in “favored substrates” 21,
25b]
2
even if the CH –O–C(=O) motif is inverted. Bottom: SAD of
methyl methacrylate (1a) shows no enantiocontrol whereas the cor-
responding Weinreb amide (1d) is dihydroxylated with 93% ee.[
28]
Scheme 3. Origin of the substrates (1a–e to 3a–e) of this study;
grey: commercially available, black: synthesized as specified below.
Reagents and conditions: i) SOCl
flux, 2 h, 75%; ii) PMB-OH (1.05 equiv.), pyridine (1.2 equiv.),
CH Cl , room temp., 18 h, 72%; iii) SOCl (1.3 equiv.), CH Cl
reflux, 1 h; HNMe(OMe)·HCl (2.0 equiv.), pyridine (4.0 equiv.),
2
(1.5 equiv.), DMF (2 drops), re-
2
2
2
2
2
,
Synthesis of the Substrates
°C, 1 h; room temp., 18 h, 82% (ref.[ : 94%); iv) pyrrolidine
2.0 equiv.), CH Cl , room temp., 4 h, 84%; v) SOCl (1.2 equiv.),
DMF (2 drops), reflux, 2.5 h, 96%; vi) iBuOH (1.5 equiv.), pyridine
Cl , 0 °C Ǟ room temp., 18 h, 86%; vii) PMB-OH
1.05 equiv.), pyridine (1.2 equiv.), CH Cl , 0 °C Ǟ room temp.,
8 h, 72%; viii) HNMe(OMe)·HCl (1.05 equiv.), pyridine
2.4 equiv.), CH Cl , 0 °C Ǟ room temp., 18 h, 78%; ix) pyrrolidine
2.2 equiv.), CH Cl , 0 °C Ǟ room temp., 18 h, 81%; x) LiOH·H
29]
0
(
Five of the ester substrates used in our study were com-
mercially available: 1a, 1b, 2a, 3a, and 3b (Scheme 3, grey
2
2
2
color). This left 10 substrates to be synthesized (Scheme 3, (1.5 equiv.), CH
2
2
(
1
(
(
2
2
black color). The derivatives of methacrylic and tiglic acid
were prepared from the corresponding carboxylic acids 24
and 26. They were first activated as the acid chlorides 25
2
2
2
2
2
O
and 27, respectively. These were then treated with an appro- (1.1 equiv.), MeOH/H O (1:1), reflux, 4 h, 88% of a E/Z = 10:90
2
priate nucleophile/base pair. This delivered the esters 1c mixture, which was recrystallized from EtOH giving the pure Z
[
29]
2 3
isomer in 44% yield; xi) PMB-Cl (1.01 equiv.), Cs CO (1.0 equiv.),
(
(
72%), 2b (86%), and 2c (72%), and the amides 1d
82%), 1e (84%), 2d (78%), and 2e (81%). Angelic acid (28)
DMF, 0 °C, 1 h; room temp., 2 h, 90%; xii) HNMe(OMe)·HCl
1.55 equiv.), THF, –20 °C, 30 min; iPrMgCl (3.0 equiv.), THF,
20 °C, 30 min, 76%; xiii) pyrrolidine (1.55 equiv.), THF, –20 °C,
yield after separating from some tiglic acid by crystalliz- 30 min; iPrMgCl (1.5 equiv.), THF, –20 °C, 30 min, 70%.
(
–
was prepared by hydrolyzing its isobutyl ester (3b; 44%
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F. Weber, R. Brückner
FULL PAPER
Results and Discussion
in terms of enantiomeric excess (74 and 88% ee), and the
yields remained somewhat lower in the α and β series (60
As expected,[28] the SAD of methyl methacrylate (1a) and 88%; entries 9 and 10, respectively) even though we
yielded racemic material (Table 1, entries 1 and 2). The iso- employed more K OsO (OH) and more ligand.
2
2
4
butyl ester 1b performed only slightly better, delivering 10
The extended reaction time of 5 d, which was required
and 16% ee with “α-AD” and “β-AD”, respectively (en- for the SADs of the Weinreb amide 1d and the pyrrolidide
tries 3 and 4). The SADs of PMB methacrylate (1c) yielded 1e (Table 1, entries 7–10), already included a trick. It might
diols with 61 and 72% ee (entries 5 and 6). The Weinreb be useful, in general, for conducting sluggish SADs. Ini-
amide 1d of methacrylic acid was dihydroxylated asymmet- tially we observed that in these reactions a significant
rically exceptionally well, as reported previously,[
27,28]
pro- amount of K [Fe(CN) ] stuck to the wall of the reaction
3 6
viding the corresponding diols with 95 and 98% ee (with flask after two days. This decreased the amount of
“
“
α-AD” and “β-AD”, entries 7 and 8, respectively). The K [Fe(CN) ] left in the reaction mixture so much that the
normal” methacrylic amide 1e performed not quite as well dihydroxylation reaction virtually stopped. As a conse-
3 6
Table 1. SADs of methacrylic, tiglic, and angelic acid derivatives.
[
a] α-AD: K
tBuOH/H O (1:1), 0 °C, time. β-AD: K
), K OsO (OH) (1.0 mol-%), tBuOH/H
analysis, the corresponding racemic diol was also prepared by using the modified Upjohn reaction described by Sharpless and co-
3
[Fe(CN)
6
] (3.0 equiv.), K
2
CO
[Fe(CN)
O (1:1), 0 °C, time. [b] Determined by analytical HPLC. To calibrate the respective HPLC
3
(3.0 equiv.), MeSO
2
NH
2
(1.0 equiv.), (DHQ)
2
PHAL (2.0 mol-%), K
2
OsO
2
(OH)
4
(1.0 mol-%),
2
3
6
] (3.0 equiv.), K
2
CO (3.0 equiv.), MeSO
3
2
NH (1.0 equiv.), (DHQD)
2
2
PHAL (2.0 mol-
%
2
2
4
2
[
30]
workers.
[c] PhSO
2
NH
2
was used instead of MeSO
2
NH
2
to facilitate separation of the product by flash chromatography. [d] These
OsO (OH) were used.
products are racemic. [e] 3.0 mol-% of the respective ligand and 2.0 mol-% of K
2
2
4
4
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Asymmetric Dihydroxylation
quence, the yields fell to 21–45%. This impediment was Table 2. Conversion, by saponification and esterification, of the di-
ols 23b–e and 7b–e from the “α-AD”-mediated SADs presented in
remedied by siliconizing the inside of the reaction flask
prior to conducting the SAD. This was considered as a po-
tential improvement for all the SAD reactions. So, from
Table 1, that is, of the diols with a butyl ester (b), a PMB ester (c),
a Weinreb amide (d), or a pyrrolidide moiety (e), into the methyl
ester containing diols 23a, syn-7a, and anti-7a. This set of transfor-
then on, we routinely siliconized the reaction flask before mations reduced the number of diols to which an absolute configu-
each SAD (for details, see the Exp. Sect.).
ration had to be (re)assigned from 15 to 3.
The SADs of the tiglic acid based esters and amides 2a–
e (Table 1, entries 11–20) succeeded with good or very good
enantiocontrol. The Weinreb amide 2d performed best (98
and 99% ee, entries 17 and 18) and the isobutyl ester worst
(81 and 85% ee, entries 13 and 14). All in all, we obtained
higher or much higher ee values than with the methacrylic
analogues (entries 1–10). Qualitatively, the dependency of
the ee value on the substituent was similar: Weinreb
amideϾ pyrrolidideϾ PMB esterϾ the two aliphatic esters.
However, isobutyl tiglate (2b) reacted with less enantiocon-
trol (entries 13 and 14) than methyl tiglate (2a; entries 11
and 12) whereas for isobutyl (1b) and methyl methacrylate
(1a) the opposite was true (entries 3 and 4 vs. entries 1 and
2).
The ee values of the SADs of the angelic acid based es-
ters 3a–c and the Weinreb amide 3d (Table 1, entries 21–28)
ranged from 90% [methyl angelate (3a) + “β-AD”, entry 22]
to 60% [PMB ester of angelic acid (3c) + “α-AD”, en-
try 25]. Curiously, the pyrrolidide 3e reacted with exception-
ally low ee values (entries 29 and 30) and was the only sub-
strate for which the (DHQ) PHAL ligand outperformed the
2
34]
[
(
DHQD) PHAL ligand.
Methyl angelate (3a) was di-
2
hydroxylated nearly as enantioselectively (entries 21 and 22)
as methyl tiglate (2a; entries 11 and 12). All the other deriv-
atives of angelic acid (3b–e) were dihydroxylated with less [a] The ee values were determined by chiral GC (see the Supporting
enantiocontrol than their tiglic acid based congeners (2b– Information). The ee values for (R)-23a (entries 1–4) and (S,S)-7a
(
entries 9–12) are given in parentheses; they are approximate values
e). Remarkably, the aliphatic esters of angelic acid (3a,b)
underwent SADs with higher enantioselectivity than the
analogous amides (3d,e). The opposite observation was
because our analyses did not baseline-separate the enantiomers.
made for the methacrylic acid based ester/amide pairs (1a,b 23a, the tiglic diols syn-7b–e into the methyl ester syn-7a,
vs. 1d,e) and their tiglic acid analogues (2a,b vs. 2d,e). The and the angelic diols anti-7b–e into the methyl ester anti-7a
“spread” between the five pairs of ee values for the “β-AD” (Table 2). This was achieved by successive hydrolysis and
and “α-AD” reactions of the derivatives 3a–e of angelic esterification reactions. It worked well for the isobutyl es-
acid (–7 to +20%; mean absolute value: 13%) is larger than ters, PMB esters, and Weinreb amides (average yield: 87%
usual. For example, the analogous spreads for the tiglic acid over the two steps), but badly for the pyrrolidides (average
[
35]
analogues 2a–e are +1 to +5% (mean value: 3%) and for yield: 24% over the two steps). Chiral GC revealed that
the methacrylic acid analogues 1a–e 0 to +11% (mean the four nonracemic “methacrylic diols” had identical con-
[
36]
value: 7%).
figurations. The same was true for the five “tiglic diols”
Measuring the ee values of the 15 diols, which are com- and likewise for the five “angelic diols”.[36] This consoli-
piled in Table 1 as pairs of enantiomers (except for the diols dation of the product portfolio obviated the need of attrib-
from methyl methacrylate; entries 1 and 2), was the prelude uting the absolute configurations of all 15 diols of Table 2
to determining their favored absolute configurations individually. Instead, we clarified their absolute configura-
(Table 2; if any, cf. entries 1 and 2 of Table 1). In doing so, tions group-wise (by GC and the experiments of Scheme 4).
we turned to the 15 diols obtained by “α-AD”-mediated
SADs (Table 1), considering their counterparts from the “β- 23b–e are R enantiomers
The methyl ester containing diol 23a and its progenitors
[
37]
because the absolute con-
AD”-mediated SADs as their mirror images.
figuration of the SAD-based Weinreb amide 23d is
[
20a,20c,20f,20k]
Five of the “α-AD”-based diols contain the carbon known.
The methyl ester containing diol syn-
framework of methacrylic acid (23a–e; “methacrylic diols”), 7a and its progenitors 7b–e are 2R,3S-configured because
another five that of tiglic acid (syn-diols 7a–e; “tiglic di- this is the absolute configuration of the carboxylic acid ob-
ols”), and the remaining five that of angelic acid (anti-diols tained by hydrolysis of this syn-diol; this configuration was
7
a–e; “angelic diols”). We facilitated their analysis by con- established by X-ray structural analysis of an enzyme com-
[
21d]
verting the methacrylic diols 23b–e into the methyl ester plex of that acid.
Finally, the methyl ester containing
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F. Weber, R. Brückner
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(
(
2S,3R)-7c from the “β-AD”-based SAD of PMB tiglate
2c) and (S,S)-7c from the “β-AD”-based SAD of PMB an-
gelate (3c), which had been prepared according to Table 1
entries 16 and 26, respectively), must be epimers. Their
(
oxidations provided the antipodal forms of the hydroxy
keto ester 29c. The dihydroxy ester (2S,3R)-7c led to the
hydroxy keto ester (S)-29c, which is levorotatory, and the
dihydroxy ester (S,S)-7c gave the hydroxy keto ester (R)-
29c, which is dextrotatory. This proves that their dihydroxy
ester precursors (2S,3R)- and (S,S)-7c are C-2 and not C-3
epimers (as was briefly mentioned above). These oxidations
were unexpectedly difficult with respect to their chemoselec-
tivity. Treatment of CH Cl solutions of a dihydroxy ester
2
2
Scheme 4. Proof that the SAD of the isomeric PMB esters 2c
tiglate) and 3c (angelate) hydroxylates C-3 with identical facial se-
lectitivity (i.e., from the Re side) but C-2 with opposite facial selec-
tivity (i.e., 2c from the Si side but 3c from the Re side). This proves
7c with pyridinium dichromate (PDC) or with 10 mol-%
(
2,2,6,6-tetramethylpiperidinyloxyl (TEMPO)/stoichiometric
PhI(OAc) resulted in glycol cleavages, even with 1 equiv. of
2
that these diols are configured in accordance with the predictions the respective oxidant. Treatment of our dihydroxy esters
from Sharpless’ mnemonic (see main text). Reagents and condi-
7c with the Dess–Martin reagent gave no bias at all between
tions: i) Bleach (total content of chlorine approx. 10%, approx.
.6 m, 1.65 equiv.), KBr (1.0 equiv.), TEMPO (0.5 equiv.), saturated
aqueous NaHCO solution/CH Cl (1:1), 0 °C, 15 min; 76% for
S)-29c, 90% for (R)-29c.
glycol cleavage and the desired oxidation. Only 50 mol-%
TEMPO combined with a stoichiometric amount of bleach
furnished the hydroxy keto esters 29c in a clean reaction.
In fact, the crude product was essentially pure.
1
3
2
2
(
The “syn”-diols (2S,3R)- and (2R,3S)-7a–e and their
1
diol anti-7a and its progenitors 7b–e are the C-2 epimers of “anti” diastereomers (R,R)- and (S,S)-7a–e reveal H NMR
1
13
the aforementioned diols. We proved this by the stereo- shifts or H NMR shift differences (Table 3) as well as
C
chemical correlations presented in Scheme 4. They destroy NMR shift differences, which might be indicators of their
the stereocenters at C-3 of diols (2S,3R)-7c (from PMB tigl- relative configurations. In this regard, the bottom line of
1
ate and “β-AD”, cf. entry 16 of Table 1) and (R,R)-7c (from Table 3 illustrates three seemingly characteristic H NMR
PMB angelate and “β-AD”, cf. entry 26 of Table 1) by oxid- shift orderings: (1)·δ(2-CH ) is smaller in the syn isomers
3
izing the respective hydroxy groups to oxo substituents. than in the anti isomers and the respective δ ranges do not
Conversely, the stereocenters at C-2 are preserved. Hence, overlap (δsyn = 1.31–1.37 ppm, δanti = 1.43–1.50 ppm). (2)
the methyl ester containing diol anti-7a originating δ(3-H) is larger in the syn isomers than in the anti isomers
(
Table 2) from our “α-AD”-mediated SADs of esters and with a δsyn – δanti maximum of +0.46 for the Weinreb amide
amides of angelic acid of Table 1 must be S,S-configured. (7d). δ(4-H ) is larger in the syn isomers than in the anti
The same is concluded from the identity of our diol anti- isomers (again, the respective δ ranges do not overlap: δsyn
a from Table 2 with an independently prepared specimen, = 1.20–1.25 ppm, δanti = 0.99–1.17 ppm). Moreover, the
which was subjected to X-ray analysis as an enzyme com- bottom line of Table 3 indicates that two of the mentioned
3
7
[
15,38]
plex.
characteristics can be combined to give an improved crite-
It is worthwhile (re)turning to the stereochemical corre- rion for distinguishing the syn- and anti-configured diols:
lations in Scheme 4 in some detail. The dihydroxy esters The methyl groups 2-CH
and 4-H display a smaller differ-
3
3
1
Table 3. H NMR shifts of 4-H
4
3
, 2-CH
3
, and 3-H in the diastereomeric diols (2S,3R)-7a–e (“syn”-7a–e) and (R,R)-7a–e (“anti”-7a–e) at
3
00 MHz in CDCl .
7
Het
δ(2-CH
syn
3
) [ppm]
anti
δ(3-H) [ppm]
δ(4-H
syn
3
) [ppm]
anti
δ(2-CH
3
) – δ(4-H
3
) [ppm]
anti
syn
anti
syn
a
b
c
d
e
OMe
OiBu
OPMB
NMe(OMe)
N(CH
1.32
1.31
1.31
1.37
1.33
1.44
1.45
1.43
1.49
1.50
3.94
3.93
3.94
4.15
4.19
3.80
3.81
3.78
3.69
3.93
1.23
1.22
1.20
1.25
1.21
1.15
1.17
1.08
0.99
1.09
0.09
0.09
0.11
0.12
0.12
0.29
0.28
0.35
0.50
0.41
2 4
)
Δδsyn–anti = –0.13 ppm
Δδsyn–anti = +0.23 ppm
Δδsyn–anti = +0.13 ppm
ΔΔδsyn–anti = +0.26 ppm
6
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Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
Table 4. 13C NMR shifts of C-1, C-2, 2-CH
3
, C-3, and C-4 in the diastereomeric diols (2S,3R)-7a–e (“syn”-7a–e) and (R,R)-7a–e (“anti”-
3
7a–e) at 101 MHz in CDCl .
7
Het
δ(C-1) [ppm]
δ(C-2) [ppm]
δ(2-CH
syn
3
) [ppm]
anti
δ(C-3) [ppm]
δ(C-4) [ppm]
syn
anti
syn
anti
syn
anti
syn
anti
a
b
c
d
e
OMe
OiBu
176.83
176.38
176.25
176.00
175.70
175.45
175.72
173.35
77.37
77.31
77.32
77.67
77.47
77.27
77.19
77.13
77.23
76.53
21.80
21.77
21.74
21.84
21.21
22.35
22.46
22.32
22.13
21.39
71.71
71.71
71.71
70.38
70.74
72.31
72.26
72.26
70.04
70.89
16.76
16.77
16.76
17.17
16.16
17.79
17.80
17.71
18.33
18.02
OPMB
NMe(OMe) 175.51
N(CH 173.63
2 4
)
Δδsyn–anti is posi- Δδsyn–anti is posi-
Δδsyn–anti
–0.46 ppm
=
Δδsyn–anti is positive or nega-
Δδsyn–anti =
–1.21 ppm
tive or negative
tive or negative
tive
ence in shift in the syn series [δ(2-CH ) – δ(4-H ) = 0.09– ure 2) both for the methacrylic backbone 1 if the C=O-con-
3
3
0
0
.12 ppm] than in the anti series [δ(2-CH ) – δ(4-H ) = taining substituent at C-α resides in the moderately stabiliz-
3 3
[
39]
[41]
.28–0.50 ppm]. Similarly, the bottom line of Table 4 re- ing SW corner, and for the tiglic and angelic backbones
1
3
veals two seemingly characteristic C NMR shift order- 2 and 3 if the methyl substituent at C-β is kept at a distance
ings: (1) δ(2-CH ) is smaller in the syn isomers than in the by the destabilizing SE corner.
3
anti isomers. (2) δ(C-4) is smaller in the syn isomers than in
the anti isomers with no overlap between the δ ranges (δsyn portance, for nondestabilizing interactions of their β-sub-
16.16–17.17 ppm, δanti = 17.71–18.33 ppm). stituent and for stabilizing interactions of their α-substitu-
The key question behind this study was the following: ent in the SAD transition state concomitantly. Angelic acid
Tiglic acid derivatives 2 allow, in order of decreasing im-
=
Do asymmetric dihydroxylations of the prototypical α,β- derivatives 3 enjoy only the former effect, being deprived of
unsaturated substrate scaffolds 1–3 take a different steric the latter. This difference fits with the observation that our
course than the Sharpless mnemonic predicts? Exempting tiglic acid derivatives 2a–e were dihydroxylated with higher
methyl methacrylate (9a), which reacted without enantio- ee values (Table 1, entries 11–20) than their angelic acid an-
control (Table 1, entries 1 and 2) and thereby is the only alogues 3a–e (Table 1, entries 21–30).
exception, the stereochemical assignments of Table 2 give
With respect to our re-examination of the facial selectiv-
an easy answer: The SAD reactions of the methacrylic (1), ity of isobutyl angelate (3b) with “β-AD” (as defined in
tiglic (2), and angelic backbones (3) each proceeded in ac- footnote a of Table 1), our result (Table 1, entry 14) de-
cordance with the Sharpless mnemonic.[ This is true (Fig- bunks the suggestion that it is engaged by AD-mix β in
40]
[12]
Figure 2. Sharpless mnemonic[40] analysis of the orientation of the substrates of this study (Het represents OR or NR [40]
) in the transition
2
state of SADs mediated by AD-mix β or β-AD (as defined in footnote a of Table 1). The facial selectivities [if existing, cf. the exception
of methyl methacrylate (9a; entries 1 and 2 of Table 1)] shown here follow from the stereochemical correlations of Table 2.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
FULL PAPER
a “Chapleur transition state”, reacting allegedly[12] as de- 254 nm and subsequently stained by using permanganate (2 g
KMnO
4
, 4 g NaHCO
3
, 100 mL of H
2
O) or vanillin stain (4.5 g va-
SO ). Macherey–Nagel &
picted in line 3 of Scheme 1. By the same token the identical
nillin, 75 mL of EtOH, 4 mL conc. H
2
4
facial selectivities of methyl angelate (3a) and isobutyl ange-
®
late (3b) with “β-AD” make the published[19] 3D course of
Co silica gel 60 (230–400 mesh) was used for flash column
chromatography.[ Chromatography conditions are documented
for the respective experiment in the following manner: (dϫh cm,
43]
the SAD of the benzyloxy-substituted ethyl angelate 19,
which is shown as line 10 of Scheme 1, untrustworthy.
x y
V mL, solv1:solv2, a:b–c:d, F –F ), which means: a column with
the inner diameter of d cm was packed with h cm silica gel, frac-
tions of V mL were collected, the product was eluted with the sol-
vents solv1 and solv2 in the ratio a:b, the ratio, if not stated other-
wise, was changed every 12 fractions in the following series (the
first ratio marks the starting point, the last ratio marks the end
point): 100:0, 100:1, 50:1, 20:1, 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3,
Conclusions
We subjected five different derivatives each of meth-
acrylic, tiglic, and angelic acid to asymmetric dihydrox-
0
x y
:100, F –F are the fractions containing the product. NMR spec-
1
ylation by using a modified Sharpless asymmetric dihydrox- tra were recorded with a Bruker AM 400 spectrometer [ H
ylation protocol. Among the methacrylic acid derivatives, (400 MHz), C (100 MHz), DQF-COSY, edHSQC, and HMBC
1
3
1
13
experiments], a Bruker DRX 500 spectrometer [ H (500 MHz),
126 MHz), DQF-COSY, edHSQC (“C,H-COSY”), and HMBC
experiments], or an automated Varian Mercury VX 300 spectrome-
C
the Weinreb amide 1d stood out in terms of yield and enan-
tiomeric excess (Table 1, entries 7 and 8): 83% yield and
(
95% ee with (DHQ) PHAL; 93% yield and 98% ee with
2
1
1
ter [ H (300 MHz)]. Spectra were referenced internally by the H
(
DHQD) PHAL. Most of the tiglic acid derivatives reacted
2
13
1
and
7.10 ppm ( C)]. The H NMR spectroscopic data are reported as
follows: Chemical shift (δ in ppm), multiplicity (s for singlet, d for
doublet, t for triplet; m for multiplet, m for symmetrical multiplet,
3
C NMR solvent signals [CDCl : 7.26 ppm ( H) and
in over 80% yield (Table 1, entries 11–20) and the enantio-
meric excesses for both amides were excellent (97–99% ee).
The derivatives of angelic acid reacted somewhat less
satisfyingly (Table 1, entries 21–30). Nonetheless methyl an-
1
3
1
7
c
3
br. for broad), coupling constant(s) (Hz; J couplings unless other-
1
3
gelate was dihydroxylated in 82% yield and with 77% ee by wise noted), integral, and assignment. The C NMR spectroscopic
using (DHQ) PHAL or in 86% yield and with 90% ee by data are reported in terms of chemical shift and assignment. For
2
AB signals the high-field part is named A and the low-field part B.
The atom numbering used for NMR assignments follows the IU-
using (DHQD) PHAL.
2
Our most important finding is that each substrate scaf-
PAC nomenclature. Primed nuclei refer to substituents. Specifically,
fold delivered the same diol enantiomer no matter whether
the locants “i”, “o”, “m”, and “p” refer to the ipso, ortho, meta,
it reacted as an ester or an amide. In addition, the stereo-
structures of all the diols were in agreement with the
and para positions of the p-methoxyphenyl groups; these locants
are assigned such that the CH -substituted aromatic carbon is des-
2
Sharpless mnemonic. Therefore we consider the latter as
fully rehabilitated with regard to the doubts that were raised
ignated as the ipso carbon. High-resolution mass spectra were re-
corded with a Thermo Exactive mass spectrometer equipped with
an orbitrap analyzer and by using the electron spray ionization
(ESI; spray voltage: 4–5 kV) or atmospheric pressure chemical ion-
ization (APCI; spray current: 5 μA) technique. Elemental analyses
were performed with an Elementar Vario El CHNS analyzer. Melt-
ing points were determined with a Büchi melting point apparatus
using open glass capillaries.[ IR spectra were recorded with a
Perkin–Elmer Paragon 1000 FT-IR spectrometer on films of the
sample on an NaCl plate. HPLC: The enantiomeric excesses (ees)
were determined by using a Merck Hitachi LaChrom L 7100
HPLC instrument; for further details, see individual experimental
descriptions. Optical rotations were measured with a Perkin–Elmer
[
9,12]
[10]
some time ago
but have not persisted (ref.
and the
current work; Figure 2).
44]
Experimental Section
General Methods and Analytic Techniques: All reactions that did
not require the presence of water were carried out under dry N
Reaction flasks were dried in an oven (65 °C) and under reduced
pressure with a heat gun prior to use. Liquids were added by sy-
ringe or through a cannula through a rubber septum. Solids were
added in a counter-current of dry N
allowed the presence of water were carried out in the laboratory
atmosphere. Solvents: THF was distilled from potassium, and
2
.
3
3
41 polarimeter at 598 nm (Na lamp) and/or 587, 546, 436, and
20
2
. Reactions that required or
65 nm (Hg lamp). The values of [α]
were calculated by using the
= (100αexp.)/(cd), in which λ [nm] is the wavelength,
exp. [°] the experimental result, c [g/100 mL] the concentration, and
λ
20
expression [α]
α
d [dm] the length of the optical cell. [α]
λ
CH
were obtained commercially as “dry” or “extra dry” solvents were
used without further purification. c-C 12, EtOAc, MeOH, EtOH,
CH Cl , and tert-butyl methyl ether (TBME) for work-up and col-
umn chromatography were distilled prior to use by using a rotary
evaporator to remove high-boiling fractions. Et O, pentane, and
CHCl for work-up and column chromatography were obtained as
2
Cl
2
over CaH
2
under dry N
2
prior to use. Other solvents that
20
λ
values are given as the
arithmetic mean of five measurements.
6
H
2
2
General Procedure A Ϫ Racemic Dihydroxylations: Citric acid
(0.75 equiv.) and the respective olefin were dissolved in tBuOH/
2
H
2
O (1:1, 1 m). K
2
OsO
2
(OH)
4
(0.25 mol-%) and N-methylmorph-
O, 1.2 equiv.) were added.
[45]
3
oline N-oxide
(“NMO”, 50% in H
2
p.a. grade solvents and used without further purification. Grignard
reagents were stored in a freezer in Schlenk flasks with PTFE screw
caps and PTFE valves. Prior to use, they were titrated by using
salicylaldehyde phenylhydrazone.[42] Chromatography: TLC on
Merck silica plates with glass as supporting material (TLC Silicagel
The resulting green solution was stirred at room temp. until the
green color disappeared. The reaction was then quenched by the
addition of a saturated aqueous Na SO solution. The phases were
2 3
separated and the aqueous phase was extracted with EtOAc (3ϫ).
The combined organic phases were washed with brine and dried
6
0 F254) was used to monitor reactions and assess purification pro- with MgSO
4
. The solvent was removed under reduced pressure.
[
43]
cedures. If possible, chromatograms were marked in UV light at The product was purified by flash chromatography on silica gel.
8
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Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
General Procedure B Ϫ Asymmetric Dihydroxylations: Finely pow-
dered K [Fe(CN) ] (3.0 equiv.), K CO (3.0 equiv.), (DHQ) PHAL
or (DHQD) PHAL (2.0 mol-%), and K OsO (OH) (1.0 mol-%) = J2-Me,4 = 1.4 Hz, 3 H, 2-Me), 1.95 (dqq, J2Ј,1Ј = J2Ј,2Ј-Me = J2Ј,3Ј
were added to precooled tBuOH/H O (1:1, 0.1 m) at 0 °C.
MeSO NH or PhSO NH (1.0 equiv.) and the respective olefin C NMR
CDCl
3
): δ = 0.94 (d, J3Ј,2Ј = J2Ј-Me,2Ј = 6.7 Hz, 6 H, 2Ј-Me, 3Ј-H
3
),
5
4
3
6
2
3
2
1.77 (dq, J4,3 = 7.2, J4,2-Me = 1.2 Hz, 3 H, 4-H
3
), 1.82 (dq, J2-Me,3
5
2
2
2
4
[46]
2
2
= 6.7 Hz, 1 H, 2Ј-H), 3.89 (d, J1Ј,2Ј = 6.7 Hz, 2 H, 1Ј-H ), 6.84 (qq,
4
13
2
2
2
2
J
3,4 = 7.1,
(100.63 MHz, CDCl
C-3Ј), 27.91 (C-2Ј), 70.55 (C-1Ј), 128.90 (C-2), 136.77 (C-3), 168.19
(C-1) ppm. edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl ):
Allows the assignment of all nonquaternary carbon atoms by their
J
3,2-Me
=
1.4 Hz, 1 H, 3-H) ppm.
were added to the suspension. The mixture was stirred at 0 °C until
the olefin could no longer be detected by TLC. The reaction was
quenched by the addition of a saturated aqueous Na
The phases were separated and the aqueous phase was extracted
with EtOAc (3ϫ). The combined organic phases were washed with
3
): δ = 12.03 (2-Me), 14.29 (C-4), 19.20 (2Ј-Me,
2
SO
3
solution.
3
1
3
1
cross-peaks with directly bonded protons [δ( C) ↔ δ( H)]: δ =
12.03 (2-Me) ↔ δ = 1.82 (2-Me); δ = 14.29 (C-4) ↔ δ = 1.77 (4-
brine, dried with MgSO
4
, and the solvent was removed under re-
duced pressure. The product was purified by flash chromatography
H
3
); δ = 19.20 (2Ј-Me, C-3Ј) ↔ δ = 0.94 (2Ј-Me, 3Ј-H
(C-2Ј) ↔ δ = 1.95 (2Ј-H); δ = 70.55 (C-1Ј) ↔ δ = 3.89 (1Ј-H
36.77 (C-3) ↔ δ = 6.84 (3-H) ppm. HRMS (pos. APCI, CH
calcd. for C
[M + H]+ 157.12285; found 157.12280
–0.3 ppm).
3
); δ = 27.91
); δ =
Cl ):
[
43]
on silica gel.
-Methoxybenzyl Methacrylate (1b):
oxyphenyl)methanol (“PMB-OH”, 3.74 mL, 4.16 g, 30.1 mmol,
.05 equiv.) in pyridine (2.78 mL, 2.72 g, 34.4 mmol, 1.2 equiv.) was
added dropwise to a solution of 25 (2.80 mL, 3.00 g, 28.7 mmol) in
CH Cl (25 mL) and the mixture was stirred overnight at room
temp. (a white precipitate formed). The reaction was quenched by
the addition of a saturated aqueous solution of NH Cl (10 mL).
O (approx. 5 mL) was added until the precipitate dissolved, the
phases were separated, and the aqueous phase was extracted with
2
1
2
2
4
A solution of (4-meth-
9 17 2
H O
(
1
4-Methoxybenzyl (E)-2-Methylbut-2-enoate (2c): A solution of
(4-methoxyphenyl)methanol (“PMB-OH”, 6.63 mL, 7.38 g,
53.4 mmol, 1.05 equiv.) in pyridine (4.93 mL, 4.83 g, 61.0 mmol,
1.2 equiv.) was added dropwise to a solution of 27 (6.03 g,
50.9 mmol) in CH Cl (50 mL) and the mixture was stirred over-
2 2
night at room temp. (a white precipitate formed). The reaction was
quenched by the addition of a saturated aqueous solution of
2
2
4
H
2
CH
2
Cl
2
(3ϫ 20 mL). The combined organic phases were dried with
MgSO
4
and the solvent was evaporated under reduced pressure.
NH
dissolved, the phases were separated, and the aqueous phase was
extracted with CH Cl (3ϫ 40 mL). The combined organic phases
were dried with MgSO and the solvent was evaporated under re-
duced pressure. The residue was distilled under reduced pressure
250, 1160, 1110, 1035, 1010 cm . H NMR (400.13 MHz, (b.p.0.1mbar = 63 °C). The product was obtained as a colorless oil
4 2
Cl (20 mL). H O (ca. 10 mL) was added until the precipitate
[43]
The residue was purified by flash chromatography on silica gel
5.5ϫ5.5 cm, 50 mL, c-C 12/EtOAc = 3:1–1:1, 15–26). The prod-
uct was obtained as a colorless oil (4.30 g, 72%). IR (film): ν˜ =
(
6
H
2
2
4
2960, 2840, 1715, 1635, 1615, 1585, 1515, 1455, 1375, 1320, 1295,
–1
1
1
4
4
3
CDCl ): δ = 1.95 [dd, J2-Me,3-H(E) = 1.6, J2-Me,3-H(Z) = 1.0 Hz, 3 H, (7.92 g, 72%). IR (film): ν˜ = 2955, 2840, 2060, 1710, 1650, 1615,
–
1 1
2
-Me], 3.81 (s, 3 H, p-OMe), 5.13 (s, 2 H, 1Ј-H
3-H(E),2-Me = 1.6 Hz, 1 H, 3-H ], 6.13 [dq, Jgem = 1.7, J3-H(Z),2-Me
1.0 Hz, 1 H, 3-H ], 6.89 (m
2
), 5.56 [dq, Jgem
=
1515, 1460, 1385, 1250, 1135, 1075, 1035, 970, 825, 735 cm . H
4
E
4
5
J
NMR (400.13 MHz, CDCl
1.0 Hz, 3 H, 4-H ), 1.84 (dq, J2-Me,3 = J2-Me,4 = 1.1 Hz, 3 H, 2-
Me), 3.81 (s, 3 H, OMe), 5.11 (s, 2 H, 1Ј-H ), 6.84–6.91 [m, 3 H,
possibly interpretable as 6.88 (qq, J3,4 = 7.1, 4J3,2-Me = 1.5 Hz, 1
): δ = 18.42 (2-Me), 55.36 (p-OMe), 66.31 (C- H, 3-H) superimposed by 6.89 (m , possibly interpretable as AAЈ
Ј), 114.01 (2 C-m), 125.69 (C-3), 128.35 (C-i)*, 129.99 (2 C-o), part of an AAЈBBЈ signal, 2 H, 2 m-H)], 7.31 (m , possibly inter-
36.45 (C-2)*, 159.67 (C-p), 167.42 (C-1) ppm. *Assignments inter- pretable as BBЈ part of an AAЈBBЈ signal, 2 H, 2 o-H) ppm.
NMR (100.63 MHz, CDCl ): δ = 12.15 (2-Me), 14.42 (C-4), 55.37
3
): δ = 1.78 (dq, J4,3 = 7.1, J4,2-Me =
Z
4
5
=
c
, possibly interpretable as AAЈ part
, possibly interpretable
as BBЈ part of an AAЈBBЈ signal, 2 H, 2 o-H) ppm. 13C NMR
100.63 MHz, CDCl
3
of an AAЈBBЈ signal, 2 H, 2 m-H), 7.32 (m
c
2
(
3
c
1
1
c
1
3
C
changeable. edHSQC: (“C,H-COSY”, 100.62/400.13 MHz,
CDCl ): Allows the assignment of all nonquaternary carbon atoms
by their cross-peaks with directly bonded protons [δ( C) ↔ δ( H)]:
3
3
(C-OMe), 66.07 (C-1Ј), 113.99 (2 C-m), 128.68 (C-i)*, 128.71 (C-
2)*, 129.94 (2 C-o), 137.49 (C-3), 159.59 (C-p), 168.08 (C-1) ppm.
13
1
δ = 18.42 (2-Me) ↔ δ = 1.95 (2-Me); δ = 55.36 (p-OMe) ↔ δ = *Assignments interchangeable. edHSQC (“C,H-COSY”, 100.62/
.81 (p-OMe); δ = 66.31 (C-1Ј) ↔ δ = 5.13 (1Ј-H ); δ = 114.01 (2 400.13 MHz, CDCl ): Allows the assignment of all nonquaternary
3
2
3
E
C-m) ↔ δ = 6.89 (2 m-H); δ = 125.69 (C-3) ↔ δ = 5.56 (3-H ) and carbon atoms by their cross-peaks with directly bonded protons
6
Z
13
1
.13 (3-H ); δ = 129.99 (2 C-o) ↔ δ = 7.32 (2 o-H) ppm. HRMS
[δ( C) ↔ δ( H)]: δ = 12.15 (2-Me) ↔ δ = 1.84 (2-Me); δ = 14.42
(C-4) ↔ δ = 1.78 (4-H ); δ = 55.37 (C-OMe) ↔ δ = 3.81 (OMe); δ
= 66.07 (C-1Ј) ↔ δ = 5.11 (1Ј-H ); δ = 113.99 (2 C-m) ↔ δ = 6.89
(2 m-H); δ = 129.94 (2 C-o) ↔ δ = 7.31 (2 o-H); δ = 137.49 (C-3)
δ = 6.88 (3-H) ppm. HRMS (pos. APCI, MeOH): calcd. for
+
(pos. APCI, MeOH): calcd. for C12
H
18NO
3
[M + NH
(206.24): calcd. C 69.89, H
4
] 224.12867;
3
found 224.12870 (+0.1 ppm). C12
H
14
O
3
2
6
.84; found C 69.65, H 6.67.
Isobutyl (E)-2-Methylbut-2-enoate (2b): A solution of 27 (2.50 mL,
.70 g, 22.8 mmol) in CH Cl (11 mL) was added dropwise to a
solution of isobutanol (3.17 mL, 2.38 g, 34.2 mmol, 1.5 equiv.) and
pyridine (2.76 mL, 2.70 g, 34.2 mmol, 1.5 equiv.) in CH Cl
11 mL) at 0 °C and the mixture was stirred overnight at room (7.62 mL, 6.60 g, 92.8 mmol, 2.2 equiv.) was added slowly to a solu-
temp. (a white precipitate formed). The reaction was quenched by tion of 27 (5.00 g, 42.1 mmol) in CH Cl (35 mL) at 0 °C. The solu-
the addition of a saturated aqueous solution of NH Cl (10 mL). tion was stirred at room temp. overnight. The reaction was
O (ca. 5 mL) was added until the precipitate dissolved, the quenched by the addition of a saturated aqueous NH Cl solution
phases were separated, and the aqueous phase was extracted with (50 mL). The phases were separated and the aqueous phase ex-
tracted with CH Cl (3ϫ50 mL). The combined organic phases
were dried with MgSO and the solvent evaporated under reduced
↔
C
C
+
13
H
H
20NO
3
[M + NH
4
] 238.14432; found 238.14440 (+0.3 ppm).
2
2
2
13
16
O (220.27): calcd. C 70.89, H 7.32; found C 70.71, H 7.22.
(E)-2-Methyl-1-(pyrrolidin-1-yl)but-2-en-1-one (2e):[47] Pyrrolidine
3
2
2
(
2
2
4
H
2
4
CH
MgSO
2
Cl
2
(3ϫ 20 mL). The combined organic phases were dried with
and the solvent was evaporated under reduced pressure.
2
2
4
4
The residue was distilled under reduced pressure (b.p. 160 °C). The
product was obtained as a colorless oil (3.06 g, 86%). IR (film): ν˜
pressure. The residue was distilled under reduced pressure
(b.p.0.1mbar 85 °C). The product was obtained as a colorless oil
(5.24 g, 81%). IR (film): ν˜ = 3490, 2970, 2875, 1660, 1615, 1425,
=
2965, 2915, 2875, 2850, 1710, 1655, 1560, 1470, 1380, 1370, 1345,
–1
1
1270, 1210, 1140, 1080, 1030 cm . H NMR (400.13 MHz, 1375, 1340, 1250, 1230, 1185, 1165, 1115, 1085, 1035, 1015, 9660,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
FULL PAPER
–1 1
915, 840 cm . H NMR (500.42 MHz, CDCl
3
, 263 K): δ = 1.62 (1.50 g, 76%). IR (film): ν˜ = 3490, 2970, 2940, 1655, 1650, 1460,
1435, 1385, 1320, 1210, 1175, 1100, 1070, 1040, 1015, 995, 915,
5
(m
c
, possibly interpretable as dq, J4,3 = 6.9, J4,2-Me = 0.9 Hz, 3 H,
–
1
4
4
-H
H, 2Ј-H
3
), 1.77 (m
c
, 3 H, 2-Me), 1.81 (m
c
, 4 H, 3Ј-H
2
, 4Ј-H
2
), 3.38 (m
c
,
870, 835 cm .
4
2
, 5Ј-H
3
2
), 5.68 (qq, J3,4 = 6.8, J3,2-Me = 1.5 Hz, 1 H, 3-
For this compound most signals in the room temp. 125 MHz
C NMR spectrum (CDCl ) appear as very broad signals or are
3
broadened to such an extent that they do not appear at all. The
cause of this seems to be the hindered rotation around the amide
1
H) ppm. C NMR (125.83 MHz, CDCl
3
, 263 K): δ = 13.33 (C-4),
13
1
3.51 (2-Me), 24.34 (C-3Ј)*, 26.07 (C-4Ј)*, 45.48 (C-2Ј)**, 48.71
C-5Ј)**, 126.46 (C-3), 133.23 (C-2), 171.98 (C-1) ppm. *,** As-
signments interchangeable. edHSQC (“C,H-COSY”, 125.83/
00.42 MHz, CDCl , 263 K): Allows the assignment of all nonqua-
ternary carbon atoms by their cross-peaks with directly bonded
(
1
bond. The 333 K 500 MHz H NMR spectrum (CDCl
clear signals, the 333 K 125 MHz C NMR spectrum (CDCl
3
) shows very
),
5
3
13
3
however, lacks the signal of the carboxy-carbon (see below). Lower-
ing the temperature to 263 K seems to slow the rotation around
13
1
protons [δ( C) ↔ δ( H)]: δ = 13.33 (C-4) ↔ δ = 1.62 (4-H
3
); δ =
13.51 (2-Me) ↔ δ = 1.77 (2-Me); δ = 24.34 (C-3Ј) and 26.07 (C-4Ј)
13
the amide bond that much that almost every C signal in the 263 K
↔
=
δ = 1.81 (3Ј-H
2
, 4Ј-H
); δ = 126.46 (C-3) ↔ δ = 5.68 (3-H) ppm.
16NO [M + H]+
2
); δ = 45.48 (C-2Ј) and 48.71 (C-5Ј) ↔ δ
13
1
25 MHz C NMR spectrum (CDCl
3
) appears twice (see below).
3.38 (2Ј-H , 5Ј-H
2
2
1
H NMR (500.42 MHz, CDCl
3
, 333 K): δ = 1.59 (dq, J4,3 = 6.9,
HRMS (pos. APCI, MeOH): calcd. for C
9
H
5J4,2-Me = 1.6 Hz, 3 H, 4-H
4
5
3
), 1.82 (dq, J2-Me,3 = J2-Me,4 = 1.6 Hz,
H, 2-Me), 3.16 (s, 3 H, NMe), 3.60 (s, 3 H, OMe), 5.41 (qq, J3,4
1
54.12319; found 154.12330 (+0.7 ppm).
-Methoxybenzyl (Z)-2-Methylbut-2-enoate (3c): Compound 28 = 6.9, J3,2-Me = 1.6 Hz, 1 H, 3-H) ppm. C NMR (125.83 MHz,
CO (5.86 g, 18.0 mmol, 1.0 equiv.) CDCl , 333 K): δ = 14.76 (C-4), 19.78 (2-Me), 32.97 (C-NMe)*,
were dissolved in DMF (36 mL) and the solution was cooled to 61.20 (C-OMe), 124.56 (C-3), 132.59 (C-2). Although two HMBC
3
4
13
4
(1.80 g, 18.0 mmol) and Cs
2
3
3
1
3C
1H
0
1
°C. 1-(Chloromethyl)-4-methoxybenzene (2.84 g, 18.2 mmol, cross-peaks, namely δ
.01 equiv.) was added to the solution and the mixture was stirred
= 171.25 (C-1) ↔ δ = 1.82 (2-Me) and
1H
1
3C
δ
= 171.25 (C-1) ↔ δ = 3.16 (NMe) ppm, can be observed at
13
for 1 h at 0 °C and 2 h at room temp. The reaction was quenched
by the addition of H O (30 mL). The phases were separated and the
aqueous phase extracted with TBME (3ϫ30 mL). The combined
organic phases were dried with MgSO and the solvent evaporated
this temperature, no C signal for C-1 can be found. * This signal
appears as a broad singlet. edHSQC (“C,H-COSY”, 125.83/
2
500.42 MHz, CDCl
3
, 333 K): Allows the assignment of all nonqua-
ternary carbon atoms by their cross-peaks with directly bonded
protons [δ( C) ↔ δ( H)]: δ = 14.76 (C-4) ↔ δ = 1.59 (4-H ); δ =
3
19.78 (2-Me) ↔ δ = 1.82 (2-Me); δ = 32.97 (C-NMe) ↔ δ = 3.16
4
1
3
1
under reduced pressure. The residue was purified by flash
chromatography (3.5ϫ20 cm, 50 mL, 10:1–3:1, 14–25). The prod-
uct was obtained as a colorless liquid (3.56 g, 90%). IR (film): ν˜ =
(NMe); δ = 61.20 (C-OMe) ↔ δ = 3.60 (OMe); δ = 124.56 (C-3)
1
2955, 2840, 1710, 1615, 1515, 1360, 1385, 1350, 1300, 1250, 1150,
↔ δ = 5.41 (3-H) ppm. H NMR (500.42 MHz, CDCl
3
, 263 K): δ
–1 1
1
=
=
085, 1040, 965, 825, 760 cm . H NMR (400.13 MHz, CDCl
3
): δ
= 1.51–1.57 (m, 3 H, 4-H
3
), 1.74–1.80 (m, 3 H, 2-Me), 3.14 (s, 3
H, NMe), 3.51 [s, 3 H, OMe (major rotamer)]*, 3.68 [s, 3 H, OMe
(minor rotamer)]*, 5.34–5.44 (m, 1 H, 3-H) ppm. *A NOESY spec-
4
5
1.90 (dq, J2-Me,3 = J2-Me,4 = 1.6 Hz, 3 H, 2-Me), 1.97 (dq, J4,3
5
3
7.2, J4,2-Me = 1.5 Hz, 3 H, 4-H ), 3.81 (s, 3 H, OMe), 5.13 (s, 2
4
H, 1Ј-H
, possibly interpretable as AAЈ part of an AAЈBBЈ signal, 2 H,
m-H), 7.32 (m , possibly interpretable as BBЈ part of an AAЈBBЈ
signal, 2 H, 2 o-H) ppm. C NMR (100.63 MHz, CDCl
5.87 (C-4), 20.69 (2-Me), 55.37 (C-OMe), 65.74 (C-1Ј), 113.99 (2
2
), 6.06 (qq, J3,4 = 7.2, J3,2-Me = 1.5 Hz, 1 H, 3-H), 6.89 trum shows cross-peaks between these signals with the same phase
(m
c
as the homo-cross-peaks. This proves that these signals belong to
the same protons in two rotamers. C NMR (125.83 MHz, CDCl ,
3
263 K): δ = 14.59 [C-4 (minor rotamer)], 15.13 [C-4 (major rot-
amer)], 19.86 [2-Me (both rotamers)], 31.66 [C-NMe (major rot-
1
3
2
c
1
3
3
): δ =
1
C-m), 127.97 (C-i)*, 128.56 (C-2)*, 129.95 (2 C-o), 138.03 (C-3), amer)], 35.10 [C-NMe (minor rotamer)], 60.40 [C-OMe (minor rot-
1
59.59 (C-p), 168.04 (C-1) ppm. *Assignments interchangeable.
edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl ): Allows the
assignment of all nonquaternary carbon atoms by their cross-peaks
amer)], 61.51 [C-OMe (major rotamer)], 124.08 [C-3 (major rot-
amer)], 125.27 [C-3 (minor rotamer)], 131.17 [C-2 (minor rotamer)],
132.40 [C-2 (major rotamer)], 167.79 [C-1 (minor rotamer)], 171.89
[C-1 (major rotamer)] ppm. edHSQC (“C,H-COSY”, 125.83/
3
13
1
with directly bonded protons [δ( C) ↔ δ( H)]: δ = 15.87 (C-4) ↔
δ = 1.97 (4-H ); δ = 20.69 (2-Me) ↔ δ = 1.90 (2-Me); δ = 55.37
C-OMe) ↔ δ = 3.81 (OMe); δ = 65.74 (C-1Ј) ↔ δ = 5.13 (1Ј-H );
δ = 113.99 (2 C-m) ↔ δ = 6.89 (2 m-H); δ = 129.95 (2 C-o) ↔ δ = protons [δ( C) ↔ δ( H)]: δ = 14.59 [C-4 (minor rotamer)] and
.32 (2 o-H); δ = 138.03 (C-3) ↔ δ = 6.06 (3-H) ppm. HRMS (pos. 15.13 [C-4 (major rotamer)] ↔ δ = 1.51–1.57 (4-H ); δ = 19.86 [2-
238.14432; Me (both rotamers)] ↔ δ = 1.74–1.80 (2-Me); δ = 31.66 [C-NMe
3
500.42 MHz, CDCl
3
, 263 K): Allows the assignment of all nonqua-
(
2
ternary carbon atoms by their cross-peaks with directly bonded
1
3
1
7
3
+
APCI, MeOH): calcd. for C13
found 238.14430 (–0.1 ppm). C13
.32; found C 70.64, H 7.14.
3 4
H20NO [M + NH ]
H
16
O
3
(220.27): calcd. C 70.89, H (major rotamer)] and 35.10 [C-NMe (minor rotamer)] ↔ δ = 3.14
(NMe); δ = 60.40 [C-OMe (minor rotamer)] ↔ δ = 3.68 [OMe
7
Z)-N-Methoxy-N,2-dimethylbut-2-enamide (3d):[47] HNMe(OMe)·
(minor rotamer)]; δ = 61.51 [C-OMe (major rotamer)] ↔ δ = 3.51
(
[
1
(
OMe (major rotamer)]; δ = 124.08 [C-3 (major rotamer)] and
25.27 [C-3 (minor rotamer)] ↔ δ = 5.34–5.44 (3-H) ppm. HRMS
pos. APCI, MeOH): calcd. for C
[M + H]+ 144.10245;
HCl (2.08 g, 21.2 mmol, 1.55 equiv.) was dissolved in THF (30 mL)
and the solution was cooled to –20 °C. Methyl (Z)-2-methylbut-2-
enoate (3a; 1.86 mL, 1.75 g, 13.7 mmol) was added and the solution
was stirred for 30 min at –20 °C. iPrMgCl (1.5 m in THF, 27.4 mL,
7 2
H14NO
found 144.10250 (+0.3 ppm).
4
1.2 mmol, 3.0 equiv.) was added dropwise to the solution and the
mixture was stirred for 30 min at –20 °C. The reaction was
quenched by the addition of a saturated aqueous NH Cl solution
30 mL). The precipitate (Mg salts) was filtered and washed with
(Z)-2-Methyl-1-(pyrrolidin-1-yl)but-2-en-1-one (3e):[47] Pyrrolidine
(1.74 mL, 1.51 g, 21.2 mmol, 1.55 equiv.) was dissolved in THF
(30 mL) and the solution was cooled to –20 °C. Methyl (Z)-2-meth-
ylbut-2-enoate (1.86 mL, 1.75 g, 13.7 mmol) was added and the
solution was stirred for 30 min at –20 °C. iPrMgCl (1.5 m in THF,
13.7 mL, 20.5 mmol, 1.5 equiv.) was added dropwise to the solution
and the mixture was stirred for 30 min at –20 °C. The reaction was
4
(
EtOAc (30 mL). The phases were separated and the aqueous phase
extracted with EtOAc (3ϫ30 mL). The combined organic phases
were dried with MgSO
pressure. The residue was distilled under reduced pressure
b.p.0.1mbar 70 °C). The product was obtained as a colorless oil
4
and the solvent evaporated under reduced
quenched by the addition of a saturated aqueous NH
4
Cl solution
(
(30 mL). The precipitate (Mg salts) was filtered and washed with
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
2
0
EtOAc (30 mL). The phases of the filtrate were separated and the
aqueous phase extracted with EtOAc (3ϫ30 mL). The combined
210 nm, t
R
= 7.39 (2S,3R), 8.69 min (2R,3S). [α]
D
= –0.4 (c =
); [α]546 = Ϯ0.0 (c = 1.10 g/100 mL, CHCl );
); [α]365 = +8.5 (c = 1.10 g/
). IR (film): ν˜ = 3465, 2985, 2950, 1735, 1450, 1380,
1265, 1190, 1135, 1090, 1015, 980, 945, 915, 870, 795, 750,
2
0
1.10 g/100 mL, CHCl
3
3
2
0
20
organic phases were dried with MgSO
4
and the solvent evaporated
[α]436 = +2.3 (c = 1.10 g/100 mL, CHCl
100 mL, CHCl
3
under reduced pressure. The residue was distilled under reduced
pressure (b.p.0.1mbar 65 °C). The product was obtained as a colorless
oil (2.46 g, 70%). IR (film): ν˜ = 3480, 2970, 2920, 2875, 1625, 1560, 680 cm . H NMR (400.13 MHz, CDCl
3
–
1
1
3
): δ = 1.23 (d, J4,3
), 1.32 (s, 3 H, 2-Me), 2.03 (br. s, 1 H, 3-OH),
3.36 (s, 1 H, 2-OH), 3.82 (s, 3 H, OMe), 3.94 (br. q, J3,4 = 6.4 Hz,
=
1
1
525, 1455, 1435, 1380, 1345, 1320, 1250, 1225, 1185, 1170, 1115,
6.4 Hz, 3 H, 4-H
3
–1 1
080, 1035, 980, 960, 915, 880, 845 cm . H NMR (500.42 MHz,
5
13
CDCl
), 1.76 (dq, J2-Me,3 = J2-Me,4 = 1.6 Hz, 3 H, 2-Me), 1.81 (m
H, 3Ј-H , 4Ј-H ), 3.24 (m , 2 H, 2Ј-H )*, 3.41 (m , 2 H, 5Ј-H
.29 (qq, J3,4 = 6.8, J3,2-Me = 1.5 Hz, 1 H, 3-H) ppm. * Assign-
3
, 333 K): δ = 1.50 (dq, J4,3 = 6.9, J4,2-Me = 1.6 Hz, 3 H, 4- 1 H, 3-H) ppm. C NMR (100.63 MHz, CDCl
3
): δ = 16.76 (C-4),
, 4 21.80 (2-Me), 53.12 (OMe), 71.71 (C-3), 77.37 (C-2), 176.83 (C-
)*, 1) ppm. edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl ): Al-
lows the assignment of all nonquaternary carbon atoms by their
4
5
H
3
c
2
2
c
2
c
2
3
4
5
13
13
1
ments interchangeable. C NMR (125.83 MHz, CDCl
14.48 (C-4), 19.60 (2-Me), 24.37 (C-3Ј)*, 25.82 (C-4Ј)*, 44.68 (C- 16.76 (C-4) ↔ δ = 1.23 (4-H
Ј)**, 46.69 (C-2Ј)**, 122.55 (C-3), 134.28 (C-2), 170.52 (C-1) ppm. Me); δ = 53.12 (OMe) ↔ δ = 3.82 (OMe); δ = 71.71 (C-3) ↔ δ =
,** Assignments interchangeable. edHSQC (“C,H-COSY”, 3.94 (3-H) ppm. HRMS: (pos. ESI, MeOH): calcd. for C Na
25.83/500.42 MHz, CDCl
, 333 K): Allows the assignment of all [M + Na]+ 171.06330; found 171.06333 (+0.2 ppm). C
(148.16): calcd. C 48.64, H 8.16; found C 48.37, H 8.00.
3
, 333 K): δ cross-peaks with directly bonded protons [δ( C) ↔ δ( H)]: δ =
=
3
); δ = 21.80 (2-Me) ↔ δ = 1.32 (2-
5
*
1
6 12 4
H O
3
6 12 4
H O
nonquaternary carbon atoms by their cross-peaks with directly
13
1
bonded protons [δ( C) ↔ δ( H)]: δ = 14.48 (C-4) ↔ δ = 1.50 (4-
); δ = 19.60 (2-Me) ↔ δ = 1.76 (2-Me); δ = 24.37 (C-3Ј) ↔ δ =
.81 (3Ј-H , 4Ј-H ); δ = 25.82 (C-4Ј) ↔ δ = 1.81 (3Ј-H , 4Ј-H ); δ
44.68 (C-5Ј) ↔ δ = 3.41 (5Ј-H ); δ = 46.69 (C-2Ј) ↔ δ = 3.24
2Ј-H ); δ = 122.55 (C-3) ↔ δ = 5.29 (3-H) ppm. HRMS (pos.
APCI, MeOH): calcd. for C
54.12320 (+0.1 ppm).
Isobutyl rel-(2R,3S)-2,3-Dihydroxy-2-methylbutanoate (syn-7b):[48]
Following the general procedure A, the title compound was pre-
pared from isobutyl (E)-2-methylbut-2-enoate (2b; 0.30 g,
H
1
=
(
3
2
2
2
2
2
1
.9 mmol), citric acid (0.28 g, 1.4 mmol, 0.75 equiv.), K
(OH) (1.8 mg, 4.8 μmol, 0.25 mol-%), and NMO (50% in H
.54 g, 2.3 mmol, 1.2 equiv.). Purification by flash chromatography
2
OsO
2
-
2
+
4
2
O,
9
H16NO [M + H] 154.12319; found
0
1
[43]
on silica gel (2.5ϫ15 cm, 20 mL, c-C
17) rendered the product as a colorless oil (0.33 g, 89%). H NMR
(300.06 MHz, CDCl ): δ = 0.95 (d, J3Ј,2Ј = J2Ј-Me,2Ј = 6.7 Hz, 6 H,
3Ј-H , 2Ј-Me), 1.24 (d, J4,3 = 6.3 Hz, 3 H, 4-H ), 1.33 (s, 3 H, 2-
6
H12/EtOAc = 3:1–1:1, 9–
Methyl rel-(2R,3S)-2,3-Dihydroxy-2-methylbutanoate (syn-7a):[48]
Following the general procedure A, the title compound was pre-
pared from methyl (E)-2-methylbut-2-enoate (2a; 0.50 g, 4.4 mmol),
1
3
3
3
citric acid (0.63 g, 3.3 mmol, 0.75 equiv.), K
1
1
2
OsO
1 μmol, 0.25 mol-%), and NMO (50% in H O, 1.2 g, 5.3 mmol,
.2 equiv.). Purification by flash chromatography on silica gel[
12/EtOAc = 3:1–1:1, 13–22) rendered
2
(OH)
4
(4.0 mg,
Me), 1.98 (d, J3-OH,3 = 7.5 Hz, 1 H, 3-OH), 2.00 (tqq, J2Ј,1Ј = J2Ј,3Ј
= J2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H), 3.39 (s, 1 H, 2-OH), 3.95 (dq,
2
43]
J3,3-OH = 8.5, J3,4 = 6.4 Hz, 1 H, 3-H), 4.01 (d, J1Ј,2Ј = 6.7 Hz, 2
(
2.5ϫ15 cm, 20 mL, c-C
the product as a colorless oil (0.57 g, 88%). H NMR (300.06 MHz,
CDCl ): δ = 1.23 (d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.32 (s, 3 H, 2-Me),
.03 (br. s, 1 H, 3-OH), 3.33 (br. s, 1 H, 2-OH), 3.82 (s, 3 H, OMe),
.95 (q, J3,4 = 6.4 Hz, 1 H, 3-H) ppm.
6
H
H, 1Ј-H ) ppm.
2
1
Isobutyl (2R,3S)-2,3-Dihydroxy-2-methylbutanoate [(2R,3S)-7b]:[48]
Following the general procedure B, the title compound was pre-
pared from isobutyl (E)-2-methylbut-2-enoate (2b; 0.25 g,
3
3
2
3
1
.6 mmol),
(0.66 g, 4.8 mmol, 3.0 equiv.), MeSO
1.0 equiv.), (DHQ) PHAL (25 mg, 32 μmol, 2.0 mol-%), and
OsO (OH) (5.9 mg, 16 μmol, 1.0 mol-%). Purification by flash
K
3
[Fe(CN)
6
]
(1.6 g, 4.8 mmol, 3.0 equiv.),
2 3
K CO
Methyl (2R,3S)-2,3-Dihydroxy-2-methylbutanoate [(2R,3S)-7a]:[48]
Following the general procedure B, the title compound was pre-
pared from methyl (E)-2-methylbut-2-enoate (2a; 0.50 g, 4.4 mmol),
NH (0.15 g, 1.6 mmol,
2
2
2
K
2
2
4
[43]
K
3
3
[Fe(CN)
.0 equiv.), MeSO
PHAL (68 mg, 88 μmol, 2.0 mol-%), and K
6
] (4.3 g, 13 mmol, 3.0 equiv.), K
NH (0.42 g, 4.4 mmol, 1.0 equiv.), (DHQ)
OsO (OH) (16 mg,
4 μmol, 1.0 mol-%). Purification by flash chromatography on sil-
2
CO
3
(1.8 g, 13 mmol, chromatography on silica gel
6
(2 15 cm, 20 mL, c-C H12/EtOAc
2
2
2
-
= 3:1–1:1, 9–11) rendered the product as a colorless oil (0.26 g,
86%; 81% ee). Analytical HPLC: Kromasil 3-AmyCoat, n-heptane/
iPrOH = 95:5, 210 nm, t = 10.29 (2S,3R), 11.43 min (2R,3S).
R
2
2
4
4
[
43]
20
20
ica gel
(2.5ϫ15 cm, 20 mL, c-C
6
H
12/EtOAc = 3:1–1:1, 13–22)
[α]
100 mL, CHCl
3Ј,2Ј = 6.7 Hz, 3 H, 3Ј-H
6.7 Hz, 3 H, 2Ј-Me), 1.23 (d, J4,3 = 6.3 Hz, 3 H, 4-H
3
D
= +5.5 (c = 0.96 g/100 mL, CHCl
3
); [α]365 = +27.0 (c = 0.96 g/
). H NMR (300.06 MHz, CDCl ): δ = 0.958 (d,
) superimposed by 0.960 (d, J2Ј-Me,2Ј
), 1.33 (s, 3
1
rendered the product as a colorless oil (0.55 g, 85%; 87% ee). Ana-
lytical HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 90:10,
3
3
J
3
=
2
0
2
10 nm, t
R
= 7.51 (2S,3R), 8.35 min (2R,3S). [α]
D
= +0.3 (c =
0
1.16 g/100 mL, CHCl
3
); [α] 52 46 = –0.2 (c = 1.16 g/100 mL, CHCl
3
);
H, 2-Me), 1.98 (d, J3-OH,3 = 9.2 Hz, 3-OH) superimposed by 1.99
(tqq, J2Ј,1Ј = J2Ј,3Ј = J2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H), 3.38 (s, 1 H, 2-
OH), 3.94 (dq, J3,3-OH = 9.2, J3,4 = 6.5 Hz, 1 H, 3-H), 4.01 (d, J1Ј,2Ј
20
20
3
[α]436 = –1.9 (c = 1.16 g/100 mL, CHCl ); [α]365 = –7.6 (c = 1.16 g/
1
1
=
3
00 mL, CHCl
6.4 Hz, 3 H, 4-H
.34 (s, 1 H, 2-OH), 3.82 (s, 3 H, OMe), 3.94 (br. s, 1 H, 3-H) ppm.
3 3
). H NMR (300.06 MHz, CDCl ): δ = 1.23 (d, J4,3
3 2
), 1.32 (s, 3 H, 2-Me), 2.02 (br. s, 1 H, 3-OH), = 6.4, 1Ј-H ) ppm.
Isobutyl (2S,3R)-2,3-Dihydroxy-2-methylbutanoate [(2S,3R)-7b]:
Following the general procedure B, the title compound was pre-
pared from isobutyl (E)-2-methylbut-2-enoate (2b; 0.25 g,
Methyl (2S,3R)-2,3-Dihydroxy-2-methylbutanoate [(2S,3R)-7a]: Fol-
lowing the general procedure B, the title compound was prepared
from methyl (E)-2-methylbut-2-enoate (2a; 0.50 g, 4.4 mmol),
1.6 mmol),
K
3
[Fe(CN)
6
]
(1.6 g, 4.8 mmol, 3.0 equiv.),
NH (0.15 g, 1.6 mmol,
PHAL (25 mg, 32 μmol, 2.0 mol-%), and
4
(5.9 mg, 16 μmol, 1.0 mol-%). Purification by flash
2 3
K CO
K
3
3
[Fe(CN)
.0 equiv.), MeSO
PHAL (68 mg, 88 μmol, 2.0 mol-%), and K
6
] (4.3 g, 13 mmol, 3.0 equiv.), K
NH (0.42 g, 4.4 mmol, 1.0 equiv.), (DHQD)
OsO (OH) (16 mg,
4 μmol, 1.0 mol-%). Purification by flash chromatography on sil-
2
CO
3
(1.8 g, 13 mmol, (0.66 g, 4.8 mmol, 3.0 equiv.), MeSO
1.0 equiv.), (DHQD)
OsO (OH)
chromatography on silica gel
2
2
2
2
2
-
2
2
2
4
K
2
2
[43]
4
6
(2 15 cm, 20 mL, c-C H12/EtOAc
[
43]
ica gel
(2.5ϫ15 cm, 20 mL, c-C
6
H
12/EtOAc = 3:1–1:1, 15–24)
= 3:1–1:1, 11–20) rendered the product as a colorless oil (0.27 g,
rendered the product as a colorless oil (0.54 g, 84%; 92% ee). Ana-
lytical HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 90:10,
86%; 85% ee). Analytical HPLC: Kromasil 3-AmyCoat, n-heptane/
iPrOH = 95:5, 210 nm, t
R
= 10.05 (2S,3R), 11.65 min (2R,3S).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 90:10, 229 nm,
FULL PAPER
20
20
[α]
D
= –7.2 (c = 0.91 g/100 mL, CHCl
3
). [α]365 = –35.0 (c = 0.91 g/
2
0
100 mL, CHCl
3
). IR (film): ν˜ = 3475, 2970, 2880, 1735, 1465, 1380,
t
R
= 15.07 (2S,3R), 17.64 min (2R,3S). [α]
D
= +1.4 (c = 1.05 g/
); [α]365 = +14.3 (c = 1.05 g/100 mL, CHCl ). IR
3
): δ = 0.938 (d, J3Ј,2Ј = 6.7 Hz, 3 H, 3Ј- (film): ν˜ = 3500, 2985, 2840, 2060, 1730, 1615, 1515, 1455, 1375,
–
1
1
20
1255, 1190, 1130, 1090, 1015, 985, 945, 790, 750, 680 cm .
H
100 mL, CHCl
3
3
NMR (400.13 MHz, CDCl
) superimposed by 0.941 (d, J2Ј-Me,2Ј = 6.7 Hz, 3 H, 2Ј-Me), 1.22
d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.31 (s, 3 H, 2-Me), 1.98 (tqq, J2Ј,1Ј
2Ј,3Ј = J2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H), 3.93 (q, J3,4 = 6.4 Hz, 1 H,
-H), 3.98 (d, J1Ј,2Ј = 6.7 Hz, 2 H, 1Ј-H ). The OH groups were not
visible in this spectrum. 13C NMR (100.63 MHz, CDCl
–
1
1
H
3
1250, 1180, 1130, 1035, 950, 825, 765, 675 cm . H NMR
(400.13 MHz, CDCl ): δ = 1.20 (d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.31
(
3
3
3
=
J
(s, 3 H, 2-Me), 1.98 (d, J3-OH,3 = 8.5 Hz, 1 H, 3-OH), 3.36 (s, 1 H,
2-OH), 3.81 (s, 3 H, p-OMe), 3.94 (qd, J3,4 = J3,3-OH = 6.6 Hz, 1
3
2
3
): δ = 16.77 H, 3-H), 5.18 (s, 2 H, 1Ј-H
C-4), 18.97, 19.01 (C-3Ј, 2Ј-Me), 21.77 (2-Me), 27.82 (C-2Ј), 71.71 AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.29 (m
C-3), 72.15 (C-1Ј), 77.31 (C-2), 176.38 (C-1) ppm. edHSQC (“C,H- interpretable as BBЈ part of an AAЈBBЈ signal, 2 H, 2 m-H) ppm.
): Allows the assignment of all
nonquaternary carbon atoms by their cross-peaks with directly
2
), 6.89 (m
c
, possibly interpretable as
(
(
c
, possibly
1
3
COSY”, 100.62/400.13 MHz, CDCl
3
3
C NMR (100.63 MHz, CDCl ): δ = 16.76 (C-4), 21.74 (2-Me),
55.37 (p-OMe), 67.74 (C-1Ј), 71.71 (C-3), 77.32 (C-2), 114.13 (2 C-
m), 127.40 (C-i), 130.10 (2 C-o), 159.94 (C-p), 176.25 (C-1) ppm.
13
1
bonded protons [δ( C) ↔ δ( H)]: δ = 16.77 (C-4) ↔ δ = 1.22 (4-
); δ = 18.97, 19.01 (C-3Ј, 2Ј-Me) ↔ δ = 0.935 (3Ј-H ) and 0.941
2Ј-Me); δ = 21.77 (2-Me) ↔ δ = 1.31 (2-Me); δ = 27.82 (C-2Ј) ↔
δ = 1.98 (2Ј-H); δ = 71.71 (C-3) ↔ δ = 3.93 (3-H); δ = 72.15 (C- with directly bonded protons [δ( C) ↔ δ( H)]: δ = 16.76 (C-4) ↔
Ј) ↔ δ = 3.98 (1Ј-H ) ppm. HRMS (pos. APCI, MeOH): calcd. δ = 1.20 (4-H ); δ = 21.74 (2-Me) ↔ δ = 1.31 (2-Me); δ = 55.37 (p-
for C [M + H] 191.12833; found 191.12830 (–0.2 ppm). OMe) ↔ δ = 3.81 (p-OMe); δ = 67.74 (C-1Ј) ↔ δ = 5.18 (1Ј-H );
(190.24): calcd. C 56.82, H 9.54; found C 56.46, H 9.44. δ = 71.71 (C-3) ↔ δ = 3.94 (3-H); δ = 114.13 (2 C-m) ↔ δ = 6.89
H
3
3
edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl
3
): Allows the
(
assignment of all nonquaternary carbon atoms by their cross-peaks
1
3
1
1
2
3
+
9
H
19NO
4
2
9 18 4
C H O
(
2 m-H); δ = 130.10 (2 C-o) ↔ δ = 7.29 (2 m-H) ppm. HRMS: (pos.
4
(
-Methoxybenzyl
rel-(2R,3S)-2,3-Dihydroxy-2-methylbutanoate
Na [M + Na]+ 277.10520; found
(250.25): calcd. C 61.41, H 7.13;
ESI, MeOH): calcd. for C13
77.10519 (Ϯ0.0 ppm). C13
found C 61.38, H 7.14.
H
18
O
5
[
48]
syn-7c): Following the general procedure A, the title compound
was prepared from 2c (0.50 g, 2.3 mmol), citric acid (0.33 g,
.7 mmol, 0.75 equiv.), K OsO (OH) (2.1 mg, 5.7 μmol, 0.25 mol-
), and NMO (50% in H O, 0.64 g, 2.7 mmol, 1.2 equiv.). Purifica-
tion by flash chromatography on silica gel (2.5ϫ15 cm, 20 mL,
c-C 12/EtOAc = 3:1–1:3, 21–46) rendered the product as a color-
less oil (0.54 g, 94%). H NMR (300.06 MHz, CDCl
4,3 = 6.4 Hz, 3 H, 4-H ), 1.31 (s, 3 H, 2-Me), 1.94 (br. s, 1 H, 3- %), and NMO (50% in H
OH), 3.34 (br. s, 1 H, 2-OH), 3.81 (s, 3 H, p-OMe), 3.94 (q, J3,4
tion by flash chromatography on silica gel[ (2.5ϫ15 cm, 20 mL,
.4 Hz, 1 H, 3-H), 5.18 (s, 2 H, 1Ј-H ), 6.89 (m , possibly interpret- c-C 12/EtOAc = 2:1–1:3, 28–36) rendered the product as a color-
able as AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.30 (m less oil (0.31 g, 84%). H NMR (300.06 MHz, CDCl
4,3 = 6.3 Hz, 3 H, 4-H ), 1.37 (s, 3 H, 2-Me), 2.02 (d, J3-OH,3
10.5 Hz, 1 H, 3-OH), 3.31 (s, 3 H, N-Me), 3.75 (s, 3 H, O-Me),
.16 (dq, J3,3-OH = 10.6, J3,4 = 6.4 Hz, 1 H, 3-H), 4.43 (s, 1 H, 2-
2
H
14
O
5
1
%
2
2
4
2
rel-(2R,3S)-2,3-Dihydroxy-N-methoxy-N,2-dimethylbutanamide
[43]
[48]
(syn-7d): Following the general procedure A, the title compound
6
H
was prepared from 2d (0.30 g, 2.1 mmol), citric acid (0.30 g,
1
3
): δ = 1.20 (d, 1.6 mmol, 0.75 equiv.), K
2
OsO
2 4
(OH) (7.7 mg, 21 μmol, 1.0 mol-
J
3
2
O, 0.59 g, 2.5 mmol, 1.2 equiv.). Purifica-
43]
=
6
2
c
6
H
1
c
,
3
): δ = 1.26 (d,
possibly interpretable as BBЈ part of an AAЈBBЈ signal, 2 H, 2 o-
H) ppm.
J
3
=
4
4
-Methoxybenzyl
(2R,3S)-2,3-Dihydroxy-2-methylbutanoate
OH) ppm.
[
48]
[(2R,3S)-7c]:
Following the general procedure B, the title com-
pound was prepared from 2c (0.50 g, 2.3 mmol), K
2.2 g, 6.8 mmol, 3.0 equiv.), K CO
MeSO NH (0.21 g, 2.2 mmol, 1.0 equiv.), (DHQ)
5 μmol, 2.0 mol-%), and K OsO (OH) (8.4 mg, 22 μmol, 1.0 mol-
). Purification by flash chromatography on silica gel[
12/EtOAc = 3:1–1:1, 11–26) rendered 63 μmol, 2.0 mol-%), and K
3
[Fe(CN)
6
]
(2R,3S)-2,3-Dihydroxy-N-methoxy-N,2-dimethylbutanamide
48]
(
2
3
(0.94 g, 6.8 mmol, 3.0 equiv.), [(2R,3S)-7d]:[ Following the general procedure B, the title com-
2
2
2
PHAL (35 mg,
pound was prepared from 2d (0.30 g, 2.1 mmol), K
(2.1 g, 6.3 mmol, 3.0 equiv.), K CO (0.87 g, 6.3 mmol, 3.0 equiv.),
PhSO NH (0.33 g, 2.1 mmol, 1.0 equiv.), (DHQ) PHAL (49 mg,
OsO (OH) (16 mg, 42 μmol, 1.0 mol-
%). Purification by flash chromatography on silica gel
(2.5 ϫ15 cm, 20 mL, c-C 12/EtOAc = 2:1–1:3, 23–34) rendered
the product as a colorless oil (0.30 g; 81%; 98% ee). Analytical
3 6
[Fe(CN) ]
4
%
2
2
4
2
3
43]
2
2
2
(2.5ϫ15 cm, 20 mL, c-C
6
H
2
2
4
[
43]
the product as a colorless oil (0.47 g, 81%; 93% ee). Analytical
HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 90:10, 229 nm,
6
H
20
t
R D
= 15.37 (2S,3R), 17.69 min (2R,3S). [α] = –1.1 (c = 1.03 g/
0
1
1
00 mL, CHCl
NMR (300.06 MHz, CDCl
), 1.31 (s, 3 H, 2-Me), 1.94 (d, J3-OH,3-H = 8.8 Hz, 1 H, 3-OH),
.34 (s, 1 H, 2-OH), 3.81 (s, 3 H, p-OMe), 3.94 (dq, J3,3-OH = 7.8,
3,4 = 6.7 Hz, 1 H, 3-H), 5.18 (s, 2 H, 1Ј-H ), 6.89 (m , possibly 2.02 (br. s, 1 H, 3-OH), 3.31 (s, 3 H, N-Me), 3.75 (s, 3 H, O-Me),
3
); [α] 32 65 = –12.8 (c = 1.03 g/100 mL, CHCl
3
).
H
HPLC: Chiralpak OD-H, n-heptane/iPrOH = 95:5, 210 nm, t
R
=
2
0
3
): δ = 1.20 (d, J4,3 = 6.3 Hz, 3 H, 4- 19.27 (S), 24.74 min (R). [α]
D
= +17.6 (c = 1.12 g/100 mL, CHCl
3
);
2
0
1
H
3
[α]365 = +54.9 (c = 1.12 g/100 mL, CHCl
CDCl
3
). H NMR (300.06 MHz,
3
3
): δ = 1.25 (d, J4,3 = 6.3 Hz, 3 H, 4-H
3
), 1.37 (s, 3 H, 2-Me),
J
2
c
interpretable as AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.30 4.16 (br. s, 1 H, 3-H), 4.44 (br. s, 1 H, 2-OH) ppm.
, possibly interpretable as BBЈ part of an AAЈBBЈ signal, 2 H,
(m
c
(
[
2S,3R)-2,3-Dihydroxy-N-methoxy-N,2-dimethylbutanamide
(2S,3R)-7d]: Following the general procedure B, the title com-
(2S,3R)-2,3-Dihydroxy-2-methylbutanoate pound was prepared from 2d (0.30 g, 2.1 mmol), K [Fe(CN)
(2.1 g, 6.3 mmol, 3.0 equiv.), K CO (0.87 g, 6.3 mmol, 3.0 equiv.),
PhSO NH (0.33 g, 2.1 mmol, 1.0 equiv.), (DHQD) PHAL (49 mg,
(0.94 g, 6.8 mmol, 3.0 equiv.), 63 μmol, 2.0 mol-%), and K OsO (OH) (16 mg, 42 μmol, 1.0 mol-
(0.21 g, 2.2 mmol, 1.0 equiv.), (DHQD) PHAL %). Purification by flash chromatography on silica gel
35 mg, 45 μmol, 2.0 mol-%), and K OsO (OH) (8.4 mg, 22 μmol, (2.5ϫ15 cm, 20 mL, c-C 12/EtOAc = 2:1–1:3, 27–35) rendered
.0 mol-%). Purification by flash chromatography on silica gel the product as a colorless oil (0.33 g, 89%; 99% ee). Analytical
12/EtOAc = 3:1–1:1, 11–26) rendered
the product as a colorless oil (0.47 g, 81%; 95% ee). Analytical
2
o-H) ppm.
4-Methoxybenzyl
3
6
]
[
(2S,3R)-7c]: Following the general procedure B, the title com-
pound was prepared from 2c (0.50 g, 2.3 mmol), K [Fe(CN)
2.2 g, 6.8 mmol, 3.0 equiv.), K CO
MeSO NH
2
3
3
6
]
2
2
2
(
2
3
2
2
4
[
43]
2
2
2
(
1
2
2
4
6
H
[
43]
(2.5ϫ15 cm, 20 mL, c-C
6
H
HPLC: Chiralpak OD-H, n-heptane/iPrOH = 95:5, 210 nm, t
19.84 (S), 24.39 min (R). [α]
R
=
);
2
0
D
= –17.7 (c = 1.34 g/100 mL, CHCl
3
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
2
0
–1 1
[
α]365 = –52.0 (c = 1.34 g/100 mL, CHCl
3
). IR (film): ν˜ = 3430,
1085, 1070 cm . H NMR (400.13 MHz, CDCl
= 6.4 Hz, 3 H, 4-H ), 1.33 (s, 3 H, 2-Me), 1.84 (br. m
)*, 1.93 (br. m , 2 H, 4Ј-H )*, 2.70 (br. d, J3-OH,3 = 6.8 Hz, 1 H,
3-OH), 3.54 (br. m , 2 H, 2Ј-H )** superimposed by 3.67 (br. m
1 H, 5Ј-H)** superimposed by 3.75 (br. m , 1 H, 5Ј-H)**, 3.97 (s,
3
): δ = 1.21 (d, J4,3
2
1
1
985, 2945, 2915, 2850, 2835, 1640, 1460, 1450, 1370, 1260, 1210,
180, 1090, 1015, 995 cm . H NMR (400.13 MHz, CDCl
.25 (d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.37 (s, 3 H, 2-Me), 2.03 (d, J3-
OH,3 = 10.0 Hz, 1 H, 3-OH), 3.31 (s, 3 H, N-Me), 3.75 (s, 3 H, O-
Me), 4.15 (m , possibly interpretable as dq, J3,3-OH = 9.2, J3,4
.6 Hz, 1 H, 3-H), 4.44 (s, 1 H, 2-OH) ppm. 1 C NMR
100.63 MHz, CDCl ): δ = 17.17 (C-4), 21.84 (2-Me), 33.90 (N-
Me), 61.04 (O-Me), 70.38 (C-3), 77.67 (C-2), 175.51 (C-1) ppm. (2-Me), 23.23 (C-3Ј)*, 27.01 (C-4Ј)*, 47.75 (C-5Ј)**, 48.03 (C-2Ј)**,
3
c
, 2 H, 3Ј-
–1 1
3
): δ =
H
2
c
2
3
c
2
c
,
c
c
=
1 H, 2-OH), 4.19 (dq, J3,3-OH = J3,4 = 6.2 Hz, 1 H, 3-H) ppm.
*,** The assignments of 3Ј-H and 4Ј-H, and of 2Ј-H and 5Ј-H are
arbitrary. C NMR (100.63 MHz, CDCl ): δ = 16.16 (C-4), 21.21
3
3
6
(
1
3
3
edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl
3
): Allows the
70.74 (C-3), 77.47 (C-2), 173.63 (C-1) ppm. *,** The assignments
assignment of all nonquaternary carbon atoms by their cross-peaks
with directly bonded protons [δ( C) ↔ δ( H)]: δ = 17.17 (C-4) ↔
of 3Ј-H and 4Ј-H, and of 2Ј-H and 5Ј-H are arbitrary, but consis-
tent with the assignment in the H NMR spectrum. edHSQC
13
1
1
1
3
4
.25 (4-H
3
); δ = 21.84 (2-Me) ↔ 1.37 (2-Me); δ = 33.90 (N-Me) ↔ (“C,H-COSY”, 100.62/400.13 MHz, CDCl
3
): Allows the assign-
.31 (N-Me); δ = 61.04 (O-Me) ↔ 3.75 (O-Me); δ = 70.38 (C-3) ↔
.15 (3-H) ppm. HRMS: (pos. ESI, MeOH): calcd. for
ment of all nonquaternary carbon atoms by their cross-peaks with
1
3
1
directly bonded protons [δ( C) ↔ δ( H)]: δ = 16.16 (C-4) ↔ δ =
); δ = 21.21 (2-Me) ↔ δ = 1.33 (2-Me); δ = 23.23 (C-
Ј)* ↔ δ = 1.84 (3Ј-H ); δ = 27.01 (C-4Ј)* ↔ δ = 1.93 (4Ј-H ); δ =
7.75 (C-5Ј) ↔ δ = 3.67 (5Ј-H) and 3.75 (5Ј-H); δ = 48.03 (C-2Ј)
δ = 3.54 (2Ј-H ); δ = 70.74 (C-3) ↔ δ = 4.19 (3-H) ppm. HRMS:
pos. ESI, MeOH): calcd. for C12
10.11061; found 210.11070 (+0.4 ppm).
+
C
7
H
15NO
4
Na [M + Na] 200.08988; found 200.08990 (+0.1 ppm). 1.21 (4-H
3
3
4
↔
2
2
rel-(2R,3S)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)butan-1-one
[
48]
(
syn-7e): Following the general procedure A, the title compound
was prepared from 2e (0.17 g, 1.1 mmol), citric acid (0.16 g,
.82 mmol, 0.75 equiv.), K OsO (OH) (4.0 mg, 11 μmol, 1.0 mol-
), and NMO (50% in H O, 0.31 g, 1.3 mmol, 1.2 equiv.). Purifica-
tion by flash chromatography on silica gel (2.5ϫ15 cm, 20 mL,
c-C 12/EtOAc = 1:1–1:3, 19–25) rendered the product as a color-
less oil (0.21 g, 100%). H NMR (300.06 MHz, CDCl
d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.34 (s, 3 H, 2-Me), 1.86 (br. m
H, 3Ј-H )*, 1.93 (br. m , 2 H, 4Ј-H )*, 3.55 (br. m , 2 H, 2Ј-H
superimposed by 3.65 (br. m , 1 H, 5Ј-H)** superimposed by 3.75
br. m
, 1 H, 5Ј-H)**, 4.20 (q, J3,4 = 6.3 Hz, 1 H, 3-H) ppm. *,** on silica gel[ (2.5ϫ15 cm, 20 mL, c-C
2
+
(
2
16 4
H O Na [M + Na] calcd.
0
%
2
2
4
2
[43]
Methyl rel-(2S,3S)-2,3-Dihydroxy-2-methylbutanoate (anti-7a):[48]
Following the general procedure A, the title compound was pre-
pared from methyl (Z)-2-methylbut-2-enoate (3a; 0.50 g,
6
H
1
3
): δ = 1.22
, 2
)** (OH)
1.2 g, 5.3 mmol, 1.2 equiv.). Purification by flash chromatography
(
3
c
4.4 mmol), citric acid (0.63 g, 3.3 mmol, 0.75 equiv.), K
2
OsO
2
-
2
c
2
c
2
4
(4.0 mg, 11 μmol, 0.25 mol-%), and NMO (50% in H
2
O,
c
43]
(
c
6
H
12/EtOAc = 3:1–1:1, 8–
1
The assignments of 3Ј-H and 4Ј-H, and of 2Ј-H and 5Ј-H are arbi-
trary. The OH groups were not visible in this spectrum.
20) rendered the product as a colorless oil (0.53 g, 82%). H NMR
(300.06 MHz, CDCl ): δ = 1.16 (d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.44
s, 3 H, 2-Me), 2.16 (d, J3-OH,3 = 8.1, 1 H, 3-OH), 3.36 (s, 1 H,
3
3
(
(
2R,3S)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)butan-1-one
2
-OH), 3.73–3.87 (m, 1 H, 3-H) superimposed by 3.81 (s, 3 H,
[
48]
[
(2R,3S)-7e]:
pound was prepared from 2e (0.30 g, 2.0 mmol), K
1.9 g, 5.9 mmol, 3.0 equiv.), K CO
(0.81 g, 5.9 mmol, 3.0 equiv.), Methyl (2S,3S)-2,3-Dihydroxy-2-methylbutanoate [(S,S)-7a]:[48] Fol-
PhSO NH (0.31 g, 2.0 mmol, 1.0 equiv.), (DHQ) PHAL (46 mg, lowing the general procedure B, the title compound was prepared
9 μmol, 3.0 mol-%), and K OsO (OH) (14 mg, 39 μmol, 2.0 mol- from methyl (Z)-2-methylbut-2-enoate (3a; 0.50 g, 4.4 mmol),
). Purification by flash chromatography on silica gel (2 15 cm, [Fe(CN) ] (4.3 g, 13 mmol, 3.0 equiv.), K CO (1.8 g, 13 mmol,
12/EtOAc = 3:1–1:3, 45–51) rendered the product as 3.0 equiv.), MeSO NH (0.42 g, 4.4 mmol, 1.0 equiv.),
a colorless oil (0.22 g, 59%; 97% ee). Analytical HPLC: Chiralpak (DHQ) PHAL (68 mg, 88 μmol, 2.0 mol-%), and K OsO (OH)
AD-3, n-heptane/iPrOH = 95:5, 230 nm, t = 12.95 (2S,3R), (16 mg, 44 μmol, 1.0 mol-%). Purification by flash chromatography
= +33.4 (c = 1.06 g/100 mL, CHCl );
NMR
), 1.34 Analytical HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 95:5,
Following the general procedure B, the title com-
OMe) ppm.
3
[Fe(CN)
6
]
(
2
3
2
2
2
5
%
2
2
2
4
[43]
K
3
6
2
3
0 mL, c-C
6
H
2
2
2
2
2
4
R
2
0
[43]
1
[
(
(
H
H
5.60 min (2R,3S). [α]
D
3
on silica gel (2.5ϫ15 cm, 20 mL, c-C
6
H12/EtOAc = 3:1–1:1, 19–
20
1
α]365
=
+112.0 (c
300.06 MHz, CDCl ): δ = 1.22 (d, J4,3 = 6.4 Hz, 3 H, 4-H
s, 3 H, 2-Me), 1.86 (br. m , 2 H, 3Ј-H )*, 1.93 (br. m , 2 H, 4Ј-
)*, 2.58 (d, J3-OH,3 = 7.5 Hz, 1 H, 3-OH), 3.55 (br. m , 2 H, 2Ј- 100 mL, CHCl
)** superimposed by 3.68 (br. m , 1 H, 5Ј-H)** superimposed NMR (300.06 MHz, CDCl
, 1 H, 5Ј-H)**, 3.93 (s, 1 H, 2-OH), 4.20 (dq, ), 1.44 (s, 3 H, 2-Me), 2.19 (d, J3-OH,3 = 7.9, 1 H, 3-OH), 3.38
3,3-OH = J3,4 = 6.6 Hz, 1 H, 3-H) ppm. *,** The assignments of
Ј-H and 4Ј-H, and of 2Ј-H and 5Ј-H are arbitrary.
=
1.06 g/100 mL, CHCl
3
).
H
36) rendered the product as a colorless oil (0.53 g, 82%; 77% ee).
3
3
2
0
c
2
c
R D
210 nm, t = 14.05 (S,S), 15.97 min (R,R). [α] = +4.7 (c = 0.94 g/
2
0
1
2
2
c
3
); [α]365 = +17.4 (c = 0.94 g/100 mL, CHCl
3
). H
c
3
): δ = 1.16 (d, J4,3 = 6.4 Hz, 3 H, 4-
by 3.76 (br. m
J
3
c
H
3
(s, 1 H, 2-OH), 3.75–3.86 (m, 1 H, 3-H) superimposed by 3.81 (s,
3 H, OMe) ppm.
(
2S,3R)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)butan-1-one Methyl (2R,3R)-2,3-Dihydroxy-2-methylbutanoate [(R,R)-7a]: Fol-
[
(2S,3R)-7e]: Following the general procedure B, the title com-
lowing the general procedure B, the title compound was prepared
pound was prepared from 2e (0.30 g, 2.0 mmol), K
3
[Fe(CN)
6
]
from methyl (Z)-2-methylbut-2-enoate (3a; 0.50 g, 4.4 mmol),
(
1.9 g, 5.9 mmol, 3.0 equiv.), K
PhSO NH (0.31 g, 2.0 mmol, 1.0 equiv.), (DHQD)
9 μmol, 3.0 mol-%), and K OsO (OH) (14 mg, 39 μmol, 2.0 mol-
). Purification by flash chromatography on silica gel (2 15 cm,
12/EtOAc = 3:1–1:3, 45–51) rendered the product as
a colorless oil (0.28 g, 76%; 98% ee). Analytical HPLC: Chiralpak
AD-3, n-heptane/iPrOH = 95:5, 230 nm, t = 12.41 (2S,3R),
= –35.9 (c = 1.32 g/100 mL, CHCl );
α]365 = –115.6 (c = 1.32 g/100 mL, CHCl ). IR (film): ν˜ = 3390,
975, 2915, 2880, 2850, 1600, 1440, 1365, 1340, 1260, 1185, 1150,
2
CO
3
(0.81 g, 5.9 mmol, 3.0 equiv.),
K
3
[Fe(CN)
3.0 equiv.), MeSO
PHAL (68 mg, 88 μmol, 2.0 mol-%), and K
44 μmol, 1.0 mol-%). Purification by flash chromatography on sil-
6
] (4.3 g, 13 mmol, 3.0 equiv.), K
NH (0.42 g, 4.4 mmol, 1.0 equiv.), (DHQD)
OsO (OH) (16 mg,
2 3
CO (1.8 g, 13 mmol,
2
2
2
PHAL (46 mg,
2
2
2
-
5
%
2
2
2
4
2
2
4
[43]
ica gel[ (2.5ϫ15 cm, 20 mL, c-C
rendered the product as a colorless oil (0.55 g, 86%; 90% ee). Ana-
lytical HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 95:5,
210 nm, t
100 mL, CHCl
(film): ν˜ = 3465, 2985, 2950, 1735, 1450, 1375, 1255, 1185, 1155,
43]
H12/EtOAc = 3:1–1:1, 13–22)
0 mL, c-C
6
H
6
R
2
0
20
1
[
2
6.15 min (2R,3S). [α]
D
3
R
= 14.56 (S,S), 15.46 min (R,R). [α]
D
= –5.1 (c = 1.12 g/
20
20
3
); [α]365 = –21.4 (c = 1.12 g/100 mL, CHCl ). IR
3 3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
FULL PAPER
1
(
(
090, 1015, 980, 910, 870, 795, 750, 700 cm–1 . 1 H NMR 1090, 1015, 985, 950, 920, 790, 750, 700 cm–1 . 1 H NMR
400.13 MHz, CDCl ): δ = 1.15 (d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.44 (400.13 MHz, CDCl ): δ = 0.960 (d, J3Ј,2Ј = 6.8 Hz, 3 H, 3Ј-H
s, 3 H, 2-Me), 2.20 (d, J3-OH,3 = 8.0 Hz, 1 H, 3-OH), 3.39 (s, 1 H, superimposed by 0.961 (d, J2Ј-Me,2Ј = 6.8 Hz, 3 H, 2Ј-Me), 1.17 (d,
-OH), 3.80 (dq, J3,3-OH = 8.0, J3,4 = 6.5 Hz, 1 H, 3-H) superim-
3
3
3
3
)
2
J
J
4,3 = 6.4 Hz, 3 H, 4-H
3
), 1.45 (s, 3 H, 2-Me), 1.99 [ddqq,
1
3
posed by 3.81 (s, 3 H, OMe) ppm. C NMR (100.63 MHz,
CDCl ): δ = 17.79 (C-4), 22.35 (2-Me), 52.97 (OMe), 72.31 (C-
), 77.27 (C-2), 176.00 (C-1) ppm. edHSQC (“C,H-COSY”, 100.62/
00.13 MHz, CDCl ): Allows the assignment of all nonquaternary
2Ј,1Ј-H(A) = J2Ј,1Ј-H(B) = J2Ј,3Ј = J2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H], 2.17
3
(s, 1 H, 3-OH), 3.42 (br. s, 1 H, 2-OH), 3.81 (q, J3,3-OH = 7.6, J3,4
= 6.6 Hz, 1 H, 3-H) ppm, AB signal [δ = 3.96, δ = 4.02 ppm, A
part additionally split by J1Ј-H(A),2Ј = 6.5 Hz, B part additionally
3
4
A
B
3
1
3
carbon atoms by their cross-peaks with directly bonded protons
split by J1Ј-H(B),2Ј = 6.6, JAB = 10.5 Hz, 2 H, 1Ј-H
); δ = 22.35 (2- (100.63 MHz, CDCl ): δ = 17.80 (C-4), 19.05 (C-3Ј)*, 19.09 (2Ј-
Me) ↔ δ = 1.44 (2-Me); δ = 52.97 (OMe) ↔ δ = 3.81 (OMe); δ = Me)*, 22.46 (2-Me), 27.79 (C-2Ј), 72.26 (C-3)**, 72.29 (C-1Ј)**,
2.31 (C-3) ↔ δ = 3.80 (3-H) ppm. HRMS: (pos. ESI, MeOH): 77.19 (C-2), 175.70 (C-1) ppm. *,** Assignments interchangeable.
2
]. C NMR
13
1
[δ( C) ↔ δ( H)]: δ = 17.79 (C-4) ↔ δ = 1.15 (4-H
3
3
7
+
calcd. for C
6
H
12
O
4
Na [M + Na] 171.06330; found 171.06333
edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl
3
): Allows the
(
+0.2 ppm).
assignment of all nonquaternary carbon atoms by their cross-peaks
1
3
1
with directly bonded protons [δ( C) ↔ δ( H)]: δ = 17.80 (C-4) ↔
δ = 1.17 (4-H ); δ = 19.05 (C-3Ј) and 19.09 (2Ј-Me) ↔ δ = 0.960
3Ј-H ) and 0.961 (2Ј-Me); δ = 22.46 (2-Me) ↔ δ = 1.45 (2-Me); δ
27.79 (C-2Ј) ↔ δ = 1.99 (2Ј-H); δ = 72.26 (C-3) and 72.29 (C-1Ј)
δ = 3.81 (3-H) ppm, and AB signal (δ = 3.96, δ = 4.02 ppm,
Isobutyl rel-(2S,3S)-2,3-Dihydroxy-2-methylbutanoate (anti-7b):[48]
Following the general procedure A, the title compound was pre-
pared from isobutyl (Z)-2-methylbut-2-enoate (3b; 0.50 g,
3
(
3
(
3
=
.2 mmol), citric acid (0.46 g, 2.4 mmol, 0.75 equiv.), K
OH) (3.0 mg, 8.0 μmol, 0.25 mol-%), and NMO (50% in H
.90 g, 3.8 mmol, 1.2 equiv.). Purification by flash chromatography
2
OsO
2
-
↔
A
B
4
2
O,
1
Ј-H
2
). HRMS (pos. APCI, MeOH): calcd. for C
9
H
9
H
19
O
O
4
0
M + H]+ 191.12833; found 191.12830 (–0.2 ppm). C
[
18
4
[
43]
on silica gel (2.5ϫ15 cm, 20 mL, c-C
4) rendered the product as a colorless oil (0.57 g, 92%). H NMR
300.06 MHz, CDCl ): δ = 0.96 (d, J3Ј,2Ј = J2Ј-Me,2Ј = 6.7 Hz, 6 H,
, 2Ј-Me), 1.17 (d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.45 (s, 3 H, 2-
6
H12/EtOAc = 3:1–1:1, 8–
(
190.24): calcd. C 56.82, H 9.54; found C 56.43, H 9.40.
1
1
(
3
3
4-Methoxybenzyl rel-(2S,3S)-2,3-Dihydroxy-2-methylbutanoate
(anti-7c):[ Following the general procedure A, the title compound
was prepared from 3c (0.30 g, 1.4 mmol), citric acid (0.20 g,
48]
Ј-H
3
3
Me), 1.99 [ddqq, J2Ј,1Ј-H(A) = J2Ј,1Ј-H(B) = J2Ј,3Ј = J2Ј,2Ј-Me = 6.7 Hz,
1
(
4
H, 2Ј-H], 2.17 (br. s, 1 H, 3-OH), 3.41 (br. s, 1 H, 2-OH), 3.81 1.0 mmol, 0.75 equiv.), K
q, J3,4 = 6.4 Hz, 1 H 3-H) ppm, AB signal [δ = 3.97, δ %), and NMO (50% in H
.03 ppm, A part additionally split by J1Ј-H(A),2Ј = 6.6 Hz, B part
tion by flash chromatography on silica gel[ (2 15 cm, 20 mL, c-
]. 12/EtOAc = 3:1–1:1, 15–21) rendered the product as a colorless
2
OsO
2 4
(OH) (1.3 mg, 3.4 μmol, 0.25 mol-
A
B
=
2
O, 0.38 g, 1.6 mmol, 1.2 equiv.). Purifica-
43]
additionally split by J1Ј-H(B),2Ј = 6.7, JAB = 10.5 Hz, 2 H, 1Ј-H
2
6
C H
1
oil (0.31 g, 90%). H NMR (300.06 MHz, CDCl
6.4 Hz, 3 H, 4-H ), 1.43 (s, 3 H, 2-Me), 2.10 (br. d, J3-OH,3
.2 Hz, 1 H, 3-OH), 3.36 (s, 1 H, 2-OH), 3.78 (dq, J3-OH,3 = J3,4
3
): δ = 1.08 (d, J4,3
Isobutyl (2S,3S)-2,3-Dihydroxy-2-methylbutanoate [(S,S)-7b]:[48]
Following the general procedure B, the title compound was pre-
pared from isobutyl (Z)-2-methylbut-2-enoate (3b; 0.50 g,
=
8
6
3
=
=
.7 Hz, 1 H, 3-H) superimposed by 3.82 (s, 3 H, p-OMe), AB signal
= 5.15, δ = 5.18 ppm, JAB = 11.9 Hz, 2 H, 1Ј-H ), 6.90 (m
possibly interpretable as AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-
H), 7.29 (m , possibly interpretable as BBЈ part of an AAЈBBЈ sig-
3
(
1
K
.2 mmol), K
1.3 g, 9.6 mmol, 3.0 equiv.), MeSO
.0 equiv.), (DHQ) PHAL (50 mg, 64 μmol, 2.0 mol-%), and
OsO (OH) (12 mg, 32 μmol, 1.0 mol-%). Purification by flash
chromatography on silica gel
2:1–1:2, 8–13) rendered the product as a colorless oil (0.56 g,
2%; 67% ee). Analytical HPLC: Kromasil 3-AmyCoat, n-heptane/
3
[Fe(CN)
6
] (3.2 g, 9.6 mmol, 3.0 equiv.), K
2 3
CO
(
δ
A
B
2
c
,
2
NH (0.30 g, 3.2 mmol,
2
2
c
2
2
4
nal, 2 H, 2 o-H) ppm.
[43]
6
(2 15 cm, 20 mL, c-C H12/EtOAc
=
9
4-Methoxybenzyl (2S,3S)-2,3-Dihydroxy-2-methylbutanoate [(S,S)-
7c]:[ Following the general procedure B, the title compound was
48]
2
0
iPrOH = 95:5, 210 nm, t
R
= 8.03 (S,S), 9.01 min (R,R). [α]
D
= –6.8
); [α] 32 65 = –36.8 (c = 1.47 g/100 mL,
): δ = 0.96 (d, J3Ј,2Ј
, 2Ј-Me), 1.17 (d, J4,3 = 6.4 Hz, 3 H,
), 1.45 (s, 3 H, 2-Me), 1.99 [ddqq, J2Ј,1Ј-H(A) = J2Ј,1Ј-H(B) = J2Ј,3Ј
2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H], 2.18 (br. d, J3-OH,3 = 7.8 Hz, 1 H,
-OH), 3.42 (s, 1 H, 2-OH), 3.81 (dq, J3,3-OH = J3,4 = 6.8 Hz, 1 H,
-H) ppm, AB signal [δ = 3.96, δ = 4.02 ppm, A part additionally
prepared from 3c (0.30 g, 1.4 mmol), K
3.0 equiv.), K CO (0.56 g, 4.1 mmol, 3.0 equiv.), MeSO
(0.13 g, 1.4 mmol, 1.0 equiv.), (DHQ) PHAL (21 mg, 27 μmol,
2.0 mol-%), and K OsO (OH) (5.0 mg, 14 μmol, 1.0 mol-%). Puri-
fication by flash chromatography on silica gel (2ϫ15 cm, 20 mL,
c-C 12/EtOAc = 3:1–1:1, 8–13) rendered the product as a colorless
oil (0.27 g, 78%; 60% ee). Analytical HPLC: Kromasil 3-AmyCoat,
n-heptane/iPrOH = 95:5, 229 nm, t = 17.74 (S,S), 19.67 min
3
[Fe(CN)
6
] (1.3 g, 4.1 mmol,
0
(
c = 1.47 g/100 mL, CHCl
3
2
3
2
NH
2
1
CHCl
J
4
=
3
3
3
). H NMR (300.06 MHz, CDCl
3
=
2
2Ј-Me,2Ј = 6.7 Hz, 6 H, 3Ј-H
3
2
2
4
[43]
-H
3
J
6
H
A
B
R
2
0
20
split by J1Ј-H(A),2Ј = 6.7 Hz, B part additionally split by J1Ј-H(B),2Ј
.7, JAB = 10.6 Hz, 2 H, 1Ј-H ].
=
(R,R). [α]
D
= –2.3 (c = 1.38 g/100 mL, CHCl
3
); [α]365 = –2.9 (c =
). H NMR (300.06 MHz, CDCl ): δ = 1.08
d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.43 (s, 3 H, 2-Me), 2.10 (br. d,
3-OH,3 = 7.6 Hz, 1 H, 3-OH), 3.35 (s, 1 H, 2-OH), 3.78 (dq, J3-OH,3
3,4 = 6.9 Hz, 1 H, 3-H) superimposed by 3.82 (s, 3 H, p-OMe),
AB signal (δ = 5.15, δ = 5.18 ppm, JAB = 11.9 Hz, 2 H, 1Ј-H ),
, possibly interpretable as AAЈ part of an AAЈBBЈ signal,
H, 2 m-H), 7.29 (m , possibly interpretable as BBЈ part of an
1
6
2
1.38 g/100 mL, CHCl
3
3
(
J
3
Isobutyl (2R,3R)-2,3-Dihydroxy-2-methylbutanoate [(R,R)-7b]: Fol-
lowing the general procedure B, the title compound was prepared
from isobutyl (Z)-2-methylbut-2-enoate (3b; 0.50 g, 3.2 mmol),
=
J
A
B
2
K
3
3
[Fe(CN)
.0 equiv.), MeSO
PHAL (50 mg, 64 μmol, 2.0 mol-%), and K
6
] (3.2 g, 9.6 mmol, 3.0 equiv.), K
NH (0.30 g, 3.2 mmol, 1.0 equiv.), (DHQD)
OsO (OH) (12 mg,
2 μmol, 1.0 mol-%). Purification by flash chromatography on sil-
2 3
CO (1.3 g, 9.6 mmol,
6.90 (m
c
2
2
2
-
2
c
2
2
4
AAЈBBЈ signal, 2 H, 2 o-H) ppm.
3
[
43]
ica gel
(2 15 cm, 20 mL, c-C
6
H
12/EtOAc = 2:1–1:2, 5–15) ren-
4-Methoxybenzyl (2R,3R)-2,3-Dihydroxy-2-methylbutanoate
[(R,R)-7c]: Following the general procedure B, the title compound
dered the product as a colorless oil (0.51 g, 84%; 82% ee). Analyti-
cal HPLC: Kromasil 3-AmyCoat, n-heptane/iPrOH = 95:5,
was prepared from 3c (0.30 g, 1.4 mmol), K
4.1 mmol, 3.0 equiv.), K CO (0.56 g, 4.1 mmol, 3.0 equiv.), Me-
SO NH (0.13 g, 1.4 mmol, 1.0 equiv.), (DHQD) PHAL (21 mg,
27 μmol, 2.0 mol-%), and K
3 6
[Fe(CN) ] (1.3 g,
2
0
210 nm, t
R
= 8.20 (S,S), 8.81 min (R,R). [α]
D
= +7.8 (c = 1.24 g/
2
3
); [α] 32 65 = +43.5 (c = 1.24 g/100 mL, CHCl
0
). IR
100 mL, CHCl
3
3
2
2
2
(film): ν˜ = 3465, 2970, 2880, 1735, 1465, 1375, 1250, 1180, 1125,
2
OsO
2
(OH)
4
(5.0 mg, 14 μmol, 1.0 mol-
14
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
%
(
). Purification by flash chromatography on silica gel[43]
2ϫ15 cm, 20 mL, c-C 12/EtOAc = 3:1–1:1, 9–16) rendered the
product as a colorless oil (0.27 g, 78%; 80% ee). Analytical HPLC:
Kromasil 3-AmyCoat, n-heptane/iPrOH = 95:5, 229 nm, t = 18.05 (R,R), 43.18 min (S,S). [α]
(2ϫ15 cm, 20 mL, c-C
6
H12/EtOAc = 1:1–1:3, 23–31) rendered the
6
H
product as a colorless oil (0.20 g, 80%; 71% ee). Analytical HPLC:
Chiralpak AD-H, n-heptane/EtOH = 95:5, 230 nm, t = 38.37
= +17.2 (c = 1.35 g/100 mL, CHCl );
[α]365 = +45.6 (c = 1.35 g/100 mL, CHCl ). IR (film): ν˜ = 3420,
2985, 2940, 2850, 1640, 1460, 1375, 1350, 11260, 1195, 1180, 1140,
R
2
0
R
D
3
20
20
(
[
S,S), 19.58 min (R,R). [α]
D
= +2.8 (c = 1.23 g/100 mL, CHCl
α]365 = +3.4 (c = 1.23 g/100 mL, CHCl ). IR (film): ν˜ = 3480, 2980,
935, 2840, 2060, 1725, 1615, 1515, 1465, 1245, 1175, 1035, 1190, 1060, 995 cm . H NMR (400.13 MHz, CDCl
3
);
3
20
3
–
1 1
2
8
6
1
1
5
3
): δ = 0.99 (d,
), 1.49 (s, 3 H, 2-Me), 3.23 (s, 3 H, N-Me),
3.69 (s, 3 H, O-Me), 4.00 (q, J3,4 = 6.4 Hz, 1 H, 3-H) ppm. The OH
20 cm–1. H NMR (400.13 MHz, CDCl
.4 Hz, 3 H, 4-H ), 1.43 (s, 3 H, 2-Me), 2.13 (br. d, J3-OH,3 = 8.2 Hz,
H, 3-OH), 3.38 (s, 1 H, 2-OH), 3.78 (dq, J3-OH,3 = J3,4 = 7.1 Hz,
H, 3-H) superimposed by 3.81 (s, 3 H, p-OMe), AB signal (δ
.15, δ = 5.18 ppm, JAB = 11.9 Hz, 2 H, 1Ј-H ), 6.89 (m , possibly
1
): δ = 1.08 (d, J4,3
=
J4,3 = 6.4 Hz, 3 H, 4-H
3
3
3
1
3
groups were not visible in this spectrum. C NMR (100.63 MHz,
CDCl ): δ = 18.33 (C-4), 22.13 (2-Me), 33.71 (N-Me), 60.88 (O-
Me), 70.04 (C-3), 77.23 (C-2), 175.72 (C-1) ppm. edHSQC (“C,H-
): Allows the assignment of all
nonquaternary carbon atoms by their cross-peaks with directly
A
=
3
B
2
c
interpretable as AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.29 COSY”, 100.62/400.13 MHz, CDCl
, possibly interpretable as BBЈ part of an AAЈBBЈ signal, 2 H,
o-H) ppm. 13C NMR (100.63 MHz, CDCl
): δ = 17.71 (C-4),
2.32 (2-Me), 55.38 (p-OMe), 67.72 (C-1Ј), 72.26 (C-3), 77.13 (C- δ = 22.13 (2-Me) ↔ 1.49 (2-Me); δ = 33.71 (N-Me) ↔ 3.23 (N-
3
(m
c
13
1
2
2
2
1
3
3
bonded protons [δ( C) ↔ δ( H)]: δ = 18.33 (C-4) ↔ 0.99 (4-H );
), 114.15 (2 C-m), 127.16 (C-i), 130.33 (2 C-o), 160.02 (C-p),
75.45 (C-1) ppm. edHSQC (“C,H-COSY”, 100.62/400.13 MHz,
Me); δ = 60.88 (O-Me) ↔ 3.69 (O-Me); δ = 70.04 (C-3) ↔ 4.00 (3-
H) ppm. HRMS: (pos. ESI, MeOH): calcd. for C
7 4
H15NO Na [M
CDCl
by their cross-peaks with directly bonded protons [δ( C) ↔ δ( H)]:
δ = 17.71 (C-4) ↔ δ = 1.08 (4-H ); δ = 22.32 (2-Me) ↔ δ = 1.43
2-Me); δ = 55.38 (p-OMe) ↔ δ = 3.81 (p-OMe); δ = 67.72 (C-1Ј)
δ = AB signal (δ = 5.15, δ = 5.18 ppm, 1Ј-H ); δ = 72.26 (C-
3
): Allows the assignment of all nonquaternary carbon atoms
+ Na]+ 200.08988; found 200.08990 (+0.1 ppm).
13
1
rel-(2S,3S)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)butan-1-one
(
3
anti-7e):[ Following the general procedure A, the title compound
was prepared from 3e (0.30 g, 2.0 mmol), citric acid (0.28 g,
.5 mmol, 0.75 equiv.), K OsO (OH) (7.2 mg, 20 μmol, 1.0 mol-
), and NMO (50% in H O, 0.55 g, 2.3 mmol, 1.2 equiv.). Purifica-
tion by flash chromatography on silica gel (2.5ϫ15 cm, 20 mL,
c-C 12/EtOAc = 3:1–0:100, 13–20) rendered the product as a col-
orless oil (0.36 g, 99%). H NMR (300.06 MHz, CDCl
d, J4,3 = 6.4 Hz, 3 H, 4-H ), 1.50 (s, 3 H, 2-Me), 1.87 (br. m
rel-(2S,3S)-2,3-Dihydroxy-N-methoxy-N,2-dimethylbutanamide H, 3Ј-H )* superimposed by 1.96 (br. m , 2 H, 4Ј-H )*, 2.61 (d,
3-OH,3 = 9.8 Hz, 1 H, 3-OH), 3.44–3.72 (m, 4 H, 2Ј-H , 5Ј-H ),
was prepared from 3d (0.60 g, 4.2 mmol), citric acid (0.60 g, 3.93 (dq, J3,3-OH = 10.0, J3,4 = 6.4 Hz, 1 H, 3-H) 4.31 (s, 1 H, 2-
48]
(
↔
A
B
2
1
2
2
4
3
1
) ↔ δ = 3.78 (3-H); δ = 114.15 (2 C-m) ↔ δ = 6.89 (2 m-H); δ =
30.33 (2 C-o) ↔ δ = 7.29 (2 o-H) ppm. HRMS (pos. APCI,
%
2
[43]
+
MeOH): calcd. for C13
72.14980 (Ϯ0.0 ppm). C13
found C 61.11, H 7.12.
H
22NO
5
[M + NH
4
]
272.14980; found
6
H
2
18 5
H O (254.28): calcd. C 61.41, H 7.14;
1
3
): δ = 1.09
, 2
(
3
c
2
c
2
[
48]
(anti-7d): Following the general procedure A, the title compound
J
2
2
3.1 mmol, 0.75 equiv.), K
2
OsO
2
(OH)
4
(16 mg, 42 μmol, 1.0 mol-%),
OH) ppm. * The assignments of 3Ј-H and 4Ј-H are arbitrary.
2
and NMO (50% in H O, 1.2 g, 5.0 mmol, 1.2 equiv.). Purification
(2.5ϫ15 cm, 20 mL, c-
6
C H12/EtOAc = 1:1–1:3, 21–33) rendered the product as a colorless
by flash chromatography on silica gel[
43]
(2S,3S)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)butan-1-one
[
(S,S)-7e]:[ Following the general procedure B, the title com-
48]
1
pound was prepared from 3e (0.30 g, 2.0 mmol), K
1.9 g, 5.9 mmol, 3.0 equiv.), K CO (0.81 g, 5.9 mmol, 3.0 equiv.),
PhSO NH (0.31 g, 2.0 mmol, 1.0 equiv.), (DHQ) PHAL (46 mg,
9 μmol, 3.0 mol-%), and K OsO (OH) (14 mg, 39 μmol, 2.0 mol-
). Purification by flash chromatography on silica gel
12/EtOAc = 1:3–0:100, 12–19) rendered
the product as a colorless oil (0.21 g, 58%, 34% ee). Analytical
] (1.4 g, 4.2 mmol, HPLC: Chiralpak OD-H, n-heptane/EtOH = 100:1, 210 nm, 40 °C,
3 6
[Fe(CN) ]
oil (0.34 g, 86%). H NMR (300.06 MHz, CDCl
=
1
3
): δ = 1.03 (d, J4,3
), 1.53 (s, 3 H, 2-Me), 2.24 (d, J3-OH,3 = 11.3 Hz,
H, 3-OH), 3.27 (s, 3 H, N-Me), 3.73 (s, 3 H, O-Me), 4.04 (dq,
(
2
3
6.4 Hz, 3 H, 4-H
3
2
2
2
5
%
2
2
4
J
3,3-OH = 11.1, J3,4 = 6.3 Hz, 1 H, 3-H), 4.31 (s, 1 H, 2-OH) ppm.
[
43]
(
7
2S,3S)-2,3-Dihydroxy-N-methoxy-N,2-dimethylbutanamide [(S,S)-
6
(2ϫ15 cm, 20 mL, c-C H
[
48]
d]: Following the general procedure B, the title compound was
[Fe(CN)
(0.58 g, 4.2 mmol, 3.0 equiv.), PhSO
0.22 g, 1.4 mmol, 1.0 equiv.), (DHQ) PHAL (33 mg, 42 μmol,
.0 mol-%), and K OsO (OH) (10 mg, 28 μmol, 2.0 mol-%). Puri-
fication by flash chromatography on silica gel (2ϫ15 cm, 20 mL,
c-C 12/EtOAc = 1:1–1:3, 23–33) rendered the product as a color-
less oil (0.17 g, 68%; 62% ee). Analytical HPLC: Chiralpak AD-
H, n-heptane/EtOH = 95:5, 230 nm, t = 38.56 (R,R), 42.88 min
prepared from 3d (0.20 g, 1.4 mmol), K
.0 equiv.), K CO
3
6
2
0
3
2
3
2
NH
2
t
R
= 34.54 (S,S), 38.09 min (R,R). [α]
D
= +11.9 (c = 0.73 g/100 mL,
). H NMR (300.06 MHz, CDCl ): δ = 1.10 (d, J4,3 = 6.4 Hz,
3 H, 4-H ), 1.51 (s, 3 H, 2-Me), 1.87 (br. m , 2 H, 3Ј-H )* superim-
posed by 1.96 (br. m , 2 H, 4Ј-H )*, 2.64 (d, J3-OH,3 = 9.5 Hz, 1 H,
3-OH), 3.44–3.72 (m, 4 H, 2Ј-H , 5Ј-H ), 3.93 (dq, J3,3-OH = 8.4,
3,4 = 6.3 Hz, 1 H, 3-H), 4.32 (s, 1 H, 2-OH) ppm. * The assign-
ments of 3Ј-H and 4Ј-H are arbitrary.
1
(
2
CHCl
3
3
3
2
2
4
3
c
2
[43]
c
2
6
H
2
2
J
R
(
1
S,S). [α]2
.11 g/100 mL, CHCl
d, J4,3 = 6.4 Hz, 3 H, 4-H
D 3
= –14.6 (c = 1.11 g/100 mL, CHCl
0
); [α]365 = –37.2 (c =
). H NMR (300.06 MHz, CDCl ): δ = 1.03
), 1.53 (s, 3 H, 2-Me), 2.24 (d, J3-OH,3
10.8 Hz, 1 H, 3-OH), 3.26 (s, 3 H, N-Me), 3.73 (s, 3 H, O-Me),
20
1
(2R,3R)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)butan-1-one
(R,R)-7e]: Following the general procedure B, the title compound
was prepared from 3e (0.30 g, 2.0 mmol), K [Fe(CN) ] (1.9 g,
.9 mmol, 3.0 equiv.), K CO (0.81 g, 5.9 mmol, 3.0 equiv.),
PhSO NH (0.31 g, 2.0 mmol, 1.0 equiv.), (DHQD) PHAL (46 mg,
9 μmol, 3.0 mol-%), and K OsO (OH) (14 mg, 39 μmol, 2.0 mol-
2R,3R)-2,3-Dihydroxy-N-methoxy-N,2-dimethylbutanamide %). Purification by flash chromatography on silica gel
(R,R)-7d]: Following the general procedure B, the title compound (2ϫ15 cm, 20 mL, c-C 12/EtOAc = 1:3–0:100, 12–19) rendered
the product as a colorless oil (0.25 g, 69%, 27% ee). Analytical
3
3
[
(
3
3
6
=
4
5
2
3
.04 (dq, J3,3-OH = 10.5, J3,4 = 6.2 Hz, 1 H, 3-H), 4.31 (s, 1 H, 2-
2
2
2
OH) ppm.
5
2
2
4
[
43]
(
[
6
H
3 6
was prepared from 3d (0.20 g, 1.4 mmol), K [Fe(CN) ] (1.4 g,
4
.2 mmol, 3.0 equiv.), K
PhSO NH (0.22 g, 1.4 mmol, 1.0 equiv.), (DHQD)
2 μmol, 3.0 mol-%), and K OsO (OH) (10 mg, 28 μmol, 2.0 mol-
). Purification by flash chromatography on silica gel
2 3
CO (0.58 g, 4.2 mmol, 3.0 equiv.), HPLC: Chiralpak OD-H, n-heptane/EtOH = 100:1, 210 nm, 40 °C,
2
0
2
2
2
PHAL (33 mg,
t
R
= 31.62 (S,S), 35.09 min (R,R). [α]
CHCl ). IR (film): ν˜ = 3380, 2975, 2880, 1595, 1455, 1365, 1295,
1185, 1150, 1095, 1015, 915, 745, 690 cm . H NMR (400.13 MHz,
D
= –15.7 (c = 1.25 g/100 mL,
4
%
2
2
4
3
[
43]
–1 1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
15

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
FULL PAPER
–
1 1
CDCl
3
): δ = 1.09 (d, J4,3 = 6.3 Hz, 3 H, 4-H
3
), 1.50 (s, 3 H, 2-Me),
770, 705 cm . H NMR (400.13 MHz, CDCl
, 2 H, 4Ј- 2-Me), 2.26 (br. s, 1 H, 3-OH), 3.53 (s, 1 H, 2-OH), 3.58 (dd, Jgem
= 11.4 Hz, 1 H, 3-H), 3.80 [m , possibly interpretable as dd, Jgem
= 11.0, J3-H(2),3-OH = 7.1 Hz, 1 H, 3-H] superimposed by 3.82 (s, 3
3
): δ = 1.35 (s, 3 H,
1.86 (br. m
c
, 2 H, 3Ј-H
)* superimposed by 1.96 (br. m
2 c
H
H
=
2
)*, 2.66 (d, J3-OH,3 = 8.0 Hz, 1 H, 3-OH), 3.47–3.71 (m, 4 H, 2Ј-
, 5Ј-H ), 3.93 (br. m , possibly interpretable as dq, J3,3-OH = J3,4
c
2
2
c
1
3
6.5 Hz, 1 H, 3-H), 4.30 (s, 1 H, 2-OH) ppm. * The assignments H, OMe) ppm. C NMR (100.63 MHz, CDCl
3
): δ = 22.06 (2-Me),
): 53.19 (OMe), 68.45 (C-3), 75.64 (C-2), 176.20 (C-1) ppm. edHSQC
δ = 18.02 (C-4), 21.39 (2-Me), 23.26 (C-3Ј)*, 26.95 (C-4Ј)*, 47.51 (“C,H-COSY”, 100.62/400.13 MHz, CDCl ): Allows the assign-
C-2Ј)**, 48.09 (C-5Ј)**, 70.89 (C-3), 76.53 (C-2), 173.35 (C- ment of all nonquaternary carbon atoms by their cross-peaks with
13
of 3Ј-H and 4Ј-H are arbitrary. C NMR (100.63 MHz, CDCl
3
3
(
1
1
3
1
) ppm. * The assignments of C-3Ј and C-4Ј are arbitrary, but con- directly bonded protons [δ( C) ↔ δ( H)]: δ = 22.06 (2-Me) ↔ δ =
1
sistent with the H NMR spectrum. ** The assignments of C-2Ј
1.35 (2-Me); δ = 53.19 (OMe) ↔ δ = 3.82 (OMe); δ = 68.45 (C-3)
and C-5Ј are arbitrary. edHSQC (“C,H-COSY”, 100.62/ ↔ δ = 3.58 (3-H) and 3.80 (3-H) ppm. HRMS: (pos. ESI, MeOH):
4
00.13 MHz, CDCl
3
): Allows the assignment of all nonquaternary
calcd. for C
(–0.1 ppm).
5 10 4
H O
Na [M + Na]+ 157.04770; found 157.04768
carbon atoms by their cross-peaks with directly bonded protons
13
1
[
δ( C) ↔ δ( H)]: δ = 18.02 (C-4) ↔ δ = 1.09 (4-H
Me) ↔ δ = 1.50 (2-Me); δ = 23.26 (C-3Ј) ↔ δ = 1.86 (3Ј-H
6.95 (C-4Ј) ↔ δ = 1.96 (4Ј-H ); δ = 47.51 (C-2Ј) and 48.09 (C-5Ј)
δ = 3.47–3.71 (2Ј-H , 5Ј-H ); δ = 70.89 (C-3) ↔ δ = 3.93 (3-
H) ppm. HRMS (pos. APCI, MeOH): calcd. for C Na [M
3
); δ = 21.39 (2-
Isobutyl rac-2,3-Dihydroxy-2-methylpropanoate (rac-23b):[48] Fol-
lowing the general procedure A, the title compound was prepared
from isobutyl methacrylate (1b; 0.53 mL, 0.50 g, 3.5 mmol), citric
2
); δ =
2
↔
2
2
2
acid (0.51 g, 2.6 mmol, 0.75 equiv.), K
8.8 μmol, 0.25 mol-%), and NMO (50% in H
.2 equiv.). Purification by flash chromatography on silica gel
(2.5ϫ15 cm, 20 mL, c-C 12/EtOAc = 3:1–1:1, 11–24) rendered
the product as a colorless oil (0.57 g, 92%). H NMR (300.06 MHz,
): δ = 0.95 (d, J3Ј,2Ј = J2Ј-Me,2Ј = 6.7 Hz, 6 H, 3Ј-H , 2Ј-Me),
(4.6 mg, 13 μmol, 1.36 (s, 3 H, 2-Me), 1.99 (tqq, J2Ј,1Ј = J2Ј,3Ј = J2Ј,2Ј-Me = 6.7 Hz, 1
2
O, 1.4 g, 6.0 mmol, 1.2 equiv.). H, 2Ј-H), 2.17 [dd, J3-OH,3-H(2) = 9.2, J3-OH,3-H(1) = 4.4 Hz, 1 H, 3-
2
OsO
2 4
(OH) (3.2 mg,
9
H18NO
3
+
2
O, 0.99 g, 4.2 mmol,
+
H] 188.12812; found 188.12817 (+0.3 ppm).
[
43]
1
Methyl rac-2,3-Dihydroxy-2-methylpropanoate (rac-23a):[48] Follow-
ing the general procedure A, the title compound was prepared from
6
H
1
methyl methacrylate (1a; 0.53 mL, 0.50 g, 5.0 mmol), citric acid CDCl
0.72 g, 3.7 mmol, 0.75 equiv.), K OsO (OH)
.25 mol-%), and NMO (50% in H
Purification by flash chromatography on silica gel (2.5ϫ15 cm,
0 mL, c-C 12/EtOAc = 3:1–1:1, 23–29) rendered the product as
a colorless oil (0.57 g, 85%). H NMR (300.06 MHz, CDCl
3
3
(
0
2
2
4
[
43]
OH], 3.53 (s, 1 H, 2-OH), 3.58 [dd, Jgem = 11.2, J3-H(1),3-OH
4.2 Hz, 1 H, 3-H], 3.80 [dd, Jgem = 11.1, J3-H(2),3-OH = 9.2 Hz, 1 H,
3-H], 4.00 (d, J1Ј,2Ј = 6.7 Hz, 1Ј-H ) ppm.
=
2
6
H
1
3
): δ =
.36 (s, 3 H, 2-Me), 2.20 (br. s, 1 H, 3-OH), 3.50 (s, 1 H, 2-OH),
.58 (d, Jgem = 11.3 Hz, 1 H, 3-H), 3.80 (br. d, Jgem = 11.6 Hz, 1
2
1
3
Isobutyl (R)-2,3-Dihydroxy-2-methylpropanoate [(R)-23b]:[48] Fol-
lowing the general procedure B, the title compound was prepared
from isobutyl methacrylate (1b; 0.53 mL, 0.50 g, 3.5 mmol),
H, 3-H) superimposed by 3.82 (s, 3 H, OMe) ppm.
Surmised Preparation of Methyl (R)-2,3-Dihydroxy-2-methylprop-
K
3
[Fe(CN)
3.0 equiv.), MeSO
PHAL (55 mg, 70 μmol, 2.0 mol-%), and K
35 μmol, 1.0 mol-%). Purification by flash chromatography on sil-
6
] (3.5 g, 11 mmol, 3.0 equiv.), K
NH (0.33 g, 3.5 mmol, 1.0 equiv.), (DHQ)
OsO (OH) (13 mg,
2 3
CO (1.5 g, 11 mmol,
[
48]
anoate [(R)-23a]:
compound was prepared from methyl methacrylate (1a; 0.30 g,
.0 mmol), K [Fe(CN) ] (3.0 g, 9.0 mmol, 3.0 equiv.), K CO
1.2 g, 9.0 mmol, 3.0 equiv.), MeSO NH
(0.29 g, 3.0 mmol, ica gel[ (2.5 ϫ 15 cm, 20 mL, c-C
.0 equiv.), (DHQ) PHAL (47 mg, 60 μmol, 2.0 mol-%), and rendered the product as a colorless oil (0.56 g, 92%; 10% ee). Ana-
OsO (OH) (11 mg, 30 μmol, 1.0 mol-%). Purification by flash lytical HPLC: Kromasil 3-AmyCoat, n-heptane/EtOH = 90:10,
chromatography on silica gel
EtOAc = 3:1–1:1, 25–33) rendered the product as a colorless oil 100 mL, CHCl
0.34 g, 85%; although AD conditions were used this compound NMR (300.06 MHz, CDCl
turned out to be racemic). Analytical HPLC: Kromasil 3-Amy- 6 H, 3Ј-H , 2Ј-Me), 1.36 (s, 3 H, 2-Me), 1.99 (tqq, J2Ј,1Ј = J2Ј,3Ј
Coat, n-heptane/iPrOH = 95:5, 210 nm, t = 12.55 (1st enantio-
mer), 13.59 min (2nd enantiomer). 1H NMR (300.06 MHz,
CDCl ): δ = 1.36 (s, 3 H, 2-Me), 2.17 [br. dd, J3-OH,3-H(2) = 8.8,
3-OH,3-H(1) = 4.3 Hz, 1 H, 3-OH], 3.49 (s, 1 H, 2-OH), 3.58 [dd, 8.7 Hz, 1 H, 3-H], 4.00 (d, J1Ј,2Ј = 6.6 Hz, 1Ј-H
Following the general procedure B, the title
2
2
2
-
2
2
4
3
3
6
2
3
43]
(
2
2
6
H12/EtOAc = 3:1–1:1, 8–23)
1
2
K
2
2
4
[
43]
20
(2.5 ϫ 15 cm, 20 mL, c-C
6
H
12
/
R D
210 nm, t = 9.96 (R), 12.73 min (S). [α] = +1.3 (c = 1.16 g/
2
0
1
3
); [α]365 = +3.9 (c = 1.16 g/100 mL, CHCl
3
).
H
(
3
): δ = 0.95 (d, J3Ј,2Ј = J2Ј-Me,2Ј = 6.7 Hz,
3
=
R
J
2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H), 2.16 [br. dd, J3-OH,3-H(2) = 7.3, J3-
OH,3-H(1) = 3.1 Hz, 1 H, 3-OH], 3.52 (s, 1 H, 2-OH), 3.58 (br. d,
gem = 10.7 Hz, 1 H, 3-H), 3.79 [dd, Jgem = 10.6, J3-H(2),3-OH
) ppm.
3
J
=
J
J
J
2
gem = 11.3, J3-H(1),3-OH = 4.3 Hz, 1 H, 3-H], 3.80 [dd, Jgem = 11.2,
3-H(2),3-OH = 9.2 Hz, 1 H, 3-H] superimposed by 3.82 (s, 3 H,
Isobutyl (S)-2,3-Dihydroxy-2-methylpropanoate [(S)-23b]: Following
the general procedure B, the title compound was prepared from
OMe) ppm.
isobutyl methacrylate (1b; 0.53 mL, 0.50 g, 3.5 mmol), K
[Fe(CN) ] (3.5 g, 11 mmol, 3.0 equiv.), K CO
3.0 equiv.), MeSO NH (0.33 g, 3.5 mmol, 1.0 equiv.), (DHQD)
PHAL (55 mg, 70 μmol, 2.0 mol-%), and K OsO (OH)
35 μmol, 1.0 mol-%). Purification by flash chromatography on sil-
3
-
Surmised Preparation of Methyl (S)-2,3-Dihydroxy-2-methylprop-
anoate [(S)-23a]: Following the general procedure B, the title com-
pound was prepared from methyl methacrylate (1a; 0.30 g,
6
2
3
(1.5 g, 11 mmol,
2
2
2
-
2
2
4
(13 mg,
3
(
1
K
.0 mmol), K
1.2 g, 9.0 mmol, 3.0 equiv.), MeSO
.0 equiv.), (DHQD) PHAL (47 mg, 60 μmol, 2.0 mol-%), and rendered the product as a colorless oil (0.58 g, 94%; 16% ee). Ana-
OsO (OH) (11 mg, 30 μmol, 1.0 mol-%). Purification by flash lytical HPLC: Kromasil 3-AmyCoat, n-heptane/EtOH = 90:10,
chromatography on silica gel
EtOAc = 3:1–1:1, 26–33) rendered the product as a colorless oil 100 mL, CHCl
0.36 g, 90%; although AD conditions were used this compound (film): ν˜ = 3455, 2965, 2880, 1735, 1465, 1380, 1280, 1220, 1135,
turned out to be racemic). Analytical HPLC: Kromasil 3-Amy-
Coat, n-heptane/iPrOH = 95:5, 210 nm, t = 12.54 (1st enantio-
mer), 13.56 min (2nd enantiomer). IR (film): ν˜ = 3445, 2985, 2955,
3
[Fe(CN)
6
] (3.0 g, 9.0 mmol, 3.0 equiv.), K
2 3
CO
(0.29 g, 3.0 mmol, ica gel[ (2.5ϫ15 cm, 20 mL, c-C
43]
2
NH
2
6
H12/EtOAc = 3:1–1:1, 17–27)
2
2
2
4
[
43]
20
(2.5 ϫ 15 cm, 20 mL, c-C
6
H
12
/
210 nm, t
R
= 10.03 (R), 12.69 min (S). [α]
D
= –2.3 (c = 1.27 g/
2
0
3
); [α]365 = –6.6 (c = 1.27 g/100 mL, CHCl ). IR
3
(
–
1 1
1055, 985, 940 cm . H NMR (400.13 MHz, CDCl
3Ј,2Ј = 6.8 Hz, 3 H, 3Ј-H ) superimposed by 0.952 (d, J2Ј-Me,2Ј
6.7 Hz, 3 H, 2Ј-Me), 1.36 (s, 3 H, 2-Me), 1.99 (tqq, J2Ј,1Ј = J2Ј,3Ј
3
): δ = 0.950 (d,
R
J
3
=
=
2880, 1735, 1455, 1380, 1280, 1230, 1135, 1055, 975, 940, 890, 815,
J
2Ј,2Ј-Me = 6.7 Hz, 1 H, 2Ј-H), 2.21 [dd, J3-OH,3-H(2) = 9.3,
16
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
J
3-OH,3-H(1) = 4.4 Hz, 1 H, 3-OH], 3.55 [d, 4J2-OH,3-H(2) = 0.6 Hz, 1 HPLC: Kromasil 3-AmyCoat, n-heptane/EtOH = 90:10, 210 nm,
2
0
H, 2-OH]*, 3.59 [dd, Jgem = 11.2, J3-H(1),3-OH = 4.3 Hz, 1 H, 3-H],
t
R
= 18.18 (R), 20.99 min (S). [α]
D
= +0.3 (c = 0.56 g/100 mL,
); [α]365 = +2.8 (c = 0.56 g/100 mL, CHCl ). IR (film): ν˜ =
3450, 2940, 2840, 1735, 1615, 1515, 1460, 1380, 1250, 1175, 1135,
2
0
3
.80 [dd, Jgem = 11.1, J3-H(2),3-OH = 9.0 Hz, 1 H, 3-H], 4.01 [m
possibly interpretable as AB signal, δ = 4.00, δ = 4.01 ppm, A
part additionally split by J1Ј-H(A),2Ј = 6.7 Hz, B part additionally
split by J1Ј-H(B),2Ј = 6.7, JAB = 10.4 Hz, 2 H, 1Ј-H ]. * No other
signal shows a coupling of 0.6 Hz, however, the 3-H signal at δ =
.80 ppm appears to be a little “broader” than all the other signals.
c
,
CHCl
3
3
A
B
–
1 1
3
1040, 920, 825, 735 cm . H NMR (400.13 MHz, CDCl ): δ = 1.34
2
(s, 3 H, 2-Me), 2.21 (br. s, 1 H, 3-OH), 3.51 (br. s, 1 H, 2-OH)
superimposed by 3.57 (d, Jgem = 11.3 Hz, 1 H, 3-H), 3.80 (d, Jgem
= 11.3 Hz, 1 H, 3-H) superimposed by 3.81 (s, 3 H, p-OMe), 5.18
3
1
3
C NMR (100.63 MHz, CDCl
3
): δ = 18.96 (C-3Ј)*, 18.99 (2Ј- (m
c
, 2 H, 1Ј-H
2
), 6.90 (m
c
, possibly interpretable as AAЈ part of an
, possibly interpretable as
Me)*, 22.11 (2-Me), 27.84 (C-2Ј), 68.48 (C-3), 72.25 (C-1Ј), 75.55 AAЈBBЈ signal, 2 H, 2 m-H), 7.29 (m
c
1
3
(
(
C-2), 175.81(C-1) ppm. * Assignments interchangeable. edHSQC
“C,H-COSY”, 100.62/400.13 MHz, CDCl ): Allows the assign-
BBЈ part of an AAЈBBЈ signal, 2 H, 2 m-H) ppm. C NMR
(100.63 MHz, CDCl ): δ = 22.00 (2-Me), 55.38 (p-OMe), 67.81 (C-
3
3
ment of all nonquaternary carbon atoms by their cross-peaks with
1Ј), 68.43 (C-3), 75.61 (C-2), 114.14 (2 C-m), 127.34 (C-2Ј), 130.06
(2 C-o), 159.95 (C-p), 175.65 (C-1) ppm. edHSQC (“C,H-COSY”,
13
1
directly bonded protons [δ( C) ↔ δ( H)]: δ = 18.96 (C-3Ј) and
8.99 (2Ј-Me) ↔ δ = 0.950 (3Ј-H
2-Me) ↔ δ = 1.36 (2-Me); δ = 27.84 (C-2Ј) ↔ δ = 1.99 (2Ј-H); δ ternary carbon atoms by their cross-peaks with directly bonded
1
3 3
) and 0.952 (2Ј-Me); δ = 22.11 100.62/400.13 MHz, CDCl ): Allows the assignment of all nonqua-
(
1
3
1
=
↔
C
68.48 (C-3) ↔ δ = 3.59 (3-H) and 3.80 (3-H); δ = 72.25 (C-1Ј) protons [δ( C) ↔ δ( H)]: δ = 22.00 (2-Me) ↔ δ = 1.34 (2-Me); δ
δ = 4.01 (1Ј-H ) ppm. HRMS: (pos. ESI, MeOH): calcd. for = 55.38 (p-OMe) ↔ δ = 3.81 (p-OMe); δ = 67.81 (C-1Ј) ↔ δ = 5.18
Na [M + Na]+ calcd. 199.09460; found 199.09463 (1Ј-H
); δ = 68.43 (C-3) ↔ δ = 3.57 (3-H) and 3.80 (3-H); δ =
114.14 (2 C-m) ↔ δ = 6.90 (2 m-H); δ = 130.06 (2 C-o) ↔ δ = 7.29
2 o-H) ppm. HRMS (pos. APCI, MeOH): calcd. for C12
2
8
H
16
O
4
2
(+0.2 ppm).
(
H20NO
5
4
2
-Methoxybenzyl rac-2,3-Dihydroxy-2-methylpropanoate (rac-
3c): Following the general procedure A, the title compound was
+
[M + NH
4
] 258.13415; found 258.13430 (+0.6 ppm).
[
48]
prepared from 1b (0.53 mL, 0.50 g, 2.4 mmol), citric acid (0.35 g,
.8 mmol, 0.75 equiv.), K OsO (OH) (2.2 mg, 6.1 μmol, 0.25 mol-
), and NMO (50% in H O, 0.68 g, 2.9 mmol, 1.2 equiv.). Purifica-
tion by flash chromatography on silica gel (2.5ϫ15 cm, 20 mL,
c-C 12/EtOAc = 3:1–1:1, 10–16) rendered the product as a color-
less oil (0.55 g, 96%). H NMR (300.06 MHz, CDCl
H, 2-Me), 2.12 (br. s, 1 H, 3-OH), 3.48 (s, 1 H, 2-OH), 3.56
d, Jgem = 11.3 Hz, 1 H, 3-H), 3.80 (d, Jgem = 9.5 Hz, 1 H, 3-H)
superimposed by 3.81 (s, 3 H, p-OMe), 5.18 (m , 2 H, 1Ј-H ), 6.89
, possibly interpretable as AAЈ part of an AAЈBBЈ signal, 2 H,
rac-2,3-Dihydroxy-N-methoxy-N,2-dimethylpropanamide (rac-
1
%
2
2
4
[48]
2
3d): Following the general procedure A, the title compound was
prepared from 1d (0.50 g, 3.9 mmol), citric acid (0.56 g, 2.9 mmol,
.75 equiv.), K OsO (OH) (3.6 mg, 9.7 μmol, 0.25 mol-%), and
NMO (50% in H O, 1.1 g, 4.6 mmol, 1.2 equiv.). Purification by
flash chromatography on silica gel (2.5ϫ15 cm, 20 mL, c-C
EtOAc = 1:1–1:3, 19–36) rendered the product as a colorless oil
2
[43]
0
2
2
4
6
H
2
1
3
): δ = 1.34 (s,
[43]
6 12
H /
3
(
1
(
0.52 g, 82%). H NMR (300.06 MHz, CDCl
3
): δ = 1.38 (s, 3 H,
c
2
2
3
3
-Me), 2.39 [br. dd, J3-OH,3-H(B) = 8.4, J3-OH,3-H(A) = 4.1 Hz, 1 H,
-OH], 3.30 (s, 3 H, N-Me), 3.62 (br. d, Jgem = 11.7 Hz, 1 H, 3-H),
.75 (s, 3 H, O-Me), 3.91 [dd, Jgem = 10.9, J3-H(2),3-OH = 8.9 Hz, 1
(m
c
2
c
m-H), 7.29 (m , possibly interpretable as BBЈ part of an AAЈBBЈ
signal, 2 H, 2 o-H) ppm.
H, 3-H], 4.52 (s, 1 H, 2-OH) ppm.
4
2
-Methoxybenzyl (R)-2,3-Dihydroxy-2-methylpropanoate [(R)-
[
48]
(R)-2,3-Dihydroxy-N-methoxy-N,2-dimethylpropanamide [(R)-
2
3c]: Following the general procedure B, the title compound was
[Fe(CN) ] (2.4 g,
(1.0 g, 7.3 mmol, 3.0 equiv.), Me-
(0.23 g, 2.4 mmol, 1.0 equiv.), (DHQ) PHAL (38 mg,
9 μmol, 2.0 mol-%), and K OsO (OH) (8.9 mg, 24 μmol, 1.0 mol-
). Purification by flash chromatography on silica gel
2.5ϫ15 cm, 20 mL, c-C 12/EtOAc = 3:1–1:1, 13-21) rendered the
product as a colorless oil (0.52 g, 90%; 61% ee). Analytical HPLC:
3d]:[ Following the general procedure B, the title compound was
48]
prepared from 1b (0.53 mL, 0.50 g, 2.4 mmol), K
.3 mmol, 3.0 equiv.), K CO
SO NH
2
3
6
prepared from 1d (0.30 g, 2.3 mmol), K
.0 equiv.), K CO (0.96 g, 7.0 mmol, 3.0 equiv.), PhSO
0.37 g, 2.3 mmol, 1.0 equiv.), (DHQ) PHAL (54 mg, 70 μmol,
3.0 mol-%), and K OsO (OH) (17 mg, 47 μmol, 2.0 mol-%). Puri-
fication by flash chromatography on silica gel
0 mL, c-C 12/EtOAc = 1:1–1:3, 13–30) rendered the product as
a colorless oil (0.32 g, 83%; 95% ee). Analytical HPLC: Chiralpak
3
[Fe(CN)
6
] (2.3 g, 7.0 mmol,
7
2
3
3
2
3
2
NH
2
2
2
(
2
4
%
(
2
2
4
[
43]
2
2
4
[
43]
(2.5 ϫ15 cm,
6
H
2
6
H
Kromasil 3-AmyCoat, n-heptane/EtOH = 90:10, 229 nm, t
R
=
2
0
AD-3, n-heptane/iPrOH = 95:5, 230 nm, t
R
= 19.86 (S), 22.67 min
18.07 (R), 21.14 min (S). [α]
D
= –0.3 (c = 0.50 g/100 mL, CHCl
3
).
2
0
20
20
1
(R). [α]
D
= +13.2 (c = 1.01 g/100 mL, CHCl
3
); [α]365 = +40.9 (c =
): δ = 1.39
[α]365 = –2.7 (c = 0.50 g/100 mL, CHCl
3
). H NMR (300.06 MHz,
1
1.01 g/100 mL, CHCl
3
). H NMR (300.06 MHz, CDCl
3
3
CDCl ): δ = 1.34 (s, 3 H, 2-Me), 2.10 [dd, J3-OH,3-H(2) = 9.1,
(
s, 3 H, 2-Me), 2.34 [br. dd, J3-OH,3-H(B) = 9.1, J3-OH,3-H(A) = 4.4 Hz,
J
J
J
3-OH,3-H(1) = 4.6 Hz, 1 H, 3-OH], 3.47 (s, 1 H, 2-OH), 3.56 [dd,
gem = 11.3, J3-H(1),3-OH = 4.5 Hz, 1 H, 3-H], 3.80 [dd, Jgem = 11.3,
3-H(2),3-OH = 8.8 Hz, 1 H, 3-H] superimposed by 3.81 (s, 3 H, p-
1
J
H, 3-OH], 3.31 (s, 3 H, N-Me), 3.63 [br. dd, Jgem = 11.4,
3-H(1),3-OH = 3.5 Hz, 1 H, 3-H], 3.76 (s, 3 H, O-Me), 3.92 [dd, Jgem
=
11.1, J3-H(2),3-OH = 9.5 Hz, 1 H, 3-H], 4.52 (s, 1 H, 2-OH) ppm.
OMe), 5.18 (m
AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.29 (m
interpretable as BBЈ part of an AAЈBBЈ signal, 2 H, 2 o-H) ppm.
c
, 2 H, 1Ј-H
2
), 6.89 (m
c
, possibly interpretable as
c
, possibly
(
S)-2,3-Dihydroxy-N-methoxy-N,2-dimethylpropanamide [(S)-23d]:
Following the general procedure B, the title compound was pre-
[Fe(CN) ] (2.3 g, 7.0 mmol,
NH
2
4
-Methoxybenzyl (S)-2,3-Dihydroxy-2-methylpropanoate [(S)-23c]: pared from 1d (0.30 g, 2.3 mmol), K
Following the general procedure B, the title compound was pre- 3.0 equiv.), K CO (0.96 g, 7.0 mmol, 3.0 equiv.), PhSO
pared from 1b (0.53 mL, 0.50 g, 2.4 mmol), K [Fe(CN) ] (2.4 g, (0.37 g, 2.3 mmol, 1.0 equiv.), (DHQD) PHAL (54 mg, 70 μmol,
.3 mmol, 3.0 equiv.), K CO (1.0 g, 7.3 mmol, 3.0 equiv.), 3.0 mol-%), and K OsO (OH) (17 mg, 47 μmol, 2.0 mol-%). Puri-
MeSO NH (0.23 g, 2.4 mmol, 1.0 equiv.), (DHQD) PHAL fication by flash chromatography on silica gel
38 mg, 49 μmol, 2.0 mol-%), and K OsO (OH) (8.9 mg, 24 μmol, 20 mL, c-C 12/EtOAc = 1:1–1:3, 14–25) rendered the product as
.0 mol-%). Purification by flash chromatography on silica gel a colorless oil (0.35 g, 93%; 98% ee). Analytical HPLC: Chiralpak
12/EtOAc = 3:1–1:1, 10–17) rendered
the product as a colorless oil (0.52 g, 90%; 72% ee). Analytical
3
6
2
3
2
3
6
2
7
2
3
2
2
4
[
43]
2
2
2
(2.5 ϫ 15 cm,
(
1
2
2
4
6
H
[43]
(
2.5 ϫ15 cm, 20 mL, c-C
6
H
AD-3, n-heptane/iPrOH = 95:5, 230 nm, t
R
= 17.88 (S), 24.38 min
2
0
20
(R). [α]
D
= –13.1 (c = 1.17 g/100 mL, CHCl
3
); [α]365 = –40.1 (c =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 17

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
FULL PAPER
–
1 1
1
.17 g/100 mL, CHCl
460, 1365, 1180, 1110, 1055, 990, 935, 865, 735, 690 cm . H 1.84 (br. m
): δ = 1.38 (s, 3 H, 2-Me), 2.39 [br. dd, H, 3-OH), 3.47 (d, Jgem = 11.4 Hz, 1 H, 3-H) superimposed by 3.53
3-OH,3-H(B) = 9.5, J3-OH,3-H(A) = 4.7 Hz, 1 H, 3-OH], 3.30 (s, 3 H,
N-Me), 3.62 [br. dd, Jgem = 11.4, J3-H(1),3-OH = 4.2 Hz, 1 H, 3-H], (m
3
). IR (film): ν˜ = 3430, 2980, 2940, 2880, 1640, 685 cm . H NMR (400.13 MHz, CDCl
3
): δ = 1.35 (s, 3 H, 2-Me),
–
1 1
1
c
2 c 2
, 2 H, 3Ј-H )*, 1.95 (br. m , 2 H, 4Ј-H )*, 2.82 (br. s, 1
NMR (400.13 MHz, CDCl
J
3
(m
c
c
, 2 H, 2Ј-H
2 c
)** superimposed by 3.61 (m , 1 H, 5Ј-H)**, 3.78
, 1 H, 5Ј-H)**, 3.98 (d, Jgem = 11.5 Hz, 1 H, 3-H), 4.21 (s, 1 H,
3
.75 (s, 3 H, O-Me), 3.92 [dd, Jgem = 11.1, J3-H(2),3-OH = 9.6 Hz, 1 2-OH) ppm. *,** The assignments of 3Ј-H and 4Ј-H, and of 2Ј-H
1
3
13
H, 3-H], 4.53 (s, 1 H, 2-OH) ppm. C NMR (100.63 MHz, and 5Ј-H are arbitrary. C NMR (100.63 MHz, CDCl
CDCl ): δ = 21.57 (2-Me), 33.70 (C-N-Me), 61.15 (O-Me), 67.78 (2-Me), 23.29 (C-3Ј)*, 26.95 (C-4Ј)*, 47.55 (C-5Ј)**, 47.90 (C-2Ј)**,
C-3), 75.99 (C-2), 174.60 (C-1) ppm. edHSQC (“C,H-COSY”,
00.62/400.13 MHz, CDCl ): Allows the assignment of all nonqua-
ternary carbon atoms by their cross-peaks with directly bonded
3
): δ = 21.07
3
(
1
68.49 (C-3), 75.73 (C-2), 172.84 (C-1) ppm. *,** The assignments
3
of 3Ј-H and 4Ј-H, and of 2Ј-H and 5Ј-H are arbitrary, but consis-
tent with the assignments in the H NMR spectrum. edHSQC
1
13
1
protons [δ( C) ↔ δ( H)]: δ = 21.57 (2-Me) ↔ δ = 1.38 (2-Me); δ
33.70 (C-N-Me) ↔ δ = 3.30 (N-Me); δ = 61.15 (O-Me) ↔ δ =
.75 (O-Me); δ = 67.78 (C-3) ↔ δ = 3.62 (3-H) and 3.92 (3-H). directly bonded protons [δ( C) ↔ δ( H)]: δ = 21.07 (2-Me) ↔ δ =
HRMS: (pos. ESI, MeOH): calcd. for C ); δ = 26.95 (C-4Ј)
Na [M + Na]+ 1.35 (2-Me); δ = 23.29 (C-3Ј) ↔ δ = 1.84 (3Ј-H
calcd. 186.07420; found 186.07423 (+0.1 ppm). ↔ δ = 1.95 (4Ј-H ); δ = 47.55 (C-5Ј) ↔ δ = 3.61 (5Ј-H) and 3.78
5Ј-H); δ = 47.90 (C-2Ј) ↔ δ = 3.53 (2Ј-H ); δ = 68.49 (C-3) ↔ δ
(“C,H-COSY”, 100.62/400.13 MHz, CDCl
3
): Allows the assign-
=
3
ment of all nonquaternary carbon atoms by their cross-peaks with
1
3
1
6
H
13NO
4
2
2
(
2
rac-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)propan-1-one (rac-
= 3.47 (3-H) and 3.98 (3-H) ppm. HRMS: (pos. ESI, MeOH):
[
48]
+
2
3e): Following the general procedure A, the title compound was
prepared from 1e (0.50 g, 3.6 mmol), citric acid (0.52 g, 2.7 mmol,
.75 equiv.), K OsO (OH) (13 mg, 36 μmol, 1.0 mol-%), and
NMO (50% in H O, 1.0 g, 4.3 mmol, 1.2 equiv.). Purification by
flash chromatography on silica gel[ (2.5ϫ15 cm, 20 mL, c-C
EtOAc = 1:1–1:3, 21–30) rendered the product as a colorless oil
calcd. for C H NO Na [M + Na] 196.09496; found 196.09500
8
15
3
(+0.2 ppm).
0
2
2
4
(Z)-2-Methylbut-2-enoic Acid (28): Isobutyl (Z)-2-methylbut-2-eno-
ate (3b; 10.0 mL, 8.90 g, 57.0 mmol) and LiOH·H O (2.63 g,
62.7 mmol, 1.1 equiv.) were dissolved in MeOH/H O (1:1, 36 mL).
): δ = 1.36 (s, 3 H, The mixture was heated at reflux for 4 h. The reaction mixture was
, 2 H, 4Ј-H
)*, 2.64 poured onto ice (20 g) and the resulting mixture was extracted with
br. s, 1 H, 3-OH), 3.48 (br. d, Jgem = 11.4 Hz, 1 H, 3-H) superim-
TBME (5ϫ50 mL). The combined organic phases were dried with
posed by 3.44–3.66 (m, 3 H, 2Ј-H
, 5Ј-H)**, 3.71–3.84 (m, 1 H, 5Ј- MgSO and the solvent removed under reduced pressure. This fur-
2
43]
6
H
12
/
2
2
1
(0.61 g, 98%). H NMR (300.06 MHz, CDCl
3
2
(
-Me), 1.86 (br. m , 2 H, 3Ј-H )*, 1.95 (br. m
c
2
c
2
2
4
H)**, 3.99 (br. d, Jgem = 11.3 Hz, 1 H, 3-H), 4.17 (s, 1 H, 2-
OH) ppm. *,** The assignments of 3Ј-H and 4Ј-H, and of 2Ј-H
and 5Ј-H are arbitrary.
nished the product (5.03 g, 50.2 mmol, 88%) as an E/Z = 10:90
mixture of stereoisomers. Recrystallization from EtOH (5 mL) fur-
nished the product as colorless crystals (2.50 g, 44%). IR (film): ν˜
=
2930, 2590, 1810, 1673, 1651, 1635, 1460, 1415, 1380, 1350, 1285,
–
1 1
(
R)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)propan-1-one [(R)-
1265, 1185, 1165, 1085, 1045, 945 cm . H NMR (400.13 MHz,
CDCl ): δ = 1.91 (dq, J
[
48]
4
5
2
3e]: Following the general procedure B, the title compound was
[Fe(CN)
(0.89 g, 6.5 mmol, 3.0 equiv.), PhSO
0.34 g, 2.2 mmol, 1.0 equiv.), (DHQ) PHAL (51 mg, 65 μmol,
.0 mol-%), and K OsO (OH) (16 mg, 43 μmol, 2.0 mol-%). Puri-
fication by flash chromatography on silica gel (2 15 cm, 20 mL,
c-C 12/EtOAc = 1:1–1:3, 22–29) rendered the product as a color-
less oil (0.22 g, 60%; 74% ee). Analytical HPLC: Chiralpak OJ-H,
= J
2-Me,4
= 1.5 Hz, 3 H, 2-Me), 2.04
3
2-Me,3
5
prepared from 1e (0.30 g, 2.2 mmol), K
.0 equiv.), K CO
3
6
] (2.1 g, 6.5 mmol, (dq, J = 7.3, J
4,2-Me 3 3,4
= 1.5 Hz, 3 H, 4-H ), 6.23 (qq, J = 7.3,
4
,3
4
13
3
(
3
2
3
2
NH
2
J3,2-Me = 1.5 Hz, 1 H, 3-H), 12.36 (br. s, 1 H, CO H) ppm.
C
2
2
NMR (100.63 MHz, CDCl ): δ = 16.08 (C-4), 20.38 (2-Me), 127.36
(C-2), 141.18 (C-3), 174.10 (C-1) ppm. edHSQC (“C,H-COSY”,
100.62/400.13 MHz, CDCl ): Allows the assignment of all nonqua-
ternary carbon atoms by their cross-peaks with directly bonded
3
2
2
4
[43]
3
6
H
1
3
1
protons [δ( C) ↔ δ( H)]: δ = 16.08 (C-4) ↔ δ = 2.04 (4-H ); δ =
3
n-heptane/iPrOH = 98:2, 210 nm, t
R
= 20.31 (R), 22.95 min (S). 20.38 (2-Me) ↔ δ = 1.91 (2-Me); δ = 141.18 (C-3) ↔ δ = 6.23 (3-
2
0
20
–
[α]
D
= +11.1 (c = 1.01 g/100 mL, CHCl
3
); [α]365 = +35.4 (c =
): δ = 1.36 calcd. 99.04460; found 99.04450 (–1.1 ppm).
, 2 H, 4Ј-
)*, 3.48 (d, Jgem = 11.4 Hz, 1 H, 3-H) superimposed by 3.48–
, 5Ј-H)**, 3.72–3.84 (m, 1 H, 5Ј-H)**, 3.99 (d, 29c): Ester syn-7c (117 mg, 460 μmol) was dissolved in CH
gem = 11.4 Hz, 1 H, 3-H) ppm. *,** The assignments of 3Ј-H and (3.7 mL) and the solution was cooled to 0 °C. Saturated aqueous
Ј-H, and of 2Ј-H and 5Ј-H are arbitrary. The OH groups are not
NaHCO solution (3.7 mL), KBr (54.8 mg, 460 μmol, 1.0 equiv.),
and 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO, 35.9 mg,
30 μmol, 0.5 equiv.) were added successively. Bleach (total content
S)-2,3-Dihydroxy-2-methyl-1-(pyrrolidin-1-yl)propan-1-one [(S)- of Cl ca. 10 %, ca. 1.6 m, 158 μL, 253 μmol, 0.55 equiv.) was
5 7 2
H) ppm. HRMS: (neg. ESI, MeOH): calcd. for C H O [M – H]
1
1
.01 g/100 mL, CHCl
3
). H NMR (300.06 MHz, CDCl
3
c 2 c
(s, 3 H, 2-Me), 1.85 (br. m , 2 H, 3Ј-H )*, 1.95 (br. m
H
2
4-Methoxybenzyl rac-2-Hydroxy-2-methyl-3-oxobutanoate (rac-
Cl
2
3
J
4
.66 (m, 3 H, 2Ј-H
2
2
3
visible in this spectrum.
2
(
2
added[ through a graduated pipette and the mixture was stirred
49]
3e]: Following the general procedure B, the title compound was
[Fe(CN) ] (2.1 g, 6.5 mmol, vigorously at 0 °C for 2 min. This was repeated twice and the mix-
(0.89 g, 6.5 mmol, 3.0 equiv.), PhSO NH ture was stirred vigorously at 0 °C for another 13 min. The reaction
0.34 g, 2.2 mmol, 1.0 equiv.), (DHQD) PHAL (51 mg, 65 μmol, was quenched by the addition of a saturated aqueous Na SO solu-
.0 mol-%), and K OsO (OH) (16 mg, 43 μmol, 2.0 mol-%). Puri- tion (1 mL). The phases were separated and the aqueous phase was
fication by flash chromatography on silica gel (2 15 cm, 20 mL, washed with CH Cl (2 ϫ 4 mL). The combined organic phases
c-C 12/EtOAc = 1:1–1:3, 25–36) rendered the product as a color- were dried with MgSO and the solvent evaporated under reduced
less oil (0.33 g, 88%; 83% ee). Analytical HPLC: Chiralpak OJ-H, pressure. Purification by flash chromatography on silica gel
= 20.25 (R), 22.25 min (S). (1.5ϫ15 cm, 15 mL, c-C 12/EtOAc = 3:1, 3–6) rendered the prod-
prepared from 1e (0.30 g, 2.2 mmol), K
.0 equiv.), K CO
3
6
3
(
3
2
3
2
2
2
2
3
2
2
4
[43]
2
2
6
H
4
[
43]
n-heptane/iPrOH = 98:2, 210 nm, t
R
6
H
2
0
20
1
[α]
D
= –13.1 (c = 1.17 g/100 mL, CHCl
3
); [α]365 = –40.1 (c = 1.17 g/
uct as a colorless oil (92.1 mg, 79 %). H NMR (300.06 MHz,
): δ = 1.58 (s, 3 H, 2-Me), 2.17 (s, 3 H, 4-H ), 3.81 (s, 3 H,
370, 1340, 1250, 1235, 1180, 1145, 1055, 975, 925, 865, 730, p-OMe), 4.15 (s, 1 H, 2-OH), AB signal (δ = 5.14, δ = 5.16 ppm,
1
1
00 mL, CHCl
3
). IR (film): ν˜ = 3385, 2970, 2880, 2240, 1600, 1445, CDCl
3
3
A
B
18
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
Asymmetric Dihydroxylation
AB = 11.9 Hz, 2 H, 1Ј-H ), 6.88 (m
J
2
c
, possibly interpretable as AAЈ
21.71 (2-Me) ↔ δ = 1.56 (2-Me); δ = 24.09 (C-4) ↔ δ = 2.16 (4-
part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.27 (m
able as BBЈ part of an AAЈBBЈ signal, 2 H, 2 o-H) ppm.
c
, possibly interpret-
H
3
); δ = 55.28 (C-OMe) ↔ δ = 3.79 (OMe); δ = 67.92 (C-1Ј) ↔ δ
= AB signal (δ = 5.12, δ = 5.16 ppm, 1Ј-H ); δ = 114.07 (2 C-m)
δ = 6.86 (2 m-H); δ = 130.19 (2 C-o) ↔ δ = 7.26 (2 o-H) ppm.
A
B
2
↔
+
4-Methoxybenzyl (S)-2-Hydroxy-2-methyl-3-oxobutanoate [(S)-29c]: HRMS (pos. APCI, MeOH): calcd. for C H NO [M + NH )
13 20 5 4
Ester (2S,3R)-7c (121 mg, 476 μmol; 95 % ee) was dissolved in 270.13360; found 270.13376 (+0.6 ppm). HRMS: (neg. APCI,
–
CH
aqueous NaHCO
.0 equiv.), and TEMPO (37.2 mg, 238 μmol, 0.5 equiv.) were
added successively. Bleach (total content of Cl ca. 10%, ca. 1.6 m,
2
Cl
2
(3.8 mL) and the solution was cooled to 0 °C. A saturated
MeOH): calcd. for C H O Cl [M + Cl) calcd. 287.06917; found
287.06927 (+0.3 ppm).
1
3
16
5
3
solution (3.8 mL), KBr (56.6 mg, 476 μmol,
1
64 μL, 262 μmol, 0.55 equiv.) was added[ through a graduated
49]
1
Acknowledgments
pipette and the mixture was stirred vigorously at 0 °C for 2 min.
This was repeated twice and the mixture was stirred vigorously at
0
°C for another 13 min. The reaction was quenched by the ad-
dition of a saturated aqueous Na SO solution (1 mL). The phases
were separated and the aqueous phase washed with CH Cl (2
mL). The combined organic phases were dried with MgSO and
the solvent evaporated under reduced pressure. Purification by
The authors thank the Studienstiftung des Deutschen Volkes for a
Ph. D. fellowship to F. W. Financial support for this study by the
Deutsche Forschungsgemeinschaft (DFG) (IRTG 1038) is grate-
fully acknowledged. The authors thank Rita M. DaSilva-Freitas
for tireless technical assistance and Katharina Bay for her contri-
butions during her Bachelor thesis. The authors thank Dr. M. Kel-
ler, F. Reinbold, and M. Schonhard for recording the NMR spec-
2
3
2
2
4
4
flash chromatography on silica gel[ (1.5ϫ15 cm, 15 mL, c-C
EtOAc = 3:1, 3–5) rendered the product as a colorless oil (92.0 mg,
43]
6
12
H /
7
6 %, 93 % ee). Analytical HPLC: Chiralpak AD-3, n-heptane/ tra, Dr. J Wörth and C. Warth for recording HRMS, F. Tönnies
20
iPrOH = 100:1, 230 nm, t
R
= 40.34 (R), 42.18 min (S). [α]
D
= –41.2
and A. Siegel for the elemental analyses, Dr. S. Braukmüller,
Dr. R. Krieger, G. Fehrenbach, and A. Schuschkowski for HPLC
analyses
c = 0.95 g/100 mL, CHCl
3
); [α] 52 46 = –50.4 (c = 0.73 g/100 mL,
0
(
0
20
CHCl
3
); [α] 42 36 = –101.8 (c = 0.73 g/100 mL, CHCl
3
); [α]365 = –210.6
): δ =
), 3.81 (s, 3 H, p-OMe), 4.14
B
= 5.16 ppm, JAB = 11.9 Hz, [1]
1
(
1
(
2
c = 0.73 g/100 mL, CHCl
3
). H NMR (300.06 MHz, CDCl
3
.58 (s, 3 H, 2-Me), 2.17 (s, 3 H, 4-H
= 5.14, δ
, possibly interpretable as AAЈ part of an
, possibly interpretable as
BBЈ part of an AAЈBBЈ signal, 2 H, 2 o-H) ppm.
3
s, 1 H, 2-OH), AB signal (δ
A
a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino,
J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M.
Wang, D. Xu, X.-L. Zhang, J. Org. Chem. 1992, 57, 2768–2771
2 c
H, 1Ј-H ), 6.88 (m
AAЈBBЈ signal, 2 H, 2 m-H), 7.27 (m
c
(in the presence of MeSO
P. Sjö, K. B. Sharpless, Tetrahedron Lett. 1992, 33, 3833–3836
in the absence of MeSO NH ).
2 2
NH ); b) footnote 6 in: K.-S. Jeong,
(
2
2
4
2
-Methoxybenzyl (R)-2-Hydroxy-2-methyl-3-oxobutanoate [(R)-
9c]: Ester (R,R)-7c (111 mg, 437 μmol; 80% ee) was dissolved in
[
2] a) B. B. Lohray, Tetrahedron: Asymmetry 1992, 3, 1317–1349;
b) R. A. Johnson, K. B. Sharpless, in: Asymmetric Catalysis in
Organic Synthesis (Ed.: I. Ojima), VCH, New York, 1993, p.
CH
aqueous NaHCO
.0 equiv.), and TEMPO (34.1 mg, 218 μmol, 0.5 equiv.) were
added successively. Bleach (total content of Cl ca. 10%, ca. 1.6 m ,
2
Cl
2
(3.5 mL) and the solution was cooled to 0 °C. A saturated
3
solution (3.5 mL), KBr (52.0 mg, 437 μmol,
227–272; c) H. C. Kolb, M. S. VanNieuwenhze, K. B.
1
Sharpless, Chem. Rev. 1994, 94, 2483–2547; d) G. Poli, C. Scol-
astico, Methoden Org. Chem. (Houben-Weyl), 4th ed. 1952,
vol. E21e (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, Germany, 1995, p. 4547–4598;
e) P. Salvadori, D. Pini, A. Petri, Synlett 1999, 1181–1190; f)
R. A. Johnson, K. B. Sharples, in: Catalytic Asymmetric Syn-
thesis 2nd ed. (Ed.: I. Ojima), Wiley-VCH, Weinheim, Ger-
many, 2000, p. 357–389; g) C. Bolm, J. P. Hildebrand, K.
Muñiz, in: Catalytic Asymmetric Synthesis 2nd ed. (Ed.: I.
Ojima), Wiley-VCH, Weinheim, Germany, 2000, p. 399–428; h)
A. Krief, C. Colaux-Castillo, Pure Appl. Chem. 2002, 74, 107–
50 μL, 240 μmol, 0.55 equiv.) was added[ through a graduated
49]
1
pipette and the mixture was stirred vigorously at 0 °C for 2 min.
This was repeated twice and the mixture was stirred vigorously at
0
°C for another 13 min. The reaction was quenched by the ad-
dition of a saturated aqueous Na SO solution (1 mL). The phases
were separated and the aqueous phase washed with CH Cl (2
mL). The combined organic phases were dried with MgSO and
the solvent evaporated under reduced pressure. Purification by
2
3
2
2
4
4
flash chromatography on silica gel[ (1.5ϫ15 cm, 15 mL, c-C
EtOAc = 3:1, 2–4) rendered the product as a colorless oil (99.0 mg,
0 %, 77 % ee). Analytical HPLC: Chiralpak AD-3, n-heptane/
43]
6
12
H /
113.
[
[
3] K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2024–2032;
Angew. Chem. 2002, 114, 2126–2135.
9
2
0
iPrOH = 100:1, 230 nm, t
R
= 40.01 (R), 43.35 min (S). [α]
D
= +34.8
4] a) H. C. Kolb, K. B. Sharpless, in: Transition Metals for Or-
ganic Synthesis (Eds.: M. Beller, C. Bolm), Wiley-VCH,
Weinheim, Germany, 2004, vol. 2, p. 275–298; b) M. C. Noe,
M. A. Letavic, S. L. Snow, S. McCombie, Org. React. 2005, 66,
109–625; c) A. B. Zaitsev, H. Adolfsson, Synthesis 2006, 1725–
1756; d) S. Kobayashi, M. Sugiura, Adv. Synth. Catal. 2006,
); [α] 52 46 = +42.0 (c = 0.77 g/100 mL,
0
(
c = 0.66 g/100 mL, CHCl
3
0
20
CHCl
3
); [α] 42 36 = +85.9 (c = 0.77 g/100 mL, CHCl
3
); [α]365 = +176.5
(
c = 0.77 g/100 mL, CHCl ). IR (film): ν˜ = 3455, 2940, 1720, 1615,
515, 1460, 1360, 1305, 1250, 1155, 1115, 1030, 915, 820, 745 cm .
3
–
1
1
1
H NMR (400.13 MHz, CDCl
3
): δ = 1.56 (s, 3 H, 2-Me), 2.16 (s,
), 3.79 (s, 3 H, OMe), 4.17 (s, 1 H, 2-OH), AB signal (δ
= 5.16 ppm, JAB = 11.9 Hz, 2 H, 1Ј-H ), 6.86 (m , possibly
348, 1496–1504.
3
5
H, 4-H
.12, δ
3
A
=
[
5] For the original presentation of the Sharpless mnemonic, see:
a) E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroeder,
K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 1968–1970; for
the first modification of the Sharpless mnemonic (the SW cor-
ner exerts attractive interactions), see: b) H. C. Kolb, P. G. An-
dersson, K. B. Sharpless, J. Am. Chem. Soc. 1994, 116, 1278–
B
2
c
interpretable as AAЈ part of an AAЈBBЈ signal, 2 H, 2 m-H), 7.26
, possibly interpretable as BBЈ part of an AAЈBBЈ signal, 2 H,
(m
c
o-H) ppm. 1 C NMR (100.63 MHz, CDCl
3
2
2
3
): δ = 21.71 (2-Me),
4.09 (C-4), 55.28 (C-OMe), 67.92 (C-1Ј), 81.08 (C-2), 114.07 (2 C-
m), 127.02 (C-i), 130.19 (2 C-o), 159.96 (C-p), 171.19 (C-1), 204.63
C-3) ppm. edHSQC (“C,H-COSY”, 100.62/400.13 MHz, CDCl ):
1291; c) P.-O. Norrby, H. C. Kolb, K. B. Sharpless, J. Am.
(
3
Chem. Soc. 1994, 116, 8470–8478; for the second modification
(the NW corner is designated as neutral and the NE corner as
attractive), see: d) P. Fristrup, D. Tanner, P.-O. Norrby, Chiral-
Allows the assignment of all nonquaternary carbon atoms by their
cross-peaks with directly bonded protons [δ(13C) ↔ δ( H)]: δ =
1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
19

Job/Unit: O43622
/KAP1
Date: 26-02-15 18:59:06
Pages: 23
F. Weber, R. Brückner
FULL PAPER
ity 2003, 15, 360–368; e) P. Fristrup, G. H. Jensen, M. L. N.
Andersen, D. Tanner, P.-O. Norrby, J. Organomet. Chem. 2006,
Nicolaou, M. Nevalainen, M. Zak, S. Bulat, M. Bella, B. S.
Safina, Angew. Chem. Int. Ed. 2003, 42, 3418–3424; Angew.
Chem. 2003, 115, 3540–3546; the angelate derived from (–)-
menthol was also subjected to an SAD in the presence of AD-
mix β.
6
91, 2182–2198; f) for the modification of gem-disubstituted
olefins, see: P. Han, R. Wang, D. Z. Wang, Tetrahedron 2011,
7, 8873–8878.
6
[
6] For selected SADs of achiral alkenes with a gem-disubstituted
[15] V. A. Marlow, D. Rea, S. Najmudin, M. Wills, V. Fülöp, ACS
Chem. Biol. 2013, 8, 2339–2344. This study included X-ray
structural analyses of enzyme complexes of the 2,3-dihydroxy-
2-methylbutanoic acids (S,S)-12 [prepared from methyl ange-
C=C bond, see: a) Z.-M. Wang, K. B. Sharpless, Synlett 1993,
6
03–604; b) K. J. Hale, S. Manaviazar, S. A. Peak, Tetrahedron
Lett. 1994, 35, 425–428; c) D. J. Krysan, Tetrahedron Lett.
996, 37, 1375–1376; d) M. C. Noe, E. J. Corey, Tetrahedron
1
late (3a) in the presence of (DHQ) PHAL] and (2S,3R)-12 [pre-
2
Lett. 1996, 37, 1739–1742; e) P. O’Brien, S. Warren, J. Chem.
Soc. Perkin Trans. 1 1996, 2129–2138; f) X. Wang, M. Zak, M.
Maddess, P. O’Shea, R. Tillyer, E. J. J. Grabowski, P. J. Reider,
Tetrahedron Lett. 2000, 41, 4865–4869; g) P. Gupta, R. A. Fer-
nandes, P. Kumar, Tetrahedron Lett. 2003, 44, 4231–4232; h)
A. Samarat, H. Amri, Y. Landais, Tetrahedron 2004, 60, 8949–
pared from methyl tiglate (2a) in the presence of (DHQD) -
2
PHAL, cf. ref.[ ].
21d]
[
16] K. Stritzke, S. Schulz, R. Nishida, Eur. J. Org. Chem. 2002,
3884–3892.
[
[
17] D. P. Curran, S.-B. Ko, J. Org. Chem. 1994, 59, 6139–6141.
18] S. Claudel, T. K. Olszewski, P. Mutzenardt, C. Aroulanda, P.
Coutrot, C. Grison, Tetrahedron 2006, 62, 1787–1798.
8
956; i) A. Avenoza, J. H. Busto, G. Jiménez-Osés, J. M. Pereg-
rina, J. Org. Chem. 2005, 70, 5721–5724; j) M. Chang, T. H.
[19] W. Xie, D. Ding, W. Zi, G. Li, D. Ma, Angew. Chem. Int. Ed.
Kim, H.-D. Kim, Tetrahedron: Asymmetry 2008, 19, 1504–
2008, 47, 2844–2848; Angew. Chem. 2008, 120, 2886–2890. a)
1508; k) G. Hirai, Y. Ogoshi, M. Ohkubo, Y. Tamura, T. Wat-
For SADs of angelate 19, see Supporting Information of the
cited paper p. S18; b) the SAD of the E isomer of angelate 19
anabe, T. Shimizu, M. Sodeoka, Tetrahedron Lett. 2009, 50,
609–3612; l) see ref.[ ; m) D. S. Siegel, G. Piizzi, G. Piersanti,
20i]
3
1
with AD-mix α is reported with opposite steric outcomes in
M. Movassaghi, J. Org. Chem. 2009, 74, 9292–9304; n) B.
Scheme 6 of that publication (with the configurations in
disagreement with Sharpless’ mnemonic) compared with in p.
S17 of the Supporting Information (in which the configura-
tions comply with SharplessЈ mnemonic). What implications, if
any, this has for that study’s objective (“Total Synthesis
and Structure Assignment of Papuamide B, a Potent Marine
Cyclodepsipeptide with anti-HIV Properties”) cannot be as-
sessed.
Gourdet, H. W. Lam, Angew. Chem. Int. Ed. 2010, 49, 8733–
[
5f]
8
737; o) see ref. ; p) T. J. Miles, A. J. Hennessy, B. Bax, G.
Brooks, B. S. Brown, P. Brown, N. Cailleau, D. Chen, S. Dabbs,
D. T. Davies, J. M. Esken, I. Giordano, J. L. Hoover, J. Huang,
G. E. Jones, S. K. Kusalakumari Sukmar, C. Spitzfaden, R. E.
Markwell, E. A. Minthorn, S. Rittenhouse, M. N. Gwynn,
N. D. Pearson, Bioorg. Med. Chem. Lett. 2013, 23, 5437–5441;
q) Y. Zhao, X. Xing, S. Zhang, D. Z. Wang, Org. Biomol.
Chem. 2014, 12, 4314–4317.
[
20] a) SAD of the methacrylic Weinreb amide 1d established the
[
28]
[
7] For selected SADs of achiral alkenes with a cis-disubstituted
C=C bond, see: a) K.-S. Jeong, P. Sjö, K. B. Sharpless, Tetrahe-
dron Lett. 1992, 33, 3833–3836; b) L. Wang, K. B. Sharpless,
J. Am. Chem. Soc. 1992, 114, 7568–7570; c) M. S. Van-
Nieuwenhze, K. B. Sharpless, Tetrahedron Lett. 1994, 35, 843–
stereocenter in both enantiomers of α-methylserine, see ref.
;
the specific rotations matched those reported in the literature
(P. J. Colson, L. S. Hegedus, J. Org. Chem. 1993, 58, 5918–
5924); b) SAD of methyl methacrylate (1a) was used to synthe-
size the substrate for carbene insertion reactions, see: A.
Bourghida, V. Wiatz, M. Wills, Tetrahedron Lett. 2001, 42,
8689–8692; the authors did not determine the enantiomeric ex-
cess of their product; it should be racemic, see ref.[ ; c) SAD
of the methacrylic Weinreb amide 1d established the stereocen-
ter in α-methyl-d-serine-β-lactone, see ref.[ ; the 3D structure
of the product was confirmed by an X-ray structural analysis
(the product crystallized in a chiral space group); d) SAD of
the methacrylic Weinreb amide 1d established the stereocenter
in the substrate for the study of the ring-opening reactions of
gem-disubstituted cyclic sulfates: A. Avenoza, J. H. Busto, F.
Corzana, J. I. García, J. M. Peregrina, J. Org. Chem. 2003, 68,
4506–4513; e) SAD of the methacrylic Weinreb amide 1d estab-
lished the stereocenter in α-methyl-d-serine building blocks: A.
Avenoza, J. M. Peregrina, E. San Martín, Tetrahedron Lett.
2003, 44, 6413–6416; f) SAD of the methacrylic Weinreb amide
1d established the stereocenter in 2-methylisoserine: A. Av-
enoza, J. H. Busto, F. Corzana, G. Jiménez-Osés, M. París,
J. M. Peregrina, D. Sucunza, M. M. Zurbano, Tetrahedron:
Asymmetry 2004, 15, 131–137; the stereostructure of the diol
was confirmed by an X-ray structural analysis of the corre-
sponding mono-OBn-NBoc-serine ester; g) SAD of the meth-
acrylic Weinreb amide 1d established the stereocenter in vari-
ous α-heteroatom-substituted α-methyl-β-alanins: A. Avenoza,
J. H. Busto, F. Corzana, G. Jimenez-Oses, J. M. Peregrina,
Chem. Commun. 2004, 980–981; h) SAD of methacryloyl N-[4-
cyano-3-(trifluoromethyl)phenyl]amide established the stereo-
center in bicalutamide: L. Thijs, R. Keltjens, G. Ettema, US
Pat. 2004/0068135, 2004. The same substrate was also dihy-
846; d) Z.-M. Wang, K. Kakiuchi, K. B. Sharpless, J. Org.
Chem. 1994, 59, 6895–6897; e) S. Superchi, F. Minutolo, D.
Pini, P. Salvadori, J. Org. Chem. 1996, 61, 3183–3186; f) J. A. B.
Laurenson, S. Meiries, J. M. Percy, R. Roig, Tetrahedron Lett.
28]
29]
2
009, 50, 3571–3573; g) E. Pavlakos, T. Georgiou, M. Tofi, T.
Montagnon, G. Vassilikogiannakis, Org. Lett. 2009, 11, 4556–
559; h) A. Schmauder, L. D. Sibley, M. E. Maier, Chem. Eur.
4
J. 2010, 16, 4328–4336; i) E. Sreedhar, A. Venkanna, N. Chand-
ramouli, K. S. Babu, J. M. Rao, Eur. J. Org. Chem. 2011, 1078–
1083; j) A. A. Singh, S. N. A. Zulkifli, M. Meyns, P. Y. Hayes,
J. J. De Voss, Tetrahedron: Asymmetry 2011, 22, 1709–1719; k)
S. Chandrasekhar, B. V. D. Vijaykumar, B. Mahesh Chandra,
C. Raji Reddy, P. Naresh, Tetrahedron Lett. 2011, 52, 3865–
3867.
[
8] For examples of SADs of achiral alkenes with a tetrasubsti-
tuted C=C bond, see: a) K. Morikawa, J. Park, P. G. An-
dersson, T. Hashiyama, K. B. Sharpless, J. Am. Chem. Soc.
1
993, 115, 8463–8464; b) H. Nemoto, J. Miyata, H. Hakamata,
M. Nagamochi, K. Fukumoto, Tetrahedron 1995, 51, 5511–
522; c) G. M. Mehltretter, C. Döbler, U. Sundermeier, M.
5
Beller, Tetrahedron Lett. 2000, 41, 8083–8087.
[
[
[
9] a) L. F. Tietze, J. Görlitzer, Liebigs Ann./Recueil 1997, 2221–
2225; b) L. F. Tietze, J. Görlitzer, Synthesis 1997, 877–885.
10] H. Burghart-Stoll, O. Böhnke, R. Brückner, Org. Lett. 2011,
3, 1020–1023.
11] H. Shao, J. K. Rueter, M. Goodman, J. Org. Chem. 1998, 63,
240–5244.
12] N. Moitessier, C. Henry, C. Len, Y. Chapleur, J. Org. Chem.
1
5
[
[
4
droxylated as a part of a study on a recyclable OsO catalyst:
2002, 67, 7275–7282.
13] H. Liu, K. G. Jensen, L. M. Tran, M. Chen, L. Zhai, C. E.
Olsen, H. Søhoel, S. R. Denmeade, J. T. Isaacs, S.
Brøgger Christensen, Phytochemistry 2006, 67, 2651–2658.
14] a) J. M. Torres-Valencia, C. M. Cerda-García-Rojas, P. Joseph-
Nathan, Tetrahedron: Asymmetry 1998, 9, 757–764; b) K. C.
S. K. Dehury, V. S. Hariharakrishnan, Tetrahedron Lett. 2007,
48, 2493–2496; i) SAD of the methacrylic Weinreb amide 1d
was suggested to establish the quarternary stereocenter in α-
tocopherol but the respective transformations were stopped be-
fore the target was reached: D. W. Knight, X. Qing, Tetrahe-
[
20
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Asymmetric Dihydroxylation
dron Lett. 2009, 50, 3534–3537; j) SAD of the methacrylic
Weinreb amide 1d established the quarternary stereocenter in
the side-chain of novel glucokinase activators: T. D. Aicher,
S. A. Boyd, M. J. Chicarelli, K. R. Condroski, J. B. Fell, J. P.
Fischer, I. W. Gunawardana, R. J. Hinklin, A. Singh, T. M.
Turner, WO 2009/042435 (examples 150 and 151); k) SAD of
the methacrylic Weinreb amide 1d established the stereocenter
in gregatin B: T. Kusakabe, Y. Kawai, K. Kato, Org. Lett. 2013,
MeOH)}, however, they differ, in: magnitude. This may be due
to the use of different solvents.
[33] Fülöp and co-workers; found quite different specific rotations
for the four stereoisomers of 7a:[
15]
1
5, 5102–5105; the specific rotation matched that reported in
the literature: K. Kobayashi, T. Ui, Tetrahedron Lett. 1975, 16,
119–4122.
21] a) SAD of benzyl tiglate established both stereocenters in
4
[
11]
(
2S,3S)-α-methylthreonine, see ref.[ ; the stereostructure of
the product was confirmed by an X-ray structural analysis of
the N-Boc derivative; b) SAD of benzyl tiglate established a
stereocenter in the acyl side-chain segment of GE3: K. Makino,
Y. Henmi, Y. Hamada, Synlett 2002, 613–615; c) SAD of the
tiglate of a complex alcohol established two stereocenters in
the neohelmanticins A–D: E. Sreedhar, R. Sateesh Chan-
dra Kumar, G. Venkateswar Reddy, A. Robinson, K. Su-
resh Babu, J. Madhusudana Rao, P. V. Srinivas, Tetrahedron:
Asymmetry 2009, 20, 440–448; the specific rotations were de-
However, specific rotations similar to ours were reported by
others (see above). It may be hypothesized that (2R,3S)-7a and
[13]
scribed as matching those of the natural products, see ref.
(
2S,3R)-7a are virtually optically inactive at 589 nm so that
and references cited therein; d) SADs of methyl tiglate with
subsequent hydrolyses provided (2R,3S)-dihydroxy-2-methyl-
“
their” specific rotations may be caused by contaminants. If
[
15]
that was true the specific rotations of Fülöp and co-workers
butanoic acid in the presence of (DHQ)
enantiomer in the presence of (DHQD)
structure of the latter was proved by the X-ray structure analy-
2
PHAL and the 2S,3R
might be caused by contamination of their products by the
corresponding AD ligand: The work-up, which they published,
mentioned neither acidic washing nor achromatography, one of
which measures would appear to be necessary for removing
that ligand. The specific rotations of the pure ligands are:
2
PHAL; the stereo-
[15]
sis of an enzyme complex of that compound, see ref. ; e) cf.
[
19b]
also ref.
22] a) SADs of l-menthyl angelate (10a) and d-menthyl angelate
10b) allowed us to prepare (R,R)- and (S,S)-2,3-epoxy-2-meth-
.
[
(
DHQ)
2
PHAL: [α] = +336 (c = 1.22 g/100 mL, MeOH);
D
PHAL: [α] = –263 (c = 1.15 g/100 mL, MeOH).
D
(
[14]
DHQD
2
ylbutanoic acid (see ref. ); b) methyl (R,R)-2,3-epoxy-2-meth-
ylbutanoate was also prepared and its specific rotation matched
that reported in the literature: B. W. Christensen, K. Anders,
Acta Chem. Scand. 1962, 16, 2466–2467; c) SAD of isobutyl
angelate (3b) might have established both stereocenters in
[
34] We considered the fact that the (DHQ)
2
PHAL ligand outper-
forms the (DHQD) PHAL ligand as remarkable and also that
2
the ee values were low. Therefore we performed these experi-
ments twice and obtained identical results.
2S,3R)-α-methylthreonine, see ref.[11], for details see the main
[35] None of the saponification/esterification sequences presented
in Table 2 should have changed the enantiopurity of the com-
pounds involved. This expectation is borne out by entries 5–8;
there, the product enantiomers were separated well by chiral
GC (cf. also footnote [a] of Table 2). Nonetheless, the data in
Table 2 indicate decreases in ee by up to 8% (entry 3) and in-
creases in ee by up to 15% (entry 4). These obvious contradic-
tions to reasonable expectation may be due to our inability to
separate entirely the product enantiomers by chiral GC; inte-
grating overlapping elution peaks did not give better results.
(
body of the text.
[
23] S.-H. Moon, Y. Ohfune, J. Am. Chem. Soc. 1994, 116, 7405–
7406.
[
24] F. Weber, R. Brückner, Org. Lett. 2014, 16, 6428–6431. Our
study required that, irrespective of the type 7 precursor we de-
cided to incorporate, it possesses a homogeneous configuration
at C-2. The configuration at C-3 was arbitrary. A priori this
qualified both tiglate and angelate scaffolds as starting struc-
tures.
25] a) E. J. Corey, A. Guzman-Perez, M. C. Noe, J. Am. Chem.
Soc. 1994, 116, 12109–12110; b) E. J. Corey, A. Guzman-Perez,
M. C. Noe, J. Am. Chem. Soc. 1995, 117, 10805–10816; c) E. J.
[
[
36] All GC traces can be found in the Supporting Information.
37] This conclusion is corroborated by the identical signs of the
specific rotations of the SAD-based Weinreb amide 23d in our
[
work[ and elsewhere
32]
[20f]
.
Corey, M. C. Noe, A. Guzman-Perez, J. Am. Chem. Soc. 1995, [38] This conclusion is corroborated at least somewhat by the ident-
117, 10817–10824.
ities of the signs of the specific rotations of the syn-configured
methyl ester-containing diols (S,S)- and (R,R)-7a in our work
[
[
26] E. J. Corey, M. C. Noe, J. Am. Chem. Soc. 1996, 118, 319–329.
27] Y. L. Bennani, K. B. Sharpless, Tetrahedron Lett. 1993, 34,
in comparison with ref.[ (cf. ref. ). Disturbingly, the abso-
lute values of these rotations differ by factors of around 5, i.e.,
some values must be wrong (cf. also footnote [e] to the table in
ref.[ ).
15]
[32]
2079–2082.
[
28] A. Avenoza, C. Cativiela, F. Corzana, J. M. Peregrina, D. Su-
32]
cunza, M. M. Zurbano, Tetrahedron: Asymmetry 2001, 12,
13]
[
39] The authors of ref.[ noticed the same shift difference and
949–957.
exploited it in a structure elucidation.
[
[
29] N. D. Smith, M. Goodman, Org. Lett. 2003, 5, 1035–1037.
30] P. Dupau, R. Epple, T. A. Allen, V. V. Fokin, K. B. Sharpless,
Adv. Synth. Catal. 2002, 344, 421–433.
[
40] The ester and amide moieties in Figure 2 are drawn with s-cis
conformations whether or not these are preferred in the respec-
tive transition. It is even conceivable that the favorite confor-
mation is substrate-dependent.
41] Figure 2 shows two ways in which methacrylates 1 fit into the
Sharpless mnemonic without substituents bigger than
hydrogen interfering with the hindered SE corner. They are de-
picted on the left-hand side of Figure 2. If, as a consequence,
no orientational bias at all results for the substrate, it reacts
without enantiocontrol. This was the case for methyl methacry-
late (1a): It gave the diol 23a as a racemic mixture (Table 1,
[
[
31] Remarkably, the specific rotations of compounds (2R,3S)- and
(
2S,3R)-7 are not only extremely small, but the algebraic sign
[
changes at shorter wavelengths (see the Exp. Sect.).
2
0
32] The specific rotations of Weinreb amides (R)-23d {[α] = +13.2
D
0
(
c = 1.01 g/100 mL, CHCl
.17 g/100 mL, CHCl )} have the same algebraic sign as those
reported, in: the literature
00 mL, MeOH); (S)-23d: [α]2
3 D
)} and (S)-23d {[α]2
= –13.2 (c =
1
3
[20f]
20
{(R)-23d: [α]
D
D
= +4.7 (c = 1.80 g/
0
1
= –4.6 (c = 1.80 g/100 mL,
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F. Weber, R. Brückner
FULL PAPER
entries 1 and 2). However, the SW corner of the SAD transi-
tion-state mnemonic was/is capable of interacting favorably
[46] To achieve good yields the flask should be siliconized by treat-
ment with SiMe Cl in the following manner: The flask is filled
2
2
with most substrates. This conjecture led to the first modifica-
2 2
with a solution of SiMe Cl in toluene (10% v/v) and sealed.
After 30 min the flask is emptied (the SiMe Cl solution can
2 2
tion of the mnemonic[
5b,5c]
and is borne out in the attributes
“preferred” versus “competing” of the alternative methacrylate
be recycled), rinsed successively with toluene (2ϫ) to wash
away excess SiMe Cl , MeOH (2ϫ) to convert the remaining
orientations in Figure 2. If our SADs of the methacrylic deriva-
tives 1b–e (10–98% ee; Table 1, entries 3–10) are viewed from
this perspective, the strengths of these SW interactions follow
the order Weinreb amideϾpyrrolidideϾPMB esterϾϾiBu es-
ter.
2
2
R SiCl groups into R SiOMe groups, and dried in an oven at
3
3
70 °C.
[
47] Compounds 2e, 3d, and 3e are described in the literature; the
description of their formation is sparse, though, and the com-
pounds were not fully characterized: O. Miyata, T. Shinada, I.
Ninomiya, T. Naito, T. Date, K. Okamura, S. Inagaki, J. Org.
Chem. 1991, 56, 6556–6564.
[
[
42] B. E. Love, E. G. Jones, J. Org. Chem. 1999, 64, 3755–3756.
43] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
2925.
[
44] The melting points are neither corrected nor uncorrected as
these terms refer to total immersion thermometers. In our labo-
ratory partial immersion thermometers are used exclusively. By
definition these need no correction for immersion depth:
G. V. D. Tiers, J. Chem. Educ. 1990, 67, 258–259.
45] In another context it was shown that transition-metal ions may
promote the degradation of N-methylmorpholine N-oxide
[
48] All diols were prepared by a) a racemic dihydroxylation, b) a
SAD by using the (DHQ)
by using the (DHQD) PHAL ligand. Full characterization
data refer to the diol from the SAD performed with the
DHQD) PHAL ligand.
2
PHAL ligand, and c) a SAD
2
(
2
[
[
49] The slightly orange mixture turned bright red upon adding ble-
ach; thereafter it gradually faded to orange again. However,
there was no clear endpoint. This meant it was impossible to
carry out this reaction as a titration.
(
NMO); T. Rosenau, A. Potthast, H. Sixta, P. Kosma, Prog.
Polym. Sci. 2001, 26, 1763–1837. As a precaution, NMO was
never handled with steel cannulas. This avoidance of transition-
metal ion contact was hoped to leave stock solutions and ali-
quots thereof unaffected.
Received: December 13, 2014
Published Online: ᭿
22
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Pages: 23
Asymmetric Dihydroxylation
Dihydroxylations Revisited
F. Weber, R. Brückner* .................. 1–23
Asymmetric Dihydroxylation of Esters and
Amides of Methacrylic, Tiglic, and Angelic
Acid: No Exception to the Sharpless
Mnemonic!
Keywords: Asymmetric catalysis / Con-
figuration determination
/ Dihydroxyl-
ation / 1,2-Diols / Enantioselectivity / Oxi-
dation
The Sharpless mnemonic is generally ac-
cepted as a predictive tool for the stereo-
chemical outcome of Sharpless asymmetric
dihydroxylation reactions. However, it was
claimed that isobutyl tiglate is dihydrox-
ylated with the opposite facial selectivity
because of a preference for a “Chapleur
transition state”. We have investigated this
claim and proved it false.
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