Asymmetric nucleophilic acylation of aldehydes via 1,1-heterodisubstituted alkenes

Article abstract of DOI:10.1002/(SICI)1521-3765(19990802)5:8<2270::AID-CHEM2270>3.0.CO;2-L

Aldehydes are asymmetrically acylated by a two step sequence that is initiated by a homologation step to 1,1-heterodisubstituted alkenes followed by asymmetric dihydroxylation. Thus, ketene O,S-acetals are efficiently prepared from aldehydes by a Peterson olefination with lithiated methoxy-phenylthiotrimethylsilyl methane 14 as the C-1 source. Although they are dihydroxylated with the Sharpless catalyst with moderate to good enantioselectivity (62-80% ee), the process is not efficient owing to the low chemical yields of the desired α-hydroxy methyl esters (7-37%). Use of the corresponding sulfoxide 24 or sulfon 25 led to an improved chemical yield of α-hydroxy methyl ester 19, but the stereoselectivity was diminished. In contrast, intermediate ketene O,O-acetals are prepared by a Horner-Wittig reaction with phosphine oxide 31 and are dihydroxylated both with good chemical and stereochemical yield. The concept is applicable to aromatic, aliphatic, and chiral aldehydes. For example, this short sequence allows exclusive and independent preparation of both diastereomeric heptoses 69 a and 69 b.

Full text of DOI:10.1002/(SICI)1521-3765(19990802)5:8<2270::AID-CHEM2270>3.0.CO;2-L

FULL PAPER
Asymmetric Nucleophilic Acylation of Aldehydes
via 1,1-Heterodisubstituted Alkenes
Holger Monenschein, Gerald Dräger, Alexander Jung, and Andreas Kirschning*[a]
Abstract: Aldehydes are asymmetrical-
ly acylated by a two step sequence that is
initiated by a homologation step to 1,1-
heterodisubstituted alkenes followed by
asymmetric dihydroxylation. Thus, ke-
tene O,S-acetals are efficiently prepared
from aldehydes by a Peterson olefina-
tion with lithiated methoxy-phenylthio-
trimethylsilyl methane 14 as the C-1
source. Although they are dihydroxyl-
ated with the Sharpless catalyst with
moderate to good enantioselectivity
(62 ± 80%ee), the process is not efficient
owing to the low chemical yields of the
desired a-hydroxy methyl esters (7 ±
37%). Use of the corresponding sulf-
oxide 24 or sulfon 25 led to an improved
chemical yield of a-hydroxy methyl
ester 19, but the stereoselectivity was
diminished. In contrast, intermediate
ketene O,O-acetals are prepared by a
Horner± Wittig reaction with phosphine
oxide 31 and are dihydroxylated both
with good chemical and stereochemical
yield. The concept is applicable to
aromatic, aliphatic, and chiral alde-
hydes. For example, this short sequence
allows exclusive and independent prep-
aration of both diastereomeric heptoses
69a and 69b.
Keywords: aldehydes ´ asymmetric
synthesis ´ C C coupling ´ dihy-
droxylations ´ Wittig reactions
O
Introduction
X
unmasking
Y
R
R
X
Z
Homologation of aldehydes by the use of various C nucleo-
philes is a key transformation in organic synthesis.[1] Appro-
priate substitution of the nucleophilic carbanion with two or
three heteroatoms (X ± Z) leads to masked formyl-anion
equivalents. In the presence of aldehydes 1, these carbanions
can be used for the preparation of masked a-hydroxy
aldehydes, carboxylic acids, or esters 2, which subsequently
have to be unmasked to give 3 (Scheme 1). The most
commonly used heteroatoms for these d1 synthons are
sulfur,[2] tin,[3] and to a lesser extent silicon[4] in some cases
in connection with oxygen substituents.[5] Additionally, the
carbanion can be stabilized by nitrogen,[6] which is often part
of a heterocycle, namely in benzothiazole[7] or 2-trimethylsil-
yl-thiazole.[8] Control of the configuration of the newly formed
stereogenic center at C-2 as well as liberation of the aldehyde
from the primary adducts are still the major challenges for all
methods developed so far. One strategy for performing the
acylation of aldehydes in an asymmetric mode uses an a-
positioned chiral center in the substrate (substrate control).[9]
In particular Dondoni and co-workers elegantly applied this
nucleophilic
alkylation
OH
OH
3
2
-HY
R
O
H
1
X
X
AD
Y
H
alkenation
R
R
Y
O
OH
H
4
5
Scheme 1. Concepts of asymmetric acylations of aldehydes.
approach, using substituted thiazoles as formyl-anion equiv-
alents.[10] Alternatively, when chiral formyl-anion equivalents
are employed (reagent control) more stereochemical flexi-
bility is gained because achiral aldehydes can be used and
both stereochemical series become principally accessable.
Typical examples for this strategy are the use of C2-symmetric
trans-1,3-dithiane S,S-dioxides,[11] chiral O,S-acetals,[12] and
amino cyanides {[R C(NR2 )CN] [M] } or formaldehyde
SAMP-hydrazones.[13] Corey and Jones described a very
different three step approach by utilizing a nucleophilic chiral
alkinylmethyl borane in an addition reaction with aldehydes.
After protection and ozonolysis of the resulting 1,2-dienyl
carbinols, a-hydroxyaldehydes are generated in up to 99% ee.
However, these reagent-based strategies are often hampered
by irreversible loss of the chiral auxiliary.
1
‡
*
[a] Dr. A. Kirschning, H. Monenschein, Dr. G. Dräger, A. Jung[‡]
Institut für Organische Chemie, Technische Universität Clausthal
Leibnizstraûe 6, D-38678 Clausthal-Zellerfeld (Germany)
Fax: (‡49)5323-72-2858
E-mail: andreas.kirschning@tu-clausthal.de
[‡] Deceased, August 9, 1998
2270
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2270 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 8

2270±2280
Table 1. Asymmetric acylation of aldehydes 7, 11, 12, and ketone 13 via ketene O,S-acetals: yields, configurations
Recently, we disclosed a new
acylation concept[15] that cir-
cumvents most of the draw-
backs described for the classical
approaches via intermediate 2.
The fundamental difference lies
in the fact that homologation
and build-up of the stereogenic
center at C-2 are separated in
time. This new strategy utilizes
a formyl-anion equivalent that
in the reaction with aldehydes
affords a prochiral 1,1-hetero-
disubstituted alkene 4. Now, the
stage is set for asymmetrically
introducing the hydroxy group
at C-2, by the means of the
Sharpless asymmetric dihy-
droxylation (AD).[16] The inter-
mediate diol 5 formed sponta-
neously collapses to the corre-
sponding a-hydroxy ester 3 if
the vinylic substituents X and Y
have leaving-group properties.
This report presents detailed investigations with various 1,1-
heterodisubstituted alkenes as intermediates and improve-
ments of the general concept.
and enantioselectivities.
1
O
2
O
R
2
R
SPh
1
2
R
1
1
R
R
SPh
R
R
OMe
Li
SiMe3
OMe
+
MeO
O
2
OH
OH
R
OMe
15-18
19-22
7, 11-13
14
Aldehyde
(Ketone)
Ketene O,S-acetal Hydroxyester
AD-mix
a[(DHQ)2PHAL]
AD-mix
b[(DHQD)2
PHAL]
(yield) [%][a]
(yield) [%][a]
(E:Z ratio)[b]
ee[%]
config
ee[%]
config
[a] Yield of isolated products after column chromatography. [b] Determined from the 1H NMR spectra.
[c] Determined by comparison with other examples.
the Peterson olefination with silyl-substituted carbanion 14 as
the nucleophile.[20] Secondly, they react with osmium tetroxide
under the Sharpless conditions to give a-hydroxy methyl
esters 19 ± 22. However, the yields of this process are far from
satisfactory. A careful search for other oxidation products was
conducted and led to the isolation of diphenyldisulfide. In
some cases, methyl esters like 23 were isolated that derive
from the regioselective addition of water to the ketene double
bond and displacement of the thiolate ion (Scheme 2). a-
Results and Discussion
Preparation and asymmetric dihydroxylation of ketene O,S-
acetals: Initial studies in our laboratories rapidly revealed that
1,1-dibromo alkene 8, which is conveniently prepared from
pentanal 6 with the Corey ± Fuchs alkenation methodology,[17]
is not a suitable substrate for the Sharpless asymmetric
dihydroxylation; formation of the desired a-hydroxy hexanoic
acid is not observed. In fact, Sharpless and co-workers pointed
NOe
8.2%
H
X
Y
H3CO
OCH3
SPh
15 (E:Z= 2:1)
a
a
CO2CH3
SPh
(Z)-15
Br
SEt
SEt
O
R
O
(2R)-19 X= OH, Y= H
23 X= Y= H
Ph
Ph
Br
SEt
H
OH
Scheme 2. a) AD-mix b, H2O, tBuOH, MeSO2NH2, 08C, 12 h; from (E/Z
2:1)-15: 37%, 80.0% ee; from (Z)-15: 31%, 80.3% ee.
8
6 R= CH3(CH2)3
7 R= Ph
9
10
out that halogenated alkenes are poor substrates for the
asymmetric dihydroxylation.[18] It is assumed that for 1,1-
dibromoalkenes steric hinderance in connection with the
reduced nucleophilicity of the olefinic double bond are
responsible for this lack of reactivity. Therefore, we turned
our attention to the use of ketene S,S-acetal 9, conveniently
prepared from benzaldehyde 7 by the Horner± Emmons
olefination with [(EtO)2P(O)C(SEt)2]Li as a nucleophile.[19]
However, also 9 could not be transformed into a-hydroxy
thiol ester 10 under the typical asymmetric dihydroxylation
conditions and in fact was almost quantitatively recovered.
Ketene O,S-acetals 15 ± 18 turned out to be the first 1,1-
heterodisubstituted alkenes that could be applied for the new
acylation strategy (Table 1). First of all, they are prepared in
excellent yield from aldehydes 7, 11, and 12 or ketone 13 by
Hydroxy phenylthiol esters, which would be generated alter-
natively if the methoxy substituent acts as a leaving group
during fragmentation of the intermediate diols, were not
detected. The high pH value of the dihydroxylation mixture
may cause hydrolysis of a possible intermediate thiol ester.
Therefore, we studied the stability of phenylacetic acid thiol
ester under basic and under hydrolysis conditions. At pH 10.5
not more than 5% of phenylacetic acid was generated within
12 h. A mixture of phenylacetic acid thiol ester in H2O/
tBuOH (1:1) or Na2SO3 left the starting material unaltered
after 12h. A similar set of experiments was performed with an
E/Z mixture (2:1) of ketene O,S-acetal 15. In fact, they are
stable under basic conditions (pH ˆ 10.5) and in the presence
of [K4Fe(CN)6] ´ 3H2O, but OsO4 causes oxidation to diphe-
nyldisulfide and various unidentified products. The enantio-
Chem. Eur. J. 1999, 5, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2271 $ 17.50+.50/0
2271

A. Kirschning et al.
FULL PAPER
purities of the hydroxylation products were moderate with ee
values between 62 ± 80%. When acetophenone 13 was
employed as the starting carbonyl compound, the asymmetric
dihydroxylation furnished atrolactinic acid methyl ester 22 in
low isolated and stereochemical yield. The latter value is in
accordance with other examples of tetrasubstituted alkenes,
which are poor substrates for the AD process.[21]
For raising the efficiency of the acylation strategy with
ketene O,S-acetals, it was necessary to improve both the
isolated yield and enantioselectivity of the dihydroxylation
step. However, neither performing the asymmetric dihydrox-
ylation at 108C instead of 08C nor a larger molar ratio of the
dihydroxylation mixture gave improved results.
We reasoned that the moderate stereoselectivity observed
for the oxidation of ketene O,S-acetals 15 ± 17 may be owing
to the fact that the E/Z mixtures obtained during the
alkenation step were employed. To test this hypothesis, the
E/Z isomers of alkene 15 were separated by flash column
chromatography on neutral Al2O3. Then, the enantiopurity of
the dihydroxylation product 19 obtained from the pure Z
isomer of 15 was compared with the ee value of mandelic
methyl ester formed from a 2:1 starting mixture (Scheme 2).
The ee ratios were determined by gas chromatography with a
modified chiral b-cyclodextrin column and were judged to be
almost identical [2:1 E/Z mixture 15: 80.0% ee; (Z)-15:
80.3% ee]. These results show that ketene O,S-acetals can be
employed as diastereomeric mixtures for the AD process, but
they also mean that the enantiopurities listed in Table 1 are
already close to the optimal values.
The sensitivity of the phenylthio group towards oxidants
could be another reason for the low isolated yields. In order to
improve the acylation method in this respect, the ketene O,S-
acetal 15 was converted into sulfoxide 24 and sulfone 25. In
fact, in terms of yields, these 1,1-heterodisubstituted alkenes
are much better substrates than 15. However, the oxidation
furnished mandelic methyl ester 19 with only low enantio-
purity (Scheme 3).
OH
OCH3
c
CO2CH3
S(O)nPh
15 n=0
24 n=1
25 n=2
(2R)-19
a
b
Scheme 3. a) NaIO4, MeOH, H2O (1:1), THF, RT, 36 h, 82%; b) mCPBA,
CH2Cl2, RT, 48 h; c) AD-mix b, H2O, tBuOH, MeSO2NH2, 08C, 12 h; from
24, 80%, 4.3% ee, from 25, 55%, 2.0% ee.
Preparation and asymmetric dihydroxylation of ketene O,O-
acetals: We extended our concept to the utilization of ketene
O,O-acetals 42 (Table 2).[15] Indeed, these 1,1-heterodisubsti-
tuted alkenes are ideally suited for this concept, because of
the excellent nucleophilicity of the alkenic double bond and
the small size of the two geminal alkoxy groups. They can
conveniently be prepared from aldehydes by the Horner±
Wittig reaction[22] with the dialkoxymethyl diphenyl phos-
phine oxides 31 and 32[23] Furthermore, they are ideal
substrates in the Sharpless asymmetric dihydroxylation[24]
Table 2. Asymmetric acylation of aldehydes 10, 11, and 26 ± 31 via ketene O,O-acetals: yields, configurations and enantioselectivities.
O
OR
, MDA
Ph2P
RO
OR
OR
OR
OR
R1
31 R= Me
O
32 R=Et
Ph
R
R1 CO2R
*
1
1
KOtBu
R
AD
P
Ph
OH
O
H
OH
H
33 - 41
42
19, 43 - 50
7, 11, 26-30
Aldehyde
Cation[a]
R
Phosphinoxide Hydroxyester (yield) [%][b]
(yield) [%][b]
AD-mix
a[(DHQ)2PHAL]
ee [%] config
AD-mix
b[(DHQD)2PHAL]
ee [%]
config
1
[a] Optimal cation. [b] Yield of isolated product after column chromatography. [c] Determined from the H NMR spectra of both diastereomeric Mosher
esters. [d] Not optimized.
2272
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2272 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 8

Asymmetric Synthesis
2270±2280
giving intermediate diols that spontaneously collapse to a-
hydroxy carboxylates (Table 2).
OH
PPh2
O
O
p(iPr)PhCHO
OCH3
OCH3
27
Ph2P
Ph2P
51
O
For this two step sequence, the Horner± Wittig alkenation
turned out to be the yield-determinig reaction. Quantitative
formation of the metallated dialkoxymethyl diphenylphos-
phine oxide was best achieved by use of lithium diisopropyl
amide (LDA) or potassium diisopropyl amide (KDA) in THF
at 1108C. Under these conditions the dark red anion is
quantitatively generated. Metallation with alternate bases like
nBuLi, or lithium or potassium hexamethyldisilazide
(LHMDA or KHMDA) was incomplete. Addition of alde-
hydes 7, 11, and 26 ± 30 to the carbanion afforded stable
phosphine oxides 33 ± 41, which after aqueous workup, could
be chromatographed on silica gel and fully characterized or
directly used for the next step (Table 2). Aromatic aldehydes 7
and 26 ± 28 gave slightly better yields with the potassium salt
of diethoxymethyl diphenylphosphine oxide. In initial studies
with enolizable aldehydes, only moderate yields in the
reaction with anion 32 were achieved,[15] so that a modified
procedure had to be developed. Attempts to improve the
yield by adding metal salts like ZnBr2, MgBr2OEt2, or
Ti(OiPr)4 and transmetallating the lithiated diphenylphos-
phine oxide 31 did not give better yields or were unsuccessful.
Only when a threefold excess of lithiated 31 was employed,
could the yield for the primary adducts be raised to a
satisfactory 70 ± 80%. In the following, the corresponding
ketene acetals 42 were liberated by KOtBu-promoted elim-
ination. Alternatively, 42 can also be prepared by direct
elimination of the metallated primary coupling product at
elevated temperature. However, we found that this procedure
gave a reduced yield of a-hydroxy carboxylic esters after AD.
After the elimination was complete the reaction mixture was
concentrated at 08C, and the crude product was enantiose-
lectively oxidized, affording the a-hydroxy carboxylates 19
and 43 ± 50 in good overall yield and excellent enantiopurity
(Table 2).[25] The intermediate 1,1-dimethoxy ketene O,O-
acetals are slightly better substrates for the AD process than
the corresponding diethoxy derivatives, which are generated
from carbanion 32. The reduced ee values for dihydroquinine
(DHQ) ligand relative to the dihydroquinidine (DHQD)
ligand is a phenomenon often observed for the AD process.[26]
It is noteworthy, that in most cases proton-induced hydrolysis
of the ketene acetals to the corresponding carboxylates did
not occur. However, oxidation is best performed in an inverse
manner by adding the precooled AD mixture to 42.
31
(rac)-52
O
H3C(CH2)8
H
OH
30
H3C(CH2)8
(rac)-53
PPh2
O
Scheme 4. Fragmentation of carbanion 31 and subsequent nucleophilic
addition of metallated phosphine oxide 51 to aldehydes 27 and 30.
OH
O
P
O
Ph
Ph
1. KOtBu
2. AD
CHO
[Ph2P(O)C(OMe)2]Li
CO2Me
OMe
O
MeO
O
O
54
55
56
Scheme 5. Overoxidation of intermediate aromatic ketene O,O-acetal.
Insights into the mechanism of overoxidation were gained
from experiments carried out with 4-methoxy mandelic acid
ethyl ester 47 (Scheme 6). Ester 47 was prepared in 57%
OH
CO2Et
O
AD
MeO
CO2Et
-2 H2O
MeO
47
57
aqueous
base
OH
OH
HO
AD
OEt
OEt
HO
OH
OH
MeO
MeO
59
58
Scheme 6. Proposed mechanism of overoxidation.
overall yield from aldehyde 28 (Table 2) along with keto ester
57, which was formed in 23% yield during the asymmetric
hydroxylation. The yield for 47 could be improved to 71%
yield if the reaction time for the asymmetric dihydroxylation
was reduced to three hours. When pure (2S)-a-hydroxy ester
47 was subjected to the Sharpless mixture again, this time for
12 h, 20% of 47 was reisolated. Additionally, the reaction
furnished keto ester 57 in substantial amounts (23%). This
observation may be rationalized on the basis of the assump-
tion of partial tautomerization of 47 to enol 58 under the basic
dihydroxylation conditions. If this isomer is dihydroxylated
again, the intermediate diol 59 would collapse spontaneously
to give a-keto ester 57. Support for this hypothesis comes from
our observation that aromatic a-hydroxy esters tend to
racemize rapidly.[15]
The use of chiral aldehydes is particularly important when
introducing a new acylation method, as numerous applica-
tions in natural-product synthesis can be envisaged. There-
fore, chiral aldehydes containing an a-aryl- (60), a-alkoxy-
(62), and b-siloxy-substituents (64) were transformed into the
corresponding a-hydroxy esters 61, 63, and 65 under the
standard conditions developed for enolizable aldehydes
(Scheme 7). Except for 62, which was employed as a 3:1
mixture epimeric at the THP group, all examples proceeded
To obtain the best results, it is also essential to control the
reaction time and temperature in the Horner± Wittig step.
Otherwise, fragmentation of carbanions 31 and 32 to lithiated
phosphine oxide 51 occurs; this can subsequently attack
aldehydes like 27 or 30, for which isolation of byproducts 52
and 53, respectively, are a clear proof (Scheme 4).
When aromatic aldehydes like 27, 28, or 54 are employed
overoxidation can occur under prolonged reaction times in
the dihydroxylation step leading to the corresponding a-keto-
esters. In fact, ketoester 56 was the only oxidation product
obtained after applying the acylation sequence on furfural 54
via intermediate 55 (Scheme 5). Attempts to suppress over-
oxidation by reducing the reaction time and the temperature
were not successful.[27]
Chem. Eur. J. 1999, 5, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2273 $ 17.50+.50/0
2273

A. Kirschning et al.
FULL PAPER
Still, no high yielding and
especially stereoselective ho-
mologation methods for alde-
hydes like 67 are known that
are so flexible so as to create
both possible diastereomers in-
dependently.[32, 33] Thus, we ex-
tended our asymmetric homo-
logation method to a-d-galacto-
dialdopyranose 67. It was first
treated with carbanion 31 to
give phosphine oxide adduct 68
as a single isomer (Scheme 8).
The sequence was terminated
in the usual manner and afford-
ed methyl esters 69a and 69b
with remarkably high diastero-
facial selectivity for both series.
However, under the dihydroxy-
lation conditions typically em-
ployed, the intermediate ke-
Scheme 7. Asymmetric acylation of chiral aldehydes 60, 62, and 64 via ketene O,O-acetals
with similar yields relative to the model systems listed in
Table 2. The stereo directing power of the two chiral Sharpless
ligands is particularly well-demonstrated in the first example,
(2R)-2-phenylpropanal 60. When dihydroquinine 1,4-phtha-
lazinediyl diether (DHQ-PHAL) is employed, catalyst con-
trol and substrate control work in the same direction
(matched case), leading to the corresponding acylation
product with good diastereose-
tene O,O-acetal was hydrolyzed to yield heptose 70 as the
major product (78%). The isolated yield for 69 (81%) could
only be improved, by the suppression of the formation of 70
(6%), when the amount of the dihydroxylation mixture
employed was tripled. It is noteworthy, that the nucleophilic
addition of 31 to dialdopyranose 67 stereoselectively afforded
68 with a stereochemistry that is consistent with an anti-
lectivity.[28] However, even the
stereochemically opposite mis-
matched series, with the dihy-
droquinidine ligand (DHQD-
PHAL), is still practical, fur-
nishing
a diastereoselectivity
close to 80%. When the stereo-
genetic center is moved one
carbon further away to the b-
position as in aldehyde 64, ster-
eocontrol at the newly formed
chiral carbon at C-2 is over-
whelmingly exerted by the di-
hydroxylation mixture so that
both diastereomers 65a and
65b can be prepared separately
with high diastereoselectivity.
Particular challenging sub-
strates are hexose-derived alde-
hydes, which would lead to the
corresponding heptoses. These
naturally rare glycosidic moiet-
ies play a role as biosynthetic
intermediates[29] or as compo-
nents of enterobacterial lipo-
polysaccharides of Gram-nega-
tive bacteria.[30] Furthermore,
they can serve as transition-
state-analogue inhibitors of gly-
cosyltransferases.[31]
Scheme 8. Preparation of heptoses 69 by asymmetric acylation of aldehyde 67.
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 0947-6539/99/0508-2274 $ 17.50+.50/0
2274
Chem. Eur. J. 1999, 5, No. 8

Asymmetric Synthesis
2270±2280
to 788C and then treated with sec-butyl lithium until the color of the
solution changed. At this point, additional sec-butyl lithium (1.44m in
cyclohexane, 1.3 equiv) was added dropwise. The reaction temperature was
monitored throughout the addition and did not exceed 758C. After 2.5 h
at ambient temperature freshly purified aldehyde (1.1 equiv) was added to
the dark red solution. The reaction mixture was allowed to warm to RT
overnight and was diluted with saturated aqueous NH4Cl. After phase
separation and extraction of the aqueous phase with dichloromethane
(5 times), the combined organic extracts were washed with water, dried
(MgSO4), and concentrated in vacuo. Further purification of the residue
was performed by column chromatography.
diastereofacial approach and the transition state model 73. In
order to validate the route via ketene O,O-acetals, the
alternate procedure via ketene O,S-acetals 71 and 72 was
also investigated. As shown in Scheme 8, alkenation of 67
with silyl-stabilized anion 14 proceeds in good yield to afford
ketene acetal 70 as a 1:1 mixture of diastereomers. Again,
however, asymmetric dihydroxylation proceeded with low
efficiency to yield both diastereomeric isomers 69a and 69b.
Oxidation of 71 to the corresponding sulfoxide 72 followed by
dihydroxylation with AD-mix b proceeded with better yield
and furnished a 1:1 mixture of heptose esters 69a and 69b.
Finally, it should be noted that our acylation route of
dialdopyranoses via ketene O,O-acetals is comparable in
terms of shortness and stereoselectivity with the method
developed by the group of Dondoni,[32] while the yields for the
homologation step need further improvement.
In conclusion, we have developed a very competitive
strategy for asymmetrically transforming and homologating
aldehydes to the corresponding a-hydroxy carboxylic esters.
The strength of the transformation described here lies in its
shortness. This is particularly evident from the fact that the
ester functionality is spontaneously liberated during the
stereoselective introduction of the hydroxy group. Further-
more, the use of an external tool for asymmetric induction,
which is available in both enantiomeric forms, allows for the
straightforward preparation of both stereochemical series.
Although the synthesis and oxidation of the intermediate
ketene O,O-acetals requires careful handling the method
should be widely applicable for a diverse number of aldehydes
and should prove very useful in natural product synthesis.
(E,Z)-1-Methoxy-2-phenyl-1-(phenylthio)ethene (15): Aldehyde
7
(265 mg, 2.5 mmol) was used to prepare the title compound 15 (587 mg,
2.43 mmol, 97%; E/Z ˆ 2:1) with the general procedure described above.
Purification and separation of the two isomers was achieved by flash
column chromatography on neutral Al2O3 (petroleum ether/ethyl acetate
50:1).
Isomer (E)-15:[20] Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.55 ±
7.00 (m, 10H, Ph), 6.09 (s, 1H, CH), 3.59 (s, 3H, OCH3); 13C NMR
ˆ
(50 MHz, CDCl3): d ˆ 158.7 (‡, C-2), 151.4 (o, C-1), 136.5 ± 127.0 (o and ‡,
Ph), 57.8 (‡, OCH3); C15H14OS: calcd C 74.34, H 5.82; found C 74.31, H
5.88.
Isomer (Z)-15:[35] Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.55 ±
ˆ
7.00 (m, 10H, Ph), 6.19 (s, 1H, CH), 3.64 (s, 3H, OCH3).
(1-E,Z; 3-E)-1-Methoxy-4-phenyl-1-(phenylthio)-1,3-butadiene (16): Al-
dehyde 11 (330 mg, 2.5 mmol) was used to prepare the title compound 16
(596 mg, 2.23 mmol, 89%; E/Z ˆ 1:4) by the general procedure described
above. Purification was achieved by column chromatography (petroleum
ether/ethyl acetate 38:1).
Isomer (E)-16:[20] Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.49 ±
7.10 (m, 10H, Ph), 6.58 (s, 1H, 2-H), 6.50 (d, J ˆ 15.7 Hz, 1H, 4-H), 6.07 (d,
J ˆ 15.7 Hz, 1H, 3-H), 3.65 (s, 3H, OCH3); 13C NMR (50 MHz, CDCl3):
d ˆ 149.6 (o, C-1), 149.6 (‡, C-4), 139.8 (‡, C-2), 138.6 ± 125.5 (o and ‡,
Ph), 116.9 (‡, C-3), 56.9 (‡, OCH3).
Isomer (Z)-16:[20] 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.49 ± 7.10
(m, 10H, Ph), 6.61 (s, 1H, 2-H), 6.56 (d, J ˆ 15.7 Hz, 1H, 4-H), 6.10 (d, J ˆ
15.7 Hz, 1H, 3-H), 3.69 (s, 3H, OCH3); 13C NMR (50 MHz, CDCl3): d ˆ
151.1 (‡, C-4), 149.6 (o, C-1), 139.8 (‡, C-2), 138.6 ± 125.5 (o and ‡, Ph),
118.2 (‡, C-3), 56.9 (‡, OCH3). C17H16OS: calcd C 76.08, H 6.01; found C
76.31, H 6.24.
Experimental Section
(E,Z)-1-Methoxy-1-(phenylthio)-1-pentene (17): Aldehyde 12 (200 mg,
2.32 mmol) was used to prepare the title compound 17 (510 mg, 2.29 mmol,
99%; E/Z ˆ 1:1) by the general procedure described above. Purification
was achieved by column chromatography (petroleum ether/ethyl acetate
1:10).
General techniques: All temperatures quoted are uncorrected. Optical
rotations: Perkin ± Elmer 243b polarimeter. 1H NMR, 13C NMR spectra:
Bruker DPX200, AMX400 spectrometer. 13C NMR multiplities:
DEPT135 method; they are reported with the following abbreviations:
o ˆ singlet (due to quaternary carbon), ‡ ˆ doublet and quartet (methine,
methyl), ˆ triplet (methylene). MS: HP5989B MASS Hewlett ± Packard
(DIP-MS) and Finnigan A 311, 70 eV (EI-MS). Unless otherwise stated, all
reactions were run under a nitrogen atmosphere. All solvents used were of
reagent grade and were further dried. Reactions were monitored by TLC
on silica gel 60PF254 (E. Merck, Darmstadt) and detected either by UV-
absorption or by staining with H2SO4/4-methoxybenzaldehyde in ethanol.
Preparative column chromatography (CC): silica gel 60 (E. Merck,
Darmstadt). GC: HPGC series 5890 Hewlett ± Packard equipped with
column RTX-50 (30 m) and FID 19231 D/E. Chiral GC: HPGC series 5890
Hewlett ± Packard equipped with FID 19231 D/E; column: heptakis-(2,6-
di-O-methyl-3-O-pentyl)-b-cyclodextrin (25 m); gas: helium; conditions:
Isomer (E)-17: Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.37 ± 7.08
(m, 5H, Ph), 5.27 (t, J ˆ 7.5 Hz, 1H, 2-H), 3.53 (s, 3H, OCH3), 2.15 (q, J ˆ
7.5 Hz, 2H, 3-H), 1.36 (sep, J ˆ 7.5 Hz, 2H, 4-H), 0.89 (t, J ˆ 7.4 Hz, 3H,
5-H); 13C NMR (50 MHz, CDCl3): d ˆ 146.7 (o, C-1), 135.2 (‡, C-2),
128.8 ± 123.6 (o and ‡, Ph), 56.6 (‡, OCH3), 28.4, 22.5 ( , C-3, C-4), 13.8
(‡, C-5).
Isomer (Z)-17: Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.37 ± 7.08
(m, 5H, Ph), 5.37 (t, J ˆ 7.5 Hz, 1H, 2-H), 3.58 (s, 3H, OCH3), 2.23 (q, J ˆ
7.5 Hz, 2H, 3-H), 1.38 (sep, J ˆ 7.5 Hz, 2H, 4-H), 0.91 (t, J ˆ 7.4 Hz, 3H,
5-H); 13C NMR (50 MHz, CDCl3): d ˆ 149.0 (o, C-1), 134.5 (‡, C-2),
128.8 ± 123.6 (o and ‡, Ph), 57.0 (‡, OCH3), 30.7, 22.5 ( , C-3, C-4), 13.7
(‡, C-5); C13H18OS: calcd C 70.22, H 8.16; found C 70.09, H 8.02.
isothermal, P(column) ˆ 175 kPa, PHe ˆ 3.5 bar, PH ˆ 1.5 bar, flow rate. The
2
absolute configuration was deduced from comparison of CD spectra with
those of authentic (2R)-43 [positive Cotton effect for (2S)-19 ± 21 and 44 ±
50, and negative Cotton effect for (2R)-19 ± 21 and 44 ± 50]. Compounds
(E,Z)-1-Methoxy-2-phenyl-1-(phenylthio)-1-propene (18): Ketone 13
(300 mg, 2.5 mmol) was used to prepare the title compound 18[36]
(595 mg, 2.32 mmol, 93%; E/Z ˆ 1:4) by the general procedure described
above. Purification was achieved by column chromatography (petroleum
ether/ethyl acetate 30:1).
8
[17] and 9[19] were synthesized according to literature procedures. Lithiated
14 was prepared as described by Hackett and Livinghouse.[20] Aldehydes 60
(97%), 62 (86%), 64 (88%), and 67 (88%) were obtained from the
corresponding alcohols with the use of the Dess ± Martin reagent.[34] a-
Hydroxy esters 19 and aldehydes 6, 7, 11, 12, and 26 ± 30, ketone 13, and
ester 23 are commercially available.
Isomer (E)-18: Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.43 ±
6.97 (m, 10H, Ph), 3.28 (s, 3H, OCH3), 2.17 (s, 3H, CCH3); 13C NMR
ˆ
(50 MHz, CDCl3): d ˆ 144.2 (o, C-1), 135.3 (‡, C-2), 131.2 ± 125.7 (o and ‡,
Ph), 57.0 (‡, OCH3), 21.1 (‡, CH3).
General procedure for the preparation of ketene O,S acetals: 1,10-
Phenanthroline (4 mgmmol 1) and dry TMEDA (1 equiv) was added to a
solution of phenoxy(phenylthio)(trimethylsilyl)methane[20] (1 equiv) in
absolute THF (2.5 mLmmol 1) under nitrogen. The solution was cooled
Isomer (Z)-18: 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.43 ± 6.97 (m,
10H, Ph), 3.50 (s, 3H, OCH3), 2.07 (s, 3H, CCH3); 13C NMR (50 MHz,
ˆ
CDCl3): d ˆ 141.7 (o, C-1), 131.5 (‡, C-2), 131.2 ± 125.7 (o and ‡, Ph), 57.0
Chem. Eur. J. 1999, 5, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2275 $ 17.50+.50/0
2275

A. Kirschning et al.
FULL PAPER
(‡, OCH3), 19.2 (‡, CH3); C16H16OS: calcd C 74.96, H 6.19; found C 75.11,
with KOH (2m), dried (MgSO4), concentrated under reduced pressure, and
purified by column chromatography on silica gel.
H 6.03.
Mandelic acid methyl ester (19): Ketene O,S-acetal 15 (242 mg, 1.0 mmol)
was used to prepare the title compound 19 (62 mg, 0.37 mmol, 37%) by the
general procedure described above. Purification was achieved by column
chromatography (petroleum ether/ethyl acetate 14:1) to afford an oil. The
enantiomeric excess was determined by chiral GC: isothermal 1118C,
26.04 min (2S), 24.32 min (2R); AD-mix a: ee(S) ˆ 76.8%; AD-mix b:
ee(R) ˆ 80.0%.
(E/Z)-(2'S,3'R,4'R,5'R,6'R)-2-[2'(3',4',5',6'-Di-O-isopropylidene)tetrahy-
dropyranyl]-1-methoxy-1-phenylthio ethene (71): Aldehyde 67 (646 mg,
2.5 mmol) was used to prepare the title compound 71 (655 mg, 1.66 mmol,
67%; E/Z ˆ 1:1) by the general procedure described above. Purification
was achieved by column chromatography (petroleum ether/ethyl acetate
15:1).
1st fraction: (Z)-71: Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ
Sulfoxide 24 (50 mg, 0.19 mmol) and sulfone 25 (50 mg, 0.18 mmol) were
ˆ
7.39 ± 7.18 (m, 5H, Ph), 5.56 (d, J ˆ 8.6 Hz, 1H, CH), 5.05 (d, J ˆ 5.2 Hz,
dihydroxylated with AD-mix
b according to the general procedure
1H, 6'-H), 4.87 (dd, J ˆ 1.6, 8.4 Hz, 1H, 2'-H), 4.61 (dd, J ˆ 2.4, 8.0, 1H, 4'-
H), 4.31 (dd, J ˆ 2.4, 5.2 Hz, 1H, 5'-H), 4.24 (dd, J ˆ 1.6, 8.4 Hz, 1H, 3'-H),
3.57 (s, 3H, OCH3), 1.58, 1.48, 1.36, 1.35 (4s, 12H, 2C(CH3)2); 13C NMR
described above to afford 19 (25 mg, 0.15 mmol, 79.6%, 4.3% ee from
24; 17 mg, 0.1 mmol, 54.7%, 2.0% ee from 25).
(E)-2-Hydroxy-4-phenyl-but-3-enoic acid methyl ester (20): Ketene O,S-
acetal 16 (126 mg, 0.47 mmol) was used to prepare the title compound 20[38]
(27 mg, 0.14 mmol, 30%) by the general procedure described above.
Purification was achieved by column chromatography (petroleum ether/
ethyl acetate 11:1). The enantiomeric excess was determined by chiral GC:
ˆ
(50 MHz, CDCl3): d ˆ 154.3 (o, C(OMe)SPh), 136.0 (‡, CH), 132.2 ±
126.6 (o and ‡, Ph), 109.3, 108.7 (o, 2C(CH3)2), 96.6 (‡, C-6'), 73.8 (‡,
C-2'), 70.9 (‡, C-3'), 70.3 (‡, C-5'), 67.3 (‡, C-4'), 26.0, 25.1, 24.4, 24.3 (‡,
2C(CH3)2).
2nd fraction: (E)-71: Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ
isothermal 1248C, 28.36 min (2S), 25.98 min (2R); AD-mix a: ee(S)
ˆ
ˆ
7.37 ± 7.10 (m, 5H, Ph), 5.33 (d, J ˆ 7.0 Hz, 1H, CH), 5.55 (d, J ˆ 5.0 Hz,
1
75.0%; AD-mix b: ee(R) ˆ 80.3%; oil; H NMR (400 MHz, CDCl3, TMS):
d ˆ 7.45 ± 7.21 (m, 5H, Ph), 6.77 (dd, J ˆ 15.4, 1.2 Hz, 1H, C-4), 6.19 (dd, J ˆ
15.4, 5.2 Hz, 1H, C-3), 4.77 (ddd, J ˆ 5.6, 5.2, 1.2 Hz, 1H, C-2), 3.62 (s, 3H,
OCH3), 3.51 (br, 1H, OH); 13C NMR (50 MHz, CDCl3): d ˆ 176.0 (o, CO),
149.3 (‡, C-4), 136.4 ± 126.2 (o and ‡, Ph), 119.7 (‡, C-3), 70.8 (CHOH),
52.3 (OCH3).
1H, 6'-H), 4.83 (dd, J ˆ 1.6, 7.0 Hz, 1H, 2'-H), 4.61 (dd, J ˆ 2.5, 8.4, 1H, 4'-
H), 4.31 (dd, J ˆ 2.5, 5.0 Hz, 1H, 5'-H), 4.19 (dd, J ˆ 1.6, 8.4 Hz, 1H, 3'-H),
3.63 (s, 3H, OCH3), 1.54, 1.50, 1.35, 1.32 (4s, 12H, 2C(CH3)2); 13C NMR
ˆ
(50 MHz, CDCl3): d ˆ 155.7 (o, C(OMe)SPh), 132.8 (‡, CH), 132.2 ± 127.2
(o and ‡, Ph), 109.7, 109.3 (o, 2C(CH3)2), 97.0 (‡, C-6'), 74.3 (‡, C-2'), 71.4
(‡, C-3'), 70.7 (‡, C-5'), 67.7 (‡, C-4'), 26.4, 26.3, 25.5, 24.7 (‡, 2C(CH3)2);
C20H26O6S: calcd C 60.89, H 6.64; found C 60.55, H 6.73.
2-Hydroxy-pentanoic acid methyl ester (21): Ketene O,S-acetal 17 (208 mg,
1.0 mmol) was used to prepare the title compound 21[39] (9 mg, 0.07 mmol,
7%) by the general procedure described above. Purification was achieved
by column chromatography (petroleum ether/ethyl acetate 4:1). The
enantiomeric excess was determined by chiral GC: isothermal 1078C,
17.21 min (2S), 13.62 min (2R); AD-mix a: ee(S) ˆ 62.3%; AD-mix b:
ee(R) ˆ 72.8%; oil; 1H NMR (200 MHz, CDCl3, TMS): d ˆ 5.15 (dt, J ˆ 4.8,
1.6 Hz, 1H, 2-H), 3.61 (s, 3H, OCH3), 2.71 (br, 1H, OH), 2.31 (dt, J ˆ 2.4,
7.6 Hz, 2H, 3-H), 1.56 (sep, J ˆ 7.4 Hz, 2H, 4-H), 0.96 (t, J ˆ 7.2 Hz, 3H,
5-H).
(E/Z)-(2'S,3'R,4'R,5'R,6'R)-Benzenesulfoxyl-2-[2'(3',4',5',6'-di-O-isopro-
pylidene)tetrahydropyranyl]-1-methoxy ethene (72): A suspension of 71
(300 mg, 0.76 mmol) and molecular sieves (3 Š, 50 mg) in dry methanol
(8 mL) at RT was treated with NaIO4 (195 mg, 0.91 mmol). Stirring was
continued for 12 h at RT, while excluding light. Another batch of NaIO4
(86 mg, 0.4 mmol) was added and stirring was continued. After 4 d the
reaction mixture was filtered and washed with water. The aqueous phase
was extracted with dichloromethane (5 times). The combined organic
extracts were dried (MgSO4) and concentrated under reduced pressure.
Purification was achieved by flash column chromatography (petroleum
ether/ethyl acetate 11:1) and yielded the title compound 72 (223 mg,
0.70 mmol; 91%) as a colorless oil, which was directly used for the next
step, the asymmetric dihydroxylation.
2-Hydroxy-2-phenyl-propionic acid methyl ester (22): Ketene O,S-acetal 18
(256 mg, 1.0 mmol) was used to prepare the title compound 22[40] (32 mg,
0.18 mmol, 18%) by the general procedure described above. Purification
was achieved by column chromatography (petroleum ether/ethyl acetate
13:1). The enantiomeric excess was determined by chiral GC: isothermal
1008C, 24.27 min (2S), 25.20 min (2R); AD-mix a: ee(S) ˆ 12.1%; AD-mix
b: ee(R) ˆ 11.0%; oil; 1H NMR (400 MHz, CDCl3, TMS): d ˆ 7.50 ± 7.45,
7.32 ± 7.15 (m, 5H, Ph), 3.71 (s, 3H, OCH3), 3.67 (br, 1H, OH), 1.72 (s, 3H,
CH3); 13C NMR (50 MHz, CDCl3): d ˆ 176.1 (o, CO), 142.7 (o, Ph), 128.3 ±
125.1 (‡, Ph), 75.7 (o, COH), 53.3 (‡, OCH3), 26.6 (‡, CH3).
Dimethoxymethyldiphenylphosphine oxide (31) and diethoxymethyldi-
phenylphosphine oxide (32): p-Chlorodiphenylphosphine (1 equiv) was
added dropwise (caution: exothermic) to freshly distilled trialkylortho-
formiate (1 equiv) under nitrogen at RT. The reaction mixture solidified
and was heated for 2 h at 1108C, by which alkyl chloride was removed.
After cooling to RT, the yellow solid was recrystallized (petroleum ether/
toluene 100:1) to afford the title compounds.
(E,Z)-2-Benzenesulfoxyl-2-methoxystyrene (24): Ketene O,S-acetal 15
(484 mg, 2.0 mmol) was suspended in H2O/MeOH (1:1). THF was added
until a clear, colorless solution resulted. After addition of NaIO4 (512 mg,
2.4 mmol) stirring was continued at RT for 12 h. Another batch of NaIO4
(512 mg, 2.4 mmol) was added. After 24 h the reaction mixture was filtered
and washed with dichloromethane (5 times). The combined organic
extracts were dried (MgSO4) and concentrated under reduced pressure.
Purification was achieved by flash column chromatography (petroleum
ether/ethyl acetate 5:1)and yielded the title compound 24 (428 mg,
1.66 mmol; 82%) as a colorless oil. 1H NMR (200 MHz, CDCl3, 258C,
ˆ
TMS): d ˆ 7.80 ± 7.21 (m, 10H, Ph), 6.41, 6.30 (s, 1H, CH, E/Z-isomers),
3.78, 3.70 (s, 3H, OCH3, E/Z isomers); C15H14O2S: calcd C 69.74, H 5.46;
found C 69.54, H 5.68.
Compound 31:[23] (scale: 50 mmol; yield: 11.45 g, 41.5 mmol; 83%);
colorless crystals; m.p. 868C; 1H NMR (200 MHz, CDCl3, 258C, TMS):
(E,Z)-2-Benzenesulfonyl-2-methoxystyrene (25): mCPBA (36 mg,
0.21 mmol) was added to a solution of ketene O,S-acetal 24 (50 mg,
0.19 mmol) in dry CH2Cl2 at RT. After 48 h the reaction mixture was
filtered, washed with an aqueous NaHCO3 solution, dried (MgSO4), and
concentrated under reduced pressure. The analytical data of 25 were in
accordance with the literature.[37] The title compound was sufficiently pure
for further use in the dihydroxylation step.
d ˆ 8.0 ± 7.80 (m, 4H, Ph), 7.60 ± 7.30 (m, 6H, Ph), 4.93 (d, JP ˆ 7.8 Hz, 1H,
H
CH(OMe)2), 3.57 (2s, 6H, 2OCH3); 13C NMR (50 MHz, CDCl3): d ˆ 131.1,
129.1 (o, Ph), 132.0 ± 128.2 (‡, Ph), 106.1 (‡, d, JP ˆ 117.1 Hz,
C
PCH(OMe)2), 58.4, 58.2 (‡, 2OCH3).
Compound 32:[41] (scale: 50 mmol; yield: 12.7 g, 45.4 mmol; 90.7%);
colorless crystals; m.p. 748C; 1H NMR (200 MHz, CDCl3, 258C, TMS):
d ˆ 8.03 ± 7.86 (m, 4H, Ph), 7.60 ± 7.38 (m, 6H, Ph), 5.07 (d, JP ˆ 7.6 Hz,
H
General procedure for the asymmetric dihydroxylation of ketene O,S-
acetals: Ketene O,S-acetal (1 equiv) was added to a suspension of AD-mix
[1 mol% (DHQ)2-PHAL for AD-mix a or (DHQD)2-PHAL for AD-mix
b] and methanesulfonamide (1.02 equiv) in water (5 mLmmol 1), tert-
butanol (4 mLmmol 1), and acetonitrile (1 mLmmol 1) at 108C. The
suspension was vigorously stirred for 6 h at 08C and reduced with sodium
1H, CH(OEt)2), 3.87, 3.71 (dq, J ˆ 9.5, 7.0 Hz, 4H, 2OCH2CH3), 1.23 (t, J ˆ
7 Hz, 6H, 2CH3); 13C NMR (50 MHz, CDCl3): d ˆ 131.4, 129.5 (o, Ph),
132.2 ± 128.1 (‡, Ph), 103.6 (‡, d, JP ˆ 118.6 Hz, PCH(OEt)2), 66.6, 66.4
C
(
, 2OCH2CH3), 15.1, 15.0 (‡, 2CH3).
General procedure for the asymmetric nucleophilic acylation via ketene
O,O-acetals: Dialkoxymethyl diphenylphosphine oxide (1.2 equiv) in
absolute THF (2 mLmmol 1) was added over a period of 30 min to a
solution of LDA or KDA (1.1 equiv) in dry THF (15 mLmmol 1) under
nitrogen at 1108C (KDA was prepared by addition of freshly sublimed
sulfite (1.5 gmmol 1). Stirring was continued for 30 min at 08C, and after
1
additional 15 min at RT water (5 mLmmol
(20 mLmmol
) and dichloromethane
1
) were added. The aqueous layer was extracted with
dichloromethane (5 times) and the combined organic extracts were washed
2276
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2276 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 8

Asymmetric Synthesis
2270±2280
KOtBu in THF to an equal amount of LDA at 1108C). During the
addition, the temperature must not raise above 1108C. After 1 h at that
temperature freshly purified aldehyde (1 equiv for aromatic aldehydes 7,
26 ± 28, and 11; 0.3 mmol for aliphatic aldehydes 29, 30, 60, 62, 64, and 67) in
dry THF (2 mLmmol 1) was added to the dark red solution. The reaction
mixture, which decolorized immediately, was hydrolyzed after 15 min with
water (4 mLmmol 1) and was allowed to warm to RT. After addition of
brine (10 mLmmol 1) and dichloromethane (10 mLmmol 1), the layers
were separated. The aqueous phase was treated with dichloromethane
(5 times), and the combined organic extracts were dried (MgSO4) and
concentrated in vacuo. In most cases the crude product was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate 1:1).
Alternatively, the crude product was used directly for the next reaction. In
this case, traces of water were removed by co-distillation with toluene prior
to use.
7.16 ± 6.90 (m, 3H, Ph), 5.77 (d, J ˆ 6.8 Hz, 1H, OH), 5.22 (d, J ˆ 6.8 Hz,
1H, CHOH), 3.86 ± 3.40 (m, 4H, 2OCH2CH3), 1.25, 1.14 (t, J ˆ 7.0 Hz, 6H,
2CH3).
Elimination and asymmetric dihydroxylation of 35 (1 mmol) according to
the standard protocol afforded the title compound 44 (156 mg, 0.68 mmol,
68%) after column chromatography (petroleum ether/ethyl acetate 15:1).
The enantiomeric excess was determined by preparing the Mosher esters of
both diastereomers[42] followed by 1H NMR analysis: AD-mix a: ee(S)
ˆ
92.7%; AD-mix b: ee(R) ˆ 94.7; amorphous solid; m.p. 858C (lit. 878C[43]);
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.93 ± 7.72 (m, 4H, naph),
7.56 ± 7.38 (m, 3H, naph), 5.31 (d, J ˆ 5.6 Hz, 1H, CHOH), 4.19, 4.11 (dq,
J ˆ 7.2, 10.6 Hz, 2H, OCH2CH3), 3.77 (d, J ˆ 5.6 Hz, 1H, OH), 1.18 (t, J ˆ
7.2 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 175.7 (o, C O), 132.1 ±
ˆ
122.3 (‡, naph), 75.8 (‡, CHOH), 62.7
OCH2CH3).
(
,
OCH2CH3), 14.3 (‡,
The adduct was dissolved in absolute THF (15 mLmmol 1) under nitrogen
and was treated with freshly sublimed potassium tert-butoxide (1.1 equiv)
in THF (2 mLmmol 1) at 08C. After 15 min the solution was concentrated
in an ice bath under reduced pressure to a volume of approximately 1 mL.
A suspension of AD-mix [1 mol% (DHQ)2-PHAL for AD-mix a or
(DHQD)2-PHAL for AD-mix b] in water (5 mLmmol 1) and tert-butanol
(5 mLmmol 1) was prepared at RT, cooled to 08C and added to the
precooled ketene acetal. After addition of methanesulfonamide
(1.02 equiv) the suspension was vigorously stirred overnight at 08C and
reduced with sodium sulfite (1.5 gmmol 1). Stirring was continued for
30 min at 08C, and after additional 15 min at RT water (5 mLmmol 1) and
dichloromethane (20 mLmmol 1) were added. The aqueous layer was
extracted with dichloromethane (5 times), and the combined organic
extracts were dried (MgSO4), concentrated under reduced pressure, and
purified by column chromatography on silica gel.
1,1-Dimethoxy-2-hydroxy-2-(4-isopropylphenyl)ethyldiphenylphosphine
oxide (36), 1-hydroxy-1-(4-isopropylphenyl)methyldiphenylphosphine ox-
ide (52), and 2-hydroxy-2-(4-isopropylphenyl)acetic acid methyl ester (45):
Aldehyde 27 (444 mg, 3.0 mmol) was used to prepare the title compounds
36 (983 mg, 2.32 mmol, 78%) and 52 (123 mg, 0.4 mmol, 13%) by the
general procedure described above.
1st fraction 36: colorless crystals; m.p. 1358C; 1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.81 ± 7.55 (m, 4H, Ph), 7.54 ± 7.17 (m, 8H, Ph), 6.90 ± 6.80
(m, 2H, Ph), 5.60 (br, 1H, OH), 5.06 (d, JP ˆ 14.3 Hz, 1H, CHOH), 3.45,
H
3.27 (2s, 6H, 2OCH3), 2.72 (sep, J ˆ 7.0 Hz, 1H, CH(CH3)2), 1.13 (d, J ˆ
7.0 Hz, 6H, 2CH3); 13C NMR (50 MHz, CDCl3): d ˆ 147.8 ± 130.1 (o, Ph),
132.8 ± 125.2 (‡, Ph), 103.5 (o, d, JP ˆ 109.8 Hz, C(OMe)2), 75.9 (‡, d,
C
JP ˆ 11.6 Hz, CHOH), 52.6, 50.4 (‡, d, JP ˆ 3.9 and 8.8 Hz,
C
C
PC(OCH3)2), 33.6 (‡, C(CH3)2), 23.9 (‡, C(CH3)2).
2nd fraction 52: colorless crystals; m.p. 1628C; 1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.84 ± 7.24 (m, 11H, Ph), 7.10 ± 6.98 (m, 3H, Ph), 5.44 (d,
1,1-Dimethoxy-2-hydroxy-2-phenyl-ethyl-1-(diphenylphosphine oxide) (33)
and mandelic acid methyl ester (19): Aldehyde 7 (318 mg, 3.0 mmol) was
used to prepare the title compound 33 (1.04 g, 2.73 mmol, 91%) by the
general procedure described above. Colorless crystals; m.p. 1428C;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.87 ± 7.61 (m, 4H, Ph),
7.56 ± 7.20 (m, 8H, Ph), 7.09 ± 6.99 (m, 3H, Ph), 5.59 (d, J ˆ 7.3 Hz, 1H, OH),
JP ˆ 5.3 Hz, 1H, PCHOH), 4.29 (br, 1H, OH), 2.83 (sep, J ˆ 6.8 Hz, 1H,
H
CH(CH3)2), 1.19 (d, J ˆ 6.8 Hz, 6H, 2CH3); 13C NMR (50 MHz, CDCl3):
d ˆ 148.8 ± 127.5 (o, Ph), 132.9 ± 126.5 (‡, Ph), 73.8 (‡, d, JP ˆ 81.2 Hz,
C
PCHOH), 33.8 (‡, C(CH3)2), 23.9, 23.6 (‡, C(CH3)2); C22H23O2P: calcd C
75.41, H 6.62; found C 75.36, H 6.71.
5.06 (dd, J ˆ 7.3, JP ˆ 13.3 Hz, 1H, CHOH), 3.37 and 3.28 (2s, 6H,
H
2OCH3); 13C NMR (50 MHz, CDCl3): d ˆ 138.5 ± 130.2 (o, Ph), 132.7 ±
Elimination and asymmetric dihydroxylation of 36 (1 mmol) according to
the standard protocol afforded the title compound 45[44] (193 mg,
0.93 mmol, 93%) after column chromatography (petroleum ether/ethyl
acetate 8:1). The enantiomeric excess was determined by chiral GC:
127.2 (‡, Ph), 103.4 (o, d, JP ˆ 109.5 Hz, C(OMe)2), 76.1 (‡, d, JP
ˆ
C
C
12.2 Hz, CHOH), 52.9, 50.5 (‡, d, JP ˆ 3.9 and 8.3 Hz, PC(OCH3)2).
C
Elimination and asymmetric dihydroxylation of 33 (1 mmol) according to
the standard protocol afforded the title compound 19 (149 mg, 0.9 mmol,
90%) after column chromatography (petroleum ether/ethyl acetate 8:1).
The enantiomeric excess was determined by chiral GC: isothermal 1088C,
30.78 min (2S), 28.93 min (2R); AD-mix a: ee(S) ˆ 93.0%, [a]2D3:5 ˆ ‡1508
isothermal 1308C, 41.13 min (2S), 38.89 min (2R); AD-mix a: ee(S)
ˆ
91.0%, [a]2D1 ˆ ‡124.38 (c ˆ 1.0, CHCl3); AD-mix b: ee(R) ˆ 96.0%,
[a]2D1
ˆ
127.28 (c ˆ 1.0, CHCl3); 1H NMR (200 MHz, CDCl3, 258C,
TMS): d ˆ 7.37 ± 7.17 (m, 4H, Ph), 5.14 (d, J ˆ 5.8 Hz, 1H, CHOH), 3.74
(s, 3H, OCH3), 3.49 (d, J ˆ 5.8 Hz, 1H, OH), 2.30 (sep, J ˆ 6.9 Hz, 1H,
CH(CH3)2), 1.24 (d, J ˆ 6.9 Hz, 6H, 2CH3); 13C NMR (50 MHz, CDCl3):
(c ˆ 0.42, CHCl3); AD-mix b: ee(R) ˆ 96.0%, [a]D23:5
ˆ
1688 (c ˆ 0.5,
CHCl3). The spectroscopic data were in accordance with those listed above.
ˆ
d ˆ 174.2 (o, C O), 149.2, 135.6 (o, Ph), 126.7, 126.5 (‡, Ph), 72.7 (‡,
1,1-Diethoxy-2-hydroxy-2-phenyl-ethyldiphenylphosphine oxide (34) and
mandelic acid ethyl ester (43): Aldehyde 7 (318 mg, 3.0 mmol) was used to
prepare the title compound 34 (1.11 g, 2.67 mmol, 89%) by the general
procedure described above. Colorless crystals; m.p. 1398C; 1H NMR
(200 MHz, CDCl3, 258C, TMS): d ˆ 7.89 ± 7.19 (m, 4H, Ph), 7.58 ± 7.19 (m,
8H, Ph), 7.12 ± 6.99 (m, 3H, Ph), 5.54 (d, J ˆ 6.8 Hz, 1H, OH), 5.04 (dd, J ˆ
CHOH), 52.8 (‡, OCH3), 33.8 (‡, CH(CH3)2), 23.8 (‡, CH(CH3)2);
C12H16O3: calcd C 69.21, H 7.74; found C 69.26, H 7.88.
1,1-Diethoxy-2-hydroxy-2-(4-isopropylphenyl)ethyldiphenylphosphine ox-
ide (37) and 2-hydroxy-2-(4-isopropylphenyl) ethyl acetate (46): Aldehyde
27 (136 mg, 1.0 mmol) was used to prepare the title compound 37 (326 mg,
0.72 mmol, 72%) by the general procedure described above. Amorphous
solid; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.83 ± 7.62 (m, 4H, Ph),
7.50 ± 7.10 (m, 8H, Ph), 6.90 ± 6.80 (m, 3H, Ph), 6.90 ± 6.86 (m, 2H, Ph), 5.58
6.8, JP ˆ 12.3 Hz, 1H, CHOH), 3.86 ± 3.56 (m, 4H, 2OCH2CH3) 1.17, 1.14
H
(t, J ˆ 7.0 Hz, 6H, 2CH3); 13C NMR (50 MHz, CDCl3): d ˆ 138.8 ± 130.4
(o, Ph), 132.6 ± 127.1 (‡, Ph), 103.3 (o, d, JP ˆ 109.3 Hz, C(OEt)2), 76.4
C
(br, 1H, OH), 5.05 (d, JP ˆ 13.2 Hz, 1H, CHOH), 4.17 ± 3.41 (m, 4H,
H
(‡, d, JP ˆ 11.2 Hz, CHOH), 60.6, 58.4 ( , d, JP ˆ 4.4 and 7.3 Hz,
C
C
2OCH2CH3), 2.73 (sep, J ˆ 7.0 Hz, 1H, CH(CH3)2), 1.26, 1.13 (2t, J ˆ
7.0 Hz, 6H, 2CH3), 1.13 (d, J ˆ 7.0 Hz, 6H, 2CH3); 13C NMR (50 MHz,
PC(OCH2CH3)2), 15.2, 14.9 (‡, 2C(OCH2CH3)2).
Elimination and asymmetric dihydroxylation of 34 (1 mmol) according to
the standard protocol afforded the title compound 43 (157 mg, 0.87 mmol,
87%) after column chromatography (petroleum ether/ethyl acetate 8:1).
The enantiomeric excess was determined by chiral GC: isothermal 998C,
52.7 min (2S), 48.6 min (2R); AD-mix a: ee(S) ˆ 98.4%, [a]2D1 ˆ ‡118.68
CDCl3): d ˆ 138.5 ± 130.2 (o, Ph), 132.7 ± 127.2 (‡, Ph), 103.4 (o, d, JP
ˆ
C
109.5 Hz, C(OMe)2), 76.1 (‡, d, JP ˆ 12.2 Hz, CHOH), 52.9, 50.5 (‡, d,
C
JP ˆ 3.9, 8.3 Hz, PC(OCH3)2).
C
Elimination and asymmetric dihydroxylation of 37 (1.0 mmol) according to
the standard protocol afforded the title compound 46[45] (196 mg,
0.88 mmol, 88%) after column chromatography (petroleum ether/ethyl
acetate 20:1). The enantiomeric excess was determined by chiral GC:
(c ˆ 1.02, CHCl3); AD-mix b: ee(R) ˆ 99.9%, [a]D21
ˆ
121.48 (c ˆ 0.92,
CHCl3). The spectroscopic data were in accordance with those listed above.
1,1-Diethoxy-2-hydroxy-2-naphtylethyldiphenylphosphine oxide (35) and
2-hydroxy-2-naphtylacetic acid ethyl ester (44): Aldehyde 26 (468 mg,
3.0 mmol) was used to prepare the title compound 35 (1.089 g, 2.52 mmol,
84%) by the general procedure described above. Amorphous solid;
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.80 ± 7.28 (m, 14H, naph),
isothermal 1158C, 105.39 min (2S), 97.65 min (2R); AD-mix a: ee(S)
ˆ
67.7%; AD-mix b: ee(R) ˆ 80.3%; oil; 1H NMR (200 MHz, CDCl3, 258C,
TMS): d ˆ 7.35 ± 7.19 (2dt, J ˆ 8.4, 2.0 Hz, 4H, Ph), 5.12 (d, J ˆ 6.0 Hz, 1H,
CHOH), 4.28, 4.15 (dq, J ˆ 7.0, 10.7 Hz, 2H, OCH2CH3), 3.46 (d, J ˆ
6.0 Hz, 1H, OH), 2.90 (sep, J ˆ 7.0 Hz, 1H, CH(CH3)2), 1.24 (d, J ˆ
Chem. Eur. J. 1999, 5, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2277 $ 17.50+.50/0
2277

A. Kirschning et al.
FULL PAPER
7.0 Hz, 6H, CH(CH3)2), 1.23 (t, J ˆ 7.0 Hz, 3H, CH3); 13C NMR (50 MHz,
111.3 Hz, C(OMe)2), 74.0 (‡, d, JP ˆ 12.2 Hz, CHOH), 52.0, 51.5 (‡, d,
C
ˆ
CDCl3): d ˆ 173.8 (o, C O), 149.1, 135.5 (o, Ph), 126.7, 126.5 (‡, Ph), 72.7
JP ˆ 5.8, 7.3 Hz, PC(OCH3)2), 34.0, 32.4 ( , PhCH2CH2); C24H27O4P:
C
(‡, CHOH), 62.1
(
,
OCH2CH3), 33.8 (‡, CH(CH3)2), 23.9 (‡,
calcd C 70.23, H 6.63; found C 70.28, H 6.60.
CH(CH3)2), 14.0 (‡, CH3); C13H18O3: calcd C 70.24, H 8.16; found C
Elimination and asymmetric dihydroxylation of 40 (1.0 mmol) according to
the standard protocol afforded the title compound 49[48] (66 mg, 0.34 mmol,
34%) after column chromatography (petroleum ether/ethyl acetate 9:1).
The enantiomeric excess of 49 was determined by chiral GC: isothermal
1308C, 31.10 min (2S), [a]2D3 ˆ ‡10.88 (c ˆ 0.88, CHCl3); 27.94 min (2R),
69.96, H 8.34.
1,1-Diethoxy-2-hydroxy-2-(4-methoxyphenyl)ethyl-1-(diphenylphosphine
oxide) (38), 4-methoxy mandelic acid ethyl ester (47), and 2-(4-methoxy-
phenyl)-2-oxoacetic acid ethyl ester (57): Aldehyde 28 (136 mg, 1.0 mmol)
was used to prepare the title compound 38 (403 mg, 0.92 mmol, 92%) by
[a]2D3
ˆ
12.08 (c ˆ 0.5, CHCl3); AD-mix a: ee(S) ˆ 93.0%; AD-mix b:
ee(R) ˆ 94.0%; oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.35 ± 7.14
(m, 5H, Ph), 4.19 (dd, J ˆ 4.1, 7.8 Hz, CHOH), 3.75 (s, 1H, OCH3), 2.74 (m,
3H, CHOH, PhCH2), 2.13 (ddt, J ˆ 4.1, 8.3, 14.0 Hz, 1H, PhCH2H'CH),
1.98 (ddt, J ˆ 6.7, 7.8, 14.0 Hz, 1H, PhCH2H'CH); 13C NMR (50 MHz,
1
the general procedure described above. Oil; H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.88 ± 7.66 (m, 4H, Ph), 7.48 ± 7.34 (m, 6H, Ph), 7.30, 6.57
(2d, J ˆ 8.6 Hz, Ph), 5.40 (d, J ˆ 6.6 Hz, 1H, OH), 4.99 (dd, J ˆ 6.6, 12.4 Hz,
1H, CHOH), 3.70 (s, 3H, OCH3), 3.69 ± 3.44 (m, 4H, 2OCH2CH3), 1.19,
1.14 (2t, J ˆ 7.0 Hz, 6H, 2CH3).
Elimination and asymmetric dihydroxylation of 38 (0.92 mmol) according
to the standard protocol afforded the title compounds 47[46] (120 mg,
0.57 mmol, 57%) and 57 (47 mg, 0.226 mmol, 23%) after column
chromatography (petroleum ether/ethyl acetate 3:1). When the reaction
time was limited to 3 h, the yield for 47 was improved to 71%.
ˆ
CDCl3): d ˆ 175.6 (o, C O), 141.0 (o, Ph), 128.5 ± 126.0 (‡, Ph), 69.6 (‡,
CHOH), 52.5 (‡, CO2CH3), 35.8, 31.0 ( , PhCH2CH2).
1,1-Dimethoxy-2-hydroxyundecyl-1-(diphenylphosphine oxide) (41), 1-hy-
droxydecyl-1-(diphenylphosphine oxide) (53), and 2-hydroxyundecanoic
acid methyl ester (50): Aldehyde 30 (156 mg, 1.0 mmol) was used to
prepare the title compound 41 (352 mg, 0.81 mmol, 81%) and 53 (63 mg,
0.17 mmol, 17%) by the general procedure described above.
1st fraction 57: oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 8.01 and
6.98 (2d, 4H, J ˆ 8.8 Hz, Ph), 4.44 (q, J ˆ 7.2 Hz, 2H, OCH2CH3), 3.90 (s,
3H, OCH3), 1.42 (t, J ˆ 7.2 Hz, 3H, OCH2CH3); 13C NMR (50 MHz,
1
1st fraction 41: colorless crystals; m.p. 788C; H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 8.1 ± 7.85 (m, 4H, Ph), 7.60 ± 7.35 (m, 6H, Ph), 3.98 ± 3.73
(m, 2H, CHOH), 3.43, 3.32 (2s, 6H, 2OCH3), 1.61 ± 0.98 (m, 16H, (CH2)8),
0.95 ± 0.79 (m, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 133.8 ± 131.0 (o,
ˆ
CDCl3): d ˆ 184.8 (o, C O), 164.5 (o, CO2), 164.1 (o, C-para), 132.5, 114.2
(‡, Ph), 125.5 (o, C-ipso), 62.1 ( , OCH2,CH3), 55.6 (‡, OCH3), 14.1 (‡,
‡
Ph), 132.5 ± 128.1 (‡, Ph), 103.9 (o, d, JP ˆ 111.3 Hz, C(OMe)2), 74.9 (‡,
CH3); LRMS (DCI): m/z (%): 226.0 (100) [M‡NH4] .
C
d, JP ˆ 12.2 Hz, CHO), 52.0, 51.3 (‡, d, JP ˆ 5.4, 7.8 Hz, C(OCH3)2), 32.9
C
C
2nd fraction 47: The enantiomeric excess of 47 was determined by chiral
(
, d, JP ˆ 1.5 Hz, C-3), 31.8 ± 22.6 ( , C-4 ± C-10), 14.2 (‡, C-11);
C
GC: isothermal 1318C, 52.1 min (2S), 47.9 min (2R); AD-mix a: ee(S)
86.1%, [a] V238.8 nm ˆ 169018, V253.8 nm ˆ 7558 , V274.6 nm ˆ 21148, V287.6 nm
14568, V280.6 nm ˆ 17428 (c ˆ 0.580mm, MeOH, 268C); AD-mix b: ee(R)
ˆ
ˆ
ˆ
C25H37O4P: calcd C 69.42, H 8.62; found C 69.38, H 8.82.
2nd fraction 53: colorless crystals; m.p. 1008C; 1H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.95 ± 7.72 (m, 4H, Ph), 7.60 ± 7.37 (m, 6H, Ph), 4.39 (d, J ˆ
9.2 Hz, 1H, PCHOH), 3.62 (br, 1H, OH), 1.79 ± 1.15 (m, 16H, (CH2)8),
0.92 ± 0.80 (m, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 132.0 ± 128.3 (‡,
88.0%, [a] V206.8 nm
ˆ
64708, V216.0 nm
ˆ
2198, V232.0 nm
ˆ
261008,
18808
V255.0 nm 10308, V273.8 nm
ˆ
ˆ
24308, V277.8 nm
ˆ
17308, V280.6 nm
ˆ
(c ˆ 0.286mm, MeOH, 26.58C); oil; 1H NMR (200 MHz, CDCl3, 258C,
TMS): d ˆ 7.34, 6.90 (2 d, J ˆ 8.8 Hz, 4H, Ph), 5.11 (d, J ˆ 5.8 Hz, 1H,
CHOH), 4.28, 4.17 (dq, J ˆ 7.2, 10.6 Hz, 2H, OCH2CH3), 3.81 (s, 3H,
Ph), 130.2, 129.4 (o, Ph), 70.6 (‡, d, JP ˆ 83.6 Hz, PCHOH), 31.8 ± 22.6
C
(
, C-3 ± C-9), 30.5 ( , d, JP ˆ 2.9 Hz, C-2), 14.1 (‡, C-10); C22H31OP:
C
calcd C 73.72, H 8.72; found C 73.88, H 8.69.
OCH3), 3.39 (d, J ˆ 5.8 Hz, 1H, OH), 1.24 (t, J ˆ 7.2 Hz, 3H, OCH2CH3);
13
ˆ
C NMR (50 MHz, CDCl3): d ˆ 173.8 (o, C O), 159.6, 130.8 (o, Ph), 127.8,
Elimination and asymmetric dihydroxylation of 41 (433 mg, 1.0 mmol)
according to the standard protocol afforded the title compound 50[49]
(152 mg, 0.7 mmol, 70%) after column chromatography (petroleum
ether/ethyl acetate 10:1). The enantiomeric excess of 50 was determined
by chiral GC: isothermal 1088C, 29.36 min (2S), [a]2D3 ˆ ‡7.28 (c 1.0,
114.9 (‡, Ph), 72.4 (‡, CHOH), 62.1 ( , OCH2CH3), 55.2 (‡, OCH3), 14.0
(‡, CH3).
1,1-Diethoxy-2-hydroxy-4-phenyl-but-3-enyl-1-(diphenylphosphine oxide)
(39) and (E)-2-hydroxy-4-phenylbut-3-enoic acid ethyl ester (48): Alde-
hyde 11 (132 mg, 1.0 mmol) was used to prepare the title compound 39
(294 mg, 0.72 mmol, 72%) by the general procedure described above.
Amorphous solid; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.92 ± 7.26
(m, 9H, Ph), 7.22 ± 6.95 (m, 6H, Ph), 6.61 (dd, J ˆ 1.3, 15.6 Hz, 1H,
CHCl3); 27.88 min (2R); [a]D21
ˆ
10.28 (c 1.0, CHCl3); AD-mix a: ee(S)
ˆ
92.0%; AD-mix b: ee(R) ˆ 98.0%; oil; 1H NMR (200 MHz, CDCl3, 258C,
TMS): d ˆ 4.19 (ddd, J ˆ 4.2, 5.6, 6.8 Hz, 1H, CHOH), 3.79 (s, 3H, OCH3),
2.70 (d, J ˆ 5.6 Hz, 1H, OH), 1.84 ± 1.20 (m, 16H, (CH2)8), 0.93 ± 0.83 (m,
13
ˆ
3H, CH3); C NMR (50 MHz, CDCl3): d ˆ 175.9 (o, C O), 70.4 (‡,
ˆ
ˆ
CH Ph), 6.12 (dd, J ˆ 5.4, 15.6 Hz, 1H, CH CHPh), 5.30 (br, 1H, OH),
4.97 (ddd, J ˆ 1.2, 5.4, 5.6 Hz, 1H, CHOH), 3.90 ± 3.42 (m, 4H,
2OCH2CH3), 1.18, 1.12 (2t, J ˆ 7.0 Hz, 6H, 2CH3); C26H29O4P: calcd C
71.54, H 6.70; found C 71.66, H 6.74.
CHOH), 52.5 (‡, OCH3), 34.4 ± 22.7 ( , (CH2)8), 14.1 (‡, CH3). C12H24O3:
calcd C 66.63, H 11.18; found C 66.66, H 11. 36.
1,1-Diethoxy-2-hydroxy-(2-furyl)ethyl-1-(diphenylphosphine oxide) (55)
and furan-2-yloxoacetic acid ethyl ester (56): Aldehyde 54 (282 mg,
3.0 mmol) was used to prepare the title compound 55 (466 mg, 1.26 mmol,
42%) by the general procedure described above. Oil; 1H NMR (200 MHz,
CDCl3, 258C, TMS): d ˆ 7.88 ± 7.67 (m, 3H, Ph), 7.49 ± 7.16 (m, 7H, Ph), 7.03
(d, J ˆ 2.5 Hz, 1H, OCHCHCH), 6.14 (d, J ˆ 3.4 Hz, 1H, OCHCH), 5.92
(dd, J ˆ 2.5, 3.4 Hz, 1H, OCHCH), 5.18 (br, 1H, CHOH), 5.04 (d, J ˆ
11.0 Hz, 1H, CHOH), 4.16 ± 3.44 (m, 4H, 2OCH2CH3), 1.09, 1.04 (2t, J ˆ
7.0 Hz, 6H, 2CH3).
Elimination and asymmetric dihydroxylation of 39 (204 mg, 0.5 mmol)
according to the standard protocol afforded the title compound 48[47]
(71 mg, 0.37 mmol, 73%) after column chromatography (petroleum
ether/ethyl acetate 12:1). The enantiomeric excess of 48 was determined
by chiral GC: isothermal 1078C, 42.83 min (2S), 41.20 min (2R); AD-mix a:
1
ee(S) ˆ 95.7%; AD-mix b: ee(R) ˆ 93.5%; oil; H NMR (200 MHz, CDCl3,
258C, TMS): d ˆ 7.43 ± 7.25 (m, 5H, Ph), 6.82 (dd, J ˆ 1.2, 15.6 Hz, PhCH ˆ
ˆ
), 6.25 (dd, J ˆ 5.4, 15.6 Hz, 1H, PhCH CH), 4.83 (ddd, J ˆ 1.2, 5.4, 5.6 Hz,
1H, CHOH), 4.32, 4.27 (2dq, J ˆ 7.0, 10.6 Hz, 2H, OCH2CH3), 3.08 (d, J ˆ
Elimination and asymmetric dihydroxylation of 55 (400 mg, 1.0 mmol)
according to the standard protocol with AD-mix a afforded the title
compound 56[50] (42 mg, 0.25 mmol, 25%) after column chromatography
(petroleum ether/ethyl acetate 19:1 and trace of NEt3). Oil; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d ˆ 8.01, (d, J ˆ 7.5 Hz, 1H, OCH), 7.67 (d,
J ˆ 7.5 Hz, 1H, OCHCHCH), 7.52 (t, J ˆ 7.5 Hz, 1H, OCHCHCH), 4.45 (q,
J ˆ 7.0 Hz, 2H, OCH2CH3), 1.43 (t, J ˆ 7.0 Hz, 3H, OCH2CH3); 13C NMR
5.6 Hz, 1H, OH), 1.32 (t, J ˆ 7.0 Hz, 3H, OCH2CH3); 13C NMR (50 MHz,
ˆ
CDCl3): d ˆ 177.2 (o, C O), 152.7 (‡, C-4), 139.0 ± 128.2 (o and ‡, Ph),
122.4 (‡, C-3), 73.5 (‡, CHOH), 62.9 ( , OCH2,CH3), 15.8 (‡, CH3).
1,1-Dimethoxy-2-hydroxy-4-phenylbutyl-1-(diphenylphosphine oxide) (40)
and 2-hydroxy-4-phenylbutyric acid methyl ester (49): Aldehyde 29
(134 mg, 1.0 mmol) was used to prepare the title compound 40 (293 mg,
0.71 mmol, 71%) by the general procedure described above. Colorless
crystals, m.p. 1328C; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 8.1 ±
7.85 (m, 4H, Ph), 7.60 ± 7.35 (m, 6H, Ph), 7.30 ± 6.95 (m, 5H, Ph), 4.05 ± 3.84
(m, 2H, CHOH), 3.39, 3.29 (2s, 6H, 2OCH3), 2.84 (ddd, J ˆ 4.8, 9.4,
14.0 Hz, 1H, PhCH), 2.52 (ddd, J ˆ 7.7, 8.7, 14.0 Hz, 1H, PhCH'), 1.96 ± 1.56
(m, 2H, PhCH2CH2); 13C NMR (50 MHz, CDCl3): d ˆ 141.7 (o, Ph), 132.9,
ˆ
(50 MHz, CDCl3): d ˆ 184.1 (o, C O), 165.6 (o, CO2Et), 151,5 (‡, OCH),
142.1 (o, OCHCHCHC), 111.0 (‡, OCHCHCH), 108.9 (‡, OCHCH), 62.2
(
, OCH2CH3), 14.9 (‡, CH3).
(2RS,3R)-1,1-Dimethoxy-2-hydroxy-3-phenylbutyl-1-(diphenylphosphine
oxide) (66) and (2RS,3R)-2-Hydroxy-3-phenylbutyric acid methyl ester
(61a,b): Aldehyde 60 (402 mg, 3.0 mmol) was used to prepare the title
compound 66 (902 mg, 2.2 mmol, 73%) by the general procedure described
131.1 (o, d, JP ˆ 9.2, 11.7 Hz, Ph), 132.4 ± 125.5 (‡, Ph), 103.9 (o, d, JP
ˆ
C
C
2278
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2278 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 8

Asymmetric Synthesis
2270±2280
above. Compound 66 was obtained as 10:1 mixture of which the major
J ˆ 5.6 Hz, JP ˆ 12.4 Hz, 1H, 2-H), 4.25 (dd, J ˆ 1.8, 4.8 Hz 1H, 5'-H),
C
isomer was isolated after column chromatography in pure form. Colorless
3.41, 3.37 (2s, 6H, 2OCH3), 2.76 (br, 1H, COH), 1.06, 1.40, 1.31, 1.30, 1.06
1
crystals; m.p. 1278C; H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 8.18 ±
(4s, 2C(CH3)2); 13C NMR (50 MHz, CDCl3): d ˆ 134.5 (o, d, JP ˆ 19.9 Hz,
C
7.98 (m, 4H, Ph), 7.58 ± 7.38 (m, 6H, Ph), 7.16 ± 7.05 (m, 3H, Ph), 6.73 ± 6.67
(m, 2H, Ph), 4.10 (ddd, J ˆ 3.5, 5.1, 9.5 Hz, 1H, CHOH), 3.41, 3.37 (2s, 6H,
2OCH3), 3.45 ± 3.24 (m, 1H, PhCH), 3.28 (d, J ˆ 9.5 Hz, 1H, OH), 1.32 (d,
J ˆ 7.0 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 146.2 ± 132.3 (o, Ph),
Ph), 132.7 (o, d, JP ˆ 21.4 Hz, Ph), 132.1 ± 127.8 (‡, Ph), 108.8, 108.7 (o,
C
2C(CH3)2), 104.6 (o, d, JP ˆ 114.2 Hz, C(OCH3)2), 96.3 (‡, C-6'), 73.0,
C
71.1, 70.8 (‡, C-5', C-4', C-3'), 71.3 (‡, d, JP ˆ 12.2 Hz, C-2'), 64.9 (‡, d,
C
JP ˆ 2.9 Hz, CHOH), 52.7, 51.4 (‡, d, JP ˆ 6.8 Hz, 2OCH3), 26.0, 25.9,
C
C
132.5 ± 125.7 (‡, Ph), 104.1 (o, d, JP ˆ 111.3 Hz, C(OMe)2), 78.4 (‡, d,
25.0, 23.9 (‡, 2C(CH3)2).
C
JP ˆ 17.0 Hz, CHO), 52.5, 52.1 (‡, d, JP ˆ 5.3, 8.8 Hz, C(OCH3)2), 40.1
C
C
Elimination and asymmetric dihydroxylation of 68 (536 mg, 1.0 mmol) by
(‡, d, JP ˆ 1.5 Hz, C-3), 14.4 (‡, CH3).
C
applying the standard protocol described above except that a threefold
excess of the AD-mix
a reagent was employed afforded the title
Elimination and asymmetric dihydroxylation of 66 (410 mg, 1.0 mmol)
according to the standard protocol afforded the title compound 61a,b[51]
(151 mg, 0.78 mmol, 78%) after column chromatography (petroleum ether/
ethyl acetate 10:1). The diastereomeric excess of 61a,b* was determined by
chiral GC: isothermal 1228C, 27.42 min (2S, 3R); 20.59 min (2R, 3R); AD-
compounds (2S)-69a (257 mg, 0.81 mmol, 81%) and 70 (18.1 mg,
0.06 mmol, 6%) after column chromatography (petroleum ether/ethyl
acetate 10:1). The diastereomeric excess was determined by 1H NMR
spectroscopy of the crude product.
1
1st fraction 70: Oil; 1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 5.49 (d,
J ˆ 5.0 Hz, 1H, 6'-H), 4.63 (dd, J ˆ 2.3, 7.8 Hz, 1H, 4'-H), 4.31 (dd, J ˆ 2.3,
5.0 Hz, 1H, 5'-H), 4.34 ± 4.19 (m, 2H, 2'-H, 3'-H), 3.71 (s, 3H, OCH3), 2.71
(dd, J ˆ 7.4, 16.2 Hz, 1H, CHCO2CH3), 2.61 (dd, J ˆ 5.8, 16.2 Hz, 1H,
mix a: de(2S) ˆ 91.0%; AD-mix b: de(2R) ˆ 77.8%; oil; H NMR (200 MHz,
CDCl3, TMS): d ˆ 7.35 ± 7.16 (m, 5H, Ph), 4.37 (m, 1H, CHOH), 3.76, 3.69*
(s, 3H, CO2CH3), 3.33 ± 3.17 (m, 1H, PhCH), 2.76, 2.57* (d, J ˆ 6.2, 7.0* Hz,
OH), 1.29, 1.15* (d, J ˆ 6.8, 6.8* Hz, 3H, PhCHCH3); 13C NMR (50 MHz,
ˆ
CDCl3): d ˆ 174.6, 174.2* (o, C O), 142.5, 140.5* (o, Ph), 128.5 ± 126.8 (‡,
CH'CO2CH3), 1.59, 1.46 (2s, 6H, C(CH3)2), 1.34 (s, 6H, 2C(CH3)2);
13
Ph), 75.0, 74.9 (‡, CHOH), 52.5, 52.2* (‡, CO2CH3), 43.4*, 43.3 (‡,
PhCH), 17.5*, 14.4 (‡, PhCHCH3); C11H14O3: calcd C 68.02, H 7.27; found
C 66.68, H 7.16.
ˆ
C NMR (50 MHz, CDCl3): d ˆ 171.5 (o, C O), 109.3, 108.8 (o, 2C(CH3)2),
96.3 (‡, C-6'), 72.3, 70.8, 70.4, 64.7 (‡, C-5', C-4', C-3', C-2'), 51.8 (‡,
OCH3), 35.4 ( , CH2CO2CH3), 25.9, 25.8, 25.0, 24.4 (‡, 2C(CH3)2);
C14H22O7: calcd C 55.62, H 7.33; found C 55.64, H 7.55.
(2S,3R,4S)-5-tert-Butyldiphenylsiloxy-2-hydroxy-4-methyl-5-tetrahydro-
pyranyloxypentanoic acid methyl ester (63): Aldehyde 62 (two isomers 3:1;
440 mg, 1.0 mmol) and lithiated diphenylphosphine oxide 31 (3.0 mmol)
were used to prepare the corresponding intermediate phosphine oxide
(350 mg, 0.49 mmol, 49%), which was directly converted into the title
compound 63 (two isomers 3:1*; 160 mg, 0.32 mmol, 65%) by applying the
general procedure described above, with AD-mix a. Oil; 1H NMR
(200 MHz, CDCl3, 258C, TMS): d ˆ 7.78± 7.61 (m, 4H, Ph), 7.50 ± 7.31 (m,
6H, Ph), 4.66 (dd, J ˆ 2.8, 3.8 Hz, 1H, OCHO (THP, tetrahydropuran)),
4.58 (dd, J ˆ 2.2, 4.2 Hz, 1H, CHOH), 5.53* [dd, 1H, OCHO (THP)), 4.12*
(dd, J ˆ 2.6, 4.6 Hz, 1H, CHOH), 4.01 ± 3.50 (m, 5H, CHOTHP, SiOCH2,
CH2O (THP)), 3.81 (s, 3H, OCH3), 3.78* (s, 3H, OCH3), 2.79* (dq, 1H,
CHCH3), 2.55 (dq, J ˆ 2.0, 7.0 Hz, 1H, CHCH3), 1.89 ± 1.25 (m, 6H, THP),
1.07 (s, 9H, tBu), 0.78 (d, J ˆ 7.0 Hz, 3H, CHCH3); 13C NMR (50 MHz,
2nd fraction: 69a: Oil; [a]D24
ˆ
45.38 (c ˆ 1, CHCl3); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d ˆ 5.57 (d, J ˆ 5.0 Hz, 1H, 6'-H), 4.64 (dd, J ˆ 2.4,
8.0 Hz, 1H, 4'-H), 4.56 (dd, J ˆ 2.3, 3.2 Hz, 1H, CHOH), 4.48 (dd, J ˆ 1.8,
8.0 Hz, 1H, 3'-H), 4.33 (dd, J ˆ 2.4, 5.0 Hz, 1H, 5'-H), 4.19 (dd, J ˆ 1.8,
3.2 Hz, 1H, 2'-H), 3.82 (s, 3H, OCH3), 3.73 (d, J ˆ 2.3 Hz, 1H, OH), 1.54,
1.49, 1.46, 1.33 (4s, 12H, 2C(CH3)2); 13C NMR (50 MHz, CDCl3): d ˆ 171.3
ˆ
(o, C O), 110.0, 109.0 (o, 2C(CH3)2), 96.4 (‡, C-6'), 72.9, 72.0, 71.0, 70.6,
67.2 (‡, C-5', C-4', C-3', C-2', CHOH), 52.6 (‡, OCH3), 25.9, 25.7, 25.0, 24.0
(‡, 2C(CH3)2).
Accordingly, a threefold excess of AD-mix b afforded (2R)-69b (248 mg,
0.78 mmol, 78%) starting from aldehyde 67 (536 mg, 1.0 mmol). Colorless
1
crystals, m.p. 1528C; [a]D23
ˆ
65.48 (c ˆ 0.5, CHCl3); H NMR (200 MHz,
CDCl3, 258C, TMS): d ˆ 5.56 (d, J ˆ 5.0 Hz, 1H, 6'-H), 4.64 (dd, J ˆ 2.5,
8.0 Hz, 1H, 4'-H), 4.43 (dd, J ˆ 1.8, 7.0 Hz, 1H, 3'-H), 4.43 (dd, J ˆ 7.2,
9.0 Hz, 1H, CHOH), 4.34 (dd, J ˆ 2.5, 5.0 Hz, 1H, 5'-H), 3.96 (dd, J ˆ 1.7,
7.2 Hz, 1H, 2'-H), 3.82 (s, 3H, OCH3), 3.24 (d, J ˆ 9.0 Hz, 1H, OH), 1.53,
1.49, 1.36, 1.33 (4s, 12H, 2C(CH3)2); 13C NMR (50 MHz, CDCl3): d ˆ 173.3
ˆ
CDCl3): d ˆ 175.3 (o, C O), 133.5, 133.4 (o, Ph), 135.8 ± 127.5 (‡, Ph), 100.8
(‡, OCO (THP)), 81.2, 71.1 (‡, C-2, C-3), 64.6, 62.5 ( , C-5, CH2O
(THP)), 52.4 (‡, OCH3), 37.6, (‡, C-4), 30.8, 25.3, 19.6 ( , 3CH2 (THP)),
26.8 (‡, tBu), 19.3 (o, tBu), 10.3 (‡, CH3); C28H40O6Si: calcd C 67.17, H
8.05; found C 67.15, H 8.24.
ˆ
(o, C O), 109.8, 108.9 (o, 2C(CH3)2), 96.4 (‡, C-6'), 71.1, 71.1, 71.0, 71.0,
(2R,4R)-4-(tert-Butyldiphenylsiloxy)-2-hydroxypentanoic acid ethyl ester
(65): Aldehyde 64 (259 mg, 0.726 mmol) and lithiated diphenylphosphine
oxide 32 (3.0 mmol) were used to prepare the corresponding intermediate
phosphine oxide (oil: 293 mg, 0.46 mmol, 64%; 2:3 diastereomeric ratio),
of which 155 mg, 0.246 mmol were directly converted into the title
compound 65 (92 mg, 0.23 mmol, 94%) by applying the general procedure
with AD-mix b. Purification was achieved by after column chromatography
(petroleum ether/ethyl acetate 1:1). The diastereomeric excess of 65 was
determined by NMR spectroscopy. Oil; [a]2D4 ˆ ‡4.18 (c ˆ 1.0, CHCl3);
1H NMR (200 MHz, CDCl3, 258C, TMS): d ˆ 7.74 ± 7.69 (m, 4H, Ph), 7.46 ±
7.36 (m, 6H, Ph), 4.36 ± 4.14 (m, 4H, OCH2CH3, 2-H, 4-H), 2.99 (br, 1H,
OH), 1.97 (ddd, 1H, J ˆ 4.0, 6.4, 13.8 Hz, 1H, 3-H), 1.85 (ddd, J ˆ 5.6, 8.8,
13.8 Hz, 1H, 3-H'), 1.29 (t, J ˆ 7.2 Hz, 3H, OCH2CH3), 1.14 (d, J ˆ 6.0 Hz,
1H, 5-H), 1.08 (s, 9H, tBu); 13C NMR (50 MHz, CDCl3): d ˆ 175.0 (o,
67.7 (‡, C-5', C-4', C-3', C-2', CHOH), 52.6 (‡, OCH3), 26.0, 25.8, 24.9, 24.2
(‡, 2C(CH3)2); C14H22O8: calcd C 52.82, H 6.97; found C 52.80, H 7.16.
Asymmetric dihydroxylation of O,S-ketene acetal 71 (118 mg, 0.3 mmol)
with the AD-mix a afforded the title compounds 69a,b (9 mg, 0.028 mmol,
9%) as a 2:1 diastereomeric mixture. In analogy, sulfoxide 72 (315 mg,
0.77 mmol) gave 69a,b (76 mg, 0.24 mmol, 31%) as a 1:1 mixture after use
of the AD-mix b under the standard conditions. In both cases, the analytical
data were in accordance with those described above.
Acknowledgments
ˆ
C O), 134.4, 134.2 (o, Ph), 135.8 ± 127.5 (‡, Ph), 68.7, 67.9 (‡, C-2, C-4),
This work[33] was generously supported by a scholarship from the Fonds der
Chemischen Industrie for G. D. We are indepted to Kai-Uwe Schöning for
providing a sample of aldehyde 62.
61.1 ( , OCH2CH3), 43.5 ( , C-3), 26.9 (‡, tBu), 23.0 (‡, C-5), 19.2 (o,
tBu), 14.1 (‡, OCH2CH3); C23H32O4Si: calcd C 68.96, H 8.05; found C
68.81, H 7.89.
(2S,2'S,3'R,4'R,5'R,6'R)-1,1-Dimethoxy-2-hydroxy-2-[2'(3',4',5',6'-di-O-iso-
propylidene)tetrahydropyranyl]ethyl-1-(diphenylphosphine oxide) (68),
(2RS,2'S,3'R,4'R,5'R,6'R)-2-hydroxy-2-[2'(3',4',5',6'-di-O-isopropylidene)-
[1] A. Dondoni, L. Colombo, in Advances in the Use of Synthons in
OrganicChemistry Vol. 1 (Ed.: A. Dondoni), JAI, London, 1993,
pp. 1 ± 49; D. J. Ager, in Umpoled Synthons (Ed.: T. A. Hase), Wiley
Interscience, New York, 1987, pp. 19 ± 72.
[2] Selected examples of sulfur-stabilized d1 synthons: E. J. Corey, D.
Seebach, Angew. Chem. 1965, 77, 1134 ± 1135; Angew. Chem. Int. Ed.
Engl. 1965, 4, 1075 ± 1976; G. Guanti, L. Banfi, A. Guaragna, E.
Narisano, J. Chem. Soc. Chem. Commun. 1986, 138 ± 140; K. Ogura, T.
Tsuruda, K. Takahashi, H. Iida, Tetrahedron Lett. 1986, 27, 3665 ± 3668.
tetrahydropyranyl]acetic
acid
methyl
ester
(69a,b),
and
(2'S,3'R,4'R,5'R,6'R)-2-[2'(3',4',5',6'-di-O-isopropylidene)tetrahydropyra-
nyl]acetic acid methyl ester (70): Aldehyde 67 (310 mg, 1.2 mmol) was used
to prepare the title compound 68 (359 mg, 0.67 mmol, 56%) by the general
procedure described above. Colorless solid, m.p. 708C; 1H NMR
(200 MHz, CDCl3, 258C, TMS): d ˆ 8.17 ± 8.03 (m, 4H, Ph), 7.5 ± 7.32 (m,
6H, Ph), 5.54 (d, J ˆ 4.8 Hz, 1H, 6'-H), 4.61 (brd, J ˆ 5.6 Hz, 1H, 2'-H), 4.56
(dd, J ˆ 1.8, 6.0 Hz, 1H, 4'-H), 4.51 (dd, J ˆ 1.0, 6.0 Hz, 1H, 3'-H), 4.47 (dd,
Chem. Eur. J. 1999, 5, No. 8
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2279 $ 17.50+.50/0
2279

A. Kirschning et al.
FULL PAPER
[3] L. Colombo, M. Di Giacomo, G. Brusotti, E. Milano, Tetrahedron Lett.
1995, 36, 2863 ± 2866; D. J. Ager, M. B. East, J. Org. Chem. 1986, 51,
3983 ± 3992; J.-P. Quintard, P. Elissondo, D. Mouko-Mpegna, J.
Organomet. Chem. 1983, 251, 175 ± 187; J.-P. Quintard, P. Elissondo,
B. Jousseaume, Synthesis 1984, 495 ± 498.
29, 2437 ± 2440; R. Gamboni, C. Tamm, Helv. Chim. Acta 1986, 69,
615 ± 620; W. Oppolzer, P. Dudfield, Helv. Chim. Acta 1985, 68, 216 ±
219.
[26] H. Becker, K. B. Sharpless, Angew. Chem. 1996, 108, 447 ± 449;
Angew. Chem. Int. Ed. Engl. 1996, 35, 448 ± 451.
[4] P. Magnus, G. Roy, Organometalics 1982, 1, 553 ± 559; J. Yoshida, S.
Matsunaga, S. Isoe, Tetrahedron Lett. 1989, 30, 219 ± 222; D. J. Ager,
J. E. Gano, S. I. Parekh, J. Chem. Soc. Chem. Commun. 1989, 1256 ±
1258.
[27] It should be noted that the ketene O,S-acetal prepared from furfural
54 and carbanion 14 (64%) can be oxidized with AD-mix b to the
corresponding (2R)-2-furyl-2-hydroxy acetic acid methyl ester 57 (4%
isolated yield; 63.1% ee).
[5] T. Mandai, M. Yamaguchi, Y. Nakayama, J. Otera, M. Kawada,
Tetrahedron Lett. 1985, 26, 2675 ± 2678; A. de Groot, B. J. Hansen,
Synth. Commun. 1983, 13, 985 ± 990; J. Otera, Synthesis 1988, 95 ± 102;
F. Chemla, M. Julia, D. F. Uguen, D. Zhang, Syn. Lett. 1991, 501 ± 502.
[6] A. R. Katritzky, Y.-X. Cheng, K. Yannakopoulou, P. Lue, Tetrahedron
Lett. 1989, 30, 6657 ± 6660; A. Katritzky, M. Drewniak-Deyrup, X.
Lan, F. Brunner, Heterocycl. Chem. 1989, 26, 829 ± 836.
[28] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. 1985,
97, 1 ± 31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1 ± 30.
[29] For selected examples refer to: R. B. Herbert, in The Biosynthesis of
Secondary Metabolites, Chapman and Hall, London, New York, 1989.
[30] F. M. Unger, Adv. Carbohydr. Chem. Biochem. 1981, 38, 323 ± 388.
[31] M. Kane-Ko, O. Kanie, T. Kajimoto, C.-H. Wong, Biorg. Med. Chem.
Lett, 1997, 7, 2809 ± 2812.
[7] E. J. Corey, D. L. Boger, Tetrahedron Lett. 1978, 19, 5 ± 8; H.
Chikashita, M. Ishibaba, K. Ori, K. Itoh, Bull. Chem. Soc. Jpn. 1988,
61, 3637 ± 3648.
[32] For selected examples for homologating carbohydrate-derived hexo-
ses like 67 refer to: A. Dondoni, A. Marra, in Preparative Carbohy-
drate Chemistry, (Ed.: S. Hanessian), Dekker, 1997, pp. 173 ± 205; F. L.
van Delft, G. A. van der Marel, J. H. van Boom, Synlett 1995, 1069 ±
1070; P. Smid, F. J. M. Schipper, H. J. G. Broxterman, G. J. P. H.
Boons, G. A. van der Marel, J. H. van Boom, Recl. Trav. Chim. Pays-
Bas 1993, 112, 451 ± 456; N. K. Khare, R. K. Sood, G. O. Aspinall,
[8] A. Dondoni, Pure Appl. Chem. 1990, 62, 643 ± 652.
[9] A. G. M. Barrett, D. J. Rys, J. Chem. Soc. Perkin Trans. I, 1995, 1009 ±
1017; L. Colombo, M. Di Giacomo, G. Brusotti, E. Milano, Tetrahe-
dron Lett. 1995, 36, 2863 ± 2866; G. Delogu, O. De Lucchi, P. Maglioli,
G. Valle, J. Org. Chem. 1991, 56, 4467 ± 4473; T. S. Abram, R. Baker,
C. M. Exon, V. B. Rao, R. W. Turner, J. Chem. Soc. Perkin Trans. I
1982, 301 ± 306.
[10] A. Dondoni, in Modern Synthetic Methods (Ed.: R. Scheffold)
Helvetica Chimica Acta, Basel, 1992, pp. 377 ± 437, and references
therein.
Â
Can. J. Chem. 1994, 72, 237 ± 246; R. Fernandez, C. Gasch, A. Gomez-
Sanchez, J. E. Vilchez, A. Lopez Castro, M. J. Dianez, M. D. Estrada,
S. Perez-Garrido, Carbohydr. Res. 1993, 247, 239 ± 248; A. Dondoni, G.
Fantin, M. Fogagnolo, A. Medici, P. Pedrini, J. Org. Chem. 1989, 54,
693 ± 702 and 702 ± 706; A. Dondoni, G. Fantin, M. Fogagnolo, A.
Medici, Tetrahedron 1987, 43, 3533 ± 3539.
[11] V. K. Aggarwal, I. W. Davies, J. Maddock, M. F. Mahon, K. C. Molloy,
Tetrahedron Lett. 1990, 31, 135 ± 138; V. K. Aggarwal, R. J. Franklin,
H. J. Rice, Tetrahedron Lett. 1991, 32, 7743 ± 7746.
[12] J. E. Lynch, E. L. Eliel, J. Am. Chem. Soc. 1984, 106, 2943 ± 2948.
[13] D. Enders, H. Lotter, Angew. Chem. 1981, 93, 831 ± 832; Angew. Chem.
Int. Ed. Engl. 1981, 20, 795 ± 796; D. Enders, P. Gerdes, H. Kipphardt,
Angew. Chem. 1990, 102, 226 ± 228; Angew. Chem. Int. Ed. Engl. 1990,
29, 179 ± 181; D. Enders, J. Kirchhoff, D. Mannes, G. Raabe, Synthesis
[33] A. Jung, Diplomarbeit, TU Clausthal 1996; H. Monenschein, Diplo-
marbeit, TU Clausthal, 1998.
[34] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 ± 7287.
[35] C. Palomo, J. M. Aizpurua, J. M. Garcia, I. Ganboa, F. P. Cossio, B.
Â
Leccea, C. Lopez, J. Org. Chem. 1990, 55, 2498 ± 2503.
[36] A. de Groot, B. J. M. Jansen, Synth. Commun. 1983, 13, 985 ± 990.
[37] G. G. Cox, D. J. Miller, C. J. Moody, E.-R. H. B. Sie, J. J. Kulagowski,
Tetrahedron 1994, 50, 3195 ± 3212.
Â
1995, 659 ± 666; D. Enders, R. Syrig, G. Raabe, R. Fernandez, C.
[38] A. Ohno, T. Yasuma, K. Nakamura, S. Oka, Bull. Chem. Soc. Jpn.
1986, 59, 2905 ± 2906; H. Yu, H. Simon, Tetrahedron 1991, 47, 9035 ±
9052; H. Stach, W. Huggenberg, M. Hesse, Helv. Chim. Acta 1987, 70,
369 ± 374.
[39] H. C. Brown, G. G. Pai, J. Org. Chem. 1985, 50, 1384 ± 1394; F.
Effenberger, U. Stelzer, Chem. Ber. 1993, 126, 779 ± 786.
[40] X.-C. He, E. L. Eliel, Tetrahedron 1987, 43, 4979 ± 4988; A. E. Mash,
J. A. Fryling, J. Org. Chem. 1991, 56, 1094 ± 1098.
[41] W. Dietsche, Liebigs Ann. Chem. 1968, 712, 21 ± 27.
[42] J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34, 2543 ±
2549; J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1986, 90, 3732 ±
2738; J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1972, 95, 512 ± 519.
[43] R. Schweitzer, Chem. Ber. 1891, 24, 546 ± 549.
[44] W. F. Barthel, S. I. Gertler, J. Org. Chem. 1958, 23, 135 ± 136.
[45] J. W. Epstein, H. J. Brabander, W. J. Fanshawe, C. M. Hofmann, T. C.
McKenzie, S. R. Safir, A. C. Osterberg, D. B. Cosulich, F. M. Lovell, J.
Med. Chem. 1981, 24, 481 ± 490.
Gasch, J.-M. Lassaletta, J.-M. Llera, Synthesis 1996, 48 ± 52.
[14] E. J. Corey, G. B. Jones, Tetrahedron Lett. 1991, 32, 5713 ± 5716; E. J.
Corey, C. M. Yu, D. H. Lee, J. Am. Chem. Soc. 1990, 112, 878 ± 879.
[15] A. Kirschning, G. Dräger, A. Jung, Angew. Chem. 1997, 109, 253 ± 255;
Angew. Chem. Int. Ed. Engl. 1997, 36, 253 ± 255.
[16] Reviews on the asymmetric dihydroxylation: D. J. Berrisford, C.
Bolm, K. B. Sharpless, Angew. Chem. 1995, 107, 1159 ± 1171; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1050 ± 1064; H. C. Kolb, M. S.
VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483 ± 2547;
R. A. Johnson, K. B. Sharpless, in Catalytic Asymmetric Synthesis
(Ed.: I. Ojima), VCH, New York, 1993, pp. 227 ± 272.
[17] E. J. Corey P. H. Fuchs, Tetrahedron Lett. 1972, 3769 ± 3772.
[18] B. K. Sharpless, personal communication.
[19] M. Mikolajczk, S. Grzejszczak, A. Zatorski, M. Mlotkowska, H. Gross,
B. Costisella, Tetrahedron, 1978, 34, 3081 ± 3088.
[20] S. Hackett, T. Livinghouse, J. Org. Chem. 1986, 51, 879 ± 885;.
[21] P.-O. Norrby, H. Becker, K. B. Sharpless, J. Am. Chem. Soc. 1996, 118,
35 ± 42; K. Morikawa, J. Park, P. G. Andersson, T. Hashiyama, K. B.
Sharpless, J. Am. Chem. Soc. 1993, 115, 8463 ± 8464.
[22] Reviews on the Horner± Wittig reaction: J. Clayden, S. Warren,
Angew. Chem. 1996, 108, 261 ± 291; Angew. Chem. Int. Ed. Engl. 1996,
35, 241 ± 270; B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863 ±
927.
[46] G. Quelet, Bull. Soc. Chim. Fr. 1950, 1075 ± 1077; W. F. Barthel, J.
Leon, S. A. Hall, J. Org. Chem. 1954, 19, 485 ± 486.
[47] L. H. P. Meijer, U. K. Pandit, Tetrahedron 1985, 41, 467 ± 472; P.
Bulugahapitiya, Y. Landais, L. Parra-Rapado, D. Planchenault, V.
Weber, J. Org. Chem. 1997, 62, 1630.
[48] R. V. Hoffman, J. Tao, J. Org. Chem. 1997, 62, 2292 ± 2297; T. Sugai, H.
Ohta, Agric. Biol. Chem. 1991, 55, 293 ± 294.
[23] T. A. M. van Schaik, A. V. Henzen, A. van der Gen, Tetrahedron Lett.
1983, 24, 1303 ± 1306.
[24] An example of an AD of a lacton-derived ketene acetal was disclosed
by D. P. Curran, S.-B. Ko, H. Josien, Angew. Chem. 1995, 107, 2948 ±
2950; Angew. Chem. Int. Ed. Engl. 1995, 34, 2683 ± 2684.
[25] For alternative strategies of the asymmetric a-hydroxylation or a-
acetoxylation of carboxylates and enolates see: Y. Wei, R. Baktha-
vatchalam, X.-M. Jin, C. K. Murphy, F. A. Davis, Tetrahedron Lett.
1993, 34, 3715 ± 3718; D. Enders, V. Bushan, Tetrahedron Lett. 1988,
[49] T. Satoh, K.-i. Onda, K. Yamakawa, J. Org. Chem. 1991, 56, 4129 ±
4134; T. Satoh, K.-i. Onda, K. Yamaka, Tetrahedron Lett. 1990, 31,
3567 ± 3570.
[50] M. Tanaka, T.-a. Kobayashi, T. Sakukura, Angew. Chem. 1984, 96,
519 ± 520. Angew. Chem. Int. Ed. Engl. 1984, 23, 518 ± 519.
[51] H. Akita, A. Furnichi, H. Koshiyi, K. Horikoshi, T. Oishi, Chem.
Pharm. Bull. 1984, 32, 1342 ± 1348.
Received: December 14, 1998 [F1493]
2280
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0508-2280 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 8