Direct asymmetric organocatalytic de novo synthesis of carbohydrates

Article abstract of DOI:10.1016/j.tet.2005.09.060

A biomimetic organocatalytic asymmetric synthesis of carbohydrates can be accomplished by a proline catalyzed aldol reaction with the dihydroxyacetone equivalent 2,2-dimethyl-1,3-dioxan-5-one and various aldehydes. The biomimetic C₃+C_n

Full text of DOI:10.1016/j.tet.2005.09.060

Tetrahedron 62 (2006) 329–337
Direct asymmetric organocatalytic de novo synthesis
of carbohydrates
Christoph Grondal and Dieter Enders
*
Institut f u¨ r Organische Chemie, Rheinisch-Westf a¨ lische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany
Received 10 May 2005; revised 10 August 2005; accepted 9 September 2005
Available online 3 October 2005
Abstract—A biomimetic organocatalytic asymmetric synthesis of carbohydrates can be accomplished by a proline catalyzed aldol reaction
with the dihydroxyacetone equivalent 2,2-dimethyl-1,3-dioxan-5-one and various aldehydes. The biomimetic C CC strategy directly
3 n
generates selectively protected carbohydrates in one step, which can be easily deprotected. Additionally, the stereoselective reduction of the
keto functions allows a direct entry to different aldopentoses.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
great value in synthetic organic chemistry, for instance as
1
4
15
chiral auxiliaries or enantiopure building blocks. In the
view of this background the de novo synthesis of
carbohydrates is of great importance. So far, a broad
spectrum of different approaches has been described, but
several steps and protecting group manipulations are
1
Triggered by the exciting reports of List et al. and
2
MacMillan et al. in the year 2000, asymmetric organo-
catalysis emerged as a rapidly growing and important field
in organic chemistry. In particular, reactions catalyzed by
3
1
6
the amino acid proline, easily available as both enantiomers,
showed a broad applicability. The proline-catalyzed aldol
necessary. This has led to new ideas for more simple
and direct entries. One alternative new route was introduced
by MacMillan et al. who disclosed a ‘two-step’ synthesis of
aldohexoses. This strategy consists of an initial proline-
catalyzed aldol reaction between a-oxygenated aldehydes,
followed by a Mukaiyama—aldol reaction to generate the
4
reaction attracted great attention, because of the importance
of this carbon–carbon bond formation in organic
chemistry. This new powerful organocatalytic method-
5
ology allows the direct cross-coupling between ketones and
aldehydes
1
b,6
7
as well as between different aldehydes with
1
7
carbohydrate. Later on, Cordova et al. were able to carry
out MacMillans concept employing solely proline
remarkable diastereo- and enantioselectivities in most cases.
Not surprisingly, the development of the basic method-
ology, as well as the first applications in organic synthesis,
1
8
catalysis. Another approach can be borrowed from mother
nature. Nature employs dihydroxyacetone phosphate
8
for example, natural product synthesis , dynamic kinetic
(DHAP) in carbohydrate biosynthesis. The carbohydrate
skeleton is assembled by an enzyme-catalyzed aldol
19
reaction between DHAP and glyceraldehyde.
9
10
resolution or desymmetrization have been reported
recently. In addition, the proline-catalyzed aldol reaction
has very recently paved the way for the direct assembly of
1
1
carbohydrates.
Hence, the application of DHAP in carbohydrate synthesis has
been investigated quite intensively employing biological
Carbohydrates are of enormous importance in the chemical,
20
methods in particular. Furthermore, dihydroxyacetone and
1
2
biological and medicinal sciences. For example, they play
key roles in many biological processes as part of
glycoproteins, nucleic acids, glycolipids, peptide- and
its derivatives could be employed as C building blocks in
3
21
asymmetric synthesis using chemical methods. The appli-
cation of organocatalytic methods were first reported by
Barbas et al. They described a direct aldol reaction of
dihydroxyacetone with various aldehydes, catalyzed by pro-
line or derivatives of the latter, but generally with moderate
1
3
proteoglycans or liposaccharides. Thus, they are import-
ant targets for the development of new drugs. Besides their
biological and medicinal importance, carbohydrates are of
2
2
diastereoselectivities and low enantioselectivities.
Keywords: Aldol reaction; Carbohydrates; Organocatalysis; Asymmetric
synthesis; Stereoselective reduction.
Based on our previous studies using 2,2-dimethyl-1,3-
dioxan-5-one (1, ‘dioxanone’) as a cyclic dihydroxy-
*
Corresponding author. Tel.: C49 241 8094676; fax: C49 241 8092127;
e-mail: enders@rwth-aachen.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.060

330
C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
Besides (S)-proline, we also applied catalysts 5–12 to our
model system. As it is shown in Table 1, especially catalyst
is also appropriate in terms of yield, diastereo- and
9
enantioselectivity under these conditions (Table 1 and
Fig. 1).
Our aim, however, was to elaborate a catalytic protocol,
based on (S)-proline as the catalyst, because of its
Scheme 1. (S)-Proline catalyzed aldol reaction of 1 with 2a.
Table 1. Optimization of the aldol reaction between 1 and 2a
a
b
c
Entry
Cat (mol%)
Temperature
Solvent
Time (h)
Yield (%)
anti/syn (%)
ee (%)
1
2
3
4
5
6
7
8
9
4 [30]
4 [20]
4 [10]
4 [20]
4 [30]
4 [20]
4 [30]
4 [30]
5 [20]
6 [30]
7 [30]
8 [30]
9 [20]
10 [20]
11 [20]
12 [20]
rt
2 8C
rt
2 8C
rt
rt
2 8C
rt
rt
rt
rt
DMSO
DMSO
DMSO/DMF
DMSO/DMF
DMSO/DMF
DMF
65
115
96
115
65
48
120
48
92
48
48
336
72
91
60
65
60
85
47
97
44
35
—
—
Traces
87
58
Traces
44
O98:2
O98:2
O98:2
O98:2
O98:2
O98:2
O98:2
O98:2
O98:2
—
—
nd
O98:2
O98:2
nd
92
93
93
91
88
90
94
90
73
—
—
nd
97
89
nd
72
d
d
d
DMF
CHCl
3
d
d
DMSO/DMF
DMSO
DMSO
DMSO/DMF
DMF
DMF
DMF
DMF
10
11
12
13
14
15
16
rt
2 8C
2 8C
2 8C
2 8C
72
72
72
nd
a
b
c
d
2
Yield of isolated 2a after column chromatography (SiO , diethyl ether, pentane).
1 13
Determined by H and C NMR spectroscopy.
Determined by HPLC using a chiral stationary phase (Chiralpak AD, n-heptane/iso-propanol 95:5, major isomer 14.9 min, minor isomer 12.2 min).
DMSO and DMF were used in a 1:1 ratio (v:v).
acetone equivalent in asymmetric synthesis, we planned to
develop a direct asymmetric organocatalytic synthesis of
carbohydrates and derivatives by a proline-catalyzed aldol
reaction between 1 and various aldehydes. In our preceeding
communication we first described this biomimetic C C
3
C -strategy, which allows the direct assembly of selectively
n
commercial availability as both enantiomers. Therefore,
we applied 4 in our further studies and investigated the
application of various aldehydes. In general, a broad scope
of aldehydes can be employed in the (S)-proline-catalyzed
aldol reaction with 1. We could show that the a-branched
aldehydes 2a, 2b, 2i, 2k–o are particularly appropiate, in
terms of yield, anti/syn-ratio and enantioselectivity. Only in
the case of aldehyde 2i a moderate ee of 68% was obtained
using (S)-proline. But by employing the TBS-protected
hydroxyproline catalyst 9, the ee could be increased to 84%.
The application of linear aldehydes like 2j led to a drastic
decrease of the yield (40%), but still excellent stereo-
selectivities (anti/synO98:2, eeZ97%) were maintained.
2
3
protected carbohydrates in one-step. Herein, we present in
detail the development of this methodology.
2
. Results and discussion
The aim of our project was to develop a practical catalytic
protocol for a proline catalyzed aldol reaction of dioxanone
1
with a broad variety of aldehydes 2 to obtain the
corresponding aldol products 3 with good to excellent
stereoselectivities and yields. Our initial investigations were
concerned with the proline-catalyzed aldol reaction of 1
with 2-methylpropanal (2a) as a model system. We chose
this system in order to optimize the reaction conditions in
terms of the yield, the diastereo- and enantioselectivity
(
Scheme 1).
For the optimization process we investigated four reaction
parameters: solvent, temperature, catalyst loading and
catalyst system. As it is shown in Table 1 we found out
that when using (S)-proline (30 mol%) as the catalyst and
DMF as solvent at 2 8C are the best conditions. The desired
anti-aldol product 3a was obtained in excellent yield (97%),
anti/syn ratio of O98:2 and a high enantiomeric excess of
Figure 1. Different catalysts used in the aldol reaction of 1 with 2a to the
corresponding aldol product 3.
9
4%.

C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
Table 2. (S)-Proline catalyzed aldol reaction of 1 with different aldehydes 2
to afford the aldol products 3
331
a
c
d
3
R
Yield
b
anti/syn (%)
ee (%)
(
%)
a
b
c
d
e
f
CH(CH
3
)
2
97
86
—
—
—
57
73
61
O98:2
O98:2
—
—
—
1.5:1
4:1
4:1
94
90
—
—
—
76 (49)
86 (75)
25 (5)
6 11
c-C H
C(CH )
3 3
CH]CHCH
H
Scheme 2. (S)-Proline catalyzed aldol reaction of 1 with various aldehydes
3
2.
C
oCl–C
6
H
5
g
h
6
H
4
with 1 in the presence of (R)-proline (Table 2, entry l)
Scheme 2).
(
e
As we already emphasized in our preceding communication,
the resulting aldol products 3i–o illustrate selectively and in
some cases doubly protected sugars and aminosugars, for
example, 5-deoxy-L-ribulose (3i), L-ribulose (3j), D-erythro-
pentos-4-ulose (3k), D-psicose (3l), 5-amino-5-deoxy-L-
psicose (3m, 3o), 5-amino-5-deoxy-L-tagatose (3n) (Fig. 2).
i
88
(
O98:2 (O98:2)
68
(84)
e
e
93)
j
CH
2
OBn
CH(OCH )
40
69
76
O98:2
94:6
O98:2
97
90
R98
k
3 2
f
l
g
For example the deprotection of 3l could be easily carried
out under acidic condition using an ion exchange resin
h
m
80
31
80
O98:2
O98:2
O98:2
R96
(Dowex W50X2-200) to quantitatively afford D-psicose 13
as a mixture of the four isomers a,b-D-psicofuranose and
a,b-D-psicopyranose (Scheme 3).
2
4
f
n
h
R96
The clearly preferred formation of the anti-aldol products
and the stated absolute configurations are consistent with the
Houk-List model for the proline-catalyzed aldol reaction.
The absolute configuration could be corroborated through
polarimetric comparison with independently synthezised
i
o
R96
2
5
aldol products (Fig. 3).
a
General reaction conditions: 2.3 mmol dioxanone, 2.3 mmol aldehyde,
0 mol% (S)-proline, 1.2 mL DMF, 2 8C, 3–6 days.
Yields of isolated 3 after flash-chromatography on silica gel.
Determined by H and C NMR spectroscopy.
Determined by HPLC on chiral stationary phases (Chiralpak AD,
Chiralpak IA 5m, Daicel IA, Daicel OJ, Whelk 01).
Catalyst 9 was used.
3
b
c
d
1
13
e
f
(
R)-proline was used as the catalyst.
g
h
i
Based on the ee value of 2l.
Based on the ee value of 2m.
Based on the ee value of 2n.
The moderate yield can be explained by a competing self-
aldolization of aldehyde 2j. Less good results were obtained
with the aromatic aldehydes 2f–h, because in all cases the
anti/syn-ratio decreased and in certain cases the ee value
also deteriorated drastically. The attempt to use sterically
demanding aldehydes like 2c or allylic aldehydes like
crotonaldehyde (2d) failed as well as the use of an aqueous
formaldehyde solution (2e).
Subsequently, we investigated the application of enantio-
merically pure, a-substituted aldehydes in the proline-
catalyzed aldol reaction with 1. We could demonstrate that
in the case of (S)-configured a-substituted aldehydes (S)-
proline is the appropriate catalyst for the aldol reaction,
whereas in the case of using (R)-proline a mismatched case
exists. (see Table 2, entry m, n and o). Indeed, the yield
decreases in the (R)-proline catalyzed aldol reaction of 1
with 2m to 31%, however, the selectivities remained at the
same level. This could be confirmed by using 2,3-O-
(
isopropylidene)-D-glyceraldehyde (2l) in the aldol reaction
Figure 2. Selectively protected sugars and aminosugars.

332
C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
As already reported in our previous publication, the
reduction of the ketone function of 3k leads to a direct
entry to selectively protected aldopentoses. This strategy
was first described by Whitesides et al. and is known as the
2
6
inversion strategy. It was our aim to show the reduction of
k and to control the relative configuration of the newly
3
generated stereogenic center. For the stereoselective
reduction of b-hydroxy ketones many powerful methods
are already described, many of them for acyclic
2
7
derivatives.
Scheme 3. Deprotection of 3l to D-psicose (13).
In the beginning of our investigations we were concerned
with the direct reduction of 3k to afford the diol 15. In order
to achieve a selective anti-reduction we chose the Evans
protocol using tetramethylammonium triacetoxyboro-
2
8
hydride, which is in general successful for acyclic cases.
We were able to apply this method to our system. To our
surprise, however, we observed a syn-selective reduction
with high diastereocontrol (O98:2). This could be
corroborated by formation of the cyclic carbonate 16 with
carbonyl diimidazole in the presence of triethylamine and
subsequent NOE-measurements (Scheme 5). The syn-
selectivity may be explained by an intramolecular hydride
transfer where the dioxanone unit exists predominantly in a
twisted boat conformation and the side-chain is located in a
pseudo-equatorial position. The hydride attacks the
carbonyl function selectively from the Si-face to generate
the syn-1,3-diol (Fig. 4).
Figure 3. Postulated transition state model.
We could also demonstrate that under proline catalysis a
self-aldolization of 1 is possible. The corresponding aldol
product 14 (57%, 94% ee) was obtained with high
enantioselectivity and represents a protected form of (S)-
dendroketose (Scheme 4).
The anti 1,3-diol of 3k could be obtained, however, after the
conversion of the alcohol function into the corresponding
TBS-ether 17. The formation of the TBS-ether was
accomplished with TBSOTf and lutidine in dichloro-
3
0
methane at K78 8C to afford 17 in 98% yield. Compound
7 was reduced with L-selectride to afford selectively the
1
anti 1,3-diol 18 (O98:2). The relative configurations of 18
are proven by NOE-measurements. The reduced aldol
products 15 and 18 represents the protected aldopentoses
D-ribose (15) and L-lyxose (18).
Scheme 4. (S)-Proline-catalyzed asymmetric self-aldolization of dioxanone
1
to the protected (S)-dendroketose 14.
Besides reduction, further transformations of the keto
function of 3k, for example, reductive amination,
Scheme 5. Stereoselective syn- and anti-reduction of 3k to 15 and 18.

C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
333
using acidic ammonium molybdate. Optical rotation values
were measured on a Perkin-Elmer P241 polarimeter.
Microanalyses were obtained with a Vario EL element
analyzer. Mass spectra were acquired on a Finnigan
SSQ7000 (EI 70 eV) spectrometer. High-resolution mass
spectra were recorded on a Finnigan MAT95 spectrometer.
1
IR spectra were taken on a Perkin-Elmer FT-IR 1760. H
1
3
and C spectra were recorded on Varian Mercury 300,
Inova 400 or Unity 500 spectrometers with tetramethyl-
Figure 4. Proposed transition-state for the syn-selective reduction of 3k to
5 using tetramethylammonium triacetoxyborohydride.
1
Scheme 6. Manipulation of the keto function of 3k.
nucleophilic 1,2-addtion, deoxygenation or olefination/
reduction and thionation will greatly expand the scope of
this method to prepare variety of diverse carbohydrates
silane as internal standard and at ambient temperature
unless otherwise stated. Analytical HPLC was performed on
Hewlett-Packard 1100 Series chromatographs. All racemic
samples were obtained according to GP 1 using equal
amounts of (S)- and (R)-proline.
(
Scheme 6).
In summary, our asymmetric, organocatalytic aldol reaction
of the dihydroxyacetone equivalent 1 with various
aldehydes represents a direct approach to simple and
selectively protected carbohydrates in practically one-step.
3
1
32
33
34
35
36
37
Compounds 2i , 2l , 2o , 9 , 10 , 11 , 12 were
synthesized by standard procedures.
Furthermore, this biomimetic C CC strategy generates the
3
n
3.2. General procedure for the (S)-proline catalyzed
aldol reaction (GP 1)
same absolute and relative configuration as the enzyme
2
9
tagatose-aldolase (tagA). Whereas the tagA-catalyzed
aldol reaction proceeds non-selective, our methodology
offers an impressively simple alternative. In addition, we
were able to show the stereoselective reduction of the aldol
product 3k to afford highly selectively both the syn- and the
anti-1,3-diols, which opens a direct entry to differently
protected D- and L-aldopentoses.
To a suspension of (S)-proline (0.1–0.3 equiv) in DMF
(0.5 mL/mmol) was added dioxanone 1 (1.0 equiv) and
stirred for 30 min at ambient temperature. After cooling
down to 2 8C the aldehyde 2 (1.0 equiv) was added and the
suspension was stored at 2 8C. After 48–120 h, the resulting
mixture was quenched with satd ammonium chloride
solution and the aqueous layer was extracted three times
with ethyl acetate. The combined organic layers were
3
. Experimental
washed with brine, dried over Na SO , filtered and
2 4
concentrated under reduced pressure. The crude product
was purified by flash column chromatography (SiO2,
3
.1. General
pentane/diethyl ether).
Starting materials and reagents were purchased from
commercial suppliers and used without further purification.
THF was freshly distilled from sodium-lead alloy under Ar.
Dichloromethane and acetonitril were freshly distilled from
CaH under Ar. Acetic acid was destilled from CrO under
Compounds 3a, 3b, 3f and 3j were obtained according to GP
2
5
and they are already fully characterised. 3l and 13 are
1
already described in our preceding communication.
2
3a
2
3
0
Ar. Preparative column chromatography: Merck silica gel
0, particle size 0.040–0.063 mm (230–240 mesh, flash).
3.2.1. Compound 3f . According to GP 1 benzaldehyde 2f
(245 mg, 2.31 mmol)) was reacted with dioxanone 1
(300 mg, 2.31 mmol) in the presence of (S)-proline
(80 mg, 0.69 mmol) to give a diastereomeric mixture of 3f
6
Analytical TLC: silica gel 60 F254 plates from Merck,
Darmstadt. Visualization of the developed chromatograms
was performed by ultraviolet irradiation (254 nm) or stained
0
and 3f , which can be easily separated on silica gel, to afford

334
C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
0
The ee of the product was measured by HPLC using a chiral
stationary phase (Chiralcel OD, n-heptane/iso-propanol
3
f (180 mg, 34%) and 3f (125 mg, 23%) as colourless oils.
product was measured by HPLC using a chiral stationary
phase (Daicel AD, n-heptane/iso-propanol 92:8) relative to
the racemic sample: major isomer 18.8 min, minor isomer
9
2
3
1
5:5) relative to the racemic sample: major isomer
4.7 min, minor isomer 26.3 min. IR (CHCl ) 3411, 3080,
21.1 min. IR (CHCl ) 3201, 2992, 2934, 2890, 1745, 1597,
3
1480, 1440, 1377, 1331, 1224, 1154, 1077, 1036, 1003,
771 cm . H NMR (300 MHz, CDCl ) d 1.36 (s, CH , 3H),
3
K1 1
031, 2989, 2899, 2257, 1748, 1600, 1490, 1460, 1375,
220, 1110, 923 cm . H NMR (400 MHz, CDCl ) d 1.36
3
3
K1 1
1.41 (s, CH , 3H), 4.02 (d, JZ17.0 Hz, CH , 1H), 4.30 (dd,
3
3
2
(
s, CH , 3H), 1.48 (s, CH , 3H), 4.03 (d, JZ17.0 Hz, CH ,
JZ17.0, 1.3 Hz, CH , 1H), 4.74 (dd, JZ4.7, 1.3 Hz, CH,
3
3
2
2
1
H), 4.28 (dd, JZ17.0, 1.4 Hz, CH , 1H), 4.45 (dd, JZ2.7,
.4 Hz, CH, 1H) 5.23 (d, JZ2.7 Hz, CH, 1H), 7.27–7.47 (m,
1H), 5.17 (d, JZ4.7 Hz, CH, 1H), 7.23 (dd, JZ7.4, 5.0 Hz,
CH, 1H), 7.38 (d, JZ7.7 Hz, CH, 1H), 7.72 (dt, JZ7.7,
1.6 Hz, CH, 1H), 8.55 (m, CH, 1H), no OH signal observed.
2
1
Ar, 4H), 8.08–8.12 (m, Ar, 1H)), no OH signal observed.
1
3
13
C NMR (100 MHz, CDCl ) d 23.2, 24.2, 67.1, 71.2, 80.0,
3
C NMR (75 MHz, CDCl ) d 23.2, 24.2, 67.0, 72.5, 77.3,
3
1
m/z (%) 165 (29) [M KC H O], 130 (10), 107 (100), 91
00.9, 126.3, 127.6, 127.8, 140.0, 207.3. MS (EI, 70 eV):
100.9, 121.8, 122.9, 136.8, 148.0, 157.5, 209.5. MS (EI,
70 eV): m/z (%) 238 (18) [M CH], 222 (3) [M KCH ]
C
C
C
4
9
3
C
C
179 (25) [M KC H O], 149 (33), 138 (22), 108 (100), 72
(
for C H O (236.27): C, 66.08; H, 6.83. Found: C, 65.85;
6), 79 (30), 77 (39) [C H ], 72 (37), 59 (87). Anal. Calcd
6
5
3 6
(19), 59 (13). Anal. Calcd for C H NO (237.10): C,
12 15 4
1
3
16
4
H, 6.91.
60.75; H, 6.37; N, 5.90. Found: C, 60.40; H, 6.14; N, 5.60.
0
3
.2.2. Compound 3g. According to GP 1 ortho-chloro-
3.2.5. Compound 3h . The ee of the product was measured
benzaldehyde 2g (325 mg, 2.31 mmol) was reacted with
dioxanone 1 (300 mg, 2.31 mmol) in the presence of (S)-
proline (53 mg, 0.46 mmol) to give a diastereomeric
by HPLC using a chiral stationary phase (Daicel AD,
n-heptane/iso-propanol 9:1) relative to the racemic sample:
major isomer 15.9 min, minor isomer 12.1 min. Mp 104–
106 8C. IR (KBr) 3195, 2991, 1743, 1597, 1480, 1439, 1377,
0
mixture of 3g and 3g (73%, 4:1), which can be easily
separated on silica gel, to afford 3g (355 mg, 57%) and 3g
0
89 mg, 14%) as colourless oils. The ee of the product was
K1 1
1330, 1225, 1153, 1079, 1033, 1003, 768 cm . H NMR
(300 MHz, CDCl ) d 1.30 (s, CH , 3H), 1.40 (s, CH , 3H),
(
3
3
3
measured by HPLC using a chiral stationary phase (Whelk
O1, n-heptane/iso-propanol 9:1) relative to the racemic
sample: major isomer 14.2 min, minor isomer 10.6 min.
4.06 (d, JZ16.6 Hz, CH , 1H), 4.31 (dd, JZ16.6, 1.4 Hz,
2
CH , 1H), 4.83 (dd, JZ2.5, 1.4 Hz, CH, 1H), 4.33 (d, JZ
2
2.5 Hz, CH, 1H), 7.26 (m, CH, 2H), 7.75 (t, JZ7.4 Hz, CH,
1H), 8.56 (m, CH, 1H), no OH signal observed. C NMR
25
13
[
a] K98.5 (c 1.04, CHCl ). IR (CHCl ) 3499, 2990, 2939,
3
D
3
2
8
896, 1744, 1441, 1380, 1224, 1164, 1094, 1036, 955, 886,
64, 758, 702 cm . H NMR (400 MHz, CDCl ) d 1.31 (s,
(75 MHz, CDCl ) d 23.2, 24.2, 60.3, 67.1, 71.3, 100.7,
3
K1 1
120.6, 122.4, 136.5, 148.1, 158.5, 209.7. MS (EI, 70 eV):
m/z (%) 238 (18) [M CH], 222 (3) [M KCH ], 179 (25)
3
C
C
CH , 3H), 1.39 (s, CH , 3H), 3.60 (s, OH, 1H), 4.01 (d, JZ
3
3
3
C
[M KC H O], 149 (33), 138 (22), 108 (100), 72 (19), 59
(13).
1
4
1
1
7
6.3 Hz, CH , 1H), 4.27 (dd, JZ16.3, 1.4 Hz, CH , 1H),
2
2
3 6
.47 (dd, JZ6.0, 1.4 Hz, CH, 1H), 5.35 (d, JZ6 Hz, CH,
H), 7.18–7.33 (m, Ar, 3H), 7.58 (dd, JZ7.7, 1.6 Hz, Ar,
1
H). C NMR (100 MHz, CDCl ) d 23.4, 24.1, 67.2, 69.8,
3
3
3.2.6. Compound 3i. According to GP 1 [1,3]-dithian-2-
aldehyde 2i (342 mg, 2.31 mmol) was reacted with
dioxanone 1 (300 mg, 2.31 mmol) in the presence of (S)-
proline (80 mg, 0.69 mmol) to give 3i (514 mg, 88%) as a
colourlesssolid. The eeofthe product was measured byHPLC
using a chiral stationary phase (Daicel OD, n-heptane/iso-
propanol 95:5) relative to the racemic sample: major isomer
6.2, 101.1, 126.8, 128.4, 129.0, 129.2, 132.9, 136.8, 209.4.
MS (EI, 70 eV): m/z (%) 199 (39), 141 (100), 130 (12), 77
15), 72 (29), 59 (62). HRMS: m/z calcd for C H O Cl–
OH (M KOH) 253.0631, found 253.0633.
(
1
3 15 4
C
0
3
.2.3. Compound 3g . The ee of the product was measured
2
3
by HPLC using a chiral stationary phase (Daicel AD,
n-heptane/iso-propanol 8:1) relative to the racemic sample:
major isomer 12.2 min, minor isomer 9.9 min. IR (CHCl3)
3
1
8.0 min, minor isomer 9.9 min. Mp 74–76 8C. [a] K77.6
(c 1.05, CHCl ). IR (KBr) 3505, 2984, 2932, 2894, 2833,
D
3
1733, 1428, 1381, 1290, 1225, 1164, 1109, 1041, 1003, 969,
881, 803, 737, 669, 647, 610, 543, 491 cm . H NMR
K1
1
499, 2990, 2939, 2896, 1744, 1441, 1380, 1224, 1164,
.
K1
1
094, 1036, 955, 886, 864, 758, 702 cm
H NMR
(300 MHz, CDCl ) d 1.46 (s, CH , 3H), 1.50 (s, CH , 3H),
3
3
3
(
400 MHz, CDCl ) d 1.25 (s, CH , 3H), 1.47 (s, CH , 3H),
3
1.96–2.12 (m, 2H), 2.44–2.61 (m, 2H), 2.86 (ddd, JZ14.0,
3
3
2
.83 (s, OH, 1H), 4.11 (d, JZ17.3 Hz, CH , 1H), 4.35 (dd,
10.2, 3.7 Hz, CH , 1H), 3.15 (ddd, JZ14.0, 10.2, 3.7 Hz,
2
2
JZ17.3, 1.4 Hz, CH , 1H), 4.56 (app-s, CH, 1H), 5.75 (br,
CH , 1H), 3.20 (s, OH, 1H), 3.89 (d, JZ7.4 Hz, CH, 1H),
2
2
CH, 1H), 7.23–7.37 (m, Ar, 3H), 7.57 (dd, JZ7.7, 1.6 Hz,
4.01 (d, JZ16.6 Hz, CH , 1H), 4.46 (dd, JZ16.6, 1.5 Hz,
2
1
3
Ar, 1H). C NMR (100 MHz, CDCl ) d 23.3, 24.4, 67.4,
CH , 1H), 4.53–4.59 (m, CH, 1H), 4.63 (dd, JZ4.2, 1.5 Hz,
3
2
1
CH, 1H). C NMR (75 MHz, CDCl ) d 23.3, 24.2, 25.0,
3
6
2
8.1, 76.6, 101.0, 126.7, 128.5, 128.9, 129.3, 131.3, 137.3,
07.1. MS (EI, 70 eV): m/z (%) 199 (39), 141 (100), 130
3
25.3, 26.2, 43.3, 66.7, 72.3, 75.3, 100.9, 207.6. MS (EI,
C
C
(
12), 77 (15), 72 (29), 59 (62).
70 eV): m/z (%) 278 (14) [M ], 148 (14) [M KC H OS ],
4 7 2
119 (100). Anal. Calcd for C H O S (278.39): C, 47.46;
11 18 4 2
H, 6.52. Found: C, 47.47; H, 6.59.
3
.2.4. Compound 3h. According to GP 1 pyridin-2-
carbaldehyde 2h (247 mg, 2.31 mmol) was reacted with
dioxanone 1 (300 mg, 2.31 mmol) in the presence of (S)-
proline (80 mg, 0.69 mmol) to give a diastereomeric
3.2.7. Compound 3k. According to GP 1 a 60% aqueous
solution of 2,2-dimethoxyacetaldehyde 2k (2.7 g,
15.4 mmol) was reacted with dioxanone 1 (2.0 g,
15.4 mmol) in the presence of (S)-proline (355 mg,
3.09 mmol) to give 3k (2.27 g, 69%) as a pale yellow oil.
0
mixture of 3h and 3h , which can be easily separated on
silica gel, to afford 3h (267 mg, 49%) as a pale yellow oil
and 3h (67 mg, 12%) as a yellow solid. The ee of the
0

C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
335
The ee of the product was measured by HPLC using a chiral
stationary phase (Daicel AD, n-heptane/iso-propanol 8:2)
relative to the racemic sample: major isomer 14.4 min,
CH , 1H), 3.85 (d, JZ17.3 Hz, CH , 1H)), 4.09 (d, JZ
2 2
5.7 Hz, CH, 1H), 4.22 (dd, JZ8.9, 3.0 Hz, CH, 1H), 4.47
(m, 1H), 5.09 (d, JZ2.8 Hz, CH , 2H), 7.0–7.37 (m, Ar,
2
2
3
13
5H), no OH signal observed. C NMR (75 MHz, C D ,
minor isomer 12.8 min. [a] K121.7 (c 1.05, CHCl ). IR
3
D
6 6
(
CHCl ): 3467, 2991, 2940, 2835, 1749, 1457, 1380, 1225,
3
70 8C) d 23.6, 24.0, 24.7, 26.5, 59.0, 64.0, 66.9, 67.1, 70.5,
75.6, 94.9, 100.9, 127.8, 128.1, 128.3, 137.4, 153.1,
K1 1
199, 1126, 1087, 982, 873, 757 cm . H NMR (400 MHz,
1
CDCl ) d 1.49 (s, 2!CH , 6H), 2.75 (s, OH, 1H), 3.40 (s,
OCH , 3H), 3.46 (s, OCH , 3H), 4.05 (d, JZ16.6 Hz, CH ,
C
209.8. MS (EI, 70 eV): m/z (%) 378 [M KCH ] (10),
3
3
3
C
C
335 [M KC H O] (12), 264 [M KC H O] (6), 234 (13),
3 6 5 9
3
3
2
1
H), 4.13 (dd, JZ7.0, 2.7 Hz, CH, 1H), 4.28 (dd, JZ16.6,
190 (13), 91 (100). Anal. Calcd for C H NO (393.43): C,
20 27 7
1
.6 Hz, CH , 1H), 4.47 (dd, JZ2.7, 1.6 Hz, CH, 1H), 4.67
61.06; H, 6.92; N 3.56. Found: C, 60.90; H, 7.01; N, 3.18.
2
1
3
(
d, JZ7.0 Hz, CH, 1H). C NMR (100 MHz, CDCl ) d
3
2
2.9, 25.0, 54.1, 55.4, 67.0, 71.1, 76.4, 100.4, 103.3, 206.1.
MS (EI, 70 eV): m/z (%) 234 (22) [M ], 190 (10), 91.1
3.2.11. Compound 14. According to GP 1 dioxanone 1
(300 mg, 2.31 mmol) was reacted with (S)-proline (80 mg,
0.69 mmol) to give 14 (171 mg, 57%) as a colourless oil.
The ee of the product was measured HPLC using a chiral
stationary phase (Chiralpak AD, n-heptane/iso-propanol
(8:2) relative to the racemic sample: major isomer 10.8 min,
C
(
100). Anal. Calcd for C H O (234.11): C, 55.27; H,
10 18 6
7
.75. Found: C, 55.01; H, 7.78.
3
.2.8. Compound 3m. According to GP 1 the protected
2
6
Garner aldehyde 2m (553 mg, 1.54 mmol) was reacted with
(200 mg, 1.54 mmol) in the presence of (S)-proline
53 mg, 0.46 mmol) to give 3m (442 mg, 80%) as a
minor isomer 9.0 min. [a] K163.7 (0.97, CHCl ). IR
D 3
1
(
(CHCl ) 3474, 2992, 2941, 2881, 1747, 1454, 1379, 1225,
3
K1 1
1160, 1076, 1040, 879, 833, 758 cm . H NMR (300 MHz,
2
5
colourless oil. [a] K86.2 (c 1.03, CHCl ). IR (CHCl )
3
CDCl ) d 1.41 (s, CH , 3H), 1.45 (s, CH , 3H), 1.48, (s, CH ,
3
D
3
3
3
3
3
1
488, 2983, 2938, 2885, 1747, 1694, 1477, 1458, 1386,
252, 1224, 1170, 1091, 948, 853, 760, 668 cm . H NMR
3H), 1.49 (s, CH , 3H), 2.99 (s, OH, 1H), 3.65 (dd, JZ11.8,
3
K1 1
1.0 Hz, CH , 1H), 3.84 (dd, JZ11.8, 1.0 Hz, CH , 1H), 4.01
2
2
(
300 MHz, C D , 70 8C) d 1.19 (s, CH , 3H), 1.20 (s, CH ,
3
(d, JZ17.0 Hz, CH , 1H), 4.02 (dd, JZ11.8, 1.2 Hz, CH ,
6
6
3
2
2
3
3
H), 1.44 (s, C(CH ) , 9H), 1.56 (s, CH , 3H), 1.72 (s, CH ,
3
1H), 4.13 (dd, JZ11.8, 1.2 Hz, CH , 1H), 4.27 (dd, JZ17.0,
2
13
3
3
3
H), 2.88 (s, OH, 1H), 3.73 (d, JZ17.0 Hz, CH , 1H), 3.76,
1.5 Hz, CH , 1H), 4.48 (d, JZ1.5 Hz, CH, 1H). C NMR
2
2
(
CH , 1H), 4.21–4.29 (m, 3H), 4.40–4.48 (m, CH, 1H).
dd, JZ9.1, 7.0 Hz, CH, 1H), 3.95 (dd, JZ17.0, 1.2 Hz,
(75 MHz, CDCl ) d 23.3, 23.4, 23.6, 24.0, 64.6, 65.3, 67.4,
68.8, 74.0, 98.5, 101.3, 208.5. MS (EI, 70 eV): m/z (%) 245
[M KCH ] (12), 187 (19), 172 (20), 131, (42), 130 (34),
3
1
3
C
NMR (75 MHz, C D , 70 8C) d 23.6, 24.0, 24.7, 26.8, 28.6,
2
C
6
6
3
5
2
9.0, 63.9, 67.2, 71.0, 75.7, 80.0, 94.5, 101.0, 152.6,
08.1. MS (EI, 70 eV): m/z (%) 344 [M KCH ] (13), 301
115 (15), 72 (58), 59 (100). HRMS: m/z calcd for
C H O –CH (M KCH ) 245.1025, found 245.1026.
C
C
3
12 20
6
3
3
C
C
[
(
M KC H O] (8), 255 [M KC H O ] (19), 200 (24), 186
3 6 5 7 3
23), 144 (23), 100 (65), 57 (100). Anal. Calcd for
3.2.12. Compound 15. Tetramethylammonium triacetoxy-
borohydride (842 mg, 3.20 mmol) was dissolved in aceto-
nitrile (1.0 mL) and acetic acid (0.37 mL, 6.4 mmol) and
cooled to K30 8C. Then ketone 3k (150 mg, 0.64 mmol,
dissolved in 0.5 mL acetonitrile) was added and stored
overnight at K24 8C in a freezer. The reaction was
quenched with 0.5 N sodium tatrate-solution (2 mL) and
extracted with dichloromethane (4!5 mL). The combined
organic layers were dried over Na SO , filtered and purified
C H NO (359.41): C, 56.81; H, 8.13; N, 3.90. Found:
1
C, 56.90; H, 8.03; N, 3.88.
7
29
7
3
.2.9. Compound 3n. According to GP 1 the protected
Garner aldehyde 2m (553 mg, 1.54 mmol) was reacted with
(200 mg, 1.54 mmol) in the presence of (R)-proline
53 mg, 0.46 mmol) to give 3n (171 mg, 31%) as a
1
(
2
D
5
colourless oil. [a] K65.7 (c 0.86, CHCl ). IR (CHCl )
3
3
2
4
3
1
1
1
548, 2983, 2937, 2885, 1746, 1698, 1387, 1252, 1225,
171, 1099, 859 cm . H NMR (300 MHz, C D , 70 8C) d
by flash chromatography (SiO , pentane/diethyl ether 1:2)
2
K1 1
to afford product 15 (143 mg, 95%) as a colourless oil.
6
6
2
4
.28 (s, CH , 3H), 1.31 (s, CH , 3H), 1.43 (s, C(CH ) , 9H),
3 3
[a] K101.3 (1.00, CHCl ). IR (CHCl ) 3435, 2991, 2937,
D 3 3
3
3
.48 (s, CH , 3H), 1.64 (s, CH , 3H), 3.53–4.42 (m, 7H), no
3
2840, 1458, 1377, 1269, 1201, 1165, 1125, 1074, 978, 864,
738, 704 cm . H NMR (500 MHz, CDCl ) d 1.38 (s, CH ,
3
1
3
K1 1
OH signal observed. C NMR (75 MHz, C D , 70 8C) d
6
6
3
3
2
9
3
3.1, 24.0 (2C), 26.7, 27.8, 60.6, 64.7, 66.8, 70.4, 75.3, 80.2,
3.9, 100.3, 153.9, 207.5. MS (EI, 70 eV): m/z (%)
3H), 1.48 (s, CH , 3H), 2.82 (s, OH, 1H), 3.49 (s, OCH ,
3 3
3H), 3.52 (s, OCH , 3H), 3.64 (dd, JZ11.0, 8.9 Hz, CH ,
3
2
C
44 [M KCH ] (13), 301 [M KC H O] (8), 255
C
1H), 3.74 (dd, JZ9.0, 6.4 Hz, CH, 1H), 3.82 (dd, JZ6.4,
3.0 Hz, CH, 1H), 3.84 (td, JZ8.9, 5.5 Hz, CH, 1H), 3.93
3
3
6
C
[
M KC H O ] (19), 200 (24), 186 (23), 144 (23), 100
5 7 3
(
5
65), 57 (100). Anal. Calcd for C H NO (359.41): C,
1
6.81; H, 8.13; N, 3.90. Found: C, 56.90; H, 8.03; N, 3.88.
(dd, JZ11.0, 5.5 Hz, CH , 1H), 4.48 (d, JZ3.0 Hz, CH,
7
29
7
2
1
1H), 1 OH signal is not observed. C NMR (75 MHz,
3
CDCl ) d 19.5, 28.4, 55.9, 56.4, 63.9, 65.3, 72.3, 74.9, 98.6,
3
C
103.4. MS (EI, 70 eV): m/z (%) 221 (7) [M KCH
3
.2.10. Compound 3o. According to GP 1 the protected
3
], 129
–CH
3
Garner aldehyde 2o (635 mg, 2.31 mmol) was reacted with
(300 mg, 2.31 mmol) in the presence of (S)-proline
80 mg, 0.69 mmol) to give 3o (726 mg, 80%) as a
(3), 75 (100), 59 (26). HRMS: m/z calcd for C10
(M–CH ) 221.1025, found 221.1025.
H
20
O
6
1
(
3
2
D
3
colourless oil. [a] K99.0 (c 1.05, CHCl ). IR (CHCl )
3
3
1
3.2.13. Compound 16. To a solution of 15 (30 mg,
0.13 mmol) in dichloromethane (1.0 mL) were added
carbonyl diimidazole (62 mg, 0.4 mmol) and triethylamine
(0.1 mL, 0.75 mmol) at rt. After 3 h satd ammonium
chloride-solution (2 mL) was added, extracted with
dichloromethane (3!5 mL) and the combined organic
3
490, 2987, 2939, 2887, 1747, 1701, 1456, 1411, 1379,
353, 1256, 1224, 1156, 1094, 862, 765, 736, 699 cm . H
K1 1
NMR (300 MHz, C D , 70 8C) d 1.12 (s, 2!CH , 6H), 1.55
6
6
3
(
s, CH , 3H), 1.73 (s, CH , 3H), 3.63 (d, JZ17.3 Hz, CH ,
3 3 2
1
H), 3.72 (d, JZ15.3 Hz, CH , 1H), 3.75 (d, JZ15.3 Hz,
2

336
C. Grondal, D. Enders / Tetrahedron 62 (2006) 329–337
layers were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (SiO , pentane/diethyl ether 1:2) to afford
dK4.9, K4.7, 18.3, 18.7, 25.9, 29.4, 55.3, 56.4, 64.3, 65.7,
69.7, 74.3, 98.7, 104.8. MS (EI, 70 eV): m/z (%) 335 (9)
C
[M KCH ], 261 (44), 203 (35), 131 (48), 75 (100), 59 (27).
2
3
the carbonate 16 (21 mg, 62%) as a colourless solid. Mp 67–
HRMS: m/z calcd for C H O Si–CH (M–CH ) 335.1890,
1
found 335.1889.
6
34
6
3
3
2
5
6
1
8
9 8C. [a] C10.7 (0.90, CHCl ). IR (KBr) 2997, 2942,
3
D
786, 1463, 1384, 1337, 1277, 1211, 1110, 1050, 984, 918,
46, 753, 689, 536 cm . H NMR (400 MHz, C D ) d 1.14
K1 1
6
6
(
s, CH , 3H), 1.27 (s, CH , 3H), 3.03 (s, OCH , 3H), 3.21 (s,
3 3 3
Acknowledgements
OCH , 3H), 3.37 (t, JZ10.2 Hz, CH , 1H), 3.48 (m, CH,
3
2
1
8
H), 3.57 (dd, JZ10.2, 5.0 Hz, CH , 1H), 3.99 (dd, JZ9.6,
2
This work was supported by the Deutsche Forschungs-
gemeinschaft (SPP Organokatalyse) and the Fonds der
Chemischen Industrie (C. G. thanks for a Kekul e´ fellow-
ship). We thank Degussa AG, BASF AG, Lanxess and
Wacker-Chemie for the donation of chemicals. The NOE-
measurements by Dr. J. Runsink are gratefully
acknowledged.
.0 Hz, CH, 1H), 4.08 (dd, JZ8.0, 2.7 Hz, CH, 1H), 4.11 (d,
1
3
JZ2.7 Hz, CH, 1H). C NMR (100 MHz, C D ) d 18.7,
2
MS (EI, 70 eV): m/z (%) 247 (14) [M KCH ], 75.2 (100)
6
6
8.9, 55.4, 56.7 61.2, 64.4, 69.1, 81.0, 100.3, 103.5, 154.7.
C
3
C
[
C H O ]. HRMS: m/z calcd for C H O –CH (M–CH )
3 7 2 11 18 7 3 3
2
47.0818, found 247.0818.
3
0
.2.14. Compound 17. To a solution of 3k (200 mg,
.85 mmol) in dichloromethane (1.5 mL) were added
dropwise TBSOTf (0.6 mL, 2.55 mmol) and lutidine
0.4 mL, 3.42 mmol) at K78 8C. After 1.5 h satd sodium
(
References and notes
hydrocarbonate-solution (2 mL) was added, extracted with
dichloromethane (3!5 mL) and the combined organic
layers were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by flash
1. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc.
2000, 122, 2395–2396. (b) Notz, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386–7387. (c) List, B. J. Am. Chem. Soc.
2000, 122, 9336–9337.
chromatography (SiO , pentane/diethyl ether 2:1) to afford
2
the TBS-protected aldol product 17 (292 mg, 98%) as a
colourless oil. [a] K101.3 (1.00, CHCl ). IR (CHCl )
2. (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243–4244. (b) Jens, W. S.; Wiener,
J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
9874–9875.
2
D
4
3
3
2
1
987, 2934, 2857, 1751, 1468, 1379, 1252, 1225, 1196,
128, 1001, 867, 839, 812, 780 cm . H NMR (300 MHz,
K1 1
CDCl ) d 0.09 (s, SiCH , 3H), 0.11 (s, SiCH , 3H), 0.88 (s,
3
3. (a) Asymmetric organocatalysis; Berkessel, A., Gr o¨ ger, H.,
Eds.; Wiley-VCH: Weinheim, 2005. (b) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 116, 5248–5286. Angew.
Chem., Int. Ed. 2004, 43, 5138–5175.
3
3
SiC(CH ) , 9H), 1.44 (s, CH , 3H), 1.47 (s, CH , 3H), 3.39
3
3
3
3
(
s, OCH , 3H), 3.47 (s, OCH , 3H), 3.89 (d, JZ15.8 Hz,
3 3
CH , 1H), 4.46 (dd, JZ7.4, 1.8 Hz, CH, 1H), 4.23 (dd, JZ
2
1
7
5.8, 1.3 Hz, CH , 1H), 4.35 (m, CH, 1H), 4.61 (d, JZ
4. For reviews see: (a) List, B. Synlett 2001, 1675–1686. (b) List,
B. Tetrahedron 2002, 58, 5573–5590. (c) List, B. Acc. Chem.
Res. 2004, 37, 548–557. (d) Notz, W.; Tanaka, F.; Barbas,
C. F., III Acc. Chem. Res. 2004, 37, 580–591.
2
1
3
.4 Hz, CH, 1H). C NMR (75 MHz, CDCl ) dK4.8,
3
K4.6, 18.1, 22.9, 24.9, 25.7, 55.6, 56.0, 67.1, 73.5, 77.8,
00.2, 105.4, 206.0. MS (EI, 70 eV): m/z (%) 333 (2)
1
C
M KCH ], 317 (6) [M KC H ], 259 (21), 233 (8), 201
C
[
(
5. (a) Mahrwald, R. Chem. Rev. 1999, 99, 1095–1120. (b)
Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004. (c) Palomo, C.; Oiarbide, M.; Garcia, J. M.
Chem. Soc. Rev. 2004, 33, 65–75.
3
2 6
28), 173 (16), 129 (71), 75 (100), 59 (15). Anal. Calcd for
C H O Si (348.2): C, 55.14; H, 9.25. Found: C, 55.16; H,
1
9
6 32 6
.19.
6
. (a) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3,
573–575. (b) Ward, D. E.; Jheengut, V. Tetrahedron Lett.
2004, 45, 8347–8350.
3
0
.2.15. Compound 18. To a solution of 18 (64 mg,
.18 mmol) in THF (0.8 mL) were added dropwise a 1 M
solution of L-selectride in THF (0.24 mL, 0.24 mmol) at
K78 8C. After 2 h the reaction mixture was warmed to rt,
then diethyl ether (4 mL) and satd ammonium chloride-
solution (2 mL) were added, stirred for 10 min and was
extracted with ethyl acetate (3!5 mL). The combined
organic phases were washed with brine (5 mL) dried over
7. (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798–6799. (b) Storer, R. I.; MacMillan, D. W. C.
Tetrahedron 2004, 60, 7705–7714. (c) Thayumanavan, R.;
Tanaka, F.; Barbas, C. F., III Org. Lett. 2004, 6, 3541–3544.
8. (a) Pihko, P. M.; Erkkil a¨ , A. Tetrahedron Lett. 2003, 44,
7607–7609. (b) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak,
B.; C o´ rdova, A. Angew. Chem., Int. Ed. 2005, 117, 1367–1369.
Angew. Chem., Int. Ed. 2005, 44, 1343–1345. (c) Mangion,
I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240–3241.
MgSO and were concentrated under reduced pressure. The
4
crude product was purified by flash chromatography (SiO2,
pentane/diethyl ether 2:1) to afford the product 18 (58 mg,
2
3
9
2%) as a colourless oil. [a] C6.1 (0.39, CHCl ). IR
D 3
(
CHCl ) 3013, 2932, 2859, 1464, 1380, 1253, 1216, 1071,
3
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38, 758, 670 cm . H NMR (400 MHz, CDCl ) d 0.12 (s,
3
8
SiCH , 3H), 0.16 (SiCH , 3H), 0.92 (s, SiC(CH ) , 9H),
1
3
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3 3
.44 (s, CH , 3H), 1.45 (s, CH , 3H), 3.42 (s, OCH , 3H),
3 3 3
.48 (s, OCH , 3H), 3.72 (s, OH, 1H), 3.83 (dd, JZ12.4,
3
.2 Hz, CH , 1H), 3.90 (t, JZ4.9 Hz, CH, 1H), 3.92–3.96
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(
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m, 2!CH, OH, 3H), 3.98 (dd, JZ12.4, 1.7 Hz, CH , 1H),
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.37 (d, JZ4.9 Hz, CH, 1H). C NMR (100 MHz, CDCl3)
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