Enantio- and diastereoselective synthesis of (protected) 2-formyl- and 2-(hydroxymethyl)-1-phenylalkane-1,3-diols from chiral 2-methoxy-3-tosyl-1,3- oxazolidines by subsequent asymmetric formylation and aldolization

Article abstract of DOI:10.1055/s-2000-6393

Trimethylsilyl enol ethers are successively converted into chirally protected α-formyl ketones by asymmetric formylation with the 2-methoxy-1,3- oxazolidine 2, transformed into the corresponding, thermodynamically determined (Z)-TMS enol ethers, and then are allowed to condense with aldehydes. All steps proceed with high stereoselectivity. Some synthetic options, arising from the three differentiated oxygen functionalities in the intermediates 8 are illustrated for the title target compounds.

Full text of DOI:10.1055/s-2000-6393

FEATURE ARTICLE
743
Enantio- and Diastereoselective Synthesis of (Protected) 2-Formyl- and 2-
(Hydroxymethyl)-1-phenylalkane-1,3-diols from Chiral 2-Methoxy-3-tosyl-
1,3-oxazolidines by Subsequent Asymmetric Formylation and Aldolization
Frank Steif, Birgit Wibbeling,# Oliver Meyer,# Dieter Hoppe*
Institut für Organische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
Fax +49(251)8339772
Received 5 January 2000
R1
R1
Abstract: Trimethylsilyl enol ethers are successively converted
into chirally protected a-formyl ketones by asymmetric formylation
with the 2-methoxy-1,3-oxazolidine 2, transformed into the corre-
sponding, thermodynamically determined (Z)-TMS enol ethers, and
then are allowed to condense with aldehydes. All steps proceed with
high stereoselectivity. Some synthetic options, arising from the
three differentiated oxygen functionalities in the intermediates 8 are
illustrated for the title target compounds.
HC(OMe)3
*
*
ArSO2N
OH
ArSO2N
O
H
B
- H2O
route a
OMe
R3
- MeOH
route b
+
D
+
O
O
H
H
R3
R1
OSiMe3
R2
R2
Key words: chiral 3-arensulfonyl-1,3-oxazolidines, asymmetric
formylation, diastereoselective aldolization, titanium enolates,
chiral alkane-1,3-diols, ketones, chiral auxiliaries
4
5
C
*
E
ArSO2N
O1
*
3
2
R3
*
2'
R2
1'
O
A
Introduction
base
Me3SiCl
N-Arenesulfonyl-1,3-oxazolidines, derived from enantio-
merically pure 1,2-amino alcohols, proved to be valuable
templates for asymmetric synthesis. In particular,
prochiral groups attached to the 2-position are attacked by
nucleophiles or electrophiles with high diastereofacial se-
lectivity.1-6 Although diastereomerically enriched 2-(2-
oxoalkyl)- or 2-(2-oxocycloalkyl)-1,3-oxazolidines A can
be prepared from the corresponding b-keto aldehydes C
and optically active N-arenesulfonyl-2-aminoalkan-1-ols
B1a,7, a more versatile route comprises the Lewis acid-cat-
alyzed condensation of silyl enol ethers E with 2-meth-
oxy-1,3-oxazolidines D, readily prepared from B(Scheme
1).8,2g
R1
*
R4CHO
ArSO2N
O
*
OSiMe3
H
R3
R1
F
*
OH
CHO
ArSO2N
O
*
R4
*
R3
R4
*
R3
*
*
*
R4
*
R3
*
*
OH OH
OH OH
G
H
I
OH
O
Scheme 1
Route b is equivalent to an electrophilic formylation under
the influence of the chiral auxiliary B, creating one (for
R2 = H) or two new stereogenic centers (for R2 π H) in A
with high diastereoselectivity.8 Under Lewis acid catalys-
is, equilibration of oxazolidines may take place giving rise
to the 2,4-cis-disubstituted 1,3-oxazolidines in large ex-
cess (>98:2).8e In this study, we investigated the utiliza-
tion of trimethylsilyl enol ethers F, derived from the
oxazolidinyl-substituted ketones (A, R1 = H), in aldol re-
actions of the Mukaiyama-type9 to form hydroxy ketones
G. Removal of the chiral auxiliary to form a protected or
unprotected formyl group of H and the diastereoselective
reduction to form triols I is possible by several means.1,2
Results and Discussion
(R)-N-Tosyl-2-aminobutan-1-ol (1)10 is smoothly con-
densed with trimethyl orthoformate to yield the cyclic
amino acetal 28e in a cis/trans ratio of 86:14 (Scheme 2).
It is usually utilized as a diastereoisomeric mixture in the
following Lewis acid-catalyzed step, since a C-2 carbeni-
um ion is the intermediate and the configuration of the
precursor at C-2 has no influence on the product compo-
sition.8e,f The zinc dichloride-mediated condensation with
the (Z)-trimethylsilyl enol ethers 3a-c gave the cis-oxazo-
lidines 4a-c as single diastereoisomers (Table 1). Re-
markably, also 4c, which bears an additional stereogenic
center in the side-chain is stereochemically homoge-
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

744
F. Steif et al.
FEATURE ARTICLE
Biographical Sketches
Dieter Hoppe, born in 1941 with R. B. Woodward at for International Coopera-
in Berlin, worked as a chem- Harvard University in Cam- tion”. He has been a coedi-
ically trained laboratory bridge (Massachusetts). Af- tor of SYNTHESIS since
technician in Hannover be- ter serving as a Privatdozent 1988 and will retire from
fore beginning his chemis- at the University of Göttin- this duty during 2000. His
try studies at the University gen he accepted a call to a areas of research relate to
of Göttingen in 1965. He re- C-4 professorship at the the development of stereo-
ceived his doctorate in 1970 University of Kiel in 1985. selective and especially
with U. Schöllkopf, submit- Later, he followed a call to enantioselective synthetic
ting a dissertation on meta- the University of Münster methods. The “(−)-sparteine
lated
isonitriles
and (1992), after he had de- method” for the generation
completed his habilitation clined a call to Hamburg of diverse chiral organolith-
there in 1977 with a topic in (1991). His work was recog- ium compounds is one of his
the area of β-lactam chemis- nized in 1993 with an Otto- major achievements.
try. From 1977 to 1978 he Bayer Award and in 1999
was a postdoctoral fellow with a “Max-Planck Award
Frank Steif, born in 1970 in In 1996, he finished his di- syl-1,3-oxazolidines in ste-
Oelde (Westfalia), began ploma thesis. The topic of reoselective synthesis.
his studies in 1991 in Mün- his dissertation, completed
ster, and joined the research in 1999, is the application of
group of D. Hoppe in 1995. enantiomerically pure N-to-
Birgit Wibbeling, born in Chemisches Institut in Mün- main topics are crystal prep-
1958, got her education as a ster in 1979. First working aration, data collection, and
chemical-technical assistant more preparatively, she routine structure analysis.
in Bückeburg and started joined the X-ray laboratory
working at the Organisch- in 1994 as a technician. Her
Oliver Meyer, born in rently completing his doc- an assistant for the X-ray
1971, studied chemistry in torate on the stereoselective crystallography department
Münster and finished his di- cyclopropanation of vinyl at the Institute of Organic
ploma thesis on dihalocar- fluorides under the supervi- Chemistry.
bene addition to vinyl sion of Professor G. Haufe.
fluorides in 1997. He is cur- Since 1997 he is working as
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantio- and Diastereoselective Synthesis
745
neous,11 indicating that 3c had been attacked exclusively Ketones 4a and 4b/5b (75:25) were smoothly converted
onto the Si-face. The relative configuration unlike12 into the diastereomerically pure (Z)-silyl enol ethers 6a or
(u,2R,1’S) in 4c is concluded from the coupling constant 6b, respectively (Table 1), by applying Cazeau’s
J
2,1’ of 8.1 Hz in the 1H NMR spectrum; as we have found conditions14 for thermodynamically controlled enoliza-
in many examples, J2,1’ in u-ketones is between 8 and 9 tion (Scheme 3). The expected (Z)-configuration was es-
1
Hz, whereas the l-diastereomers exhibit 4-5 Hz.13
tablished by NOE in the H NMR spectra. Fortunately,
also from the cis-trans mixture 4b/5b, only the cis-isomer
6b was isolated (Table 1). Most probably, equilibration
from 2,4-trans to the thermodynamically favoured 2,4-cis
isomer is here a very facile process since the electron-do-
nating power of the b-oxyvinyl group supports the forma-
tion of a ring-opened cationic intermediate.15 We were
unable to convert 4c under these conditions into the corre-
sponding trisubstituted TMS enol ether 6c.
R1
H
R2
3,4,5
a
b
c
C6H5
CH3
Ts N
OH
H
H
1
CH3 C6H5
HC(OMe)3
Ref. 8e
Several attempts to perform aldol additions of 4a,b with
aldehydes under Mukaiyama conditions failed.9 Finally,
the following procedure (Conditions A) turned out to be
successful: To a solution of 4a,b in dichloromethane, tita-
nium(IV) tetrachloride was added at -78°C. The solution
was allowed to warm to 0°C (light red colour) before the
aldehyde 7 was added in five-fold excess to the reaction
mixture. After aqueous workup, mixtures of syn/anti-al-
dols 8 with large excess of anti-8 were isolated (Table 2).
The pure diastereoisomers anti-8a-j were obtained by
OSiMe3
R2
Hb
Ha
Hb
Ha
R1
4
5
3a-c
+
N
H
R1
O
N
O
N
H
R1
O
2
Ts
Ts
Ts
ZnCl2 • Et2O (1.1 eq),
H
H
R2
R2
CH2Cl2, 4h, 0°C
OMe
1'
4
2
O
O
cis/trans: 86:14
5
ratio 75:25 to 100:0
Scheme 2
Table 1 Compounds 4-6 Prepared
Substrates
R1
R2
Producta
Yield (%)
Ratio (dr)
mp (°C) (Et2O)
[a] 2D0 (c, CH2Cl2)
Configuration
2 + 3a
2 + 3b
H
H
H
CH3
H
C6H5
CH3
CH3
C6H5
C6H5
CH3
4a
4b
5b
4c
6a
6b
85
>98:<2
75:25
-
>98:<2
>98:<2
>98:<2
182
oil
oil
113
138
oil
+ 67.9 (1.13)
+ 13.0 (1.11)
– 56.3 (1.08)
+ 22.3 (1.09)
+163.8 (0.98)
+ 89.6 (1.05)
2R,4R
2R,4R
2S,4R
2R,2(1S),4R
2(1Z),2R,4R
2(1Z),2R,4R
60b
20c
85
2 + 3c
2 + 4a
2 + 4b/5b
65-78
68
H
a Satisfactory microanalyses obtained: C, H, N 0.4.
b Less polar diastereoisomer on silica gel.
c More polar diastereoisomer on silica gel.
H
O
N
O
Me3SiCl, LiI, NEt3
Conditions A, B, C
4a or
O
Ti
Ts
H
N
O
N
O
N
H
O
2
2
Ts
R2
Ts
R2
Ts
4b/5b
THF/CH2Cl2, 5 d, 20°C
+ R3CHO (7)
+
H
1''
H
1''
H
2'
H
2'
R2
R3
R3
OSiMe3
1'
1'
R3
TS 9A
R2
O
OH
O
OH
anti-8
Conditions A:anti/syn >
syn-8
6a R2 = Ph, 65-78%, dr 100:0
6b R2 = CH3, 68% , dr 100:0
H
2
H
95:5 (R = Ph)
=
O
Conditions B:anti/syn
= 28:72 for 8d
N
O
Ti
O
R3
Ts
7,8
R2
R3
b
g
a
d
f
c
e
h
i
j
R2
C6H5
C2H5
C6H5
C6H5
CH3
C6H5
C6H5
C6H5
n-C3H8
C6H5
CH3
CH3
CH3
CCl3
TS 9B
(S)-CH(CH3)OTBS
CH(CH3)2 CH2CH(CH3)2 C6H5
CH(CH3)2 C6H5
Ti = TiCl3
Reagents and conditions:
Conditions A: i) TiCl4, -78°C, CH2Cl2; ii) 7a-g, 7j, 24 h, 0°C
Conditions B: i) TiCl4, 20°C, CH2Cl2; ii) 7d, 6 h, 20°C
Conditions C: i) TiCl4, -78°C, CH2Cl2; ii) 7h,i, Ti(OPr-i)4, 24 h, 0°C
Scheme 3
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

746
F. Steif et al.
FEATURE ARTICLE
flash chromatographic separation. The a-methyl silyl enol chair-like topology, placing R3 into a pseudoaxial posi-
ether 4b, under Conditions A, could be brought to conden- tion. Alternatively, a twist-boat TS 9B with pseudoequa-
sation only with chloral (7j) (Table 2, Entry 11). The X- torial R3 has to be discussed. Although few precedences
ray crystal structure16 of the major diastereoisomer anti- for titanium-mediated anti-diastereoselective aldol reac-
8d (Figure 1) gives evidence for the correct stereochemi- tions are known,19 studies with stereodefined titanium ke-
cal assignment.
tone enolates are too scarce to give preference to one of
these two pathways.20
Cyclic transition states (TS 9A and TS 9B) are considered
to be typical for titanium enolates. Usually, Mukaiyama
reactions, which are triggered by the activation of the car-
bonyl component, proceed through an open-chain transi-
tion state to give predominantly syn-aldols.9
A control experiment under Conditions B which supports
the open-chain reaction path was performed with 4a and
2-methylpropanal (7d) by mixing 4a, TiCl4 and 7d in
CH2Cl2 and keeping the solution at room temperature:
anti-8c and syn-8c were isolated in a ratio of 28:72 (Table
2, Entry 5). The aldol reaction can be coupled also with ef-
ficient diastereofacial selectivity at the carbonyl group: 4a
furnished with (S)-O-TBS-lactaldehyde21 (7g) the stereo-
homogeneous adduct anti-8g (Table 2, Entry 8).
For less reactive carbonyl compounds, addition of titani-
um tetra(isopropoxide) to the solution of the intermediate
titanium enolate was required (Conditions C, Table 2, En-
tries 9-11). We assume that the effect of this additive is
to slow down decomposition reactions. syn-8 was pro-
duced in slight excess, giving evidence for an open-chain
reaction mechanism to proceed. It is evident from the fol-
lowing arguments, that the second diastereoisomers syn-8
differ from anti-8 in the configuration at C-2’and not at
C-1’:
Figure 1 X-ray structure of anti-8d16
We assume that the aldol addition proceeds through inter-
mediate titanium enolates.17 Two cyclic transition states
with the topicity Si,Re18 lead to the observed configura-
tion of the major diastereoisomers anti-8: TS 9A has a
Table 2 Prepared Compounds 8a-j
Entry Substrates
R2
R3
Productsa Yield anti/syn
mp (°C)
(Et2O)
[a] 2D0(c, CH2Cl2) Configuration
(%)
(Conditions)
1
2
3
4
5
6a + 7a
6a + 7b
6a + 7c
6a + 7d
6a + 7d
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
C2H5
C3H8
CH(CH3)2
CH(CH3)2
8a
8b
8c
74
77
71
77b
>98:<2 (A)
>98:<2 (A)
>98:<2 (A)
94:6 (A)
oil
46
+25.6 (1.08)
+23.5 (1.15)
+22.7 (1.02)
+23.0 (0.98)b
2R,2(1R,2S),4R
2R,2(1R,2S),4R
2R,2(1R,2S),4R
2R,2(1R,2S),4R
2R,2(1R,2S),4R
2R,2(1R,2R),4R
2R,2(1R,2S),4R
2R,2(1R,2R),4R
2R,2(1R,2S),4R
2R,2(1R,2R,3S),4R
2R,2(1R,2S),4R
2R,2(1R,2R),4R
2R,2(1R,2R),4R
2R,2(1R,2S),4R
2R,2(1R,2R),4R
120
anti-8d
anti-8d +
syn-8d
8e
117b
58c
70
28:72 (B)
>98:<2 (A)
90:10 (A)
-
-
d
d
6
7
6a + 7e
6a + 7f
C6H5
C6H5
CH2CH(CH3)2
C6H5
139-141
+20.1 (1.00)
anti-8f + 79e
syn-8f
138-140e +23.3 (1.02)e
8
9
6a + 7g
6b + 7d
C6H5
CH3
CH(CH3)OTBS 8g
CH(CH3)2
63
>98:<2 (A)
26:74 (C)
oil
oil
oil
+25.3 (0.99)
–17.4 (0.51)
–21.5 (0.42)
anti-8h + 11f
syn-8h
anti-8i +
syn-8i
8j
29g
10
11
6b + 7e
6a + 7j
CH3
CH3
C6H5
70h
28
38:62 (C)
>98:<2 (A)
53-58h
170
+49.2 (1.02)h
–13.5 (1.01)
CCl3
a Satisfactory microanalyses obtained: C, H, N± 0.4.
b Diastereomeric mixture of anti-8d and syn-8d (94:6), which was not separable by flash chromatography.
c Diastereomeric mixture of anti-8d and syn-8d (28:72), which was not separable by flash chromatography.
d Not determined.
e Diastereomeric mixture of anti-8f and syn-8f (90:10), which was not separable by flash chromatography.
f Less polar diastereoisomer on silica gel.
g More polar diastereoisomer on silica gel.
h Diastereomeric mixture of anti-8i and syn-8i (38:62), which was not separable by flash chromatography.
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantio- and Diastereoselective Synthesis
747
ï The 1H NMR coupling constants between 2-H and 1’-H
both in the adducts anti-8 (6.3 Hz) and syn-8 (5.4 Hz) are
typical for a like relationship.22 Thus, the second dia-
stereoisomers have equal configuration at C-1’ and must
differ at the stereocenter C-2’.
N
H
O
H
N
H
O
H
N
H
O
H
Ts
Ts
Ts
R3
Ph
R3
Ph
R3
a)
Ph
+
ï Only one diastereoisomer is detected from the reaction
of the optically active aldehyde 7g with silyl enol ether 6a.
According to the Felkin-Anh rule23 Re-attack at the car-
bonyl group is expected to occur preferentially, enforcing
the diastereoselectivity at C-2’for Re-attack but diminish-
ing it for Si-attack.
O
OH
OH OH
OH OH
anti-8a-d
syn-10
anti-10
b)
The aldols 8 were reduced with diisobutylaluminium
hydride24 (DIBALH) in THF at -78°C (Conditions D,
Scheme 4) or lithium aluminium hydride25 (Et2O, 0°C;
Conditions E); Conditions D provided the anti-1,3-diols
10 in excess, whereas Conditions E gave rise preferential-
ly to syn-diols 10. Separation of the diastereomers 10
turned out to be very facile on the stage of the acetonides
cis- and trans-12; therefore mixtures of syn- and anti-10
were carried through the step of 11. Thiolysis1 of the ox-
azolidines with 1,3-propanedithiol in the presence of
methanesulfonic acid yielded the 1,3-dithianes syn-/anti-
11. The relative configuration of product anti-11b was es-
tablished by an X-ray crystal structure analysis26 (Figure
2).
S
S
S
S
+
Ph
R3
Ph
R3
OH OH
OH OH
syn-11
anti-11
c)
S
S
S
S
2
+
Ph
Ph
Ph
R3
Ph
Ph
Ph
R3
2'
1''
1'
O
O
O
O
cis-12
trans-12
d)
d)
OH
R3
OH
R3
O
O
O
O
cis-13
trans-13
e)
e)
OH
R3
OH
R3
Figure 2 X-ray structure of anti-11b26
OH OH
OH OH
syn-14
anti-14
Reagents and conditions: a) DIBALH/THF, 24 h, -78°C (Conditions
D) or LiAlH4/Et2O, 24 h, 0°C (Conditions E); b) HS(CH2)3SH/
CH2Cl2, 7 h, 0 Æ 20°C; c) 2-methoxypropene, PPTS (cat.)/CH2Cl2, 2
h, 0°C; d) i. CaCO3 (15 equiv)/CH3I (20 equiv)/acetone/H2O, 24 h, D;
ii. LiAlH4/THF, 2 h, 20°C; e) HS(CH2)3SH/MeSO3H (cat.)/CH2Cl2, 2
h, 0°C. For R3, yields, and ratios, see Table 3.
Diols 11 were protected by means of 2-methoxypropene/
PPTS to form the acetonides cis- and trans-12, which
could be separated by column chromatography, providing
exclusively crystalline products. Deprotection of the
masked formyl group was performed by the standard
method27,25b (see step d in Scheme 4). The intermediate al-
dehydes were immediately reduced to give the alcohols
cis- or trans-13. No epimerization could be detected in
this step.
Scheme 4
feasability of complete deprotection.28 Since triols 14
have a very good solubility in water, we chose a trans-
dithioacetalization with propane-1,3-dithiol for removal
of the isopropylidene bridge, since it does not require
aqueous workup (Scheme 4, step e).
For any synthetic uses, many options are given, since the
hydroxymethyl group in 13 can be brought selectively to
the required oxidation level before further conversion.
With the conversion of some 1,3-dioxanes 13 into triols
14 (Table 3, Entries 30-36) we have demonstrated the
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

748
F. Steif et al.
FEATURE ARTICLE
Table 3 Compounds 10-14 Prepared
Entry Substrate
R2
R3
Producta
Yield
(%)
Ratio (d.r., mp (°C)
method) (Et2O)
[a] 20
Configuration
D
(c, CH2Cl2)
1
2
8a
8b
8d
C6H5
CH3
anti-10a
anti-10a +
syn-10a
anti-10b
anti-10b +
syn-10b
70
>98:<2 (D) 136
+92.2 (1.02)
2R,2(1S,2S),2{1(1R)},4R
2R,2(1S,2S),2{1(1R)},4R
2R,2(1S,2S),2{1(1S)},4R
2R,2(1S,2S),2{1(1R)},4R
2R,2(1S,2S),2{1(1R)},4R
2R,2(1S,2S),2{1(1S)},4R
2R,2(1S,2S),2{1(1R)},4R
72b
65
18:82 (E)
–
–
c
c
3
4
C6H5
C6H5
C2H5
>98:<2 (D) 128
+91.6 (0.72)
60b
84d
18:82 (E)
–
–
c
c
5
6
CH(CH3)2 anti-10c +
syn-10c
91:9 (D) 155-157d +93.8 (1.01)d
anti-10c +
syn-10c
62b
89f
9g
18:82 (G)
90:10 (D) 75
191
–
–
2R,2(1S,2S),2{1(1S)},4R
2R,2(2R),2{1(1R)},4R
2R,2(1S,2S),2{1(1R)},4R
1R,2S,3S
1R,2S,3S
1S,2S,3S
1R,2S,3S
1R,2S,3S
1S,2S,3S
1R,2S,3S
c
c
7
8
9
8fe
C6H5
C6H5
C6H5
CH3
anti-10d +
syn-10d
anti-11a
anti-11a +
syn-11a
anti-11b
anti-11b +
syn-11b
–74.1 (1.06)
+74.7 (0.50)
+55.6 (1.00)
anti-10a
syn-10a
75
>98:<2
116
10
60b
79
18:82
>98:<2
-
–
c
c
11
12
anti-10b
syn-10b
C6H5
C6H5
C2H5
92
+58.1 (1.04)
69b
67d
18:82
91:9
-
-
c
c
13
14
anti-10c
syn-10c
CH(CH3)2 anti-11c +
syn-11c
101-103d +68.2 (1.01)d
anti-11c +
-
syn-11c
53b
74
92
63g
87
62g
72f
72g
88
81
94
81
89
73
78
85
62
76
84
77
60
60
77
18:82
>98:<2
_c
_c
1S,2S,3S
1R,3R
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
anti-10d
anti-11a
syn-11ab
anti-11b
syn-11bb
anti-11cd
syn-11cb
anti-11d
trans-12a C6H5
cis-12a
trans-12b C6H5
cis-12b
trans-12c
cis-12c
trans-12d C6H5
trans-13a C6H5
cis-13a
trans-13b C6H5
cis-13b
trans-13c
cis-13c
C6H5
C6H5
C6H5
CH3
anti-11d
trans-12a
cis-12a
trans-12b
cis-12b
131
114
136
124
150
155
126
189
87
oil
63
76
48
78
91
oil
oil
oil
oil
oil
oil
–33.7 (1.04)
+51.4 (1.07)
+50.2 (1.01)
+40.2 (0.99)
+36.6 (1.01)
+38.8 (1.06)
+39.3 (1.00)
+17.0 (1.02)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1R,2S,3S
1S,2S,3S
1R,2S,3S
1S,2S,3S
1R,2S,3S
1S,2S,3S
1R,3R
C6H5
C6H5
C6H5
C2H5
CH(CH3)2 trans-12c
cis-12c
C6H5
CH3
trans-12d
trans-13a
cis-13a
trans-13b
cis-13b
+100.9 (1.04) 1R,2S,3S
–26.0 (0.99)
+85.0 (1.00)
–47.2 (1.03)
+82.1 (1.10)
–39.8 (1.08)
–33.4 (1.01)
+59.9 (0.45)
–32.5 (0.44)
+43.9 (1.03)
–44.5 (1.06)
+44.7 (1.12)
–40.2 (1.02)
–39.0 (0.97)
1S,2S,3S
1R,2S,3S
1S,2S,3S
1R,2S,3S
1S,2S,3S
1R,3R
1R,2S,3S
1S,2S,3S
1R,2S,3S
1S,2S,3S
1R,2S,3S
1S,2S,3S
1R,3R
C2H5
C6H5
CH(CH3)2 trans-13c
cis-13c
C6H5
CH3
trans-13d
anti-14a
syn-14a
anti-14b
syn-14b
C2H5
C6H5
CH(CH3)2 anti-14c
syn-14c
trans-13d C6H5
C6H5
anti-14d
oil
a Satisfactory microanalyses obtained: C, H, N 0.4.
b Diastereomeric mixture of anti/syn (18:82), which were not separable by flash chromatography.
c Not determined.
d Diastereomeric mixture of anti/syn (91:9), which were not separable by flash chromatography.
e Diastereomeric mixture of anti-8f and syn-8f (90:10).
f Less polar diastereoisomer on silica gel.
g More polar diastereoisomer on silica gel.
Conclusions
access to both enantiomeric series. Good flexibility is pro-
vided in the individual reaction steps, allowing the differ-
The strategy underlying this work, consists of the subse- entiation between the three functional groups. Moreover,
quent asymmetric formylation and aldolization, each with the high crystallization tendency of N-sulfonyl-1,3-ox-
good stereocontrol, at a silyl enol ether at the same carbon azolidines permits easy purification, diastereomer separa-
atom to provide carbon chains with three consecutive ste- tion, and structural elucidation. It can be predicted, that
reocenters and a, b, g-trifunctionalization. The chiral aux- many more substitution patterns than these which have
iliary, available in both enantiomeric forms29 allows
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantio- and Diastereoselective Synthesis
749
turned to dark red in color, and stirring was continued for 24 h at
0°C. For workup, H2O (70 mL) was added, the mixture intensively
stirred, and the phases separated (after adding sat. aq NaCl, 50 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 50 mL), the
combined CH2Cl2 solutions dried (Na2SO4/NaHCO3) and evaporat-
ed in vacuo. Purification of 8 was performed by recrystallization
from Et2O/pentane (1:1) for 8f or by column chromatography
(Et2O/pentane, 1:1, 1% Et3N, silica gel) for 8a-e, 8g-j. For yields,
ratios, and data see Tables 2, 5, and 7.
been demonstrated are easily accessible by the extension
of substrates and applied reactions.
All experiments involving organometallic reagents were carried out
under Ar in dried glassware. All solvents were purified by distilla-
tion and dried, if necessary, prior to use. 1H and 13C NMR spectra
were recorded on a Bruker WM 300 spectrometer. Optical rotations
were recorded on a Perkin-Elmer polarimeter 241. Mps were ob-
tained on Gallenkamp melting point apparatus MFB-595 and are
uncorrected. Products were purified by flash column chromatogra-
phy on silica gel (40-64 mm). Microanalyses were performed in the
Organisch-Chemisches Institut der WWU Münster with a Perkin-
Elmer Elemental Analyzer 240.
Conditions B
TiCl4 (0.05 mL, 0.46 mmol) was added dropwise to a solution of si-
lyl enol ether 6a (223 mg, 0.50 mmol) in anhyd CH2Cl2 (5 mL) kept
under Ar at 20°C. The solution turned to dark red in color. Then 2-
methylpropanal (7d; 0.23 mL, 2.52 mmol) was added and the mix-
ture stirred at 20°C for 6 h. For workup and purification see Condi-
tions A.
2-(2-Oxoalkyl)-1,3-oxazolidines 4a-5b; General Procedure
To a solution of (2R,4R)- and (2S,4R)-4-ethyl-2-methoxy-3-tosyl-
1,3-oxazolidine (2; ratio 86:14; 2.85 g, 10.0 mmol) and the (Z)-tri-
methylsilyl enol ether15 3a-c (11.0 mmol) in CH2Cl2 (30 mL) was
added a 2.2 M solution of ZnCl2∑OEt2 in CH2Cl2 (5.0 mL, 11.0
mmol) at 0°C and the mixture stirred at 0°C for 4 h. Then, sat. aq
NaCl (20 mL) was added, the organic phase separated and the aque-
ous phase extracted with CH2Cl2 (3 × 15 mL). The combined
CH2Cl2 solutions were dried (Na2SO4), evaporated to dryness, and
the residue purified by crystallization from Et2O (for 4a) or by chro-
matography on silica gel with Et2O/pentane (1:2 for 4c and 1:1 for
4b/5b). For yields, ratios, and data see Tables 1, 4, and 6.
Conditions C
Silyl enol ether 6b (2.69 g, 7.00 mmol) was treated as described in
Conditions A. Ti(OPr-i)4 (2.10 mL, 7.00 mmol) was added at 0°C
before the aldehyde 7 (35 mmol). Stirring was continued for 24 h
before workup was accomplished. Due to precipitation of titanium
oxide hydrates, addition of H2O (up to 800 mL) was required.
Diols 10; General Procedures
Reduction of Aldols 8 with Diisobutylaluminium Hydride
(DIBALH); Conditions D
To a solution of aldol 8 (5.00 mmol) in anhyd THF (50 mL), kept
under Ar at -78°C, was added dropwise a 1 M solution of DIBALH
in hexane (20 mL, 20 mmol) and the mixture stirred at -78°C for 24
h. For workup, H2O (20 mL, caution, H2!) was carefully added and
the mixture was allowed to warm to 20°C. The jelly percipitate
formed was dissolved in Et2O (50 mL) and 2 N NaOH (60 mL) with
intensive stirring. The layers were separated, the aqueous phase ex-
tracted with Et2O (3 × 100 mL, each), the combined organic solu-
tions dried (Na2SO4), and evaporated in vacuo. The crude product
was purified by flash chromatography (Et2O/pentane, 1:1, silica
gel). For yields, ratios and data see Tables 3, 5, and 7.
b-(1,3-Oxazolidin-2-yl)alkenyl Trimethylsilyl Ethers 6a,b; Gen-
eral Procedure
To a stirred solution of the ketone 4a (10.0 mmol) and anhyd LiI
(400 mg, 3.00 mmol) in anhyd THF/CH2Cl2 (40 + 40 mL) was add-
ed Me3SiCl (2.5 mL, 20 mmol) at ~20°C. After 30 min, Et3N (1.7
mL, 12.0 mmol) was continuously added portionwise. The mixture
was stirred for 5 d at 20°C and then carefully evaporated nearly to
dryness. The crude product including Et3N•HCl was diluted by add-
ing CH2Cl2 (15 mL) and this mixture was filtered with Et2O/pentane
(1:3) through a column filled with silica gel, which had been sus-
pended before with the same solvent. Elution of unreacted ketone
4a was performed with EtOAc (500 mL). Best yields were
achieved, when reusing the column after washing it with pentane (1
L). For yields and characterization see Tables 1, 4, and 6.
Reduction with LiAlH4; Conditions E
A solution of aldol 8 (3.50 mmol) in anhyd Et2O (30 mL) was added
dropwise at 0°C to a suspension of LiAlH4 (266 mg, 7.00 mmol) in
Et2O (30 mL) and the mixture stirred at 0°C for 24 h. For workup,
2 N HCl (20 mL, caution, H2!) was carefully added, the layers were
separated, the aqueous phase extracted with Et2O (3 × 50 mL), the
combined Et2O solutions dried (Na2SO4/NaHCO3), and evaporated
in vacuo. Flash chromatography (Et2O/pentane, 1:1, silica gel)
yielded the pure diols 10. For yields, ratios, and data see Tables 3,
5, and 7.
Aldols 8a-j; General Procedures
Conditions A
TiCl4 (0.77 mL, 7.00 mmol) was added dropwise to a solution of si-
lyl enol ether 6a (3.12g, 7.00 mmol) in anhyd CH2Cl2 (70 mL) kept
under Ar at -78°C. The solution turned to yellow in color and a red
precipitate formed. After redissolution of the precipitate (15 min),
the mixture was allowed to warm rapidly (within 5 min) to 0°C. Al-
dehyde 7 (35 mmol) was added before the reaction mixture had
Table 4 Selected Spectroscopic Data of Compounds 4-6
Product
IR (film)
1H NMR (300 MHz, CDCl3), d, J (Hz)
n (cm-1)
a
a
a
a
2-H (J2,1’
)
1’-Ha
4-H (J4,5a
)
5-Ha (J5a,5b
)
5-Hb (J4,5b)
4b
4c
5b
6a
6b
1710, 1345, 1165
1665, 1335, 1150c
1710, 1345, 1165
1345, 1165, 845c
1345, 1165, 845
5.29 (d, 8.3)
5.57 (d, 8.1)
5.50 (d, 7.9)
5.86 (d, 8.3)
5.72 (d, 8.3)
2.85, 3.20 (dd)b
3.78 (dq)
3.51-3.59 (m, 6.0)
3.57-3.66 (m, 6.9)
3.87-3.94 (m, 6.5)
3.75-3.81 (m, 6.2)
3.58-3.67 (m, 6.2)
3.24 (dd, 8.8)
3.33 (dd, 8.8)
3.98 (dd, 8.3)
3.49 (dd, 8.7)
3.31 (dd, 8.8)
3.64 (dd, 2.6)
3.51 (dd, 4.5)
3.67 (dd, 3.1)
3.72 (dd, 3.1)
3.58-3.67 (m)
2.80, 3.32 (dd)b
5.22 (d)
4.61 (dd)
a d = doublet, q = quartet, m = multiplet.
b Diastereotopic protons.
c In KBr.
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

750
F. Steif et al.
FEATURE ARTICLE
Table 5 Selected Spectroscopic Data of Compounds 8a-j and 10-14
Product
IR (KBr)
n (cm-1
1H NMR (300 MHz, CDCl3), d, J (Hz)
2’-Ha,b 2’-OHa,b 1’’-Ha,b
)
2-Ha,b
(J2,1’
1’-Ha,b
1’’-OHa,b
(J1’’,1’’-OH)
)
(J1’,2’ (J2’,2’-OH (J1’,1’’
)
)
)
8a
8b
8c
anti-8d
syn-8d
8e
8f
8g
3520, 1710, 1345, 1165a
3490, 1660, 1355, 1165
3470, 1655, 1345, 1165
3550, 1670, 1345, 1165
3550, 1670, 1345, 1165
3490, 1670, 1345, 1165
3440, 1660, 1345, 1165
3430, 1690, 1335, 1165d
3490, 1695, 1335, 1155d
3510, 1690, 1335, 1150d
3380, 1690, 1355, 1165
3440-3320, 1335, 1155
3530-3340, 1340, 1160
3510, 3400, 1330, 1150
3590-3500, 1330, 1155
3510,1335, 1150
5.48 (d, 6.2)
5.49 (d, 6.2)
5.27 (d, 6.2)
5.48 (d, 6.3)
5.50 (d, 5.4)
5.64 (d, 6.4)
5.44 (d, 6.9)
5.49 (d, 6.3)
5.24 (d, 5.3)
5.62 (d, 8.9)
5.42 (d, 8.6)
4.60 (d, 1.2)
5.03 (d, 6.2)
4.61 (d, 0.9)
4.84 (d, 5.3)
4.60 (d, 1.2)
4.56 (d, 3.6)
5.94 (d, 9.4)
4.39 (d, 2.9)
3.90 (d, 3.6)
4.39 (d, 3.1)
3.86 (d, 3.3)
4.34 (d, 3.1)
3.83 (d, 3.1)
4.33 (d, 3.6)
3.62 (d, 2.4)
3.91 (d, 1.4)
3.63 (d, 2.4)
3.90 (d, 1.4)
3.66 (d, 2.4)
3.90 (d, 1.0)
3.68 (d, 2.4)
4.04 (dd)
4.07 (dd)
4.04 (dd)
4.17 (dd)
4.31 (dd)
4.01 (dd)
4.72 (dd)
4.26 (d)
3.24 (dd)
2.96 (dd)
3.75 (d)
2.61 (m)
2.40 (m)
2.71 (t)
4.36 (m, 2.6) 3.56-3.64 (m)
-
-
3.99-4.07 (m, 2.6) 3.55 (d, 8.6)
4.09-4.18 (m, 2.4) 3.55 (d, 8.8)
3.70-3.78 (m, 2.1) 3.91 (d, 9.1)
-
-
-
-
-
-
3.88 (d, 3.6)
4.24 (ddd, 2.4)
5.22 (d, 2.9)
4.80 (d)
3.88 (ddd, 4.1)
3.75 (ddd, 3.3)
3.448 (dd, 1.2)
4.68 (dq, 1.4)
4.11 (m, 1.9)
4.32 (dq, 1.2)
3.46-3.59 (m)
-
-
3.53 (d, 9.2)
-
-
c
-
-
-
3.93-3.98 (m)
3.31 (d, 8.8)
3.20 (d, 6.2)
6.09 (d, 9.3)
3.23 (s)
-
-
anti-8h
syn-8h
8j
-
-
-
-
-
-
anti-10a
syn-10a
anti-10b
syn-10b
anti-10c
syn-10c
anti-10d
anti-11a
syn-11a
anti-11b
syn-11b
anti-11c
syn-11c
anti-11d
5.59 (d)
5.30 (t, 5.0)
5.52 (d)
3.99 (d, 2.2)
3.38 (d, 4.5)
4.01 (d, 2.1)
2.85 (d, 7.4)
3.18 (d, 2.2)
2.82 (d, 6.4)
3.26 (d, 2.9)
2.46 (ddd) 3.87 (m, 1.7)
2.94 (d) 3.94 (dd)
2.75 (ddd) 3.67-3.71 (m, 1.7) 2.96 (d, 4.8)
5.25 (dd, 6.7) 3.35 (d, 4.5)
5.50 (d)
5.17 (d, 8.1)
5.03 (d)
5.33 (t, 4.3)
4.11 (d, 2.2)
3.20 (d, 3.3)
3.92 (d, 2.4)
3.63 (d, 3.8)
3.36 (s)
3460-3320, 1340, 1160
3500-3400, 1330, 1150
3460-3370
2.28 (dt)
2.02 (m)
2.07 (dq)
2.03 (m)
2.10 (dt)
2.26 (q)
2.24 (m)
2.36 (q)
5.74 (dd, 1.2)
4.47 (ddq, 2.9)
4.41 (dq, 1.9)
3.96 (d, 5.7)
2.53 (d, 4.5)
2.67-2.85 (m) 5.24 (d, 7.4)
5.31 (t, 4.1)
3600-3400
3510-3400
4.16-4.23 (m, 2.4) 2.58 (d, 5.0)
3.66 (d, 3.6)
3420-3260
4.15-4.19 (m, 3.1) 2.65-2.89 (m) 5.25 (dd, 7.9) 3.32 (d, 1.3)
3.97 (ddd, 2.2) 2.71 (d, 5.3) 5.35 (t, 3.4) 3.86 (d, 3.6)
5.24 (dd, 8.1) 3.22 (d, 3.3)
3540-3420
3440-3390
3.87-3.98 (m, 2.9) 2.55 (d, 6.2)
3400-3200
5.61 (dd, 2.6)
3.35 (d, 5.5)
5.14 (t, 3.8)
5.17 (d, 5.3)
4.98 (d, 10.5)
5.14 (d, 5.2)
4.96 (d, 10.5)
5.04 (d, 5.0)
4.95 (d, 10.3)
5.41 (d, 5.3)
5.18 (d, 5.0)
4.95 (d, 10.5)
3.76 (d, 4.5)
trans-12a 3020, 2950, 2875
2.20 (ddd) 4.35 (dq, 7.3)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
cis-12a
trans-12b 2960, 2910, 2870
cis-12b 2970, 2915, 2810
trans-12c 2965, 2915, 2870
cis-12c 3010, 2910, 2850
3050, 2970, 2880
1.83 (dt)
2.21 (m)
1.90 (dt)
2.38 (ddd) 4.05 (dd, 7.2)
1.94 (m) 3.97 (dd, 10.3)
2.86 (ddd) 5.23 (d, 7.9)
4.26 (dq, 10.0)
4.11 (dt, 7.4)
4.03 (ddd, 8.3)
trans-12d 3015, 2965, 2870
trans-13a 3220, 3010, 2970, 2870
3.30-3.48 (m) 1.98 (dq)
3.94 (dq, 7.4)
4.27 (dq, 10.3)
cis-13a
3460-3380, 3010, 2970, 3.30 (dd, 5.5) 1.52 (m)
2885d
3.57 (dd, 7.2)
trans-13b 3300-3240, 3010, 2965, 3.34 (dd, 4.3) 2.01 (ddd) 3.73 (dt, 7.6)
2890 3.45 (dd, 4.3)
3500-3450, 3015, 2985, 3.28 (d)
2880 3.56 (dd, 2.6)
-
-
-
-
5.17 (d, 4.8)
4.94 (d, 10.5)
5.12 (d, 4.5)
4.92 (d, 10.5)
-
-
-
-
cis-13b
1.81 (ddt) 4.05 (dt, 10.7)
trans-13c 3450-3440, 3010, 2980, 3.34 (dt, 3.8) 2.08-2.14 3.61 (dd, 7.0)
2860
3.45-3.52 (m) (m)
3.27 (dt, 2.9) 1.65 (tt)
3.55 (dt, 3.1)
cis-13c
3470, 3010, 2980, 2900
3.99 (dd, 10.5)
trans-13d 3560, 3010, 2965, 2890
3.38-3.49 (m) 1.30 (dd)
3.62, 3.82 (d) 1.66 (m)
3.41-3.46(m) 1.91-1.96 4.19 (m, 12.3)
3.54 (dt, 3.6) (m)
3,62 (dd, 4.2) 1.58-1.77 3.95 (q, 4.5)
3.84 (dd, 4.7) (m)
3.45 (dd, 4.7) 1.99 (dt)
3.56 (dd, 4.7)
3.60-3.67 (m) 1.86 (ddd) 3.78-3.91 (m, 4.2) 2.90 (d, 5.3)
3.78-3.91 (m)
3.42 (dd, 3.0) 2.04 (tt)
3.61 (dd, 4.4)
3.37 (m, 3.1) 1.97 (m)
3.72 (dt, 4.3)
4.90 (d, 7.9)
4.18 (qu, 5.9)
-
5.41 (d, 5.4)
5.23 (t, 3.5)
-
anti-14a
syn-14a
3400-3240, 3010, 2950
3400-3240, 3010, 2950
3.24 (s)
4.02 (d,3.8)
3.41-3.46 (m) 4.91 (d, 8.29 3.61 (s)
c
c
anti-14b
syn-14b
anti-14c
syn-14c
anti-14d
3360-3240, 3005, 2870
3460-3380, 3010, 2970
3400-3300, 3005, 2940
3420-3340, 3005, 2940
3510, 3010, 2980, 2880
-
-
5.27 (d, 3.3)
4.95 (d, 7.6)
5.40 (t, 2.4)
5.11 (d, 7.1)
-
-
c
c
3.89 (ddd, 5.8)
3.78-3.91 (m)
3.71 (t, 5.3)
1.84 (s)
2.85 (s)
5.18 (m, 6.4)
3.64 (d, 3.6)
5.18 (m, 4.5) 3.93 (d, 4.3)
a For 13 and 14 the numbering does not follow the IUPAC nomenclature.
b s = singlet, d = doublet, t = triplet, q = quartet, qu = quintet, m = multiplet.
c Not detected.
d Film.
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantio- and Diastereoselective Synthesis
751
Table 6 Selected 13C NMR Data of Compounds 4-6
b-(1,3-Dithian-2-yl)-a,g-alkanediols 11; General Procedure
To a solution of oxazolidine 10 (3.00 mmol) in anhyd CH2Cl2 (30
mL) at 0°C were added propane-1,3-dithiol (1.36 mL, 13.5 mmol)
and MeSO3H (0.19 mL, 3.00 mmol) and this mixture was stirred for
7 h. During this time, the temperature was allowed to rise to 20°C.
For workup, solid powdered K2CO3 (620 mg, 4.5 mmol) was added,
after 10 min stirring the solids were filtered off, the solvent evapo-
rated, and the residue purified by column chromatography on silica
gel with Et2O/pentane (1:1). For yields, dr's, and data of 11 see
Tables 3, 5, and 7.
Product
13C NMR (75 MHz, CDCl3), d
C-2
C-1’
C-2’
4b
4c
5b
6a
6b
88.33
94.21
87.23
87.21
86.94
50.61
45.63
47.45
108.57
106.99
204.88
201.24
204.58
154.43
153.00
5-(1,3-Dithian-2-yl)-1,3-dioxanes 12; General Procedure
A solution of diol 11 (2.00 mmol), pyridinium tosylate (PPTS, 151
mg, 0.60 mmol), and 2-methoxypropene (0.42 mL, 4.40 mmol) in
anhyd CH2Cl2 (25 mL) was stirred for 2 h at 0°C. Sat. aq NaCl (20
mL) was added, the aqueous phase extracted with CH2Cl2 (3 × 20
mL, each). After drying (Na2SO4) and evaporation of the solvent,
the acetonide 12 was purified by LC (Et2O/pentane, 1:12, silica gel).
Diastereomeric mixtures of cis- and trans-12 could be separated by
column chromatography. For yields and data see Tables 3, 5, and 7.
Table 7 Selected 13C NMR Data of Compounds 8a-j and 10-14
Product
13C NMR (75 MHz, CDCl3), d
a
a
a
C-2a
C-1’
C-2’
C-1’’
8a
8b
8c
anti-8d
syn-8d
8e
8f
8g
91.57
91.62
91.62
92.49
93.23
91.66
91.78
91.74
91.64
91.34
90.62
92.10
92.88
92.19
93.10
92.33
93.38
91.08
55.97
55.92
54.15
54.28
51.00
51.82
56.85
54.21
52.39
52.00
49.92
49.85
49.12
53.19
61.24
59.48
61.40
59.34
61.95
59.24
60.65
61.09
61.87
61.29
62.44
61.31
62.28
60.32
55.77
54.26
54.52
51.49
51.58
54.70
56.93
47.60
58.75
60.21
52.83
51.67
53.31
49.94
52.00
47.75
49.14
54.66
47.85
50.45
47.98
50.69
48.16
51.25
47.61
49.17
48.20
49.44
48.98
49.41
47.26
49.82
51.08
49.85
49.24
47.34
46.73
45.05
51.13
52.07
52.76
50.03
51.11
47.17
47.99
52.80
66.52
72.21
70.32
76.49
77.64
68.70
73.48
72.16
76.36
75.19
83.97
66.52
66.25
71.20
72.17
71.48
73.54
73.61
67.87
69.54
72.61
73.54
72.80
73.64
72.14
65.52
67.41
70.54
72.18
71.61
74.30
71.62
66.27
66.40
70.05
70.90
70.65
73.22
70.31
67.73
69.21
73.33
74.59
73.24
76.00
72.88
201.81
202.18
202.24
202.86
201.64
202.35
199.84
202.44
208.44
208.05
211.81
70.81
72.41
72.22
72.89
76.44
76.05
69.42
72.52
74.03
73.79
73.74
77.88
77.43
73.90
71.00
74.19
71.24
74.28
72.89
74.46
72.16
69.70
73.52
71.18
73.63
73.59
73.92
71.94
73.43
75.64
73.81
75.29
77.80
78.79
73.93
5-(Hydroxymethyl)-1,3-dioxanes cis- and trans-13; General
Procedure
To a well-stirred mixture of acetonide 12 (1.00 mmol) and CaCO3
(1.50 g, 15.0 mmol) in acetone/H2O (8 + 1 mL) was added MeI
(1.24 mL, 20.0 mmol). The mixture was refluxed for 24 h before
MgSO4 (approx. 0.5 g) was added for removal of H2O. The solids
were filtered off, the solvent evaporated, and the residue dissolved
in THF (10 mL). This solution was added dropwise to a suspension
of LiAlH4 (190 mg, 5.00 mmol) in anhyd THF (15 mL) and stirring
was continued for 3 h. After diluting the mixture with Et2O (10 mL),
successively H2O (0.19 mL; caution, H2!), 15% aq NaOH solution
(0.19 mL), and H2O (0.57 mL) were added. After addition of
MgSO4 (~0.5 g), the solids were filtered off, and the solution con-
centrated in vacuo. Purification was accomplished by column chro-
matography (Et2O/pentane, 1:2, silica gel). For yields and data see
Tables 3, 5, and 7.
anti-8h
syn-8h
8j
anti-10a
syn-10a
anti-10b
syn-10b
anti-10c
syn-10c
anti-10d
anti-11a
syn-11a
anti-11b
syn-11b
anti-11c
syn-11c
anti-11d
trans-12a
cis-12a
trans-12b
cis-12b
trans-12c
cis-12c
trans-12d
trans-13a
cis-13a
trans-13b
cis-13b
trans-13c
cis-13c
trans-13d
anti-14a
syn-14a
anti-14b
syn-14b
anti-14c
syn-14c
anti-14d
Triols 14; General Procedure
A solution of acetonide 13 (1.00 mmol), propane-1,3-dithiol (0.30
mL, 3.00 mmol) and MeSO3H (2 drops) in CH2Cl2 (5 mL) was
stirred for 4 h at 0°C. Solid K2CO3 (200 mg, 1.45 mmol) was added
and stirring was continued for 10 min before the solids were filtered
off and the solution was concentrated in vacuo. Column chromato-
graphy with Et2O on silica gel yielded the triols 14 as colorless vis-
cous oils. For obtainig analytically pure samples, drying at 0.1 mbar
was essential. For yields and data see Tables 3, 5, and 7.
Acknowledgement
Generous support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
References
#
X-Ray structure analyses.
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a For 13 and 14 the numbering does not follow the IUPAC nomencla-
ture.
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

752
F. Steif et al.
FEATURE ARTICLE
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0.40 × 0.25 × 0.10 mm, a = 10.327(1), b = 10.918(1),
c = 10.457(2) Å,b = 91.72(1)°, V = 1178.5(3) Å3, rcalc = 1.256
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P21 (No. 14), l = 1.54178 Å, T = 223 K, w/2q scans, 2773
reflections collected (±h, ±k, -l), [(sinq)/l] = 0.62 Å-1, 2619
independent and 2425 observed reflections [I _ 2 s(I)], 286
refined parameters, R = 0.039, wR2 = 0.103, max. residual
electron density 0.33 (-0.27) e Å-3, Flack parameter 0.00(2),
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(8) (a) Conde-Frieboes, K.; Hoppe, D. Synlett 1990, 99.
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(26) X-ray crystal structure analysis of anti-11b: formula
C15H22O2S2, M = 298.45, colourless crystal
0.40 × 0.35 × 0.20 mm, a = 8.847(2), b = 8.621(2),
c = 10.871(2) Å, b = 109.63(1)°, V = 780.9(3) Å3,
(9) Reviews:
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(11) For a similiar result with appropriate lithium and cesium
enolates, see Ref. 2f.
(12) For like and unlike notation see:
r
calc = 1.269 g cm-3,m = 30.50 cm-1, empirical absorption
correction via y scan data (0.975 _C _ 0.999), Z = 2,
monoclinic, space group P21 (No. 4), l = 1.54178 Å, T = 223
K, w/2q scans, 1782 reflections collected (±h, +k, +l), [(sinq)/
l] = 0.62 Å-1, 1696 independent and 1688 observed
reflections [I _ 2 s(I)], 176 refined parameters, R = 0.041,
wR2 = 0.109, max. residual electron density 0.62 (-0.48) e
Å-3, Flack parameter 0.04(2), hydrogens calculated and
riding. Data sets were collected with an Enraf Nonius CAD4
diffractometer. Programs used: data reduction MolEN,
Seebach, D.; Prelog, V. (see p. 4) Angew. Chem. Int. Ed. Engl.
1982, 21, 654.
(13) See Refs 7,8 for example.
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Enantio- and Diastereoselective Synthesis
(28) For the synhesis of related triols see:
753
structure solution SHELXS-97, structure refinement
SHELXL-97, graphics SCHAKAL-92. Crystallographic data
(excluding structure factors) for the structures reported in this
paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CSD-138306 (anti-8d) and CSD-138307 (anti-11b). Copies
of the data can be obtained free of charge on application to The
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: int. Code +44(1223)336033, e-mail:
(a) Seebach, D.; Lapierre, J.-M.; Jaworek, W.; Seiler, P. Helv.
Chim. Acta 1993, 76, 459
(b) Knochel, P.; Lütjens, H. Tetrahedron Asymmetry 1994, 5,
1161.
(29) The enantiomeric series is formed from (S)-N-tosylamino
alkanols, derived from naturally occuring amino acids; see
Refs 7,8.
deposit@ccdc.cam.ac.uk].
(27) (a) Fetizon, M.; Jurion, M. J. Chem. Soc., Chem. Commun.
1972, 382.
Article Identifier:
1437-210X,E;2000,0,05,0743,0753,ftx,en;P00700SS.pdf
(b) Wang Chang, H. L. Tetrahedron Lett. 1972, 19, 1989.
Synthesis 2000, No. 5, 743–753 ISSN 0039-7881 © Thieme Stuttgart · New York