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A stereoselective and novel approach to the synthesis of 1,3-diols: simple
control of diastereoselectivity
Rainer Mahrwald*† and Bilgi Gündogan
Institut für Organische und Bioorganische Chemie der Humboldt-Universität Berlin, Hessische Str. 1-2, D-10115 Berlin, Germany
Table 1 Diastereoselective synthesis of 1,3-diols
Complete control of simple diastereoselectivity in the
synthesis of 1,3-diols was realized through the use of a one-
Yielda
(%)
Ratiob
syn/anti
pot aldol addition and reduction process.
Entry
R1
R2
Method Compound
The diastereoselective synthesis of syn and anti 1,3-diols is
currently of considerable interest, as these synthons are
frequently found in a variety of polyketide natural products.
Those diols with two chemically distinct hydroxy groups are of
particular interest, as they are suitable building blocks for
further stereoselective transformations. Multistep and more
particular syntheses were found in the literature (hydro-
silylation1 or alkylmagnesation2 of suitable alkenes, oxidative
cleavage of double bonds,3 reductive rearrangement of alkenyl
acetals4). Moreover there are only a few examples of procedures
for synthesising anti diols.5
Herein, we describe a simple and more general one-pot
procedure for the synthesis of both syn and anti 1,3-diols by the
utilization of titanium Lewis acids. Our studies on diaster-
eoselective aldol additions in the presence of titanium Lewis
acids have outlined a new series of highly regio-6 and stereo-
selective reactions.6,7 Very recently, we described the ster-
eoselective aldol addition of aldehydes with enolizable alde-
hydes in the presence of titanium(IV) chloride.7 The reactions
were accomplished with the aid of an amine base. Surprisingly,
substituting a titanium(IV) alkoxide as a base resulted in
complete reduction of the intermediate b-hydroxy aldehydes
when used in a one-pot procedure (Scheme 1).
Importantly, equimolar amounts of titanium(IV) alkoxides
were added to a mixture of each starting aldehyde and 1 equiv.
titanium(IV) chloride. When using a chloroisopropoxytitanium
agent [i.e. ClTi(OPri)3, Cl2Ti(OPri)2 or Cl3Ti(OPri)] in place of
both titanium(IV) chloride and the titanium(IV) alkoxide no
reactions occurs; neither aldol additions nor reduction processes
are observed.‡
Reactions were carried out in toluene or CH2Cl2; when using
oxygen-containing solvents (Et2O, THF) this described aldol
addition-reduction sequence failed to occur.
1
2
3
4
5
6
7
8
Ph
Ph
Et
Me
Et
Me
Me
Me
Et
A
A
A
A
B
B
B
B
1ac
1bd
1ce
1df
1ac
1bd
1cg
1dh
73
68
81
48
81
72
71
43
9/91
12/88
13/87
15/85
92/8
90/10
86/14
92/8
Pri
Ph
Ph
Et
Me
Me
Pri
a Isolated yields. b Determined for the crude products by 1H and 13C NMR
spectroscopy. Method A: Ti(OPri)4 was added to a mixture of 1 equiv. of
TiCl4 and 1 equiv. of the corresponding starting aldehyde (ref. 5).
(Scheme 1). Method B: the b-hydroxy aldehydes were synthesized by a
literature procedure (ref. 7). After 16 h, 1 equiv. of LiAlH4 was added to the
c
d
e
crude reaction mixture (Scheme 2). Ref. 8. Ref. 2. Ref. 1 and 12.
f Ref. 11. g Ref. 1 and 9. h Ref. 10.
OH
R1 CHO
i, ii
R1
OH
+
R2
R2
CHO
syn - 1
Scheme 2 Reagents and conditions: i, TiCl4, base, 278 °C; ii, LiAlH4
additional reduction process to the corresponding diols takes
place.
Reversal and thus complete control of the simple diaster-
eoselectivity using this one-pot aldol addition-reduction se-
quence was realized through the synthesis of the corresponding
syn 1,3-diols. This was achieved by reduction of the crude aldol
reaction mixture7 with LiAlH4. The 1,3-diols thus obtained
were isolated with a high degree of syn selectivity (see entries
5–8, Table 1 and Scheme 2).
The reaction mechanism is thus likely to be very similiar to a
Meerwein–Ponndorf reduction. No reduction was observed by
using tertiary titanium(IV) alkoxides [e.g. titanium(IV) alkoxides
derived from from ButOH or BINOL]. Thermodynamic equili-
bration occurs during the reduction process. The isolated
1,3-diols were formed with a high degree of anti selectivity
(entries 1–4, Table 1). Similar observations were made in
catalytic equilibration processes of hydroxy aldehydes.7
Utilizating the TiCl4/Ti(OPri)4 system at low temperature
(278 °C) only equilibration of the formed 3-hydroxy aldehydes
is observed, whereas at higher temperatures (0–10 °C) an
This work was supported by Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie.
Notes and References
† E-mail: rainer = mahrwald@rz.hu-berlin.de
‡ General procedure for 1a: propanal (0.72 ml, 10.0 mmol) and
benzaldehyde (1.02 ml, 10.0 mmol) were dissolved in CH2Cl2 ( 20 ml)
under inert conditions. TiCl4 (1.1 ml, 10.0 mmol) was added and the
solution was cooled to 210 °C. After 30 min at this temperature, Ti(OPri)4
(1.5 ml, 5.0 mmol) was carefully added and the solution was stirred for
further 16 h at 5 °C, after which water was added (30 ml) and the resulting
emulsion filtrated through silica gel–sand. The filtrate was extracted with
Et2O (100 ml) and brine (30 ml) until neutral. The organic layer was
separated, dried (Na2SO4), fitrated and evaporated in vacuo. The pure anti
1,3-diol 1a was separated by flash chromatography using hexane–EtOAc
(80:20) as eluent.
OH
R1 CHO
i, ii
R1
OH
+
R2
R2
CHO
anti - 1
1 K. Tamao, T. Nakajima, R. Sumiya, H. Arai, N. Higuchi and Y. Ito,
J. Am. Chem. Soc., 1986, 108, 6090.
Scheme 1 Reagents and conditions: i, TiCl4, CH2Cl2, 5 °C; ii, Ti(OPri)4
Chem. Commun., 1998
2273
Mahrwald, Rainer
