Synthesis and stereoselective aldol reaction of dihydroxyacetone derivatives

Article abstract of DOI:10.1016/S0040-4039(00)00969-2

Efficient synthetic methods for 1,3-di-O-benzyldihydroxyacetone (3) and 1,3-O-cyclohexylidenedihydroxyacetone (8) were developed. TiCl₄-mediated aldol reaction of the silyl enol ether of 3 with aldehydes gave syn aldol products while the reacti

Full text of DOI:10.1016/S0040-4039(00)00969-2

Tetrahedron Letters 41 (2000) 5909±5913
Synthesis and stereoselective aldol reaction of
dihydroxyacetone derivatives
Kwan Soo Kim* and Sung Don Hong
Department of Chemistry, Yonsei University, Seoul 120-749, South Korea
Received 2 May 2000; revised 7 June 2000; accepted 9 June 2000
Abstract
Ecient synthetic methods for 1,3-di-O-benzyldihydroxyacetone (3) and 1,3-O-cyclohexylidenedihy-
droxyacetone (8) were developed. TiCl4-mediated aldol reaction of the silyl enol ether of 3 with aldehydes
gave syn aldol products while the reaction of the silyl enol ether of 8 with aldehydes a€orded anti aldol
products. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aldol reactions; diastereoselection; enol ethers; enolates.
Enzyme-catalyzed aldol reactions have become one of the most useful biotransformations in
organic synthesis.1 Four dihydroxyacetone phosphate (DHAP)-dependent aldolases are especially
useful for the enantiopure synthesis of ketose sugars and possess an almost perfect ability to
control the stereochemistry of the aldol products. Nevertheless, both enzymes and commercial
DHAP are expensive and relatively unstable and the preparation and handling of DHAP are also
not straightforward.2 More importantly, although the enzymes accept quite a wide range of
aldehyde acceptor substrates, they do not accept many useful aldehydes such as aromatic
aldehydes, sterically hindered aliphatic aldehydes, and a,b-unsaturated aldehydes. Therefore, the
chemical aldol reaction of dihydroxyacetone (DHA) derivatives with aldehydes, which could
provide various intermediates for ketose sugars, would be a useful supplement or alternative to
the enzymatic aldol reaction of DHAP. Surprisingly, however, only a few reactions of enolate of
DHA derivatives are known3 and the aldol reaction of DHA derivatives with aldehydes have not
been investigated,4 perhaps partly because of dicult accessibility to proper DHA derivatives.
Di-O-acyl-DHA is readily available by the direct acylation5 of the commercial DHA (exists as a
dimer), whereas the direct alkylation and the acetalization of the two hydroxyl groups in DHA
have not been realized so that syntheses of di-O-alkyl and acetal derivatives of DHA remain quite
cumbersome procedures.6 Herein, we report the new ecient method for the synthesis of DHA
derivatives including DHA silyl enol ethers and their stereoselective aldol reactions with aldehydes.
* Corresponding author. E-mail: kwan@alchemy.yonsei.ac.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00969-2

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Selective deprotection of tri-O-benzylglycerol (1), which was readily obtained by perbenzylation
of glycerol with benzyl bromide and NaH in DMF, was performed with SnCl4 by the known
procedure7 and the subsequent oxidation of the resultant 1,3-di-O-benzylglycerol (2) with PCC
gave desired 1,3-di-O-benzyl-DHA (3) (Scheme 1). Treatment of the ketone 3 with KN(SiMe3)2
and then addition of TBDMSCl at ^78ꢀC a€orded a mixture of the Z-silyl enol ether 4 and the
E-silyl enol ether 5.8 Flash column chromatography on SiO2 provided pure 4 and 5 in the ratio of
95:5 in 80% yield.9 The assignment of stereochemistry in 4 and 5 was made on the basis of NOE
experiments. Thus, NOE was observed between the vinyl proton at C-1 and the methylene protons
at C-3 in Z-isomer 4 but not in E-isomer 5.
Scheme 1. Reagents and conditions: (i) SnCl4 (1.5 equiv.), CH2Cl2, room temp., 2 h, 81%; (ii) PCC, room temp., 5 h,
72%; (iii) KN(SiMe3)2 (1.2 equiv.), ^78ꢀC, 20 min, then TBDMSCl (1.2 equiv.), ^78ꢀC, 4 h, 80%
Reaction of 2-methylene-1,3-propandiol (6) with cyclohexanone in the presence of TsOH and
subsequent ozonolysis of the resulting cyclohexylidene 7 a€orded 1,3-O-cyclohexylidene-DHA (8)
(Scheme 2). Deprotonation of ketone 8 with KN(SiMe3)2 followed by treatment of the resulting
enolate with TBDMSCl provided silyl enol ether 9 in 78% yield.
Scheme 2. Reagents and conditions: (i) cyclohexanone (1.3 equiv.), TsOH (cat.), benzene, 4 h, 91%; (ii) O3, ^78ꢀC,
then Me2S, 90%; (iii) KN(SiMe3)2 (1.2 equiv.), ^78ꢀC, 20 min, then TBDMSCl (1.2 equiv.), ^78ꢀC, 4 h, 78%
Aldol reaction of the lithium enolate of dibenzyl-DHA 3 with propionaldehyde a€orded an
inseparable 58:42 mixture of syn product 10 and anti product 11 in 80% yield and a similar result
was obtained with benzyloxyacetaldehyde as the electrophile, as shown in Table 1. On the other
hand, the aldol reactions of the lithium enolate of the cyclohexylidene-DHA 8 with both aldehydes
were completely stereoselective to provide only anti aldol products 14 and 15, respectively. When
the inseparable mixture of aldol products 10 and 11 (58:42) was treated with benzoyl chloride and
pyridine in methylene chloride at room temperature, anti aldol 11 was preferentially benzoylated
to give the benzoate 16 and the unreacted syn aldol 10. Carefully repeated ¯ash column chroma-
tography provided pure 10 in 30% yield and a small amount of pure 16.10 Thus, the stereo-
chemistry of the aldol products 10 and 11 was determined by the conversion of 10 and 16 into known
compounds, 5,6-dideoxy-2-threo-hexulose and 5,6-dideoxy-2-erythro-hexulose, respectively.11 The
stereochemistry of 12 and 13 was also determined by a similar manner: again, anti isomer 13 was

5911
more reactive under the benzoylation condition and each separated isomer was converted to
known compounds threo-pentulose and erythro-pentulose, respectively.12 The stereochemistry of
aldol products 14 and 15 was also determined by their conversion to 5,6-dideoxy-2-erythro-hexulose
and erythro-pentulose, respectively.
Table 1
Aldol reactions of the lithium enolates of DHA derivatives with aldehydes
Mukaiyama-type aldol reactions of silyl enol ethers 4 and 9 with aldehydes turned out to be
more stereoselective than the direct aldol reactions of the lithium enolates of 3 and 8. Reaction of
4 and 9 with aldehydes such as propionaldehyde and benzyloxyacetaldehyde mediated by Lewis
acids a€orded aldol products together with silylated aldol products. Without isolation of the
products, treatment of the product mixture with n-Bu4NF or with dilute hydrochloric acid
a€orded desilylated aldol products. The highest diastereoselection was achieved by employing
TiCl4 as the Lewis acid (Table 2). For example, a solution of propionaldehyde (0.54 mmol) and
TiCl4 (0.54 mmol) in CH2Cl2 (1 ml) was stirred at 0ꢀC for 30 min. After the solution was cooled
to ^78ꢀC, a CH2Cl2 solution (2 ml) of silyl enol ether 4 (0.45 mmol) was added slowly to this
solution. After 5 h of stirring at ^78ꢀC, the reaction was quenched with 30 ml of 1 M NaHCO3
and extracted with CH2Cl2. After evaporation of the dried CH2Cl2 solution, the residue was
dissolved in 2 ml of THF. To this solution was added n-Bu4NF (0.3 ml of 1 M solution in THF)
at room temperature. After stirring for a further 4 h, the reaction mixture was diluted with 30 ml
of Et2O and washed with 1 M NaHSO4 followed by chromatography to give a mixture of 10 and
11 in 85% yield (10:11=95:5). TiCl4-mediated reaction of 4 with benzyloxyacetaldehyde almost
exclusively gave the syn product 12 (syn 12/anti 13=>99.5:<0.5).
.
Other Lewis acids such as BF3 OEt2 and SnCl4 showed much reduced stereoselectivity. The
Lewis acid-promoted aldol reaction of the cyclohexylidene silyl enol ether 9 with both aldehydes
gave exclusively anti aldol products 14 and 15 regardless of which Lewis acid was used. Other
aldehydes such as benzaldehyde and phenylacetaldehyde also showed the similar stereoselectivity
in the aldol reaction with both silyl enolate and lithium enolate.13 The stereochemical outcome of
TiCl4-mediated aldol reactions of silyl enol ethers 4 and 9 with aldehydes could be explained by

5912
Table 2
Lewis acid-mediated aldol reactions of silyl enol ethers of DHA derivatives
assuming a transition state of the Zimmermann±Traxler type14 rather than the usual acyclic
extended transition state or the silatropic ene reaction mechanism.15 Similar stereochemical results
in the aldol reactions of O-silyl ketene acetals with aldehydes have been reported.14,16 We are
currently searching for a chiral catalyst for the enantioselective aldol reaction of DHA derivatives
with high ee.
Acknowledgements
This research was supported by a grant from the Center for Molecular Design and Synthesis
(CMDS) at KAIST and by grant 971-0302-014-2 from the Basic Research Program of the
KOSEF.
References
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5913
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1
9H), 3.78 (s, 2H), 4.47 (s, 2H), 4.76 (s, 2H), 5.75 (s, 1H), 7.25±7.37 (m, 10H); 13C NMR (CDCl3, 62.9 MHz) ꢀ ^4.3,
18.1, 25.9, 70.1, 71.3, 74.0, 127.5, 127.8, 127.9, 128.1, 128.4, 128.6, 131.6, 132.9, 137.4, 138.5. Compound 5:
Rf=0.72 (silica gel, hexane:ethyl acetate, 3:1); 1H NMR (CDCl3, 250 MHz) ꢀ 0.07 (s, 6H), 0.86 (s, 9H), 4.09 (s, 2H),
4.45 (s, 2H), 4.68 (s, 2H), 6.09 (s, 1H), 7.23±7.34 (m, 10H). All new compounds gave satisfactory spectroscopic and
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(m, 1H), 3.94 (d, J=9.8 Hz, 1H), 4.37 (s, 2H), 4.47±4.64 (m, 4H), 7.25±7.36 (m, 10H); 13C NMR (CDCl3, 62.9
MHz) ꢀ 10.1, 25.7, 73.5, 73.7, 73.8, 74.1, 86.0, 127.9, 128.2, 128.5, 128.6, 128.7, 136.8, 137.1, 208.1. Compound 16:
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