Catalytic enantioselective addition of diethylzinc to 1,3-dithian-2-yl substituted aliphatic aldehydes: A new approach to optically active 2-(hydroxyalkyl)-1,3-dithianes

Article abstract of DOI:10.1016/S0957-4166(00)00029-X

Asymmetric synthesis of 2-(hydroxyalkyl)-1,3-dithianes was achieved in good yields of up to 81% by using various 1,3-dithian-2-yl-substituted aliphatic aldehydes as substrates in the catalytic enantioselective addition of diethylzinc. With fair enantiomeric ratios of up to 85:15 in the enantiocontrolled ethylation step this synthetic approach provides an entry towards potential chiral building blocks. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00029-X

Tetrahedron: Asymmetry 11 (2000) 1067±1071
Catalytic enantioselective addition of diethylzinc to
1,3-dithian-2-yl substituted aliphatic aldehydes:
a new approach to optically active
2-(hydroxyalkyl)-1,3-dithianesy
Jorg Wilken,a Martin Winter,b Ingfried Stahlb and Jurgen Martensc,*
aHoneywell, Specialty Chemicals, Riedel-de Haen GmbH, Wunstorfer Str. 40, 30926 Seelze, Germany
È
bUniversitat Gesamthochschule Kassel, Heinrich-Plett-Str. 40, 34109 Kassel, Germany
È
cFachbereich Chemie der Universitat Oldenburg, Carl-von-Ossietzky-Str. 9-11, D-26129 Oldenburg, Germany
È
Received 4 January 2000; accepted 18 January 2000
Abstract
Asymmetric synthesis of 2-(hydroxyalkyl)-1,3-dithianes was achieved in good yields of up to 81% by
using various 1,3-dithian-2-yl-substituted aliphatic aldehydes as substrates in the catalytic enantioselective
addition of diethylzinc. With fair enantiomeric ratios of up to 85:15 in the enantiocontrolled ethylation
step this synthetic approach provides an entry towards potential chiral building blocks. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The broad application of 1,3-dithianes as protecting groups for the carbonyl functionality,1 as
nucleophilic acyl anion equivalents,2 or as masked methylene functions,3 prompted us to develop
a general synthetic approach to chiral 2-(hydroxyalkyl)-1,3-dithianes which give access to highly
versatile chiral building blocks such as (hydroxyalkyl)aldehydes or -ketones with a stereogenic
secondary alcohol function. The enantiocontrolled catalytic dialkylzinc reaction seemed to hold
considerable promise in this direction since the starting materialsÐ1,3-dithian-2-yl substituted
aldehydesÐare readily available from 1,3-dithianes,4 and deprotection of the resulting alkylation
products 2 accomplished by various methods5 should result in the desired products.
* Corresponding author. E-mail: juergen.martens@uni-oldenburg.de
y
Dedicated to Heribert O€ermanns on the occasion of his 62nd birthday.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00029-X

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2. Results and discussion
Initial experiments were focused on the evaluation of some general aspects of the diethylzinc
reaction: looking at the results displayed in Tables 1 and 2 it becomes apparent that the ethyl-
ation of short chain aliphatic aldehydes possessing a cyclic S,S-moiety would pose diculties.
The problems in reaching satisfactory enantioselectivities in the reaction of short, straight chain
aldehydes6 are displayed in Table 1 (four examples, maximum e.r.: 83:17, entry 4).
Table 1
Enantioselective addition of diethylzinc to aliphatic aldehydes at room temperature catalyzed by ligands
A and B
Table 2
Addition of diethylzinc to benzaldehyde at room temperature (20±25ꢀC) catalyzed by 1,3-dioxane,
1,3-dithiane and 2-methyl-1,3-dithiane; product: (RS)-1-phenylpropan-1-ol; reaction time: 24 h
Table 2 demonstrates a signi®cant `ligand acceleration' for the otherwise very slow diethylzinc
addition to benzaldehyde7 caused by substrate-like structures such as 1,3-dithiane (or 1,3-dioxane).
Thus, the reaction rate of the catalyst-promoted ethylation reaction, which has to be considerably
faster than the competing substrate-catalyzed pathway (yielding the corresponding racemic
secondary alcohols and responsible for low e.r.s), is of utmost importance for an ecient stereo-
selective conversion of 1,3-dithian-2-yl substrates.
To slow down the unwanted side reaction and to enhance the accelerating e€ect and the
stereocontrol of the catalyst a non-polar solventÐhexaneÐwas chosen. Due to the precipitation
of a diethylzinc/dithiane complex in hexane/toluene mixtures (Table 3, entry 9)Ðsigni®cantly
diminishing the aldehyde concentration in solutionÐthe isolated yield after 48 h reaction time is

J. Wilken et al. / Tetrahedron: Asymmetry 11 (2000) 1067±1071
1069
Table 3
Enantioselective addition of diethylzinc to 1,3-dithian-2-yl-substituted aliphatic aldehydes (substrate
1a±c11±13) at room temperature (20±25ꢀC) catalyzed by ligands A, B and C; products: 2a±c
only 6%. The molar ratio of diethylzinc to 3-(2-methyl-1,3-dithian-2-yl)propanal had to be
increased to 3:1 to get a detectable conversion of the substrate. An excess of more than 4 equiv.
diethylzinc in hexane does not increase the yield any further (entry 9).
As a consequence, toluene was chosen as the solvent for the following experiments. An excess
of 2 equiv. of diethylzinc in toluene,8 and a reaction time of 20 h at room temperature, proved to
be sucient for the conversion of 1,3-dithian-2-yl substituted aldehydes (entries 10±12): 1-(2-
methyl-1,3-dithian-2-yl)-3-pentanol (product 2a, Scheme 1), 1-(1,3-dithian-2-yl)-3-pentanol (product
2b) and 1-(2-phenyl-1,3-dithian-2-yl)-2-butanol (product 2c) are obtained in maximum yields of 69,
76 and 81% (Table 3, entries 11, 14 and 17), respectively. The limitations in terms of enantio-
selectivity using (+)-N-methyl-ephedrine (Table 3, ligand A: entries 9, 13 and 16) as the catalyst
precursor prompted us to test other ligands (B and C)9 to improve the stereocontrol in the ethyl-
ation reaction. The results obtained with these ligands are also given in Table 3: With e.r.s ranging
Scheme 1.

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from 75:25 to 85:15 (Table 3, entries 14, 15, 17 and 18) structures B and C exhibit a very good
performanceÐconsidering the low ligand concentration of only 3 mol% used in these reactions.
In conclusion, the catalytic enantioselective addition of diethylzinc to 1,3-dithian-2-yl-sub-
stituted aliphatic aldehydes provides a practical method for the preparation of highly versatile,
enantiomerically enriched building blocks. With enantiomeric ratios of up to 85:15 (for 1-(1,3-
dithian-2-yl)-3-pentanol 2b) promising results were obtained utilizing only 3 mol% of the catalyst
precursor. A process optimization focused on the reaction temperature, catalyst concentration
and ligand structure is currently under way.
Acknowledgements
We express our thanks to Degussa-Huls AG, Hoechst AG, Witco GmbH, the Fonds der
Chemischen Industrie and the Zentrale Forschungsforderung der Universitat Gesamthochschule
Kassel for the generous provision of chemicals and for ®nancial support.
References
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11. Synthesis of 3-(2-methyl-1,3-dithian-2-yl)-propanal 1a via lithiation of 2-methyl-1,3-dithiane with n-butyllithium,
alkylation with 2-(2-bromoethyl)-1,3-dioxolane (yield after ¯ash chromatography: 91%) and, ®nally, removal of
the aldehyde-protecting group by hydrolysis with 2N HCl (yield after distillation: 95%), a colorless oil (b.p.:
110ꢀC at 0.2 torr), product characterization by H and 13C NMR spectroscopy.
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12. Synthesis of 3-(1,3-dithian-2-yl)-propanal 1b via lithiation of 1,3-dithiane with n-butyllithium, alkylation with 2-
(2-bromoethyl)-1,3-dioxolane (yield: 88%) and treatment with 2N HCl (yield after distillation: 92%); product: a
1
colorless oil, characterization by H and 13C NMR spectroscopy.
13. Synthesis of 2-(2-phenyl-1,3-dithian-2-yl)-ethanal 1c via lithiation of 2-phenyl-1,3-dithiane with n-butyllithium,
alkylation with bromoacetaldehyde diethyl acetal (yield: 73%) and treatment with 2N HCl (yield after crystal-
lization from methanol: 71%); product: slightly green crystals; product m.p.: 62ꢀC, characterization by H and
1
13C NMR spectroscopy.