Enantioselective allyltitanations. Synthesis of optically active 1,2- diol units: Useful intermediates for the preparation of biologically active compounds

Article abstract of DOI:10.1016/S0957-4166(99)00390-0

1,2-Diol units were synthesized with excellent enantiomeric excess by using an enantioselective allyltitanation of α-alkoxy-substituted aldehydes.

Full text of DOI:10.1016/S0957-4166(99)00390-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3859–3862
Enantioselective allyltitanations. Synthesis of optically active
1,2-diol units: useful intermediates for the preparation of
biologically active compounds
Janine Cossy,a,∗ Samir Bouzbouz a,∗ and Jean Claude Caille b
aLaboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
bPPG-Sipsy, Route de Beaucouzé, 49242 Avrillé Cedex, France
Received 9 August 1999; accepted 3 September 1999
Abstract
1,2-Diol units were synthesized with excellent enantiomeric excess by using an enantioselective allyltitanation
of α-alkoxy-substituted aldehydes. © 1999 Elsevier Science Ltd. All rights reserved.
For developing more efficient drugs, the synthesis of analogues or isosteric compounds has been
the focus of intense research synthetically and medicinally.1 For example, a new structural class of
protein kinase C inhibitors related to the naturally occuring staurosporine, such as LY 333531, has been
developed and synthesized from A and the bis-alkylating agent derived from triol derivative 1.2–4 In the
case of the isosteric phosphonate (IP) of ganciclovir monophosphate (GMP), which is an effective in
vitro and in vivo inhibitor of human cyto-megalovirus (HCMV) replication, its synthesis was performed
from B and chlorodiol derivative 2.5
In support of these studies, a synthetic route that would be useful for the preparation of compounds
(−)-1 and (+)-2 is required. For our part, we used an enantioselective allyltitanation of aldehydes to
synthesize these two compounds.
∗
Corresponding authors. E-mail: janine.cossy@espci.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00390-0

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Compound (−)-1 was first synthesized from the expensive (R)-1-chloro-2,3-propanediol (ee=98%)
in five steps with an overall yield of 45–55%.2,4 In the case of compound (+)-2, a limited number of
methods exist for the construction of this synthon. For example, it can be synthesized from L-arabinose
in eight steps with an overall yield of 4%.5 Here, we report a simple synthesis of compound (−)-
1 and (+)-2 from the inexpensive allylic alcohol 5, with high yield and with excellent enantiomeric
excess, by using an enantioselective allyltitanation of an aldehyde with optically active cyclopentadienyl
dialkoxyallyltitanium complexes (R,R)-3 or (S,S)-4.6
The synthesis of compound (−)-1 was achieved from allylic alcohol 5 in five steps (Scheme 1). The
allylic alcohol was transformed to the trityl ether 6 (TrCl, pyr, yield 99%) and oxidized to the aldehyde
7 (yield 90%) by oxidative cleavage of the double bond, using NaIO4/OsO4 in ether/H2O. Cyclo-
pentadienyl[(4R,trans)-2,2-dimethyl-α,α,α0 ,α0-tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O0]-2-
propenyltitanium (R,R)-36 was then added to aldehyde 7 (ether, −78°C) to produce the homoallylic
alcohol (−)-8 with an (S)-configuration and with an enantiomeric excess up to 95%.7 The allylation of
(−)-8 by allyl bromide under basic conditions (KOBut/THF) afforded (−)-94 in 98% yield. Ozonolysis
of (−)-9 in a 1:1 mixture of CH2Cl2/MeOH at −50°C followed by the treatment of the reaction mixture
with a 0.05 N solution of NaBH4 in NaOH gave diol (−)-14 in 83% yield. Compound (−)-1 was thus
synthesized from allylic alcohol with an overall yield of 66.6% and with an enantiomeric excess up to
95%.
The synthesis of compound (+)-2 was also achieved from allylic alcohol 5 in six steps (Scheme 2).
After treatment of the allylic alcohol with benzoyl chloride in pyridine at 25°C the corresponding
ester 10 was obtained (97%) and converted to aldehyde 11 by using NaIO4/OsO4 (ether/H2O, 25°C,
yield: 92%). Treatment of aldehyde 11 with the cyclopentadienyl[(4S,trans)-2,2-dimethyl-α,α,α0 ,α0-

J. Cossy et al. / Tetrahedron: Asymmetry 10 (1999) 3859–3862
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Scheme 1. Synthesis of the 1,2-diol unit used in the synthesis of LY 333531a
tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O0 ]-2-propenyltitanium (S,S)-46 (ether, −78°C) afforded
the homoallylic alcohol (+)-128 with an (R)-configuration and with an enantiomeric excess up to 96%.7
It is worth noting that this allyltitanation is chemoselective as the ester functionality is not reactive
under these conditions. Treatment of (+)-12 with dimethoxymethane in methylene chloride in the
presence of diisopropylethylamine provided the methoxymethyl ether (−)-138 in a 93% yield. At this
point, compound (−)-13 was transformed to the primary alcohol (+)-148 by oxidative cleavage of the
unsaturation (O3, CH2Cl2, −78°C), and the in situ reduction of the resulting aldehyde (NaBH4, 0°C).
Conversion of the primary alcohol (+)-14 to the chloride (CCl4, PPh3, CH3CN) gave compound (+)-25
in 81% yield. Chloride (+)-2, which is used in the synthesis of IP, was synthesized in six steps with an
overall yield of 54% and with an enantiomeric excess up to 96%.
Scheme 2. Synthesis of the 1,2-diol unit used in the synthesis of IPa
The use of optically active allyltitanium reagents for the allylation of aldehydes is a very versatile
approach as (S)- or (R)-allylic alcohols can be obtained with good yield and with high enantiomeric
excess. This is illustrated by the synthesis of compounds (−)-1 and (+)-2 which were obtained in a few
steps from a very inexpensive starting material. We have to point out that sensitive functional groups are

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tolerated when the allytitanation reaction is used due to the selectivity of the reagents and to the neutral
aqueous conditions employed in the work-up. Furthermore, the chiral ligand, TADDOL, can be recovered
and recycled to synthesize the titanium complexes (R,R)-3 and (S,S)-4.6
Acknowledgements
The authors are indebted to Dr. R. O. Duthaler for the generous gift of chiral cyclopentadienyl
dialkoxyallyltitanium complexes, C. Ferroud and A. Salguières for HPLC analysis and to PPG-Sipsy
for financial support.
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