Enantioselective synthesis of syn- and anti-1,3-diols via allyltitanation of unprotected β-hydroxyaldehydes

Article abstract of DOI:10.1021/ol991349y

(Formula presented) Syn- or anti-1,3-diols units were synthesized with excellent diastereomeric excess from unprotected chiral β-hydroxyaldehydes by using an enantioselective allyltitanation.

Full text of DOI:10.1021/ol991349y

ORGANIC
LETTERS
2000
Vol. 2, No. 4
501-504
Enantioselective Synthesis of syn- and
anti-1,3-Diols via Allyltitanation of
Unprotected â-Hydroxyaldehydes
,†
Samir BouzBouz* and Janine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received December 14, 1999
ABSTRACT
syn- or anti-1,3-diols units were synthesized with excellent diastereomeric excess from unprotected chiral â-hydroxyaldehydes by using an
enantioselective allyltitanation.
The 1,3-diol subunit is commonly found in many natural
products.1 The presence of alternating hydroxy groups on a
contiguous carbon chain can be found in a variety of
bioactive organic compounds, including macrolide antibiotics
such as Roxaticin (Figure 1).1b A great variety of methodolo-
used.2,3 In the case of the reductive decyanation of cyano-
hydrin acetonides, syn-1,3-diols are exclusively formed.4 anti-
1,3-Diols are formed by regioselective reductive opening of
the epoxy ring of trans-R-epoxyalcohols.5
The other methods that allow the synthesis of 1,3-diol
subunits are C-C bond-forming reactions. Depending on the
substrates, reagents, and conditions, syn- or anti-1,3-diols
can be synthesized. For example, the reductive lithiation of
O,S-acetals gives lithioethers, which can be alkylated to
provide anti-1,3-diols at low temperature and syn-1,3-diols
when they are alkylated at 0 °C.6,7 The stereocontrolled
homologation of chiral O-glycosylated alkyl radicals by ethyl
trifluoroacetoxyacrylate can result in the clean formation of
syn- and anti-1,3-diols depending on the glycosyl auxiliary.8
Figure 1. Roxaticin.
(2) (a) Narasaka, K.; Pai, F.-C. Chem. Lett. 1980, 1415. (b) Narasaka,
K.; Pai, F.-C. Tetrahedron 1984, 40, 2233. (c) Chen, K. M.; Hardtmann,
G. E.; Prasad, K. Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28
155. (d) Chen, K. M.; Gunderson. K. G.; Hardtmann, G. E.; Prasad, K.
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 1923.
(3) (a) Anwar, S.; Davis, A. P. Tetrahedron 1988, 44, 3761. (b) Evans,
D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
(c) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
(4) Rychnovsky, S. D.; Griesgraber G. J. Org. Chem. 1992, 57, 1559.
(5) Weigand, S.; Bru¨ckner, R. Synlett 1997, 225.
gies have been developed to synthesize these 1,3-diols. An
important way to access these compounds is through a
diastereoselective reduction of â-hydroxyketones since syn-
or anti-diols are obtained depending on the reducing agent
† E-mail: samir.bouzbouz@espci.fr.
(1) (a) Oishi, T.; Nakata, T. Synthesis 1990, 635. (b) Rychnovsky, S. D.
Chem. ReV. 1995, 95, 2021.
(6) Rychnovsky, S. D.; Mickus, D. E. Tetrahedron Lett. 1989, 30, 3011.
(7) Rychnovsky, S. D.; Skalitzky, D. J. J. Org. Chem. 1992, 57, 4336.
10.1021/ol991349y CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/28/2000

Table 1. Preparation of Optically Active syn- or anti-1,3-Diols from â-Hydroxyaldehydes
Sequential ring openings of the C2-symmetric bis-epoxide
through organometallics led to an elegant synthesis of
enantiopure anti-1,3-diols,9-11 and the attack of organome-
tallic reagents on the epoxy ring of â-hydroxyepoxides led
to syn-1,3-diols.12 When 2,2-dimethyl-1,3-dioxan-5-one SAMP-
hydrazones are R,R′-bis-alkylated, precursors of anti-1,3-diols
are obtained.13 In the case of O-protected â-hydroxyalde-
hydes, which are well-suited for the chelation-controlled
addition of organometallic reagents, a wide variety of anti-
configurated 1,3-diols can be obtained.14 Unprotected â-hy-
droxyaldehydes can also be transformed into anti-1,3-diols
via allylboration.15 Syn-selective additions to O-protected or
unprotected â-hydroxyaldehydes are not generally possible
unless one exploits addition reactions with reagent control
of diastereoselectivity.16 Here, we would like to report that
syn- or anti-1,3-diols can be obtained with good to excellent
enantiomeric excess by allyltitanation of nonprotected â-hy-
(8) Graner, P.; Anderson, J. T. Org. Lett. 1999, 1, 1057.
(9) Ley, S. V.; Anthony, N. J.; Armstrong, A.; Brasca, M. G.; Clarke,
T.; Culshaw, D.; Greck, C.; Grice, P.; Jones, A. B.; Lygo, B.; Madin, A.;
Sheppard, R. N.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1989, 45,
7161.
(10) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J.
Org. Chem. 1991, 56, 5161.
(11) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001.
(12) Lipshutz, B. H.; Moretti, R. Crow, R. Tetrahedron Lett. 1989, 30,
15.
(13) Enders, D.; Hendertmark, T. Tetrahedron Lett. 1999, 40, 4169.
(14) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556. (b)
Additions with anti-preference but without chelation control: Evans, D.
A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537.
(15) Kabalka, G. W.; Narayana, C.; Reddy, N. K. Tetrahedron Lett. 1996,
37, 2181.
502
Org. Lett., Vol. 2, No. 4, 2000

Scheme 1. Preparation of Optically Active Homoallylic Alcohols and â-hydroxyaldehydes
droxyaldehydes of type B with cyclopentadienyldialkoxy-
titanium complexes (R,R)-I or (S,S)-II, the anti-1,3-diols 16,
18, and 20 were isolated in high yield (75-83%) and with
diastereoisomeric excesses up to 93%. The formation of syn-
or anti-1,3-diols from unprotected â-hydroxyaldehydes of
type B, by using complex (R,R)-I or (S,S)-II, is general and
the results are summarized in Table 1.
The relative stereochemistry of the 1,3-diols was deter-
mined on compounds 15-22 by converting them to ac-
etonides and analyzing their 13C NMR chemical shifts.21 For
example, the syn-1,3-diol acetonide 23, synthesized from 15,
displays acetal methyl resonances at 19.6 and 30.1 ppm and
the acetal carbon resonates at 98.3 ppm, while the methyl
resonances of the anti-1,3-diol acetonide 24, synthesized
from 16, are at 24.8 ppm and the acetal carbon resonates at
100.1 ppm (Scheme 2).
allyltitanium complexes (R,R)-I or (S,S)-II17 (Figure 2).
â-Hydroxyaldehydes 10-14 were prepared in two steps
by allyltitanation of aldehydes of type A. Treatment of
aldehydes 1-4 with either complexe (R,R)-I or (S,S)-II in
ether at - 78 °C afforded homoallylic alcohols 5-9 with
good enantiomeric excess (ee ) 93-96%)18,19 and in high
yield (85-92%). The transformation of these homoallylic
alcohols to the corresponding â-hydroxyaldehydes 10-14
was achieved by using sodium periodate in the presence of
a catalytic amount of osmium tetraoxide.20
These â-hydroxyaldehydes were unstable and were treated
directly with the allytitanium complexes. When the unpro-
tected â-hydroxyaldehydes 10-14 were treated with the
(R,R)-I, or (S,S)-II complexes, the syn-1,3-diols 15, 17, 19,
21, and 22 were obtained in high yield (78-85%) and with
diastereoisomeric excesses up to 93%. When â-hydroxy-
aldehydes 10, 11, and 12 were treated with the same allyl-
Scheme 2. Formation of Acetonides
It is noteworthy that this methodology affords 1,3-diols
with good to excellent chemical yields and with excellent
diastereomeric excesses regardless of the starting â-hydroxy-
aldehydes. The yield in 1,3-diols depends on the success of
Figure 2. Formation of 1,3-diols.
Org. Lett., Vol. 2, No. 4, 2000
503

the formation of â-hydroxyaldehydes of type B. Sensitive
protecting groups, such as benzoyl and trityl groups, are
tolerated due to the mild reaction conditions and to the neutral
aqueous conditions employed in the workup. Furthermore,
the chiral ligand, TADDOL, can be recovered and recycled
to synthesize the titanium complexes (R,R)-I and (S,S)-II.17
The formation of 1,3-diols from unprotected â-hydroxy-
aldehydes indicates that during this allyltitanation reaction,
the titanium complexes were not chelated to a hydroxy group
since the formation of syn- and anti-1,3-diols depends only
on the (R,R)- or (S,S)-allyltitanium complexes used and not
on the (R)- or (S)-configuration of â-hydroxyaldehydes of
type B. This enantioselective allyltitanation of unprotected
â-hydroxyaldehydes allows an efficient preparation of syn-
or anti-1,3-diols without any protective and deprotective
steps, which enhances the synthetic potential of this orga-
nometallic allylation.
(16) (a) Brown’s allyl-B(Ipc)2: Schreiber, S. L.; Goulet, M, T. J. Am.
Chem. Soc. 1987, 109, 8120. (b) Enolate of (2-hydroxy-1,2,2-triphenylethyl)-
acetate: Mahler, U.; Devant, R. M.; Braun, M. Chem. Ber. 1988, 121, 2035.
(c) 2,5-Dimethylborolane enolate of (1,1-diethylpropylthio)acetate: Du-
plantier, A. J.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7079. (d) 2-(R-
Chloroallyl)-4,5-dicyclohexyl-1,3-dioxo-2-borolane: Hoffman, R. W.;
Stu¨rmer, R. Synlett 1990, 759. (e) Functionalized organozinc reagents: Soai,
K.; Hatanaka, T.; Yamashita, T. J. Chem. Soc., Chem. Commun. 1992, 927.
Knochel, P.; Brieden, W.; Rozema, M. J.; Eisenberg, C. Tetrahedron Lett.
1993, 34, 5881, and references cited heiren.
Acknowledgment. The authors are indebted to Dr. R.
O. Duthaler for a generous gift of chiral cyclopentadienyl-
dialkoxyallyltitanium complexes and C. Ferroud and A.
Falguie`res for HPLC analysis.
(17) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(18) The enantiomeric excess of homoallylic alcohols was determined
by HPLC analysis, Chiralcel-AD2 column (hexane/2-propanol).
(19) All new homoallylic alcohols exhibited satisfactory spectroscopic
data (1H and 13C NMR, IR, MS).
(20) Demuth, M.; Ritterskamp, P.; Weight, E.; Schaffner, K. J. Am. Chem.
Soc. 1986, 108, 4149.
Supporting Information Available: Spectroscopic and
analytical data for 15-24 as well as representative experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31.
945.
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