Synthesis of chiral 1,3-diols by radical-mediated regioselective opening of 2,3-epoxy alcohols using cp2TiCl

Article abstract of DOI:10.1016/S0040-4039(02)00241-1

Radical-mediated opening of chiral 2,3-epoxy alcohols 1a-e, regioselectively at the 2-position, using cp₂TiCl in the absence of a hydrogen source leads to the formation of the 1,3-diols 2a-e.

Full text of DOI:10.1016/S0040-4039(02)00241-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2313–2315
Synthesis of chiral 1,3-diols by radical-mediated regioselective
opening of 2,3-epoxy alcohols using cp2TiCl
Tushar K. Chakraborty* and Sanjib Das
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 November 2001; revised 17 January 2002; accepted 31 January 2002
Abstract—Radical-mediated opening of chiral 2,3-epoxy alcohols 1a–e, regioselectively at the 2-position, using cp2TiCl in the
absence of a hydrogen source leads to the formation of the 1,3-diols 2a–e. © 2002 Published by Elsevier Science Ltd.
Although nucleophilic ring-opening reactions of epox-
ides are routinely used by synthetic organic chemists to
construct a wide variety of structural moieties for use in
the total synthesis of natural products, corresponding
radical-mediated methods have found fewer applica-
tions.1 A novel radical-mediated epoxide opening reac-
tion using cp2TiCl and cyclohexa-1,4-diene was
developed by us2 and successfully employed to con-
struct 1,3-diols that are found in many polyketide
natural products.3–5 However, one hurdle that made its
application in large-scale preparations somewhat prob-
lematic was the need for an excess of the hydrogen
donor, cyclohexa-1,4-diene, a cancer suspect agent. In
this communication, we now report that the same reac-
tion can be performed with almost equal efficiency in
the absence of any hydrogen source. This method is
particularly valuable for the synthesis of 2-alkyl-1,3-
diols.
time, typically 12–18 h. No 1,2-diol was formed in any
of these reactions. The presence of cyclohexa-1,4-diene,
previously used2–5 as the hydrogen source for similar
transformations, was found to be redundant. The
results of our study are summarized in Table 1.
In THF–MeOH (2:1) cp2TiCl opens a,b-epoxy
ketones,10 whereas under nonprotic conditions it often
leads to b-hydride elimination to give olefins as the
major products as observed by us earlier in certain
substrates11,12 and also by others.13 In the present study
where the reactions were carried out in THF alone, no
b-hydride elimination was noticed. Although the iso-
lated yields are somewhat lower as compared to our
earlier results,2 diastereoselectivities for the trisubsti-
tuted substrates 1c–e were found to be excellent with no
trace (2c) or very little of other isomers (2d, 2e) seen in
the 1H NMR spectra of the products. The slight
decrease in the yields can be attributed to the longer
lifetime of the highly reactive radical intermediates in
the reaction medium that probably leads to unidentified
side-reactions. The six-membered cyclic Ti(IV) complex
II (Scheme 1), with a stable carbon radical at the
2-position that was postulated by us2,14 to be the inter-
mediate in this epoxide opening reaction possibly
remains intact due to the absence of any hydrogen
source until the reaction was subjected to an aqueous
work-up using dilute HCl.15 Hydrogen abstraction by
the carbon radical (II“III) is believed to be faster than
the acid hydrolysis of TiꢀO bonds and is consistent
with the excellent diastereoselectivities observed in these
reactions. This is further supported by the fact that the
same reaction using a catalytic amount of the Ti-
reagent according to the reported procedure8,9 led to
complete loss of diastereoselectivity, a fact that was
observed by us earlier. As the cyclic Ti(IV)-intermediate
While Ti(III) is known to open trisubstituted epoxides
at the more substituted carbon in presence of cyclo-
hexa-1,4-diene,6 in the absence of any hydrogen donor
it converts disubstituted 2,3-epoxy alcohols readily into
their corresponding 3-hydroxy allylic alcohols.7 In
recent years, a Ti-catalytic version of the former reac-
tion has been developed.8,9 We observed that di- as well
as trisubstituted 2,3-epoxy alcohols 1a–e open regiose-
lectively at the 2-position on treatment with cp2TiCl,
generated in situ from cp2TiCl2, to give the correspond-
ing 1,3-diols as the only isolable products when the
reactions were allowed to run for a longer period of
Keywords: epoxy alcohols; Katsuki–Sharpless reactions; epoxide
opening; 1,3-diol.
* Corresponding author. Fax: +91-40-7160387, 7160757; e-mail:
chakraborty@iict.ap.nic.in
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00241-1

2314
T. K. Chakraborty, S. Das / Tetrahedron Letters 43 (2002) 2313–2315
Table 1. Opening of 2,3-epoxy alcohols (1) using cp2TiCl
changed from red to dark green. It was then cooled to
−20°C and a solution of epoxy alcohol 1 in dry THF
was added slowly with a syringe. The final volume of
the reaction mixture was about 15 mL per mmol of 1.
The reaction mixture was allowed to warm to room
temperature over a period of 2 h and stirring continued
for an additional 12–16 h while the color of the reaction
mixture changed from dark green to dark blue. The
reaction was then quenched by slow addition of 1N
HCl and extracted with EtOAc. Regular work-up was
followed by purification of the crude product by stan-
was believed to be responsible for the observed diastereo-
facial selectivity during the hydrogen abstraction by the
radical center at the 2-position, protonation of the
TiꢀO bonds as soon as they were formed by collidine.
HCl in the catalytic version of the reaction8,9 results in
the loss of selectivity as it opens up the intermediate.
The starting materials listed in Table 1 were prepared
according to reported procedures (1a,16 1b,17 1c17 and
1d4) from the corresponding allylic alcohols using
Sharpless asymmetric epoxidation and kinetic resolu-
tion methods.18,19 The chiral allylic alcohol (>96% e.e.
by Mosher ester method), obtained during the prepara-
tion of 1d by kinetic resolution, was subjected to
mCPBA epoxidation to give a mixture of syn and anti
epoxy alcohols (3:2 ratio) that could be easily separated
by column chromatography to furnish pure 1e. Reduc-
tion of cp2TiCl2 was carried out using dry activated Zn
powder with or without ZnCl2. The optimum ratios of
the reagents in both methods are given in Table 1. In a
typical experiment, cp2TiCl2 was added to a magneti-
cally stirred suspension of dry activated Zn powder in
dry THF (with, or without, freshly fused anhydrous
ZnCl2) at room temperature under a nitrogen atmo-
sphere. The mixture was stirred at room temperature
for 1 h while the color of the reaction mixture gradually
R2
R2
cp2TiCl,
THF
O
O
R3
R3
R1
R1
OH
OTiIIIcp2
1
I
[R2 = H or Me]
R2
R2
H
R3
R1
R1
R3
.
Hydrogen
dil. HCl
2
O
O
O
O
abstraction
IV
IV
Ti
Ti
Cp2
Cp2
III
II
Scheme 1.

T. K. Chakraborty, S. Das / Tetrahedron Letters 43 (2002) 2313–2315
2315
dard silica gel column chromatography to furnish the
diol 2. The products were compared with known com-
pounds prepared by us earlier2–5,14,17 and confirmed
further by 13C NMR analysis of their acetonides.
4. Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett. 2001,
42, 1375–1377.
5. Chakraborty, T. K.; Das, S.; Raju, T. V. J. Org. Chem.
2001, 66, 4091–4093.
6. RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am.
Chem. Soc. 1990, 112, 6408–6409.
7. Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem.
Soc., Chem. Commun. 1990, 843–844.
8. Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem.,
Int. Ed. 1998, 37, 101–103.
9. Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.
Soc. 1998, 120, 12849–12859.
The findings communicated here for the synthesis of
chiral 1,3-diols from 2,3-epoxy alcohols using a Ti(III)-
mediated ring opening reaction that can be carried out
with excellent diastereoselectivity with trisubstituted
substrates will find useful applications in the synthesis
of many natural products that carry such structural
moieties.
10. Hardouin, C.; Chevallier, F.; Rousseau, B.; Doris, E. J.
Org. Chem. 2001, 66, 1046–1048.
11. Chakraborty, T. K.; Dutta, S. Tetrahedron Lett. 1998, 39,
101–104.
Acknowledgements
12. Chakraborty, T. K.; Laxman, P. J. Ind. Chem. Soc. 2001,
78, 45–47.
13. Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.; Valdi-
via, M. V. J. Org. Chem. 2001, 66, 4074–4078.
14. Chakraborty, T. K.; Das, S. J. Ind. Chem. Soc. 1999, 76,
611–616.
The authors wish to thank Drs. A. C. Kunwar and M.
Vairamani for NMR and mass spectroscopic assistance,
respectively, and UGC, New Delhi for research fellow-
ship (S.D.).
15. The referee has pointed out that THF can also be consid-
ered as the hydrogen atom source for the transformation
of II“III (Scheme 1).
16. Rao, A. V. R.; Chakraborty, T. K.; Purandare, A. V.
Tetrahedron Lett. 1990, 31, 1443–1446.
17. Chakraborty, T. K.; Das, S. unpublished results.
18. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
References
1. (a) Li, J. J. Tetrahedron 2001, 57, 1–24; (b) Taylor, S. K.
Tetrahedron 2000, 56, 1149−1163. It is not possible to list
all the references here. However, a quick search in http://
organic.chemweb.com under ‘ring opening of epoxides’
will provide a complete list of relevant references.
2. Chakraborty, T. K.; Dutta, S. J. Chem. Soc., Perkin
Trans. 1 1997, 1257–1259.
19. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299.
3. Chakraborty, T. K.; Das, S. Chem. Lett. 2000, 80–81.