Asymmetric dihydroxylation of heteroaromatic acrylates

Article abstract of DOI:10.1016/S0040-4039(02)02605-9

N- and O-Heteroaromatic acrylates were dihydroxylated with high ees and good yields. While the AD of pyridyl and pyrryl acrylates afforded diverse yields under the present reaction condition, some corresponding N-substituted pyridyl and pyrryl acrylates (

Full text of DOI:10.1016/S0040-4039(02)02605-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 493–495
Asymmetric dihydroxylation of heteroaromatic acrylates
Zhi-Xiang Feng and Wei-Shan Zhou*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 3 September 2002; revised 7 November 2002; accepted 15 November 2002
Abstract—N- and O-Heteroaromatic acrylates were dihydroxylated with high ee’s and good yields. While the AD of pyridyl and
pyrryl acrylates afforded diverse yields under the present reaction condition, some corresponding N-substituted pyridyl and pyrryl
acrylates (1d, 1e, 1g) proved to be appropriate substrates. The diols obtained can be used as chiral building blocks for the
synthesis of various biologically active molecules. © 2002 Elsevier Science Ltd. All rights reserved.
The important application of optically active a-hydroxy-
furyl and a-hydroxypyrryl derivatives is that they can
be converted into the dihydropyranone derivatives via
oxidation1 with mCPBA, NBS, TBHP or by kinetic
resolution methods.2 Furthermore, a-hydroxyfuryl
compounds can be converted to be a-aminofurfuryls3
which can be easily transformed into the dihydropyri-
done derivatives by the similar methods as mentioned
above.4 Both dihydropyranone and dihydropyridone
derivatives are very useful for the synthesis of various
biologically active compounds such as piperidine alka-
loids,5 polyhydroxy indolizidine alkaloids,6 styryl
lactones7and steroids.8 Meanwhile, pyridyl-substituted
diols are a class of potentially valuable versatile build-
ing blocks for the synthesis of polyhydroxy indolizidine
alkaloids.9
ral diols which can be also regarded as a type of
a-hydroxyheteroaromatic derivatives, although recently
ADs of other different vinyl furan derivatives3c,10 and
thiophene acrylates have been reported.11
Herein we report our first application of AD to the
furyl acrylates as well as pyridyl and pyrryl acrylates, to
give chiral building blocks (Scheme 1).12
The acrylates 1a–g were readily synthesized by Wittig–
Horner reactions from the corresponding aldehydes and
1f can be also prepared by Heck reaction13 from 2-
chloropyridine. Initially, like Bonini’s groups results,11
we found that when all substrates were subjected to the
standard AD condition (1 mol% of the ligand), they
reacted very slowly at room temperature. So we
increased the amount of the ligand from 3 to 10 mol%
and found that more ligand accelerates the reaction but
different yields under the conditions of 3 and 10 mol%
of the ligands were the same after 24 h. Therefore, we
chose to perform the AD reaction with 3 mol% of the
ligand. The AD of 1a proceeded smoothly in 73 and
75% yields based on 55 and 60% conversions at 25°C
Our laboratory has prepared chiral a-hydroxyfuryl7a
and a-hydroxypyrryl1d derivatives using kinetic resolu-
tion. However, we have not found in the literature
examples of successful asymmetric dihydroxylation
(AD) of heteroaromatic acrylates such as furyl, pyrryl
and pyridyl acrylates for preparing corresponding chi-
Scheme 1.
Keywords: asymmetric dihydroxylation; heteroaromatic acrylates; building blocks.
* Corresonding author. Tel.: 86-21-64163300; fax: 86-21-64166128; e-mail: zhws@pub.sioc.ac.cn
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02605-9

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Z.-X. Feng, W.-S. Zhou / Tetrahedron Letters 44 (2003) 493–495
with >99% ee’s (entries 1 and 2). However, when
increasing the electron density in the furan moiety by
inclusion of a methyl substituent, the AD occurred with
lower enantioselectivity (entry 4, 90% ee). The reactions
of 1a and 1b were carried out at room temperature for
only 12 h, since after that period, many by-products
appeared due to the decomposition of furyl ring. Occa-
sionally, we found that the ee changed slightly if 3
mol% (DHQD)2PHAL was added to the reaction mix-
ture of 1a containing 3 mol% (DHQ)2PHAL after 1 h
(entries 1 and 3), which revealed that osmium almost
fully coordinated with (DHQ)2PHAL after 1 h and
(DHQD)2PHAL rarely substituted (DHQ)2PHAL from
the complex. This observation provided the evidence
for the mechanism of AD:14 the second catalytic cycle
was inhibited under the reaction conditions, so that
high ee’s (96.0 and 99.2%) were obtained. Pyrrole
derivative 1c proved to be a problematic substrate
(entries 5 and 6), most likely due to the coordination of
the nitrogen atom with osmium and the sensitivity of
the pyrrole ring to oxidation. The yield from 1c was
very low and the product was unstable. However,
unlike their asymmetric aminohydroxylation (AA),15
N-tosyl and N-benzyl protected pyrrole acrylates 1d
and 1e proved to be excellent substrates for the AD and
the reaction time could be prolonged to 24 h because of
the stability of protected pyrrole ring to oxidation,
resulting in full conversion, good yields, and high ee’s
(entries 7–10, 89–95% isolated yields of diols, >98%
ee’s).
To explore new concise routes to synthesize biologically
active polyhydroxyindolizidine alkaloid lentiginosine16
and its analogs, we hope to employ the pyridyl-substi-
tuted diol derivatives as the key building blocks. Based
on this idea, we made efforts to extend the AD to
pyridyl acrylate 1f. Unfortunately, the AD proceeded
sluggishly and only 18–20% yields were obtained with
substantial recovery of the starting material (entries
11 and 12), a result similar to that of the AA of
Table 1. Asymmetric dihydroxylation of heteroaromatic acrylatesa

Z.-X. Feng, W.-S. Zhou / Tetrahedron Letters 44 (2003) 493–495
495
2-vinylpyridine reported previously.17 More ligand
proved to be profitable for the AD of electron deficient
olefins,11 but increasing 10 mol% of the ligand did not
improve the yield. A reasonable explanation is that the
nitrogen atom on the pyridine ring interferes with the
catalytic cycle by chelating with osmium. Therefore, we
turned to a pyridine derivative in which the nitrogen
functionality is blocked in order not to interfere with
the catalytic cycle. We chose the N-oxide 1g, which can
be easily obtained from 1f by oxidation with
mCPBA.15b Indeed, this derivative readily underwent
AD, giving rise to the N-oxide of pyridyl-substituted
diols with good yields and excellent enantioselectiviti-
ties (entries 13 and 14, 75% and 80% yields based on 52
and 53% conversions, >99% ee’s). The derivatives
obtained were particularly favorable for the synthesis of
polyhydroxyindolizidine alkaloid lentiginosine and its
analogs, the accompanying paper describes the total
synthesis of lentiginosine.18
1999, 10, 3649–3658; (d) Battaglia, A.; Barbaro, G.;
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polyhydroxyindolizidine alkaloid lentiginosine16,18 and its
analogs are in progress.
In conclusion, the furyl acrylates as well as the N-pro-
tected pyridyl and pyrryl acrylates could be asymmetri-
cally dihydroxylated with good yields and high
enantioselectivities, but N-exposed pyridyl and pyrryl
acrylates afforded very low yields in the present reac-
tion conditions. The corresponding chiral diol deriva-
tives give very useful access to the synthesis of various
biologically active compounds.
10. (a) Taniguchi, T.; Ohnishi, H.; Ogasawara, K. J. Chem.
Soc., Chem. Commun. 1996, 12, 1477–1478; (b) Takeuchi,
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11. Bonini, C.; D’Auria, M.; Fedeli, P. Tetrahedron Lett.
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12. The sterochemical assignments were based on the Sharp-
less empirical rule.
13. Iyer, S.; Ramesh, C. Tetrahedron Lett. 2000, 41, 8981–
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14. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
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Acknowledgements
We thank the National Natural Science Foundation of
China for the financial support of this work (29732061).
We also thank Professor Li-Jun Xia and Zuo-Ding
Ding for performing the HPLC analysis. We thank Ms.
Li Huang for assistance in preparing starting materials.
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