Angewandte
Chemie
DOI: 10.1002/anie.200801765
Natural Products
A Short Route to a-Tocopherol**
Kegang Liu, Antoinette Chougnet, and Wolf-D. Woggon*
a-Tocopherol (1) is the biologically most significant member
of the vitamin E family and known to act as a very efficient
[
1,2]
radical-chain-breaking antioxidant in tissues.
The isolation
of pure 1 from natural sources,that is,from all photosynthetic
organisms,is quite difficult because the compound appears in
various amounts along with other vitamin E chromanols. The
challenge to preparing enantiomerically enriched 1 derives
from the stereogenic centers at C2,C4 ’,and C8 ’. In most
published reports,the focus was either on the synthesis of
chiral chromanols or on the generation of the side chain
stereochemistry; there are only a few examples of complete
Scheme 1. Domino aldol/oxa-Michael reaction. Reagents and condi-
tions: a) 4–S-11, benzoic acid, toluene; b)PCC, 4 M.S., DCM; 90%.
PCC=pyridinium chlorochromate, M.S.=molecular sieves; DCM=di-
chloromethane.
[
3,4]
syntheses of 1.
[
5]
6]
We recently published a biomimetic synthesis of 1,
which was based on the mechanism of chromanol formation
[
as catalyzed by the enzyme tocopherol cyclase from Cyano-
[7]
bacteria Herein we report an alternative strategy employing
Table 1: Various proline derivatives promoting the reaction of 3 and 2.
[
8,9]
a diastereoselective domino aldol/oxa-Michael reaction
as
[10]
the key step by using a diarylprolinol derived catalyst.
Phytol was quantitatively oxidized to phytenal (2;
[
11]
Scheme 1),
which was then reacted with ortho-hydroxy
[
12]
aldehyde 3 by using various proline-derived organocata-
[
13,10b]
lysts (4–S-11)
(Table 1). Optimal conditions were
[
a]
[b]
[c]
Entry
Amine
Solvent
t [h]
Yield [%]
de [%]
obtained by using S-11,to yield hemiacetal 12-S,which was
subsequently oxidized to lactone 13-S in an overall yield of
1
2
3
4
5
6
7
8
9
4
5
6
7
8
8
9
Et O
67
69
120
96
110
68
72
21
33
18
10
27
41
31
13
58
27
55
n.d.
n.d.
44
87
75
90
97
2
5
2% and with a de value of 97%. The absolute configuration
n-hexane
toluene
toluene
CH Cl
at C2 of 13-S was deduced from the a-tocopherol that was
derived from 13-S,whereas the relative configuration was
inferred from an X-ray crystallographic structure of related
lactone 14-S,made from citral by the same reaction sequence
2
2
toluene
toluene
toluene
toluene
(
Figure 1).
The formation of lactol 12-S suggests a reaction sequence
10
S-11
72
72
such as the one depicted in Scheme 2. The initially produced
iminium salt (15) leads to dienamine 16,which reacts with
[
a] 30 mol%, all reactions were performed at RT. [b] Yields of isolated 12-
S. [c] Diastereomeric excess (de)was determined for corresponding
lactone 13-S by chiral HPLC analysis. TES=triethylsilyl; n.d.=not
determined.
[*] Dr. K. Liu, Prof. A. Chougnet, Prof. W.-D. Woggon
Departement Chemie
Universität Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-1113
salicylaldehyde 3 to yield the intermediate 17 (aldol reaction).
Compound 17 which then cyclizes diastereoselectively to give
1
2-S (oxa-Michael addition) and releases the proline deriv-
E-mail: wolf-d.woggon@unibas.ch
ative. The aldol reaction is the key step that controls the
stereoselectivity of the formation of the syn arrangement of
the six-membered lactol.
[
**] We thank the Swiss National Science Foundation for financial
support, Dr. T. Netscher (DSM)for a generous sample of natural
phytol and Dr. M. Neuburger for X-ray crystallographic analysis.
To our delight,benzylic lactone 13-S was readily hydro-
genated quantitatively to afford acid 18-S (Scheme 3). Only
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801765.
Angew. Chem. Int. Ed. 2008, 47, 5827 –5829
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5827
Liu, Kegang
