Highly efficient total synthesis of (+)-citreoviral

Article abstract of DOI:10.1002/anie.200454212

Only eight steps were required for the total synthesis of (+)-citreoviral (3) from chiral imide 1 in 18% overall yield. The key steps included a highly anti-selective aldol reaction, the stereoselective iodolactonization of a γ,δ-unsaturated β-hydroxyimid

Full text of DOI:10.1002/anie.200454212

Angewandte
Chemie
biological activities, these compounds have attracted a great
deal of attention from a synthetic point of view. Indeed, total
syntheses of citreoviral and citreoviridin have already been
reported by several groups.[5]
We recently reported a general methodology for the
stereoselective construction of 1,2-diols including a stereo-
genic quaternary carbon center by a titanium-mediated aldol
reaction of lactate-bearing chiral oxazolidin-2-one.[6] Control
of all the stereogenic centers is possible by the correct choice
of chiral oxazolidin-2-one and the protecting group for the
hydroxy function of the lactate unit (benzyl or TBS)
(Scheme 1). In the tetrahydrofuran moiety of citreoviral and
Scheme 1. Stereoselective construction of 1,2-diols that include a
stereogenic quaternary carbon center.
Natural Products Synthesis
citreoviridin, we can recognize several 1,2-diol units and we
expected that our methodology could be effectively utilized
for the synthesis of citreoviral and related compounds. Since
the transformation of citreoviral into citreoviridin has already
been established, we focused on the synthesis of citreoviral.
The tetrahydrofuran moiety of citreoviral includes two
sets of adjacent secondary and tertiary alcohol groups. Our
retrosynthetic analysis for the synthesis of 1 is shown in
Scheme 2. Although the structure of 1 presents many
opportunities for the use of our 1,2-diol-forming reaction,
we decided to employ the strategy starting from an anti
aldol product, as the stereoselectivity of anti aldol
reactions is generally higher (> 50:1) than that of syn
aldol reactions (ꢁ 10:1). Our first analysis of the oxy-
genated furan 3, the core structure of 1, is shown as
route A in which 4 would be synthesized by coupling of 5
and 6. Although our anti aldol reaction should be
effective in this route, there are two problems: 1) stereo-
selective construction of aldehyde 5 and 2) possible intra-
molecular SN2 reaction of the tertiary alcohol group at the
carbon center bearing the halide function. To avoid the long
sequence required for the synthesis of 5 and the potentially
problematic (albeit unprecedented) SN2 reaction, we chose
route B via the bicyclic intermediate 7 (Scheme 2). This route
also involves an intramolecular SN2 reaction with the tertiary
alcohol function, but the iodide 8 has the preferred con-
Highly Efficient Total Synthesis of (+)-Citreoviral
Yoshihisa Murata, Tomoyuki Kamino, Toshiaki Aoki,
Seijiro Hosokawa, and Susumu Kobayashi*
(ꢀ)-Citreoviridin (2) was isolated by Hirata and co-workers
from Penicillium citreoviride[1] as a potent inhibitor of the
mitochondrial ATPase and oxidative phosphorylation[2] and
was recently reported to exhibit anti-HIV activity.[3] Structur-
ally related (+)-citreoviral (1) was also isolated from the same
microorganism.[4] These compounds have a highly substituted
and oxygenated tetrahydrofuran moiety as a common sub-
unit. Owing to the structural complexity as well as significant
formation 8’[7] in which the tertiary alcohol group interacts
[*] Y. Murata, T. Kamino, T. Aoki, S. Hosokawa, Prof. S. Kobayashi
Faculty of Phamaceutical Sciences
*
ꢀ
strongly with the C I bond; thus the desired SN2 reaction
Tokyo University of Science
2641 Yamazaki, Nodashi, Chiba 278-8510 (Japan)
Fax : (+81)4-7121-3671
should proceed smoothly. The iodide 8 can be obtained by
stereospecific iodolactonization of 9. There have been a
number of precedents for the iodolactonization of g,d-
unsaturated b-hydroxycarboxylic acids,[8] and theoretical
calculations of the transition states were investigated in
E-mail: kobayash@rs.noda.tus.ac.jp
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 3175 –3177
DOI: 10.1002/anie.200454212
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3175

Communications
Scheme 2. Retrosynthetic analysis.
detail by Houk et al.[9] Imide 9 would be obtained by our anti-
selective aldol reaction between tiglic aldehyde (10) and
lactate derivative 6.
iodolactone 11 in 92% yield as a single isomer. The employ-
ment of an imide[10] as the substrate for iodolactonization
accompanied by removal of the chiral auxiliary as well as the
high selectivity were quite important from a practical point of
view. The stereochemistry of g-lactone 11 was confirmed by
NOE studies, as shown in Scheme 3. The stereochemical
course of the present iodolactonization could be explained by
considering the “inside alkoxy effect”,[9] as depicted in the
transition state A.
The benzyl group in g-lactone 11 was cleanly removed by
exposure to BCl3 in CH2Cl2 to obtain the free tertiary alcohol
8 in 79% yield (Scheme 3). Next, we attempted the critical
intramolecular SN2 reaction of tertiary alcohol 8. After a
number of attempts with various bases and additives, we
finally obtained the desired bicyclic lactone 7 in 92% yield by
treatment of 8 with AgNO3 in DMF. The structure of 7 was
confirmed unambiguously by conversion into the known
benzoate 12.[5c] The spectral data of 12 were in good agree-
ment with reported data. Thus, the tetrahydrofuran moiety of
1 was constructed in four steps in a completely stereoselective
manner from chiral imide 6.
The actual synthesis of the (+)-citreoviral core 3 is shown
in Scheme 3. According to the established protocol, 6 was
treated with LDA followed by Ti(OiPr)3Cl; the reaction of
the resulting titanium enolate with 10 afforded the anti aldol 9
in 71% yield. The stereoselectivity of this reaction is excellent
(anti/syn > 99:1), and we could not detect the formation of
any other isomers. Iodolactonization of the resulting aldol
adduct 9 was next attempted. Unsaturated imide 9, which
includes a chiral auxiliary, was treated directly with I2 and
NaHCO3 in CH3CN/H2O (4:1) at room temperature. As
expected, iodolactonization proceeded smoothly to afford
The bicyclic lactone 7 was transformed into 1 by employ-
ing a sequence of reactions similar to those reported by
Overman and co-workers[5c] (Scheme 4). Reduction of 7 with
DIBAL at ꢀ788C in CH2Cl2 generated the lactol 13 in 94%
yield. Wittig reaction of 13 with (carboethoxyethylidene)tri-
phenylphosphorane in refluxing benzene yielded a mixture of
a,b-unsaturated esters (E/Z = 6:1), from which the desired
isomer (E)-14 was isolated in 82% yield by chromatographic
separation. The a,b-unsaturated d,e-dihydroxyester 14 was
treated directly with DIBAL to afford triol 15 in 82% yield.
Finally, selective oxidation of allylic alcohol 15 with BaMnO4
completed the total synthesis of (+)-citreoviral (1). The data
for synthetic 1 were identical in all respects with reported
Scheme 3. Reagents and conditions: a) LDA, Ti(OiPr)3Cl; then 10, THF, ꢀ78!
ꢀ408C, 71%; b) I2, NaHCO3, MeCN/H2O (4:1), room temperature, 92%; c) BCl3,
CH2Cl2, ꢀ78!08C, 79%; d) AgNO3, DMF, room temperature, 92%; e) BzCl, NEt3,
DMAP, CH2Cl2, room temperature, 79%. LDA=lithium diisopropylamide,
DMF=N,N-dimethylformamide, DMAP=4-dimethylaminopyridine.
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Chemie
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Scheme 4. Reagents and conditions: a) DIBAL, CH2Cl2, ꢀ788C, 94%; b) (carbo-
ethoxyethylidene)triphenylphosphorane, benzene, reflux, 82%; c) DIBAL, CH2Cl2,
08C, 82%; d) BaMnO4, benzene, reflux, 58%. DIBAL=diisobutylaluminum
hydride.
[10] R. H. Bradbury, J. M. Revill, J. E. Rivett, D. Water-
son, Tetrahedron Lett. 1989, 30, 3845 – 3848.
data. The eight-step sequence from 6 gave enantiomerically
pure 1 in 18% overall yield.
In conclusion, we have completed a highly efficient total
synthesis of (+)-citreoviral through a route involving an anti-
selective aldol reaction, the iodolactonization of an unsatu-
rated imide, and the intramolecular SN2 reaction of a tertiary
alcohol. This short and highly stereoselective route can be
applied to a variety of highly oxygenated bioactive com-
pounds.
Received: March 8, 2004 [Z54212]
Keywords: alcohols · aldol reaction · lactones · natural products ·
.
total synthesis
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