Asymmetric total synthesis of botcinins C, D, and F

Article abstract of DOI:10.1021/ol801066y

(Chemical Equation Presented) Stereoselective total synthesis of botcinins C, D, and F is effectively carried out through asymmetric aldol reactions, 6-endo ring closure, and SmI2-mediated 3,4-trans or -cis stereoselective intramolecular Reformatsky react

Full text of DOI:10.1021/ol801066y

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3153-3156
Asymmetric Total Synthesis of
Botcinins C, D, and F
Hiroki Fukui and Isamu Shiina*
Department of Applied Chemistry, Faculty of Science, Tokyo UniVersity of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
shiina@rs.kagu.tus.ac.jp
Received May 8, 2008
ABSTRACT
Stereoselective total synthesis of botcinins C, D, and F is effectively carried out through asymmetric aldol reactions, 6-endo ring closure, and
SmI2-mediated 3,4-trans or -cis stereoselective intramolecular Reformatsky reaction. Rapid esterification of the main skeleton of botcinins with
the chiral side chain using MNBA and DMAP produced botcinin D, an antifungal chemical against a pathogen of rice blast disease.
Botcinins, metabolites isolated from Botrytis cinerea, have
antifungal activities against Magnaporthe grisea, a pathogen
of rice blast disease.1 Botcinins have a peculiar structure
consisting of a γ-hydroxy-R,ꢀ-unsaturated carboxylic acid
part with an aliphatic alkyl long chain and a bicyclic moiety
including a six-membered cyclic ether fused to a six-
membered lactone in which all of the carbon atoms except
the carbonyl carbon possess a chiral center. In this paper,
we report an effective method for the synthesis of hexahydro-
pyrano[3,2,b]pyran-2(3H)-one and the first stereoselective
total synthesis of botcinins C, D, and F.
be stereoselectively prepared from a lactic acid derivative 9
by four-carbon extension.
The synthetic route to the precursor of the fused-ring
system corresponding to 5 is depicted in Scheme 2. First,
the protection of (S)-11 and the successive reduction of 12
afforded the chiral aldehyde 13. The diastereoselective
Mukaiyama aldol reaction of 13 with 10 gave the desired
adduct 14 as a single stereoisomer. The reduction of 14
provided diol, which was then converted to the monopro-
tected alcohol 16 via 15. Oxidation of 16, olefination of the
resulting aldehyde 17, and successive reduction of the
coupling product yielded allylic alcohol 18. The asymmetric
epoxidation of 18 produced the desired epoxy alcohol 19 as
a single diastereomer. Alcohol 19 was oxidized to form the
corresponding aldehyde, and the carbonyl group was masked
by the Wittig reaction to give the vinyl epoxide 20.5 After
deprotection of the TBS group in 20, the six-membered cyclic
ether 21 was obtained via the acid-promoted 6-endo ring
closure in the presence of PPTS.4 After combining 21 with
The retrosynthetic analysis of botcinins is described as
shown in Scheme 1. It is assumed that the side chain 1a and
1b could be constructed by the enantioselective aldol reaction
of 3 with 4, followed by chain elongation according to our
previous method.2 The bicyclic part 2 should be prepared
from 5 using an aldol-type cyclization. Cyclic ether3 5 could
be constructed from 6 using the 6-endo ring closure according
to Nicolaou’s strategy.4 The chiral linear compound 6 should
(1) (a) Tani, H.; Koshino, H.; Sakuno, E.; Cutler, H. G.; Nakajima, H.
J. Nat. Prod. 2006, 69, 722–725. (b) Tani, H.; Koshino, H.; Sakuno, E.;
Nakajima, H. J. Nat. Prod. 2005, 68, 1768–1772.
(4) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K.
J. Am. Chem. Soc. 1989, 111, 5330–5334.
(5) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M.
J. Am. Chem. Soc. 2006, 128, 16989–16999.
(2) Shiina, I.; Takasuna, Y.; Suzuki, R.; Oshiumi, H.; Komiyama, Y.;
Hitomi, S.; Fukui, H. Org. Lett. 2006, 8, 5279–5282.
(6) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J. J. Am.
Chem. Soc. 1991, 113, 8036–8045.
(3) Another method for the synthesis of the similar cyclic system has
been reported. See: (a) Chakraborty, T. K.; Goswami, R. K. Tetrahedron
Lett. 2007, 46, 6463–6465.
(7) Fukuyama, T.; Lin, S.-C.; Li, L.-P. J. Am. Chem. Soc. 1990, 112,
7050–7051.
10.1021/ol801066y CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

Scheme 1
.
Structure of Botcinins and Retrosynthetic Analysis
Table 1. Diastereoselectivity of the Reformatsky Reaction
yield (%)
entry
solvent
THF
THF/HMPA 8:1
THF/HMPA 8:1
THF/HMPA 8:1
THF/HMPA 1:1
THF/HMPA 1:1
temp (°C) 23a 23b 23c total
1
2
3
4
5
6
-18
0
46
13
13
20
13
14
30
19
15
23
21
14
0
30
40
37
30
36
76
62
68
80
64
64
-18
-43
0
-18
2-bromopropionic acid using EDCI, the key intermediate
aldehyde 22 was furnished by ozonolysis of the double bond.
For the preparation of the desired bicyclic compounds
23a-d, the SmI2-promoted Reformatsky reaction was ex-
amined according to Molander’s studies6 as shown in Table
1. When the reaction was accelerated by SmI2 in the absence
of HMPA (entry 1), the ꢀ-oriented alcohols 23a and 23b
were predominantly obtained. It was anticipated that the 3,4-
trans diastereomers 23a and 23b could be produced via the
chelation control as depicted in transition state A. On the
other hand, the 3,4-cis diastereomer 23c was preferentially
produced by the addition of HMPA to the reaction mixture
(entries 2-6) because the addition of HMPA might reduce
the chelation effect of the substrate to the Sm metal so that
the alternative transition state B might be preferred. Another
transition state C leading to the product 23d might have much
higher energy due to 1,3-diaxial repulsion between two
methyl groups. The total yields of 23a-c increased up to
Scheme 2. Synthesis of the Six-Membered Cyclic Ether
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Org. Lett., Vol. 10, No. 14, 2008

80% under the suitable reaction conditions at a low temper-
ature (entry 4), and there is no advantage using other
additives such as water or alcohols to improve the stereo-
selectivities and yields for the cyclization.
Scheme 4. Synthesis of Botcinins C, D, and F
The chiral side chains 1a and 1b were prepared according
to our previous study as shown in Scheme 3.2 First, the
Scheme 3. Synthesis of the Side Chain Moiety
asymmetric aldol reaction of aldehydes 4a/b with enol silyl
ether 24 was carried out in the presence of a catalytic amount
of the chiral diamine-Sn(II) complex 25, and the desired
ꢀ-hydroxy thioesters 26a/b were obtained in good yields with
high enantioselectivities (93% ee for 26a and 86% ee for
26b). After transforming the aldol adducts into the corre-
sponding TBS ethers 27a/b, siloxy aldehydes 28a/b were
prepared in satisfactory yields.7 The formation of cyanohy-
drins, mesylation of the hydroxyl groups, and successive
substitution with phenylselenol afforded a mixture of the
diastereomeric isomers 29a/b. The oxidative elimination of
the phenylseleno groups in 29a/b, followed by reduction with
DIBAL-H and oxidation8 of the resulting aldehydes 31a/b
yielded the optically active R,ꢀ-unsaturated carboxylic acids
1a/b.
Installation of the side chain to the main skeleton to form
botcinins C, D, and F was carried out as depicted in Scheme
4. For the preparation of botcinins C and F, 23c was
converted to either the monohydroxy acetate 2a or TES ether
2b. The coupling of 2a with side chain 1b was carried out
in the presence of 2-methyl-6-nitrobenzoic anhydride (MNBA)
and DMAP to produce the corresponding ester 32 in a good
Org. Lett., Vol. 10, No. 14, 2008
3155

yield,9 whereas the combining 2b with 1a also provided 33
in a high yield. Finally, the total synthesis of botcinins C
and F was successfully accomplished by cleaving the
protective groups in their precursors. Next, the R,ꢀ-unsatur-
ated lactone 34 was prepared from the mixture of 23a and
23b by elimination and was then transformed into the
corresponding alcohol 35 through deprotection of the PMB
group. The MNBA-promoted acylation of 35 with 1a10
followed by cleavage of the TBS group also afforded botcinin
D in a high yield.
or -cis stereoselective intramolecular Reformatsky reaction
were employed for the construction of the main skeletons
and the side chains. Effective acylation of the sterically
hindered alcohol with the side chain was attained by a very
rapid coupling using MNBA and DMAP giving botcinin D,
an antifungal chemical against a pathogen of rice blast
disease.
Acknowledgment. The authors are grateful to Prof.
Nakajima (Tottori Univ.) for giving the spectral data of
botcinins. This study was partially supported by a Grants-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports and Culture, Japan.
In summary, we achieved the first enantioselective total
synthesis of botcinins C, D, and F. Stereoselective aldol
reactions, 6-endo ring closure, and SmI2-mediated 3,4-trans
(8) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2003, 5, 3021–3024.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem.
2004, 69, 1822–1830. (b) Shiina, I. Chem. ReV. 2007, 108, 239–278.
(10) For the coupling reaction of 35 and 1a, EDCI was not effective
and the corresponding ester 36 was obtained in only 9% yield.
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Org. Lett., Vol. 10, No. 14, 2008