Catalytic Asymmetric Hetero Diels−Alder Reactions
Scheme 3. Synthesis of (+)-Prelactone Ca
A R T I C L E S
Scheme 4. Synthesis of (+)-9-Deoxygoniopypyronea
a Reaction conditions: (a) Zr(OtBu)4 (10 mol %), (S)-2c (15 mol %),
PrOH (120 mol %), H2O (20 mol %), toluene/tBuOMe (2/1), -30 °C, 67
h, 89%, trans/cis ) 6/1, 93% ee; (b) NaBH4-CeCl3, EtOH-CH2Cl2, -78
°C, 92%, ds ) 96/4; (c) Dowex 50W-X2, LiBr, H2O, THF, 0 °C, 79%; (d)
Ag2CO3-Celite, benzene, reflux, 96%.
a Reaction conditions: (a) H2CdC(OSiMe3)SEt, Sc(OTf)3 (20 mol %),
CH2Cl2, -78 °C; (b) Bu2SnH2, CH2Cl2, 0 °C, 88% (two steps, 7a/7b )
63/37); (c) Cu(OTf)2, CH3CN, 60 °C, 95%; (d) TiCl4, CH2Cl2, room
temperature, 96%; (e) TPAP (15 mol %), NMO, CH2Cl2, room temperature,
93%.
important natural products. At first, we planned the synthesis
of (+)-Prelactone C21 (Scheme 3), which was isolated from the
concanamycin-producing Streptomyces sp.22 (+)-Prelactone C
contains a 2,3-trans-dialkylpyran ring system, and we chose the
asymmetric HDA reaction of crotonaldehyde with 1-tert-butoxy-
3-trimethylsiloxy-1,3-pentadiene (1f) as a key step. The reaction
was performed under the optimized conditions using the chiral
zirconium catalyst, and the desired adduct (3) was obtained in
89% yield with good trans-selectivity (trans/cis ) 6/1), and
the enantiomeric excess of the trans-adduct was 93%. After
separation of the diastereomers, the trans-pyranone derivative
was reduced using sodium borohydride in the presence of cerium
chloride to give allylic alcohol 4 in excellent yield and
diastereoselectivity (90%, 96/4).23 The allylic alcohol 4 was then
hydrated using acidic resins in the presence of water to produce
lactol 5,24 which was oxidized selectively using the Fetizon
reagent to afford Prelactone C (6) in excellent yield.25 All
physical data of 6 were consistent with those of the literature.
Next, we conducted the asymmetric synthesis of (+)-9-
deoxygoniopypyrone26 (Scheme 4), which has cytotoxicity
against human tumor cell. As shown in Table 4, the HDA
reaction of benzaldehyde with 1-benzyloxy-4-tert-butoxy-2-
trimethylsilyloxy-1,3-butadiene (1h) proceeded in 95% yield
with excellent cis-selectivity (cis/trans ) >30/1), and the desired
cis-adduct was obtained with 97% ee. For introduction of a two-
carbon unit into the pyran ring in 1,4-addition manner, several
kinds of enolates were first employed, but the desired Michael
reaction proceeded sluggishly. We then investigated Lewis acid-
mediated Mukaiyama-Michael reactions with silicon enolates.27
After screening several Lewis acids, we found that Sc(OTf)3
was effective in this reaction,28 and the desired reaction
proceeded smoothly to afford the desired Michael adduct as a
single diastereomer. The stereochemistry of the product was
determined by NOE experiments. Because it was revealed that
epimerization at the C5′ position of the product occurred easily
under workup conditions, the following reduction of the ketone
moiety was carried out without further purification. We then
examined several reducing reagents and found that Bu2SnH2
was effective in affording the desired alcohol (7) in excellent
yield, albeit the diastereoselectivity was moderate.29 Alcohols
7a and 7b obtained were separated by silica gel chromatography,
and the structure of 7b was confirmed by X-ray crystal structure
analysis.30 The undesired product 7b could be converted to the
starting ketone 10 without any epimerization using tetrapropy-
lammonium perruthenate (TPAP) oxidation.31 The alcohol 7a
was readily cyclized in the presence of copper(II) triflate (Cu-
(OTf)2) to afford the literature known compound 8 in high
yield.32 Deprotection of 8 was achieved according to the
literature method, and (+)-9-deoxygoniopypyrone (9) was
obtained in high yield.33 All physical data of 9 were consistent
with those of the literature.
As discussed in the Introduction, favored products in the HDA
reactions using chiral Lewis acid catalyst systems were 2,3-
cis-disubstituted pyranones. On the other hand, in the reactions
with 4-methyl Danishefsky’s diene using the chiral zirconium
complex reported here, remarkable 2,3-trans-selectivity was
observed. This unique selectivity is not easily explained by the
concerted [4 + 2] cycloaddition mechanism, because of the
(21) (a) Bindseil, K. U.; Zeeck, A. HelV. Chim. Acta 1993, 76, 150. (b) Boddien,
C.; Gerber-Nolte, J.; Zeeck, A. Liebigs Ann. 1996, 1381. Asymmetric total
synthesis of (+)-Prelactone C has already been reported. However, in every
case, many reaction steps were required. See: (c) Esumi, T.; Fukuyama,
H.; Oribe, R.; Kawazoe, K.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S.
Tetrahedron Lett. 1997, 38, 4823. (d) Chakraborty, T. K.; Tapadar, S.
Tetrahedron Lett. 2001, 42, 1375.
(22) Westley, J. W.; Liu, C.-M.; Seilo, L. H.; Evans, R. H.; Troupe, N.; Blount,
J. F.; Chiu, A. M.; Todaro, L. J.; Miller, P. A. J. Antibiot. 1984, 37,
1738.
(23) Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. J. Am.
Chem. Soc. 1988, 110, 4368.
(24) Sabesan, S.; Neira, S. J. Org. Chem. 1991, 56, 5468.
(25) (a) Fetizon, M.; Golfier, M. C. R. Acad. Sci. 1968, 267, 900. (b) Keck, G.
E.; Kachensky, D. F. J. Org. Chem. 1986, 51, 2487. (c) Danishefsky, S. J.;
Simoneau, B. J. Am. Chem. Soc. 1989, 111, 2599.
(26) (a) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Mclaughlin, J. L. J. Nat.
Prod. 1991, 54, 1034. (b) Mukai, C.; Hirai, S.; Hanaoka, M. J. Org. Chem.
1997, 62, 6619. (c) Surivet, J. P.; Vate`le, J. M. Tetrahedron 1999, 55,
13011. (d) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahedron
1999, 55, 2493.
(27) (a) Saigo, K.; Osaki, M.; Mukaiyama, T. Chem. Lett. 1976, 163. (b)
Lichtenthaler, F. W.; Nishiyama, S.; Weimer, T. Liebigs Ann. Chem. 1989,
1163. (c) Iwasaki, H.; Kume, T.; Yamamoto, Y.; Akiba, K. Tetrahedron
Lett. 1987, 28, 6355. (d) Danishefsky, S. J.; Simoneau, B. J. Am. Chem.
Soc. 1989, 111, 2599.
(28) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993, 472. To
the best of our knowledge, this is the first example of the Michael reaction
of silicon enolates with pyranone derivatives using a catalytic amount of a
Lewis acid.
(29) Clive, D. L.; He, X.; Postema, M. H. D.; Mashimbye, M. J. Tetrahedron
Lett. 1998, 39, 4231.
(30) See Supporting Information.
(31) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc.,
Chem. Commun. 1987, 21, 1625.
(32) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, G. S. J.
Am. Chem. Soc. 1977, 99, 6756. It is noteworthy that the combination of
the S-ethyl thioester and a Cu(II) salt gave an excellent yield.
(33) See ref 26b.
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