benzene resulted exclusively in the formation of aldehyde 4
within 10 min. When a similar reaction was performed with
a continuous H2-supply using a H2-balloon, the reaction
yielded both aldehyde 4 and saturated alcohol 5 in a 3:2 ratio.
Use of base (NEt3 or Na2CO3) was necessary to prevent
deprotection5 of Bn, PMB, and TBS groups present in the
substrate. However, no reaction was observed using Pd/C
or Pd(OH)2 without activation using H2-gas. A plausible
mechanism is illustrated in Scheme 2.3g
Our methodology was applied to the synthesis of the
C5-C13 tetrahydropyran core unit 35 of (-)-brevisamide
(25) (Figure 1). Marine polycyclic ethers have attracted the
Figure 1. (-)-Brevisamide (25).
Scheme 2
.
Plausible Mechanism for the Isomerization of Allylic
Alcohols
attention of numerous synthetic organic chemists due to their
unique structures and potent bioactivities. Recently, Wright
and co-workers have reported the isolation and characteriza-
tion of brevisamide (25), a new marine cyclic ether alkaloid,
from cultures of Karenia breVis.11 The structure consists of
a single tetrahydropyran ring with 3ꢀ-methyl and 5R-
hydroxyl groups, a 3,4-dimethylhepta-2,4-dienal side chain,
and an acetylated terminal amine. Four total syntheses of
25 have been reported12 in the literature in recent years.
The synthesis of the tetrahydropyran unit 35 commenced
with an asymmetric aldol addition reaction of thiazolidi-
nethione propionate 2713 to the benzyloxybutanal 26 using
TiCl4 and (-)-sparteine as the base. This led to aldol product
28 in 90% isolated yield. The secondary hydroxyl group of
28 was protected as silyl ether 29 using TBSOTf and 2,6-
lutidine. Treatment of thioimide 29 with DIBAL-H14 fol-
lowed by Wittig olefination furnished R,ꢀ-unsaturated ester
30 in 88% yield over two steps. Hydrogenation of 30 using
Pd/C in EtOAc failed to give the saturated ester 31. It is
assumed that the catalyst was poisoned by the presence of
the residual thiozolidinethione auxiliary, which had proved
to be difficult to fully separate from ester 30 by chromatog-
raphy (Scheme 3).
To illustrate the scope of the new protocol, the optimized
conditions were applied to a wide variety of substrates bearing
different sensitive functional groups such as MOM, Bn, PMB,
and TBS ethers. All of these survived the reaction conditions,
producing the desired saturated aldehydes in good to excellent
yield. The results are outlined in Table 2. Cinnamyl alcohol 21
(Table 2) was readily isomerized to 3-phenylpropanal 22 in 92%
yield. In the literature, 3-arylpropanals are usually obtained
indirectly by rather sophisticated and tedious procedures (e.g.,
by the reduction of trans-cinnamaldehyde6 or 3-phenylpropionyl
chloride or its derivatives7 or by the oxidation of 3-arylpropanol8
or the hydroformylation of styrene9), which inhibit its wide-
spread usage. Our method is more effective even in the case of
trisubstituted allyl alcohol 19. In the case of a substrate
containing a free hydroxy group as in 23, a tandem isomeriza-
tion/cyclization process in one step afforded the corresponding
lactol 24 as the sole product in 88% yield. Whereas, Chickos
et. al10 observed formation of saturated 1,4-butane diol along
with 2-hydroxytetrahydrofuran during the hydrogenation of 1,4-
butyne diol using Pd catalysts.
Scheme 3. Synthesis of R,ꢀ-Unsaturated Ester 30
(5) Mori, A.; Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.; Sajiki,
H. H. Org. Lett. 2006, 8, 3279–3281.
(6) (a) Terstiege, I.; Maleczka, R. E. J. Org. Chem. 1999, 64, 342–343.
(b) Guin, D.; Baruwati, B.; Manorama, S. V. Org. Lett. 2007, 9, 1419–
1421.
(7) For 3-phenylpropionyl chloride: (a) Jia, X.; Liu, X.; Li, J.; Zhao,
P.; Zhang, Y. Tetrahedron Lett. 2007, 48, 971–974. (b) Maeda, H.; Maki,
T.; Ohmori, H. Tetrahedron Lett. 1995, 36, 2247–2250. (b) For 3-phenyl-
propionyl acid: (c) Goossen, L. J.; Ghosh, K. Chem. Commun. 2002, 836–
837. (d) Uchiyama, M.; Furumoto, S.; Saito, M.; Kondo, Y.; Sakamoto, T.
J. Am. Chem. Soc. 1997, 119, 11425–11433. (d) For 3-phenylpropionyl
amide: (e) Shono, T.; Masuda, H.; Murase, H.; Shimomura, M.; Kashimura,
S. J. Org. Chem. 1992, 57, 1061–1063. (f) Spletstoser, J. T.; White, J. M.;
Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408–3419.
(8) (a) Karimi, B.; Abedi, S.; Clark, J. H.; Budarin, V. Angew. Chem.
2006, 118, 4894–4897. (b) Karimi, B.; Abedi, S.; Clark, J. H.; Budarin, V.
Angew. Chem., Int. Ed. 2006, 45, 4776–4779. (c) Crich, D.; Neelamkavil,
S. J. Am. Chem. Soc. 2001, 123, 7449–7450. (d) Shibuya, M.; Tomizawa,
M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128, 8412–8413.
(9) Yu, S.; Chie, Y.-m.; Guan, Z.-h.; Zou, Y.; Li, W.; Zhang, X. Org.
Lett. 2009, 11, 241–244.
The ester group in compound 30 was therefore reduced
using DIBAL-H to provide E-allylic alcohol 32 (Scheme 4).
(11) Satake, M.; Bourdelais, A. J.; Van Wagoner, R. M.; Baden, D. G.;
Wright, J. L. Org. Lett. 2008, 10, 3465–3468.
(12) (a) Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L.; Satake,
M.; Tachibana, K. Org. Lett. 2009, 11, 217–220. (b) Fadeyi, O. O.; Lindsley,
C. W. Org. Lett. 2009, 11, 3950–3952. (c) Ghosh, A. K.; Li, J. Org. Lett.
2009, 11, 4164–4167. (d) Lee, J.; Panek, J. S. Org. Lett. 2009, 11, 4390–
4393.
(10) Chickos, J. S.; Uang, J. Y.-J. J. Org. Chem. 1991, 56, 2594–2596.
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