our attention to its synthesis and subsequent design of
molecular probes.7 Satake reported the first total synthesis
based on a stepwise construction of the substituted tetrahy-
dropyran ring and Suzuki-Miyaura coupling of the frag-
ments.8a Very recently, Lindsley and co-worker reported
another route to brevisamide.8b Herein, we disclose an
asymmetric total synthesis of brevisamide based upon a
strategic facile assembly of the highly substituted tetrahy-
dropyran ring using Jacobsen’s asymmetric hetero-Diels-Alder
reaction.9 The strategy renders high convergence and flex-
ibility to structural modulation.
Scheme 1. Synthesis of Dihydro-2H-pyranone 12
Figure 2. Retrosynthetic analysis of 2.
triethylsilyl diene 5 in 84% yield. Jacobsen’s asymmetric
catalytic hetero-Diels-Alder reaction of diene 5 and alde-
hyde 6 with 10 mol % Jacobsen’s chromium catalyst 10,9a
in the presence of molecular sieves (4 Å) at 23 °C for 7
days, afforded the desired cycloadduct 11 in 52% isolated
yield. Cycloadduct 11 was obtained with high diastereose-
lectivity (dr ) 95%). The major diastereomer has shown high
enantiomeric purity (ee ) 96%). Of particular note, Jacobsen
and co-workers have reported a very similar reaction with
an equally slow rate compared to other dienes.9b Our
synthetic strategy calls for the introduction of a hydroxyl
group at the R position of the carbonyl group in 12. This
was achieved by Rubottom oxidation of 11 using m-
chloroperoxybenzoic acid solution in toluene in the presence
of aqueous NaHCO3 buffer at 0 °C in 60% yield.13
Epoxidation proceeded from the less hindered side affording
12 as a single isomer. The stereochemical outcome of the
Rubottom oxidation was confirmed by NOE experiment (see
the Supporting Information).
The retrosynthesis of our route is shown in Figure 2.
Strategic bond disconnection of brevisamide provides a
coupling reaction.10 The functionalized tetrahydropyran
moiety 3 can be assembled through an asymmetric hetero-
Diels-Alder reaction between diene 5 and aldehyde 6 using
Jacobsen’s catalyst.9a The resulting cycloadduct can be
converted to 3 with a few additional steps of functional group
manipulation. The other half of the Suzuki-Miyaura cou-
pling partner is diene 4. It could be easily constructed using
Negishi’s zirconium-catalyzed carboalumination-iodination
reaction11 from the known starting material 7.
The synthesis of the functionalized tetrahydropyran moiety
3 is outlined in Scheme 1. Aldehede 812 is converted to enone
9 via addition of ethylmagnesium bromide followed by
Swern oxidation to provide 9 in 84% yield in two steps. It
was treated with TESOTf in the presence of Et3N to afford
The synthesis of functionalized tetrahydropyran derivative
3 is shown in Scheme 2. A modified Wolff-Kishner reduc-
tion14 protocol was utilized for the reduction of ketone 12.
Accordingly, ketone 12 was first converted to its correspond-
ing hydrazone with tosylhydrazine in ethanol. The resulting
hydrazone was reduced with NaBH3CN under pH 3 to
provide the corresponding hydrazine. Treatment of this
hydrazine with NaOAc in EtOH at 75 °C afforded deoxy-
genated product 13 in 76% yield for the three steps. Pro-
(6) Satake, M.; Bourdelais, A. J.; Wagoner, R. M. V.; Baden, D. G.;
Wright, J. L. C. Org. Lett. 2008, 10, 3465–3468.
(7) Chem. Eng. News, 2008, 86, 36-37.
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M.; Tachibana, K. Org. Lett. 2009, 11, 217–220. (b) Fadeyi, O. O.; Lindsley,
C. W. Org. Lett., 2009,ASAP.
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(12) Fournier, J.-F.; Mathieu, S.; Charette, A. B. J. Am. Chem. Soc.
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