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Organic Synthesis workbook li - Bittner C.

Bittner C. Organic Synthesis workbook li - John Wiley & Sons, 2001. - 292 p.
ISBN: 3-527-30415-0
Download (direct link): bittnerorganicsynthesisworkbook2001.pdf
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Problem
Hints
Solution
Discussion
30
2 (-)-Bafilomycin Ai
Problem
Hints
Solution
Discussion
15
The methylketone is enolized and transformed into the TMS ether.
Aldehyde 14 is reacted with the enolate under Mukaiyama conditions.
The aldol product is deprotected.
Ring closure in the deprotection step creates (-)-bafilomycin Aj.
2. 14, BFrOEt2, -78 C, 30 min, 85 %
3. TAS-F, DMF, H20, r. t 4 h, 93 %
Mukaiyama found that Lewis acids can induce silyl enol ethers to attack carbonyl compounds, producing aldol-like products.22 The reaction proceeds usually at -78 C without selfcondensation and other Lewis acids such as TiCl4 or SnCl4 are commonly used. The requisite silyl enol ether 27 was prepared by treatment of ketone 13 with lithium hexamethyl disilazide (LiHMDS) and trapping the kinetic enolate with chlorotrimethylsilane. When the silyl enol ether 27 was mixed with aldehyde 14 in the presence of BF3OEt2 a condensation occurred via transition state 28 to produce the product 29 with loss of chlorotrimethylsilane. The induced stereochemistry in Mukaiyama reactions using methylketones and a,/?-chiral aldehydes as substrates
2 (-)-Bafilomycin A i
31
was thoroughly investigated by Evans23 and Roush. They found that anti substituted tt-methyl-/?-alkoxy aldehydes react highly Felkin selective to give the 1,3-anti product diastereomer. The Felkin-Anh model24 is used to interpret the contributions of torsional, steric and electronic factors from the stereogenic center a to the reacting carbonyl. The nucleophile attacks in a trajectory coming over the smallest substituent, with the largest substituent pointing away.
TMSO OTBS
27
, Nu
FgB-O^CH-H
0 \/
H 5 OTBS 28
Deprotection of the silyl ether protecting groups had failed in previous attempts with conventional deprotecting agents. TAS-F [Tris-(dimethylamino)sulfonium difluorotrimethylsilicate, fMe;iN)3S+F2SiMe3 is one example of new silyl deprotection reagents which are mild and work under neutral conditions.25 Other reagents are based on hypervalent fluoride complexes of tin26 and phosphorus. TBAT (Bu4N+Ph3SiF2~) for example is crystalline and soluble in most organic solvents and deprotection can be afforded under water free neutral conditions.27
Even though all the silyl protecting groups are removed in this step, affording 30, only the alcohol at C-23 will react with the ketone, since it is able to form the stable six-membered heterocycle. The deprotection concludes the total synthesis of (-)-bafilomycin ].
30
15
2 (-)-Bafilomycin At
2.4 Conclusion
The total synthesis of (-)-bafilomycin A, by Roush et al. demonstrates the importance of protecting group selection. The impressive synthesis was only possible because of careful protecting group orchestration. The strategy relies not only on different classes of protecting groups but also on the stabilities and reactivities of functional groups towards protection and deprotection. The challenge of synthesizing Bafilomycin also resulted in the application of TAS-F, a new mild fluoride source, as substitute for the basic TBAF in deprotection of alcohols. Roush et al. also demonstrated the power of their asymmetric crotylation protocol using chiral diisopropyltartrate-crotylboronates. The synthesis also inspired extensive work on the selectivities in the Mukaiyama-aldol reaction using methyl ketones. Many other important reactions are used during the synthesis showing the broad range of methods that is necessary to achieve a complex synthetic goal.
2.5 References
1 G. Werner, H. Hagenmaier, K. Albert, H. Kohlshorn, H. Drautz, Tetrahedron Lett. 1983, 24, 5193-5196.
2 J. Haung, G. Albers-Schonberg, R. L. Monaghan, K. Jakubas,
S. S. Pong, O. D. Hensens, R. W. Burg, D. A. Ostlind, J. Antibiot. 1984, 37, 970-975.
3 E. J. Bowman, A. Siebers, K. Altendorf, Proc. Natl. Acad. Sci. USA 1988, 85, 7972-7976.
4 D. A. Evans, M. A. Calter, Tetrahedron Lett. 1993, 34, 6871-6874.
5 K. Toshima, T. Jyojima, H. Yamaguchi, Y. Noguchi, T. Yoshida, H. Murase, M. Nakata, S. Matsumura, J. Org. Chem.
1997, 62, 3271-3284.
6 K. A. Scheidt, A. Tasaka, T. D. Bannister, M. D. Wendt, W. R. Roush, Angew. Chem. Int. Ed. 1999, 38, 1652-1655; Angew. Chem. 1999, 111, 1760-1762.
7 H. C. Brown, S. K. Gupta, J. Am. Chem. Soc. 1971, 93, 1816-1818.
8 D. A. Evans, G. C. Fu, A. H. Hoveyda, J. Am. Chem. Soc. 1992,114, 6671-6679.
9 A. J. Mancuso, D. Swern Synthesis, 1981, 165-185.
10 E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 12, 3769-3772.
11 E. Negishi, D. E. Van Horn, T. Yoshida, J. Am. Chem. Soc. 1985,107, 6639-6647.
12 . E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863-927.
13 a) A. J. Pearson, W. J. Roush (ed.) Handbook of Reagents for Organic Synthesis - Activating Agents and Protecting Groups, John Wiley & Sons, Chichester 1999; b) T. W. Greene, P. G. W. Wuts, Protective Groups in Organic Synthesis, 2nd ed.;
2 (-)-Bafilomycin A/
33
John Wiley & Sons: New York, 1991; c) P. J. Kocienski, Protecting Groups; Georg Thieme Verlag: Stuttgart, 1994.
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