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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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25 26 27
Deprotection of silyl ethers can be accomplished by using a variety of reagents such as TBAF, BF3-OEt2, alkali metal tetrafluoroborate and HF. Here, PPTS is used to distinguish the TBS from the TPS group. Thus, the rearranged 27 cleaves selectively the least bulky silyl group to form mono-protected 8.12
4 Dysidiolide
67
Problem
HO
1.
2.
3.
4.
Step 1 is a halogenation.
The second reaction is a nucleophilic substitution.
Finally, the protected alcohol is converted to an aldehyde.
1. I2, Ph3P, imidazole, CH2Cl2,r. t., 10 min, 97 %
2. 2-Bromopropene, fBuLi, Cul, Et20, -30 > 0 C, 30 min, 97 %
3. TBAF, THF, r. t., 8.5 h, 96 %
4. Dess-Martin periodinane, pyridine, CH2C12, r. t., 1 h, 94 %
First an iodination of the alcohol is accomplished by treatment with iodine in presence of Ph3P and imidazole.13 Successive iodide displacement with the nucleophilic vinyl cuprate derived from 2-lithiopropene (2-bromopropene, /BuLi) finished the emplacement of the C-l side chain. Cleavage of the TPS ether by tetrabutylammonium fluoride and subsequent oxidation with the Dess-Martin periodinane provides aldehyde 9.
Hints
Solution
Discussion
68
4 Dysidiolide
Problem
Hints
Step 1 yields a separable mixture of diastereomeric carbinols. Only the 2-(/?)-diastereomer is further used.
A photochemical oxidation finishes the synthesis.
Solution
1. 3-Bromofuran, BuLi, THF, -78 C, 30 min, 98 %
2. 02, hv, Rose Bengal, ;'Pr2EtN, CH2C12, -78 C, 2 h, 98 %
Discussion
28
29
Rose Bengal
Treatment of 9 with 3-lithiofuran (3-bromofuran, BuLi) affords a 1:1 mixture of diastereomeric carbinols, which are readily separated by silica gel chromatography. However, the undesired C-2'-epimer of 28 is efficiently converted to the other diastereomer by oxidation of the alcohol with Dess-Martin periodinane and subsequent stereoselective oxazaborolidine-catalyzed reduction to give the desired 2'-(7?)-carbinol exclusively. This recycling of the undesired 2'-(5)-epimer allows for the transformation of 9 to 28 in 95 % yield overall.
Photochemical oxidation of 28 with singlet oxygen furnishes dysidiolide (1) as a white solid. The most common method for generating '02 in solution is the dye-sensitized photochemical excitation of triplet oxygen. The mechanism involves the excitation of an appropriate dye with visible light to generate the corresponding excited singlet state. Rapid intersystem crossing (ISC) provides the excited state of the sensitizer, which undergoes energy transfer with triplet oxygen to form singlet oxygen, regenerating the ground state of the sensitizer. Common sensitizers are organic dyes such as Rose Bengal (29), methylene blue and certain porphyrin derivatives (see Chapter 1). In addition, to the soluble dye, polymer-bound dyes such as polystyrene-bound Rose Bengal may also be used for the generation of '02.
4 Dysidiolide
In principle, singlet oxygen undergoes three classes of reaction with alkenes: an ene type reaction forming allylic hydroperoxides, [4+2]-cycloadditions with cisoid 1,3-dienes and 1,2-cycloadditions with electron-rich or strained alkenes. Here, the 3-alkylfuran 30 is regioselectively oxidized by '02 in presence of a hindered base to form the corresponding y-hdxbutnolide 32.14 Actually the mechanism is a Diels-Alder reaction with oxygen as dienophile to form endoperoxide 31.
30 31 32
However, the formation of dysidiolide (1) requires the regiospecific removal of the hydrogen at C-l on the endoperoxide 31. This is achieved by treatment with a hindered base such as diisopropylethylamine (Hiinigs base) at low temperature in order to favor base-catalyzed decomposition rather than thermal decomposition.
4.4 Conclusion
The above-described problem demonstrates the first enantioselective synthesis of dysidiolide, a C25 isoprenoid antimitotic agent. The central transformations are the sulfenylation-dehydrosulfenylation sequence to prepare an eu,/?-enone, the biomimetic cationic 1,2-rearrangement to form stereoselectively the bicyclic scaffold, vinyl cuprate displacement of an iodide furnishing the C-l side chain and the photochemical oxidation of furan to generate the j^hydroxy-butenolide functionality.
This synthesis is completed in 22 steps with an overall yield of approximately 12 %.
4.5 References
1 B. Baratte, L. Meijer, K. Galaktionov, D. Beach, Anticancer Res. 1992,12, 873-880.
2 J. B. A. Millar, P. Russell, Cell 1992, 68, 407-410.
3 S. R. Magnuson, L. Sepp-Lorenzino, N. Rosen, S. J. Danishefski, J. Am. Chem. Soc. 1998, 120, 1615-1616.
70
4 Dysidiolide
4 G. P. Gunasekera, P. J. McCarthy, M. Kelly-Borges, E. Lobkorsky, J. Clardy, J. Am. Chem. Soc. 1996, 118, 8759-8760.
5 a) J. Boukouvalas, Y.-X. Cheng, J. Robichaud, J. Org. Chem. 1998, 63, 228-229; b) H. Miyaoka, Y. Kajiwara, Y. Yamada, Tetrahedron Lett. 2000, 41, 911-914; c) D. Demeke, C. J. Forsyth, Org. Letters 2000, 2, 3177-3179.
6 E. J. Corey, . E. Roberts, J. Am. Chem. Soc. 1997, 119, 12425-12431.
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