Synthetic Applications of the Carbonyl Generating Grob Fragmentation

Following hydrogenation of 28, we added a vinyl cerium reagent to ketone 29. The complete selectivity in this addition step is the results of steric control. Deoxygenation or dehydration of the tertiary hydroxyl (30) proved tricky as unwanted Grob-fragmentation of the trifluoromethyl ether proved quite facile. This problem was finally alleviated by employing Burgess’ reagent for the dehydration (31). Conjugate additions and reductions of the enone afforded primarily the undesired C12-epimer of the methyl ketone. By performing a hydrogenation in the presence of potassium hydroxide the desired thermodynamically more stable C12-epimer (32) could be accessed selectively. Following a Wittig olefination (33) and reduction the installation of the C12-isopropyl group was completed (34). We next turned out attention to the C4-hydroxyl group. Deprotection of the methyl ether was accomplished using selenium dioxide (35), which set the stage for substrate controlled installation of the C4-hydoxyl group via a directed epoxidation (36). Conversion of the primary alcohol to an iodide followed by a reductive zinc mediated opening of the epoxide yielded allylic alcohol 37. Isomerization of the allylic alcohol was challenging, but could be done forcefully with selenium dioxide and the aid of oxidative workup conditions. With trifluoroethyl ether protected vinigrol (38) in hand, the final challenge we were confronted with was deprotection of the C8a-tertiary alcohol. With no reported examples of removing this stable “protecting” group being used in synthesis, we needed to develop conditions that were compatible with the rest of the vinigrol architecture. Finally, we found that we could convert 38 to 39 by treatment with LDA and then selectively dihydroxylate the difluorovinyl ether to afford vinigrol (1).

in the total synthesis of structurally ..

16/06/2012 · The first total synthesis of (±)-pallambins C and D has ..

Grob fragmentation | Syntheticnature

Disappointed by our two previous failed attempts, we had no choice but to employ a bolder approach to unite the two fully functionalized fragments. Such retrosynthetic analysis is shown in , in which we continued to envisage forming the C6–C7 olefin as the final coupling. At the onset of this study, 1,3-diene–ene cross metatheses were poorly explored transformations and had not been used in natural product synthesis (). However, we believed that this would be a viable approach because: (1) a ruthenium catalyst would preferentially react with the olefin of monoene 70 rather than the conjugated olefins of diene 69; (2) the resulting ruthenium alkylidene 71 would preferentially react with 70 to form 67, but this is reversible at elevated temperature and could be minimized by adding 70 slowly to the reaction mixture; (3) eventually, alkylidene 71 would react with the electronically and sterically most accessible terminal olefin of 69 to form the thermodynamically favored 72; and (4) when ruthenium alkylidene 68 does form, this ruthenium species will react with 70 faster than 69 to form 72 and 66 respectively. This hypothesis was also corroborated by the Crimmins group in the crucial cross-coupling step.

Total Synthesis of Cyathin A3 and Cyathin B2

With both coupling partners in hand, the stage was set to test the Nozaki-Hiyama-Kishi coupling. To our disappointment, treatment of vinyl iodide 1 and ketoaldehyde 2 under Nozaki-Hiyama-Kishi conditions, caused proto-deiodination of 1 and decomposition of the ketoaldehyde. Similarly, treatment of vinyl iodide 53 and ketoaldehyde 2 to Nozaki-Hiyama-Kishi conditions gave diene 55 and decomposition of the fragile ketoaldehyde. Therefore, we opted to modify our strategy and attempted a lithium-halogen exchange between nBuLi and 53 to generate the corresponding alkenyllithium, but did not find any appreciable coupling to ketoaldehyde 2. Having realized the fragile nature of ketoaldehyde 2 and the difficulty of forming the C5–C6 bond in the late stages of a synthesis, we began to explore other coupling possibilities.

66) Total synthesis of a novel oxa-bowl natural product paracaseolide A via a 'putative' biomimetic pathway
An example of a Grob-like fragmentation in organic synthesis is the expansion of ..

Total Synthesis of Ferrugine and Synthetic Studies Towards ..

The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C(7b) quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule.

Baran 6 and co-workers reported the first total synthesis of vinigrol and ..

Total synthesis of ()-parvifoline and ()-isoparvifolinone

With the B-ring fragment 2 in hand, we embarked on the preparation of the A-ring fragment 1 as shown in . We chose the styryl unit to mask an aldehyde that would effectively suppress the volatility of otherwise low molecular weight intermediates. With this in mind, the preparation of acid 3 began by the homologation of cinnamaldehyde by the action of TMSCHN2 to give enyne 25 in 84% yield. The Corey-Fuchs method was less efficient, and the Seyforth-Ohira-Bestmann method, gave 1-(1-methoxybut-3-ynyl)benzene. Subsequent Carreira asymmetric alkynylation of 25 with acetaldehyde generated propargylic alcohol 6 in 41% yield with 86:14 er. In this reaction, slow addition of acetaldehyde to the reaction mixture proved to be crucial since rapid addition resulted in the aldol condensation of acetaldehyde. Recrystallization of 6 further improved the er to 98:2. Unfortunately the catalytic version of the asymmetric alkynylation reaction was unsuccessful. After acetylation of propargylic alcohol 6, the resulting ester, 26, was converted to aldehyde 27 by ozonolysis in 89% yield. Ensuing oxidation of aldehyde 27 and partial reduction of the resulting alkyne using Lindlar's catalyst afforded acid 3 in 75% yield for the 2 steps, and in 6 total steps from cinnamaldehyde. More recently, we converted enyne 26 to acid 28 in 1 step via osmium tetroxide-mediated oxidative cleavage and subsequent partial reduction afforded 3 in 60% yield for the 2 steps. Therefore, acid 3 can now be prepared in 5 steps from cinnamaldehyde.

23/12/2017 · Total synthesis of the published structure ..

This Letter provides the first example of the total synthesis of ..

To complete the total synthesis of vinigrol we needed to address three final challenges: 1) convert the C12 ketone to an isopropyl group, 2) add the C4-hydroxyl group and 3) deprotect the C8atrifluoroethyl ether. We started our endgame journey by first tackling the C12-isopropyl group installation ().