Boron oxide aldol reactions

Our persistence with the boron-mediated aldol reaction of 4 and 5 was rewarded when the reaction was conducted without recourse to the usual oxidative workup. Other work conducted by our group had shown that oxidative cleavage of certain aldol borinates under standard conditions (H2O2, pH 7 buffer, H20/Me0H) led to poor yields of the aldol products. In the case of 44, the oxidative step was omitted and the reaction mixture was placed directly on silica gel and then eluted to afford aldol adduct 44 in excellent yield (89%) and with improved diastereoselectivity (90 10 ds) relative to the corresponding lithium conditions.17... 

Excellent results have been obtained by using boron enolates (alkenyloxyboranes or enol borinates), in what is commonly known as a boron-mediated aldol reaction. The boron enolates are prepared easily from the corresponding ketone and a dialkylboron trifluoromethanesulfonate (dialkylboron triflate, R2BOTf) or chloride (R2BCI) and a tertiary amine base. Boron enolates react readily with aldehydes to give, after oxidative work-up of the resulting borinate species, high yields of the desired aldol product (1.58). 

Impressively short is a total synthesis by Ian Paterson [281], who uses a lactate ester as chiral auxiliary. This is subsequently converted into a ketone via a Grignard reaction with its Weinreb amide. The boron-mediated aldol reaction, after an oxidative work-up, gives the aldol with a diastereoselectivity of >98 %. Since also the reaction with propionaldehyde shows the same diastereoselectiv-... 

The first total synthesis of archazohd A 111, disclosed by Menche et al. [89], was achieved from the assembly of three main building blocks - ketone 104, aldehyde 105, and alkene 107 (Scheme 6.20). The synthesis was accomplished first by employing a boron-mediated aldol reaction of 105 and 104 followed by a two-step elimination to give iodide 106. Heck reaction of 106 with 107 using dichloropaUadium catalyst and tetra-n-butylammonium chloride (TBACl) additive followed by reaction with phosphonate 108 furnished alkene 109 with E/Z selectivity (6 1). Oxidative removal of the PMB group in 109 and Swern oxidation afforded ketophosphonate 110. 

A number of modifications were made to meet scale-up requirements. In the preparation of the common intermediate, LiBH4 was used in place of LiAlH4 in Step A-2 and a TEMPO-NaOCl oxidation was used in place of Swern oxidation in Step A-3. Some reactions presented difficulty in the scale-up. For example, the boron enolate aldolization in Step B-l gave about 50% yield on the 20- to 25-kg scale as opposed to greater than 75% on a 50-g scale. The amide formation in Step B-3 was modified to eliminate the use of trimethylaluminum, and the common intermediate 17 could be prepared on a 30-kg scale using this modified sequence. The synthesis of the C(l)-C(6) segment V was done by Steps C-l to C-5 in 66% yield on the scale of several kg. 

Boron-mediated ketone-ketone aldol reactions have been described, using boron enolates formed with dicyclohexylboron chloride and triethylamine.124 Following addition of the acceptor ketone to form a boron aldolate, oxidation with peroxide yields the aldol product. 

Monohydroboration of 1-alkynes followed by oxidation gives the corresponding aldehydes in high yields.-" Oxidation of the vinyl carbon-boron bond produces the enol, which then tautomerizes to the carbonyl group. To minimize aldol condensation of the aldehyde formed during oxidation, the reaction should be carried out at pH 8 or in buffered medium. " ... 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

In order to unambiguously ascertain the Cio stereochemistry, the Hoffmann group elected to separately synthesize both C(o epimers of aldehyde 269 (Scheme 9-73) via aldol additions of both enantiomers of ketone 18 to aldehyde 273 [88]. Notably, the boron-mediated syn aldol reactions of this ketone are non-selective in the absence of chiral ligands (see Scheme 9-8 for selective syn aldol reactions of 18). In this case, the C7 hydroxyl was ultimately oxidized to a ketone, and the Cg stereocenter epimerized during cyclization so the lack of selectivity was not detrimental to the synthesis. 

Condensation catalyst. Boric acid (also boron oxide and 10-hydroxy-10.9-boroxarophenanthrene)123 has been used as catalyst for aldol condensation and subsequent dehydration. The reaction is carried out in refluxing m-xylene under a Dean-Stark trap for removal of water. Examples126 ... 

The synthesis of the fragment C3-C13 was achieved in five steps from 169. Treatment of the tosylated stereotetrad 169 with 5 equivalents of lithium acetylide in DMSO led an acetylenic compound which was treated with ra-Buli and methyl iodide, and then reduced by Na/NH3 to produce the E-geometry of the C12-C13 double bond with concomitant removal of the PMB group at C5, giving the primary alcohol 170 (49% yield for the three-step sequence). Swern oxidation of 170 gave the corresponding aldehyde which was involved in an Evans-type asymmetric aldol reaction with the boron enolate A to produce the adduct 171 (dr > 95/5, 90% yield). (Scheme 33). 

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