Crotylboration, asymmetric

A valuable feature of the Nin/Crn-mediated Nozaki-Takai-Hiyama-Kishi coupling of vinyl iodides and aldehydes is that the stereochemistry of the vinyl iodide partner is reflected in the allylic alcohol coupling product, at least when disubstituted or trans tri-substituted vinyl iodides are employed.68 It is, therefore, imperative that the trans vinyl iodide stereochemistry in 159 be rigorously defined. Of the various ways in which this objective could be achieved, a regioselective syn addition of the Zr-H bond of Schwartz s reagent (Cp2ZrHCl) to the alkyne function in 165, followed by exposure of the resulting vinylzirconium species to iodine, seemed to constitute a distinctly direct solution to this important problem. Alkyne 165 could conceivably be derived in short order from compound 166, the projected product of an asymmetric crotylboration of achiral aldehyde 168. 

The C29-C34 fragment, trans vinyl iodide 159, is distinguished by two contiguous stereogenic centers, and it was surmised that both could be introduced in a single step through the application of Brown s effective asymmetric crotylboration methodology (see Scheme 48).79 Depro-... 

Asymmetric crotylboration. The reaction of an achiral, unhindered aldehyde with (E)-(R,R)-2 gives anti- and syrc-homoallylic alcohols in the ratio of about 20 1 ... 

Kinetic resolution can be accomplished by addition of allyl boronates to aldehyde groups adjacent to the tricarbonyliron fragment [59]. For the synthesis of ikaruga-mycin, Roush and Wada developed an impressive asymmetric crotylboration of a prochiral meso complex using a chiral diisopropyl tartrate-derived crotylborane (Scheme 1.25) [60]. In the course of this synthesis, the stereo-directing effect of the tricarbonyliron fragment has been exploited twice to introduce stereospedfically a crotyl and a vinyl fragment. 

The myxalamides and the phenalamides have attracted some synthetic attention. A partial synthesis of myxalamide D (4) was reported by Cox and Whiting in which an anti aldol reaction was used to set the C-12/C-13 stereochemistry.4 In addition, a total synthesis of 2 was described by Andrus In this approach, an asymmetric alkylation set the distal stereocenter (C-16), while an asymmetric crotylboration created the anti stereorelationship at C-12/C-13. In contrast to the other synthetic efforts, the approach to 1 described in this chapter would enable a single asymmetric reaction early in the synthesis to produce the anti C-12/C-13 relationship as well as set the distal C-16 stereocenter.5... 

Asymmetric Crotylboration . Reagents for crotylboration are prepared from 2,5-dimethyl-S-methoxyborolane (eq 5) by addition of (Z)- or ( )-crotylpotassium under standard conditions. Reactions with representative achiral aldehydes are 93-96% diastereoselective and 86-97% enantioselective for the major diastereomer (eqs eq 12 and eq 13). Results with chiral aldehydes conform to the rule of double asymmetric synthesis. ... 

Hoffmann and co-workers completed the first synthesis of both denticulatins via a C9-C10 aldol bond construction (Scheme 9-70) [87], In this case, aldehyde 266 was assembled using asymmetric crotylboration reactions to introduce the C4-CS stereocenters. The (Z)-boron enolate 267 was then reacted with aldehyde 266 to afford the desired anh-Felkin adduct with 80% selectivity where the minor diastereomer resulted from reaction of the enantiomer of the starting ketone. Unfortunately, the C5-PMB ether protecting group could not be removed without epi-merization at C o, and denticulatins A and B were formed in equimolar amounts. 

A final example of the use of tartrate-derived crotylboronates in natural product synthesis is illustrated in the formal total synthesis of ikarugamicin (Scheme II-11) [179]. Here, Roush and Wada used the asymmetric crotylboration of meso-(t/" -2,4-hexadien-1,6-dial)iron tricarbonyl 266 with (S,S)-(E)-219 to set three stereocenters in their synthesis of the a,s-indacene unit of ikarugamycin. This key reaction provided 267 in 90% yield and >98% ee. Homoallylic alcohol 267 was converted to the allylic acetate 268, which underwent stereoselective ethylation with EtsAl with retention of stereochemistry. The resulting adduct 269 was subsequently elaborated to as -indacene unit 271 through a 15-step synthetic sequence, including the intramolecular Diels-Alder reaction of 270. 

The synthesis of the northern spiroacetal segment 394 features the selective ringopening of a symmetric 1,4-bis-epoxide 389 by successive introduction of the Cl 1-C15 unit 388 and C21-C28 phenylsulfonylpyran 391 (Scheme 57). Addition of vinyl lithium of 388, prepared via Brown asymmetric crotylboration, to a symmetric... 

The synthesis of the CD segment 532 also started with dithiane 525. One-pot unsymmetric bisalkylation of 525 with 523 and 524 also effectively afforded coupling product 529, after methylation. Deprotection of TBS and acetonide followed by dethioketalization afforded a 2 1 mixture of 530 and 531. Treatment of 530 with HCIO4 effected epimerization to 531. Functional group manipulation converted 531 to iodide 532, which was coupled with thioacetal 533, prepared by Roush asymmetric crotylboration, to give adduct 534. The thioketal 534 was converted into 535 via reduction of ketone (dr = 1 3.5) and introduction of a phenyl-sulfone group. 

Asymmetric crotylboration and subsequent methylation furnishes 1105 with >20 1 dia-stereoselectivity. Introduction of the protected terminal hydroxyl group is accomplished by ozonolysis, reductive work-up, and j 7-methoxybenzylation. The epoxide is formed by intramolecular cyclization of the deprotected primary alcohol with the mesylated secondary alcohol. 

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