Crotylboration

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 ... 

In earher work, the Hall group found that catalytic amounts of triflic acid promoted the addition of aUylboronates to aldehydes [132], While aUylboration reactions catalyzed by chiral Lewis acids in general led to only low levels of enan-tioselection [133], Hall found that chiral LBA 1 catalyzes the asymmetric addition of allyl- and crotylboronates to various aldehydes to provide products in excellent yields and moderate to high ee s (Scheme 5.71) [134]. Further, double diastereose-lective crotylboration could also be achieved with high selectivities using the... 

Z)-Crotylboration of Boc-prolinal with Chiral (Z)-Crotylboronate 47 Synthesis of fcrf-Butyl 2-(l-Hydroxy-2-methylbut-3-enyl)pyrroKdine-l-carboxylate (48) 81 ... 

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... 

The metal-catalyzed allylboration is efficient to control both diastereoselectivity and enantioselectivity. The Sc(OTf)3-catalyzed reaction of chiral allyl boronates resulted in 90-98% ee for representative aldehydes (Equation (158)).624 628 629 The first catalytic enantioselective allylboration and crotylboration was achieved by a chiral lanthanide catalyst (Equation (159)).630... 

Brown s crotylboration protocol was used effectively in the synthesis of azu-mamide A 28. Azumamides are unusual cyclic peptides that show potent inhibitory activity on histone deacetylase enzymes. A highly diastereo- and enan-tioselective (dr >99% 98% ee) crotylation of 3-benzyloxypropanal with the chiral reagent ( >crotyl-1Ipc2borane (l19E) afforded the homoallylic alcohol 29. Subsequent reductive ozonolysis and K2CO3-mediated hydrolysis of the acetate furnished the diol 3016 (Scheme 3.1m). 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

Roush et al. applied the diastereoselective crotylboration methodology in the total synthesis of bafilomycin Ai (66), a potent vacuolar ATPase inhibitor that displays broad antibiotic activity27 (Scheme 3.lx). In the synthesis, the known aldehyde (R)-67 was treated with ( )-crotylboronate (R,R)-43E to provide an 85 15 mixture of the homoallylic alcohol 68 and the undesired 3,4-anti-4,5-syn diastereomer with an isolated 78% yield of 68. Alcohol protection as a TBS ether followed by hydroboration mediated by Wilkinson s catalyst efficiently provided the primary alcohol 69. 

Liu and Zhou applied Roush s crotylboration to the stereoselective synthesis of the orostanal 70, a novel sterol that induces apoptosis in human acute promyelotic leukemia cells28 (Scheme 3.ly). The aldehyde 72, prepared from hyodeoxycholic acid methyl ester, underwent asymmetric reaction with crotylboronate (R,R)-43E to furnish 73. Hydrogenation of the terminal alkene followed by Swem oxidation gave the ketone 74. Methylenation of the ketone and removal of the protective groups afforded orostanal in 50% yield. 

Another synthetic application of Roush s crotylboration methodology using a (Z)-crotylboronate can be found in the formal synthesis of (+)-discodermolide (75)29 (Scheme 3.1z). The aldehyde (S)-67, which was prepared from the Roche ester, reacted with (Z)-crotylboronate (S,S)-43Z to give the syn-homoallylic alcohol 76. Silylation of alcohol and oxidative cleavage of the alkene 77 provided the aldehyde 78, from which the final product (75) can be synthesized according to a known procedure.30... 

In earlier studies, we reported remarkable rate and diastereoselectivity enhancements in allyl- and crotylborations involving a-hydroxyketones,6 a-oxocarboxylic acids7 and fi-hydroxyaldehydes and ketones, We now wish to report that fi-allyldiisopropoxyborane reacts with (3-ketoacids to produce tertiary homoallylic 13-hydroxycarboxylic acids. The reaction presumably proceeds through a bicyclic transition state (Scheme 1) to yield the desired product in good yield (Table 1). 

Crotylboration of Aldehydes. The crotyl analogs of this reagent (Icr2BCrt) likewise provide very high levels of enantio- and diastereoselectivity (>99% de) when condensed with aldehydes. By varying the geometry of the crotyl group (Z or E) and the (-b)-carene isomer used in the... 

The ( )- and (Z)-crotylboronates provide selectivity in the best cases comparable to that obtained with other crotylboration procedures. Combining ease of preparation, stability, and selectivity the tartrate-modified (E)- and (Z)-crotylboronates are highly useful propionate enolate equivalents. 

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. ... 

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. 

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. 

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