Crotylboration reaction

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... 

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. 

This is exactly what can be achieved by the crotylboration reaction using chiral crotylboronates, Crotylboronates add to aldehydes displaying high simple diastereoselectivity, i.e. E-crotylboronates 9 lead to the tmff-homoallylic alcohols 10, whereas Z-crotylboronates 11 generate the yn-homoallylic alcohols 12 [23]. 

A quick analysis of 9(S)-dihydroerythronolide A 19 shows that 7 of the 11 stereocenters could be created using reagent control of diastereoselectivity by crotylboration reactions. The stereogenic centers at C6 and C12 having a tertiary alcohol function are presently outside the scope of stereoselective crotylboration reactions. Here we have to rely on other methods. For instance, the use of lactic acid enolates developed by Seebach [28] appeared attractive to generate the tertiary centers both at C6 and Cl2. 

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... 

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... 

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. 

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). 

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. 

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. 

To clarify the reaction mechanism, the reaction of tricrotylborane with nitrobenzene was performed (Scheme 4). Amine (8) (80%) proved to be the sole product of crotylboration of PI1NO2. A mixture of dimethyl-1,5-hexadienes (7 isomers, 80%) was also obtained. 

This reaction was first reported by Roush in 1985. It is an enantioselective synthesis of a chiral alcohol by the condensation between a crotylboronate derived from diisopropyl-(/ ,/ )-tartrate and an achiral aldehyde. Therefore, it is known as the Roush crotylboration, ... 

The individual steps of the stereoselective crotylboration are detailed in Scheme 10.21, which demonstrates how establishment of the stereogenic centers is linked to the skeletal bond-forming reactions. 

As shown in Scheme 17, this alternate approach to 85 woriced beautifully. Thus, adopting an alternate asymmetric reaction as a means to attach the butanone-Iike spacer to 88, this aldehyde was exposed to the indicated (+)-Ipc-derived crotylboration reagent in an event that afforded 133 with complete diastereoselectivity. Subsequent methylation of the newly formed alcohol followed by a Wacker oxidation step then served to create methyl ketone 134. With these steps completing the synthesis of the required four-carbon spacer in 44 % overall yield, the substrate was then treated with LiHMDS and TMSCl to generate a sdyl enol ether (135) in... 

Reactions of reagents 1 and 2 with metal-complexed aromatic, propargylic and dienylic aldehydes provides homoallylic alcohol products with improved selectivity compared to their uncomplexed counterparts. The reaction of benzaldehyde chromium tricarbonyl complex 14 with (R,R)-1 followed by oxidative decomplexation provided ( -15 in 90% yield and 83% ee. The (JE)-crotylboration of 14 with (R,R)-2 provided 16 in 90% yield and 92% ee. Reaction of aldehyde 14 with (. -crotylboronate 3, however, provided adduct 17 in only 41% ee. 

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