Brown crotylation

As outlined in Schemel3, the synthesis of the C15-C24 subunit 56 started with an Evans aldol reaction between the aldehyde 57 and 58 [108-111], Transformation into aldehyde 59 and a Brown crotylation then gave 60 [117], which was converted into 56 in five steps. 

Asymmetric allylboration has also been applied to y-methoxyallyl derivatives. Isomerically pure (Z)-y-methoxyallyldiisopinocampheylborane (rf31), prepared from Ipc2lSOMe and the lithium anion of allyl methyl ether, reacts with various aldehydes to afford the yyn - j-m e (boxy homoallylic alcohol (32a) in a highly regio- and stereoselective manner17 (Scheme 3.In). This one-pot synthesis of enantiomerically pure 1,2-diol derivatives went as smoothly as the asymmetric Brown crotylation, affording products with uniformly high diastereoselectivity. 

The acid portion of 1 was assembled by enantio-and diastereocontrolled addition of Z-crotyl borane to the aldehyde 8, following the Brown protocol. Hydroboration and oxidation led to 9, which was condensed with the allenyl silane 10 to give 11 with high diastereocontrol. Conversion of the alcohol to the iodide followed by three-carbon homologation by the Myers procedure then led to 1, which was cyclized with > 10 1 regio- and diasterocontrol to give 12. Ozonolysis and methylenation of the less hindered ketone then delivered 3. 

The double bond in 7 is cleaved to an aldehyde by ozonolysis (see Chapter 5) and subsequent reductive workup with tnbutylphos-phine Crotylation with reagent 25.15 developed by Brown, produces only a single diastereomer, which is then transformed into benzoate 8 with benzoyl chloride in pyridine. 

Barrett and Lebold used the Brown asymmetric crotylation to prepare the homoallyhc alcohol 22 in the total synthesis of nikkomycin B 21, a natural product that exhibits fungicidal, insecticidal, and acaricidal activities14 (Scheme 3.1k). 

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). 

Anhydrous CrClj reacts with xs C3H5MgCI in ether at —30 to — 20°C to form red, volatile Cr( -C3H5)3 in ca. 60% yield . A detailed procedure is available, and Cr(// -methallyl)3 and Cr( j -crotyl)3 are prepared similarly . These 15-electron complexes are electron-pair acceptor acids and form stable adducts with donor bases such as pyridine and dioxane. Heating Cr(r/ -C3H5)3 in refluxing dioxane affords brown... 

The Brown asymmetric crotylation is a highly regioselective and stereospecific reaction. Many organoboranes are now commercial available. Reviews (a) Denmark, S. E. Alrnstcad, N. G. In Modem Carbonyl Chemistry, Otera, J, Ed. Wiley-VCH Weinheim, 2000 Chapter 10 Allylation of Carbonyls Methodology and Stereochemistry,... 

Brown s crotyl borane 158 (chapter 24) provides reagent control through a chair-like six-membered ring in the formation of 159. Oxidation of the alkene (ozone with oxidative workup) gives the free acid marked in 160 and on removal of the benzylic group the freed amine (circled) cyclises to it to give the pyrrolidone required (147 as its methyl ester). The synthesis can easily be completed from there. 

Results of reactions of chiral a-methyl aldehydes and several chiral crotyl- and allyl-boron reagents are summarized in Tables 8 and 9. It is apparent from these data that the Brown (Ipc)2B(crotyl) and (Ipc)2B(allyl) reagents (51), (52) and (219) consistently give excellent results for the synthesis of each product diastereomer (Table 8, entries 3-6, 11, 16, 20, and 24 Table 9, entries 1,2, 10 and 18). This is true also for their reactions with chiral a- and 3-alkoxy aldehydes (Scheme 49).i. i4S-i50 Thg tartrate crotylboronates (18) and (19) also display excellent selectivity in the synthesis of crotyl diastereomers (136), (137) and (139) (Table 8, entries 7,10,13,17,25 and 28), but are much less selective for the syndesis of crotyl diastereomer (138), especially from -alkoxy-substituted aldehydes such as (253). Tartrate allylboronate (224) is also less effective than (Ipc)2Ballyl (219) for the synthesis of (257) and (258) in Table 9, and of (266) and (267) in Scheme 49.Substantial improvements in selectivity have been realized by using the taitramide-based allylboronate (228), and the results with this reagent (Table 9, entries 4, 7, 9, 12, 14, 17, 20 and 22) compare very favorably with those obtained with (219). The data... 

Insight into the structure of several allyl/crotyl organometallic reagents has been obtained spectroscopically. Kramer and Brown have examined the NMR spectra of 3-allyl-9-BBN and 3-crotyl-9-BBN... 

Asymmetric allylation and crotylation, synthetically equivalent to the aldol reaction, have been extensively studied and have become a very useful procedure for preparation of propionate units. Among various chiral ligands on boron-developed, isopinocampheyl- and tartrate-derived reagents, 51 and 52, which were developed by Brown et al. [18] and Roush et al. [19], respectively, are the most commonly used (Scheme 7). Reaction of aldehyde with (Sl-Sla or 52a gave anu -adduct 54, while that using (Z)-51b or 52b afforded syn-adduct 53 with high asymmetric selectivity. 

Reactions of fiber with crotyl chloride, methyl iodide and butyl chloride have led to an improvement in dimensional stability. Decay resistance has also been investigated for wood treated with fatty dialkyldimethylammonium chlorides and bromides. Treated wood showed good resistance against brown rot fungi [40]. 

The synthesis began with Yb(OTf)3-catalyzed oxymercuration [88] of ho-moallyUc alcohol 204 [89], prepared by asymmetric allylation with Brown s reagent, to generate organomercury chloride 205. Rh(I)-catalyzed formy-lation [90] of 205 in the presence of DABCO (0.5 equiv.) furnished aldehyde 206. Stereoselective crotylation of 206 via Brown s reagent, followed by regioselective Rh(I)-catalyzed hydroformylation provided lactol 203. Dia-... 

The synthesis of 252 began with Brown s asymmetric crotylation to aldehyde 261. The resulting homoallyl alcohol was converted benzyl ester 262, which was reduced to give lactol acetate 263. Axial allylation to 263 formed 2,6-trans-tetrahydropyran 264, which was subjected to ozonolysis to give an aldehyde. Addition of alkenylzinc, prepared by hydrozircona-tion of an alkyne 265, to the aldehyde mediated by chiral ligand 266 yielded allyl alcohol 267 with a 5.1 1 diastereoselectivity [110]. The stereochemistry of the major isomer was found, unexpectedly, to be the S-form at Cl7, which rendered the macrolactonization to adopt the Mitsunobu reaction. The iodide 252, prepared from 267 in three steps, reacted with... 

The ester 71 was synthesized from known aldehyde 12 (Scheme 13). Brown asymmetric crotylation of 72 provided the alcohol 73 with excellent enantio-and diastereoselectivity (e.r. 96 4, d.r. >20 1). Silylation of 73 was followed by removal of the MPM group to give the alcohol 74, which was oxidized to the corresponding carboxylic acid 75 and then condensed with known alcohol 76 to deliver the ester 71. 

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