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A convenient one-pot synthesis of benzoboroxoles has been developed via the reaction of o-bromobenzyl alcohols with NaH, nBuLi, and B(OiPr)3 followed by acidic hydrolysis. Applications of these benzoboroxoles have been demonstrated in Pd-catalyzed cross-coupling reactions and the protocol has been extended for the synthesis of a chiral benzoboroxole. Exceptionally short synthesis of a potent antifungal agent AN2690 and several of its analogs has also been realized.

Diastereoselective dihydroxylation of dihydropyranones and subsequent regioselective alpha-deoxygenation provides 1,3-trans-beta-hydroxy-delta-lactones stereoselectively. This protocol has been applied for the synthesis of C(1)-C(8) and C(15)-C(21) subunits of (+)-discodermolide.

A novel synthetic strategy for the total synthesis of fluorinated analog of blastmycinolactol has been developed using α-pinene based alkoxyallylboration, chelation controlled diastereoselective reduction, and a single step lactonization of the 1,4-diol to the γ-lactone as key steps.

Asymmetric “allyl”boration of pentafluorobenzaldehyde with various α-pinene based “allyl”boranes provides homoallylic alcohols in high de and ee; the alcohols have been converted into δ-lactones via acryloylation, ring-closing metathesis and hydrogenation. Pentafluorophenyl analog of key pharmacophore of statin drugs has been synthesized using diastereoselective epoxidation and regioselective reduction as key steps.

The development of asymmetric synthesis during the past two decades aided organic chemists considerably in the synthesis of complex natural products. Organoborane chemistry continues to play an important role in asymmetric synthesis. One of the important reactions that has become very common in the arsenal of synthetic chemists is allylboration and related reactions. Another important reaction that has recently attained enormous importance in organic chemistry is the ring-closing metathesis (RCM) reaction. Indeed, a combination of allylboration and RCM reactions provides an excellent route to cyclic ethers, lactones, lactams, etc. Herein, we describe a sequential asymmetric allylboration and RCM reaction protocol that has been utilized for the synthesis of several alpha-pyrone-containing natural products,particularly biologically active molecules.

Acrylic esters of homoallylic alcohols prepared in 92–96% ee via the asymmetric allylboration of appropriate aldehydes with B-allyldiisopinocampheylborane, upon ring-closing metathesis in the presence of 10 mol% of Grubbs' catalyst provided the corresponding 6-substituted dihydropyran-2-ones. These were diastereoselectively epoxidized and regioselectively reduced to furnish optically pure analogs of statin drugs. This procedure allows for the development of a combinatorial library of analogs of these drugs.

Acrylic esters of homoallylic alcohols prepared in 92–97% ee via the asymmetric allylboration of appropriate aldehydes with B -allyldiisopinocampheylborane, when refluxed in dichloromethane in the presence of 10 mol% of Grubbs' catalyst provided the natural enantiomers of ( S )-(+)-parasorbic acid, ( R )-(–)-massoia lactone, and ( R )-(+)-goniothalamin. ( S )-(–)-Hexadecanolide was prepared by hydrogenating the corresponding lactenone synthesized using the above sequence.

3-Butyn-2-one condenses with itself in the presence of 0.1 molar equiv of Dabco providing 80% yield of E -3-(1-buten-3-yn-2-oxy)-buten-2-one. Substitution at the acetylene terminus prevents the condensation. However, such ketones can be condensed with terminal acetylenic ketones to provide the cross-coupled products in high yields.

[α-(Ethoxycarbonyl)vinyl]diisobutylaluminum and its β-methyl and -phenyl analogs react with activated ketones, such as α-keto esters, α-acyl cyanides, and α-acetylenic ketones to provide the corresponding α-hydroxyalkenylated products in high yields.

N-boronomethyltrialkylammonium salts were prepared via the reaction of trialkyl amines with α-halomethylboronates. These compounds were utilized as selective catalysts for acetylation of primary alcohols and aldehydes.

A short protocol for the practical scale synthesis of several ω-borono-α-amino acids is described via the alkylation of benzophenone glycinimines with various electrophiles.

Ethyl acrylate and acrylonitrile fail to undergo efficient Baylis-Hillman reaction with fluoral, but provide good yields of products with pentafluorobenzaldehyde. Alternately, unsubstituted and β-substituted [α-(ethoxycarbonyl)vinyl]aluminum react with perfluoroalkyl and -aryl aldehydes and ketones to provide the α-hydroxyalkenylated fluoro-organic compounds in good to excellent yields.

Carboranyl aldehydes react with alpha,beta-unsaturated esters, ketones, and nitriles in the presence of DABCO to provide functionalized carboranyl alcohols in good yields. Acetates of these alcohols undergo a facile isomerization with a variety of nucleophiles and afford structurally interesting carboranes. Biological evaluation of these molecules exhibited impressive antiproliferative activity for brain and breast cancer cells.

Alkyl propiolate couples with itself in the presence of catalytic DABCO under very mild conditions to provide a quantitative yield of E-hex-2-en-4-yne dioates. Hydrogenation of these enyne dioates using Lindlar catalyst provides the corresponding E,Z-diene dioate, a common structural motif found in an array of natural products.

Optically pure allylic amines have been synthesized from α,β-unsaturated aldehydes via allylboration with (−)-B-allyldiisopinocampheylborane, followed by Overman rearrangement. By incorporating crotyl and alkoxyallylboration, functionalization at δ-position was readily accomplished. By applying this methodology, the synthesis of several chiral α-amino acids has been achieved.

[α-(Ethoxycarbonyl)vinyl]diisobutylaluminum and its β-methyl and -phenyl analogs react with activated ketones, such as α-keto esters, α-acyl cyanides, and α-acetylenic ketones to provide the corresponding α-hydroxyalkenylated products in high yields.

Asymmetric allylboration of aldehydes containing an adjacent ester group with B -allyldiisopinocampheylborane, followed by hydrolysis and cyclization, provides the corresponding allyl substituted lactones in high yields and ≥92% enantiomeric excess. Hydrogenation of these lactones provides the corresponding propyl substituted lactones without any loss of optical purity.

3-Butyn-2-one condenses with itself in the presence of 0.1 molar equiv of Dabco providing 80% yield of E -3-(1-buten-3-yn-2-oxy)-buten-2-one. Substitution at the acetylene terminus prevents the condensation. However, such ketones can be condensed with terminal acetylenic ketones to provide the cross-coupled products in high yields.

Replacing carcinogenic HMPA with NMO, a higher yielding, enviornmentally benign procedure for the vinylalumination of carbonyl compounds with [α-(ethoxycarbonyl)- vinyl]diisobutylaluminium and its β-methyl or -phenyl analogs, as well as [α-(acetyl)vinyl]diisobutylaluminium has been developed.

Acrylic esters of homoallylic alcohols prepared in 92–97% ee via the asymmetric allylboration of appropriate aldehydes with B -allyldiisopinocampheylborane, when refluxed in dichloromethane in the presence of 10 mol% of Grubbs' catalyst provided the natural enantiomers of ( S )-(+)-parasorbic acid, ( R )-(–)-massoia lactone, and ( R )-(+)-goniothalamin. ( S )-(–)-Hexadecanolide was prepared by hydrogenating the corresponding lactenone synthesized using the above sequence.

The product formation and yields for the Baylis–Hillman reaction of fluorine-containing carbonyl compounds depend on a balance between the reactivities of the carbonyl and olefin partners.

A short protocol for the practical scale synthesis of several omega-borono-alpha-amino acids is described via the alkylation of benzophenone glycinimines with various electrophiles.

S N 2′ reaction on the acetates obtained from vinylalumination or Baylis–Hillman products, followed by in situ reduction afforded allylic alcohols. Upon conversion to trichloroacetimidates and [3,3]-sigmatropic rearrangement, the corresponding N -protected β-substituted allylic amines were obtained in good yields. Utilization of hydroxy group as the nucleophile furnished allylic hydroxy esters, which were converted to protected α-methylene-β-amino acids via Overman rearrangement.

[reaction: see text] Optically pure allylic amines have been synthesized from alpha,beta-unsaturated aldehydes via allylboration with (-)-B-allyldiisopinocampheylborane, followed by Overman rearrangement. By incorporating crotyl and alkoxyallylboration, functionalization at delta-position was readily accomplished. By applying this methodology, the synthesis of several chiral alpha-amino acids has been achieved.

A modified hydroalumination protocol for the preparation of [alpha-(ethoxycarbonyl)vinyl]diisobutylaluminum and its beta-methyl or -phenyl analogues was developed. These vinylaluminum reagents react with aldehydes and ketones to provide the corresponding functionalized allyl alcohols in good to excellent yields. Perfluoroalkyl and -aryl carbonyl compounds, alpha-keto esters, alpha-acyl cyanides, and alpha-acetylenic ketones provide the corresponding alpha-hydroxyalkenes in high yields. The allyl alcohol product ratios from the vinylalumination of unsymmetrical alpha-diketones with [alpha-(ethoxycarbonyl)vinyl]diisobutylaluminum and its beta-methyl or -phenyl analogues depend on the steric and electronic environments of the ketones as well as the reagents. The products from the vinylalumination of alpha-bromoaldehydes and -ketones were cyclized with K2CO3 or KF under nonaqueous conditions to provide functionalized vinylepoxides in high yields. Vinylaluminations of keto-protected pyruvaldehyde provided the products, which were converted to alpha-alkylidene-beta-hydroxy-gamma-lactones.

The development of asymmetric synthesis during the past two decades aided or- ganic chemists considerably in the synthesis of complex natural products. Organoborane chemistry continues to play an important role in asymmetric synthesis. One of the important reactions that has become very common in the arsenal of synthetic chemists is allylboration and related reactions. Another important reaction that has recently attained enormous impor- tance in organic chemistry is the ring-closing metathesis (RCM) reaction. Indeed, a combi- nation of allylboration and RCM reactions provides an excellent route to cyclic ethers, lac- tones, lactams, etc. Herein, we describe a sequential asymmetric allylboration and RCM reaction protocol that has been utilized for the synthesis of several α-pyrone-containing nat- ural products, particularly biologically active molecules.

[reaction: see text] A series of novel functionalized achiral and chiral allylboronates have been synthesized via the nucleophilic addition of boronates on allyl acetates derived via vinylalumination or Baylis-Hillman reaction of aldehydes. These reagents, upon allylboration with aldehydes, furnish beta-substituted-alpha-methylene-gamma-butyrolactones stereoselectively.

Chiral β-syn-alkoxyhomoallylic alcohols derived from alkoxyallylboration of aldehydes upon oxidation provided the corresponding chiral ketones. Chelation-controlled nucleophilic addition to these ketones occurred in a highly stereoselective manner to afford anti-homoallylic tertiary alcohols. This methodology has been applied for the synthesis of the C1−C11 subunit of C8-epi-fostriecin.

[reaction: see text] Chiral beta-syn-alkoxyhomoallylic alcohols derived from alkoxyallylboration of aldehydes upon oxidation provided the corresponding chiral ketones. Chelation-controlled nucleophilic addition to these ketones occurred in a highly stereoselective manner to afford anti-homoallylic tertiary alcohols. This methodology has been applied for the synthesis of the C(1)-C(11) subunit of C(8)-epi-fostriecin.

The synthesis of the C7C21 fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using α-pinene-derived reagents is described.

A convenient synthesis of (+)-goniodiol, (-)-8-epigoniodiol, and (+)-9-deoxygoniopypyrone has been developed via asymmetric alkoxyallylboration and ring-closing metathesis pathways.

A study of the effect of fluorine substitution in Baylis-Hillman reactions of various fluorocarbonyl partners with acrolein, methyl vinyl ketone, ethyl acrylate, and acrylonitrile has been made.

H. C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393, U.S.A. Manuscript received 26 October 1999 Asymmetric allylboration of 2-octynal with (+)-B-allyldiisopinocampheylborane provides the corresponding homoallylic alcohol in 80% yield. The alkynenol is stereoselectively hydrogenated in the presence of Lindlar catalyst, converted to the corresponding acrylic ester, and cyclized by rcfluxing in dichloromethane in the presence of 10 mol% of Grubbs' catalyst to provide the natural enantiomer of (R)-(-)-argentilactone in 44% overall yield.

The product formation and yields for the Baylis–Hillman reaction of fluorine-containing carbonyl compounds depend on a balance between the reactivities of the carbonyl and olefin partners.