Total Synthesis of Potent Antitumor Agent (−)‐Lasonolide A: A Cycloaddition‐Based Strategy

A detailed account of the enantioselective total synthesis of (?)‐lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α‐alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3‐dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero‐Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.     

Enantioselective total synthesis of macrolide antitumor agent (-)-lasonolide A

[structure: see text] An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels-Alder reaction as the key step. Three stereocenters were enantioselectively installed in this single step reaction.     

Total synthesis of (+)-brasilenyne. Application of an intramolecular silicon-assisted cross-coupling reaction

The first enantioselective total synthesis of (+)-brasilenyne (1) has been achieved in 19 linear steps, with 5.1% overall yield from l-(S)-malic acid. The construction of the oxonin core containing a 1,3-cis,cis diene unit was accomplished with a tandem ring-closing metathesis/silicon-assisted intramolecular cross-coupling reaction. In addition, a key propargylic stereogenic center was created through a novel, highly diastereoselective ring opening of a 1,3-dioxolanone promoted by TiCl(4). This reaction proceeded through an oxocarbenium ion intermediate and the asymmetric induction was fully controlled by l-malic acid residue. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.     

Asymmetric total synthesis of (+)-danicalipin A

A convergent asymmetric total synthesis of (+)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by 1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product.     

Stereoselective synthesis of the macrolactone core of (+)-neopeltolide

A stereoselective synthesis of the macrolactone core of the potent anticancer agent neopeltolide is disclosed. The key steps of the synthesis include asymmetric allylation using Krische' protocol, conjugate reduction using MacMillan's methodology, and an asymmetric hetero-Diels-Alder reaction using Jacobsen's catalyst. Substrate controlled diastereoselective 1,3-anti reduction of a keto alcohol, Luche reduction followed by Ireland-Claisen rearrangement, oxymercuration, and reductive lithiation are other key steps.     

Asymmetric synthesis of densely functionalized medium-ring carbocycles and lactones through modular assembly and ring-closing metathesis of sulfoximine-substituted trienes and dienynes

An asymmetric synthesis of densely functionalized 7-11-membered carbocycles and 9-11-membered lactones has been developed. Its key steps are a modular assembly of sulfoximine-substituted C- and O-tethered trienes and C-tethered dienynes and their Ru-catalyzed ring-closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C-tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α-lithiation of alkenylsulfoximines, 3) alkylation, hydroxy-alkylation, formylation, and acylation of α-lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α-formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine-substituted trienes with the second-generation Ru catalyst stereoselectively afforded the corresponding functionalized 7-11-membered carbocyles. RCDEM of diastereomeric silyloxy-substituted 1,6,12-trienes revealed an interesting difference in reactivity. While the (R)-diastereomer gave the 11-membered carbocyle, the (S)-diastereomer delivered in a cascade of cross metathesis and RCDEM 22-membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine- and bissilyloxy-substituted carbocycles were performed including deprotection, cross-coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine-substituted homoallylic alcohol with unsaturated carboxylic acids gave the O-tethered trienes, RCDEM of which yielded the sulfoximine-substituted 9-11-membered lactones. RCEYM of a sulfoximine-substituted 1,7-dien-10-yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second-generation Ru catalyst gave the 9-membered exo 1,3-dienyl carbocycle, the first-generation Ru catalyst furnished a truncated 9-membered 1,3-dieny carbocycle having one CH(2) unit less than the dienyne.     

Direct one-pot highly enantioselective assembly of polyketide and carbohydrate synthons

A short, direct, catalytic, enantioselective synthesis of polyketide segments and carbohydrates is presented. The novel, direct, one-pot, organocatalytic asymmetric tandem cross-aldol/Horner-Wittig-Emmons reactions assemble polyketide and carbohydrate derivatives in good yield with 93-98% ee. The one-pot catalytic asymmetric tandem reaction was applied to a highly enantioselective formal de novo synthesis of the rare carbohydrate, l-altrose.     

Asymmetric total synthesis of (-)-pironetin employing the SAMP/RAMP hydrazone methodology

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C(8)-C(14) 2 and C(7)-C(2) 15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric alpha-alkylation of diethyl ketone permitted the introduction of the C(10) stereogenic center of 2, whereas the stereocenters C(4) and C(5) of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the alpha,beta-unsaturated delta-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.     

A simple, short, and flexible synthesis of viridiofungin derivatives

Described herein is a simple, flexible, and efficient synthesis of the skeleton of the viridiofungins, a family of microbial secondary metabolites. The synthesis utilizes an asymmetric aldol reaction of a chiral oxazolidinone, a diastereoselective alkylation of a chiral 1,3-dioxolan-2-one, and a geometrically selective alkene cross-metathesis reaction as the key C-C bond-forming steps.     

A facile asymmetric synthesis of Δ-2-Hydroxybakuchiol,Bakuchiol and ent-Bakuchiol

A facile asymmetric synthesis of Δ³-2-Hydroxybakuchiol, Bakuchiol, and ent-Bakuchiol is described through one common intermediate bearing a chiral all-carbon quaternary carbon center, which involves stereoselectively unconjugated alkylation of the α,β-unsaturated imide bearing Evans' auxiliary, Takai–Utimoto reaction, Negishi reaction, and Heck reaction as key steps.     

Stereoselective total synthesis of the proposed structure of 2-epibotcinolide

[Structure: see text] The total synthesis of pseudo 2-epibotcinolide (1b) through several featured synthetic approaches has been attained. First, the chiral linear precursors of the nine-membered ring compound is stereoselectively constructed by the asymmetric aldol reaction for producing beta-hydroxy ester units. Second, the key cyclization reaction to form the nine-membered lactone moiety is efficiently achieved by the extremely facile and powerful mixed-anhydride method promoted by 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters.     

Enantioselective formal hydration of alpha,beta-unsaturated imides by Al-catalyzed conjugate addition of oxime nucleophiles

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to alpha,beta-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to alpha,beta-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis.     

Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propioloylpyrazoles and acryloylpyrazoles induced by chiral π-cation catalysts

A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular π-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to β-lactams via reductive cleavage of the N-O bond using SmI(2).     

Modular evolution of a chiral auxiliary for the 1,3-dipolar cycloaddition of isomünchnones with vinyl ethers

[reaction: see text]. The 1,3-dipolar cycloaddition reaction has long been recognized as a powerful methodology in organic synthesis. More recently, this reaction has become a popular manifold for the construction of chemical diversity. Herein, we report the development of a chiral template for the facially selective cycloaddition of isomünchnones, a common class of 1,3-dipoles. The modular format of the asymmetric unit allowed a systematic optimization of selectivity. In addition, the chiral auxiliary was removed through an unusually facile ester aminolysis.     

The use of enantiomerically pure ketene dithioacetal bis(sulfoxides) in highly diastereoselective intramolecular nitrone cycloadditions. Application in the total synthesis of the beta-amino acid (-)-cispentacin and the first asymmetric synthesis of cis-(3R,4R)-4-amino-pyrrolidine-3-carboxylic acid

Intramolecular 1,3-dipolar nitrone cycloaddition onto an enantiomerically pure ketene dithioacetal dioxide using a three-carbon tether gave the corresponding 5,5-disubstituted isoxazolidine as a single diastereomer in good yield. This reaction has been used as the key step in an asymmetric synthesis of the naturally occurring antibiotic, (-)-cispentacin. An asymmetric synthesis of 4-amino-pyrrolidine-3-carboxylic acid has also been carried out using the intramolecular nitrone cycloaddition as the stereocontrolling step.     

Total synthesis of prostaglandin F2alpha using nickel-catalyzed stereoselective cyclization of 1,3-diene and tethered aldehyde via transmetalation of nickelacycle with diisobutylaluminum acetylacetonate

Total synthesis of prostaglandin F2alpha utilizing a nickel(0)-catalyzed cyclization of 1,3-diene and tethered aldehyde was achieved. The cyclization proceeded via a transmetalation of nickelacycle with diisobutylaluminum acetylacetonate (iBu2-ALAC). Thus, the reaction of 19, having a side chain corresponding to the alpha-chain in PGF2alpha with Ni(cod)2 (10 mol %), PPh3 (20 mol %), and 1,3-cyclohexadiene (25 mol %) in the presence of iBu2-ALAC (1.5 eq) proceeded stereoselectively to give the cyclized product 26 in 54% yield. During the cyclization of 19, the Z-olefin at C-5 in the side chain completely retained its geometry, and the four contiguous chiral carbon centers in PGF2alpha were stereoselectively constructed. Transformation of the key intermediate 19 into PGF2alpha was successfully achieved.     

Enantioselective synthesis of (-)-basiliskamide A

Basiliskamide A is an antifungal polyketide natural product isolated by Andersen and co-workers from a Bacillus laterosporus isolate, PNG-276. A nine-step enantioselective synthesis of (-)-basiliskamide A is reported, starting from commercially available β-hydroxy ester 7. The synthesis features a highly diastereoselective mismatched double asymmetric δ-stannylallylboration reaction of aldehyde 5 with the bifunctional allylborane reagent 4.     

Total Synthesis of (+)-Papuamine: An Antifungal Pentacyclic Alkaloid from a Marine Sponge, Haliclona sp

The total synthesis of (+)-papuamine, the antipode of the C(2)-symmetric, optically active, pentacyclic diamine natural product, starting from a chiral diol is described. The diol is available via an asymmetric Diels-Alder reaction between 1,3-butadiene and di-(-)-menthyl fumarate. The key transformation in the synthesis is an intramolecular Pd(0)-catalyzed (Stille) coupling reaction to form the central 13-membered diazadiene macrocyclic ring.     

The asymmetric Maitland-Japp reaction and its application to the construction of the C1-C19 bis-pyran unit of phorboxazole B

The synthesis of the C1-C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an asymmetric Maitland-Japp reaction and a second Maitland-Japp resolution/cyclization reaction. The longest linear sequence was 14 steps, and the C1-C19 bis-pyran unit was formed in an impressive 10.4% yield.     

A direct organocatalytic entry to sphingoids: asymmetric synthesis of D-arabino- and L-ribo-phytosphingosine

The organocatalytic asymmetric synthesis of D-arabino- and L-ribo-phytosphingosine is described employing a diastereo- and enantioselective (S)-proline-catalyzed aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one and pentadecanal as the key step.