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The stereochemistry of the lipophilic side chain of (+)-rakicidin F had not been determined until recently. Using our lithiation-borylation methodology ("assembly line synthesis") we were able to efficiently prepare the all-syn isomer as well as the C-21 epimer of the side chain, and comparison with the natural product suggested that the natural product had all-syn stereochemistry. Completion of the total synthesis using a macrolactamization of the northern amide enabled us to confirm Wang and Chen's stereochemical findings for the structure of (+)-rakicidin F.

A highly diastereoselective, visible-light-induced [3 + 2] cycloaddition between N-sulfonyl cyclopropylamines and electron-deficient olefins is reported. The reactions proceed via the oxidation of a sulfonamide aza-anion by an organic photocatalyst to generate a nitrogen-centered radical. Strain-induced ring opening and intermolecular addition to the olefin generate an intermediate carbon-centered radical that is reduced to an anion prior to 5-exo cyclization. This enables a highly diastereoselective construction of trans-cyclopentanes possessing synthetically useful functional groups.

A visible-light photoinduced fragmentation borylation of O-phthalimido cycloalkanols with bis(catecholato)diboron is described. Structurally diverse keto and formyloxy alkyl boronic esters are shown to be conveniently prepared by radical-mediated ring opening of cyclic alcohols and hemiacetals, respectively. The reactions proceed under mild conditions in the absence of additives or photocatalysts, display excellent functional group tolerance, and are shown to allow cleavage of 4-, 5-, 6-, and 7-membered ring substrates. The mechanism proceeds via sequential homolytic N–O and C–C bond cleavages, the latter of which involves β-scission of an alkoxy radical, generating a carbonyl and an alkyl radical that is trapped by the diboron reagent. Spectroscopic studies suggest direct photoexcitation of either the phthalimide or diboron substrates with blue light can initiate a radical chain mechanism.

A 12-step asymmetric synthesis of thromboxane B2 (TxB2) from 2,5-dimethoxytetrahydrofuran is described. The synthesis employs our organocatalytic aldol reaction of succinaldehyde to give a key bicyclic enal intermediate. From here, the synthetic strategy involves a conjugate addition of an alkenyl side chain to the bicyclic enal, Baeyer–Villiger oxidation, and a highly Z-selective Wittig olefination of a hemiacetal. Key to success was minimizing redox operations and the manipulation of functional groups in the correct order.

Bicyclo[1.1.1]pentanes (BCPs) have found application as bioisosteres of aromatic rings in drug development. However, catalytic construction of this motif with adjacent stereocenters with high enantioselectivity from readily available starting materials still constitutes a significant synthetic challenge. Herein we report a direct stereoselective synthesis of α-chiral allylic BCPs by 1,3-difunctionalization of [1.1.1]propellane with Grignard reagents and allyl carbonates using iridium catalysis. This mild protocol proceeds via initial organometallic addition to [1.1.1]propellane followed by asymmetric allylic substitution, providing the products with high enantioselectivities over a broad range of substrates. Further derivatization of the products demonstrates the applicability of this method to the preparation of structurally diverse libraries of chiral BCP derivatives.

The veterinary drug Alfaprostol and prostaglandin PGF2α have been synthesized in just nine steps. The strategy involved the conjugate addition of an alkyne to a bicyclic enal, available in three steps by a proline-catalyzed aldol reaction of succinaldehyde. In the case of Alfaprostol, this resulted in the shortest synthesis reported to date. For PGF2α, this approach improved our previous route by making the 1,4-addition and ozonolysis more operationally simple.

An enantiospecific coupling between alkylboronic esters and lithiated aryl hydrazines is described. The reaction proceeds under transition-metal-free conditions and is promoted by acylation of a hydrazinyl arylboronate complex, which triggers a N–N bond cleavage with concomitant 1,2-metalate rearrangement. Judicious choice of the acylating agent enabled the synthesis of ortho- and para-substituted anilines with essentially complete enantiospecificity from a wide range of boronic ester substrates.

A concise synthesis of stereodefined C-substituted morpholines, piperazines, azepines, and oxazepines in moderate to excellent yields (27% to 75%) is reported by reaction of 1,2- or 1,3-amino alcohol/1,2- or 1,3-diamine with an α-phenylvinylsulfonium salt. High levels of regio- and diastereoselectivity (from 2:1 to >20:1) are observed through judicious choice of base (Cs2CO3) and solvent (CH2Cl2). Reactions are performed at ambient temperature and open to air and do not require anhydrous solvent. The deprotection of the N-sulfonamide protecting groups (N-Ts and N-Ns) is also demonstrated. Factors affecting regio- and diastereocontrol are discussed.

Boron-ate complexes derived from primary and secondary boronic esters and aryllithiums have been isolated, and the kinetics of their reactions with carbenium ions studied. The second-order rate constants have been used to derive nucleophilicity parameters for the boron-ate complexes, revealing that nucleophilicity increased with (i) electron-donating aromatics on boron, (ii) neopentyl glycol over pinacol boronic esters, and (iii) 12-crown-4 ether.

The veterinary drug Alfaprostol and prostaglandin PGF

CF(3)-substituted vinyl diphenylsulfonium triflate is an effective annulation reagent for the formation of α-CF(3) substituted, epoxide-fused heterocycles (pyrrolidines, piperidines, and tetrahydrofurans). This simple method affords a variety of valuable heterocyclic building blocks in a highly diastereoselective manner (dr20:1).

The lithiation/borylation-protodeboronation of a homoallyl carbamate was applied to the synthesis of (+)-sertraline and (+)-indatraline. Due to the presence of the alkene, significant modifications of the methodology were required (use of 12-crown-4, TMSCl, H(2)O), or a solvent switch to CHCl(3), to achieve high yields and high selectivities.

Sulfur ylides stabilized by Ar, vinyl, or amide groups react with five-membered-ring tert-butylsulfinyl aminals to give functionalized chiral, nonracemic aziridines in high yield and with good selectivities (up to 15:1 trans:cis, up to >95:5 trans dr, always >95:5 cis dr). The intermediate aziridines can be converted into pyrrolidines or piperidines depending on the reaction conditions.

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

[reaction: see text]. A user-friendly, one-pot process for catalytic cyclopropanation of alkenes from tosylhydrazones is described. The cyclopropanation of N-vinylphthalimide provides a new route to 2-arylcyclopropylamines, and this is exemplified in the efficient synthesis of the HIV-1 reverse transcriptase inhibitor 6.

Trimethylsilyldiazomethane has been found to add directly to N-sulfonyl (Ts and SES) imines to afford aziridines in good yields and high cis stereoselectivities. The silyl group can be substituted by treatment with a fluoride source and electrophiles again with high selectivity. Complete regioselectivity is observed in ring opening of these aziridines with nucleophiles.

Asymmetric lithiation of substituted benzylamines, N-Boc-pyrrolidine, or N-Boc-indoline using Beak's methodology was followed by electrophilic quench with trialkylboranes. The resulting borate intermediates rearrange with concomitant C-N bond breakage to give, after oxidation, chiral secondary alcohols with high enantioselectivity.

The lithiation of trans- and cis-stilbene oxides (+/-)-1 and 8 has been investigated. While with 8, lithiation occurred exclusively at the benzylic position, with the trans isomer (+/-)-1, ortho-lithiation competed with alpha-lithiation depending upon the experimental conditions. The configurational stability of the alpha-lithiated cis- and trans-stilbene oxides (+/-)-2 and (+/-)-9, respectively, was proved as well as that of scalemic stilbene oxide (R,R)-2.

[reaction: see text] Baylis-Hillman adducts were found to be excellent dienophiles in Diels-Alder reactions, providing essentially complete diastereocontrol (although mixtures of endo/exo isomers) with all dienes.

3-Methyl vinyl aziridine undergoes a mild MgI2-promoted S(N)2' ring opening and concomitant cyclization with fumarate Michael acceptors to give trisubstituted pyrrolidines. The process is efficient and highly diastereoselective. This methodology has been applied to a concise asymmetric synthesis of (+)-allo-kainic acid.

The synthesis of highly enantioenriched alpha-heterocyclic tertiary alcohols has been achieved via lithiation-borylation of a configurationally stable lithiated carbamate and heterocyclic pinacol boronic esters followed by oxidation. Protodeboronation of the alpha-heterocyclic tertiary boronic esters using TBAF center dot 3H(2)O or CsF gave highly enantioenriched 1-pyridyl-1-arylethanes in high er.

[reaction: see text] Enyne metathesis has been used to prepare bridged azabicycles and applied in a short asymmetric synthesis of the tropane ferruginine. A Grubbs first generation catalyst proved to be superior to the second generation catalyst in the enyne metathesis reaction.

2-Vinylaziridines undergo a mild Pd-catalyzed ring-opening cyclization reaction with an ambient atmosphere of carbon dioxide to give 5-vinyloxazolidinones. The process is high yielding as well as regio- and stereoselective.

The synthesis of imidazolinium salts from the reaction of formamidines and (2-bromoethyl)diphenylsulfonium triflate is described. A variety of symmetrical and unsymmetrical imidazolinium triflate salts were synthesized in high yield in short reaction times under mild conditions. Aromatic and aliphatic N-substituents work well. The reaction is proposed to proceed via generation of a vinyl sulfonium salt intermediate from the bromoethylsulfonium triflate.

Tertiary allyl- or crotylsilanes have been prepared in high er and dr via the lithiation−borylation reaction of alkyl carbamates with silaboronates. Using a related strategy, quaternary allylsilanes could be accessed in similarly high er.

Reaction of bromoethylsulfonium salt with 1,2-/1,3-aminoalcohols gave six- and seven-membered rings in good-to-excellent yields. The reactions proceed through generation of a vinyl sulfonium salt followed by annulation to give 1,4-heterocyclic compounds such as morpholines and benzoxazepines in a simple procedure. The method accommodates a range of nitrogen substituents and the amino alcohol can be substituted by amino thiols and diamines to give thiomorpholines, piperazines and benzodiazepines.