Effective asymmetric synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)

A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) analogue of the CC-1065 and duocarmycin alkylation subunits is detailed that employs an effective enzymatic desymmetrization reaction of prochiral diol 12 using a commercially available Pseudomonas sp. lipase. The optically active monoacetate (S)-13 is furnished in exceptional conversions (88%) and optical purity (99% ee) and serves as an intermediate for the preparation of either enantiomer of CBI. Similarly, the Pseudomonas sp. lipase resolved the racemic intermediate 19, affording advanced intermediates of CBI in good conversions and optical purity (99% ee), and provided an alternative approach to the preparation of optically active CBI derivatives.     

Stereospecific Synthesis of Enantiopure [6]Helicene Containing a Seven-Membered Ring and [7]Helicene by Acid-Promoted Stepwise Alkyne Annulations of Doubly Axial-Chiral Precursors**

Enantiopure [6]helicene containing an embedded seven-membered ring and carbo[7]helicene (>99 % ee) with opposite helicity were simultaneously and quantitatively (>99 %) synthesized with a perfect stereospecificity through stepwise acid-promoted intramolecular alkyne annulations of doubly axial-chiral cyclization precursors. The helical handedness of the [6]- and [7]helicenes was fully stereocontrolled by the doubly axial chirality of the precursors as a result of complete axial-to-helical chirality transfer. The cyclizations proceeded in a stepwise manner; the first six-membered ring formation was followed by the kinetically controlled seven- or six-membered ring formation with or without helix-inversion of a [4]helicene intermediate generated during the first cyclization step, thus quantitatively producing enantiopure circularly polarized luminescent [6]- and [7]helicenes with opposite helicity.     

Synthesis of Optically Active endo,endo Bicyclo[2.2.2]octane-2,5-diol, Bicyclo[2.2.2]octane-2,5-dione, and Related Compounds

Optically active C(2)-symmetric (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol ((+)-12; 98% ee) and several selectively protected optically active intermediates useful for synthetic transformations were synthesized via a 1,2-carbonyl transposition route starting from the easily available optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one ((-)-2). The synthetic route also allowed the preparation of optically active (1S,4S)-bicyclo[2.2.2]octane-2,5-dione ((+)-14; 98% ee).     

Enantioselective synthesis of bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of arenes with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones

A strategy to rapidly assemble enantiomerically pure bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of tethered pi-nucleophiles with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones is described. The approach begins with the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-2-ones bearing a tethered pi-nucleophile at the 6-position by intramolecular Rh(II)-catalyzed cyclopropanation of allylic diazoacetates, prepared from the corresponding (Z)-allylic alcohols. Me2AlOTf-induced intramolecular Friedel-Crafts cyclization provides medium-sized carbocycles and heterocycles in high yields without requiring high-dilution or slow substrate addition techniques. The scope and limitations of this synthetic methodology are presented.     

Asymmetric nitroallylation of arylboronic acids with nitroallyl acetates catalyzed by chiral rhodium complexes and its application in a concise total synthesis of optically pure (+)-gamma-lycorane

[reaction: see text]A new rhodium-catalyzed highly enantioselective nitroallylation of 2-nitrocyclohex-2-enol esters with arylboronic acids is described. A rhodium complex of [RhOH(COD)]2 and optically pure BINAP is the optimal catalyst that provides good yields and high enantioselectivities ranging from 90 to 99% ee for various arylboronic acids at 50 degrees C. A concise total synthesis of optically pure (+)-gamma-lycorane in overall 38% yield was achieved on the basis of this new method.     

Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)

Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.     

Asymmetric electrochemical lactonization of diols on a chiral 1-azaspiro[5.5]undecane N-oxyl radical mediator-modified graphite felt electrode

A graphite felt electrode modified with (6S,7R,10R)-4-amino-2,2,7-trimethyl-10-isopropyl-1-azaspiro[5.5]undecane N-oxyl was prepared for electrocatalytic oxidation of diols; electrolysis of diols on the modified electrode yielded optically active lactones (92.0-96.4%), with an enantiopurity of 82-99% ee.     

Features and applications of [Rh(CO)(2)Cl](2)-catalyzed alkylations of unsymmetrical allylic substrates

A novel regio- and stereoselective [Rh(CO)2Cl]2-catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity of the reaction favors product ratios in which substitution occurs at the carbon bearing the leaving group. When an enantiomerically enriched carbonate (> or = 99% ee) was examined, the Rh(I)-catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. As an application of the Rh(I)-catalyzed allylic alkylation, a series of novel domino reactions have been developed that couple the unique regio- and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. Implementation of such processes provides a rapid and efficient entry to a variety of bicyclic carbon skeletons from simple precursors.     

Novel chiral calix[4]arenes by direct asymmetric epoxidation reaction

We report the first asymmetric synthesis of trans optically active (+) C 2 1,3-bisarylepoxide of calix[4]arene in excellent chemical yield and >99% ee, and its enantiospecific conversion to the corresponding bis-dioxolane.     

Palladium-Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio-, Diastereo-, and Enantioselective Construction of Benzofuro[3,2-b]azepine Skeletons

The palladium-catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran-derived azadienes furnishes chiral benzofuro[3,2-b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd-trimethylenemethane can enrich the arsenal of Pd-TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition-metal-catalyzed asymmetric [4+3] cyclization.     

Design, synthesis and biological evaluation of optically pure functionalized spiro[5,5]undecane-1,5,9-triones as HIV-1 inhibitors

A single-step amino acid-catalyzed diastereoselective three-component synthesis of optically pure highly functionalized spiro[5,5]undecane-1,5,9-triones preferentially over the four stereoisomers was accomplished in very good yields with >99% ee/de. Preliminary cell culture-based in vivo screening on these molecules revealed that cis-1aca and cis-1jca are better lead compounds for HIV-1 treatment than the known antiretroviral drug azidothymidine (AZT).     

Synthesis and Properties of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI) Alkylation Subunit: Magnitude of Electronic Effects on the Functional Reactivity

The synthesis of 7-methoxy-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (MCBI), a substituted CBI derivative bearing a C7 methoxy group para to the C4 carbonyl, is described in efforts that establish the magnitude of potential electronic effects on the chemical and functional reactivity of the agents. The core structure of the MCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors (15 and 20) followed by 5-exo-trig aryl radical-alkene cyclization (24 --> 25, 32 --> 33) for completion of the synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation of 28 for introduction of the activated cyclopropane. Two approaches to the implementation of the key 5-exo-trig free radical cyclization are detailed with the former proceeding with closure of 24 to provide 25 in which the required product functionalization was introduced prior to cyclization and the latter with Tempo trap of the cyclization product of the unfunctionalized alkene substrate 32 to provide 33. The latter concise approach provided the MCBI subunit and its immediate precursor in 12-13 steps in superb overall conversions (27-30%). Resolution of an immediate MCBI precursor and its incorporation into both enantiomers of 39-46, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-MCBI (29) revealed that introduction of the C7 methoxy group accelerates the rate of solvolysis by only 1.2-1.06x. This remarkably modest effect is inconsistent with C4 carbonyl protonation as the slow and rate-determining step of solvolysis or acid-catalyzed nucleophilic addition but is consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction. This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. For the natural enantiomers, this unusually small electronic effect on functional reactivity had little or no perceptible effect on their DNA alkylation selectivity, efficiency, and relative rates or on their biological properties. Perceptible effects of the C7 methoxy substituent on the unnatural enantiomers were observed and they proved to be 4-40x more effective than the corresponding CBI-based unnatural enantiomers and comparable in cytotoxic potency with the MCBI natural enantiomers. This effect is most consistently rationalized not by a C7 methoxy substituent effect on functional reactivity but rather through introduction of additional stabilizing noncovalent interactions which increase the unnatural enantiomer DNA alkylation efficiency and further stabilize its inherently reversible DNA alkylation reaction.     

Chiral 6-phenyl-2,3-bismethylenemethoxycarbonyl-[1,4]-dioxane as a designer synthon for an efficient and short synthesis of optically pure 2,6-dioxabicyclo[3.3.0]octane-3,7-dione

Chiral 6-phenyl-2,3-bismethylenemethoxycarbonyl-[1,4]-dioxane, synthesized by the PET cyclization of 8, has been used as a designer synthon for an efficient and short synthesis of optically pure 2,6-dioxabicyclo[3.3.0]octane-3,7-dione.     

Palladium‐Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio‐, Diastereo‐, and Enantioselective Construction of Benzofuro[3,2‐b]azepine Skeletons

The palladium‐catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran‐derived azadienes furnishes chiral benzofuro[3,2‐b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd‐trimethylenemethane can enrich the arsenal of Pd‐TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition‐metal‐catalyzed asymmetric [4+3] cyclization.     

N-propargylamides via the asymmetric michael addition of B-alkynyl-10-TMS-9- borabicyclo[3.3.2]decanes to N-acylimines

[Structure: see text] The asymmetric synthesis of N-propargylamides through Michael addition of the alkynylborane 1 to N-acylimines is reported. The N-acetylimines provide the best substrates for the process exhibiting high selectivity (56-95% ee) with predictable stereochemistry. In several cases, 5 crystallizes in essentially pure form (97-99% ee) and a single-crystal X-ray structure was also obtained for 5g (R1=R2=Me, R3=o-Cl-C6C4). The process regenerates 4 for its direct conversion back to 1 and facilitates the efficient recovery of the pseudoephedrine.     

Beta-silylated homopropargylic amines via the asymmetric allenylboration of aldimines

The asymmetric synthesis of alpha-trimethylsilylpropargylic carbamines (7) through the addition of allenylboranes 4 to N-H aldimines is reported. The insertion of TMSCHN2 into enantiomerically pure B-alkynyl-10-TMS-9-borabicyclo[3.3.2]decanes 3 followed by a sterically driven 1,3-suprafacial borotropic shift proceeds with complete stereospecificity to produce 4 in diastereomerically and enantiomerically pure form. These reagents give 7 (51-85%, syn/anti >99%, 92-9% ee) permitting the recovery of 8 (53-63%). Allenylboranes 4 also provide a convenient route to optically pure allenylsilanes 13 (55-94%) through their protonolysis. [reaction: see text]     

Nonracemic alpha-allenyl carbinols from asymmetric propargylation with the 10-trimethylsilyl-9-borabicyclo[3.3.2]decanes

[reaction: see text] The asymmetric propargylboration of aldehydes at -78 degrees C in <3 h with 1 provides silylated alpha-allenyl carbinols 6 (60-87%) in high ee (94% to >98% ee). The reagents 1 are easily prepared in both enantiomeric forms with a simple Grignard procedure and air-stable borinate complexes 2. The ozonolysis of 6 proceeds smoothly through an acylsilane intermediate to give a TMS ester, which is hydrolyzed to the alpha-hydroxy acid quantitatively with water.     

Chemoenzymatic synthesis of pyrrolo[2,1-b]quinazolinones: lipase-catalyzed resolution of vasicinone.

A facile synthesis of bronchodilatory pyrrolo[2,1-b]quinazoline alkaloids by azidoreductive cyclization strategy employing TMSCl-NaI and bakers' yeast is described. Both the chemical and enzymatic methods are mild and take place at room temperature in good yields. Further, synthesis and resolution of vasicinone has been carried out by employing different lipases. It has been observed that lipase PS provides acetate of (S)-vasicinone in 98% ee.     

Lipase-catalyzed domino kinetic resolution/intramolecular Diels-Alder reaction: one-pot synthesis of optically active 7-oxabicyclo[2.2.1]heptenes from furfuryl alcohols and beta-substituted acrylic acids

The first lipase-catalyzed domino reaction is described in which the acyl moiety formed during the enzymatic kinetic resolution of furfuryl alcohols (+/-)-3 with a 1-ethoxyvinyl ester 2 was utilized as a part of the constituent structure for the subsequent Diels-Alder reaction. The preparation of ester 2 from carboxylic acid 1 and the subsequent domino reaction were carried out in a one-pot reaction. Therefore, this procedure provides a convenient preparation of the optically active 7-oxabicyclo[2.2.1]heptene derivatives 5, which has five chiral, non-racemic carbon centers, from achiral 1 and racemic 3. The overall efficiency of this process was dependent on the substituent at the C-3 position of 3, and the use of the 3-methylfurfuryl derivatives, (+/-)-3 b and (+/-)-3 f, exclusively produced diastereoselectivity with excellent enantioselectivity to give (2R)-syn-5 (91->/=99 % ee) and (S)-3 (96->/=99 % ee). Similar procedures starting from the 3-bromofurfuryl alcohols (+/-)-3 h-j provided the cycloadducts (2R)-syn-5 j-q (93->/=99 % ee), in which the bromo group was utilized for the installation of bulky substituents to the 7-oxabicycloheptene core.     

Synthesis and evaluation of duocarmycin and CC-1065 analogues incorporating the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-3-azaindol-4-one (CBA) alkylation subunit

An efficient eight-step synthesis (53% overall) and the evaluation of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-3-azaindol-4-one (CBA) and its derivatives containing an aza variant of the CC-1065/duocarmycin alkylation subunit are detailed. This unique deep-seated aza modification provided an unprecedented 2-aza-4,4-spirocyclopropacyclohexadienone that was characterized chemically and structurally (X-ray). CBA proved structurally identical with CBI, the carbon analogue, including the stereoelectronic alignment of the key cyclopropane, its bond lengths, and the bond length of the diagnostic C3a-N2 bond, reflecting the extent of vinylogous amide (amidine) conjugation. Despite these structural similarities, CBA and its derivatives were found to be much more reactive toward solvolysis and hydrolysis, much less effective DNA alkylating agents (1000-fold), and biologically much less potent (100- to 1000-fold) than the corresponding CBI derivatives.