Substituted naphthalenones as a new structural class of HIV-1 reverse transcriptase inhibitors.

A novel substituted naphthalenone (TGG-II-23A) has been found that inhibits HIV-1 infection of CEM-SS cells at concentrations that are not cytotoxic. Time of addition experiments indicate that TGG-II-23A functions at a stage of the HIV-1 life cycle at or near reverse transcription. Cell free assays confirmed that TGG-II-23A inhibits HIV-1 reverse transcriptase. Similar to other non-nucleoside inhibitors, TGG-II-23A was specific for HIV-1 and failed to inhibit the replication of HIV-2. The binding site of TGG-II-23A appears to be in close proximity to that of the TIBO-like inhibitors, since a TIBO-resistant HIV-1 was also resistant to TGG-II-23A treatment. TGG-II-23A is a mixed non-competitive inhibitor that exhibits the same template:primer selectivity as other non-nucleoside inhibitors. TGG-II-23A therefore represents a new structural entry into the TIBO/Nevirapine class of inhibitors of HIV-1 reverse transcriptase.

Total Synthesis of (-)-Tetrahydropalmatine via Chiral Formamidine Carbanions: Unexpected Behavior with Certain Ortho-Substituted Electrophiles.

A method has been developed by alkylation of chiral lithioformamidines to construct protoberberine alkaloids with a C(9) and C(10) D-ring substitution pattern. This ring pattern was established using an ortho-substituted hydroxymethylbenzene electrophile protected as a silyl ether to ultimately provide (-)-tetrahydropalmatine in 88% ee. Additionally, we have discovered limitations with ortho-substituted electrophiles in the asymmetric formamidine alkylation. These electrophiles have the potential to disrupt the lithium formamidine chelate and cause the selectivity in the alkylation to be uncharacteristically low. The total synthesis of (+/-)-canadine and (-)-tetrahydropalmatine along with the limitations to the formamidine alkylation technology are delineated herein.

A Novel Asymmetric Route to the 1,3-Disubstituted Tetrahydroisoquinoline, (-)-Argemonine.

Chiral bicyclic lactam 13 was converted to the natural product (-)-argemonine 9 in six steps. This novel route to argemonine represents a general strategy for the preparation of chiral 1,3-disubstituted tetrahydroisoquinolines.

Oxidation of Oxazolines and Thiazolines to Oxazoles and Thiazoles. Application of the Kharasch-Sosnovsky Reaction.

Using a modification of the Kharasch-Sosnovsky reaction, the oxidation of oxazolines and thiazolines bearing a variety of 2-alkyl substituents (chiral and achiral) were smoothly oxidized to their corresponding oxazoles and thiazoles, respectively. The key feature involved in the successful implementation of this important oxidation was the use of a mixture of Cu(I) and Cu(II) salts to enhance the oxidation of the intermediate captodative radical, 24. The main limitation of this method was shown when the oxidation failed with oxazolines/thiazolines lacking the carboalkoxy group at C-4.

Total Synthesis of Bistratamide D.

The total synthesis of the macrocyclic hexapeptide bistratamide D is reported. The synthetic strategy involved assembly of enantiomerically pure oxazole, thiazole, and oxazoline segments derived from amino acids. Macrocyclization of the hexapeptidic aminooxazoline-oxazole-thiazole carboxylic acid fragment was accomplished by activation with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

An Asymmetric Route to Novel Chiral Cyclohexenones with Spiro-Connected Cyclopentenes. Further Utility of Chiral Bicyclic Thiolactams and the [3,3] Thio-Claisen Products.

Sequential allylation of chiral, nonracemic thiolactam 8 affords clean thio-Claisen [3,3] products 11. The stereoselectivity of the rearrangement was found to be on the order of 10-11:1, with the exo-endo products responsible for the mixture. Addition of hydride or methyllithium-cerium chloride gave clean addition to the thiolactam in the form of its iminium salts 12. Hydrolysis gave 4,4-dialkylcyclohexenones 15, which were cyclized to the cyclopentene derivatives 16 using Grubbs' catalyst.

Enantioselective synthesis of rigid 2-aminotetralins. Utility of silicon as an oxygen and nitrogen surrogate in the tandem addition reaction.

Dimethylphenylsilyllithium undergoes a highly diastereoselective conjugate addition to chiral naphthyloxazoline 11. Electrophilic trapping of the resulting aza-enolate affords the tandem addition product (12) in high yields as a single diastereomer. The silicon, thus incorporated, may be protodesilylated and undergoes a Tamao oxidation to afford the corresponding alcohol. By chemical modification of the oxazoline, both the gamma-lactone (28) and the delta-lactone (37) were prepared. Reduction of each lactone followed by oxidation of the ensuing diol gave the keto aldehyde. Double reductive amination of the 1,4-dicarbonyl (from the gamma-lactone) allowed the synthesis of two novel hexahydrobenz[e]indoles, 20 and 35. Double reductive amination of the 1,5-dicarbonyl (from the delta-lactone) gave access to two novel octahydrobenzo[f]quinolines, 41 and 43. An unprecedented rearrangement of nitro alcohol 26 into lactone 28 is described and a reasonable mechanism for its formation postulated.

Asymmetric synthesis of 2-alkyl-perhydroazepines from [5,3,0]-bicyclic lactams.

The synthesis and utility of a novel class of [5,3,0]-bicyclic lactams are described. Produced by the cyclodehydration of (R)-phenylglycinol with omega-keto acids, lactams 4-6 were obtained as separable diastereomeric mixtures ( approximately 2:1) in low yields ( approximately 40%). Higher chemical yield (up to 61%) was realized via an alternate route involving ring closure metathesis of 2-allyl-N-acroyl oxazolidines, 8. Stereoselective reductions of the syn-bicyclic lactams, 4a and 5a, occurred with the use of alane or lithiumaluminum hydride, affording azepine alcohols, 11a and 15a, of the R configuration at the 2-position, in good to moderate yields (50-88%). High selectivity was also observed in the diisobutylaluminum hydride reduction of the epimeric anti lactams, 4b and 5b, affording azepine alcohols, 11b and 15b, of the S configuration at C-2. Hydrogenolytic cleavage of the N-benzyl moiety afforded chiral 2-substituted perhydroazepines, (R)- and (S)-12, in good yields and good enantiomeric excesses (84-94%).

An asymmetric approach to spirocylic systems: a formal synthesis of zizaene.

A general route to enantiopure spirocarbocycles is described. The use of various chiral bicyclic lactams 1 that have been doubly alkylated with olefinic halides gives good yields of alpha,alpha-disubstituted chiral lactams 2 which were cyclized to spiro-olefins using ring closure metathesis methodology (Grubbs' catalyst). These spirolactams 3, formed in generally excellent yields, were shown to be smoothly transformed into spirocyclopentenone 6, spirocyclohexenone, 7, and spirolactams 8. Further demonstration of this spirocyclization methodology was featured in a formal synthesis of zizaene, by preparing in enantiomeric form the Coates' intermediate 21. This synthetic effort provided additional examples of the synthetic versatility of chiral bicyclic lactams 2a,b.

Studies on the total synthesis of disorazole C1. An advanced macrocycle intermediate.

Synthesis of protected tetradehydro-(6,6'-S)-(14,14'-S)-(16,16'-R)-disorazole (3), a potential precursor to the natural product disorazole C1 (1), is described. Key features of this work include (a) an unprecedented sequential 1,5 O --> O silyl rearrangement/Horner-Wadsworth-Emmons reaction used to construct 18, (b) a highly convergent Sonogashira reaction between the dienyl iodide 7 and the alkyne 8 to assemble the dienyne monomeric fragment 5, and (c) the selective cyclization of 5 to give either the cyclic monomer 23 or the dimer 3.

Synthesis and chiroptical properties of a novel C2-symmetric binaphthyl phosphortriamide ("chiral HMPA").

By use of an asymmetric Ullmann coupling involving chiral naphthalene oxazolines 1, the title compounds were prepared in good yields and with high diastereoselectivity. Hydrolysis of the binaphthyl oxazolines 2 led to the di-aldehydes 5, which were transformed into the azepine derivative, 6. The latter was treated with the appropriate phosphoryl halide to access the chiral HMPA systems 7 and 9. The CD spectra of the chiral azepine 6 and the chiral phosphoramides 7 and 9 were measured and showed a strong positive CD couplet near 225 nm, consistent with the P axial chirality (S configuration). Semi-empirical CNDO/S molecular orbital calculations of the CD spectrum of 6 satisfactorily reproduced the major features of the observed spectrum.