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Addition of sulfonyl carbanions with or without an electrophilic tether has been shown, under certain conditions, to add to α,β-unsaturated oxazolines in good yields and high de's. When 4-bromobutylsulfonyl carbanions are added to unsaturated oxazolines, three contiguous stereocenters are formed and good yields of 1,2,3-substituted cyclohexanes are obtained as a 5:1 mixture of only two diastereomers. The sulfonyl substituent may be reductively cleaved to form selectively 1,2-disubstituted cyclohexanes.

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.

Three enantiomerically and geometrically pure building blocks representing fragments of the antifungal antibiotic viridenomycin have been prepared.

A second generation approach toward the synthesis of viridenomycin is described. Three key fragments of the molecule have been synthesized in stereochemically pure form. Initial studies toward the coupling of these fragments with the aim of assembling the macrocycle are detailed. Final efforts to reach the title compound are documented.

Cyclobutannulation of the bicyclic lactam with allyldimethyltritylsilane is accomplished in high yield with good diastereoselectivity. The resulting tricyclic system is converted to a enantiomerically pure cyclobutane-fused pyrrolidine.

The enantioselective synthesis of branched polyhydroxylated pyrrolidines from a novel α-methylene bicyclic lactam (4b) is described.

Chiral 3-alkyl-3-arylpyrrolidines were prepared from the substituted bicyclic lactams. Stereoselectivity in the alkylation of bicyclic lactams was improved by using an alkyl triflate or tosylate as the electrophile.

The enantioselective synthesis of (+)-euphococcinine (1), a homotropane alkaloid, has been achieved in five steps from bicyclic lactam 5.

The stereocontrolled synthesis of the monomeric subunit of the macrolide dimer disorazole C 1 ( 1 ) has been accomplished by convergent coupling of 3 and 4 using the Stille method.

The asymmetric synthesis of the hydroindolone core ( 5 ) of the Amaryllidaceae alkaloids employing chiral bicyclic lactams is described. The vicinal quaternary and tertiary stereocenters were assembled via an addition of lactam 14 enolate to acrolein.

A remote steric effect in the bicyclic lactam oxazolidine ring has been shown to affect the stereochemical outcome in the thio-Claisen rearrangement taking place in the piperidone ring.

Pd, Ni, and Lewis acid catalyzed rearrangements occur under milder conditions than the thermal version of the titled rearrangements.

Enantiomerically pure cis -2,4-disubstituted piperidines were synthesized from chiral thiolactam 2 in six steps via a highly diastereoselective homoenolate alkylation which set the stereochemistry at the C4 carbon. In addition, two cleavage methods were used to cleave the lactam to the desired piperidines with a high level of diastereoselection at the newly created C2 stereocenter.

A remote steric effect in the Sakurai addition to unsaturated esters containing small to large alkyl groups has been detected which leads to either cyclobutane or allyl adducts.

Axially chiral binaphthyls 3a and 3b were synthesized taking, advantage of Ullman coupling of 4a and 4b, respectively. The binaphthyls were shown to be stable to atropisomerization. Binaphthol 3b was resolved with (−)-(1S)-menthyl chloroformate (11). R-axis diastereomer of bisoxazoline 3b was used for enantioselective cyclopropanation of styrene with ethyl diazoacetate.

By employing the appropriate chiral bicyclic lactams, the asymmetric total synthesis of four enantiopure azasugars mentioned in the title were successfully achieved. A series of diastereoselective oxidations ( OsO 4 NMO ) followed by diastereoselective reductions (BH3, 9-BBN) gave good yields of the trisubstituted (16) and tetrasubstituted (2,3,4) pyrrolidine and piperidines respectively.

A novel asymmetric oxazoline ketenimine rearrangement has been observed to construct α-quaternary substituted ketones. Levels of asymmetric induction in the ketones, of up to 87% ee, were observed for this unusual rearrangement.

Using chiral bicyclic lactams, containing an α,β-unsaturation, the key precursor of (−)-indolizomycin was obtained in optically pure form. The sequence involved a > 20:1 diastereoselective cyclopropanation of the unsaturated lactam 5 employing sulfoxonium methylide. TiCl 4 mediated addition of allyltrimethylsilane afforded pyrrolidone 7 in a diastereomeric ratio of > 20:1. The appropriately substituted pyrrolidone 2 was prepared by debenzylation and subsequent alkylation with 3-bromoproponic ester. The six step sequence from commercially available starting materials was performed in 26% overall yield.

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.

Two synthetic approaches to the title compounds using the chiral non-racemic lactam 3 via additions to the lactam carbonyl lead to the requisite chiral cyclohexen-2-ones.

A nonracemic bicyclic lactam has been used to construct a chiral cyclopentane containing vicinal quaternary carbon centers in optically pure form, which is common to all of the title compounds. An oxazoline-mediated asymmetric Ullmann coupling was then utilized to establish chirality about the biaryl axis of mastigophorenes A and B. Through the course of this synthesis, it was clearly demonstrated that smaller chiral auxiliaries lead to higher levels of atroposelection, a previously unknown phenomenon of the asymmetric Ullmann coupling.

(S)-Gossypol (S)-1 , a yellow pigment of cottonseed, has been accessed by a total asymmetric synthesis. The sequence leading to (S)-gossypol (S)-1 was highlighted by four oxazoline mediated reactions, including coupling of ortho-(methoxy)aryloxazolines with Grignard reagents, butyllithium based ortho-lithiation of aryloxazolines, stereocontrolled Ullmann couplings of bromonaphthyloxazolines, and ethoxyvinyllithium hexamethylphosphoric triamide complex based ortho-lithiation of aryloxazolines.

By double alkylation of chiral isoquinoline formamidines, a 71% yield of the bis-1,3(1-tetrahydroisoquinolinyl)propane was formed in >95% ee. Macrocyclization using 2-bromoacetyl bromide gave the [9]-ring diazaheterocycle (11) and the [18]-ring tetra-azaheterocycle (12) in 24 and 57% yields, respectively. After reduction of these lactams, the title compounds 13 and 15 were obtained. X-ray structures are presented for these novel chiral ring systems.

Ethoxyvinyllithium (EVL) adds cleanly to unsaturated oxazolines, which upon hydrolytic work-up afford the corresponding ketones in high yields and excellent diastereoselectivity.

The use of chiral bicyclic lactams, in their thiocarbonyl form 9, has been shown to serve as important intermediates for producing α-quaternary alkyl derivatives 8, which were readily transformed into the title compound (−)-1. The reversibility of the thio-Claisen rearrangement, 15⇌8, was clearly demonstrated and appears to be unprecedented. Solvent effects to alter the equilibrium position were studied and found to have only a moderate, but beneficial effect. The title compound was obtained in 14% overall yield in 10 steps from bicyclic lactam, 9.

The alkylation of cyano enamines 1 and 7 with α,ω-dihalides (or dihalide equivalents), followed by hydrolysis to reveal the lactam carbonyl, provided lactams 8 and 10 containing a tethered electrophile. Intramolecular cyclization of the pendant halide onto the lactam enolate provided tricyclic lactams 9 and 13, which were subjected to a second enolate alkylation to form a quaternary stereocenter. In the case of nor-ephedrine tricyclic lactam 13, the intermolecular was highly endo selective, and the resultant lactams 14 were subjected to partial reduction and hydrolytic auxiliary cleavage to provide enantiopure octalones 16 and 17. From this chemistry came the synthesis of the “Woodward ketone” 19, an intermediate in the total synthesis of a number of steroids. Finally, the methoxymethyl bicyclic (or tricyclic) lactams 33 were shown to undergo nonreductive cleavage of the chiral auxiliary to provide 3,4-dihydropyridones containing a quaternary center.

Further examination of the titled compound has shown that deprotonation of benzylic and allylic carbons are unexpectedly different than those observed with conventional lithium bases.

Bicyclic Lactam 2 was transformed into α-cyanoenamine 8 in a four-step, high-yielding process. γ-Metalation of 8 was achieved using LiTMP in THF/HMPA, and the resultant homoenolate equivalent underwent stereoselective alkylation and subsequent hydrolysis to provide lactams of type 10 as a single diastereomer. Partial reduction and hydrolysis of lactams 10 furnished enantiopure 5-substituted cyclohexenones 13 in good overall yield.

Attempts to repeat the spirocyclization of isoquinoline carboxylic acids, 4, 5, 8, and 9 to the spiroketones, 6 led only to the formation of the N-carboxyanhydrides, 7.

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.

A survey of the utilitarian bicyclic lactams is presented. These chiral templates have provided, and continue to provide, access to a plethora of natural and unnatural carbocyclic products in high enantiomeric purity. Their synthetic versatility has recently grown with the development of new methods for the construction of heterocycles. In addition to the cyclopentenone, cyclohexenone and hexahydroindenone systems, products derived from bicyclic lactams now include optically active piperidines, pyrrolidines, pyrrolidinones and tetrahydroisoquinolines. These favourable properties make the bicyclic lactams highly adaptable tools for asymmetric synthesis.

Simple acidic hydrolysis of epoxyamides 4 , derived from 1-tetralones, furnishes the corresponding 2-tetralones in good yield.

The reduction of S-(+)-serine methyl ester silyl ether with NaBH 4 followed by acidic workup produced the chiral serinol derivatives with minimum racemization. Addition of MeMgBr gave the functionalized amine diol in high yield with no racemization.

An unsymmetrical biaryl coupling between the Grignard of N-benzyl-7-bromoindoline 25 and the appropriately substituted (o-methoxyaryl)oxazoline 15 leads to an intermediate biaryl which can be elaborated in one step to the 1H-pyrrolo[3,2,1-de]phenanthridine ring system. This simple two-step sequence provides general access to the pyrrolophenanthridine alkaloids 2−6.

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.

An improved synthesis of methyl phenylsulfinate 2 by treatment of diphenyl disulfide with bromine in the presence of methanol has been developed. Use of this reagent in the preparation of α,β-unsaturated ketones, nitriles and lactams is described.

The C 2 -symmetric dimethyl amines ( 1a, 1b ) were prepared in high stereoselectivity by carbanion alkylation of their respective formamidines.

Metalation-alkylation of isoindoline 5 in the form of its chiral formamidine, 6 leads to C 2 -dialkylated derivatives in high ee's.

Stereoselective, conjugate additions of primary amines to chiral α-iodo α, β-unsaturated bicyclic lactams are described. Typical yields of the resulting aziridinolactams ranged from 60–90% with facial diastereoselectivities of >98:2 in all cases. Selected optically pure aziridinobicyclic lactams were transformed, by reductive cleavage, into chiral 2-alkyl, 3, 4-aziridinopyrrolidines.

Tertiary amine N-oxides were used to stereospecifically epoxidize chiral unsaturated bicyclic lactams in high yields (90–99%) at room temperature. This appears to be the first reported example of tertiary amine N-oxides acting as epoxidizing agents in the absence of a metal catalyst.