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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.

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.

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.

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.

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.

The ellagitannins are galloyl esters of glucose that contain at least one chiral biaryl (digalloyl) subunit. Included in this family are the tellimagrandins (1-3). The first asymmetric synthesis of (S)-4,4',5,5',6,6'-hexamethoxy-2,2'-diphenic acid, a ubiquitous subunit in ellagitannins, is reported by utilization of an intermolecular oxazoline-mediated asymmetric Ullmann coupling. Attachment of this acid to an appropriate glucose core resulted in the synthesis of an ellagitannin

A route to the titled compounds in >99% ee was achieved from sequential diastereoselective alkylations of chiral, nonracemic bicyclic lactams 6 and 15. An intramolecular addition of the organolithium species derived from 17a-c and 28a-d gave, after hydrolysis, diketones 25a-c and 30a-d, which were cyclized to the titled compounds 4a-c and 31a-d. As an example of the versatility of this method, the ABC ring system of the triterpene stelliferin A, isolated from marine organisms, was prepared in high enantiomeric excess

The formation of chiral amino alcohols by reduction of amino acids has been the subject of considerable effort due to their importance in asymmetric synthesis? peptide and pharmaceutical chemistry: resolution of racemic mixtures: synthesis of insecticidal compounds: and others. From the earliest reports by Karrer in 1921, amino alcohols were prepared by reduction of the corresponding amino acid esters with sodium in ethanol.& Subsequently, lithium aluminum hydride6b and sodium borohydride& were employed and furthermore, free amino acids were shown to be reduced directly by sodium bis(2-methoxyethoxy)aluminum hydride? the borane-dimethyl sulfide complex activated by boron trifluoride-etherate,w lithium aluminum hydride? lithium borohyride with trimethylchl~rosilane,~~ sodium borohydride-trimethyl~hlorosilane,~g or boron trif l~orideetherate.~~ Very recently, while this manuscript was being prepared, a report appeared describing an efficient reduction of amino acids and derivatives using sodium borohydride and sulfuric

Conjugate additions of RCuCNLi to the chiral α,β-unsaturated lactam 4 gives almost exclusive exo addition-a reversal in stereochemistry when cuprates were added to chiral lactam 1. The lactams 5 were transformed into 4-substituted pyrrolidinones 8 via a three-step sequence which involved decarbalkoxylation, silane reduction and metal-ammonia benzylamine cleavage. The chemical yields as well as the enantiomeric purity were very high for this process. As an example of the usefulness of this scheme, the antidepressant (-)-Rolipram was prepared in good overall yield

Cycloaddition of various sulfur ylides to the chiral unsaturated lactams 1a, 1b led to cyclopropanated products containing a monosubstituted appendage. The stereochemical outcome is such that all the products are mainly (or exclusively) the kinetically controlled endo-syn-8, -9, or endo-anti-10. The latter occurs by virtue of an epimerization to the thermodynamically favored product. Removal of the chiral auxiliary following Wittig reaction on the intermediate carbinol amines (11, 15) gave chiral, nonracemic 1,2,3-trisubstituted cyclopropanes containing various functionalities (13, 16)

Attachment of the chiral formamidine moiety to 6-methoxy-1,2,3,4-tetrahydroisoquinoline afforded the key chiral, nonracemic precursor 8, upon which the azasteroid skeleton was constructed. Asymmetric alkylation with α-halo esters or β-halo ethers gave 15 and 22, respectively, in high ee's. Cyclization, following enamine formation with cyclopentanedione or cyclopentanone, led to the chiral steroidal skeletons 6 and 5, respectively

A series of synthetic manipulations on the naphthalene nucleus, containing a 1-(2-oxazolinyl) moiety, is described. Nucleophilic additions afford both regio- and stereoselective products in the 1- and 4-positions. The latter is oxidatively transformed in the 4-keto system 4 which can undergo various substitutions as well as carbonyl transpostions

The trans-2,3-disubstituted pyrrolidine moiety, found in the pyrrolizidine alkaloids as well as other natural product, has been accessed from the α,β-unsaturated bicyclic lactams 1d and 10. Conjugate addition of lower order cyanocuprates to lactams 1d and 10 resulted in endo entry of the cuprate with high diasterelectivity. Other cuprates were investigated and resulted in diminished or opposite stereoselectivities. Further transformation of the β-subtituted lactams provided the title compounds in good overall yield and high enantiomeric excess

o-Chloro-β-phenethylamines, transformed into the N-tert-butylformamidines, were found to be excellent precursors to indolines following benzyne formation. A series of methoxy-substituted o-chlorophenethylamines containing an N-alkyl or aryl substitutent were subjected to sec-butyllithium producing the ortho-lithiated aromatic which subsequently lost lithium chloride at temperatures ranging from -78 to -50 o C. The resulting benzyne was intramolecularly trapped providing the titled heterocycles. Quenching the reaction resulted in elimination of the tert-butyl isocyanide (isolated after aqueous workup as tert-butylformamide)

An efficient procedure for the preparation of the title compounds in high enantiomeric purity has been realized starting from 3-acylpropionic acids. Stereoselective reduction of chiral bicyclic lactams 2a-h, prepared from the corresponding γ-keto acid and (R)-phenylglycinol, using alane or triethylsilane with titanium tetrachloride provided the N-substituted pyrrolidines and pyrrolidinones, respectively. Subsequent cleavage of the phenylglycinol returned the desired amines and lactams. The enantiomeric purity of these compounds was determined to be >98% by chiral stationary-phase HPLC

1A short stereoselective route to a variety of chiral α,β-unsaturated oxazolines derived from (S)-tert-leucinol is described.Addition of organolithium reagents to this chiral oxazoline occurs in a Michael fashion,giving rise to adducts with high diastereoselectivity.Reductive cleavage of the oxazoline leaves the β,B-disubstituted aldehydes in >93% ee

The stereochemistry of alkylation of α-lithio-N-(N'-tert-butylformimidoyl)-4-tert-butylpiperidines was studied. Monoalkylation proceeded to give equatorial 2-substituted piperidines, which in turn gave diequatorial 2,6-disubstituted piperidines when subjected to a second lithiation-alkylation procedure. The stereochemical result of the second alkylation is in contrast to α-lithio-2-substituted piperidines that are stabilized by the N-(tert-butoxycarbonyl)group; these gave the axial 6-substituted piperidines on treatment with electrophiles. A mechanistic rationalization of these results is given that invokes nonbonding interactions between the stabilizing groups and piperidine ring substituents

A route to (−)-pseudo and (−)-allo isomers of yohimban is described. This asymmetric synthetic approach to indole alkaloids is based on the stereocontrolled alkylation of α-amino carbanions mediated by chiral formamidines. The stereochemically pure enantiomer of the alkylated β-carboline 7 is utilized to bias the subsequent intramolecular Diels-Alder cycloaddition of the N-dienamide 8 or the homologous N-acrylamide 12 derived from the alkylated carboline 11. In this fashion, suitable choice of diene and dienophile partners led to the pseudo- and alloyohimban isomers 1b and 1c, respectively

The sequential alkylation of bicyclic lactams by various alkyl halides leads to 2,2-dialkyl-3-benzoyl carboxylic esters in high ee's and to optically active 2-(α,α-quaternary substituted) oxazolines which are also precursors to carboxylic acids or their methyl esters. Under certain hydrolysis conditions, the products are optically active 2,2-dialkyl-1,2-dihydronaphthalenes

The first asymmetric total synthesis of the unnatural enantiomer of (-)-A9(12)-capnellene has been achieved in 14.1 % overall yield. The synthesis is based on the chiral nonracemic bicyclic lactam 15 derived from inexpensive (S)-valinol and levulinic acid. The goal of the synthesis, which was accomplished, was to reach the intermediate 13, originally reported in racemic form, and carry out the last step to the title compound.

The studies performed with chiral oxazolines as vehicles for a number of C-C bond-forming reactions are traced back to the early 1970s. The main source of chirality in these studies was derived from chiral, nonracemic amino alcohols which, themselves, were prepared from amino acids. The formation of chiral oxazolines from these materials provided interesting and useful starting materials for these studies. The factors responsible for high optical yields during that era were attributed to rigidity or precomplexation of the reactants, thus providing a more well-defined topography during the reaction course. A number of C-C bond reaction types are described including alkylations, additions, and organometallic reactions. The ee's of many of the products arrived at are well above 90%. This level of ee was virtually unprecedented in the early to mid 1970s. In addition to the synthetic emphasis, several mechanistic questions, arising in other areas, were also undertaken due to the accessibility of the appropriate requisite chiral materials.

Addition of allylsilane gave cyclobutanes at low temperature and cyclopentanes at higher temperature

Metalation of the title compounds indicated that the formamidine-equipped indolines or 1,2,3,4-tetrahydroquinolines give rise solely to C-2 alkylation products (5, 6) whereas the corresponding N-t-Boc systems give only ortho aryl alkylation (7, 8)

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).

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.

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%).

Molecular mechanics studies on the lithiated chiral formamidines 1 and 3 provide an explanation for the observed degree of facial selectivity during alkylation. The energetic origin of the conformers which predominate prior to each alkylation step are found visibly to arise from angle strain and H-H repulsions

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.

Chiral and achiral 3-methoxynaphthalen-2-yl oxazolines 4a,b failed to undergo an aromatic nucleophilic displacement of the 3-methoxy group with organolithium reagents and instead afforded dihydronaphthalenes 9 and 14 in 30-95% yield. Dihydronaphthalenes 9 (racemic) and 14 (nonracemic) were easily converted into the corresponding aldehydes 15. Alternatively, aldehydes 15 were prepared via tandem addition of Grignard reagents to imines 17 in 50-65% yield. Aldehydes 15 served as precursors to 3,3, 4-trisubstituted 2-tetralones 16. Use of methyl chloroformate to trap the azaenolate derived from 17f and i-PrMgCl afforded, in 65% yield, a versatile synthetic intermediate 23 which may serve to access 4-alkyl-, 3,4-dialkyl-, 3,4-disubstituted and 3,3, 4-trisubstituted 2-tetralones with diverse substitution patterns.

The title compounds have been prepared from 3-acylpropionic acids 2 and (−)-R-phenylglycinol in a three-step sequence in >98% enantiomeric excess. The R group in 2 ultimately becomes the 2-substituent in the chiral pyrrolidine

Excellent diastereofacial selectivities over a wide range of temperatures (−78 to 25 o C) were obtained with the title compounds with use of chiral oxazolines derived from (S)-valinol or (S)-tert-leucinol. These are the first useful levels of asymmetric induction observed without the presence of the chelating methoxyl groups. The dihydronaphthylcarbinols and aldehydes resulting from these additions were obtained in >98% ee

Metallation sequentielle d'un lactame tricyclique chiral (LDA ou LDA/halogenures de zirconocene) et alkylation quaternaire pour donner des produits diastereomeriques dans un rapport 6-54: 1. Reduction et hydrolyse conduisent au produit principal en trois etapes avec une purete enantiomerique superieure a 99%

L'alkylation de la tetrahydroisoquinoleine est grandement facilitee par la formation d'une formamidine tres reactive obtenue a partir de 2-amino-2-methyl-propanol

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.

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.