Alkylation of phenylglycinol-derived oxazolopiperidone lactams. Enantioselective synthesis of beta-substituted piperidines

The stereochemical outcome of the alkylation of a variety of phenylglycinol-derived oxazolopiperidone lactams is studied. The influence of the configuration of the C-8a stereocenter and the effect of the substituents at the C-8 and C-8a positions on the stereoselectivity of the reaction are discussed. The synthetic utility of these alkylation reactions is illustrated with the synthesis of cis and trans 3,5-disubstituted, 2,5-disubstituted, and 2,3,5-trisubstituted enantiopure piperidines, and the indole alkaloids 20R- and 20S-dihydrocleavamine.     

Enantioselective synthesis of alkaloids from phenylglycinol-derived lactams

This review is focused on recent synthetic achievements and ongoing work in our laboratory using phenylglycinol-derived oxazolopiperidone lactams as starting materials for the enantioselective synthesis of piperidine-containing alkaloids: madangamines, 2,5-disubstituted decahydroquinoline and 1-substituted tetrahydroisoquinoline alkaloids, the indole alkaloids 20S- and 20R-dihydrocleavamine and quebrachamine, and indole alkaloids of the uleine and silicine groups.     

Stereoselective conjugate addition reactions to phenylglycinol-derived, unsaturated oxazolopiperidone lactams

Phenylglycinol-derived, unsaturated oxazolopiperidone lactams are extremely useful building blocks that undergo stereoselective conjugate addition reactions with organocuprates, enolates, and sulfur-stabilized anions, allowing the stereocontrolled introduction of substituents at the piperidine 4-position. The factors governing the exo- or endo-facial selectivity are discussed. The methodology can be used for the preparation of a variety of enantiopure piperidines, including pharmaceuticals, alkaloids precursors, piperidine-fused derivatives, as well as complex piperidine-containing natural products.     

Enantioselective formal synthesis of uleine alkaloids from phenylglycinol-derived bicyclic lactams

A two-step route for the enantioselective construction of the tetracyclic ring system of uleine alkaloids, involving the stereoselective conjugate addition of an appropriate indole-containing nucleophile to a chiral bicyclic delta-lactam and the subsequent cyclization on the indole 3-position of the resulting 4,5-disubstituted 2-piperidone, has culminated in the formal total synthesis of several alkaloids of this group.     

Enantioselective spirocyclizations from tryptophanol-derived oxazolopiperidone lactams

A straightforward synthetic route to enantiopure spiro[indole-3,3'-indolizidines] is reported. The key step is a Lewis acid promoted cyclization of a Na-tosyltryptophanol-derived oxazolopiperidone lactam in the presence of Et3SiH.     

Enantioselective synthesis of 3,3-disubstituted oxindoles through Pd-catalyzed cyanoamidation

The first enantioselective cyanoamidation of olefins provides quick access to a variety of 3,3-disubstituted oxindoles. The combination of Pd(dba)2, an optically active phosphoramidite, and N, N-dimethylpropylene urea (DMPU) in decalin were found to be the best conditions.     

Enantioselective synthesis of piperidine,indolizidine, and quinolizidine alkaloids from a phenylglycinol-derived delta-lactam

Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.     

Stereoselective α-amidoalkylation of phenylglycinol-derived lactams. Synthesis of enantiopure 5,6-disubstituted 2-piperidones

The stereochemical outcome of α-amidoalkylation reactions of chiral nonracemic bicyclic lactams 2b and 2c with indole, allyltrimethylsilane, TMSCN and Grignard reagents to gain access to enantiopure 5,6-disubstituted 2-piperidones is discussed.     

Diastereoselective synthesis of 3,3-disubstituted oxindoles from atropisomeric N-aryl oxindole derivatives

Diastereoselective synthesis of 3,3-disubstituted oxindoles has been examined by transformations involving nucleophilic addition, alkylation, and cycloaddition using chiral racemic N-aryl oxindoles bearing C–N axial chirality. The most striking features of this approach are high diastereoselectivities (up to >95:<5) when using ortho-monosubstituted N-aryl oxindoles and easy removal of the p-(benzyloxy)aryl moiety in the axially twisted amides by a mild two-step sequence.     

Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams

Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (−)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.     

Asymmetric synthesis of 3,3-disubstituted isoindolinones

An anionic chiral auxiliary-mediated asymmetric alkylation of carbamate 2 affords 3,3-disubstituted isoindolinones 3 in moderate to high de. The chiral auxiliary can be removed and recovered under mild conditions, and the resulting enantiopure lactams further elaborated.     

Diastereoselective synthesis of 5,5-disubstituted 3,3-difluorotetrahydrofurans

The diastereoselective synthesis of 5,5-disubstituted 3,3-difluorotetrahydrofurans 2 was achieved using β,β-difluorohomoallylic alcohols 1 as the key starting material in the presence of ICl (3.0?equiv) and tert-BuOK (1.5?equiv) in THF. The corresponding iodocyclization products 2 were obtained in good to moderate yields with excellent diastereo- and regioselectivities (d.r.?=?>20/1, 5-endo-trig only).     

Chiral oxazolopiperidone lactams: versatile intermediates for the enantioselective synthesis of piperidine-containing natural products

Phenylglycinol-derived oxazolopiperidone lactams are exceptionally versatile building blocks for the enantioselective construction of structurally diverse piperidine-containing natural products and bioactive compounds. These lactams are readily available in both enantiomeric series by cyclocondensation of the chiral amino alcohol with a delta-oxo acid derivative and allow the substituents to be introduced at the different ring positions in a regio- and stereocontrolled manner, providing access to enantiopure polysubstituted piperidines bearing virtually any type of substitution pattern, and also quinolizidines, indolizidines, perhydroquinolines, hydroisoquinolines, as well as complex indole alkaloids. Of particular interest are cyclocondensation reactions with racemic or prochiral delta-oxo (di)acid derivatives in processes involving dynamic kinetic resolution and/or differentiation of enantiotopic or diastereotopic ester groups, as they directly lead to lactams that already incorporate the carbon substituents on the heterocyclic ring. The use of (S)-3,4-dimethoxyphenylalaninol or (S)-tryptophanol in the above cyclocondensation reactions expands the potential and the scope of the methodology, providing a straightforward route to enantiopure benzo[a]- and indolo[2,3-a]quinolizidines.     

Enantioselective synthesis of alpha-terpineol and nephthenol by intramolecular acyloxazolidinone enolate alkylations

Enolate anions generated from norterpenyl bromides bearing oxazolidinone chiral auxiliaries at the chain termini underwent efficient, stereo-biased cyclizations to form 6- and 14-membered rings in novel synthetic routes to alpha-terpineol and nephthenol enantiomers.     

Aza-[3,3]-Claisen enolate rearrangement in vinylaziridines: stereoselective synthesis of mono-, di-, and trisubstituted seven-membered lactams

Several 2,3-disubstituted vinylaziridines have been N-acylated and subjected to LiHMDS in THF at -78 degrees C. Upon warming to room temperature, the resulting amide enolates underwent a highly stereoselective [3,3]-sigmatropic rearrangement to give mono-, di-, and trisubstituted seven-membered lactams in good yields. The scope and limitations of the process have been investigated by using variously substituted vinylaziridines. A kinetically controlled process proceeding through a six-membered boatlike transition state assembly has been invoked to explain the stereochemical outcome of the reaction.     

Conjugate additions to phenylglycinol-derived unsaturated delta-lactams. Enantioselective synthesis of uleine alkaloids

The stereochemical outcome of the conjugate addition of a variety of stabilized nucleophiles (2-indoleacetic enolates and sulfur-stabilized anions) to the phenylglycinol-derived unsaturated lactams trans-2, cis-2, and its 8-ethyl-substituted analogue 10 is studied. The factors governing the exo or endo facial stereoselectivity are discussed. This methodology provides short synthetic routes to either cis- or trans-3,4-disubstituted enantiopure piperidines as well as efficient routes for the enantioselective construction of the tetracyclic ring system of uleine alkaloids, both in the normal and 20-epi series. The formal total synthesis of several alkaloids of this group is reported.     

Avoiding the classical resolution during the synthesis of MeO-BIPHEP and 3,3′-disubstituted derivatives

The Ullmann coupling of 1 (R = H) gives a 2:1 mixture of diastereomers 2 (R = H) in 81% yield that are easily separated by silica gel chromatography. This procedure avoids the generally cumbersome and sometimes difficult resolution step with DBTA. Similar Ullmann couplings and separation of the corresponding diastereomers are employed with other derivatives of 1 (R = OtBu, iPr, Ph, and mesityl) ultimately affording a new series of 3,3′-disubsituted-MeO-BIPHEP derivatives. The use of these new derivatives in palladium-catalyzed asymmetric Heck reaction, Pd-catalyzed polyene cyclizations and rhodium-catalyzed hydrogenations is also reported.     

Domino carbopalladation-cross-coupling for the synthesis of 3,3-disubstituted oxindoles

This study examines a domino carbopalladation-cross-coupling reaction for the formation of valuable oxindole scaffolds. Furthermore, the reaction sequence forges vicinal stereocenters in a stereospecific manner through the formation of two carbon-carbon bonds and, thereby, rapidly generates complexity. The reaction gives high yields for a variety of acrylamide substrates, and various organoboranes have also been evaluated for the cross-coupling. This work offers insight into the relative rates determining a successful carbopalladation-cross-coupling reaction and how to favor the desired reaction pathway.