Catalytic Enantioselective Aza‐pinacol Rearrangement

The first catalytic enantioselective asymmetric aza‐pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza‐ortho ‐xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.     

Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles

The first catalytic asymmetric cascade reaction of 7‐vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin‐derived 3‐indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo‐ and enantioselective synthesis of C7‐functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94–>99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7‐functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel–Crafts process, in which dual H‐bonding activation of the two reactants plays a crucial role.     

Catalytic Asymmetric Phase‐Transfer Michael Reaction and Mannich‐Type Reaction of Glycine Schiff Bases with Tartrate‐Derived Diammonium Salts

Catalytic asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with chiral two‐center organocatalysts, tartrate‐derived diammonium salts (TaDiASs), are described. On the basis of conformational studies, optimized TaDiASs with a 2,6‐disubstituted cyclohexane spiroacetal were newly designed. These TaDiASs catalyzed the asymmetric Michael and Mannich‐type reactions of glycine Schiff bases with higher enantioselectivity than previous catalysts. In the Mannich‐type reaction, aromatic N‐Boc‐protected imines (Boc=tert‐butoxycarbonyl) as well as enolizable alkyl imines were applicable. As a synthetic application of the catalytic asymmetric Mannich‐type reaction with the optimized TaDiASs, we developed a catalytic asymmetric total synthesis of (+)‐nemonapride, which is an antipsychotic agent.     

Asymmetric Henry reaction catalysed by L‐proline derivatives in the presence of Cu(OAc)2: isolation and characterization of an in situ formed Cu(II) complex

Synthesis of asymmetric β‐nitroalcohols by the Henry reaction is one of the most exploited carbon–carbon bond‐forming reactions owing to the versatility of both functional groups for synthetic manipulation by functional group interconversion. Here we report synthesis of a series of proline‐derived compounds to study their catalytic activities for asymmetric Henry reaction in the presence of Cu(OAc)₂.H₂O. The proline derivative, 2‐((E)‐(((S)‐1‐benzylpyrrolidinyl)diphenylmethylimino)methyl)phenol 1 showed optimum catalytic activity. The catalytic species Cu(II)–1 complex, formed in situ, was isolated and characterized by various spectroscopic techniques and X‐ray crystallography to show a cis‐N₂O₂ coordination geometry. Asymmetric β‐nitroalcohols were achieved without the use of added base, unlike most of the reported protocols. Copyright © 2014 John Wiley & Sons, Ltd.     

Configurational Assignment of ‘Cryptochiral’ 10‐Hydroxystearic Acid Through an Asymmetric Catalytic Synthesis

An asymmetric catalytic total synthesis of (S)‐10‐hydroxystearic acid ( 1 ) for comparison of its absolute configuration to that of samples obtained by fermentative hydration of oleic acid is reported. The synthesis involves two catalytic key‐steps, namely Ru‐catalyzed anti‐Markovnikov hydration of 9‐decynoic acid ( 7 ) to 10‐oxodecanoic acid ( 5 ), followed by titanium‐mediated asymmetric catalytic addition of dioctylzinc ( 25 ) to 5 in presence of the chiral ligand N,N’‐((1R,2R)‐cyclohexane‐1,2‐diyl)bis(1,1,1‐trifluoromethanesulfonamide) ( 6 ). The synthesis is short and efficient and avoids use of protecting groups. Ozonolysis of 10‐undecynoic acid ( 9 ) to 5 provides an alternative entry point into the synthetic route. The double dehydrobromination of (ω,ω‐1)‐dibromoalkanoic acids to ω‐alkynoic acids under a variety of conditions was investigated with 10,11‐dibromoundecanoic acid ( 11 ) as model substrate and using qNMR to quantify all reaction products. The synthetic approaches presented here have the potential to be generalized to the asymmetric catalytic synthesis of a variety of n‐hydroxy‐fatty acids.     

Asymmetric Total Synthesis of (−)‐Erogorgiaene and Its C‐11 Epimer and Investigation of Their Antimycobacterial Activity

A short, nine‐step, highly enantioselective synthesis of (?)‐erogorgiaene and its C‐11 epimer is reported. The key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy‐Cope rearrangement and cationic cyclisation. (?)‐Erogorgiaene exhibited promising antitubercular activity against multidrug‐resistant strains of Mycobacterium tuberculosis.     

A Strategy for Synthesizing Axially Chiral Naphthyl‐Indoles: Catalytic Asymmetric Addition Reactions of Racemic Substrates

A new strategy for enantioselective synthesis of axially chiral naphthyl‐indoles has been established through catalytic asymmetric addition reactions of racemic naphthyl‐indoles with bulky electrophiles. Under chiral phosphoric acid catalysis, azodicarboxylates and o‐hydroxybenzyl alcohols served as bulky but reactive electrophiles that were attacked by C2‐unsubstituted naphthyl‐indoles, which underwent a dynamic kinetic resolution to afford two series of axially chiral naphthyl‐indoles in good yields (up to 98 %) and high enantioselectivities (up to 98:2 er).     

Asymmetric α‐Hydroxylation of a Lactone with Vinylogous Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst: Catalytic Enantioselective Synthesis of a Key Intermediate for (20S)‐Camptothecin Analogues

We have developed a catalytic asymmetric synthesis of (S)‐4‐ethyl‐6,6‐(ethylenedioxy)‐7,8‐dihydro‐4‐hydroxy‐1H‐pyrano[3,4‐f]indolizine‐3,10(4H)dione ( 5 a ), a synthetic intermediate for (20S)‐camptothecin analogues. A key step in this synthesis is an asymmetric α‐hydroxylation of a lactone with a vinylogous pyridone structure ( 8 a ) by using a guanidine–urea bifunctional organocatalyst. The present oxidation was successfully applied to the synthesis of C20‐modified derivatives of (+)‐C20‐desethylbenzylcamptothecin ( 13 ).     

Asymmetric Hydroalkoxylation of Non‐Activated Alkenes: Titanium‐Catalyzed Cycloisomerization of Allylphenols at High Temperatures

The asymmetric catalytic addition of alcohols (phenols) to non‐activated alkenes has been realized through the cycloisomerization of 2‐allylphenols to 2‐methyl‐2,3‐dihydrobenzofurans (2‐methylcoumarans). The reaction was catalyzed by a chiral titanium–carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. The catalyst was generated by mixing titanium isopropoxide, the chiral ligand (aS)‐1‐(2‐methoxy‐1‐naphthyl)‐2‐naphthoic acid or its derivatives, and a co‐catalytic amount of water in a ratio of 1:1:1 (5 mol % each). This homogeneous thermal catalysis (HOT‐CAT) gave various (S)‐2‐methylcoumarans with yields of up to 90 % and in up to 85 % ee at 240 °C, and in 87 % ee at 220 °C.     

Synthesis of Enantiopure C3‐Symmetric Triangular Molecules

An asymmetric synthesis of C ₃‐symmetric triangular macrocycles is reported. 1‐Methylsulfonyl‐4‐(4‐vinylphenyl)‐1,2,3‐triazole undergoes a rhodium(II)‐catalyzed cyclotrimerization to establish an enantiopure C ₃‐symmetric triangular macrocycle motif. This method can be applied to the synthesis of an enantiopure hydrocarbon, which owes its chirality to asymmetric distribution of H/D atoms on the benzene rings.     

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.     

Catalytic Asymmetric Total Synthesis of Exiguolide

The catalytic asymmetric total synthesis of (−)-exiguolide, a complex 20-membered macrolide embedded with a bis(tetrahydropyran) motif, is reported. The convergent synthesis involves the construction of the C1–C11 tetrahydropyran segment via catalytic asymmetric allylation and Prins cyclization, and the formation of the C12–C21 phosphonate segment via catalytic asymmetric cyclocondensation reaction and Johnson–Claisen rearrangement. The synthesis of 15-epi-exiguolide is also described.     

Asymmetric Synthesis of the C(33) – C(37) Fragment of Amphotericin B

We have devised an expeditious, efficient, asymmetric synthesis of the C(33) – C(37) fragment of amphotericin B that proceeds in 14 steps and 16% overall yield from tiglic aldehyde ((E)‐2‐methylbut‐2‐enal) with complete stereocontrol. The route described herein relies on the application of recently developed methods in catalytic asymmetric synthesis for stereocontrol through enantio‐ and diastereoselective functionalization of a substituted sorbate derivative.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (?)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (?)‐quebrachamine, are reported herein.     

Formal Total Synthesis of Fostriecin by 1,4‐Asymmetric Induction with an Alkyne–Cobalt Complex

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis‐cis‐trans‐triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4‐relationship is considered difficult, we have developed a notable 1,4‐asymmetric induction that utilizes an alkyne–cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3‐asymmetric induction with a higher‐order alkynyl‐zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis‐cis‐trans‐triene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.     

Enantioselective Synthesis of 3,3′‐Diaryl‐SPINOLs: Rhodium‐Catalyzed Asymmetric Arylation/BF3‐Promoted Spirocyclization Sequence

The enantioselective synthesis of a series of C₂‐symmetric 3,3′‐diarylated 1,1′‐spirobiindane‐7,7′‐diols (3,3′‐diaryl‐SPINOLs) was developed by sequential Rh‐catalyzed twofold asymmetric conjugate arylation/BF₃‐promoted diastereoselective spirocyclization (>20:1 d.r. and >99 % ee for all examples). Some phosphoramidite ligands were prepared from the 3,3′‐Ph‐SPINOL and applied to several catalytic asymmetric reactions, and the 3,3′‐diarylated ligands showed higher enantioselectivities than the privileged nonsubstituted ligands.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (−)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (−)‐quebrachamine, are reported herein.     

Synthesis of Each Enantiomer of Rocaglamide by Means of a Palladium(0)‐Catalyzed Nazarov‐Type Cyclization

A recently reported Pd⁰‐catalyzed asymmetric Nazarov‐type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (?)‐rocaglamide (natural) and (+)‐rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.     

Catalytic Asymmetric Addition of Meldrum’s Acid,Malononitrile, and 1,3‐Dicarbonyls to ortho‐Quinone Methides Generated In Situ Under Basic Conditions

A new approach to the utilization of highly reactive and unstable ortho‐quinone methides (o‐QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o‐QM intermediates are formed in situ from 2‐sulfonylalkyl phenols through base‐promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o‐QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum’s acid, malononitrile and 1,3‐dicarbonyls. The catalytic transformations give new and general entries to 3,4‐dihydrocoumarins, 4H‐chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)‐tolterodine and (S)‐4‐methoxydalbergione from the catalytic adducts.