Practical Stereo‐ and Regioselective,Copper(I)‐Promoted Strecker Synthesis of Sugar‐Modified α,β‐Unsaturated Imines

The regio‐ and stereoselective, Lewis acid catalyzed Strecker reaction between Me₃SiCN and different aldimines incorporating a 2,3,4,6‐tetrakis‐O‐pivaloyl‐D ‐glucopyranosyl (Piv₄Glc) chiral auxiliary has been worked out. Depending on the conditions used, high yields (up to 95%) and good diastereoselectivities (de > 86%) were achieved under mild conditions (Table 1), especially with CuBr ? Me₂S as catalyst. Our protocol allows the ready preparation of asymmetric β,γ‐unsaturated α‐amino acids such as (R)‐2‐amino‐4‐phenylbut‐3‐enoic acid ( 13 ; Scheme 2) and congeners thereof.     

Rhodium(III)‐Catalyzed ortho Alkenylation of N‐Phenoxyacetamides with N‐Tosylhydrazones or Diazoesters through CH Activation

A coupling reaction of N‐phenoxyacetamides with N‐tosylhydrazones or diazoesters through Rh^III‐catalyzed C? H activation is reported. In this reaction, ortho‐alkenyl phenols were obtained in good yields and with excellent regio‐ and stereoselectivity. Rh–carbene migratory insertion is proposed as the key step in the reaction mechanism.     

Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (?)‐ 1a and (?)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group (Schemes 2 and 6). Properly N‐protected chiral trans‐oxirane precursors provided (2R,3R)‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis‐oxiranes was unsuccessful for steric reasons. Inversion at OH? C(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO₂ led to (2R,3S)‐macrocycles. The synthesized (?)‐(2R,3S)‐3‐hydroxycelacinnine ((?)‐ 1b ) was identical to the natural alkaloid.     

Efficient Regio‐ and Stereoselective Conversions of Oxiranes and Aziridines into β‐(Nitrooxy)‐Substituted Alcohols and Amines by Using Bismuth Nitrate

Oxiranes and aziridines efficiently undergo ring opening with bismuth nitrate at room temperature to furnish the corresponding β‐(nitrooxy)‐substituted alcohols and amines respectively. The conversions are highly regio‐ and stereoselective and afford the nitrooxy‐compounds in excellent yields within a short period of time.     

The Regio‐ and Stereoselective Synthesis of trans‐2,3‐Dihydropyridine N‐oxides and Piperidines

Reactivity N? Own : Pyridine N‐oxides can be used for the complete regio‐ and stereoselective synthesis of trans‐substituted piperidines. The sequential addition of Grignard reagents and aldehydes or ketones to pyridine N‐oxides yields a complete regio‐ and stereoselective trans 2,3‐addition reaction in high yields, and the substituted 2,3‐dihydropyridine N‐oxide can be reduced to form 2,3‐trans‐substituted piperidines (see scheme).

     

Synthesis of β‐Chlorohydrins in Water

2,4,6‐Trichloro‐1,3,5‐triazine (TCT, cyanuric chloride) was found to mediate the regio‐ and stereoselective ring opening of epoxides in H₂O in the presence of morpholine at room temperature to afford the corresponding β‐chlorohydrins in excellent yields (Table). The transformation is very simple, fast, efficient, and ecologically beneficial.     

Highly Regio‐ and Stereodivergent Access to 1,2‐Amino Alcohols or 1,4‐Fluoro Alcohols by NHC‐Catalyzed Ring Opening of Epoxy enals

Described is an unprecedented NHC‐catalyzed (NHC=N‐heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three‐step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio‐ and stereodivergent synthesis of either 1,2‐amino alcohols/diamines or 1,4‐fluoro alcohols with excellent diastereo‐ and enantiopurity.     

Enantioselective Access to (−)‐Ambrox® Starting from β‐Farnesene

Starting from inexpensive (E)‐β‐farnesene ( 1 ), an eight‐step enantioselective synthesis of the olfactively precious Ambrox^® ((?)‐ 2a ) has been performed. The crucial step is the catalytic asymmetric isomerization of (2E,6E)‐N,N‐diethylfarnesylamine ( 3 ) to the corresponding enamine (?)‐(R,E)‐ 4a , applying Takasago's well‐known industrial methodology. The resulting dihydrofarnesal ((+)‐(R)‐ 5 ) (90% yield, 96% ee), obtained after in situ hydrolysis (AcOH, H₂O), was then cyclized under catalytic SnCl₄ conditions, via its corresponding unreported enol acetate (?)‐(R)‐ 4b , to afford trans‐decalenic aldehyde (+)‐ 6a . Subsequent transformations furnished bicyclic ketone (?)‐ 8a and unsaturated nitrile (+)‐ 11 , both reported as intermediates to access to (?)‐ 2a .     

A Synthetic Route to Chiral Dihydrobenzothiazines through Ring Opening of Activated Aziridines with 2‐Halothiophenols/Copper‐Powder‐Mediated C−N Cyclization

A simple protocol for the synthesis of dihydrobenzothiazines through regio‐ and stereoselective S_N2‐type ring opening of N‐tosylaziridines with sulfur nucleophiles followed by copper‐powder‐mediated intramolecular C?N cyclization in excellent yields (up to 95 %) with high diastereo‐ and enantioselectivity (up to >99 %) is reported.     

Syntheses of Enantiomerically Pure 2‐Substituted Pyrrolidin‐3‐ones via Lithiated Alkoxyallenes – An Auxiliary‐Based Synthesis of both Enantiomers of the Antibiotic Anisomycin

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the ‘diacetone‐fructose’‐substituted allene 1 and the N‐Boc‐protected imine precursor 2a . Addition of an excess of lithiated 1 to 2a provided a 2 : 1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion (Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin‐3‐ones (2R)‐ 5a and (2S)‐ 5a . A similar sequence yielded the N‐Tos‐protected compounds (2R)‐ 5b and (2S)‐ 5b . Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio‐ and stereoselective hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional‐group transformations led to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)‐ 9 of the natural occurring enantiomer, whereas the (2S) series furnished the antipode (2S)‐ 9 . The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues.     

CO2‐Activation for γ‐Butyrolactones and Its Application in the Total Synthesis of (±)‐Heteroplexisolide E

An efficient nickel(0)‐catalyzed highly regio‐ and stereoselective hydrocarboxylation of homopropargylic alcohols with ZnEt₂ in the presence of CO₂ (1 atm, balloon) to synthesize α‐alkylidene‐γ‐butyrolactones is described. The catalyst is highly active and can be applied for the synthesis of (optically active) mono‐ or bicyclic α‐alkylidene‐γ‐butyrolactones with excellent regio‐ and stereoselectivity and good functional group tolerance. The potential of the reaction has been demonstrated in the first synthesis of (±)‐heteroplexisolide E.     

δ‐Peptide Analogues of Pyranosyl‐RNA,Part 1 , Nucleo‐δ‐peptides Derived from Conformationally Constrained Nucleo‐δ‐amino Acids: Preparation of Monomers

Cyclic nucleo‐δ‐amino acids that constitute monomers of a conformationally constrained nucleo‐δ‐peptide base‐pairing system have been prepared. Their synthesis starts with an enantioselectively catalyzed chirogenic Diels‐Alder reaction, proceeds via a regioselective ε‐iodolactamization process, and ends with a regio‐ as well as diastereoselective introduction of nucleobases through S_N2‐type opening of a transiently formed N‐acylaziridine ring. Extensive use of X‐ray crystal‐structure analysis has been made to support structure assignments.     

(+)‐Tartaric Acid‐Catalyzed High Regio‐ and Stereoselective Aminobromination of Olefins

(+)‐Tartaric acid‐catalyzed aminobromination of α,β‐unsaturated ketones, α,β‐unsaturated esters and simple olefins utilizing TsNH₂/NBS as the nitrogen/halogen sources at room temperature without protection of inert gases achieved good yields (up to 92% yield) of vicinal haloamino products with excellent regio‐ and stereoselectivity, even just 10% of (+)‐tartaric acid was used as catalyst. The regio‐ and stereochemistry was unambiguously confirmed by X‐ray structural analysis of products 2b and 12c . The electron‐rich and deficient olefins show significant differences in activity to the aminobromination reaction and give the opposite regioselectivities. The 21 cases have been investigated which indicated that our protocol has the advantage of a large scope of olefins. Additionally, tartaric acid as catalyst has the advantage of avoiding any hazardous metals retained in products.     

Copper‐Catalyzed Borylcupration of Allenylsilanes

A highly regio‐ and stereoselective copper‐catalyzed borylcupration of 1,2‐allenylsilanes affords an unexpected regioreversed allylic boronate bearing an extra C?Si bond at the 3‐position, with a thermodynamically disfavored Z geometry. Such stereodefined allylic boronates containing an extra alkenyl silane moiety are very useful organodimetallic reagents for organic synthesis.     

Synthesis of Multiantennary Complex Type N‐Glycans by Use of Modular Building Blocks

A modular set of oligosaccharide building blocks was developed for the synthesis of multiantennary N‐glycans of the complex type, which are commonly found on glycoproteins. The donor building blocks were laid out for the elongation of a core trisaccharide acceptor (β‐mannosyl chitobiose) conveniently protected with a single benzylidene moiety at the β‐mannoside. Through two consecutive regio‐ and stereoselective couplings the donors gave N‐glycans with three to five antennae in high yields. Due to the consistent protection group pattern of the donors the deprotection of the final products can be performed by using a general reaction sequence.     

Amide‐Controlled Highly Selective Catalytic Borylcupration of Allenes

A novel copper‐catalyzed, highly regio‐ and stereoselective borylcupration of substituted 2,3‐allenamides with bis(pinacolato)diboron producing Z‐β‐borylated β,γ‐unsaturated enoamides has been demonstrated. Due to the unique effect of the amide‐group, perfect regio‐ and stereoselectivity and good to excellent yields have been achieved, which were rationalized by a DFT study.     

Allenyl‐β‐lactams: versatile scaffolds for the synthesis of heterocycles

The hybrid allenic β‐lactam moiety represents an excellent building block for carbo‐ and heterocyclization reactions, affording a large number of cyclic structures containing different sized skeletons in a single step. This strategy has been studied under thermal and radical‐induced conditions. More recently, the use of transition‐metal catalysis has been introduced as an alternative that relies on the activation of the allenic component. On the other hand, the intramolecular version has attracted much attention as a strategy for the synthesis of bi‐ and tricyclic compounds in a regio‐ and stereoselective manner. This overview focuses on the most recently developed cyclizations on 2‐azetidinone‐tethered allenes along with remarkable early works accounting for the mechanism, as well as for the regio‐ and diastereoselectivities of the cyclizations. DOI 10.1002/tcr.201100011     

Rh‐Catalyzed Reaction of Propargylic Alcohols with Aryl Boronic Acids–Switch from β‐OH Elimination to Protodemetalation

It is known that Rh‐catalyzed reaction of propargylic alcohols with aryl metallic reagents undergoes S_N2’‐type reaction affording allenes via a sequential arylmetalation and β‐OH elimination process. Here we report a Rh/Ag‐cocatalyzed reaction of propargylic alcohols with organoboronic acids affording stereo‐defined (E)‐3‐arylallylic alcohols via arylmetalation and protodemetalation with a high regio‐ and stereoselectivity under very mild conditions. The reaction exhibits a good substrate scope and the compatibility with synthetically useful functional groups with no racemization for optically active propargylic alcohols. Such a reaction may also be extended to homopropargylic alcohols with a remarkable regioselectivity and exclusive E‐stereoselectivity.     

Direct Umpolung of Glycals and Related 2,3‐Unsaturated N‐Acetylneuraminic Acid Derivatives Using Samarium Diiodide

The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate‐derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reacts with ketones at the C3 position with high stereoselectivity; carbon–carbon bond formation takes place only anti to the substituent at the C4 position of the dihydropyran ring. For the sialic acid series, the completely regio‐ and stereoselective coupling process of the samarium reagent occurs at the anomeric carbon atom and provides a new approach to the α‐C‐glycosides of N‐acetyl neuraminic acid.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.