Revisiting a classic approach to the Aspidosperma alkaloids: an intramolecular Schmidt reaction mediated synthesis of (+)-aspidospermidine

[reaction: see text] A total synthesis of (+)-aspidospermidine (1) is described. The key reactions used in the synthesis of this pentacyclic Aspidosperma alkaloid were a deracemizing imine alkylation/Robinson annulation sequence, a selective "redox ketalization", and an intramolecular Schmidt reaction. A Fischer indolization step carried out on a tricyclic ketone mirrored the sequence reported by Stork and Dolfini in their classic aspidospermine synthesis.     

Intramolecular reactions of benzylic azides with ketones: competition between Schmidt and Mannich pathways.

The Lewis acid-promoted reactions of benzylic azides with ketones can proceed by two major pathways. The azido-Schmidt reaction involves simple addition of azide to the ketone followed by rearrangement and ring expansion. In addition, benzylic azides can undergo prior rearrangement to afford iminium ions that can subsequently participate in a Mannich reaction. A series of ketones containing an alpha CH2(CH2)nCH(N3)Ph substituent (n = 1-3) was prepared to investigate the dependence of products on ketone ring size and tether length. For all ketones examined, good yields of bicyclic lactams arising from intramolecular Schmidt reaction were obtained when a four-carbon linker was used (n = 1 in the above formulation), but Mannich products predominated for the longer tethers examined (n = 2, 3).     

Asymmetric total synthesis of dendrobatid alkaloids: preparation of indolizidine 251F and its 3-desmethyl analogue using an intramolecular Schmidt reaction strategy

Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels-Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] --> [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F.     

Chemoselective Schmidt reaction mediated by triflic acid: selective synthesis of nitriles from aldehydes

An excellent utility of Schmidt reaction of aldehydes to access corresponding nitriles in an instantaneous reaction is demonstrated. The reaction of aldehydes with NaN(3) and TfOH furnishes the corresponding nitriles in near quantitative yields and tolerates a variety of electron-withdrawing and electron-donating substituents on the substrates. Formanilides, a common side product in Schmidt reaction, is not observed in this reaction. Besides these advantages, the salient feature of this reaction is that it exhibits a remarkable chemoselectivity, as acid and ketone functionalities are well tolerated under the reaction conditions. The reaction is easily scalable, high yielding, and nearly instantaneous.     

Electronic and steric effects on the intramolecular Schmidt reaction of alkyl azides with secondary benzyl alcohols

The intramolecular Schmidt reaction of simple azido secondary benzyl alcohols has been realized for the first time. Investigation of the electronic and steric effects of the substrates on the product outcome was conducted. Unique intramolecular Schmidt rearrangements were observed with the formation of a cinnamaldehyde derivative and aryl aldehydes, respectively. Using this protocol, an efficient synthesis of dihydrobenzotriazine derivatives was achieved. Moreover, a practical approach to 2-aryl-1-pyrrolines was also accessed.     

Study on modification of polymers with the aid of the Schmidt reaction

A study of the Schmidt reaction on several polymers with pendant carboxylic and ketone moieties was carried out. Four polymers were used as starting materials: (1) poly(methyl vinyl ketone), (2) poly(acrylic acid), (3) a copolymer of methyl vinyl ketone and acrylic acid, and (4) a copolymer of styrene and acrylic acid. Most reactions were conducted in an acetic acid medium with the exception of one reaction on poly(acrylic acid) which was done in dioxane and another on copolymer of styrene and acrylic acid done in chloroform. It was found that a Schmidt reaction on poly(acrylic acid) in acetic acid solution will lead to intermolecular reactions of the intermediate with the solvent in preference to reactions with neighboring carboxyl groups on the polymer backbone. A tendency of poly(acrylic acid) to form cyclic anhydrides under these reaction conditions interferes with the yield of acetamide units.     

An expeditious total synthesis of (+/-)-stenine

(+/-)-Stenine was synthesized in eight steps from a known ketophosphonate reagent. The key step was an exo-selective Diels-Alder/intramolecular Schmidt domino reaction that afforded three of the four rings and four stereocenters in a single reaction.     

Stereocontrol in a combined allylic azide rearrangement and intramolecular Schmidt reaction

Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution and a preliminary mechanistic study are reported. The synthetic potential of this method is demonstrated in the context of an enantioselective synthesis of an advanced intermediate leading toward pinnaic acid.     

Azidomercurations of alkenes: mercury-promoted Schmidt reactions

Azides bearing a suitably disposed alkene, when treated with either mercuric perchlorate or mercuric trifluoromethanesulfonate, produce bicyclic iminium ions. This new version of the Schmidt reaction proceeds by capture of the mercuronium ion intermediate by the azide to produce an aminodiazonium ion, which suffers a 1,2-shift to give an iminium ion (e.g., 10 --> 16 --> 17 --> 18). Reduction of the iminium ion may then be carried out to produce an amine. Compared to earlier work on the protic acid-promoted intramolecular Schmidt reaction of azido-alkenes, the mercury-promoted Schmidt reaction has several advantages. First, the acid-promoted Schmidt reaction of azido-alkenes requires that the intermediate carbocations be tertiary, allylic, benzylic, or propargylic. The mercury-promoted method has no such limitation; thus even 1,2-disubstituted alkenes may be used. Second, the mercury-promoted method is milder, allowing the presence of acid-sensitive functionality. The protic version, typically employing trifluoromethanesulfonic acid, is limited in its functional group tolerance. Third, whereas carbocation rearrangement is often observed prior to cyclization/rearrangement in the acid-promoted Schmidt reaction, the mercury-promoted method avoids this problem. Fourth, the presence of the mercurio group during the rearrangment may alter the regioselectivity of the 1,2-migration. Finally, the mercury-bearing iminium ions that are the result of the Schmidt reaction were found to be sensitive to protodemercuration, precluding their use in other transformations.     

Synthetic studies on the taxane skeleton: effective construction of eight-membered carbocyclic ring by palladium-catalyzed intramolecular α-alkenylation of a methyl ketone

A new method for the construction of the eight-membered carbocyclic ring in the taxane skeleton is described. The palladium-catalyzed intramolecular α-alkenylation of a methyl ketone effectively constructed the eight-membered carbocyclic ring in the taxol model compound. To the best of our knowledge, this reaction is the first example of forming an eight-membered carbocyclic ring by the palladium-catalyzed intramolecular α-alkenylation of a ketone.     

First asymmetric total synthesis of (+)-sparteine

[reaction: see text] The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement.     

Asymmetric total synthesis of dendrobatid alkaloid 251F

The dendrobatid alkaloid (-)-251F was synthesized. The key steps of the synthesis were (1) an asymmetric Diels-Alder reaction to establish four of the necessary stereocenters in the target, (2) a ring-opening/ring-closing metathesis reaction to establish a key [3.3.0] bicyclic intermediate, and (3) an intramolecular Schmidt reaction.     

Regiocontrol in an intramolecular Schmidt reaction: total synthesis of (+)-aspidospermidine

[reaction--see text] A total synthesis of (+)-aspidospermidine (1) is described, featuring an intramolecular Schmidt reaction as the key step. The effects of stereochemistry and protecting group status on the regio- and chemoselectivity of this reaction were examined.     

An efficient synthesis of δ-glyconolactams by intramolecular Schmidt–Boyer reaction under microwave radiation

δ-Glyconolactams were first synthesized by the intramolecular Schmidt–Boyer reaction using corresponding δ-azidosugars as starting material. The reaction could be efficiently performed in good yields of 61–69% under microwave radiation in acid condition, providing an alternative protocol to iminosugar δ-lactam.     

Synthesis of benzo-fused heterocycles by intramolecular α-arylation of ketone enolate anions

A two-step synthesis of six-, seven-, eight-, and nine-member benzo-fused heterocycles in good to excellent yields is reported. The synthetic strategy involves the generation of a new intramolecular α-aryl ketone bond by the photostimulated S(RN)1 reaction of ketone enolate anions linked to a pendant haloarene as the key step. On the other hand, an intramolecular C(Ar)-C(Ar) coupling led to the formation of five- and six-member benzo-fused heterocycles (9H-carbazole and phenanthridine) when an aromatic amide anion is competitively formed.     

Synthesis of the 4-azatricyclo[5.2.2.0(4,8)]undecan-10-one core of daphniphyllum alkaloid calyciphylline A using a Pd-catalyzed enolate alkenylation

[reaction: see text] The ABC ring system of the natural product calyciphylline A has been synthesized. The key steps were a palladium-catalyzed intramolecular coupling of an amino-tethered vinyl bromide with a ketone using potassium phenoxide as the base to generate the C-ring and a hydroxyl-directed hydrogenation of an exocyclic double bond to give the azatricyclic ketone 1.     

Total synthesis of (±)-maistemonine and (±)-stemonamide

The first total synthesis of polycyclic Stemona alkaloid maistemonine has been achieved. The efficient approach features a stereoselective intramolecular Schmidt reaction, a ketone-ester condensation, and a Reformatsky reaction. Additionally, another Stemona alkaloid stemonamide was divergently synthesized from a common intermediate.     

Asymmetric total synthesis of pseurotin A

The asymmetric total syntheses of pseurotin A and 8-O-demethylpseurotin A have been accomplished. Key reactions are a NaH-promoted intramolecular cyclization of an alkynylamide to form a gamma-lactam, an aldol reaction of a benzylidene-substituted ketone, and the late-stage introduction of the benzoyl group by a selective oxidation of a benzylidene moiety with dimethyldioxirane (DMD). [reaction: see text]     

Stereospecific Construction of Chiral Tertiary and Quaternary Carbon by Nucleophilic Cyclopropanation with Bis(iodozincio)methane

The reaction of a ketone having a leaving group at the α‐position, such as α,β‐epoxy ketone or α‐sulfonyloxy ketone, with bis(iodozincio)methane affords a zinc alkoxide of cyclopropanol. The reaction proceeds by nucleophilic addition of the dizinc to the carbonyl group and a sequential intramolecular nucleophilic substitution of the introduced iodozinciomethyl group to the adjacent electrophilic carbon that has a leaving group. When an optically active α,β‐epoxy ketone or α‐sulfonyloxy ketone is treated with the dizinc, a zinc alkoxide of cyclopropanol having a chiral tertiary or quaternary carbon in the cyclopropane ring is obtained, and the obtained zinc alkoxide of cyclopropanol acts as a chiral homoenolate. When it is treated with an electrophile in the presence of copper cyanide, it gives an optically active α‐tertiary or ‐quaternary ketone that retains high optical purity.     

Asymmetric total synthesis of (-)-azaspirene,a novel angiogenesis inhibitor

The asymmetric total synthesis of (-)-azaspirene, an angiogenesis inhibitor, has been accomplished, establishing its absolute stereochemistry. The key steps are a MgBr2.OEt2-mediated, diastereoselective Mukaiyama aldol reaction, a NaH-promoted, intramolecular cyclization of an alkynylamide, and the aldol reaction of a ketone containing functionalized gamma-lactam moiety without protection of tert-alcohol and amide functionalities.