A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

Total Syntheses of (±)‐Fawcettimine, (±)‐Fawcettidine, (±)‐Lycoflexine,and (±)‐Lycoposerramine‐Q

The total syntheses of four fawcettimine‐related Lycopodium alkaloids, (±)‐fawcettimine, (±)‐fawcettidine, (±)‐lycoposerramine‐Q, and (±)‐lycoflexine, were completed in a highly stereoselective manner. The Pauson–Khand reaction of 4‐methylidene‐6‐siloxyoct‐1‐en‐7‐yne followed by regio‐ and stereoselective hydrogenation led to the short‐step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6‐5‐9‐membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

Synthesis of the Anti‐HIV Agent (−)‐Hyperolactone C by Using Oxonium Ylide Formation–Rearrangement

Starting from readily available (S)‐styrene oxide an asymmetric synthesis is described of the naturally occurring anti‐HIV spirolactone (?)‐hyperolactone C, which possesses adjacent fully substituted stereocenters. The key step involves a stereocontrolled Rh^II‐catalysed oxonium ylide formation–[2,3] sigmatropic rearrangement of an α‐diazo‐β‐ketoester bearing allylic ether functionality. From the resulting furanone, an acid‐catalysed lactonisation and dehydrogenation gives the natural product.     

Facile Synthesis of (±)‐Parahigginone Methyl Ether and (±)‐Curcuphenol

Using Grinard coupling as a key step, a facile synthetic approach to (±)‐parahigginone methyl ether 1 and (±)‐curcuphenol 2 has been achieved by five steps with 42.3% and 58.6% overall yield, respectively.     

Vicinal Dianion of Triethyl Ethanetricarboxylate: Syntheses of (±)‐Lichesterinic Acid, (±)‐Phaseolinic Acid, (±)‐Nephromopsinic Acid, (±)‐Rocellaric Acid,and (±)‐Dihydroprotolichesterinic Acid

The vicinal dianion 2 derived from triethyl ethanetricarboxylate reacted regioselectively with aldehydes and ketones at C(β) to provide paraconic acid derivatives 5a – f in moderate to high yields as mixtures of diastereoisomers. The paraconic acid derivatives 5e and 5f were utilized as the starting materials for the syntheses of (±)‐lichesterinic acid ( 12 ), (±)‐phaseolinic acid ( 13 ), (±)‐nephromopsinic acid ( 14 ), (±)‐rocellaric acid ( 15 ), and (±)‐dihydroprotolichesterinic acid ( 16 ).     

Diastereoselective Total Syntheses of (±)‐Caseabalansin A and (±)‐18‐Epicaseabalansin A via Intramolecular Robinson‐type Annulation

Highly diastereoselective total syntheses of (±)‐caseabalansin A ( 1 ) and (±)‐18‐epicaseabalansin A ( 2 ) are described in this paper. We revealed that the intramolecular Robinson‐type annulation of an alkynone was effective in the stereocontrolled construction of the bicyclic skeleton of 1 and 2 . Further transformation of the resulting enone, including diastereoselective reduction by LiAlH(OtBu)₃, hydroxy‐group‐directed hydrogenation, cyclization to form the cyclic acetal moiety, and introduction of a side chain by a C(sp³)?C(sp³) Stille coupling reaction, resulted in the total syntheses of (±)‐ 1 and (±)‐ 2 .     

Total Synthesis of the Alkaloid (±)‐Aspidophytine Based on Carbonyl Ylide Cycloaddition Chemistry

The Rh^II‐catalyzed cycloaddition cascade of an indolyl‐substituted α‐diazo imide was used for the total synthesis of the complex pentacyclic alkaloid (±)‐aspidophytine. Treatment of the resulting dipolar cycloadduct with BF₃?OEt₂ induces a domino fragmentation cascade. The reaction proceeds by an initial cleavage of the oxabicyclic ring and formation of a transient N‐acyl iminium ion which reacts further with the adjacent tert‐butyl ester and sets the required lactone ring present in aspidophytine. A three‐step sequence was then used to remove both the ester and OH groups. Subsequent functional group manipulations allowed for the high‐yielding conversion to (±)‐aspidophytine.     

Photoinduced and thermal reactions of α‐cyano‐β‐bromomethylcinnamide with 1‐benzyl‐1,4‐dihydronicotinamide

The photoinduced reaction of a mixture of (Z)‐α‐cyano‐β‐bromomethylcinnamide (1) and (E)‐α‐cyano‐β‐bromomethylcinnamide (2) with 1‐benzyl‐1, 4‐dihydronicotinamide produces a mixture of the (E)‐ and (Z)‐ isomers of α‐cyano‐β‐methylcinnamide (3 and 4). Using spin‐trapping technique for monitoring reactive intermediate, it is shown that the reaction proceeds via electron transfer‐debromination‐H abstraction mechanism. The thermal reaction of the same substrate with BNAH at 60°C in the dark gives three products: the (E)‐ and (Z)‐isomers of α‐cyano‐β‐methylcinnamide and a dehydrodimeric product; 2, 7‐dicyano‐3, 6‐diphenylocta‐2, 4, 6‐trien‐1, 8‐dioic amide (7). Based on product analysis, scavenger experiment and cyclic voltammetry, an electron transfer‐debromination‐disproportionation mechanism is proposed.     

New conditions for synthesis of (±)‐2‐monosubstituted and (±)‐2,2‐disubstituted 2,3‐dihydro‐4(1H)‐quinazolinones from 2‐nitro‐ and 2‐aminobenzamide

An efficient synthesis of (±)‐2‐monosubstituted and (±)‐2,2‐disubstituted 2,3‐dihydro‐4(1H)‐quinazolinones has been developed using a dissolving metal reduction‐condensative cyclization strategy. Treatment of 2‐nitrobenzamide and an aldehyde or ketone with iron powder in refluxing acetic acid affords high yields of the title compounds. More complex ring systems are available by incorporating additional reactive functionality γ to the carbonyl of the aldehyde or ketone substrate. The scope and limitations of the process along with optimized procedural details are presented. The same target molecules are also accessible by reaction of 2‐aminobenzamide with aldehydes and ketones in refluxing acetic acid. J. Heterocyclic Chem., (2011).     

Concise Stereoselective Synthesis of Oxaspirocycles with 1‐Tosyl‐1,2,3‐triazoles: Application to the Total Syntheses of (±)‐Tuberostemospiroline and (±)‐Stemona‐lactam R

A 4‐substituted‐1‐tosyl‐1,2,3‐triazole‐based stereoselective synthesis of structurally diverse oxaspirocycles is reported. The synthesis involves Rh‐catalyzed loss of nitrogen from 4‐substituted‐1‐tosyl‐1,2,3‐triazoles, Grignard reaction, and a ring‐closing metathesis reaction as key steps. By employing readily available and stable 4‐substituted‐1‐tosyl‐1,2,3‐triazoles as surrogates of diazo compounds and nitrogen sources, two types of oxaspirocycles were obtained. The latter compounds, which contain adjacent nitrogen stereocenters, could serve as the core structures of many natural products. This chemistry has been successfully applied to the total syntheses of (±)‐tuberostemospiroline and (±)‐stemona‐lactam R.     

Total Synthesis of (±)‐Eusiderin G and (±)‐Eusiderin M

(±)‐Eusiderin G and (±)‐Eusiderin M were first synthesized from pyrogallol, in which the Claisen Rearrangement was used to afford two important C₆‐C₃ units.     

Synthesis and Conformational Analysis of Hybrid α/β‐Dipeptides Incorporating S‐Glycosyl‐β2,2‐Amino Acids

We synthesized and carried out the conformational analysis of several hybrid dipeptides consisting of an α‐amino acid attached to a quaternary glyco‐β‐amino acid. In particular, we combined a S‐glycosylated β^2,2‐amino acid and two different types of α‐amino acid, namely, aliphatic (alanine) and aromatic (phenylalanine and tryptophan) in the sequence of hybrid α/β‐dipeptides. The key step in the synthesis involved the ring‐opening reaction of a chiral cyclic sulfamidate, inserted in the peptidic sequence, with a sulfur‐containing nucleophile by using 1‐thio‐β‐D ‐glucopyranose derivatives. This reaction of glycosylation occurred with inversion of configuration at the quaternary center. The conformational behavior in aqueous solution of the peptide backbone and the glycosidic linkage for all synthesized hybrid glycopeptides was analyzed by using a protocol that combined NMR experiments and molecular dynamics with time‐averaged restraints (MD‐tar). Interestingly, the presence of the sulfur heteroatom at the quaternary center of the β‐amino acid induced θ torsional angles close to 180° (anti). Notably, this value changed to 60° (gauche) when the peptidic sequence displayed aromatic α‐amino acids due to the presence of CH–π interactions between the phenyl or indole ring and the methyl groups of the β‐amino acid unit.     

First Total Synthesis of (±)‐Celaphanol A

The first total synthesis of (±)‐Celaphanol A was accomplished starting from α‐cyclocitral and 3,4‐dimethoxy benzyl chloride in six steps. The intramolecular cyclization with BF₃·Et₂O and enolization in t‐BuOK/t‐BuOH were the key steps. The process of intramolecular cyclization afforded an all‐cis isomer intermediate for synthesis of aromatic tricyclic diterpenes.     

Synthesis of (±)‐Lasubine II Using N‐Methoxyamines

The synthesis of (±)‐lasubine II has been achieved through a three‐component allylation capitalizing on the unique properties of N‐methoxyamines. This reaction enabled the installation of all the carbon atoms of lasubine II in a single operation. The N‐methoxy group was efficiently used for the subsequent nitrone formation. A single‐step cyclization of isoxazolidines or N‐methoxyamines to form functionalized piperidine rings was also developed.     

Total Synthesis of (±)‐Corymine

The first total synthesis of the hexacyclic indole alkaloid (±)‐corymine is described. Starting from the readily available N‐protected tryptamine, the title compound was achieved in 21 steps in 3.4 % overall yield. Key steps of the synthesis include: a) the addition of a malonate to a 3‐bromooxindole to afford 3,3‐disubstituted oxindole, b) the formation of a 12‐membered cyclic enol ether by intramolecular O‐propargylation, immediately followed by propargyl Claisen rearrangement to provide the α‐allenyl ketone stereospecifically, c) DMDO oxidation to install a hydroxy group in a highly stereoselective manner, and d) the SmI₂‐mediated reductive C−O bond cleavage to remove the α‐keto carboxyl group.     

A Concise Total Synthesis of (±)‐Vibralactone

Disclosed is a five‐step synthesis of (±)‐vibralactone, a biologically active terpenoid natural product. A key photochemical valence isomerization of 3‐prenyl‐pyran‐2‐one produces both the all‐carbon quaternary stereocenter and the β‐lactone at an early stage. Cyclopropanation of the resulting bicyclic β‐lactone produces a strained housane structure that is converted to the natural product through a sequential ring expansion and reduction strategy. This concise and modular route to the natural product provides the shortest total synthesis of (±)‐vibralactone reported to date.     

Total Syntheses of the Spermine Alkaloids (−)‐(R,R)‐Hopromine and (±)‐Homaline

The diastereoselective synthesis of the spermine alkaloid (R,R)‐hopromine ( 2 ) is described. The as yet unknown absolute configuration of naturally occurring (−)‐hopromine ( 2 ) is (R,R) and was established by comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of the characteristic bis‐8‐membered lactam scaffold was carried out by convergent build‐up of basic chiral azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous syntheses of 4‐alkyl‐hexahydro‐1,5‐diazocin‐2(1H)‐ones 21a and 21b were the introduction of the unbranched alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt)₃‐assisted cyclization of the open‐chain intermediates 20a and 20b , respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared from commercially available (+)‐L ‐aspartic acid ( 12 ). Based on the synthetic strategy developed for (R,R)‐hopromine ( 2 ), a rapid access to the parent alkaloid homaline ( 1 ) in its (±)‐form is given.     

Synthesis of (±)‐Nephromopsinic, (−)‐Phaseolinic,and (−)‐Dihydropertusaric Acids

The formal syntheses of (±)‐nephromopsinic acid, (−)‐phaseolinic acid, and the first total synthesis of (−)‐dihydropertusaric acid from (±)‐ and (−)‐7‐oxabicyclo[2.2.1]hept‐5‐en‐2‐one are described. These syntheses take advantage of a previously reported radical rearrangement (1,2‐acyl migration). A remarkable iodide‐mediated cleavage of a bicyclic system, followed by the introduction of the γ‐chains via a mixed Kolbe electrolysis, are the key steps of these syntheses. This approach is general and could be applied for the preparation of all kinds of paraconic acids with excellent control of the stereochemistry.