Total Synthesis of (±)‐Aspidophylline A

A total synthesis of aspidophylline A, a pentacyclic akuammiline‐type monoterpene indole alkaloid, is described. The synthesis features: 1) rapid access to a fully functionalized dihydrocarbazole through the desymmetrization of readily available 2‐allyl‐2‐(o‐nitrophenyl)cyclohexane‐1,3‐dione; 2) an intramolecular azidoalkoxylation of an enecarbamate to install both the furoindoline ring and the azido functionality; and 3) an intramolecular Michael addition for the construction of the 2‐azabicyclo[3.3.1]nonane ring system.     

Concise total synthesis of (-)-8-epigrosheimin

A highly efficient route was developed to synthesize (-)-8-epigrosheimin in four steps from aldehyde 2 based on a substrate-controlled method. The key steps of the synthesis included (1) a stereo- and regioselective allylation addition, (2) an intramolecular translactonization, and (3) an aldehyde-ene cyclization.     

The synthesis of (+)-allopumiliotoxin 323B'

This paper describes the synthesis of (+)-allopumiliotoxin 323B' (1) using the intramolecular [3 + 2]-cycloaddition reaction of the (Z)-N-alkenylnitrone 4. This synthesis began with (R)-tert-butyl-3-hydroxy-pent-4-enoate [(R)-13] which was obtained by enzymatic resolution with Amano PS lipase. A series of manipulations gave intermediate 17 and in situ coupling with 4-benzoyloxybutanal lead to the (Z)-N-alkenylnitrone 4 which underwent an intramolecular [3 + 2]-cycloaddition reaction to give the isoxazolidine 3 as the major cycloadduct. Isoxazolidine 3 provided the piperidinone 24 which upon diastereofacial selective addition of MeMgBr gave the required tertiary alcohol 25. Formation of the indolizidine core 2 was achieved by an intramolecular S(N)2 reaction. The side chain was assembled from a Wittig reaction between the phosphorane 8 and the enantiomerically pure aldehyde 9. Further modifications afforded the aldehyde 7 which underwent an aldol condensation with the potassium enolate of the indolizidone core 2. Dehydration gave the enone 37 which was converted into the anti-diol 38 by intramolecular hydride reduction. Finally, deprotection of the BOM protecting group gave (+)-allopumiliotoxin 323B' (1).     

A palladium-catalyzed synthesis of isatins (1H-Indole-2,3-diones) from 1-(2-haloethynyl)-2-nitrobenzenes

An inherently regiospecific synthesis of isatins (1H-indole-2,3-diones) starting from 1-halo-2-nitrobenzenes is described. The isatins are formed by an intramolecular palladium-catalyzed annulation of 2-(2-haloethynyl)-1-nitrobenzenes via the formation of 2-haloisatogens.     

A New Enantioselective Approach to Total Synthesis of the Securinega Alkaloids: Application to (-)-Norsecurinine and Phyllanthine

An inexpensive proline derivative and chiral control feature in the total synthesis of securinega alkaloids (-)-norsecurinine (1) and phyllanthine (2). Key steps in the synthesis of 1 include an intramolecular ketonitrile coupling and application of a radical-based generation of N-acylimines. The total synthesis of 2 utilizes a stereoselective imino Diels - Alder construction of the methoxypiperidine ring.     

Asymmetric Total Synthesis of Onoseriolide,Bolivianine, and Isobolivianine

In this article, we describe our efforts on the total synthesis of bolivianine ( 1 ) and isobolivianine ( 2 ), involving the synthesis of onoseriolide ( 3 ). The first generation synthesis of bolivianine was completed in 21 steps by following a chiral resolution strategy. Based on the potential biogenetic relationship between bolivianine ( 1 ), onoseriolide ( 3 ), and β‐(E)‐ocimene ( 8 ), the second generation synthesis of bolivianine was biomimetically achieved from commercially available (+)‐verbenone in 14 steps. The improved total synthesis features an unprecedented palladium‐catalyzed intramolecular cyclopropanation through an allylic metal carbene, for the construction of the ABC tricyclic system, and a Diels–Alder/intramolecular hetero‐Diels–Alder (DA/IMHDA) cascade for installation of the EFG tricyclic skeleton with the correct stereochemistry. Transformation from bolivianine to isobolivianine was facilitated in the presence of acid. The biosynthetic mechanism and the excellent regio‐ and endo selectivities in the cascade are well supported by theoretical chemistry based on the DFT calculations.     

Efficient construction of novel α-keto spiro ketal and the total synthesis of (±)-terreinol

The first total synthesis of (±)-terreinol is described. An intramolecular Pd(II)-catalyzed cycloisomerization of a 2-(1′-alkynyl)benzyl alcohol via an apparent 6-endo diagonal pathway led to the 1H-isochromene ring system, which was further converted to the desired spiro ketal via an iodine-mediated intramolecular spiro-cyclization.     

Synthesis of 1,2,5- and 1,2,3,5-substituted pyrroles from substituted aziridines via Ag(I)-catalyzed intramolecular cyclization

An efficient synthesis of 1,2,5- and 1,2,3,5-substituted pyrroles has been achieved from the sequential reactions including a ring-opening of 1-(aziridin-2-yl)propargylic alcohols by various nucleophiles under mild condition followed by an intramolecular cyclization using Ag(I) catalyst.     

Synthesis of pterocellin A

The first total synthesis of pterocellin A (1) was achieved in 10 linear steps from commercially available kojic acid (6) and 2-bromo-3-pyridinol (11) in a convergent sequence. The key constructive steps are a directed lithiation to couple two pyridines and an intramolecular nucleophilic aromatic substitution to form 1. [structure: see text]     

Reduction of 4-(haloalkyl)azetidin-2-ones with LiAlH4 as a powerful method for the synthesis of stereodefined aziridines and azetidines

[reaction: see text] A new synthesis of stereodefined aziridines and azetidines, starting from 4-(1- or 2-haloalkyl)azetidin-2-ones, is described. Treatment of the latter compounds with LiAlH(4) gave 1,2-fission of the beta-lactam, followed by an intramolecular nucleophilic substitution of the halogen, giving rise to the formation of 2-(1-alkoxy-2-hydroxyethyl)aziridines in the case of 4-(1-haloalkyl)azetidin-2-ones and of 2-(1-alkoxy-2-hydroxyethyl)azetidines in the case of 4-(2-haloalkyl)azetidin-2-ones. The resulting 2-(1-alkoxy-2-hydroxyethyl)aziridines were transformed into the corresponding trans-3,4-substituted oxolanes via an intramolecular nucleophilic ring opening, triggered by AlCl(3).     

Multigram Synthesis of a Chiral Substituted Indoline Via Copper-Catalyzed Alkene Aminooxygenation

(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthesis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its bis(allyl)aniline by-product by distillation under reduced pressure.     

The enantioselective synthesis of (-)-lycoramine with the Birch-Cope sequence

The first enantioselective synthesis of (-)-lycoramine has been achieved in 14 steps and 5% overall yield from the biaryl derivative 1. The synthesis applies the previously developed Birch-Cope sequence to create the key arylic quaternary stereocenter of (-)-lycoramine with excellent enantioselective control. The product of the Birch-Cope sequence, a versatile 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one, was elaborated through an intramolecular conjugate addition of a phenol to create the dihydrofuran ring. Chemoselective elaboration of the allyl group into an amide followed by a modified Pictet-Spengler reaction generated the azepine ring.     

Diastereoselective total synthesis of both enantiomers of epolactaene

A stereocontrolled total synthesis of both the (+)- and (-)-epolactaene ((+)- and (-)-1) enantiomers from tetrahydropyran-2-ol is described. The following reactions in this synthesis are particularly noteworthy: (1) the stereoselective construction of the conjugated (E,E,E)-triene by a combination of kinetic deprotonation and thermodynamic equilibration, (2) the E-selective Knoevenagel condensation of beta-ketonitrile 33 with a chiral 2-alkoxyaldehyde, (3) a diastereoselective epoxidation achieved using a bulky nucleophile (TrOOLi) and an appropriate protecting group, (4) the mild hydrolysis of an alpha-epoxy nitrile by silica gel on TLC facilitated by hydroxyl-mediated, intramolecular assistance.     

Microwave-assisted synthesis of new polysubstituted dienaminoesters and their cyclization to 3-bromo-2(1H)-pyridinones

A microwave-assisted, telescoped synthesis, involving a Michael-type addition followed by intramolecular cyclization, provides an effective entry to the polysubstituted 3-bromo-2(1H)-pyridinone core.     

Total synthesis of (-)-pseudolaric acid B

We report the enantioselective synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon, which displays interesting antifungal, antifertility, and cytotoxic activity against multidrug resistant cell lines. Our synthesis utilizes a highly efficient metal-catalyzed [5 + 2] vinylcyclopropane-alkyne intramolecular cycloaddition to construct the polyhydroazulene core of the natural product. Elaboration to the tricyclic scaffold of the pseudolaric acids was completed with an intramolecular alkoxycarbonyl radical cyclization to form the quaternary center and a highly diastereoselective cerium acetylide addition to a methyl ketone for introduction of the acid side chain.     

Total synthesis of TAK-kinase inhibitor LL-Z1640-2 via consecutive macrocyclization and transannular aromatization

The biomimetic total synthesis of LL-Z1640-2 (3) is reported without the use of phenol protection. The aromatic unit was constructed via the transannular aromatization of macrocyclic triketo-ester 2, which in turn was synthesized by macrolactonization using an intramolecular trapping of a triketo-ketene derived from dioxinone 1.     

Efficient and divergent synthesis of fully substituted 1H-pyrazoles and isoxazoles from cyclopropyl oximes

Efficient and divergent one-pot synthesis of fully substituted 1H-pyrazoles and isoxazoles from cyclopropyl oximes based on reaction conditions selection is reported. Under Vilsmeier conditions (POCl3/DMF), substituted 1 H-pyrazoles were synthesized from 1-carbamoyl, 1-oximyl cyclopropanes via sequential ring-opening, chlorovinylation, and intramolecular aza-cyclization. In the presence of POCl3/CH2Cl2, substituted isoxazoles were obtained from the cyclopropyl oximes via ring-opening and intramolecular nucleophilic vinylic substitution (SNV) reactions.     

Synthesis of N-acyl-2-pyrrolidinones from the corresponding N-acyl-GABA derivatives

In this work, the synthesis of 1-(pyridine-3-carbonyl)pyrrolidin-2-one ( 1a ) and 1-(2-propyl-1-pentanoyl)pyrrolidin-2-one ( 1b ) by cyclization of the corresponding GABA derivatives, is reported. Two different methods are developed. For the synthesis of 1a , the parent molecule 4-[(pyridine-3-carbonyl)-amino]butanoic acid ( 2a ) is treated first with thionyl chloride and then with triethylamine. The second derivative, 1b , is produced by an intramolecular dehydration of 4-(2-propylpentanoylamino)butanoic acid ( 2b ) using an acid catalyst.     

Synthesis of a new conformation-constrained L-tyrosine analogue as a potential scaffold for SH2 domain ligands

The enantioselective synthesis of a new tricyclic tyrosine analogue is reported. This conformation-constrained SH2 domain ligand scaffold 2 was designed on the basis of the natural ligand, whose structure contains the elements of a tyrosine moiety having chi(1) and chi(2) angles constrained to values observed for a phosphotyrosyl (pTyr) residue bound to the p56(lck) SH2 domain. It represents a unique, highly constrained amino acid, which may be of value in signal transduction studies. Three key steps, an asymmetric tandem Michael addition, an intramolecular Friedel-Crafts reaction, and an intramolecular Mannich reaction, were successfully applied in the presented synthetic route.     

Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.