Sulfoxide‐Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)‐Isopaucifloral F, (+)‐Quadrangularin A,and (+)‐Pallidol

The synthesis of enantiomerically pure 3‐aryl substituted indanones is developed using an enantioselective sulfoxide‐based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para‐tolyl sulfoxide‐containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)‐isopaucifloral F, (+)‐quadrangularin A, and (+)‐pallidol.     

Stereoselective total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (−)-(6S,2′S)-epi cryptocaryalactone

The total synthesis of (+)-(6R,2′S)-cryptocaryalactone and (−)-(6S,2′S)-epi cryptocaryalactone is reported based on stereoselective reduction of δ-hydroxy β-keto ester to install 1,3-polyol system, cis Wittig olefination, and lactonization as the key steps. The synthesis of (−)-(6S,2′S)-epi cryptocaryalactone is also reported using syn-benzylidene acetal formation and a preferential Z-Wittig olefination reaction and lactonization as the key steps.     

X-Ray Investigation of Chiral β-Hydroxyketone Derived From (+)-Isomenthone

X-ray analysis was carried out to study the molecular structure of β-hydroxyketone, which is one of the minor products of selective aldol condensation of (−)-menthone with 4-carbomethoxybenzaldehyde. The cyclohexanone ring of the compound has a practically undistorted chair conformation with an axial orientation of the 1-methyl group and the bulkiest 2-[1′-hydroxy-1′ -(4-carbomethoxyphenyl)]methyl substituent and the equatorial orientation of the isopropyl group in the 4 position. The stereochemical configuration was found to be (1R,2R,4 R, 1′ S), supporting that the compound belongs to the group of (+)-isomenthones; i.e., the starting (-)-menthone undergoes (to a certain extent) epimerization under the reaction conditions used. In crystal, there is intermolecular hydrogen bonding >C=O...HO- (the -O...H- bond length is 2.15 Å). The molecular conformation in hydroxyketone crystals differs from the one which prevails in solutions (according to previous NMR data) and which is characterized by an inverted cyclohexanone ring and intramolecular hydrogen bonding >C=O...HO.Original Russian Text Copyright © 2004 by S. V. Shishkina, T. G. Drushlyak, L. A. Kutulya, N. S. Pivnenko, and O. V. Shishkin__________Translated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 5, pp. 933–940, September–October, 2004.     

Highly enantioselective fluorescent sensor for chiral recognition of amino acid derivatives

A highly enantioselective fluorescent sensor, containing benzylaminomethyl groups at 3,3′-position of 1,1′-bi-2-naphthol (BINOL), has been used to conduct the chiral recognition of α-amino acid derivatives. It is observed that one enantiomer of N-Boc-proline can increase the fluorescence intensity of the binaphthyl fluorophores by over 57-fold, while the other enantiomer can cause only sixfold fluorescence enhancement. Such unusually highly enantioselective response demonstrates that this sensor is potentially useful in the enantioselective recognition of amino acid derivatives.     

A concise total synthesis of (+)-FR900482 and (+)-FR66979

The concise, enantioselective total synthesis of the potent antitumor antibiotics (+)-FR900482 and (+)-FR66979 are described. Sharpless asymmetric epoxidation technology has been deployed to construct the optically active aziridine-containing fragment that is joined to the aromatic moiety in a highly convergent manner. Dimethyldioxirane effects the remarkable one-step deprotection/oxidative cyclization of an eight-membered ring amino-ketone to the unique hydroxylamine hemiketal ring system that is a distinctive structural motif of FR900482. This reaction has been exploited in a concise 33-step enantioselective total synthesis of FR900482.     

Bifunctional chiral synthons via biochemical methods, 4. Chiral precursors to (+)-biotin and (−)-a-factor.

The chirons 3 and 4, derived from enzymic enantioselective hydrolysis of 1 and 2, are converted into the chiral lactones 5 and 6, key precursors to (+)-biotin and (?)-A-factor, respectively.     

Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess (> 99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral beta-keto esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro substituent).     

Enantioselective Total Synthesis of (+)‐Neostenine

A chirality transfer approach using acyclic polyol intermediates for the synthesis of (+)‐neostenine ( 1 ) has been developed. The sequential Overman/Claisen rearrangement of an allylic 1,2‐diol was especially useful, installing two contiguous stereocenters with complete diastereoselectivity in a one‐pot sequence. The SmI₂‐mediated cyclization and the subsequent chemoselective reduction of a lactam moiety accomplished the first enantioselective total synthesis of (+)‐neostenine ( 1 ).     

A new asymmetric synthesis of 2,6-cis-disubstituted 4-methylenepiperidines: total synthesis of (+)-alkaloid 241D and (+)-isosolenopsin A

A highly diastereoselective synthesis of 2,6-cis-disubstituted-4-methylenepiperidines based on a Mannich type intramolecular cyclization of an allylsilane on an iminium ion is described. The synthetic potential of this methodology is demonstrated by the enantioselective synthesis of two natural piperidine alkaloids: (+)-alkaloid 241D and (+)-isosolenopsin A.     

2-Nitroguanidine Derivatives: IX. Reaction of 1-Amino-2-nitroguanidine with Oxalic Acid as a Method of Synthesis of 3(5)-Nitroamino-1,2,4-triazole-5(3)-carboxylic Acid and 5,5′-Bi(3-nitroamino-1,2,4-triazole) Salts

A new procedure for the synthesis of 5(3)-nitroamino-1,2,4-triazole-3(5)-carboxylic acid and 5,5′ -bi(3-nitroamino-1,2,4-triazole) potassium salt has been developed. It includes cyclization of [2-(N²-nitro-carbamimidoyl) hydrazino]oxoacetic acid and 2,2′-bis(N ²-itrocarbamimidoyl)oxalohydrazide, respectively, which are prepared by reaction of 1-amino-2-nitroguanidine with oxalic acid. The reaction of 5(3)-nitroamino-1,2,4-triazole-3(5)-carbohydrazide with 1-methyl-2-nitro-1-nitrosoguanidine leads to N′ -(N ²-nitrocarbamimidoyl)-5(3)-nitroamino-1,2,4-triazole-3(5)-carbohydrazide whose intramolecular cyclization in the presence of bases may be regarded as a new method of synthesis of 5,5′-bi(3-nitroamino-1,2,4-triazole) salts.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 3, 2005, pp. 447–450.Original Russian Text Copyright © 2005 by Metelkina, Novikova, Berdonosova, Berdonosov.For communication VIII, see [1].     

Synthesis of a new isomer of creatinine and its use in the preparation of the food mutagen 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PHIP)

Base-induced cyclization of N′-cyanomethyl-N′-methylurea gives 1-methyl-4-amino-imidazol-2-one, this in turn is condensed with 3-hydroxy-2-phenylacrolein to yield an imidazo[4,5-b]pyridine which is converted into 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PHIP).     

Polyhydroxylated pyrrolizidines. Part 3: A new and short enantiospecific synthesis of (+)-hyacinthacine A2

(1R,2R,3R,7aR)-1,2-Dihydroxy-3-hydroxymethylpyrrolizidine (+)-Hyacinthacine A₂ 1 has been synthesized by Wittig's methodology using [(2′S,3′R,4′R,5′R)-3′,4′-dibenzyloxy-N-tert-butyloxycarbonyl-5′-tert-butyldiphenylsilyloxymethylpyrrolidin-2′-yl]carbaldehyde 3, prepared from a partially protected DMDP 2, and the appropriated ylide, followed by cyclization by an internal reductive amination process of the resulting unsaturated aldehyde 4 and total deprotection.     

Total Synthesis of (+)‐β‐Himachalene

An enantioselective synthesis of (+)‐β‐himachalene ( 2 ) was accomplished starting from (1S,2R)‐1,2‐epoxy‐p‐menth‐8‐ene ( 3 ) in 15 or 16 steps with an overall yield of ca. 6% (Schemes 3, 5, and 6). Key transformations include an Ireland–Claisen rearrangement, a Corey oxidative cyclization, and a ring expansion.     

Catalytic enantioselective conjugate addition of dialkyl zinc reagents to α,β-unsaturated ketones mediated by new phosphite ligands containing binaphthalene/1,2-diphenylethane moieties: a practical synthesis of (R)-(−)-muscone

New diastereoisomeric phosphites based on either (R)- or (S)-2,2′-dihydroxy-1,1′-binaphthyl (BINOL) and having the chiral alcoholic moiety derived from the monobenzyl ether of (R,R)-1,2-diphenylethane-1,2-diol have been prepared and used as chiral ligands in the enantioselective copper-catalyzed 1,4-addition of diethylzinc to chalcone and 2-cyclohexen-1-one (enantiomeric excesses up to 48%). With the (aR,R,R) ligand dimethylzinc adds enantioselectively to (E)-cyclopentadecen-2-en-1-one to give (R)-(−)-muscone (68% yield, 78% ee). This provides an efficient access to a valuable ingredient of the perfume industry. However, with the (aS,R,R) ligand, (S)-(+)-muscone is obtained with longer reaction times (37% yield and 10% ee) with a very high double diastereoselection effect being observed.     

Radical Cyclization Route to the Stereoselective Synthesis of (+)‐trans‐Cognac Lactone and (+)‐trans‐Aerangis Lactone

Stereoselective total synthesis of two chiral lactones, (+)‐trans‐cognac lactone (1b) and (+)‐trans‐aerangis lactone (2c), has been achieved from the same intermediate using a radical‐based cyclization route.     

Synthesis of (+)-Multifidene

(+)-Multifidence ((+)- 1 ) has been synthesized starting from (R)-(cyclopent-2-enyl)methanol ((+)- 2 ) via its chloroformate 4 , Co-mediated radical cyclization reaction to the lactone (+)- 6 , and introduction of the olefinic side chains.     

A short enantioselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and a formal synthesis of (+)-nocardione B

A short enantioselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and the formal synthesis of (+)-nocardione B is described. The synthesis is completed in six steps in overall yields of 8% for eleutherin and 14% for allo-eleutherin. The synthetic strategy features an efficient combination of the Dötz annulation reaction with a chiral alkyne and an oxa-Pictet Spengler reaction as the keys steps in the stereodivergent synthesis of (+)-eleutherin and (+)-allo-eleutherin. The synthesis of (S)-(+)-2-(2′-hydroxypropyl)-5-methoxy-1,4-naphthoquinone entails the formal synthesis of (+)-nocardione B.     

Synthesis of (+)-carpamic acid from (+)-alanine

(+)-Carpamic acid [(2′R,5′S,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoic acid, 1] was synthesized from (S)-alanine, employing intramolecular and reductive amination of acyclic amino ketone 8 as the key step to generate the piperidine ring.     

Facile and efficient total synthesis of (+)-preussin

[structure] The enantioselective total synthesis of (+)-preussin, a potent antifungal agent, has been achieved. The key steps are a Pd(0)-catalyzed oxazoline-forming reaction from L-phenylalanine, hydrogenolysis, and subsequent diastereoselective reductive cyclization of the intermediate aminoketone to pyrrolidine using Pearlman's catalyst.     

New approaches to synthesis of tris[1,2,4]triazolo[1,3,5]triazines

Thermal cyclization of 3-R-5-chloro-1,2,4-triazoles (R = Cl, Ph) afforded 2,6,10-tri-R- tris[1,2,4]triazolo[1,5-a:1′,5′c:1″,5″-e][1,3,5]triazines 5 (R = Ph) and 7 (R = Cl). These compounds are first representatives of this class of heterocycles, whose structures were unambiguously established. Treatment of these compounds with nucleophiles (H₂O/NaOH, NH₃) results in the triazine ring opening to give compounds consisting of three 1,2,4-triazole rings linked in a chain. For example, treatment of cyclic compound 5 with aqueous alkali affords 3-phenyl-1-3-phenyl-1-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,2,4-triazol-5-yl-1H-1,2,4-triazol-5-one. Treatment of 3,7,11-triphenyltris[1,2,4]triazolo[4,3-a:4′,3′c:4″,3″-e][1,3,5]triazine (2) with HCl/SbCl₅ leads to the triazine ring opening giving rise to 5-(3-chloro-5-phenyl-1,2,4-triazol-4-yl)-3-phenyl-4-(5-phenyl-1H-1,2,4-triazol-3-yl)-1,2,4-triazole. Thermal cyclization of the latter produces 3,7,10-triphenyltris[1,2,4]triazolo[1,5-a:4′,3′c:4″,3″-e][1,3,5]triazine (13). Thermolysis of both cyclic compound 2 and cyclic compound 13 is accompanied by the Dimroth rearrangement to yield 3,6,10-triphenyl-tris[1,2,4]triazolo[1,5-a:1′, 5′-c:4″,3″-e][1,3,5]triazine (14). Compounds 13 and 14 are the first representatives of cyclic compounds with this skeleton. ¹³C NMR spectroscopy allows the determination of the isomer type in a series of tris[1,2,4]triazolo[1,3,5]triazines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 706–712, March, 2005.