Radical cyclization studies directed toward the synthesis of BMS-200475 ‘entecavir’: the carbocyclic core

Two routes are presented for the conversion of d-diacetone glucose (5a) into a protected carbocyclic core of BMS-200475 (Entecavir). The reduction of two terminal epoxides with Cp₂TiCl to form carbon radicals and their cyclizations with a terminal acetylene and an α,β-unsaturated ester lead ultimately to allylic alcohol 11a, a candidate for Mitsunobu coupling with guanine.     

A New Route for Synthesis of Entecavir

2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopen tyl]-6H-purin-6-one (entecavir, Scheme 1) is a novel carbocyclic 2-deoxyguanosine analog drug which has potent and selective anti hepatitis B virus (HBV) activity1-3. Entecavir is also effective against lamivudine-resistant YMDD mutants4. The US Food and Drug Administration (FDA) approved entecavir as a new preferred drug for the treatment of HBV after lamivudine in March, 2005. Scheme 1 The structure o…     

Synthesis and Biological Evaluation of Entecavir 4'-Ester Derivatives

Entecavir can significantly inhibit the replication of HBV-DNA, reduce the HBV-DNA level in blood se- rum. But suffering from low oral bioavailability, entecavir has low intestinal membrane permeability and poor meta- bolic stability. In this study, 12 different derivatives of entecavir 4＇-ester were regioselectively synthesized and their apical-to-basolateral permeabilities across Caco-2 cells and HBV-DNA inhibitory efficacies were evaluated. Most of the compounds showed high permeabilities across Caco-2 cells compared with entecavir, compounds 5b and 5e also exhibited comparable anti-HBV activities with that of entecavir, especially.     

Enantioselective synthesis of BMS-204352 (MaxiPost) using N-fluoroammonium salts of cinchona alkaloids (F-CA-BF4)

The enantioselective synthesis of a potent Maxi-K potassium channel opener (BMS-204352) mediated by N-fluoroammonium salts of cinchona alkaloids is described. Two synthetic pathways were evaluated. An ee as high as 88% was achieved (>99% after a single recrystallisation).     

Enantioselective fluorination mediated by N-fluoroammonium salts of cinchona alkaloids: first enantioselective synthesis of BMS-204352 (MaxiPost)

We have employed a cinchona alkaloid/Selectfluor-mediated enantioselective fluorination of the oxindole 2 to achieve the first enantioslective synthesis of BMS-204352 (MaxiPost, S-1), an effective opener of maxi-K channels. Fluorination occurred to produce S-1 with 84% ee using the bis-cinchona alkaloid (DHQ)(2)AQN. Recrystallization produced enantiomerically pure (>99% ee) product. Quinidine-mediated fluorination of 2 gave the (R)-antipode of 1 with 68% ee.     

(±)-耳壳藻内酯的全合成研究(Ⅱ)

以2,6,6-三甲基环己-2-烯-1,4-二酮为原料, 经选择性羰基保护、Wittig反应、脱保护基、 腈基水解和还原等5步反应合成了目标化合物, 总产率可达6.0%.     

Synthesis of (-)-chaetominine

The tricyclic hydroxy imidazolidinone was converted to chaetominine in seven steps in 22% overall yield. The key step was the construction of the delta-lactam by heating an amino ester with a catalytic amount of DMAP in toluene at reflux.     

左旋异松蒎酮的合成

研究了以(－)-α-蒎烯为原料合成(－)-异松蒎酮的反应. 以四氢呋喃为溶剂, 硼氢化钠与三氟化硼乙醚溶液生成的硼烷不经分离直接与α-蒎烯发生反马氏加成反应, 生成二异松蒎烷基硼; 采用四水合过硼酸钠或NaOH-H₂O₂氧化硼氢化物得到(＋)-异松蒎醇, 产率为89.5%, 纯度97.4%, 熔点为55～56 ℃, 比旋光度 ＋28.31 (c 5.55, CH₃OH). 以钒磷氧化物为催化剂、双氧水作氧化剂, 将(＋)-异松蒎醇氧化得到(－)-异松蒎酮, 产率88% 以上, 纯度96.0%, 比旋光度为 －10.58 (c 5.51, CH₃OH). 采用IR, MS, ¹H NMR, ¹³C NMR等对(＋)-异松蒎醇和(－)-异松蒎酮结构进行了表征.     

Synthesis of benzothiazepines (review)

Methods for the preparation of benzothiazepines, which are grouped with respect to their structural features (1,2-, 1,3-, and 1,4-thiazepines), are correlated. Methods for the synthesis of compounds of each type are discussed in the case of the most thoroughly studied representatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1443–1452, November, 1986.     

Synthesis of (±)-pentalenene

A total synthesis of (±)-pentalenene (1), based on transannulation of the bicyclo[6.3.0] undecadiene (15) in the presence of boron trifluoride etherate, is described.     

(E)-烯基甲苯基硅醇的合成

从烯丙基甲苯基氨基硅烷出发,经过基化反应,得到(E)-烯基氨基硅烷, 然后水解成(E)-烯基硅醇。研究了烯丙基氨硅烷碳负离子烷基化学反应的区域选择性,建立了去除α-异构体的方法。     

Synthesis of (-)-tetracycline

We describe a convergent, enantioselective synthesis of (-)-tetracycline (1) from benzoic acid (17 steps, 1.1% yield). Benzoic acid was transformed into the AB precursor 2 in 10 steps (11% yield), as previously described, and the latter compound was activated toward Diels-Alder cycloaddition by the introduction of an alpha-phenylthio group (two steps, 66% yield). Heating of the resulting alpha-(phenylthio)enone (3) with the triethylsilyloxybenzocyclobutene derivative 4 at 85 degrees C gave the endo-Diels Alder adduct 5 in 64% yield. Deprotection and oxidation of the latter intermediate gave the 2-(phenylthio)-1,3-diketone 7, which was oxidized with m-chloroperoxybenzoic acid in the presence of trifluoroacetic acid. The sulfoxide intermediate(s) formed eliminated upon warming to 35 degrees C to give the anyhydrotetracycline derivative 8. Intermediate 8 underwent spontaneous autoxidation at 23 degrees C to form the hydroperoxide keto-9 stereoselectively. Without isolation, hydrogenolysis of 9 in the presence of palladium black gave (-)-tetracycline (42% yield from 7), indistinguishable from an authentic sample.     

Synthesis of halogenopyridines (review)

Published data on the synthesis of derivatives of pyridines containing halogen atoms directly at the carbon atoms of the pyridine ring are reviewed.Moscow State Textile Academy, Moscow 117918. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1155–1187, September, 1996. Original article submitted July 6, 1994.     

Synthesis of (±)warburganal

From readily available starting materials a short stereospecific synthesis of the biologically active molecule warburganal (1) has been achieved in 20% overall yield.     

Synthesis of(±)-descarboxylquadrone

The synthesis of a biologically active anlogue of the antitumor agent quadrone, termed descarboxylquadrone ($\text{3}$), is described.     

Synthesis of clavulones (claviridenones)

New marine eicosanoid clavulones (claviridenones) were synthesized from the Corey lactone and D-glutamic acid.