Efficient trans-acetoacylation mediated by ytterbium(III) triflate as a catalyst under solvent-free condition

A simple and efficient trans-acetoacylation method for the synthesis of β-keto ester derivatives has been described using ytterbium(III) triflate as a new catalyst under solvent-free condition. This method was found to be efficient and convenient for the synthesis of a wide variety of β-keto ester derivatives.     

Total synthesis of (-)-callipeltoside A

A total synthesis of (-)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, developed to circumvent issues related to the reversible nature of acylketene formation from β-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described.     

Concise enantiospecific, stereoselective syntheses of (+)-crispine A and its (-)-antipode

An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.     

Stereoselective synthesis of the C15-C26 fragment of the antitumor agent (-)-dictyostatin

The synthesis of the C15-C26 fragment of (-)-dictyostatin is reported in 10 steps and 28% overall yield. The key steps are the two stereoselective sulfoxide-directed processes: a Reformatsky-type reaction and a β-keto sulfoxide reduction.     

Total synthesis of (-)-anamarine

Total synthesis of polyhydroxy δ-pyranone natural product (-)-anamarine is accomplished from D-(-)-tartaric acid. The main feature of the synthesis is the utility of hitherto unexplored β-keto phosphonate derived from tartaric acid amide and further elaboration involving stereoselective reduction.     

Concise synthesis and revision of the proposed biogenesis of helicascolides

A concise synthesis of helicascolides A, B and C was achieved in three to five steps from commercially available materials. The key transformations of the synthesis include an Evans-Metternich anti-aldol reaction of the known β-keto imide 10 and strategic base-mediated one-pot cyclization/alkylation. Based on the new chemical evidence of ring-opening reaction of β-keto ester under biocompatible basic conditions, Krohn’s proposal for the biosynthetic relationship between helicascolide A (1) and a naturally co-existing acyclic dienone 4 was suggested in a reverse manner.     

Total syntheses of (Sp)-(+)- and (Rp)-(-)-spiniferin-1, a pair of unusual natural products with planar chirality

(S(p))-(+)-Spiniferin-1 and (R(p))-(-)-spiniferin-1, a pair of unusual marine natural products with planar chirality, were firstly synthesized via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction. The chiral resolution and palladium-catalyzed β-H elimination of allylic alcohol derivatives were considered as the key steps of these divergent syntheses.     

A stereodivergent strategy for the preparation of corynantheine and ipecac alkaloids, their epimers, and analogues: efficient total synthesis of (-)-dihydrocorynantheol, (-)-corynantheol, (-)-protoemetinol, (-)-corynantheal, (-)-protoemetine, and related natural and nonnatural compounds

Here we present a general and common catalytic asymmetric strategy for the total and formal synthesis of a broad number of optically active natural products from the corynantheine and ipecac alkaloid families, for example, indolo[2,3-a]- and benzo[a]quinolizidines. Construction of the core alkaloid skeletons with the correct absolute and relative stereochemistry relies on an enantioselective and diastereodivergent one-pot cascade sequence followed by an additional diastereodivergent reaction step. This allows for enantio- and diastereoselective synthesis of three out of four possible epimers of the quinolizidine alkaloids that begin from common and easily accessible starting materials by using a common synthetic route. Focus has been made on excluding protecting groups and limiting isolation and purification of synthetic intermediates. This methodology is applied in the total synthesis of the natural products (-)-dihydrocorynantheol, (-)-hirsutinol, (-)-corynantheol, (-)-protometinol, (-)-dihydrocorynantheal, (-)-corynantheal, (-)-protoemetine, (-)-(15S)-hydroxydihydrocorynantheol, and an array of their nonnatural epimers. The potential of this strategy is also demonstrated in the synthesis of biologically interesting natural product analogues not accessible through synthetic elaboration of alkaloid precursors available from nature, for example, thieno[3,2-a]quinolizidine derivatives. We also report the formal synthesis of (+)-dihydrocorynantheine, (-)-emetine, (-)-cephaeline, (-)-tubulosine, and (-)-deoxytubulosine.     

A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]- 5-[(methanesulfonyloxy)methyl]-2- pyrrolidinone

A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5-[(methanesulfonyloxy)methyl]-2-pyrrolidinone (1) is described. The key transformations involve a highly efficient reaction sequence consisting of ethoxycarbonylation, alkylation, hydrolysis, and decarboxylation to produce compound 10. The process described herein is practical, robust, and cost-effective, and it has been successfully implemented in a pilot plant to produce a multikilogram quantity of mesylate 1.     

A concise total synthesis of (-)-maoecrystal Z

The first total synthesis of (-)-maoecrystal Z is described. The key steps of the synthesis include a diastereoselective Ti(III)-mediated reductive epoxide coupling reaction and a diastereoselective Sm(II)-mediated reductive cascade cyclization reaction. These transformations enabled the preparation of (-)-maoecrystal Z in only 12 steps from (-)-γ-cyclogeraniol.     

Enantioselective total synthesis of both the stereoisomers of dihydrokawain-5-ol

The enantioselective synthesis of both the stereoisomers of dihydrokawain-5-ol is described. The key features of the synthetic strategy include (a) Sharpless asymmetric dihydroxylation, (b) Wittig olefination, and (c) formation of β-keto ester to access the highly enantiomerically pure kavalactones.     

The reformatsky reaction of 1-acyl-3,5-dimethylpyrazoles. A convenient preparation of 4-amino-3-oxoalkanoic acid derivatives

The conversion of N-acylpyrazoles into β-keto esters was accomplished efficiently by the treatment with α-bromo esters and zinc dust. Using this Reformatsky reaction of N-acylpyrazoles, 4-(protected amino)-3-oxoalkanoic acid derivatives were conveniently prepared as the key intermediates in the synthesis of statines.     

Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1butenyl]phenoxyacetic acid

The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.     

Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile

(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.     

A practical synthesis of (-)-kainic acid

A highly practical stereoselective total synthesis of (-)-kainic acid is described. This synthesis features the stereoselective alkylation of an iodolactone intermediate that was efficiently prepared from (+)-carvone and introduction of carboxylic acid by hydrolysis of a nitrile accompanied by epimerizaion. This synthetic route enabled us to obtain 14.6 g of (-)-kainic acid.     

Preparation of ethyl 5(s),6-epoxy-3(r)-(methoxymethoxy)hexanoate: a key chiral intermediate for mevinolin and compactin.

The synthesis of Ethyl 5(S),6-Epoxy-3(R)-(methoxymethoxy)hexanoate, a key chiral synthon for the β-hydroxy-δ-lactone portion of Mevinolin and Compactin, $\text{via}$ a regiospecific ring opening of a tetrahydrofuran derivative by dimethylboron bromide, is described.     

Total synthesis of (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine

The first total syntheses of new monoterpene alkaloids (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine, corresponding to the natural enantiomers, have been accomplished. The strategy for the synthesis of these natural products utilized 6-epi-incarvilline as a common precursor, which was assembled by a three-component coupling reaction using (4S)-4-siloxy-2-cyclopenten-1-one to construct an appropriately trisubstituted cyclopentanone, followed by ring closure to the cis-perhydro-2-pyrindine skeleton by means of a reductive Heck-type reaction. Furthermore, topochemically controlled [2 + 2] photodimerization of cinnamic acid derivatives in the solid state for the stereospecific construction of a 1,2,3,4-tetrasubstituted cyclobutane ring was also investigated as a means to access (-)-incarvillateine.     

A versatile and efficient synthesis of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone

A versatile and efficient method for the preparation of (2S)-2-(hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone from l-(−)-phenylalanine 2 utilising the aromatic system as a masked β-keto aldehyde was developed. The key step in the sequence is an intramolecular cyclisation of 6 to give 2,3-dihydropyridin-4-ones.     

A chemoenzymatic dynamic kinetic resolution approach to enantiomerically pure (R)- and (S)-duloxetine

The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of β-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.     

Oxidation,With Chiral Retention,of Benzyloxycarbonyl Threonine Methyl Ester

A simple oxydative procedure converted Z-L-threonine methyl ester into the corresponding (2S)-β-keto ester: Starting material for the synthesis of labelled threonine derivatives.