Synthesis of ceramide analogues having the C(4)-C(5) bond of the long-chain base as part of an aromatic or heteroaromatic system

Two efficient and stereoselective methods are described for the preparation of aryl and heteroaryl ceramide analogues 2 and 3. The first route involves the addition of an aryllithium or a heteroaryllithium reagent (7a or 25a, respectively) to the L-serine-derived aldehyde 4, followed by hydrolysis of the oxazolidine, liberation of the amino group, and N-acylation. The second route, which was used to prepare arylceramide analogue 2 in eight steps and 28% overall yield starting with 3-bromobenzaldehyde, utilizes a Heck reaction to afford (E)-alpha,beta-unsaturated ester 16, then osmium-catalyzed asymmetric dihydroxylation for the introduction of the desired chirality at C-2 and C-3. Regioselective alpha-azidation of alpha-O-nosyl-beta-hydroxyester 18 with sodium azide, followed by LiAlH(4) reduction of the azido and ester groups and N-acylation, complete the synthesis of arylceramide analogue 2.     

Concise enantioselective total syntheses of (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine and (+)-norchelidonine by a Pd II-catalyzed ring-opening strategy

New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.     

A concise and stereoselective synthesis of squalamine

[reaction: see text] A short and highly stereoselective synthesis of the novel steroid squalamine (1) was accomplished in nine steps from easily available methyl chenodeoxylcholanate 2. Our synthesis featured improved dehydrogenation of 4 followed by conjugate reduction to construct the trans AB-ring system and efficient asymmetric isopropylation of aldehyde 6 to introduce the C-24R-hydroxyl group.     

Asymmetric synthesis of (-)-tetrahydrolipstatin: an anti-aldol-based strategy

A stereoselective synthesis of (-)-tetrahydrolipstatin is described. The synthesis involves an asymmetric ester derived titanium enolate anti-aldol reaction, a nitro-aldol reaction to append the C-2' C(11) side chain, and a diastereoselective reduction of a beta-hydroxy ketone to an anti-1,3-diol functionality followed by its elaboration to (-)-tetrahydrolipstatin.     

Total synthesis of (−)-funebrine via Au-catalyzed regio- and stereoselective γ-butyrolactonization of allenylsilane

The stereoselective total synthesis of (−)-funebrine from 2-butyn-1-ol was described. The crucial steps in the synthesis involved the stereoselective enolate Claisen rearrangement of the (S)-α-acyloxy-α-alkynylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the Paal-Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.     

The application of vinylogous iminium salt derivatives to an efficient synthesis of the pyrrole containing alkaloids Rigidin and Rigidin E

Studies directed on the synthesis of the pyrrole containing marine natural products Rigidin and Rigidin E via vinylogous iminium salts are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole from a vinamidinium salt followed by acylation at the 5-position of pyrrole. Halogenation and aminocarbonylation at the 3-position of pyrrole followed by hydrolysis of the ester group at C-2 and subsequent Curtius rearrangement generates the pyrrolopyrimidine skeleton. A final deprotection step completes the synthesis of Rigidin and Rigidin E.     

Enantiopure oxazolidinones as chiral acids in the asymmetric protonation of N-Boc pyrrole derived enolates

The first use of geminally disubstituted oxazolidinones as chiral protonating agents is described: these new acids are able to directly protonate an enolate generated by the ammonia free partial reduction of an electron deficient pyrrole and give up to 68% ee in the pyrroline product.     

抗革兰氏阴性菌耐格霉素的形式合成

耐格霉素是具有抗革兰氏阴性菌活性的天然产物.以廉价易得的3-羰基-4-氯丁酸乙酯为原料,以八步29%的总收率实现了耐格霉素的形式合成.该工作改进了文献的合成路线,利用生物催化不对称还原高立体选择性引入C-5位的手性羟基,并将危险的叠氮引入反应放在合成后期,降低合成路线的操作风险.分子中C-3位的仲碳胺基手性中心通过Ellamn试剂介导的不对称Mannich反应构建.该路线易于放大,有望为构建耐格霉素类似物分子库以及高通量药物筛选奠定基础.     

Total syntheses of epothilones B and d

A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde 5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid 52, and macrolactonization.     

Highly enantioselective phase-transfer-catalyzed alkylation of protected alpha-amino acid amides toward practical asymmetric synthesis of vicinal diamines, alpha-amino ketones, and alpha-amino alcohols

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.     

Highly enantioselective synthesis of a fluorescent amino acid

A high enantiomeric excess (>99.5%) synthesis of 2-amino-3-(7-methoxy-4-coumaryl) propionic acid ( Amp) is described. The two step synthesis route of this non-proteinogenic amino acid includes an oxazinone derivative as glycine enolate, which is alkylated with the fluorogenic group.     

Enantioselective total synthesis of semperoside a

A versatile and concise strategy has been developed (Scheme 1) for the enantioselective synthesis of semperoside A 1 which is endowed with an unusually glucosylated iridane structure. The crucial step was a Hg(II)-mediated electrophilic heteroatom cyclization of beta-glucoside 4 that readily led to the iridane skeleton while installing the C-2 and C-3 stereocenters with complete stereocontrol. This expeditious route is unprecedented among synthetic approaches to iridoid glycosides and smoothly overcomes the hemiacetals glucosidation issue. The present inaugural total synthesis of semperoside A was achieved in 10 steps and 17% overall yield from the enantiomerically pure lactone 8, thus proving the absolute stereochemistry of 1 unequivocally.     

Establishing the absolute configuration of the asbestinins: enantioselective total synthesis of 11-acetoxy-4-deoxyasbestinin D

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2-C-11-cyclized cembranoid natural products.     

Electronically Mediated Selectivity in Ring Opening of 1-Azirines. The 3-X Mode: Convenient Route to 3-Oxazolines

The mild base-promoted reaction of methyl 2-phenyl-1-azirine-3-acetate (1) with aldehydes and acetone provides a new and simple route to the 3-oxazolines 5, which are formed in good yields by the electrophilic trapping of an imino anion produced by C-N bond cleavage in the 1-azirine enolate intermediate 6. Chloranil oxidation of 5 containing an aromatic substituent at C-2 affords oxazoles 7, while reaction of 5 containing an aliphatic group at C-2 produces 5-methylene-3-oxazolines 8 and 5-spiro-2-oxazolines 9 in addition to 7.     

Synthetic studies toward mannopeptimycin-E: synthesis of the O-linked tyrosine 1,4-alpha,alpha-manno,manno-pyranosyl pyranoside

[structure: see text] The enantioselective synthesis of the C-4' acylated 1,4-alpha,alpha-manno,manno-disaccharide fragment of mannopeptimycin-E has been achieved in seven steps from d-tyrosine. The route relies upon diastereoselective palladium-catalyzed glycosylation, diastereoselective reduction, and diastereoselective bis-dihydroxylation. The efficiency of the synthesis is demonstrated by the high overall yield (37%) and the preparation of various analogues.     

De novo asymmetric synthesis of anamarine and its analogues

[reaction: see text] The enantioselective synthesis of anamarine has been achieved in 21 steps. The route relies on enantio- and regioselective Sharpless dihydroxylation of dienoate ester and zinc borohydride reduction to establish the C-8-C-11 stereochemistry. A diastereoselective Leighton allylation established the desired C-5 stereochemistry. The route has also been used to prepare two diastereoisomers of anamarine in 14 steps.     

New synthesis of condensed heterocycles from isoxazole derivatives VI. 2,5-Dimethyl-3-aeetyl-7-amino-1H-pyrrolo[3,2-b] pyridine

A new synthesis of pyrrolo[3,2-b] pyridine starting with pyrrole ring is described. The procedure allows the synthesis of 4-azaindoles bearing a sensitive group at C-7. The nitration of 4b with nitric acid and acetic anhydride at ?15° gave 5 . The hydrogenation of 5 led to simultaneous reduction of N-hydroxy and nitro groups and to hydrogenolysis of the isoxazole nucleus, affording an appropriate chain of atoms to building up the pyrrolo[3,2-b] pyridine ring.     

Acetyltrimethylsilane, trifluoromethyltrimethylsilane, and prenyl esters: a three-component system for the synthesis of gem-difluoroanalogues of monoterpenes

The preparation of 3,3-difluoro-6-methylhept-5-en-2-one 1, a key intermediate for the synthesis of 4,4-difluoroterpenes, and applications in linalool and geraniol series are described. The process involves 1,1-difluoro-2-trimethylsilyoxypropene, an enol silyl ether prepared from acetyltrimethylsilane and trifluoromethyltrimethylsilane, and its reaction in situ with prenyl benzoate, under catalysis by trimethylsilyl trifluoromethanesulfonate. Optimized conditions leading to either the desired enol silyl ether or the unprecedented methyl(trifluoromethyl)trimethylsilyl carbinol 4 have been achieved. The prenylation of the enol silyl ether gives a 9/1 mixture of regioisomers, in favor of the expected ketone 1. Treatment of 1 with vinylmagnesium bromide leads to (+/-)-4,4-difluorolinalool 7. Reaction with the lithium enolate of ethyl diethylphosphonoacetate, and then LAH reduction, converts 1 to 4,4-difluorogeraniol 11, with complete stereoselectivity.     

Efficient synthesis of the key intermediate triptophenolide methyl ether for the synthesis of (−)-triptolide

An efficient synthesis of triptophenolide methyl ether 4 from the readily available abietic acid 3 in nine steps is described and successfully applied to the synthesis of (−)-triptolide 1. The route is of characteristic of low cost, high yield and easy operation. In addition, every reaction in this route has been successfully scaled-up to a 100 g substrate level without loss of yield.     

Enantioselective total synthesis of (+)-leucascandrolide A macrolactone

[reaction: see text] The enantioselective synthesis of the (+)-leucascandrolide A macrolactone has been achieved in 20 linear steps from 1,3-propanediol. The key steps in the synthesis are a reductive cleavage of bicyclic ketal 5 to establish the C15 stereogenic center and a diastereoselective aldol of the boron enolate of methyl ketone 3 to aldehyde 4 in preparation for a heteroconjugate addition for the introduction of the C3 stereocenter.