Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A)

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective alpha-alkoxyallylation reactions using the gamma-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.     

Synthesis of the C29-C44 portion of spongistatin 1 (altohyrtin A)

Two synthetic approaches to the C29-C44 portion of spongistatin 1 (altohyrtin A) have been developed. The key step of the first approach relies on the Claisen rearrangement of glucal 18 to provide ester 20a. This intermediate was advanced to silyl enol ether 30, which was coupled under Mukaiyama aldol conditions with aldehyde 3. Cyclization of this aldol adduct completed our first synthesis of the C29-C44 portion of spongistatin 1, requiring 25 total steps and occurring in 2.4% yield over the longest linear sequence (21 steps). We have also developed a second-generation approach based on the C-glycosidation of glucal 43. Through equilibration of the corresponding C-glycosides 49a/b and 50a/b the desired C-glycoside (50a) was obtained in good yield. Aldol condensation of this ketone provided cyclization precursor 67, which undergoes acid-catalyzed ketalization to close the E-ring of the spongistatins. An oxidation/reduction protocol was employed to set the C37 stereocenter. Protection of the C37 carbonol and selective unmasking of the C44 carbonol completed our second generation synthesis. This approach requires 27 steps and occurred in 13.2% yield over the longest linear sequence (18 steps).     

Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.     

Synthesis of the C16-C28 spiroketal subunit of spongistatin 1 (altohyrtin A): the pyrone approach

The synthesis of the CD spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated pyrone to an aldehyde and subsequent acid-catalyzed spirocyclization. A stereoselective hydrogenation and subsequent conformational inversion establish the C19 stereocenter and the axial-equatorial spiroketal center.     

Synthesis of (R)-1-benzyloxy-3-buten-2-ol - a potential chiral synthon from L-(+)-tartaric acid: Its applications in natural product syntheses

A practical synthesis of (R)-3-butene-1,2-diol derivatives from (R,R)-tartaric acid and their applications for the syntheses of (R)-ethyl-5-benzoyloxy-5-formyl pentanoate (2), a useful synthon for the preparation of arachidonic acid metabolites and (R)-γ-caprolactone (3), a pheromone of Trogoderma species, are described.     

合成(R)-2-异戊氧基丙醇的新方法

以(R)-1,2-丙二醇为原料,经伯醇羟基保护、仲醇O-异戊基取代、脱羟基保护三步反应合成了手性醇(R)-2-异戊氧基丙醇,其结构经NMR和MS确证.     

A modular approach to marine macrolide construction. 4. Assembly of C36-C51 and C29-C44 building blocks and evaluation of key coupling reactions targeting spongistatin 1 (altohyrtin A)

Routes have been developed for the stereocontrolled elaboration of two highly functionalized sectors of spongistatin 1. The approach to ring F takes advantage of B-alkyl Suzuki-Miyaura coupling to install the C44-C45 bond. The E-ring pyran moiety was generated by acylation of an alpha-sulfonyl carbanion, the stereogenic centers of which were incorporated by sequential asymmetric aldol reactions. [structure: see text].     

Synthesis of the C(2)-C(13) fragment (the A-B spiroketal unit) of spongistatin 1 (altohyrtin A): use of a common intermediate for the synthesis of both spongistatin spiroketals

[reaction: see text] A convergent synthesis of 14 corresponding to the A-B spiroketal core of spongistatin 1 has been accomplished via an iodo-spiroketalization reaction of glycal 9, which was synthesized in three steps from a late-stage intermediate used in our synthesis of the C-D spiroketal fragment of spongistatin 1. Elaboration of 14 to the A-B spiroketal 15 was accomplished in three steps.     

Synthesis of 1,2-dihydroxyindolizidines from 1-(2-pyridyl)-2-propen-1-ol

1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available picolinaldehyde, resulted a good starting material for the synthesis of the indolizidine skeleton. In particular, a simple process involving bromination, reduction, and nucleophilic substitution (via elimination and addition) allowed an easy conversion of the starting material into (±)-lentiginosine in ~27% overall yield.     

Synthesis of 3-(4-bromophenyl)-1-morpholino-2-phenylalkan-3-ol hydrochlorides

Reactions of 1-(4-bromophenyl)-3-morpholino-2-phenylpropan-1-one with various Grignard compounds in diethyl ether gave a broad series of tertiary amino alcohols, 3-(4-bromophenyl)-1-morpholino-2-phenylalkan-3-ol hydrochlorides, that can be regarded as Trihexyphenidyl analogs.     

沙库必曲中间体(R)-2-(叔丁氧羰基氨基)-3-(联苯-4-基)丙醇的合成

采用D-酪氨酸衍生物为原料,与苯磺酰氯反应制得叔丁氧羰基保护的D-苯丙氨醇苯磺酸酯,经还原,再在5 mol% N-杂环卡宾(NHC)钯催化剂(IMes)Pd(Py)Cl作用下与苯硼酸经过Suzuki-Miyaura偶联反应得到沙库必曲重要中间体(R)-2-(叔丁氧羰基氨基)-3-(联苯-4-基)丙醇,总产率大于57%,ee值大于99%。     

利用工业废弃物中获得的(R)-5-甲基-δ-戊酸内酯为原料合成(2R,6R)-2,6,10-三甲基十一醇

(2R,6R)-2,6,10-三甲基十一醇(1)是维生素E、维生素K和植醇的基本结构单元. 利用从甾体皂甙元氧化降解产生的工业废弃物中所获得的手性化合物(R)-5-甲基-δ-戊酸内酯(6), 先将其转化成为化学性质稳定的(4R)-甲基-5-甲氧甲氧基戊酸甲酯(7), 再经十二步反应, 以14.1%的总收率合成得到了目标化合物(2R,6R)-2,6,10-三甲基十一醇(1).     

A practical synthesis of (R)-3-chlorostyrene oxide starting from 3-chloroethylbenzene

A novel and practical synthesis of (R)-3-chlorostyrene oxide (−)-1 was achieved starting from commercially available 3-chloroethylbenzene 3. Enantiopure (−)-3-chlorostyrene bromohydrin (−)-5 was obtained by the treatment of racemic (±)-5 with lipase QL in the presence of acylating reagents. 3-Chloro-α,β-dibromoethylbenzene 4, a precursor of (±)-5, was synthesized via the expeditious bromination of 3 which was developed by these authors.     

Novel boracycles from 2-amino-2-methylpropan-1-ol and borane methyl sulfide: Synthesis and X-ray crystal structures

On reacting the simple 1,2-amino alcohol: 2-amino-2-methylpropan-1-ol, with borane methyl sulfide (BMS), the expected five member oxazaborolidine ring is not obtained. Instead, two polycyclic structures with trigonal boron atoms 6 and 7 were obtained, and their structure were determined by X-ray crystallography. Compound 6 was obtained in 39% yield and compound 7 was obtained in 7% yield.     

3,6-Thioanhydro sugar derivatives. An enantiospecific synthesis of (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane as the key intermediate for thioswainsonine

Methyl 2-O-benzyl-3,6-thioanhydro-α-D-mannopyranoside ( 9 ) was obtained in eight steps from the commercially available methyl α-D-glucopyranoside. Compound 9 was transformed into (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane ( 14 ) by acid hydrolysis of its 2,4-di-O-benzyl derivative 10 followed by reaction of the not isolated 2,4-di-O-benzyl-3,6-thioanhydro-D-mannose ( 11 ) with ethoxycarbonylmethylenetriphenylphosphorane to give an = 1:1 E/Z mixture of the corresponding α,β-unsaturated ester ( 12 ). Finally, catalytic hydrogenation of 12 to ethyl (R)-4-benzyloxy-4-[(2′R)3′R,4′S)-3′-benzyloxy-4′-hydroxythiolan-2′-yl]butanoate ( 13 ) and subsequent reduction with lithium aluminum hydride gave the title compound 14 .