Efficient N-heterocyclic carbene-catalyzed O- to C-acyl transfer

[reaction: see text] An N-heterocyclic carbene promotes the rearrangement of alpha-amino acid derived O-acyl carbonates to their corresponding C-acylated isomers, generating a C-C bond and a quaternary stereocenter with high efficiency, under mild reaction conditions and with low catalyst loadings.     

The first example of enantioselective allyl transfer from a linear homoallylic alcohol to an aldehyde

[reaction: see text] The first example of enantioselective linear homoallylic alcohol transfer reaction was revealed. In all cases, the whole rearrangement is thermodynamically favorable and a steric effect is the driving force of this reaction. The preservation of the stereocenter and olefin geometry together with the isolation of gamma-adduct homoallylic alcohols in one isomeric form have warranted the proposed mechanism.     

Enantioselective total synthesis of (-)-dactylolide

[reaction: see text] The enantioselective total synthesis of (-)-dactylolide is reported. The absolute stereochemistry of the tetrahydropyran was established by catalytic asymmetric Jacobsen hetero-Diels-Alder reaction. The remote C19 stereocenter was introduced by a sequence of chelation-controlled Grignard addition and Ireland-Claisen rearrangement.     

Approach to the synthesis of cladiell-11-ene-3,6,7-triol

[reaction: see text] The synthesis of an advanced intermediate in the synthesis of the title compound has been achieved. Key steps include an Ireland-Claisen rearrangement to install the C7 tertiary alcohol stereocenter, an SN2' reaction of an alkoxymethyl Cu reagent, and a diastereoselective Re-catalyzed allylic alcohol transposition.     

Reductive Asymmetric Aza-Mislow-Evans Rearrangement by 1,3,2-Diazaphospholene Catalysis**

1,3,2-diazaphospholene hydrides (DAP−H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus-enolate provides a potential platform for reductive α-functionalizations. In this respect, asymmetric C-heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2-diazaphospholene-catalyzed three-step cascade reaction of N-sulfinyl acrylamides comprised of conjugate reduction, [2,3]-sigmatropic aza-Mislow-Evans rearrangement and subsequent S−O bond cleavage. The obtained enantio-enriched α-hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo-defined P-bound N,O-ketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α-carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAP−H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow-Evans processes.     

Platinum-catalyzed tandem diboration/asymmetric allylboration: access to nonracemic functionalized 1,3-diols

[reaction: see text] A single-pot tandem catalytic diene diboration/carbonyl allylation reaction is described that uses a commercially available chiral diboron reagent. The chirality of the intermediate diboration adduct is transferred to the product in the carbonyl allylation reaction, thereby providing access to enantioenriched chiral products. Notably, the reaction allows for construction of a quaternary stereocenter and furnishes a synthetically versatile C-B bond in the reaction product.     

Synthesis of (+)-conagenin

An efficient total synthesis of (+)-conagenin was achieved. The right fragment of conagenin, alpha-methylserine containing a quaternary stereocenter attached to nitrogen, was synthesized using allyl cyanate-to-isocyanate rearrangement. The left fragment, 2,4-dihydroxy-3-methylpentanoic acid, has three contiguous stereogenic centers, which was efficiently constructed by enantioselective monoreduction of 2-alkyl-1,3-diketones reported by Cossy, and chelation-controlled stereoselective reduction of beta-hydroxy ketone. These two fragments were coupled through intramolecular amide bond formation with high efficiency.     

A synthetic approach to diverse 3-acyltetramic acids via O- to C-acyl rearrangement and application to the total synthesis of penicillenol series

For the efficient approach to medicinally important α-branched 3-acyltetramic acids, the key reaction of O- to C- acyl rearrangement using α-amino-acid-derived 4-O-acyltetramic acids was extensively examined in the presence of various metal salts. Use of CaCl(2) or NaI dramatically changed the results in the reaction efficiency and rapidly brought about the desired α-branched 3-acyltetramic acids in markedly improved yields. We also discuss an epimerization at C5 stereocenter under the rearrangement conditions as well as the tolerance for structural variation at C3 and C5. In addition to the preceding success in the total synthesis of new cytotoxic tetramic acid, penicillenol A(1), this methodology could be also applied to the first total synthesis of penicillenol A(2).     

A concise route to the C3–C23 fragment of the macrolide palmerolide A

A concise route to the C3–C23 part of the macrolide palmerolide A was developed. This part features the 7,10,11-trihydroxy sector containing the 8E-double bond as well as the 14,16-diene subunit. The stereocenter at C-7 originated from a Noyori reduction on alkynone 8. The substrate 16 containing an enyne was obtained via a Claisen rearrangement. The vicinal diol at C10,C11 was created by a Sharpless asymmetric dihydroxylation. After selective protecting group manipulations the propargylic alcohol was reduced with Red-Al to the E-alkylic alcohol 26. The conjugated diene in the fragment 40 resulted from a Stille cross-coupling reaction between the vinylstannane derived from alkyne 30 and the vinyl iodide 39. The latter could conveniently be prepared by an aldol/Wittig strategy.     

Stereoconvergent palladium-catalyzed carbonylation of both E and Z isomers of a 2-trifloxy-1,3-butadiene

[reaction: see text] Carbonylation of the illustrated Z-tetrasubstituted enol triflate followed by tandem silyloxy-Cope rearrangement leads to the CP-263, 114 core ring system with the all-carbon quaternary stereocenter intact in 46% yield. Subjection of the corresponding E isomer to the same conditions gives the same product in 56% yield. This observation is explained by a mechanism involving isomerization of a pi-allyl palladium species involving an allenic intermediate.     

Michael Initiated Ring Closure (MIRC) reaction on in situ generated benzylidenecyclohexane-1,3-diones for the construction of chromeno[3,4-b]quinoline derivatives

One-pot synthesis of chromeno[3,4-b]quinoline derivatives have been achieved in good yields through Michael Initiated Ring Closure (MIRC) by employing three-component condensation of aromatic aldehydes, 3-aminocoumarins, and cyclic 1,3-diketones in the presence of catalytic amount of p-toluenesulfonic (p-TSA) acid in ethanol under reflux condition. The salient features of this protocol are: simple reaction procedure, shorter reaction time, good yields, avoidance of aqueous work-up, and column-chromatographic separation. The merit of this process is highlighted by its high bond efficiency of producing three new bonds and one stereocenter in a single operation.     

Stereoselective olefin isomerization leading to asymmetric quaternary carbon construction

Chemo- and stereoselective Ir(I)-catalyzed isomerization of 1,1-disubstituted and trisubstituted allylic ethers and in situ [3,3] sigmatropic rearrangement of the resulting allyl vinyl ethers provide for the highly stereoselective construction of quaternary carbon stereocenters. The olefin isomerization-Claisen rearrangement (ICR) sequence allows adjacent quaternary-tertiary stereocenter relationships to be established with excellent diastereoselection. Several complementary strategies for enantioselective quaternary carbon synthesis derive directly from the ICR reaction design.     

A divergent and selective synthesis of isomeric benzoxazoles from a single N-Cl imine

A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-hydroxyaryl N-H ketimines is described. The reaction proceeds in two distinct pathways through a common N-Cl imine intermediate: (a) N-O bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole, respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the rearrangement and the electron-deficient rings favoring the N-O bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl migration for the formation of 2-substituted benzoxazole is proposed.     

Copper-Catalyzed Enantioselective Doyle–Kirmse Reaction of Azide-Ynamides via α-Imino Copper Carbenes

[2,3]-Sigmatropic rearrangement reaction involving sulfonium ylide (Doyle–Kirmse reaction) generated from metal carbenes represents one of the powerful methods for the construction of C(sp³)−S and C−C bonds. Although significant advances have been achieved, the asymmetric versions via the generation of sulfonium ylides from metal carbenes have been rarely reported to date, and they have so far been limited to diazo compounds as metal carbene precursors. Here, we describe a copper-catalyzed enantioselective Doyle–Kirmse reaction via azide-ynamide cyclization, leading to the practical and divergent assembly of an array of chiral [1,4]thiazino[3,2-b]indoles bearing a quaternary carbon stereocenter in generally moderate to excellent yields and excellent enantioselectivities. Importantly, this protocol represents a unique catalytic asymmetric Doyle–Kirmse reaction via a non-diazo approach and an unprecedented asymmetric [2,3]-sigmatropic rearrangement via α-imino metal carbenes.     

Enantioselective synthesis of a PKC inhibitor via catalytic C-H bond activation

[reaction: see text] The syntheses of two biologically active molecules possessing dihydropyrroloindole cores (1 and 2) were completed using rhodium-catalyzed imine-directed C-H bond functionalization, with the second of these molecules containing a stereocenter that can be set with 90% ee during cyclization using chiral nonracemic phosphoramidite ligands. Catalytic decarbonylation and direct indole/maleimide coupling provide efficient access to 2.     

环庚烷正离子重排反应的从头算研究

先采用HF方法,基组采用STO-3G,对环庚烷正离子的重排机理进行了初步粗略的从头算研究,较快地找到了反应过程中的部分过渡态。然后再采用MP2/3-21G方法精确计算了整个重排过程中的各个过渡态的几何构型、零点能,同时对反应路径也进行了计算,以作进一步的过渡态验证。得出的结论是:环庚烷正离子的重排是环的缩小过程,在生成甲基环己烷叔正碳离子的过程中,经历了2个过渡态;首先是C(1)C(7)的键长变长、C(1)C6的键长变短,β位H(20)逐渐远离与之相连的C(1),与C(7)形成化学键;然后是与C+相连的H(16)逐渐远离C+,与β位的C(1)形成化学键,产生稳定的甲基环己烷叔正碳离子椅式结构,甲基环己烷叔正碳离子还有可能进一步重排为一个含伯正碳离子的甲基环己烷结构,计算了每一步重排反应所需的活化能。     

Absolute configuration of anti-HIV-1 agent (-)-concentricolide: total synthesis of (+)-(R)-concentricolide

The first enantioselective total synthesis of (+)-(R)-concentricolide, the enantiomer of an anti-HIV-1 agent isolated from Daldinia concentrica, from 2-iodophenol in 7 steps reveals the (S)-configuration for the natural form of the furanophthalide. The key features include an anionic ortho-Fries rearrangement to furnish 3-iodosalicylamide, facile construction of the benzofuran system employing the tandem Sonogashira coupling annulation reaction, directed ortho metalation to introduce a propanoyl group, as well as CBS reduction, establishing the stereocenter enantioselectively.     

A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach

A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters.     

Total synthesis of epothilone A

[reaction: see text]Epothilones A (1) and B (2) are potent antitumor natural products with a Taxol-like mechanism of action. A total synthesis of epothilone A (1) is reported, which utilized chiral silane-based bond construction methodology to introduce the key C-6 and C-7 stereocenters of fragment 4. The C-15 stereocenter of fragment 5 was established by a lipase-mediated kinetic resolution. The fragments were assembled with a Suzuki coupling reaction and an aldol condensation and cyclized with a Yamaguchi-type macrolactonization reaction.