Synthesis of the C21-C34 fragment of antascomicin B

The C21-C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ireland-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 β-configuration. The fragment possesses 7 of the 11 fixed stereocenters contained in the natural product.     

An efficient synthesis of the carbocyclic core of zoanthenol

A concise strategy for the synthesis of the carbocyclic portion of zoanthenol is disclosed. The key step involves a 6-endo radical-mediated conjugate addition that constructs the quaternary stereocenter at C(12) and closes the B ring in a stereoselective manner. The synthesis of the C-ring fragment uses an enantioselective desymmetrization to simultaneously establish the absolute stereochemistry of two vicinal quaternary stereocenters. In only 17 steps from known compounds, the route affords an ABC ring system containing all three quaternary stereocenters and appropriate functionality to complete the synthesis of zoanthenol.     

Stereoselective synthesis of the cis-275B decahydroquinoline ring system

The Diels-Alder precursor was constructed from readily available d-glutamic acid utilizing a series of functional group transformations. The stereocenter of the amino acid provided the desired stereochemistry at C2 and diastereoselectively directed the intramolecular Diels-Alder cyclization. This simultaneously generated the three remaining stereocenters and yielded a bicyclic intermediate with all four stereocenters of the target decahydroquinoline 275B.     

Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C22-C34 fragment of the molecule

A stereoselective synthesis of the C22-C34 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using d-quinic acid as the starting material and highly stereoselective aldol reactions were employed, as key steps, to build the remaining stereocentres at C23, C26 and C27.     

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.     

Total synthesis of herbimycin A

[structure: see text] Herbimycin A (HA) belongs to a class of antibiotics known as the benzoquinoid ansamycins. Members of this class have shown promising biological activity as Hsp90 inhibitors. An enantioselective synthesis of HA is described, employing asymmetric syn-crotylation methodology to introduce the C10, C11, C14, and C15 stereocenters. The C6-C7 stereocenters were introduced using Brown's alpha-pinene-derived gamma-methoxy allylborane reagent. The C12 stereocenter was established by diastereoselective hydroboration.     

Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C1-C21 fragment of the molecule

A stereoselective synthesis of the C1-C21 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using, as key steps, highly stereoselective Aldol reactions to build the C1-C17 fragment and a Nozaki-Hiyama-Kishi reaction to couple it with the remaining C18-C21 moiety.     

A synthesis of the C1-C15 domain of the halichondrins

A concise route to the C1-C15 domain of the halichondrins is described. The key reaction is the conversion of a furfuryl alcohol to a pyranone. The stereocenter of this pyranone serves as the starting point for the other eight stereocenters.     

Enantioselective total synthesis of (+)-gigantecin: exploiting the asymmetric glycolate aldol reaction

The enantioselective synthesis of the potent, selective, cytotoxic, annonaceous acetogenin, (+)-gigantecin, has been completed. An asymmetric glycolate aldol serves to establish the stereocenters at C13,14 and at C21,22. A Carreira asymmetric acetylide addition is used to establish the C17 stereocenter.     

A concise,selective synthesis of the polyketide spacer domain of a potent bryostatin analogue

[reaction: see text] A concise, asymmetric synthesis of the polyketide spacer domain portion (C1-C13) of a highly potent bryostatin analogue was developed. The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters, while a substrate directed syn reduction sets the C9 stereocenter. The spacer domain 1 is obtained in 10 steps with a 25% overall yield and is readily incorporated into the synthesis of 2.     

Exploration of the enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters

Quaternary stereocenters on a 2-cyclohexen-1-one ring are synthesized with good to excellent levels of enantioselectivity. The quaternary stereocenter is created through a new synthetic sequence involving three reactions: the enantioselective Birch reduction-allylation, enol ether hydrolysis, and the Cope rearrangement. To illustrate the ability of the sequence to enantioselectively generate complex structures, a variety of substrates are described. Notably, the sequence works for the enantioselective generation of vicinal quaternary-tertiary stereocenters, the generation of congested arylic quaternary stereocenters, and hydroxyalkyl substituted quaternary stereocenters.     

A concise total synthesis of (+/-)-1-epiaustraline

[reaction: see text] A concise total synthesis of 1-epiaustraline 3 is described that utilizes a diastereoselective Birch reduction of an electron-deficient pyrrole and a chelation-controlled vinyl Grignard addition to an aldehyde to introduce the C7 stereocenter. The C1 and C2 stereocenters were set through an OsO(4)-catalyzed dihydroxylation.     

Stereoselective synthesis of pyrrolidine derivatives via reduction of substituted pyrroles

The heterogeneous catalytic hydrogenation of highly substituted pyrrole systems was studied. These aromatic systems could be fully reduced with excellent diastereoselectivity to afford functionalized pyrrolidines with up to four new stereocenters. It is likely that the reaction is a two-step hydrogenation sequence, and that initial reduction of the C=X bond provides a stereocenter that directs the subsequent reduction of the pyrrole.     

Asymmetric synthesis of naturally occurring (−)-seimatopolides A and B

Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E-selective cross metathesis (CM) reaction between two suitable fragments followed by macrolactonization reaction is the main highlight of our synthesis for the two natural products. The fragment containing 6S,7S,9R stereocenters for seimatopolide A has been synthesized from l-tartaric acid as a chiral pool starting material, by employing (R)-CBS-mediated stereoselective keto reduction reaction. Another fragment, which is common for both the molecules, containing the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B has been prepared from n-decanal by adopting (R)-CBS-mediated keto reduction and Brown asymmetric allylation reaction.     

Enantioselective Total Synthesis of (+)‐Flavisiamine F via Late‐Stage Visible‐Light‐Induced Photochemical Cyclization

The structural features Kopsia alkaloids, in particular multiple all‐carbon quaternary stereocenters in a caged and strained polycyclic skeleton, poses particular challenges for enantioselective total synthesis. Herein, we reported the first total synthesis of (+)‐flavisiamine F. The synthetic approach involved a room‐temperature Overman rearrangement for introducing the chiral amine at C21, a TMS‐promoted ketal Claisen rearrangement for constructing the all‐carbon quaternary stereocenter at C20, and a late‐stage visible‐light‐induced photochemical cyclization for establishing the all‐carbon quaternary stereocenter at C7.     

Stereoselective synthesis of the C(1)-C(11) fragment of peloruside A

A highly stereoselective synthesis of the C(1)-C(11) fragment 4 of peloruside A has been accomplished via a stereoselective double allylboration and an intramolecular epoxide opening to provide the functionally dense C(3)-C(11) segment 14. A glycolate aldol reaction was then employed to introduce the remaining stereocenters at C(2)-C(3). [reaction: see text]     

Solution-phase parallel synthesis with oligoethylene glycol sorting tags. Preparation of all four stereoisomers of the hydroxybutenolide fragment of murisolin and related acetogenins

The principles of the oligoethylene glycol (OEG) mixture synthesis are illustrated with the synthesis of all four possible stereoisomers of a hydroxybutenolide fragment common to murisolin and many other acetogenins. Modified dimethoxybenzyl groups with varying numbers of OEG units (-CH2CH2O-) are used to protect alcohols and serve as codes for configurations at two stereocenters. The encoded isomers are carried through several steps in a sequence of mixing prior to the reaction and then demixing during the separation to give individual pure products. A new tagging scheme is introduced in which a stereocenter bearing a hydroxy group is given two different tags. These initially redundant tags then serve to encode the configuration of another (untagged) stereocenter by appropriate pairwise reactions of the tagged precursors. The experimental features (reaction, analysis, separation, and characterization) of OEG mixture synthesis are detailed and are compared to and contrasted with those of fluorous mixture synthesis.     

Total synthesis of (+/-)-bipinnatin J

[reaction: see text]. The total synthesis of (+/-)-bipinnatin J was achieved through a concise route that features the use of a silver ion promoted S(N)1-type gamma-alkylation of a siloxyfuran and a diastereoselective Cr(II)-mediated macrocyclization to provide bipinnatin J (1), wherein the remote furanone stereocenter at C10 induced the relative stereochemistry of the two additional stereocenters.     

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C−C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C−C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities. In comparison to the previous method for the construction of tertiary and quaternary stereocenters via carbene gem-difunctionalization reactions, this reaction features an unprecedented gem-dialkylation process via sequential installation of two C−C bonds on the carbene center in one reaction, providing an essential complement to the asymmetric construction of all-carbon quaternary stereocenters using common and readily available starting materials.     

Synthetic studies on antascomicin A: construction of the C18-C34 fragment

Stereoselective synthesis of the C18-C34 fragment of antascomicin A is described. Construction of the C27-C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson-Claisen rearrangement, which was converted to iodide 2 by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide 2 and sulfone 3 furnished the C18-C34 fragment.