An alternative total synthesis of bolivianine

An alternative total synthesis of bolivianine in twelve steps is herein reported on the basis of our previous successful bioinspired total synthesis. The present total synthesis features straightforward transformation from an aldol product to the butenolide of the target molecule, and stereoselective DielsAlder cycloaddition to construct ring E, as well as the final spontaneous IMHDA process.     

Asymmetric total synthesis of clavolonine

The asymmetric total synthesis of clavolonine (1) has been achieved based on chiral auxiliary multiple-use methodology. Our synthetic route features stereoselective transformations on the cyclohexane ring utilizing the steric environment of the chiral auxiliary and an intramolecular Mannich reaction to construct the fused ring system.     

A highly stereoselective synthesis of the C10–C31 (BCDEF ring) portion of pinnatoxin A

An efficient, highly stereoselective synthesis of the C10–C31 (BCDEF ring) portion of pinnatoxin A has been achieved utilizing tandem double hemiketal formation/intramolecular hetero-Michael addition to construct the 6,5,6-dispiroketal (BCD ring) system and subsequent intramolecular ketalization to form the 5,6-bicycloketal (EF ring) system as key steps.     

Convergent synthesis of the E'FGH' ring fragment of ciguatoxin 1B via an acetylene cobalt complex strategy

[reaction: see text] A convergent synthesis of the E'FGH' ring fragment of ciguatoxin has been accomplished through (i) coupling between the E' ring-acetylide and the H' ring-aldehyde, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (iii) conversion to a carbonyl function, and (iv) reductive hydroxy-ketone cyclization to construct the G ring.     

Total Synthesis of Notoamides F,I, and R and Sclerotiamide

The total synthesis of the natural indole alkaloids (+)‐notoamide F, I, and R and (?)‐sclerotiamide is described. The four heptacyclic compounds were synthesized in 10–12 steps in a convergent and highly stereoselective manner from the readily available Seebach acetal. Key steps of the synthesis include a stereoselective oxidative aza‐Prins cyclization to construct the bicyclo[2.2.2]diazaoctane, and a cobalt‐catalyzed radical cycloisomerization to create the cyclohexenyl ring.     

Total Synthesis of Notoamides F,I, and R and Sclerotiamide

The total synthesis of the natural indole alkaloids (+)‐notoamide F, I, and R and (−)‐sclerotiamide is described. The four heptacyclic compounds were synthesized in 10–12 steps in a convergent and highly stereoselective manner from the readily available Seebach acetal. Key steps of the synthesis include a stereoselective oxidative aza‐Prins cyclization to construct the bicyclo[2.2.2]diazaoctane, and a cobalt‐catalyzed radical cycloisomerization to create the cyclohexenyl ring.     

Enantioselective total synthesis of FR900482

The development of two approaches for the enantioselective total synthesis of FR900482 is described. A precursor for the formation of the benzazocine ring was assembled effectively by a modification of the Sonogashira coupling of an aryl triflate with a chiral acetylene unit derived from tartaric acid and the subsequent novel ketone formation via conjugate addition of pyrrolidine to the o-nitrophenylacetylene derivative. The first-generation approach to the key pentacyclic intermediate of our racemic total synthesis utilizes an intramolecular Mitsunobu reaction of an omega-hydroxynitrobenzenesulfonamide to form the benzazocine ring and a stepwise sequence to construct the hydroxymethyl group at the C(7) position. The key intermediate could be synthesized in optically pure form via formation of the characteristic hydroxylamine hemiacetal and a stereoselective epoxide formation. In the second-generation approach, the N-hydroxybenzazocine ring could be constructed directly from an omega-formylnitrobenzene derivative by intramolecular reductive hydroxylamination. The crucial stereoselective hydroxymethylation and the formation of the hydroxylamine hemiacetal could be performed efficiently by a one-pot sequence. After leading to the pentacyclic key intermediate, the total synthesis of (+)-FR900482 was accomplished by a modification of our protocol established in the racemic total synthesis. Stereochemical issues involved in the hydroxymethylation at the C(7) position and formation of the hydroxylamine hemiacetal are also discussed in detail.     

Regioselective epoxide ring opening. Steroselective synthesis of a tetrahydropyran ring

The stereoselective synthesis of a 2-substituted tetrahydropyran with adjacent alkoxy-bearing stereogenic centre is described. The key steps of this synthesis were the stereoselective epoxidation of an allylic alcohol and the regioselective epoxide ring opening by lithium aluminum hydride. The regio and stereoselective synthesis of a trihydroxyselenide and a trihydroxysulfide is also described. The latter compounds are not suitable for cyclization to tetrahydrofuran ring.     

Concise stereoselective synthesis of marine sesterterpene, 16-deacetoxy-12-epi-scalarafuran acetate and its 14-epimer via intramolecular Diels-Alder addition

The stereoselective synthesis of C12 oxygenated marine scalaranic sesterterpene 16-deacetoxy-12-epi-scalarafuran acetate and its 14-epimer were described. A highly stereoselective intramolecular Diels-Alder addition was designed as the key step to construct the ring D, and the absolute configurations of natural 16-deacetoxy-12-epi-scalarafuran acetate was supported by the X-ray diffraction analysis of single crystal of corresponding 16-deacetoxy-12-epi-scalarafuran.     

Enantioselective synthesis of trans-4-methylpipecolic acid

An asymmetric synthesis for the preparation of both enantiomers of trans-methylpipecolic acids is described. It is based on Sharpless epoxidation as a chirality source, regioselective ring opening with allylamine, and ring-closing metathesis to construct the piperidine ring. The stereogenic center at C-4 is set by stereoselective hydrogenation that is directed by the alcohol functionality of an intermediate and proceeds with good diastereomeric control (trans/cis 16/1). Crystallization of the Boc-protected amino acid afforded the target products with excellent chemical (98% de) and enantiomeric purity (99% ee).     

Stereoselective total synthesis of xyolide

A stereoselective total synthesis of xyolide is described employing MacMillan α-hydroxylation, Steglich esterification, and ring closing metathesis as key steps. The use of organocatalytic MacMillan α-hydroxylation to construct two of the chiral centers of the xyolide makes this approach attractive.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Asymmetric Total Synthesis of Propindilactone G,Part 2: Enantioselective Construction of the Fully Functionalized BCDE Ring System

The enantioselective synthesis of the fully functionalized BCDE tetracyclic ring system of propindilactone G ( A ) is reported. Several synthetic methods were developed and applied to achieve this goal, including: 1) an asymmetric Diels–Alder reaction in the presence of Hayashi′s catalyst for the synthesis of optically pure key intermediate 3 ; 2) an intramolecular Pauson–Khand reaction (PKR) for the stereoselective synthesis of the BCDE ring with an all‐carbon chiral quaternary center at the C13 position by using the TMS‐substituted acetylene as the substrate; and 3) Pd‐catalyzed reductive hydrogenolysis for the stereoselective synthesis of the fully functionalized BCDE tetracyclic ring system. The chemistry developed herein provided a greater understanding of the total synthesis propindilactone G ( A ) and its analogues.     

Total synthesis and biological evaluation of neodysiherbaine A and analogues

Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.     

Stereoselective total synthesis of dihydrocorynantheol

[reaction: see text] A stereoselective synthesis of the indole alkaloid dihydrocorynantheol (1) from indole-3-acetic acid has been achieved by a sequence involving 9 as a key intermediate. The synthesis of the unsaturated lactam ring in 9 highlights a series of catalytic organometallic reactions featuring two ring-closing metatheses and a zirconocene-catalyzed carbomagnesation. Since no protecting groups were used, the present synthesis of 1 is exceedingly concise, consisting of only eight distinct operations.     

Convergent synthesis of the E'FGH ring fragment of ciguatoxin 1B via an acetylene cobalt complex strategy

A convergent synthesis of the E'FGH ring fragment 28 of ciguatoxin 1B, a principal toxin causing widespread seafood poisonings "ciguatera", has been accomplished through (i) coupling between the E' ring-acetylide 9 and the H ring-aldehyde 20, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (iii) conversion to a carbonyl function under high-pressure hydrogenation, and (iv) reductive hydroxyketone cyclization to construct the G ring. In the (1)H NMR analysis of 28 at room temperature, a considerable broadening phenomenon was observed due to the slow conformational changes of the FG ring, as reported for natural ciguatoxin 1B. When measured in pyridine at -20 degrees C, the spectra of 28 exhibited a 3.5:1 mixture of two conformational isomers (UP and DOWN conformers).     

Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-α-methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expansion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine intermediate that was transformed into (+)-lentiginosine.     

Iminium Ion Cascade Reactions: Stereoselective Synthesis of Quinolizidines and Indolizidines

A novel iminium ion cascade reaction has been developed that allows for the stereoselective synthesis of a variety of substituted aza-fused bicycles. The combination of amino allylsilanes and aldehydes (or ketones) was used to synthesize a number of quinolizidines and indolizidines in a one-pot reaction sequence. This technology has been used to effect the facile syntheses of several indolizidine and quinolizidine natural products including (±)-epilupinine, (±)-tashiromine, and (−)-epimyrtine. Substrate scope has been examined varying the type of amino allylsilanes (primary, secondary, and conjugated) and carbonyl compounds (aldehydes and ketones) to give a variety of fused ring structures. Varying the components chosen allows for the inclusion of synthetically useful functional groups at different positions on the core structure. The methodology has been used to construct the tricyclic core structures present in the cylindricine family and halichlorine.     

Synthetic studies on (+)-manzamine A: stereoselective synthesis of the tetracyclic core framework

The stereoselective synthesis of the tetracyclic intermediate 3 for (+)-manzamine A (1) has been achieved. The key features of this stereoselective synthesis of 3 are the Rh-catalyzed asymmetric hydrogenation and a diastereoselective intermolecular Diels-Alder reaction. The 8-membered ring is efficiently constructed utilizing our Ns-strategy.     

Expedient enantioselective synthesis of the δ4-oxocene cores of (+)-laurencin and (+)-prelaureatin (‡)

An expedient enantioselective synthesis of the Δ(4)-oxocene cores present in (+)-laurencin and (+)-prelaureatin was accomplished in eight steps via a novel one-pot regio- and stereoselective ring cyclization-fragmentation-expansion cascade from the tetrahydrofuran precursors which were prepared by stereocontrolled cyclization from vinylsilanes. This process is highlighted by an intramolecular oxo-carbenoid insertion and a β-silyl fragmentation sequence.