Total synthesis of (-)-martinellic acid via radical addition-cyclization-elimination reaction

The asymmetric total synthesis of martinellic acid, the first pyrrolo[3,2-c]quinoline alkaloid found in nature, is described. Three key steps in our synthesis of (-)-martinellic acid are the Bu(3)SnH-promoted radical addition-cyclization-elimination (RACE) reaction of an oxime ether with an alpha,beta-unsaturated ester to generate the pyrrolo[3,2-c]quinoline core, a chemoselective lactam carbonyl reduction, and guanidinylation under Mitsunobu reaction conditions. The key radical cyclization has also been investigated by using SmI(2). (-)-Martinellic acid was synthesized from commercially available methyl 4-bromo-3-methylbenzoate in fewer steps than previous syntheses and in an improved overall yield.     

Formal total synthesis of (±)-martinellic acid

A concise formal total synthesis of the pyrrolo[3,2-c]quinoline containing natural product, martinellic acid, has been achieved from a pyrroloquinol-2-one through addition of a copper acetylide to an iminium ion. Global deprotection and alkyne reduction then provides the tricyclic triamine, which can be converted to martinelline and martinellic acid.     

Total synthesis of (−)-incarvilline

An enantioselective synthesis of (−)-incarvilline is presented, employing a three-component coupling reaction and an intramolecular enone-olefin [2+2] photocycloaddition followed by a SmI₂-induced cyclobutane ring-opening reaction.     

Total synthesis of (−)-cleistenolide

The total synthesis of (−)-cleistenolide, a novel natural product recently isolated from the annonaceae species cleistochlamys kirkii oliver, is described. The synthesis proceeds starting from easily accessible d-manitol using a selective benzoylation, a selective acetonide deprotection, silylprotection and ring-closing metathesis reaction.     

Total synthesis of (−)-centrolobine

Stereoselective synthesis of (−)-centrolobine, an anti-Leishmania agent, was accomplished via an intramolecular Barbier-type reaction of iodo-ester with n- or t-butyllithium followed by Lewis acid-promoted Et₃SiH reduction of the resulting hemiacetal.     

Total synthesis of (−)-xanthatin

The first enantioselective total synthesis of xanthatin, a xanthanolide sesquiterpenoid exhibiting potent antibacterial activity against MRSA, has been accomplished from an optically pure bicyclic lactone, previously synthesized by our group.     

Total synthesis of (−)-muricatacin

A total synthesis of (−)-muricatacin has been achieved using a commercially available starting material and our furan approach to oxacyclic systems, the proven scope of which is thus broadened.     

Total synthesis of (−)-clavosolide A

The total synthesis of (−)-clavosolide A is achieved employing a radical-mediated route to build the substituted tetrahydropyran unit, a Yamaguchi reaction to construct the diolide aglycon and the Schmidt method for the final glycosidation step.     

Total synthesis of (−)-amathaspiramide F

The stereoselective total synthesis of the marine alkaloid, (−)-amathaspiramide F (1), was achieved from the α-hydroxy-α-ethynylsilane 2. The key steps involved in the synthesis were (1) the enolate Claisen rearrangement of the α-acyloxy-α-alkenylsilane for the stereoselective construction of the consecutive C5 and C9 chiral centers of 1 (erythro configuration), (2) the construction of aza-spirohemiaminal 28, and (3) dibromination during the final stage of the total synthesis. The reaction of the (Z)-α-acyloxy-α-alkenylsilane 22 possessing the Boc-homoallylglycine ester as the acyloxy group underwent stereoselective enolate Claisen rearrangement to give the desired erythro product 23. On the other hand, the reaction of the α-acyloxy-α-alkenylsilane (Z)-5 having Boc-proline gave the unexpected threo product 6. Oxidative cleavage of the vinylsilane group of 23 followed by treatment with heptamethyldisilazane as the methylamine equivalent gave aza-spirohemiaminal 28. The problematic regioselective dibromination to 28 was achieved using n-Bu₄NBrCl₂.     

Total synthesis of (−)-petrosiol E

(−)-Petrosiol E, a metabolite of sponge Petrosia strongylata, has been synthesized in 32% overall yield from cheap natural d-xylose in 10 steps. Our strategy provides an efficient way for the total synthesis of other petrosiol members, featuring the three contiguous stereogenic centers are easily constructed from d-xylose chiral template.     

Total synthesis of (−)-Englerin A

A novel and efficient total synthesis of Englerin A is reported. The synthesis featured an intramolecular olefin metathesis ring closure reaction and a highly stereoselective oxygen bridge formation induced by an iodonium ion. This strategy can be used for the synthesis of natural products Englerin A and Englerin B and can provide flexibility in the preparation of various 9-substituted analogues of Englerin A for further structure–activity relationship studies.     

Total synthesis of (−)-radicamine B

The synthesis of a chiral cyclic nitrone with l-arabino configuration and its application in the total synthesis of radicamine B is reported. An agreement in the spectral data with natural radicamine B but specific rotation with an opposite sign warranted a revision of the absolute configuration of radicamine B.     

Total synthesis of (−)-incarvilline and (−)-incarvillateine

An enantioselective, concise total synthesis of (−)-incarvilline and (−)-incarvillateine has been achieved in longest linear 9 steps (24.3% overall yield) and in 11 steps (16.5% overall yield) from (−)-carvone, respectively. The present synthesis features a notable Favorskii rearrangement of the O-protected chlorohydrin derivative of (−)-carvone to construct four of the five contiguous stereocenters on the bicyclic piperidine moiety and DMAP-catalyzed esterification of incarvilline with α-truxillic acid anhydride to generate incarvillateine skeleton.     

Total synthesis of (−)-baconipyrone C

A highly stereoselective asymmetric total synthesis of marine polypropionate (−)-baconipyrone C has been achieved. Utilization of desymmetrization technique to create five stereogenic centres, Sharpless epoxidation, Gilman's reaction and resolution of methyl group using enzyme PS-C is the highlight of the synthesis.     

A diastereodivergent strategy for the asymmetric syntheses of (−)-martinellic acid and (−)-4-epi-martinellic acid

Asymmetric syntheses of (−)-martinellic acid and (−)-4-epi-martinellic acid were achieved in 20 steps from commercially available starting materials using a diastereodivergent strategy. The conjugate addition of lithium (R)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (E)-3-[2′-(N,N-diallylamino)-5′-bromophenyl]propenoate and alkylation of the resultant β-amino ester with methyl bromoacetate were used as the key steps to install the C(9b) and C(3a) stereogenic centres, respectively. Subsequent cyclisation to the corresponding pyrroloquinolin-2-one and reduction of the C(4)-carbonyl group was followed by two complementary procedures for olefination and concomitant intramolecular Michael addition, which gave both C(4)-epimers of this tricyclic molecular architecture in >99:1 dr. Subsequent elaboration of these templates provided access to (−)-martinellic acid and, for the first time, (−)-4-epi-martinellic acid.     

Total synthesis of (−)-physovenine from (−)-3a-hydroxyfuroindoline

Total synthesis of calabar bean alkaloid (−)-physovenine (−)-3 has been achieved in a concise manner starting from optically active (−)-3a-hydroxyfuroindoline (−)-2, synthesized via modified Sharpless epoxidation of tryptophol 1. Our strategy involved a stereospecific radical substitution reaction and regioselective oxidation at the C5 position.     

Enantioselective synthesis of (−)-galantinic acid

An efficient enantioselective synthesis of (−)-galantinic acid 1, a non-proteogenic amino acid is described using Sharpless asymmetric epoxidation, dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfite as the key steps.     

Enantioselective synthesis of (−)-pinellic acid

An enantioselective convergent approach toward the total synthesis of pinellic acid 1 from 1,9-nonanediol is described. The synthetic strategy features iterative Sharpless asymmetric dihydroxylation, Sonogashira coupling and Birch reduction.     

Total synthesis of (+)-epiepoformin and (−)-phyllostine

An efficient asymmetric total synthesis of naturally occurring cyclohexeneoxides, (+)-epiepoformin and (−)-phyllostine has been achieved using the chiral building block available from the base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone. Since (−)-theobroxide was derived from the same precursor of (+)-epiepoformin, the formal total synthesis of (−)-theobroxide has also been achieved.     

Total synthesis of (S)-(−)-cyclooroidin

The first total synthesis of enantiopure (S)-(−)-cyclooroidin is described. Absolute configuration of this natural product has been confirmed by comparison of the optical rotation value of our synthetic sample with the one measured on natural cyclooroidin.