Total Synthesis and Biological Evaluation of (+)‐Gambieric Acid A and Its Analogues

In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B‐ring exocyclic enol ether 32 was prepared through a Suzuki–Miyaura coupling of the B‐ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A‐ring by using diastereoselective bromoetherification as the key transformation. Suzuki–Miyaura coupling of 32 with acetate‐derived enol phosphate 49 , followed by ring‐closing metathesis of the derived diene, produced the D‐ring. Subsequent closure of the C‐ring through a mixed thioacetalization completed the synthesis of the A/BCD‐ring fragment 8 . The A/BCD‐ and F′GHIJ‐ring fragments (i.e., 8 and 9 ) were assembled through Suzuki–Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven‐membered F′‐ring. After the oxidative cleavage of the F′‐ring, the E‐ring was formed as a cyclic mixed thioacetal (i.e., 70 ) and then stereoselectively allylated by using glycosylation chemistry. Ring‐closing metathesis of the diene 3 thus obtained closed the F‐ring and completed the polycyclic ether skeleton. Finally, the J‐ring side chain was introduced by using a Julia–Kocienski olefination in the presence of CeCl₃ to complete the total synthesis of gambieric acid A ( 1 ), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.     

Modular Total Synthesis of (–)‐Palmyrolide A and (+)‐(5S,7S)‐Palmyrolide A via Ring‐Closing Metathesis and Alkene Isomerization†

A pentamodule assembly approach has been established for total synthesis of the naturally occurring (–)‐palmyrolide A and (+)‐5,7‐epi‐palmyrolide A. By using the racemic tert‐butyl carbinol‐containing alkyl iodide, the two diastereoisomeric macrolides could be obtained from the same sequence of reactions, demonstrating the flexibility of the multimodule assembly strategy for diverted total synthesis.     

Total Synthesis of (−)‐Enigmazole A

Total synthesis of (?)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone.     

Organocatalytic,Asymmetric Total Synthesis of (−)‐Haliclonin A

The first total synthesis of the alkaloid (?)‐haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3‐alkenyl cyclohex‐2‐enone to set the stereochemistry of the all‐carbon quaternary stereogenic center. The synthesis also features a Pd‐promoted cyclization to form the 3‐azabicyclo[3,3,1]nonane core, a SmI₂‐mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.     

The Total Synthesis of (−)‐Nitidasin

Nitidasin is a pentacyclic sesterterpenoid with a rare 5‐8‐6‐5 carbon skeleton that was isolated from the Peruvian folk medicine “Hercampuri”. It belongs to a small class of sesterterpenoids that feature an isopropyl trans‐hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans‐hydrindanone, followed by chemoselective epoxidation, ring‐closing olefin metathesis, and redox adjustment.     

Total Synthesis and Biological Evaluation of the Antibiotic Lysocin E and Its Enantiomeric,Epimeric, and N‐Demethylated Analogues

Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid‐phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N‐demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.     

Total Synthesis and Structural Revision of (+)‐Uprolide G Acetate

The first, asymmetric total synthesis of the proposed structure of (+)‐uprolide G acetate (UGA) is reported, and the spectral properties of the synthetic compound clearly differed from those reported for natural UGA. On the basis of comprehensive analysis of the NMR data, two possible structures for the natural UGA were proposed and their total synthesis achieved, thus leading to the identification and confirmation of the correct structure and absolute configuration of the natural UGA. This synthesis was enabled by development of a novel synthetic strategy, which revolved around three key cyclization reactions: an Achmatowicz rearrangement, Sharpless asymmetric dihydroxylation/lactonization, and ring‐closing metathesis. These synthetic studies pave the way for further studies on this class of structurally unusual cytotoxic cembranolides.     

Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation

Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.     

Total Synthesis of (+)‐Dibromophakellin

Two members of a family of pyrrole–imidazole marine alkaloids, (+)‐dibromophakellin and the nonnatural congener (+)‐phakellin, were synthesized enantioselectively from 4‐hydroxy‐L ‐proline. The chiral aminal at C10 was constructed efficiently by means of an Overman‐type [3,3] sigmatropic rearrangement of an enamide (see scheme).

     

Concise Synthesis and Biological Assessment of (+)‐Neopeltolide and a 16‐Member Stereoisomer Library of 8,9‐Dehydroneopeltolide: Identification of Pharmacophoric Elements

We describe herein a concise synthesis of (+)‐neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond‐forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross‐metathesis reaction directed by H‐bonding, and a ring‐closing metathesis conducted under non‐high dilution conditions. Moreover, we developed a 16‐member stereoisomer library of 8,9‐dehydroneopeltolide to systematically explore the stereostructure–activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF‐7 human breast adenocarcinoma, HT‐1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure–activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.     

Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

A highly stereoselective and efficient total synthesis of trans‐dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester–enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six‐ring vinylogous ester intermediate, which is generated from the γ,δ‐unsaturated ester functional group of the Claisen rearrangement product in an efficient three‐step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel–Crafts‐type cyclization to form the B ring via an isocyanate intermediate derived from an N‐Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N‐Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.