Total Synthesis of Tiacumicin B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective β-Glycosylations

A total synthesis of tiacumicin B, a natural macrolide whose remarkable antibiotic properties are used to treat severe intestinal infections, is reported. The strategy is in part based on the prior synthesis of the tiacumicin B aglycone, and on the decisive use of sulfoxides as anomeric leaving groups in hydrogen-bond-mediated aglycone delivery (HAD). This new HAD variant permitted highly β-selective rhamnosylation and noviosylation. To increase convergence, the rhamnosylated C1–C3 fragment thus obtained was anchored to the C4–C19 aglycone fragment by adapting the Suzuki–Miyaura cross-coupling used for the aglycone synthesis. Ring-size-selective macrolactonization provided a compound engaged directly in the noviolysation step with virtually total β selectivity. The final efficient removal of all the protecting groups provided synthetic tiacumicin B.     

Total Synthesis of Tiacumicin B: Study of the Challenging β-Selective Glycosylations**

We give a full account of the total synthesis of tiacumicin B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicin B aglycone and on unique 1,2-cis-glycosylation steps. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly β-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. The rhamnosylated C1–C3 fragment was anchored to the C4–C19 aglycone fragment by a Suzuki–Miyaura cross-coupling. Ring-size-selective Shiina macrolactonization provided a semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total β-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicin B.     

Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure–activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high‐yielding intramolecular Suzuki cross‐coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one‐pot Corey–Peterson olefination and an ene–diene cross‐metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof.     

Stereoselective Synthesis of the Halaven C14–C26 Fragment from D‐Quinic Acid: Crystallization‐Induced Diastereoselective Transformation of an α‐Methyl Nitrile

Crystallization‐induced diastereoselective transformation (CIDT) of an α‐methyl nitrile completes an entirely non‐chromatographic synthesis of the halichondrin B C14–C26 stereochemical array. The requisite α‐methyl nitrile substrate is derived from D ‐quinic acid through a series of substrate‐controlled stereoselective reactions via a number of crystalline intermediates that benefit from a rigid polycyclic template. Therefore, all four stereogenic centers in the Halaven C14–C26 fragment were derived from the single chiral source D ‐quinic acid.     

Enantioselective Total Synthesis of (−)‐Hosieine A

The first total synthesis of (?)‐hosieine A was accomplished and features an unprecedented nitroso–ene cyclization to construct the 2‐azabicyclo[3.2.1]octane ring system. Phosphine‐enabled stereoselective bromohydrination provided interesting mechanistic insights into the anti‐Markovnikov process. Also noteworthy is the retention of stereochemistry at C9 in the facile radical debromination initiated by Et₃B/air.     

Chemoenzymatic Total Synthesis of (+)‐Galanthamine and (+)‐Narwedine from Phenethyl Acetate

The stereoselective total synthesis of unnatural (+)‐galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis‐cyclohexadi–enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)‐galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)‐galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds.     

Total Synthesis of (2Z)‐[(4R,5R,6S)‐6‐(β‐D‐Glucopyranosyloxy)‐4,5‐dihydroxycyclohex‐2‐en‐1‐ylidene]ethanenitrile,a Cyanoglucoside from Ilex warburgii

The total synthesis of the noncyanogenic cyanoglucoside 1 , originally isolated from Ilex warburgii, was achieved in nine steps (9% overall yield), starting from an optically pure Diels–Alder adduct ((+)‐ 3 ). The key step of the synthesis, the glycosidation, was carried out under Koenigs–Knorr conditions closely related to those developed for the total syntheses of (?)‐lithospermoside and (?)‐bauhinin. We had to tune the protecting groups used for the two free cis‐configured OH groups of the aglycone, which afforded the desired β‐d‐ glucoside intermediate 15 in very good yield (62%).     

Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B,Lipiarmycin A3)

Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug‐resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18‐membered macrolactone is reported herein. The key reactions include ring‐closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium‐sized fragments, thus leading to a flexible yet convergent synthetic route.     

Synthesis and Biophysical Studies on 35‐Deoxy Amphotericin B Methyl Ester

The use of molecular editing in the elucidation of the mechanism of action of amphotericin B is presented. A modular strategy for the synthesis of amphotericin B and its designed analogues is developed, which relies on an efficient gram‐scale synthesis of various subunits of amphotericin B. A novel method for the coupling of the mycosamine to the aglycone was identified. The implementation of the approach has enabled the preparation of 35‐deoxy amphotericin B methyl ester. Investigation of the antifungal activity and efflux‐inducing ability of this amphotericin B congener provided new clues to the role of the 35‐hydroxy group and is consistent with the involvement of double barrel ion channels in causing electrolyte efflux.     

Synthesis of Linear (Z)‐α,β‐Unsaturated Esters by Catalytic Cross‐Metathesis. The Influence of Acetonitrile

Kinetically controlled catalytic cross‐metathesis reactions that generate (Z)‐α,β‐unsaturated esters selectively are disclosed. A key finding is that the presence of acetonitrile obviates the need for using excess amounts of a more valuable terminal alkene substrates. On the basis of X‐ray structure and spectroscopic investigations a rationale for the positive impact of acetonitrile is provided. Transformations leading to various E,Z‐dienoates are highly Z‐selective as well. Utility is highlighted by application to stereoselective synthesis of the C1–C12 fragment of biologically active natural product (?)‐laulimalide.     

First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

We have accomplished the first total synthesis of an isomerically pure naphthoquinonopyrano‐γ‐lactone dimer, γ‐actinorhodin, in eleven steps. Two steps exploit pairs of peri‐MeO groups as unusual selectivity controls. The respective MeO groups convey the steric bulk of a bromo or iodo substituent located ortho to one MeO group as steric hindrance into the vicinity of the second MeO group. This relay effect was indispensable for exerting regiocontrol in an aromatic bromination and diastereocontrol in an oxa‐Pictet–Spengler cyclization. The absolute configuration of our target compound was established in an asymmetric Sharpless dihydroxylation of a β,γ‐unsaturated ester, which was synthesized in a Heck coupling of a bromoiodonaphthalene with ethyl vinylacetate. The dihydroxylation provided the γ‐hydroxylactone moiety of the bromonaphthalene that was used as the substrate in the oxa‐Pictet–Spengler cyclization. Dimerization to the core of γ‐actinorhodin occurred by two Suzuki couplings.     

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.     

Asymmetric Total Synthesis of (+)‐Ryanodol and (+)‐Ryanodine

(+)‐Ryanodine ( 1 ) is the ester derivative of 1H‐pyrrole‐2‐carboxylic acid and the complex terpenoid (+)‐ryanodol ( 2 ), which possesses eleven contiguous stereogenic centers on the ABCDE‐ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1 , the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3‐hydroxy group must be acylated in a site‐selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE‐ring 7 . Stereoselective construction of the C3‐secondary, C2‐ and C6‐tertiary alcohols was achieved by three nucleophilic reactions. The C9‐ and C10‐trisubstituted carbon centers were regio‐ and stereoselectively introduced by hydroboration/oxidation of the six‐membered C‐ring, which was formed by the ring‐closing metathesis reaction. Direct esterification of the C3‐alcohol with pyrrole‐2‐carboxylic acid proved unsuccessful; therefore, we developed a new, two‐step protocol for attachment of the pyrrole moiety. The C3‐hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3‐bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1 .     

Total Synthesis of Enantiopure Pyrrhoxanthin: Alternative Methods for the Stereoselective Preparation of 4‐Alkylidenebutenolides

A new stereocontrolled total synthesis of the configurationally labile C₃₇‐norcarotenoid pyrrhoxanthin in enantiopure form has been completed. A highly stereoselective Horner–Wadsworth–Emmons (HWE) condensation of a C₁₇‐allylphosphonate and a C₂₀‐aldehyde was used as the last conjunctive step. Both a Sonogashira reaction to form the C₁₇‐phosphonate and the final HWE condensation proved to be compatible with the sensitive C7–C10 enyne E configuration. Regioselective (5‐exo‐dig) silver‐promoted lactonization reactions of three alternative pent‐2‐en‐4‐ynoic acid precursors with increased complexity, including a fully functionalized C₂₀‐fragment, were explored for the preparation of the γ‐alkylidenebutenolide fragment. This survey extends the existing methodologies for the preparation of oxygen‐containing carotenoids (xanthophylls) and streamlines the synthesis of additional members of the C₃₇‐norcarotenoid butenolide family of natural products.     

Total Synthesis of (−)‐Haouamine B Pentaacetate and Structural Revision of Haouamine B

The enantiocontrolled total synthesis of (?)‐haouamine B pentaacetate was accomplished via an optically active indane‐fused β‐lactam, which was prepared by a newly developed Friedel–Crafts reaction. Subsequent cleavage of the β‐lactam and an intramolecular McMurry coupling reaction provided the core indane‐fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zubía.     

Total Synthesis of (−)‐Lithospermoside

The total synthesis of the naturally occurring noncyanogenic cyanoglucoside (?)‐lithospermoside ( 1 ) was achieved starting from optically pure oxatrinorbornenone (+)‐ 2 in 12 steps and 10% overall yield. The key step of the synthesis, the glycosidation, turned out to be very sensitive to steric hindrance, and we had, therefore, to optimize the choice of the protection used for the two other OH functions of the aglycone. Finally, the desired β‐D ‐glucoside 15 was obtained in a very good yield (72%) under Koenigs–Knorr‐glycosidation conditions, closely related to those used for the total synthesis of (?)‐bauhinin.     

Hydrogen Bond Mediated Aglycone Delivery: Synthesis of Linear and Branched α‐Glucans

A Hydrogen bond mediated aglycone delivery (HAD) method was applied to the synthesis of α‐glucans, which are abundant in nature, but as targets represent a notable challenge to chemists. The synthesis of linear oligosaccharide sequences was accomplished in complete stereoselectivity in all glycosylations. The efficacy of HAD may diminish with the increased bulk of the glycosyl acceptor, and may be an important factor for the syntheses of oligomers beyond pentasaccharides. The synthesis of a branched structure proved more challenging, particularly with bulky trisaccharide acceptors.     

Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

Total Synthesis of the Postulated Structure of Fulicineroside

A total synthesis of the proposed structures of fulicineroside and its aglycone fulicinerine is reported. The tetrasubstituted dibenzofuran substructure was accessible either through a Pd‐mediated ortho‐metalation or by an Ir‐catalyzed meta‐borylation. The synthesis of the β,β,α‐linked trisaccharide consisting of D ‐olivose, L ‐rhodinose, and L ‐rhamnose was challenged by the unprecedented β‐linked rhodinose. A Pd‐catalyzed β‐selective glycosylation of a 4‐epi‐rhodinose and a subsequent Mitsunobu inversion provided selectively the β‐linked L ‐rhodinose‐L ‐rhamnose disaccharide. Comparison with the reported data for the natural product and the aglycone suggests a misassignment of the structure of the natural product.     

Hydrogen‐Bond‐Mediated Aglycone Delivery (HAD): A Highly Stereoselective Synthesis of 1,2‐cis α‐D‐Glucosides from Common Glycosyl Donors in the Presence of Bromine

Described herein is the expansion of the picoloyl protecting‐group assisted H‐bond mediated aglycone delivery (HAD) method recently introduced by our laboratory. At first it was noticed that high α‐stereoselectivity is only obtained with S‐ethyl glycosyl donors and only in the presence of dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST), in high dilution, and low temperature. Combining the mechanistic studies of the HAD reaction and bromine‐promoted glycosylations allowed a very effective method to be devised that allows for highly stereoselective α‐glycosidation of practically all common leaving groups (S‐phenyl, S‐tolyl, S/O‐imidates) at regular concentrations and ambient temperature.