Enantioselective total synthesis of peloruside A: a potent microtubule stabilizer

An enantioselective total synthesis of (+)-peloruside A (1) is described. Peloruside A (1) is a potent microtubule stabilizer with significant clinical potential. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C24 segment 3 by a novel aldol protocol followed by Yamaguchi macrolactonization of the resulting seco-acid, selective methylation of hemi-ketal and removal of the protecting groups to peloruside A.     

Total synthesis and biological evaluation of (-)-apicularen A and its analogues

The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10-C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-, and C10-C11 dehydrated apicularen A 3-5 were also prepared. Cytostatic activities of (-)-apicularen A and the three analogues for three different cancer cell lines are described.     

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the AB-spiroacetal segment

The convergent synthesis of the C1-C15 AB-spiroacetal subunit of altohyrtin A/spongistatin 1 is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc(2)BCl mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.     

Total Synthesis of Mycalolides A and B through Olefin Metathesis

An asymmetric total synthesis of the trisoxazole marine macrolides mycalolides A and B is described. This synthesis involves the convergent assembly of highly functionalized C1–C19 trisoxazole and C20–C35 side‐chain segments through the use of olefin metathesis and esterification as well as Julia–Kocienski olefination and enamide formation as key steps.     

Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement.

A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.     

Studies on a urea-directed Stork-Crabtree hydrogenation. Synthesis of the C1-C9 subunit of (+)-zincophorin

A detailed account on the stereoselective synthesis of the C1-C9 subunit of (+)-zincophorin is described here. This approach features the first application of a stereoselective inverse electron demand hetero-[4 + 2] cycloaddition of chiral allenamides in natural product synthesis. The C1-C9 subunit matches Cossy's intermediate, thereby constituting a formal total synthesis. In addition, details of an unusual urea-directed Stork-Crabtree hydrogenation observed during these efforts are also disclosed here.     

Stereoselective formal total synthesis of (+)-methynolide

A highly stereoselective and convergent formal total synthesis of (+)-methynolide is described. The salient features of this synthesis have been the construction of the C1-C7 and C8-C11fragments via a desymmetrization approach, Sharpless asymmetric epoxidation of an allyl alcohol, respectively, and linkage of both the fragments by Nozaki-Hiyama-Kishi reaction.     

Formal total synthesis of borrelidin: synthesis of C1-C11 fragment via desymmetrization strategy

A stereoselective formal total synthesis of borrelidin is described. The synthetic strategy for synthesis of C1-C11 fragment features desymmetrization of Diels-Alder adduct, Sharpless asymmetric epoxidation, regioselective opening of chiral epoxide, and alkylation using Evans chiral auxiliary.     

Total synthesis of (+)-lysergic acid

A stereocontrolled total synthesis of (+)-lysergic acid (1) is achieved using three metal-catalyzed methodologies for the construction of three key rings. Highlights of the synthesis include Pd-catalyzed indole synthesis to form the B ring, a RCM reaction to form the D ring, and an intramolecular Heck reaction to form the C ring.     

Synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-b]pyrazines by palladium catalyzed amidation of 2-chloro-3-amino-heterocycles

A facile synthesis of imidazo[4,5-b]pyridines and -pyrazines is described using a Pd-catalyzed amide coupling reaction. This reaction provides quick access to products with substitution at N1 and C2. A model system relevant to the natural product pentosidine has been demonstrated, as well as the total synthesis of the mutagen 1-Me-5-PhIP.     

Total Synthesis of (−)‐Lundurine A and Determination of its Absolute Configuration

A 15‐step total synthesis of (?)‐lundurine A ( 1 ) from easily accessible (S)‐pyrrolidinone 18 is reported. A Simmons‐Smith reaction allows the efficient, simultaneous assembly of the cyclopropyl C ring, the six‐membered D ring, the seven‐membered E ring, and the quaternary carbon stereocenters at C2 and C7. The absolute configuration of natural (?)‐lundurine A was deduced to be 2R,7R,20R based on the stepwise construction of the stereocenters during the total synthesis.     

Total Synthesis of Aplydactone by a Conformationally Controlled C−H Functionalization

A concise, protecting-group-free total synthesis of the unusual brominated sesquiterpene aplydactone is described. Our synthesis features a [2+2] photocycloaddition, a Wolff ring contraction, an unusual remote C−H functionalization to establish the highly strained tetracyclic core, and a hydrogen-atom transfer (HAT) reaction to access the bromine-containing stereocenter. A finely tuned conformation of the α-diazoketone precursor is the key for the success of the late-stage transannular C−H insertion to deliver a bridged six-membered ring and a quaternary stereocenter (C6) between two quaternary carbon atoms (C1 and C7).     

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.     

A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins)

A practical second-generation synthesis of an advanced intermediate in our total synthesis of altohyrtin C (spongistatin 2) has been developed. A new approach to the C1-C15 (AB) portion features a vinyllithium addition to an aldehyde followed by a palladium-catalyzed allylic reduction to install the troublesome C13-C15 segment. Our general approach to the C16-C28 (CD) spiroketal has been retained, but some improvements have been made. Most notably, the kinetically controlled CD-spiroketalization reaction now proceeds in high yield with excellent diastereoselection. This new strategy uses the anti-aldol coupling used in our first-generation synthesis to join AB and CD fragments. A total of 9.6 g of intermediate 57 has been produced using this improved route.     

Total synthesis of (-)-callystatin A

A total synthesis of the cytotoxic polyketide marine natural product callystatin A is described. The route features chiral allenylmetal additions to construct the polypropionate C15-22 segment and an sp(2)-sp(3) Suzuki coupling to join the C1-C11 and C12-C22 subunits.     

Total synthesis of hyacinthacine A1 and 3-epi-hyacinthacine A1

[reaction: see text] Total synthesis of hyacinthacine A(1) and its epimer at C3 is described. The synthesis includes a stereocontrolled carboazidation of a chiral allylsilane as a key step. C-Si bond oxidation and reduction of the azide, with ring-closure, complete the total synthesis, which establishes the absolute configuration of 3.     

(-)-Lytophilippine A: synthesis of a C1-C18 building block

The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d-galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%).     

Total synthesis of apoptolidin: construction of enantiomerically pure fragments

A general strategy for the total synthesis of the antitumor agent apoptolidin (1) is proposed, and the chemical synthesis of the defined key building blocks (4, 5, 6, 8, and 9) in their enantiomerically pure forms is described. The projected total synthesis calls for a dithiane coupling reaction to construct the C(20)-C(21) bond, a Stille coupling reaction to form the C(11)-C(12) bond, and a Yamaguchi macrolactonization to assemble the macrolide ring, as well as two glycosidation reactions to fuse the carbohydrate units onto the molecule. First and second generation syntheses to the required fragments for apoptolidin (1) are described.     

Total synthesis of (+)-tubelactomicin A. 2. Synthesis of the upper-half segment and completion of the total synthesis

[reaction: see text]. We have completed the total synthesis of natural (+)-tubelactomicin A (1), a 16-membered macrolide antibiotic. This Letter presents a highly efficient synthesis of the upper-half segment (C14-C24) and the completion of the total synthesis featuring a high-yielding Stille coupling for the connection of the upper-half and lower-half segments and Mukaiyama macrolactonization for the construction of the entire structure of 1.     

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.