A facile synthesis of the basic steroidal skeleton using a Pauson-Khand reaction as a key step

A high-yield synthesis of steroid-type molecules under mild reaction conditions is achieved in two steps involving nucleophilic addition of alkynyl cerium reagent to an easily enolizable carbonyl compound (beta-tetralone) followed by an intramolecular Pauson-Khand reaction.     

Total synthesis of cruentaren B

A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C11 benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C7-C8 bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C12-C20 polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C21-C28 tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an SN2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.     

Asymmetric total syntheses of (-)-jorumycin, (-)-renieramycin G, 3-epi-jorumycin, and 3-epi-renieramycin G

The total synthesis of (-)-jorumycin (1) and (-)-renieramycin G (2) has been accomplished in 25 and 23 steps, respectively, from 5-benzyloxy-2,4-dimethoxy-3-methyl-benzyl alcohol. The synthesis features a substrate-tunable stereoselective intramolecular Pictet-Spengler-type reaction for the construction of the key pentacyclic core of both targets, bearing either the natural configuration or the epimeric configuration at C-3. With access to a C-3 epi-pentacyclic framework, 3-epi-jorumycin (32) and 3-epi-renieramycin G (34) were also successfully synthesized. Furthermore, preliminary biological evaluation of 3-epi-jorumycin (32), in addition to relevant synthetic intermediates, revealed that significant cytotoxicity had been retained in these compounds. Therefore, these early studies constitute the basis for a new structure activity relationship (SAR) investigation for this class of antitumor antibiotics.     

Total synthesis of pamamycin-649B

The first total synthesis of the macrodiolide antibiotic pamamycin-649B (1) was achieved by using sultone methodology. The diethyl substituted larger hydroxy acid fragment was constructed in a concise fashion through domino elimination/alkoxide-directed 1,6-additions of ethyllithium to sultones derived from intramolecular Diels-Alder reaction of furan-containing vinylsulfonates. Intermolecular Yamaguchi esterification of the two hydroxy acid building blocks and subsequent Yamaguchi cyclization eventually provided the target macrocycle 1. Since the final lactonization with formation of the ester linkage between C1' and the C8 oxygen proceeded with complete C2' epimerization, the more readily available C2' epimeric smaller fragment could be used to streamline the synthetic sequence.     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

Total synthesis of (+)-nafuredin-γ using a highly stereoselective Ti-mediated aldol reaction

An efficient total synthesis of (+)-nafuredin-γ has been achieved in 10 steps from (E)-3-(tributylstannyl)propenal. The synthesis features direct construction of an anti-1,2-diol moiety via a Ti-mediated aldol reaction of lactyl derivative and rapid fragment assembly, which relied on well-established Pd chemistry.     

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.     

Synthesis of the C7-26 fragment of amphidinolides G and H

A new approach to the synthesis of the C7-26 fragment of amphidinolides G and H was developed. In the sequence, the C7-18 portion of this fragment was synthesized using an acetylide coupling protocol, while an Evans alkylation and Sharpless asymmetric dihydroxylation were employed as key steps in construction of the C19-26 subfragment. Finally, both of these units were joined by utilizing an aldol coupling reaction to produce the target C7-26 fragment in good yield.     

Enantioselective total synthesis of the potent antitumor agent (-)-mucocin using a temporary silicon-tethered ring-closing metathesis cross-coupling reaction

The enantioselective total synthesis of the annonaceous acetogenin (-)-mucocin (1) was accomplished using a triply convergent 12-step sequence (longest linear sequence) in 13.6% overall yield. This represents the first application of the temporary silicon-tethered (TST) ring-closing metathesis (RCM) cross-coupling reaction and the enantioselective alkyne/aldehyde addition to the synthesis of a complex annonaceous acetogenin. Moreover, all three fragments required for the coupling reactions are conveniently prepared in 5-6 steps from two readily available enantiomerically enriched epoxides. Finally, this synthesis stimulated the development of a new approach for the construction of 3-hydroxy-2,6-disubstituted tetrahydropyrans, using the bismuth tribromide-mediated reductive etherification reaction, which represents a motif that is prevalent in a wide range of pharmacologically significant natural products.     

Total Synthesis and Biological Assessment of Mandelalide A

A new convergent total synthesis of the marine macrolide mandelalide A ( 1 ) has been developed that is based on macrocyclic ring closure by a Shiina‐type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross‐coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid‐catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the α‐ and β‐AD‐mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A ( 1 ) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK‐N‐SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 μm ).     

The total synthesis of (--)-lemonomycin

The first total synthesis of the novel glycosylated tetrahydroisoquinoline antitumor antibiotic (-)-lemonomycin has been accomplished (15 steps from 9). The highly convergent synthesis relies on a key asymmetric dipolar cycloaddition to set the stereochemistry of the aglycone core, a Suzuki fragment coupling to connect the diazabicycle to the aryl subunit, and a stereoselective Pictet-Spengler reaction that incorporates the aminoglycoside subunit directly into the core structure without the need for late-stage glycosylation or protecting group manipulations. The novel aminoglycoside was prepared using a highly diastereoselective Felkin-controlled acetate aldol addition reaction to a threonine-derived ketone.     

Total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor

The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the beta-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs.     

Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: total synthesis of (+)-wailupemycin B

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19 % yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18 % yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59 % yield) the cyclohexanone 28 was obtained in five steps (54 % yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53 % yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5).     

Efficient synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F

The synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F was achieved by using a vinyloguous Mukaiyama aldol reaction on a chiral aldehyde with a silyloxyfuran and by using a C-glycosylation of a lactol derivative with an acetyl oxazolidinethione. From the available chiral acetonide-glyceraldehyde, all the stereogenic centers were perfectly induced along the synthesis. The C(1)-C(9) fragment was synthesized as a vinyl stannane at C(9) in 10 steps, with 16% yield.     

Iodine-promoted five-component reaction using fragment assembly strategy to construct dihydrooxepines

An iodine-promoted fragment assembly strategy for the synthesis of fused heterocycles has been established. It provides an efficient route to construct pyrazolone-oxepine-pyrazoles from phenylhydrazines, aryl methyl ketones and acetoacetate esters. Notably, acetoacetate esters play two distinct pivotal roles in the five-component reaction by realizing the unique reactivities of methyl, methylene and carbonyl groups to construct 3-methyl-5-pyrazolone skeletons and by the reaction of methyl and carbonyl groups to form a C (sp3)-O bond.     

Synthesis of the C1-C16 fragment of ionomycin using a neutral (eta3-allyl)iron complex

Key steps in the synthesis of the C1-C16 polyketide fragment of ionomycin were the nucleophilic addition of an organocuprate to a neutral (eta3-allyl)iron complex and the construction of a beta-diketone moiety by the Rh-catalysed rearrangement of an alpha-diazo-beta-hydroxyketone.     

Enantioselective Total Synthesis of (+)‐Steenkrotin A and Determination of Its Absolute Configuration

The first enantioselective total synthesis of (+)‐steenkrotin A has been achieved in 18 steps and 4.2 % overall yield. The key features of the strategy entail a Rh‐catalyzed O?H bond insertion followed by an intramolecular carbonyl‐ene reaction, two sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations, and a cascade intramolecular aldol condensation/vinylogous retro‐aldol/aldol process with inversion of the relative configuration at the C7 position. The absolute configuration of (+)‐steenkrotin A was determined based on the stepwise construction of the stereocenters during the total synthesis.     

Stereoselective synthesis of the C15-C26 fragment of the antitumor agent (-)-dictyostatin

The synthesis of the C15-C26 fragment of (-)-dictyostatin is reported in 10 steps and 28% overall yield. The key steps are the two stereoselective sulfoxide-directed processes: a Reformatsky-type reaction and a β-keto sulfoxide reduction.     

Concise and stereoselective synthesis of the N7-C25 fragment of psymberin

[reaction: see text] The N7-C25 fragment of the potent and selective cytotoxic agent psymberin has been prepared through a short (12 linear steps, 15 total steps) and stereoselective sequence. Highlights of this route include a very rapid construction of the pentasubstituted arene, a substrate-controlled diastereoselective fragment coupling using a Mukaiyama aldol reaction, and an efficient entry into a key tetrahydropyranyl cyanide.     

A concise route to the right wing of ciguatoxin

A concise route to the HIJKLM-ring fragment 10 of ciguatoxin (CTX) and 51-hydroxyCTX3C was developed in which oxiranyl anion addition and intramolecular carbonyl olefination were utilized as key transformations. The present procedure requires only 23 steps from the I-ring 5, while 35 steps were employed in a previous synthesis of the corresponding right wing 11 of CTX3C. The high efficiency of the present synthesis ensures a supply of 10 for total synthesis and biomedical applications.