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A new and efficient synthesis of the non-sedating histamine H1 receptor antagonist Bilastine is reported. The new route employs a convergent strategy, with a longest linear sequence of five steps, giving slightly improved yields over the previous routes. The use of anhydrous metal-halogen exchange, hazardous ethylene oxide, and a tedious protection of the carboxylic acid function are all avoided.

The complexity and low tractability of antibiotic macrolides pose serious challenges to addressing the problem of resistance through semi- or total synthesis. Here we describe a new strategy involving the preparation of a complex yet tractable macrocycle and the transformation of this macrocycle into a range of erythronolide congeners. These compounds represent valuable sectors of erythromycinoid structure space and constitute intermediates with the potential to provide further purchase in this space. The routes are short. The erythronolides were prepared in three or fewer steps from the macrocycle, which was prepared in a longest linear sequence of 11 steps.

The first total synthesis of (+)-7-bromotrypargine, a β-carboline alkaloid from Ancornia sp. is reported. The synthesis proceeds in nine steps, eight steps longest linear sequence, in 36.9% overall yield. Biological characterization found that (+)-7-bromotrypargine is a H3 antagonist, and a selective inhibitor of the dopamine transporter (DAT) and norepinephrine transporter (NET), without inhibiting the serotonin transporter (SERT). Moreover, unlike electron rich congeners, (+)-7-bromotrypargine is not cytotoxic and thus represents an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries for the synthesis of unnatural analogues.

Concise and protecting-group-free total syntheses of the marine oxylipins hybridalactone (1) and three members of the ecklonialactone family (2-4) were developed. They deliver these targets in optically pure form in 14 or 13 steps, respectively, in the longest linear sequence; five of these steps are metal-catalyzed and four others are metal-mediated. The route to either 1 or 2-4 diverges from the common building block 22, which is accessible in 7 steps from 2[5H]furanone by recourse to a rhodium-catalyzed asymmetric 1,4-addition reaction controlled by the carvone-derived diene ligand 35 and a ring-closing alkene metathesis (RCM) catalyzed by the ruthenium indenylidene complex 17 as the key operations. Alternatively, 22 can be made in 10 steps from furfural via a diastereoselective three-component coupling process. The further elaboration of 22 into hybridalactone as the structurally most complex target with seven contiguous chiral centers was based upon a sequence of cyclopropanation followed by a vanadium-catalyzed epoxidation, both of which were directed by the same free hydroxy group at C15. The macrocyclic scaffold was annulated to the headgroup by means of a ring-closing alkyne metathesis reaction (RCAM). In response to the unusually high propensity of the oxirane of the targeted oxylipins for ring opening, this transformation had to be performed with complexes of the type [(Ar(3)SiO)(4)Mo≡CPh][K·OEt(2)] (43), which represent a new generation of exceedingly tolerant yet remarkably efficient catalysts. Their ancillary triarylsilanolate ligands temper the Lewis acidity of the molybdenum center but are not sufficiently nucleophilic to engage in the opening of the fragile epoxide ring. A final semireduction of the cycloalkyne formed in the RCAM step to the required (Z)-alkene completed the total synthesis of (-)-1. The fact that the route from the common fragment 22 to the ecklonialactones could follow a similar logic showcased the flexibility inherent to the chosen approach.

The marine macrolide bryostatin 7 is prepared in 20 steps (longest linear sequence) and 36 total steps. A total of 5 C-C bonds are formed using hydrogenative methods. The present approach represents the most concise synthesis of any bryostatin reported, to date, setting the stage for practical syntheses of simplified functional analogues.

The second-generation enantioselective total synthesis of aspergillide C, a new type of 14-membered macrolide isolated from a marine-derived fungus, has been accomplished in a longest linear sequence of 15 steps from a chiral building block in 19% overall yield employing the 6-exo-trig transannular oxy-Michael reaction as the key step.

The asymmetric total synthesis of (−)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing l-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet–Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection–deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.

A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps.

The first and highly efficient total synthesis of (−)-brevisin has been achieved. The title compound was synthesized in only 29 steps (longest linear sequence) from commercially available starting materials. The synthesis provided over 70 mg of a marine polycyclic ether compound.

Racemic and optically active 4-hydroxy-2-hydroxymethyl-1,7-dioxaspiro[5.5]undecanes were prepared in six steps from butane-1,2,4-triol and valerolactone with the longest linear sequence being four steps.

Asymmetric total synthesis of bryostatin 16 was achieved in 26 steps in the longest linear sequence and in 39 total steps from aldehyde 10. A Pd-catalyzed alkyne−alkyne coupling was employed for the first time as a macrocyclization method in a natural product synthesis. A route to convert bryostatin 16 to a new family of bryostatin analogues was developed. Toward this end, 20-epi-bryostatin 7 was synthesized from a bryostatin 16-like intermediate; the key step involves a Re-catalyzed epoxidation/ring-opening reaction. Preliminary biological studies indicated that this new analogue exhibits nanomolar anti-cancer activity against several cancer cell lines.

A unique and practical synthetic sequence for rapid access to polyketides and to further the spiroacetals derived from them, which utilizes a bidirectional Hosomi-Sakurai allylation approach around key allylsilanes in the synthesis of the AB and CD ring systems of spongistatin 1 and 2, is reported. The synthesis of the AB spiroacetal 9 requires 13 steps, with a longest linear sequence of seven steps in an overall yield of 27%. The synthesis of the CD spiroacetal 13 requires 15 steps, with a longest linear sequence of 11 steps in an overall yield of 30%. Both syntheses start from but-3-enol.

The search for the causitive agent for Paederis dermatitis, an inflammatory condition that results from contact with beetles of the Paederis family, resulted in the isolation of pederin (1).[1] Pederin subsequently inspired a substantial wave of investigation that led to the determination of its correct structure,[2] the observation of its potent cytotoxicity,[3] the postulation of protein synthesis inhibition as its likely mode of biological activity,[4] the identification of the 60S subunit of the ribosome as its potential biological target,[5] and the establishment of bacterial symbionts as its true biogenetic source.[6] Pederin’s interesting biological activity and challenging structural features have spawned significant synthetic efforts, resulting in several total, formal, and analog syntheses.[7] A noteworthy advance in pederin accessibility was recently disclosed by Rawal,[7f] who reported that pederin could be prepared through a 12 step (longest linear sequence) route. In accord with our interest in the pederin family of molecules,[8] we report our total synthesis of 1. In addition to the brief linear sequence, this approach highlights the utility of a late stage multicomponent construction of the N-acylaminal structure that allows for the efficient construction of analogs with structural variation in each of three distinct subunits.

Streptolydigin is a highly potent, broad-spectrum antibiotic produced by Streptomyces lydicus, which inhibits bacterial RNA polymerase. We describe the first synthesis of streptolydigin, which was assembled in a highly convergent and fully stereocontrolled fashion with a longest linear sequence of 24 steps starting from commercially available precursors. The assembly process entailed preparation of fully elaborated streptolic and ydiginic subunits of the natural product, followed by a highly efficient union in a three-step one-pot procedure, which included Dieckmann cyclization with a concomitant imide opening, Horner-Wadsworth-Emmons olefination, and desilylation.

Racemic and optically active 4-hydroxy-2-hydroxymethyl-1,7-dioxaspiro[5.5]undecanes were prepared in six steps from butane-1,2,4-triol and valerolactone with the longest linear sequence being four steps.

The isolation and structural characterization of architecturally novel and biologically important natural products is often followed by a flurry of synthetic activity. The indolo[2,3-a]carbazoles K252a (1) and staurosporine (2)' have been no exception, and several papers describing possible synthetic routes and derivatizations of the natural material have ap~ e a r e d . ~ . ~ In addition, four approaches to the naturally occuning aglycon K252c (3a, also known as staurosporinone) have been Classified by the last covalent bond(s) formed, these approaches include cycloaromatization (A)? double nitrene C-H insertion (B,B'),4b nitrene C-H insertion (B'),k,d and maleimide reduction (C) (see Scheme l)!e-g In this communication we report the development of a unique approach to 3 wherein coupling of diazolactam 4' and 2,2'-biindole (5)* initiates cycloaromatization to form bond D.9 Application of this strategy allows efficient access to both the parent aglycon (3a) and the selectively protected derivative (3c) employed in the total synthesis reported herein. Overall, preparation of the enantioenriched furanose 6 and aglycon unit 3c and their conversion to 1 require only 11 synthetic operations with a longest linear sequence of seven steps. The feasibility of our carbenoid approach to 3 was initially assessed by reaction of 4a (1.0 equiv) with indole (3.0 equiv) in the presence of catalytic Rhz(OAc)4 (0.01 equiv, Scheme 2). After only 12 h, TLC analysis indicated complete consumption of 4, and standard workup and isolation procedures furnished 71° in 65% yield. Similar conditions proved ineffective for the coupling of 4a with 5, and it was only after considerable

The first total synthesis of the natural product (+)-K252a (2) has been achieved in 12 steps from commercially available materials, with a longest linear sequence of seven steps and an overall yield of 21%. The synthetic strategy employs novel rhodium carbenoid chemistry in the construction of both the indolocarbazole aglycon (4) and the carbohydrate moiety (9).

A highly convergent total synthesis of macrolactin A (1) utilizes modern asymmetric catalytic C–C coupling methods. The longest linear sequence in the route is 16 steps with an average yield of 86% per step. This total synthesis is valuable, because 1, which has been shown to possess activity against HIV, is not readily accessible from its natural source, a taxonomically unclassified deep-sea bacterium.

OSW-1 (1), an acylated disaccharide cholestane saponin from Ornithogalum saudersiae with exceptionally potent antitumor activity, was first synthesized from commercially available dehydroisoandrosterone, L-arabinose, and D-xylose in total 27 steps with the longest linear sequence of 14 steps and in 6% yield.

An effective total synthesis of (−)-callystatin A (1), member of the leptomycin family of antibiotics, has been achieved. The synthesis features Evans extended aldol methodology to construct the northern polypropionate subunit and two separate Julia olefinations to assemble the conjugated dienes. The total synthesis proceeded in 2.3% overall yield with the longest linear sequence of 15 steps.

A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C(1)-C(6) (7), C(9)-C(16) (8), and C(17)-C(24) (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.

The total synthesis of (-)-macrolactin A, a 24-membered macrolide, has been achieved using a newly developed 1,3-diol synthon for the introduction of two key stereogenic centers. The synthon was derived from sequential use of the Noyori asymmetric reduction followed by chiral sulfoxide methodology. Tellurium-derived cuprate organometallics offered an efficient and highly stereoselective means for installation of the C8 Z/E-diene, while the C15 E/E-segment was derived from a Julia-Lythgoe olefination. Yamaguchi lactonization was used to secure the macrocycle in a convergent approach with the longest linear sequence of 19 steps from Noyori alcohol 6.

The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route. Our final synthesis involves no step requiring cryogenic (-25 degrees C) conditions; comprises a total of four steps, only three of which are in the longest linear synthesis; and features the use of two consecutive iron-catalyzed Friedel-Crafts substitutions.

The chinensiolides are a family of guaiane type alpha-methylene gamma-lactone natural products recently isolated from Ixeris chinensis Nakai, a plant used in Chinese folk medicine. The first enantioselective total synthesis of (+)-chinensiolide B was accomplished in 15 steps for the longest linear sequence with an overall yield of 6.7% starting from inexpensive and readily available (R)-carvone. A highly stereoselective and E/Z-selective tandem allylboration/lactonization reaction between two highly functionalized partners was exploited as a key step. The synthesis also highlights several solutions to chemoselectivity issues arising from the reactive alpha-methylene gamma-lactone. For instance, a ring-closing metathesis formed the requisite seven-membered ring in a chemoselective fashion while avoiding the reactivity of the conjugated alpha-methylene unit.

A short, highly convergent total synthesis of racemic isostrychnine, and thus strychnine, has been completed. The route involves 14 steps in the longest linear sequence and is highlighted by a cobalt-mediated [2 + 2 + 2]cycloaddition of an alkynylindole nucleus to acetylene.

A short and highly stereoselective synthesis of (-)-nakadomarin A has been developed using combinations of catalyst-controlled bond formations, one-pot multistep procedures, and powerful route-shortening reaction cascades. Several unprecedented chemical transformations were developed, including a highly Z-selective, eight-membered-ring-forming intramolecular Julia-Kocienski reaction, a highly diastereoselective intramolecular furan/iminium ion cyclization, and a sulfonic acid-controlled Z-selective macrocyclic ring-closing metathesis. In conjunction with a diastereoselective nitro olefin Michael addition under bifunctional organocatalysis and a nitro-Mannich/lactamization cascade, these transformations allowed the construction of this architecturally complex natural product in significant quantities in 12 steps (longest linear sequence) from commercially available starting materials.

An enantioselective total synthesis of (+)-cassiol is reported. The complex derived from Pd2(pmdba)3 and enantiopure t-BuPHOX ligand catalyzes enantioconvergent decarboxylative alkylation to generate the quaternary carbon stereocenter at an early stage. The overall synthetic strategy involves a convergent late-stage coupling of two fragments. The synthesis features a longest linear sequence of eight steps.

A concise total synthesis of neopeltolide macrolactone has been accomplished in 14 steps in the longest linear sequence, 15 steps overall from commercially available materials. The present synthesis was highlighted by successful exploitation of ether transfer methodology and a radical cyclization reaction to directly establish the requisite stereochemistry of the tetrahydropyran core.

An enantioselective total synthesis of (+)-cassiol is reported. The complex derived from Pd(2)(pmdba)(3) and enantiopure t-BuPHOX ligand catalyzes enantioconvergent decarboxylative alkylation to generate the quaternary carbon stereocenter at an early stage. The overall synthetic strategy involves a convergent late-stage coupling of two fragments. The synthesis features a longest linear sequence of eight steps.

The enantioselective formal synthesis of the polyketide marine natural product (-)-clavosolide A is presented. The construction of the beta-C-glycoside subunit is highlighted by a one-pot oxocarbenium cation formation/reduction sequence. Yamaguchi dimerization afforded the diolide aglycon in 18 steps (longest linear sequence).

[structure: see text] Xerulin, an inhibitor of cholesterol biosynthesis, has been synthesized from commercially available (E)-1-bromopropene, acetylene, and propynoic acid in five steps (longest linear sequence) in 30% overall yield and >96% stereoselectivity. The preparation of (E)-iodobromoethylene and its use in the Pd-catalyzed cross coupling are two of the novel aspects of the synthesis reported herein.

The first total synthesis of bulbophylol-B (1) has been achieved with the longest linear sequence of 12 steps and an overall yield of 17.9% via a new and practical approach to construct the dihydrodibenz[b,f]oxepin skeleton employing Wittig, selective reduction, and intramolecular Ullmann reactions as key steps.

The first total synthesis of (-)-achilleol B was achieved using a convergent approach with a longest linear sequence of 14 steps. Three key steps were employed, including an enantioselective Robinson annelation for the construction of the bicyclic moiety. The monocyclic synthon was prepared through a Ti(III)-mediated cylization of a chiral monoepoxide obtained via asymmetric dihydroxylation of geranylacetone. The asymmetric preparation of these subunits also permitted us to achieve the enantioselective synthesis of elegansidiol, achilleol A, and farnesiferol B.

A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa−Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.

Synthesis of the C9-C28 subunit of didemnaketal B has been developed. This subunit was convergently prepared from four chiral synthons and at the longest linear sequence required 16 steps.

A modular synthesis of the marine natural product largazole and related synthetic analogs is described. Largazole was prepd. in 10% overall yield through a synthetic route with a longest linear sequence of nine steps. Activity tests showed the necessity of the thiobutenyl moiety for antiproliferative activity.

Routiennocin is a member of a family of polycyclic pyrrole ether antibiotics that simultaneously uncouple oxidative phosphorylation and inhibit ATPase as a result of selective complexation of divalent metal ions. We describe a concise synthesis of routiennocin with the longest linear sequence of 8 steps. Our synthesis features a unique bi-directional strategy, which entails a sequential ring-opening/cross metathesis of a highly strained cyclopropenone acetal. This approach enables rapid and highly convergent assembly of the fully extended polyketide subunit of this natural product from readily available homoallylic alcohol precursors.

ZACA-lipase-catalyzed acetylation tandem process has been shown to proceed satisfactorily with either TBS-protected 4-penten-1-ol or 3-buten-1-ol to provide the corresponding enantiomerically pure (R)-2-ethyl-1-alkanols. Either (R)-5 or (R)-6 was converted to 3 in seven steps. The other fragment 4 was synthesized in nine steps from (-)-(S)-citronellol. Conversion of 3 and 4 into 99% pure fluvirucinine A1 was achieved in four steps via amidation-ring closing metathesis, the overall yield in the longest linear sequence being 34% (13 steps).

Triterpene seco-glycosides constitute a small family of the plant saponins which feature a terminal seco-saccharide appendage deriving supposedly from oxidative scission of a monosaccharide unit. Herein, we have developed synthetic approaches for the first time to the access to these molecules. Betavulgaroside III (1), a representative congener occurring in Beta vulgaris and Achyranthes fauriei, is successfully synthesized in a total of 31 steps with L-arabinose, D-glucose, and oleanolic acid as starting materials. The longest linear sequence requires 23 steps and in an overall 0.9% yield (from D-glucose). The synthesis features oxidative elaboration of the seco-saccharide unit prior to assembly of the triterpene 3,28-bisglycoside. This tactic has been proven superior, in the attempts to the synthesis of the more easily accessible 2 ''-epi-betavulgaroside III (2), to that employing oxidative cleavage of the terminal saccharide unit at an advanced triterpene 3,28-bisglycoside scaffold.

Lobatoside E, a novel and complex cyclic triterpene saponin showing potent antitumor activities, has been synthesized for the first time, employing a highly modular approach. The synthesis, starting with oleanolic acid, D-glucose, D-galactose, L-arabinose, and L-rhamnose, requires a total of 73 steps, with the longest linear sequence of 31 steps and in 1.2% overall yield.

A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa−Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.

(S,R,R,S,R,S)-4,6,8,10,16,18-Hexamethyldocosane (1) was synthesized in 11% yield in 11 steps in the longest linear sequence fromor =98% pure (S)-beta-citronellal and 6 additional steps for the preparation of 11 in 23% yield from propene. Five of the six asymmetric carbon centers were generated catalytically and stereoselectively by the ZACA reaction (5 times), one lipase-catalyzed acetylation, and two chromatographic operations.

ZACA-lipase-catalyzed acetylation tandem process has been shown to proceed satisfactorily with either TBS-protected 4-penten-1-ol or 3-buten-1-ol to provide the corresponding enantiomerically pure (R)-2-ethyl-1-alkanols. Either (R)-5 or (R)-6 was converted to 3 in seven steps. The other fragment 4 was synthesized in nine steps from (-)-(S)-citronellol. Conversion of 3 and 4 into 99% pure fluvirucinine A1 was achieved in four steps via amidation-ring closing metathesis, the overall yield in the longest linear sequence being 34% (13 steps).

An efficient and practical total synthesis of aigialomycin D 1 is described. This concise synthetic route features the use of readily available starting materials with the key transformations being the formation of the macrocycle by RCM under microwave irradiation conditions to effect complete E-selectivity, and regio- and stereospecific formation of the 1′,2′-double bond. The synthesis of aigialomycin D is achieved with the longest linear sequence of only 11 steps and an overall yield of 19%.

The cytotoxic title compd. (-)-cribrostatin 4 (I) was synthesized from five readily available starting materials in a longest linear sequence of 21 steps and 4.3% overall yield. The key step in the construction of the pentacyclic core of I was a domino sequence involving beta elimination and an intramol. phenolic Mannich reaction. [on SciFinder (R)]

The total synthesis of a new member of the pederin family of natural products, psymberin 1, was accomplished. Using a recently reported novel and efficient PhI(OAc)2 mediated oxidative entry to 2-(N-acylaminal)-substituted tetrahydropyrans as the key step, this total synthesis was executed in a convergent and efficient manner. The longest linear sequence of this synthesis was 22 steps starting from known 6.

A highly convergent total synthesis of macrolactin A (1) utilizes modern asymmetric catalytic C–C coupling methods. The longest linear sequence in the route is 16 steps with an average yield of 86% per step. This total synthesis is valuable, because 1, which has been shown to possess activity against HIV, is not readily accessible from its natural source, a taxonomically unclassified deep-sea bacterium.

The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments.

[Structure: see text] The total synthesis of the marine diolide (-)-clavosolide A has been achieved in 17 steps (longest linear sequence) from commercially available crotonaldehyde exploiting the Petasis-Ferrier union/rearrangement tactic to construct the requisite aglycon monomer. A one-pot esterification/lactonization employing the Yamaguchi protocol, followed by bis-glycosidation, furnished (-)-clavosolide A.

[reaction: see text] (+)-Epolactaene was synthesized in 14 steps in the longest linear sequence. The synthesis is highlighted by a highly efficient preparation of the lactone intermediate 4, which only requires three steps from the commercially available (S)-3-butyn-2-ol. It also features a fully stereocontrolled synthesis of the intermediate 9, which was constructed through the use of Zr-catalyzed methylalumination of alkynes and a series of Pd-catalyzed organozinc cross-coupling reactions, such as homopropargylation, direct ethynylation, and alkenylation of the methyl ester of (Z)-alpha-iodocrotonic acid (3).