Asymmetric total synthesis of halicholactone.

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisallylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The use of RCM (ring-closing metathesis) methodology (4-->35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.     

A ring-closing metathesis approach to a synthesis of the B ring of eleutherobin

A short and efficient RCM route is reported for the construction of the key nine-membered B ring of eleutherobin starting from the readily available 1,2,5,6-diisopropylidene-d-glucose.     

Synthesis of cyclic α-hydrazino acids

Synthesis of five-, six-, seven-, eight-, and nine-membered cyclic α-hydrazino acids from a common starting material ‘diethylmalonate’ with 26, 16, 34, 13.5, and 13.33% overall yields is described. Sequential allylation or homoallylation and electrophilic amination followed by cyclization gave the desired rings. The methyl esters of eight- and nine-membered rings were synthesized by RCM and the corresponding free acids were generated after hydrolysis in the presence of 1 M BBr₃ solution in DCM.     

An expeditious route to eight- and nine-membered carbocycles based on a RCM-ring fragmentation strategy

The presence of a temporary one-atom internal tether in 1,9-deca- and 1,10-undecadienes allows their efficient ring-closing metathesis (RCM). Cleavage of the bridging tether of the resulting bicycles provides eight- or nine-membered carbocycles, medium-sized rings that are difficult to assemble using other currently available procedures.     

Synthesis of eight- and nine-membered carbocycles through a ring-closing metathesis/ring fragmentation strategy: a rapid and versatile approach to bicyclo[6.4.0]- and bicyclo[7.4.0]alkene ring systems

Ring-closing metathesis (RCM) of cis-2,6-dialkenyl-2-hydroxy-1-cyclohexanones affords bicyclo[3.n.1]alkenones that are easily converted into eight- or nine-membered carbocycles by oxidative cleavage of the keto-bridging tether. Since the starting cyclohexanones are readily assembled from commercially available 1,2-cyclohexanedione, the overall process constitutes a rapid and versatile route to medium-sized carbocycles, which are otherwise difficult compounds to assemble using currently available procedures. If one of the alkenes of the cyclohexanone chains is replaced by an alkyne, the subsequent RCM produces 1,3-diene systems capable of undergoing stereoselective Diels-Alder reaction with activated dienophiles. Oxidative cleavage of the keto bridge of the resulting tricycles leads to 8-6 and 9-6 fused bicarbocycles with up to four stereocenters.     

Asymmetric total synthesis and formal total synthesis of the antitumor sesquiterpenoid (+)-eremantholide A

[structure: see text]. A new asymmetric total synthesis of (+)-eremantholide A is reported in which a Hoveyda-Grubbs ring-closing metathesis (RCM) reaction is used to assemble the nine-membered oxonin ring, and an enolate alkylation between the 3(2H)-furanone 2 and O-triflate 3 is exploited for C(9)-C(10) bond construction. An Evans asymmetric aldol reaction and a Sharpless asymmetric epoxidation served to stereoselectively install the C(6), C(7), and C(8) stereocenters of the target structure.     

Enantioselective synthesis of [1,2]-oxazinone scaffolds and [1,2]-oxazine core structures of FR900482

Several chiral unsaturated [1,2]-oxazinone heterocycles have been synthesized by iridium-catalyzed allylic substitution and ring-closing metathesis (RCM) reaction in high yields with excellent enantiomeric excesses. In addition, the synthesis of [1,2]-oxazine core structures of FR900482 was achieved via iridium-catalyzed allylic substitution, followed by RCM and Heck reactions, respectively.     

A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics

The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI beta-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II beta turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-membered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic epsilon-lactam 12 closely agrees with the reference gamma-lactam 3 a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3 b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II beta turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.     

An Evans-Tishchenko-ring-closing metathesis approach to medium-ring lactones

A new approach to the synthesis of medium-ring lactones is reported based on sequential Evans-Tishchenko and ring-closing metathesis (RCM) reactions. High diastereoselectivity (>95:5) is demonstrated in the Evans-Tishchenko reaction of unsaturated aldehydes with unsaturated beta-hydroxy ketones, and conditions for the RCM cyclization of the resultant dienes have been optimized to give high yields of medium ring lactones. The synthetic utility of this sequence is demonstrated through generation of the fully functionalized core of octalactin A. [reaction: see text].     

Ring-closing metathesis of sulfoximine-substituted N-tethered trienes: modular asymmetric synthesis of medium-ring nitrogen heterocycles

A synthesis of sulfoximine-substituted medium-ring nitrogen heterocycles (MRNHs) having a high degree of substitution has been developed. Its key steps are the modular asymmetric synthesis of sulfoximine-substituted N-tethered trienes and their Ru-catalyzed ring-closing metathesis (RCM) reaction. The highly substituted N-tethered trienes were obtained enantio- and diastereopure through 1) the diastereoselective aminoalkylation of sulfoximine-substituted allyltitanium complexes with N-tert-butylsulfonyliminoester, 2) N-allylation of homoallylic N-sulfonyl amines, 3) allylation, hydroxylalkylation, and formylation of α-lithioalkenylsulfoximines, and 4) allylation of α-formylalkenylsulfoximines. The Ru-catalyzed RCM reaction of the sulfoximine-substituted 1,7,10- and 1,7,12-trienes stereoselectively afforded the corresponding nine-, ten-, and eleven-membered MRNHs in good yields. An interesting difference in reactivity was noted in the case of a sulfoximine-substituted 1,7,10-triene and its corresponding 1,10-diene. While the triene readily underwent a RCM reaction, the diene reacted only in the presence of Ti(OiPr)(4) under formation of the corresponding MRNH. The feasibility of a removal of the sulfoximine auxiliary and the N-sulfonyl protecting group from the MRNHs were demonstrated through reduction and cleavage, respectively, of a nine-membered heterocycle, both of which proceeded readily and gave the corresponding cyclic alkene and amine, respectively.     

Total synthesis of aspercyclide C

The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide.     

Synthesis of (+)-didemniserinolipid B: application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis

The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis (RRCM) was developed, which increased the yield of the RCM. The resulting 6,8-dioxabicyclo[3.2.1]octene core was selectively functionalized by complimentary dihydroxylation and epoxidation routes to install the C10 axial alcohol. This bicyclic ketal core was further functionalized by etherification and an alkene cross metathesis with an unsaturated alpha-phenylselenyl ester en route to completing the total synthesis.     

Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst.     

Convenient strategy for the synthesis of highly functionalizable hydroxylated unsaturated azepanes

A convenient approach to the construction of dihydroxylated unsaturated azepanes featuring a functional group (ethoxycarbonyl)methyl or (cyano)methyl at C-2 was achieved from a pent-4-enal synthon obtained in four steps from d-xylose. The key step of the sequence relied on the conjugate addition of allylamine to α,β-unsaturated ester or nitrile, prepared by Wadsworth-Emmons olefination. Subsequent RCM afforded the target unsaturated azepanes.     

General strategy for the syntheses of corynanthe, tacaman, and oxindole alkaloids

We report herein the total synthesis of the corynanthe alkaloid dihydrocorynantheol and the formal syntheses of the indole alkaloids tacamonine, rhynchophylline, and hirsutine. The strategies for assembling the corynanthe and tacaman skeletal frameworks comprised of both the classical ABD --> ABCD and ABC --> ABCD approaches wherein the variously substituted piperidinone D-rings were formed via ring-closing metathesis (RCM) followed by a 1,4-addition to introduce the requisite side chain at C(15). Since 1,4-additions to alpha,beta-unsaturated lactams represent an underdeveloped field, we conducted a series of studies with two unsaturated lactams employing organocuprates and metal enolates as the nucleophiles. These studies revealed that organocuprates derived from Grignard reagents and either stoichiometric amounts of CuCN or catalytic amounts of CuBr.DMS complex are excellent nucleophiles for such additions; TMSCl was a crucial additive for optimizing these reactions. The anion derived from ethyl 1,3-dithiolane-2-carboxylate was also an excellent nucleophile in these 1,4-additions, although the stereochemistry of such 1,4-additions to carboline-derived, unsaturated lactams was sensitive to substitution on the indole nitrogen atom. The ABD --> ABCD approach to these alkaloids featured a novel one-pot sequence of an RCM reaction and a zirconocene-catalyzed carbomagnesation followed by a second RCM to generate the D-ring.     

Ring-closing metathesis of chiral allylamines. Enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline

The ring-closing metathesis (RCM) of two types of unsaturated chiral allylamines III, easily available from enantiomerically enriched epoxy alcohols, has been studied. Fully protected allylamines IIIa [(1)R = CH(2)-(CH(2))(n)()-CH=CH(2); (2)R = Boc; (3)R = PMB] have been prepared from unsaturated epoxy alcohols, whereas bis-allylamines IIIb ((1)R = Ph, (2)R = allyl,(3)R = Boc or PMB) have been prepared from 2,3-epoxy-3-phenylpropanol. Both types have been subjected to RCM to provide either cyclic allylamine I or II. The synthetic potential of these intermediates has been demonstrated by the enantioselective synthesis of (2S,3R,4S)-3,4-dihydroxyproline.     

Studies towards the total synthesis of Phostriecin

A synthetic approach toward the phostriecin, an antitumor natural product is described. The key features of the present synthesis are Wittig reaction, synthesis of homoallylic alcohol using Brown’s protocol (alkoxyallylboration) and RCM for the creation of unsaturated lactone moiety of phostriecin.     

Selective Transformation of Norbornadiene into Functionalized Azaheterocycles and β-Amino Esters with Stereo- and Regiocontrol

Novel functionalized azaheterocycles with multiple chiral centers have been accessed from readily available norbornene β-amino acids or β-lactams across a stereocontrolled synthetic route, based on ring-opening metathesis (ROM) of the staring unsaturated bicyclic amino esters, followed by selective cyclization through ring-closing metathesis (RCM). The RCM transformations have been studied under various experimental conditions to assess the scope of conversion, catalyst, yield, and substrate influence. The structure of the starting norbornene β-amino acids predetermined the structure of the new azaheterocycles, and the developed synthetic route took place with the conservation of the configuration of the chiral centers.     

Effect of ring fusion stereochemistry on double bond geometry. Unexpected formation of nine-membered cyclic ether with E-configurated double bond through RCM

Formation of a nine-membered cyclic ether with E-configurated double bond was observed during construction of 5-9-5 tricycles through RCM of dienes. Ring fusion stereochemistry in the products oxonenes was found to have profound influence on the olefin geometry. cis-anti-cis 5-9-5 tricycle was obtained with Z-configurated olefin while cis-syn-cis 5-9-5 system was obtained with E- as well as Z-configurated double bond with the former predominating.     

A short and concise synthetic route to (−)-coniceine

(−)-Coniceine, the simplest framework of indolizidine alkaloids, has been successfully accessed using a route in which ruthenium-catalyzed ring-closing olefin metathesis (RCM) was the key reaction to establish the unsaturated bicyclic lactam system.