Metathesis precursor

Metathesis of N-tosylated ene-amides and yne-amides has been less extensively investigated. An example of the RCM of ene-amides is a new indole synthesis developed by Nishida [79] metathesis precursor 96 (prepared by ruthenium-catalyzed isomerization of the corresponding allyl amide) is cy-clized to indole 97 in the presence of 56d (Eq. 13). 

RCM was also used in Yamamoto s total synthesis of the marine neurotoxin gambierol (81) [62], to close the central seven-membered E ring, thereby completing the octacyclic polyether core 80 (Scheme 15). Following previously developed methodology [63], metathesis precursor 79 was produced as the major epimer, by boron trifluoride etherate-mediated intramolecular allylation of a-chloroacetoxy ether 78. Subsequent treatment of 79 with catalyst C produced the octacyclic ether 80 in 88% yield. 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

An early example of cyclopentene-opening/double RCM leading to bis-dihy-dropyran 380 (the C22-C34 segment of the potent antitumor agent halichondrin A) was disclosed by Burke et al. (Scheme 74) [158]. In this case, the ROM-RCM sequence was performed with catalyst B, leading from cyclopentene 379 to 380 in 71% yield. When metathesis precursor 379 was exposed to catalyst A, only one... 

RRM of enantiopure cyclopentene 382, induced by commercially available catalyst C, was the key step in Blechert s total synthesis of the bis-piperidine alkaloid (+)-astrophylline (384) [159]. Exposure of metathesis precursor 382 to only 1 mol% C provided within 2 h bicycle 383 in 82% yield (Scheme 75). 

Blechert s synthesis of the piperidine alkaloid (-)-halosaline (387) by Ru-catalyzed RRM is outlined in Scheme 76 [160]. In the presence of 5 mol% of catalyst A, the ring rearrangement of metathesis precursor 385 proceeded cleanly with formation of both heterocyclic rings in 386. In situ deprotection of the cyclic silyl ether in 386, followed by selective reduction and removal of the to-syl group led to 387. 

Clark and coworkers utilized enyne RCM for constructing the AB ring fragment of the manzamine alkaloids (Scheme 83) [177]. Exposing metathesis precursor 423 and ethylene gas to catalyst A provided bicycle 424 in near quantitative yield. Regioselective hydroboration of the vinyl group in 424, followed... 

RCM of a dienyne was also a key step in Mori s recent total synthesis of the alkaloid erythrocarine (447) [183]. The tetracyclic framework of447 was elaborated in the penultimate step, by exposing the hydrochloride of metathesis precursor 445 (1 1 diastereomeric mixture at the carbinol center) to first-generation catalyst A. The tandem process occurred smoothly within 18 h at room temperature leading to tetracycles 446 (1 1 mixture) in quantitative yield. Deprotection of the a-acetoxy isomer 446a led to 447 (Scheme 88). 

In 1998 it was revealed that allenylidene-ruthenium complexes, arising simply from propargylic alcohols, were efficient precursors for alkene metathesis [12], This discovery first initiated a renaissance in allenylidene metal complexes as possible alkene metathesis precursors, then it was observed and demonstrated that allenylidene-ruthenium complexes rearranged into indenylidene-ruthenium intermediates that are actually the real catalyst precursors. The synthesis of indenylidene-metal complexes and their efficient use in alkene metathesis are now under development. The interest in finding a convenient source of easy to make alkene metathesis initiators is currently leading to investigation of other routes to initiators from propargylic derivatives. 

The evidence that mthenium-allenylidenes were easy to make and eflEcient alkene metathesis precursors motivated several groups to design new allenylidene metal complexes and to explore their impact on alkene metathesis. Nolan first reported... 

The enantiomerically pure oxazolidinone derivative 7 (Scheme 4),14,20 was converted into the metathesis precursor 6 by a sequence of carbamate hydrolysis, amide alkylation and protection of the secondary alcohol as the TBDMS ether in a 95% overall yield. Subsequent [Ru-1] catalysed ROM-RCM converted 6 into the desired dihydropyrrole 5. 

The key step is the synthesis of the metathesis precursor, which was required in both the cis- and trans- configurations. The cz .v-configuration was obtained via enantioselective domino allylic alkylations (Scheme 6, 15a and 15b). For the rra/zs-configuation, an allylic alkylation was used to introduce the first amine, but the second amine was introduced via the Mitsunobu reaction25 to achieve an inversion of the stereocentre (Scheme 6,16a and 16b). 

Once all the metathesis precursors were available, the synthesis was continued by detailed investigations of the RRM. The metatheses were carried out in CH2CI2 with 5 mol % of [Ru-1], To reiterate, the reaction was carried out in the presence of ethylene in order to accelerate the metathesis and to avoid the formation of side products. The first RRM was carried out with the cis- precursor 15a at room temperature and showed slow conversion to the dihydropyridine 19 (Scheme 7). The conversion was accelerated by performing the reaction at 35 °C, yielding 19 (79%) after 2 days. A mixture of 15a and 19 in a 1 5.5 ratio was... 

Scheme 11. Assembly of the metathesis precursor en route to woodrosin I. [a] BF3Et20, CH2Cl2/hexane, - 20°C, 68% [b] (i) NaOMe cat., MeOH, quant. (ii) compound 54, BF3Et20, CH2Cl2/hexane, -20°C, 82% [c] NaOMe cat., MeOH, 88% Id] BF3Et20, CH2Cl2, -20°C, 86% [e] CljCCN, Cs2C03, CH2Cl2, 54% [f] TMSOTf cat., CH2Cl2, -20°C, 84%.

SCHEME 4 En route to the ring-closing metathesis precursors. 

With this key union effected, only a few operations separated 48 from the substrate needed to test enyne metathesis (i.e. 12, Scheme 9). First, the controlled exposure of this compound (48) to 2 equivalents of TBAF in THF at 0°C effected the lysis of both the phenolic silyl ether and the TMS group append onto the terminal position of the alkyne, but, importantly, not the TIPS group on the other acetylene group. As such, in the next operation partial reduction with Lindlar s catalyst (Pd on BaS04 poisoned with quinoline) was accomplished selectively on only one alkyne to provide the needed terminal olefin. Finally, cleavage of the alky-nyl TIPS moiety under more forcing conditions (TBAF, THF, 25 °C), followed by silylation of both the allylic hydroxy and the phenolic groups (TBSCl, imid, DMF), then completed the assembly of enyne metathesis precursor 12 in 62% overall yield from 48. 

In a similar manner to that for pyridines, pyridazines 68 were synthesized from functionalized hydrazines 66 via pyridazones 67 using an RCM/elimination/ triflation approach (09CC3008). The metathesis precursors 66 were synthesized in two steps from commercially available tosyl hydrazide (not shown). Substituents can be incorporated at aU ring positions, which was clearly exemplified by the introduction of a methyl group in different positions of the pyridazine (Scheme 19). 

Metathesis cascades have underpinned the synthesis of diverse small molecule libraries.Metathesis is a superb pairing reaction for the build-couple-pair approach first, it can yield many dilferent ring systems and, second, alkenes (and alkynes) are compatible with the many reactions that may be used to connect building blocks. Metathesis has been used to prepare a library of natural product-like molecules (Scheme 1.7). Initially, unsaturated building blocks were attached iteratively to fluorous-tagged linker to yield metathesis precursors 20. Crucially, alternative attachment reactions were used such that the building blocks were connected through bonds that either did, or... 

The observation that the isolated yields of macrocyclization products in RCM reactions can be influenced by the proximity of a Lewis-basic carbonyl to the site of metathesis has been made by other groups as well. Grubbs [29] and Fiirstner [30] have each reported similar problematic macrocyclizations due to the position of the olefin in a metathesis precursor. In each case, the formation of cyclic chelates between the Lewis-acidic Ru atom in the catalyst and a carbonyl moiety in the substrate was responsible for the low yields. 

Of course, challenges exist in the use of aUcene and enyne RCM for the assembly of aromatic rings. Firstly, while the methodology may not rely on the use of preformed aromatic rings, the metathesis precursors still need to be synthesized, and this synthesis can still be particularly challenging. Secondly, the experimental procedures, yields associated with the reactions, and the costs associated with the use of precious metal catalysts for the metathesis reaction may limit their use, particularly in an industrial setting. However, if cheaper, more air- and water-tolerant catalysts can be developed, this method for the synthesis of substituted benzene rings may find wider application. 

As early as 1998 it was revealed that allenylidene-ruthenium complexes eould behave as alkene metathesis precursors (Scheme 18) [10]. They are easy to prepare from simple propargyUc alcohols and constitute the first well-defined ionic 18-electron catalj precursors with respect to the neutral 16-electron Grubbs or Hoveyda catalysts [42]. 

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