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Organic Synthesis Based on Ruthenium Carbene Catalyzed Metathesis Reactions and Pyridinium Salt Photochemistry
Organic Synthesis Based on Ruthenium Carbene Catalyzed Metathesis Reactions and Pyridinium Salt Photochemistry
Journal of the Korean Chemical Society. 2010. Jun, 54(3): 261-268
Copyright © 2010, The Korean Chemical Society
  • Received : May 10, 2010
  • Accepted : May 19, 2010
  • Published : June 20, 2010
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About the Authors
대원 조
Patrick S. Mariano
mariano@unm.edu

Abstract
In this account, three synthetic methodologies that serve as the basis for new strategies for the preparation of selected natural products are briefly introduced. One process, involving ruthenium carbene catalyzed ring rearrangement metathesis developed by Grubbs and his coworkers, transforms alkene-tethered cycloalkenes to thermodynamically more favored alkene-tethered cycloalkenes. Another ruthenium carbene promoted reaction, referred to as dienyne metathesis, was uncovered in early studies by Grubbs and his collaborators. This process converts dienynes to fused bicyclic conjugated dienes. Finally, a novel photo-electrocyclization reaction of pyridinium salts, which leads to the formation of 4-aminocyclopenten-3,5-diol derivatives, is discussed. Examples are provided to show the utility of these methodologies in natural product synthesis. Emphasis is given to studies in which pyridinium salt photochemistry is coupled with ring rearrangement and dienyne metathesis in routes for the synthesis of polyhydroxyalted indolizidine alkaloids and the construction of the tricyclic core of the lepadiformine and cylindricine alkaloids.
Keywords
INTRODUCTION
Since its advent in the mid 1900s, the flurry of activity centered on natural product synthesis has been driven in part by the desire to test new synthetic methodologies through their application to the construction of complex molecular structures. This feature, coupled with the development of mature procedures for designing approaches to targets, led to an enormous effort during the 1970-90 period aimed at the preparation of naturally occurring substances, especially those with interesting biological properties. The wave nature of interest in new methodologies that flowed through the organic synthesis community during this period is exemplified by related publications describing syntheses based on the same methodology. Reflecting this phenomenon are the grouped reports from numbers of research laboratories that describe the use of methodologies, such as 2+2-photocycloaddition of enones and alkenes, intramolecular Diels-Alder reactions, in targeted synthesis.
Albeit to a lesser degree, this trend has continued in recent years. Ruthenium carbene (Ru=C) catalyzed metathesis reactions exemplify newer methodologies that have attracted the wide interest of synthetic chemists. 1 As a consequence of the pioneering work of Grubbs and his coworkers, simple methods for performing incredibly versatile metathesis reactions were developed. In this “account,” two interesting Ru=C promoted metathesis reactions will be discussed in the context of synthesis. One process, termed ring rearrangement metathesis (RRM), 2 transforms alkene tethered cycloalkenes 1 into new alkene tethered cycloalkenes 2 via the pathway shown in 1 . Thermodynamic factors ( e.g. release of ring strain) serve as driving forces for these processes. Another useful Ru=C induced reaction, referred to as dienyne metathesis (DYM), 3 takes place by a multi-stepped pathway in which a bis-alkene tethered alkyne 3 is transformed into a bicyclic conjugated diene 4 ( 2 ).
Although much less spectacular and not as generally useful, photochemical reactions of pyridinium salts (PSP) represent a novel method for generating highly functionalized aminocyclopentenes from simple pyridine precursors in a highly stereocontrolled manner. 4 This process, outlined in 3 , is initiated by excited state Nasarov-type cyclization of pyridinium salts 5 followed by stereocontrolled, exo-face nucleophilic addition to the intermediate bicyclic allylic cation 6 to form the bicyclic aziridine 7 . Owing to the inherent ring strain present in 7 , SN 2 -type ring opening takes place either in a second synthetic step or under the photoreaction conditions to yield amino-cyclopentenes 8 with rigorously enforced trans, trans stereochemistry.
Two aims stimulated the preparation of this “account.” Firstly, we wanted to summarize recent developments made in the applications of RRM, DYM and PSP methodologies in natural product synthesis. This is done below by describing selected examples in which these methods play key roles in routes for preparation of the targets. The second goal was to present the results of two studies carried out in our laboratory that focus on the combined use of PSP and Ru=C promoted metathesis processes in the construction of the structural backbones of two important natural product families. Although the results of most of the author’s efforts described in this “account” have been published, some of the work has not yet been reported.
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- Ring Rearrangement Metathesis (RRM)
The seminal studies carried out by Zuecher, Hashimoto and Grubbs 5 on simple substrates demonstrated the high synthetic potential of Ru=C catalyzed RRM reactions. Selected examples from these earlier efforts are given in 4 . For example, the symmetric bis-alkene tethered cycloalkenes 9 , 12 and 13 are efficiently converted to the corresponding rearranged products by treatment with 3 - 6 mol % of the first generation Grubbs catalyst 10 6 under mild conditions (45 ℃, C 6 H 6 ). It should be noted the processes probed by Grubbs and his coworkers in this early effort represent special cases of RRM reactions in which initially formed Ru-alkylidene products ( e.g. 11 , 4 ) undergo a final ring closing metathesis step.
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Additional examples of RRM reactions of simple substrates are found in studies by Stragies and Blechert, reported in 1998. 9 One example taken from this work ( 5 ) involves the transformation of the alkene tethered norbornene 14 to the hydroindene 15 , catalyzed by using the ruthenium carbene 10 . This process is terminated by cross metathesis between the ruthenium alkylidene product and allytrimethylsilane.
Owing to the unique features of and mild conditions employed in these reactions, along with a high tolerance for diverse functional groups, RRM reactions have found wide application to the synthesis of natural and non-natural, biologically relevant substances. An early example was provided by Stragies and Blechert 10 in their synthesis of the piperidine alkaloid (-)-halosaline ( 19 , 6 ). Two key features of this route are worth noting. Firstly, the sequence begins with the enantiomerically enriched cyclopentendiol mono-acetate 16 , generated by enzymatic desymmetrization of the corresponding meso bis-acetate. This substance is then converted to the aminocyclopentenol 17 , which undergoes RRM in a CH 2 Cl 2 solution containing ruthenium carbene 10 to produce the tetrahydropyridine derivative 18 . This substance serves as a late stage intermediate in the synthesis of 19 .
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Other targeted synthesis applications of RRM processes developed by Blechert and his coworkers are outlined in 7 . These include approaches to (-)-indolizidine 167B ( 20 ), 11 (+)-dihydrocuscohygrin ( 21 ) 12 and (+)-dumetorine ( 22 ), 13 all of which rely in the use of Grubbs’ chemistry and exemplify highly concise routes for target preparation.
Another particularly interesting use of RRM chemistry comes from investigations by Nicolaou and his coworkers, 14 in which a novel strategy for construction of complex, cyclic polyethers was developed. In this effort, the bis-pyranyl cyclobutene 24 ( 8 ), which serves as the substrate for the key RRM reaction, was generated by condensation of cis-3,4-dichlorocyclobutene with two equivalents of the sodium alkoxide derived from pyranyl alcohol 23 . Treatment of 24 with the second generation Grubbs ruthenium carbene catalyst 25 15 promotes efficient conversion to the rearranged tetracyclic polyether 26 .
The final application of the RRM process that we will discuss comes from the work of Schreiber and his coworkers 16 aimed at the development of novel methods for diversityoriented-organic-synthesis (DOOS). The key goal of DOOS is to prepare libraries of organic structures that can potentially govern ( e.g. inhibit or activate) important biochemical pathways. Efforts in this area require the availability of techniques to produce a large array of different, structurally complex, yet related products in a concise manner. For this purpose, Schreiber and his coworkers designed a methodology that employs the tandem use of a group of well-known, complexity generating processes, including the Ugi-4 component condensation, Diels-Alder reaction, and RRM. The sequence, exemplified by the route shown in 9 , enables rapid construction of a library of structurally complex tetracyclic bis-azepinanes 27 .
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- Dienyne Metathesis (DYM).
Many recent advances have been made in the application of DYM processes to the synthesis of natural and non-natural products. An excellent review of studies in the area prior to2005 has been written by Lee. 17 As a result, the examples of DYM chemistry highlighted below have been selected on the basis of their relevance to recent studies carried out in our laboratory.
As can be seen by viewing the general pathway outlined in 2 above, DYM reactions transform bis-alkene tethered alkynes to bicyclic conjugated dienes. Grubbs and Choi 18 were the first to describe this reaction in studies using a simple set of substrates. One example, shown in 10 , employs the 2 nd generation Grubbs catalyst 25 to promote reaction of the cyclohexylacrylate derivative 28 that yields the tricyclic lactine 29 . In this process, a remarkable transformation occurs to convert a simply prepared substrate into a structurally complex product in a remarkably efficient manner.
Employment of the DYM process in target oriented synthesis is found in the approach to the tetracyclic alkaloid (-)-securinine ( 34 , 11 ) developed by Honda and his coworkers. 19 The route begins with preparation of the N-Boc piperidine dienyne 31 from the α-pipecolic acid thioester 30 . The key DYM step in the sequence is catalyzed by the 3 rd generation Grubbs 20 catalyst 32 and transforms 31 to the piperidine substituted bicyclic dihydrofuran 33 . Conversion of 33 to the target 34 consists of lactone formation, δ-bromination, and cyclization.
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Hatakeyama and his coworkers 21 described a novel strategy for the synthesis of the erythrina alkaloid erythravine ( 39 , 12 ) that is based on a design which incorporates DYM reaction of the bis-alkene substituted alkyne 36 . The route starts with conversion of the phenethyl amine derivative 35 to 36 . The tetracyclic diene 37 + 38 was then generated as a 3:2 mixture of diastereomers by 10 catalyzed reaction of 36 . The major isomer 37 was then converted to the racemic target 39 . It should be noted that Mori and his coworkers 22 accomplished a racemic synthesis of the closely related erythrina alkaloid erythrocarine that follows a plan that is closely related to the one employed by Hatakeyama.
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- Pyridinium Salt Photochemistry (PSP).
In an interesting report in 1972, Kaplan, Wilzbach and Pavlik 23 described the unusual photochemical reaction of N-methylpyridinium chloride ( 40 ) in aqueous base solution that produces the bicyclic allylic alcohol 42 ( 13 ). These workers suggested a reasonable mechanism for this process that involves excited state electrocyclization to form the intermediate bicyclic allylic cation 41 followed by hydroxide addition to the least hindered exo-face. Over a decade later, Mariano, Yoon and their coworkers 24 observed that a similar excited state process is involved in the photochemical conversion of N-substituted pyridinium salts 43 to trans, trans-4-amino-cyclopentendyl ethers 45 ( 14 ). In these cases, reactions are promoted by irradiation of methanol solutions that do not contain base and, consequently, N-protonated bicyclic aziridines 44 are generated and they undergo secondary SN 2 ring opening to form 45 . This observation led to efforts exploring a strategy for preparation of unsymmetrically substituted 4-aminocyclopentene derivatives that involves irradiation of pyridinium salts in basic solutions containing one nucleophile followed by acid promoted aziridine ring opening with a second nucleophile (see 3 above). 25
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The interesting discovery 25 that pyridine participates in a similar reaction sequence when irradiated in an aqueous acid solution led the way to novel methods for the preparation of stereochemically diverse 4-aminocyclopentendiol derivatives in enantioenriched forms. As shown in 15 , irradiation of a pyridine solution in aqueous perchloric acid, followed by basic workup and peracetylation leads to efficient formation of the trans, trans-amino-cyclopentendiyl diacetate 46 . This substance can be desymmetrized by using enantioselective enzymatic hydrolysis with electric eel acetylcholinesterase (EEACE). This process generates the mono-diol 47 in ca . 80% ee. 26 Moreover, implementation of alcohol inversion procedures enables formation of a stereo diverse family of enantio-enriched, selectively protected 2-aminocyclopentendiol derivatives, exemplified by 48 - 50 ( 15 ).
This interesting PSP based methodology has been applied to the synthesis of a variety of natural products, including (+)-mannostaten A, 26 , 27 the aminocyclitol of (-)-allosamizoline, 28 both enantiomers of trehazolamine, 29 (-)-cephalotaxine, 30 and non-natural products such as 3-amino-3-deoxyaldopentoses. 31 The indolizidine alkaloids (-)-swainsonine and (+)-castanospermine have also been targets of efforts we carried out in which strategies based on PSP and RRM processes were used. The latter studies along with an investigation focused in the construction of the structural backbone of lepadiformine and cylindricine alkaloids are discussed in the remaining sections of this “account.”
- A Strategy for Preparation of the Polyhydroxylated Indolizidines (-)-Swainsonine and (+)-Castanospermine.
Recognizing the unique features of PSP processes and the broad generality of RRM chemistry, Song, Zhao and Mariano 32 , 33 embarked on an investigation of an application of these reactions to the synthesis of biologically active members of the polyhydroxylated indolizidine natural product family. The general strategy employed for this purpose is outlined in 16 . The starting materials for these preparative routes were 4-aminocyclopentene derivatives 51 , generated by using PSP methods (see above). We envisaged that RRM reactions would transform the corresponding N-allylamides 52 into the corresponding 2-allyl-1,2,3,6-tetrahydropyridines 53 that contain functionality needed to execute indolizidine ring formation and hydroxyl introduction to form the target indolizidines 54 .
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As part of this approach, interesting aspects regarding the control of the regiochemical outcomes of the RRM reactions of the N-allylacetamidocyclopentenes needed to be addressed. This is exemplified in 17 , which portrays the two possible routes that could be followed in ruthenium carbene catalyzed reactions of the generalized N-acetamide derivative 55. Obviously, regiochemical control is required for the strategy for polyhydroxylated indolizidine synthesis to be efficient. As a consequence of this question, a number of cyclopentene derivatives were prepared and subjected to RRM reactions. Two examples of the observations made in this effort are given in 18 . It is clear from viewing these examples that an exceptionally high degree of regiocontrol, governed by stereochemistry attends these processes. In each case, reaction takes via formation and selective cycloaddition of the exocyclic ruthenium alkylidene ( 60 and 61 , 19 ) across the endocyclic alkene moiety. It appears that the courses of these reactions are governed by formation of tricyclic ruthenocyclobutanes 62 and 64 , in which the bulky ligated ruthenium is bonded to the old cyclopentene moiety in an anti disposition relative to the OBn (in 64 ) or OTBDMS (in 62 ) groups. It should be noted that this preference exists despite the fact that formation of 62 and 64 encounters steric conjestion between the nitrogen containing two-atom bridge and the β-OTBS (in 64 ) and OBn (in 62 ) groups.
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Molecular mechanics calculations on simple analogs were carried out to determine if the regiochemical preferences seen in these reactions are indeed the result of the dominance two competing steric interactions. For this purpose, gemdimethyl analogs of 62 and 64 ( i.e. 66 and 67 , 20 ) were used. The results show that 66 , the analog of 64 , is of significantly lower energy than its regioisomer 67 , the analog of 65 . Thus, it appears that the regiochemical courses of RRM reactions of 60 and 61 are directed by steric interactions between the highly ligated ruthenium center and the syn OBn and OTBS groups.
With these results in hand, efficient routes for the synthesis of two representative naturally occurring polyhydroxylated indolizidines were designed. In the approach to (-)-swainsinine ( 69 , 21 ), the preference for exo vs. endo alkene, α-acetate guided dehydroxylation (→ 68 ) was used advantageously to produce the late stage intermediate 68 . In contrast, the activation (directing effect of allylic hydroxyl groups on epoxidation reactions (→ 71 , 22 ) along with stereoelectronically mandated trans-diaxial epoxide ring opening (→ 72 ) were the cornerstones of late stage steps in the preparation of (+)-castanospermine ( 73 ).
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- Construction of the Tricyclic Structure of Members of the Lepadiformine and Cylindricine Alkaloid Families
The results of studies in the area of PSP provided a foundation for a new strategy to construct the tricyclic backbone 74 of members of the lepadiformine and cylindricine alkaloids, exemplified by lepadiformine C ( 75 ) and cylindricine B ( 76 ) ( 23 ). Earlier, we observed a remarkably high degree of regiocontrol in photocyclization reactions of the cyclopenta-fused pyridinium perchlorate 77 ( 24 ). 34 Specifically, irradiation of 77 in an aqueous base solution leads to nearly exclusive formation of the tricyclic allylic alcohol 79 , arising by selective addition of hydroxide to the intermediate allylic cation 78 . In addition, reaction of 79 with acetic acid followed by per-acetylation produces the spirocyclic triacetyl derivative 80 , which was converted to the corresponding butenamide 81 by using an unfortunately laborious sequence. 35 As anticipated, RRM reaction of 81 ,promoted by the ruthenium carbene catalyst 25 , produces the indolizidine 82 . If it were not for the large effort required to prepare 81 , this sequence would represent a viable approach to synthesis of the tricyclic core of the lepadiformines and cylindricines since functionality is present in 82 to execute introduction of the final six-membered ring.
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At this point, we recognized that a much more direct approach existed for preparation of the basic structure shared by these alkaloids. The strategy takes advantage of dienyne metathesis (DYM) reaction of the proline derived acrylamide 83 ( 25 ). In order to test this proposal, 83 was prepared in enantiomerically pure form from L-proline by using the route outlined in 25 . As anticipated, treatment of this dienyne with the 2 nd generation Grubbs catalyst 25 in CH 2 Cl 2 at reflux leads to exceptionally clean ( ca . 100 %) conversion to the tricyclic dienamide 84 , which possess the alkaloid tricyclic structure. The results of this unpublished work 35 provide the framework of novel strategies for the preparation of members of the lepadiformine and cylindricine alkaloid families.
SUMMARY
The studies described above point out how remarkably efficient ruthenium carbene catalyzed metathesis reactions can be combined with pyridinium salt photochemistry in devising strategies for the preparation of biomedically relevant natural and non-natural products. It is hoped that this account will stimulate further interest in these areas.
Acknowledgements
Support for studies carried out in Mariano’s laboratory by grants from the National Institutes of Health and National Science Foundation are acknowledged. In addition, Mariano expresses his deep appreciation to the late Keiyu Ueno of the Dojindo Laboratories for the early financial support given to his program.
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