Handbook of Metathesis, Volume 2: Applications in Organic Synthesis

By Robert H. Grubbs and Daniel J. O'Leary

The second edition of the "go-to" reference in this field is completely updated and features more than 80% new content, with emphasis on new developments in the field, especially in industrial applications. No other book
covers the topic in such a comprehensive manner and in such high quality.

Edited by the Nobel laureate R. H. Grubbs and D. J. O´Leary, Volume 2 of the 3-volume work focusses on applications in organic synthesis. With a list of contributors that reads like a "Who's-Who" of metathesis, this is an
indispensable one-stop reference for chemists in academia and industry.

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Volume 1: Catalyst Development and Mechanism, Editors: R. H. Grubbs and A. G. Wenzel - http://www.wiley.com/WileyCDA/WileyTitle/productCd-3527339485.html

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• Language: English
• Publisher: Wiley
• Release date: Mar 2, 2015
• ISBN: 9783527694044

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Editors

Prof. Robert H. Grubbs

California Inst. of Technology

Div. Chem. and Chemical Eng.

1200 E. California Blvd

Pasadena, CA 91125

United States

Prof. Daniel J. O'Leary

Pomona College

Dept. of Chemistry

645 North College Avenue

Claremont, CA 91711

United States

Handbook of Metathesis

Second Edition

Set ISBN (3 Volumes): 978-3-527-33424-7

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Vol 1: Catalyst Development and Mechanism, Editors: R. H. Grubbs and A. G. Wenzel ISBN: 978-3-527-33948-8

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Preface

In 2003, the first edition of the Handbook of Metathesis comprehensively covered the origins of the olefin metathesis reaction and the myriad of applications blossoming from the development of robust, homogeneous transition-metal catalysts. In the intervening 10 years, applications and advances in this field have continued to exponentially increase. To date, 3732 publications regarding olefin metathesis have been reported; of these, 2292 have been reported since 2003!¹ By 2005, olefin metathesis had become so integral to the field of organic synthesis that the Nobel Prize in Chemistry was awarded to the field (Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock) [1, 2].

In light of these many advancements, a second edition of the Handbook is quite timely. Early on in the planning, it was decided that rather than simply updating the 2003 edition, the second edition would instead emphasize important advancements (e.g., new ligands, diastereoselective metathesis, alkyne metathesis, industrial applications, self-healing polymers) that have occurred during the past decade. In addition, the past 10 years have seen important developments in our understanding of the metathesis mechanism utilizing both computational and mechanistic studies. A greater knowledge of catalyst decomposition, product purification, and the use of supported catalysts and nontraditional reaction media have further enhanced the utility of metathesis systems. A number of new applications are now becoming commercialized based on these new catalyst systems. For example, the first pharmaceutical that uses olefin metathesis in a key step is now commercially available, and a biorefinery that utilizes a homogeneous catalyst is now in production.

Similar to the first edition of this Handbook, contributions have been arranged into three volumes. Volume I (Anna Wenzel, coeditor) emphasizes recent catalyst developments and mechanism and is intended to provide a foundation for the applications discussed throughout the rest of the Handbook. Volume II (Dan O'Leary, coeditor) covers synthetic applications of the olefin metathesis reaction, and polymer chemistry is the topic of Volume III (Ezat Khosravi, coeditor). Chapter topics have been selected to provide comprehensive coverage of these areas of olefin metathesis. Contributors, many of whom are pioneers in the field, were chosen based on their firsthand experience with the topics discussed.

We wish to sincerely thank all the contributors for their diligence in writing and editing their chapters. Our goal was to comprehensively cover the complete breadth of the olefin metathesis reaction – this Handbook would not have been possible without all their time and effort! It was truly a pleasure and an honor to work with everyone!

Claremont, CA

Durham, UK

Pasadena, CA

Anna G. Wenzel, Daniel J. O'Leary

Ezat Khosravi, and

Robert H. Grubbs

November 20th, 2014

¹ Data obtained from keyword searches conducted within the ISI Web of Science (accessed 1/18/2014).

References

1. Nobel Prizes.org Development of the Metathesis Method in Organic Synthesis, http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2005/advanced-chemistryprize2005.pdf (accessed 18 January 2014).

2. Rouhi, M. (2005) Chem. Eng. News, 83, 8.

List of Contributors

Rambabu Chegondi

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

Samuel J. Danishefsky

Columbia University

Department of Chemistry

Havemeyer Hall

MC 3106

3000 Broadway

New York, NY 10027

USA

Benjamin G. Davis

University of Oxford

Department of Chemistry

Mansfield Road

Oxford, OX1 3TA

UK

Vittorio Farina

Janssen Pharmaceutica NV

Turnhoutseweg 30

2340 Beerse

Belgium

Alois Fürstner

Max-Planck-Institut für Kohlenforschung

Kaiser-Wilhelm-Platz 1

45470 Mülheim/Ruhr

Germany

Paul R. Hanson

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

András Horváth

Janssen Pharmaceutica NV

Turnhoutseweg 30

2340 Beerse

Belgium

Amir H. Hoveyda

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467

USA

Adam Johns

Materia Inc

60 N. San Gabriel Blvd

Pasadena, CA 91107

USA

R. Kashif M. Khan

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467

USA

Daesung Lee

University of Illinois

Department of Chemistry

845 West Taylor Street

Chicago, IL 60607-7061

USA

Jingwei Li

University of Illinois

Department of Chemistry

845 West Taylor Street

Chicago, IL 60607-7061

USA

Yuya A. Lin

University of Oxford

Department of Chemistry

Mansfield Road

Oxford, OX1 3TA

UK

Soma Maitra

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

Steven J. Malcolmson

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467

USA

Lisa A. Marcaurelle

H3 Biomedicine Inc.

300 Technology Square

Cambridge, MA 02139

USA

Bogdan Marciniec

Adam Mickiewicz University in Poznań

Faculty of Chemistry

Umultowska 89b

61-614 Poznań

Poland

Jana L. Markley

University of Kansas

Department of Chemistry

1251 Wescoe Hall Drive

Lawrence, KS 66045

USA

Youn H. Nam

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467-3860

USA

Daniel J. O'Leary

Pomona College

Department of Chemistry

645 North College Avenue

Claremont, CA 91711

USA

Gregory W. O'Neil

Western Washington University

Department of Chemistry

516 High Street

Bellingham, WA 98225

USA

Piotr Pawluć

Adam Mickiewicz University in Poznań

Faculty of Chemistry

Umultowska 89b

61-614 Poznań

Poland

Richard Pederson

Materia Inc

60 N. San Gabriel Blvd

Pasadena, CA 91107

USA

Cezary Pietraszuk

Adam Mickiewicz University in Poznań

Faculty of Chemistry

Umultowska 89b

61-614 Poznań

Poland

Alan Rolfe

H3 Biomedicine Inc.

300 Technology Square

Cambridge, MA 02139

USA

Marc L. Snapper

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill, MA 02467-3860

USA

Diana Stoianova

Materia Inc

60 N. San Gabriel Blvd

Pasadena, CA 91107

USA

Sebastian Torker

Boston College

Department of Chemistry

Merkert Chemistry Center

Chestnut Hill

MA 02467, USA

Christopher D. Vanderwal

University of California

Department of Chemistry

1102 Natural Sciences II

Irvine, CA 92697-2025

USA

Maciej A. Walczak

Columbia University

Department of Chemistry

Havemeyer Hall

MC 3106

3000 Broadway

New York, NY 10027

USA

List of Abbreviations

1

General Ring-Closing Metathesis

Paul R. Hanson, Soma Maitra, Rambabu Chegondi and Jana L. Markley

1.1 Introduction

Olefin metathesis catalyzed by transition-metal–carbene complexes is among the most powerful and important carbon–carbon bond-forming reactions in modern synthetic organic chemistry [1]. Metathesis transformations, including cross-metathesis (CM), ring-closing metathesis (RCM), enyne metathesis, alkyne metathesis, and ring-opening metathesis polymerization (ROMP), have gained prominence due to the high activity, high thermal stability, and excellent functional group compatibility of well-defined transition-metal alkylidene catalysts which have become available over the last two decades (Figure 1.1).

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Figure 1.1 List of catalysts.

In 1980, the Villemin [2] and Tsuji and Hashiguchi [3] research groups individually reported the first RCM of a diene with tungsten metal complexes (Scheme 1.1, Eq. 1–2). In 1990, Schrock discovered the molybdenum metathesis complex [Mo]-I [4]. In 1992, Grubbs and coworkers employed [Mo]-I in the first transition-metal–carbine-catalyzed RCM of a diene for the synthesis of a cyclic ether (Eq. 3; Scheme 1.1) [5]. In 1995, Grubbs and coworkers developed the more active, thermal, and air-stable, moisture-tolerant ruthenium–carbene complexes termed the Grubbs first-generation catalyst G-I [6] and the Grubbs second-generation catalyst G-II [7]. Additional metathesis catalysts such as the Hoveyda–Grubbs catalyst HG-II [8] followed, with many commercially available at present.

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Scheme 1.1 Early RCM examples.

Since its inception, RCM has continued to be a widely utilized metathesis reaction in a variety of settings including materials, small-molecule, and natural-product synthesis [1]. As illustrated in Scheme 1.2, the primary RCM reactions are divided into three general types: (i) ring-closing diene metathesis (RCM); (ii) ring-closing enyne metathesis (RCEM); and (iii) ring-closing alkyne metathesis (RCAM). In 1971, Chauvin and coworkers proposed a mechanism of the general alkene metathesis which involves the initial formation of the metal carbene species III as a key propagating intermediate [9]. Subsequent intramolecular [ c1-math-0001 ] cycloaddition of III with a distal olefin forms the metallacyclobutane intermediate IV, while retro [ c1-math-0002 ] reaction affords the final cyclized product (Scheme 1.2). Casey and Burkhardt [10], Katz and McGinnis [11], and Grubbs [12] later confirmed this mechanism with experimental evidence. The intent of this chapter is to highlight recent advances since the publication of the first edition of this Handbook in 2003 [13]. Some concepts, such as RCEM and RCAM, are covered in greater depth in later chapters.

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Scheme 1.2 General ring-closing metathesis reactions.

1.2 Carbocycles (Introduction)

The abundance of carbocyclic moieties in synthetic intermediates, as well as in many natural products, has led to numerous synthetic efforts employing RCM toward their formation [14a,b]. This section provides a highlight of the work accomplished in this field since 2003. The section is divided into three subcategories based on the ring size.

1.2.1 Small-Sized Carbocycles

In 2003, Trost and coworkers reported the synthesis of the cyclopentyl core 4 of the antibiotic antitumor agent viridenomycin (5) (Scheme 1.3) [15]. Starting with diketone 1, alkylation via dynamic kinetic resolution was performed to establish the quaternary center in 2, which underwent an RCM reaction to yield the densely functionalized cyclopentenone subunit 3. A series of transformations were used to complete an 11-step synthesis of the cyclopentyl core 4 of viridenomycin (5).

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Scheme 1.3 Synthetic studies toward viridenomycin.

In 2006, Fustero and coworkers reported the synthesis of an array of fluorinated cyclic α-amino esters (Scheme 1.4) [16]. Diene 6 was subjected to RCM to afford fluorinated cyclic α-amino ester 7 in good yield. In 2012, Xie and coworkers demonstrated another application of RCM in synthesizing entecavir (10), an oral carbocyclic analog of 2-deoxyguanosine having a selective activity against hepatitis B virus [17]. The key transformation of the synthesis included RCM of the diene moiety 8 to yield the five-membered carbocycle 9, which was further transformed to entecavir over five steps (Scheme 1.4).

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Scheme 1.4 Syntheses of fluorinated amino acid derivatives and entecavir.

In 2006, Saicic and coworkers published the synthesis of (Z)-configured, medium-sized cycloalkenes using RCM (Scheme 1.5) [18]. The synthesis started with functionalized cyclohexene moiety 11, which underwent RCM to provide the bicyclic product 12. The bicyclic adduct was then subjected to reduction, mesylation, and Grob fragmentation to afford the macrocyclic product 13, which was converted to (±)-periplanone C (14) in two steps. The trans stereochemistry of the hydroxyl and ester groups in 12, as well as the presence of the isopropyl handle, was found to be crucial for the desired product formation.

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Scheme 1.5 RCM approach to (±)-periplanone C.

In addition to these small-membered carbocycles, RCM has also been applied successfully in synthesizing carbasugars and nucleoside derivatives. In 2006, Ghosh and coworkers reported the enantioselective synthesis of biologically important carbasugars starting from a single enantiomer of glyceraldehyde (Scheme 1.6) [19]. Cyclization of dienol 15 afforded the RCM product 16 in good yield. In 2003, Nielsen and coworkers utilized RCM to synthesize the conformationally restricted nucleoside 19 [20]. Diene 17 was subjected to RCM to afford 18, which was subsequently converted to the tricyclic nucleoside 19.

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Scheme 1.6 RCM syntheses of carbasugars and nucleoside derivatives.

In 2010, Maffei and coworkers utilized RCM to prepare five- and six-membered cycloalkenyl bisphosphonates (Scheme 1.7) [21]. The five-membered RCM substrate 21, prepared by dialkylation of tetraethyl methylene bisphosphonate (21) with allyl and methallyl bromide, was subjected to RCM reaction by using the G-I or G-II catalyst. However, the reaction outcome was strongly influenced by olefinic substitution, and no reaction was observed when both olefins were disubstituted. The RCM precursor 25 was obtained by conjugate addition of olefinic Grignard reagents to tetraethyl vinylidene bisphosphonate (23). Both five- and six-membered cases afforded relatively good yields. Overall, these examples demonstrated the utility of RCM to quickly access several biologically important geminal bisphosphonates.

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Scheme 1.7 Syntheses of five- and six-membered cycloalkenyl bisphosphonates.

In 2011, Srikrishna and coworkers reported the enantiospecific synthesis of the challenging ABC ring system of the marine diterpene aberrarane (30) and related derivatives (Scheme 1.8) [22]. The reaction sequence started with the conversion of readily available (S)-campholenaldehyde (27) to bicyclic diene 28. Subsequent RCM afforded the ABC ring system 29 in good yield. In 2007, Singh and coworkers accomplished the stereoselective formal synthesis of hirsutic acid (34) with a similar tricyclic framework [23]. Salicyl alcohol (31) was subjected to several transformations to afford the diene 32, which underwent RCM to provide the hirsutic acid tricyclic core 33 in 70% yield.

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Scheme 1.8 RCM approaches to aberrarane ABC ring system and hirsutic acid.

In 2011, Mehta and coworkers demonstrated the utility of RCM in forming carbocycles in the context of the total synthesis of 11-O-methyldebenzoyltashironin, a tetracyclic oxygenated natural product (Scheme 1.9) [24]. The highly substituted allyl benzene derivative 35 was subjected to oxidative dearomatization by treatment with bis(trifluoroacetoxy)iodobenzene (BTIB) in the presence of an olefin partner. The intermediate thus obtained was heated in toluene to afford a [ c1-math-0003 ] cycloadduct 36. The cycloadduct 37 then underwent RCM to furnish the tricyclic core structure 38, en route to 11-O-methyldebenzoyltashironin (38).

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Scheme 1.9 RCM in the total synthesis of 11-O-methyldebenzoyltashironin.

In 2012, Crimmins and coworkers reported the synthesis of aldingenin B (42), a secondary metabolite with a complex molecular architecture (Scheme 1.10) [25]. The key transformations included an asymmetric aldol reaction, RCM, and directed dihydroxylation. Starting from 39, two contiguous stereocenters were installed in diene 40 over two steps, and subsequent RCM gave access to one of the six-membered rings in the tricyclic framework of 42. The substituted cyclohexene 41 was carried forward to complete the synthesis of aldingenin B.

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Scheme 1.10 RCM approaches to aldingenin B and (+)-harringtonolide.

In 2012, Abdelkafi and coworkers achieved the first asymmetric synthesis of the oxygen-bridged CD ring system 46 contained within the norditerpene alkaloid (+)-harringtonolide (Scheme 1.10) [26]. The challenging ring structure was constructed via a stereoselective intramolecular Diels–Alder reaction, RCM, and a one-step cascade cyclization of an epoxy alcohol intermediate. For the RCM process, cycloadduct 43 was converted to substituted cyclohexene 44, which cyclized in the presence of G-II to provide 5,6-fused ring system 45. This 5,6-fused ring system was later subjected to a series of reactions to afford the caged structure 46 of (+)-harringtonolide.

Yoshida and coworkers reported a general approach to substituted aromatic compounds using RCM/dehydration and RCM/tautomerization reactions. Initially, they synthesized phenols 48 from 1,4,7-trien-3-ones 47 via the ketonic tautomer using G-I and G-II catalysts (Eq. 1; Scheme 1.11) [27, 27]a. Similarly, benzenes 50 and styrenes 52 were prepared by RCM/dehydration of 1,4,7-octatriene-3-ols 49 (Eq. 2; Scheme 1.11) [27]b and RCEM/elimination of 3-acetoxy-4,7-ocadien-1-ynes 51 (Eq. 3; Scheme 1.11), [27c] respectively. In a manner related to their aforementioned RCM/elimination sequence, the authors developed an RCM/oxidation/deprotection of nitrogen-containing dienes 53 to furnish 3-hydroxypyridines 54 in excellent yields (Eq. 4; Scheme 1.11) [27d]. Recently, Yoshida and coworkers also utilized a new and efficient tandem RCEM/RCM/dehydration approach to the synthesis of biaryl compounds 56 from tetraenynes 55 in the presence of the G-II catalyst (Eq. 5; Scheme 1.11) [27e].

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Scheme 1.11 RCM/dehydration and RCM/tautomerization approaches to substituted aromatic compounds.

1.2.2 Medium-Sized Carbocycles

In 2012, Stoltz and coworkers reported an efficient synthesis of bi- and tricyclic systems bearing a quaternary carbon stereocenter via an enantioselective decarboxylative allylation and RCM (Scheme 1.12) [28]. Decarboxylation of the allyl ester 57 with (S)-t-Bu-PHOX and Pd2(pmdba)3 in toluene provided vinylogous ester 58 in 91% yield and 88% ee, which was further subjected to various Grignard reagents (with CeCl3 additive) to deliver the cycloheptenone derivatives 59a–f. RCM of these compounds in the presence of HG-II catalyst furnished bi- and tricyclic fused carbocycles 60a–f in excellent yields.

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Scheme 1.12 Syntheses of cyclic systems bearing quaternary carbon stereocenters.

In their 2011 study of pleuromutilin, Sorensen and coworkers highlighted the importance of nonbonding steric interactions in RCM reactions, which can play a significant role in the formation of products 62 and 64 from dienes 61 and 63, respectively (Scheme 1.13) [29]. In this work, the authors found that the C14 hydroxyl stereochemistry governs the RCM event as a result of steric interactions with the proximal C16 methyl group in the metallacyclobutane transition state (cf. 66 and 68), where the C14-epimer (67) failed to undergo RCM. In addition, an RCM rate enhancement was also observed with the bulky C14 hydroxyl protecting groups in diene 61, which was proposed to arise as a consequence of a bias favoring conformer 65B over 65A in the metathesis cycle (Scheme 1.13).

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Scheme 1.13 Synthetic studies toward pleuromutilin.

In 2011, Nakada et al. published the first enantioselective total synthesis of (+)-ophiobolin A (73) using RCM as one of the key steps (Scheme 1.14) [30]. The challenging eight-membered carbocyclic ring was constructed by RCM of diene 71, which in turn was synthesized by the coupling of 69 and 70. Further functional group manipulation provided the natural product 73.

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Scheme 1.14 Total synthesis of (+)-ophiobolin A.

In 2011, Dixon and coworkers developed a scalable route to the highly functionalized core of daphniyunnine B (78) (Scheme 1.15) [31]. The cis-fused amide 76 was obtained in 52% yield via a stereo- and regiocontrolled intramolecular Michael addition and tandem enolate allylation through sequential addition of base and allyl chloride 75. Subsequent Claisen rearrangement of 76 in refluxing mesitylene provided the enolic RCM precursor in 53% yield. RCM using either HG-II or G-II furnished the unique seven-membered enol ether 77 in good yield.

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Scheme 1.15 Route to daphniyunnine B core ring system.

Yang et al. successfully completed the stereoselective total synthesis of pseudolaric acid A (85) in 16 steps from commercially available starting materials (Scheme 1.16) [32]. They effectively utilized a SmI2-mediated intramolecular radical cyclization and RCM for the construction of the unusual trans-fused [5.7]-bicyclic core of 85. Diene 81 was synthesized in 82% yield from the allylation of the β-ketoester 79 with 3-bromo-2-methylpropene (80). Michael addition of diene 81 with acrolein in the presence of NaOMe, followed by Wittig olefination, provided the diester 82 in 78% yield. The SmI2-mediated alkene-ketyl radical annulation reaction of 82 in the presence of HMPA (10 equiv), followed by silylation, furnished the desired product 83 as major product (about 10 : 1 E/Z) in 78% yield. The construction of the bicycle 84 was achieved in 96% yield by RCM of 83 in the presence of G-II. A 10-step elaboration of bicycle 84 provided (±)-pseudolaric acid (85).

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Scheme 1.16 Stereoselective total synthesis of pseudolaric acid A.

In 2010, Hall and coworkers developed an enantioselective route to (+)-chinensiolide B using diene metathesis to generate the central seven-membered ring (Scheme 1.17) [33]. The synthesis was initiated by the coupling of the fragment 88 with the subunit 87 (prepared from carvone (86) in six steps) in the presence of BF3·OEt2 to provide the trans-γ-lactone product 89 in 87% yield with 19 : 1 diastereoselectivity. Selective TBDPS deprotection and Grieco elimination gave the desired triene 90b in 60% yield along with undesired Michael by-product 90a in 20% yield. Triene 90b was subjected to G-II in CH2Cl2 to generate the seven-membered carbocycle 91 chemoselectively in 93% yield. Additional functional group manipulation of 91 afforded the natural product in four steps.

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Scheme 1.17 Enantioselective route to (+)-chinensiolide B.

In 2009, Vanderwal and coworkers [34] reported an elegant allylsilane RCM and subsequent electrophilic desilylation for the synthesis of exo-methylidene containing six-, seven-, and eight-membered cycloalkane motifs present in many terpene natural products (Scheme 1.18). The route provided the synthesis of teucladiol (98) in just five steps from cyclopentenone (93). Conjugate addition of vinyl bromide 94 with enone 93 led to an intermediate enolate, which was trapped with aldehyde 95 to provide diene 96. Silylation followed by RCM delivered the seven-membered carbocycle 97 in excellent yield. Subsequent diastereoselective addition of methylcerium and electrophilic desilylation afforded synthetic (±)-teucladiol.

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Scheme 1.18 Synthesis of (±)-teucladiol.

In 2010, the Vanderwal group reported the synthesis of a variety of analogs from RCM product 101, synthesized from diene 100 as outlined in Scheme 1.19. These included poitediol 102, dactylol 103, isodactylol 104, and the chlorinated analog 105, each made from 101 in one or two high-yielding steps [35]. The development of this chemistry is discussed in greater detail by Prof. Vanderwal in chapter 8.

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Scheme 1.19 Synthesis of poitediol, dactylol, iso-dactylol, and chlorinated analog.

In 2006, Gais and coworkers reported the stereoselective synthesis of highly functionalized medium-sized carbocycles via RCM reaction from chiral sulfoximines (Scheme 1.20) [36]. When allylic sulfoximine 106 was treated with n-BuLi, ClTi(OiPr)3, and various aldehydes at −78 °C, it afforded the corresponding sulfoximine-substituted homoallylic alcohols 107a,b in 70–75% yield with ≥96% de. Silylation with TESCl gave sulfoximines 108a,b, and subsequent α-allylation provided E-sulfoximine-substituted trienes 109a,b as single isomers. RCM of these trienes with G-II furnished the Z-configured 9- and 10-membered carbocycles 110 and 111 with yields of 96 and 90%, respectively. Similar reactions of 108a,b with 4-pentenal provided silylated allylic alcohols 112a,b with 1 : 1 diastereoselectivity. These isomers were subjected to RCM to give carbocycles (R)-113, (S)-113, and (R)-114 in good yields. In the 11-membered RCM reaction, a minor amount of the E-isomer (R)-115 was detected.

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Scheme 1.20 Functionalized carbocycles via RCM reaction from chiral sulfoximines.

In 2006, Chavan and coworkers reported the first enantiospecific total synthesis of (−)-parvifoline (122, Scheme 1.21) [37]. (R)-(+)-citronellal (116) served as the starting material, which was converted into enone 117 (1 : 1 dr) with a known procedure. Rubottom oxidation of enone 117 provided the α-hydroxy-enone 118 in 70% yield, followed by 1,2-addition with MeMgI, acetylation of the secondary alcohol, and 1,3-carbonyl transposition with PCC (pyridinium chlorochromate) to afford enone 119 in excellent yield. Enone 119 was treated with methallyl magnesium chloride under Barbier conditions, followed by Dess–Martin oxidation, to furnish tertiary alcohol 120. Mesylation of alcohol 120 and subsequent hydrolysis using KOH in MeOH gave the requisite phenol intermediate 121 in 79% yield. The key RCM of phenol 121 using G-II in toluene furnished (−)-parvifoline (122) in 90% yield.

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Scheme 1.21 Enantiospecific total synthesis of (−)-parvifoline.

In 2004, Rychnovsky and coworkers reported chirality transfer in the transannular radical cyclization of cyclodecene 128 to produce bicyclo[5.3.0]decane 129 (Scheme 1.22) [38]. They synthesized the radical precursor 128 in 88% yield using a 10-membered RCM of diene 127. The synthesis of the RCM substrate began with a Mukaiyama–Keck aldol reaction of aldehyde 123 using silyl ether 124 to afford the β-hydroxy ester 125 in 89% yield and 89% ee. Silyl protection, followed by reduction and iodination, gave alkyl iodide 126 in excellent yield. Coupling of the iodide 126 with allyl dibenzylmalonate gave the requisite diene 127 in 96% yield.

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Scheme 1.22 Ten-membered RCM construction of a radical precursor.

In 2004, Martin and coworkers synthesized a number of enantiomerically enriched fused carbocycles via a γ-lactone tether-mediated RCM (Scheme 1.23) [39]. Regioselective opening of epoxy alcohol 130 using thiophenyl acetic acid gave the ester 131, followed by a sequence consisting of oxidative cleavage, Wittig reaction, stereoselective intramolecular Michael addition, and ester hydrolysis to provide the γ-lactone 132. Diene 134 was synthesized from 132 via the intermediate 133 using a chemo- and stereoselective contra-steric alkylation with a variety of alkenyl halides. RCM with G-II provided the bicyclic structures 135 in moderate to good yield depending on the ring size.

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Scheme 1.23 Synthesis of carbocycles fused to γ-lactones.

In 2003, Madsen and coworkers used a seven-membered RCM for the efficient syntheses of enantiopure calystegine B2, B3, and B4 starting from glucose, galactose, and mannose, respectively (Scheme 1.24) [40]. The synthesis of calystegine B2 started from benzyl-protected iodoglycoside 136, which is available in three steps from d-glucose. A Zn-mediated fragmentation of 136, coupled with in situ benzyl imine formation and Barbier-type allylation, gave a product which was Cbz-protected to provide diene 137 with 5 : 1 diastereoselectivity. After separation of the major diastereomer by chromatography, the major isomer was subjected to RCM, followed by hydroboration–oxidation, and DMP (Dess–Martin-periodinane) oxidation to generate the ketones 138 and 139 in 81% overall yield and 1 : 3 regioselectivity, respectively. These regioisomers could be easily separated by chromatography, and hydrogenolysis of 139 generated calystegine B2 (141) in excellent yield. Hydrogenolysis of the minor ketone 138 provided the hemiketal 140. Using the same approach, calystegines B3 (143) and B4 (145) were synthesized from benzyl-protected methyl 6-iodo-galactopyranoside 142 and benzyl-protected methyl 6-iodo-mannopyranoside 144, respectively.

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Scheme 1.24 Seven-membered RCM of carbohydrate derivatives for calystegine syntheses.

1.2.3 Spiro Carbocycles

RCM has also played an important role in the synthesis of spirocycles. In 2002, Suga and coworkers synthesized azaspiro compounds possessing a pyrrolidine skeleton using electroauxiliary-assisted sequential α-alkyl/allylation followed by RCM (Scheme 1.25) [41]. Disilylpyrrolidine 147 was prepared from monosilylpyrrolidine 146 using Beak's method (addition of sec-BuLi in Et2O with HMPA as an additive, followed by TMSCl addition). For a more efficient electrochemical oxidation, pyrrolidine 147 was converted into the methyl ester 148 via a deprotection/protection sequence. Oxidation of methyl carbamate 148 using the cation pool method at −78 °C generated a 2-silylpyrrolidinium ion which reacted with nucleophiles such as allyltrimethylsilane or homoallylmagnesium bromide to generate products 149 and 150, respectively. Further oxidation of these products gave the dialkylated RCM precursors, which afforded the corresponding spirocyclized products.

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Scheme 1.25 Azaspirocycle RCM syntheses.

In 2004, Trost and coworkers described the synthesis of α-hydroxycarboxylic acid derivatives using 5-alkyl-2-phenyl-oxazol-4-one (157) as a nucleophile (Scheme 1.26) [42]. Starting with 157, 5,5-disubstituted-phenyloxazolone derivatives 158 were prepared via Mo-catalyzed asymmetric allylic alkylation (AAA). The reaction product thus obtained was subjected to RCM conditions (when R = allyl) to afford the spirocyclic RCM products 159 in excellent yield. Further hydrolysis of 159 afforded the cyclic hydroxy carboxamide 160.

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Scheme 1.26 α-Hydroxycarboxylic acids from spirocyclic-RCM products.

In 2005, Kim et al. [43] reported a formal synthesis of (−)-perhydrohistrionicotoxin (168) starting from 6-oxopipecolic acid (161) (Scheme 1.27). A Claisen rearrangement and an RCM reaction were utilized as key steps for the construction of the azaspirocyclic skeleton. The synthesis began with the preparation of ester 163 by coupling the racemic acid 161 with allylic alcohol (S)-162 on a multi-gram scale. Ester-enolate Claisen rearrangement of 163 under Kazmaier conditions produced the desired isomer 164 in high yield (75%) and stereoselectivity (30 : 1). Ester 164 was reduced under Luche conditions, and subsequent oxidation and allylation generated homoallyl alcohol 165 in excellent yield. The spirocycle was formed by RCM with G-II to produce olefin 166 in 84% yield. Deoxygenation of 166 was readily accomplished with the Barton–McCombie procedure to provide the lactam 167 in 54% overall yield. Finally, oxone-mediated epoxidation (30 : 1 dr) and DIBAL-H reduction afforded (–)-perhydrohistrionicotoxin (168) in good yield.

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Scheme 1.27 Formal synthesis of (−)-perhydrohistrionicotoxin

In 2006, Kim and coworkers reported the synthesis of the key fragment 172, which contains the azaspirocyclic core structure of (–)-lepadiformine (173) (Scheme 1.28) [44]. To this end, ester 169 was converted to the RCM precursor 170, which was then elaborated to azaspirocycle 171 in excellent yield. This material was further processed to provide the azaspirocycle 172 in good yield.

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Scheme 1.28 RCM approach to the azaspirocyclic core structure of (−)-lepadiformine.

In 2010, Grubbs, Stoltz, and coworkers described the enantioselective syntheses of the chamigrene family of sesquiterpenes (Scheme 1.29) [45]. The key transformations included enantioselective decarboxylative allylation followed by RCM to generate the spirocyclic framework with an all-carbon quaternary center. In the course of the synthesis of laurencenone B (178), enol carbonate 174 was subjected to enantioselective decarboxylative allylation to provide the α,ω-diene 175. This diene was treated with three different RCM catalysts (G-II, HG-II, and 177). While all three performed well, optimum results were obtained with the catalyst 177, which had been designed for the metathesis of sterically hindered substrates. The authors further elaborated laurencenone B in two steps to (+)-elatol (179). These syntheses represent elegant applications of RCM in accessing complex spirocyclic cores.

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Scheme 1.29 Catalyst screen used in the synthesis of (+)-laurencenone B and (+)-elatol.

In 2012, Dhara and coworkers reported the synthesis of a number of 5,5-spirocyclic hydantoins by utilizing RCM (Scheme 1.30) [46]. Dienes/trienes 180 were treated with G-II in CH2Cl2 to yield the spirocyclic products 181 in excellent yield. Interestingly, when 180 is a triene (R³ = allyl), they observed the formation of spirocycles preferentially over other possible fused RCM products. The utility of this methodology was then demonstrated by converting one of the RCM products to the cyclopentene amino acid 182.

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Scheme 1.30 Synthesis of 5,5-spirocyclic hydantoins.

1.3 Synthesis of Bridged Bicycloalkenes

RCM has also been applied to the synthesis of highly strained bridged ring systems contained in a number of biologically active natural products and small molecules. The main challenge associated with the construction of these systems is the possibility of ROMP or initiation of unwanted cascade reactions. This section summarizes recent advances in the preparation of strained bridged molecules since 2003 [47].

In 2011, Ohyoshi and coworkers reported their synthetic studies toward 13-oxyingenol utilizing spirocyclization and RCM [48]. Stereoselective alkylation of ketone 183 in the presence of LDA afforded bicyclic compound 184 in excellent yield (Scheme 1.31). Bicyclic diene 184 underwent quantitative RCM to generate bridged tricyclic ketone 185, which was then functionalized to provide the 13-oxyingenol tetracycle 186.

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Scheme 1.31 RCM approach to 13-oxyingenol.

In 2009, Sintim et al. reported the total synthesis of oxazinidinyl platensimycin (194) using a dynamic RCM to construct the bridged tricyclic core (Scheme 1.32) [49]. An epimeric mixture of the dienes 188 and 189 (ratio 1 : 3.7), prepared in three steps from vinylogous ester 187, were cyclized with HG-II (5 × 3.2 mol%) in the presence of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to furnish the bicyclo[3.2.1]oct-2-ene 189 in 69% yield along with a small amount of enone 191. This study is a seminal example of a dynamic RCM process involving base-promoted epimerization. The addition of DDQ was necessary to minimize the formation of the olefin migration product 191. Bicycle 190 was subsequently epoxidized and opened with CH3Li to afford the tricyclic alcohol 192 in good yield. Oxidation of alcohol 192 and subsequent debenzylation provided the bridged tricyclic ring core 193 in excellent yield. Oxazinidinyl platensimycin (194) was synthesized from 193 in three steps.

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Scheme 1.32 The total synthesis of oxazinidinyl platensimycin.

In 2009, Magauer and coworkers reported the first total synthesis of the novel sesquiterpenoids (+)-echinopine A (198) and B (199) (Scheme 1.33) [50]. The rare and highly strained [7.5.5.3] all-carbon bridged framework in ketone 199 was prepared by RCM of bicyclo[3.3.0]diene 196, synthesized in several steps from readily available 1,5-cyclooctadiene (195). The total synthesis of echinopines A and B was completed from olefin 197 in eight steps.

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Scheme 1.33 The first total synthesis of (+)-echinopine A.

In 2008, Mulzer and coworkers developed a protecting-group-free formal synthesis of (−)-platencin (203) in five steps using a chiron approach (Scheme 1.34) [51]. Synthesis of the RCM precursor 201 was achieved using a Diels–Alder reaction between (−)-perillaldehyde (200) and the Rawal diene (1-(dimethylamino)-3-(tert-butyldimethylsiloxy)-1,3-butadiene [52], followed by Wittig methylenation. RCM using G-II furnished the platencin tricyclic core 202 in good yield.

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Scheme 1.34 RCM to the strained tricyclic core of (−)-platencin.

In 2008, Becker and coworkers accomplished the total synthesis of the tetracyclic marine diterpene (+)-vigulariol (207) (Scheme 1.35) [53]. The synthesis commenced with the conversion of cyclohexene 204 to diene 205, which readily isomerized under RCM conditions and afforded the tricyclic olefin 206 ( c1-math-0004 ) in a low 17% yield. This product was further converted to (+)-vigulariol. In 2009, Campbell and coworkers reported a synthesis of the antimalarial agent (+)-polyanthellin A (212), whose tetracyclic core structure resembles that of vigulariol [54]. The metathesis substrate 210 was prepared by means of a [3 + 2] cycloaddition with the donor–acceptor cyclopropane 208 and aldehyde 209 (Scheme 1.35). The diene 210 underwent RCM in the presence of HG-II to provide the tricyclic olefin 211 in 70% yield.

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Scheme 1.35 Syntheses of (+)-vigulariol and (+)-polyanthellin A.

The formal total synthesis of (+)-catharanthine (217) reported by Doris and coworkers was based on an unprecedented RCM to form an azabicyclo[2.2.2]alkene system (Scheme 1.36) [55]. Isoquinuclidine 215 was synthesized by RCM of cis-substituted piperidine 214, readily prepared from N-benzyloxycarbonyl-l-serine (213). This RCM was proposed to proceed by the less favored boat conformation, which is required to bring the olefins into proximity with each other. The amide 216 was prepared after carbamate deprotection and 3-indoleacetic acid coupling. This advanced intermediate was converted to the natural product over several subsequent steps.

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Scheme 1.36 Formal total synthesis of (+)-catharanthine.

In 2005, Kuramochi and coworkers reported the total synthesis of garsubellin A (221) (Scheme 1.37) [56]. In addition to its important biological activity, garsubellin A has several challenging structural features, including a tricyclic core and two all-carbon quaternary stereocenters. Starting with the O-allyl substrate 218, a stereoselective Claisen rearrangement was utilized to build the congested quaternary center present in 219. The crucial B ring was formed by RCM to afford the bicyclic product 220 in excellent yield. This product was then further subjected to various transformations to provide garsubellin A (221).

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Scheme 1.37 B-ring formation in the total synthesis of garsubellin A.

1.4 Synthesis of Heterocycles Containing Si, P, S, or B

1.4.1 Si-Heterocycles

The formation of Si-heterocycles has been greatly facilitated by RCM. In 2012, Čusak described numerous applications of RCM forming Si-heterocycles in an elegant review article [57]. In this section, we will briefly highlight significant contributions to the field. Additional information is provided by Marciniec and coworkers in chapter 9.

In 2003, Evans and coworkers reported silicon-tether-mediated diastereoselective RCM studies of prochiral alcohols [58]. Starting with the Si-tethered triene 222, RCM and subsequent hydrogenation afforded the cis- and trans-silaketals 223 and 224 in different ratios based upon the size of the ring being formed (Scheme 1.38). The exclusive formation of trans-silaketal 224 in the case of seven- and eight-membered rings was rationalized by the formation of the favored transition state 225, in which one of the silyl iPr groups and the propenyl substituent adopt pseudoequatorial positions. That same year, the Evans group reported an elegant temporary silicon-tethered RCM strategy for the concise total synthesis of (−)-mucocin (229), a potent antitumor agent [59]. As shown in Scheme 1.38, advanced fragments 226 and 227 were coupled at a late stage of the synthesis to form a mixed bis-alkoxy silane fragment in 74% yield. Subsequent RCM in the presence of 1.8 equiv of the G-I catalyst yielded 227 in 83% yield. Global deprotection and diimide reduction afforded mucocin in an overall 13.6% yield for the 12-step sequence.

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Scheme 1.38 Silicon-tether-mediated diastereoselective ring-closing metathesis.

In 2004, Denmark and coworkers reported the total synthesis of (+)-brasilenyne (233), a potent antifeedant with a unique nine-membered cyclic ether core containing a 1,3-cis,cis-diene subunit (Scheme 1.39) [60]. Subjecting the silyl vinyl ether intermediate 230 to RCM in the presence of Mo-I yielded cyclic silyl intermediate 231 in 93% yield. The RCM product 231 was then transformed to the cyclic ether 232 by an intramolecular silicon-assisted cross-coupling reaction. This crucial intermediate was then converted to the desired natural product (+)-brasilenyne (233).

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Scheme 1.39 Total synthesis of (+)-brasilenyne.

In 2007, Jacobsen and coworkers reported the development of a catalytic asymmetric transannular Diels–Alder (TADA) reaction and demonstrated its utility in the synthesis of the sesquiterpene 11,12-diacetoxydrimane (238, Scheme 1.40) [61]. Trienol 234 was first silylated and then subjected to RCM in the presence of the G-I catalyst to yield the E,E-diene 235 in excellent yield and good selectivity. The RCM product was then subjected to TADA in the presence of catalyst 236 to yield the sesquiterpene core structure 237 with >20 : 1 diastereoselectivity. Olefin 237 was subsequently converted to 11,12-diacetoxydrimane (238).

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Scheme 1.40 RCM product as substrate for asymmetric transannular Diels–Alder reaction.

In 2010, Kobayashi and coworkers reported an elegant RCM study leading to the selective formation of eight-membered E-, and Z-products in differentially substituted Si-tethered dienes (Scheme 1.41) [62]. Subjecting diene 239 to RCM in the presence of HG-II (10–20 mol%) formed either the E-configured 240 or the Z-configured 241 via the crown-like TS 242 or chair-like TS 243, respectively. The authors summarized the factors favoring the formation of E-configured eight-membered rings as follows: (i) a cis relationship of R¹ and R² substituents, (ii) an anti-relationship between the C4-OH/C3-Me groups within the homoallylic alcohol component, (iii) the presence of the C2′-methyl group within the allylic alcohol component, and (iv) the presence of a bulky C3′ substituent.

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Scheme 1.41 Eight-membered E or Z products from differentially-substituted Si-tethered dienes.

1.4.2 P-Heterocycles

In 2009, Hoveyda, Gouverneur, and others reported the desymmetrization of prochiral phosphinates and phosphine oxides using enantioselective RCM for the synthesis of enantiomerically enriched five-, six-, and seven-membered P-stereogenic heterocycles (Scheme 1.42) [63]. Interestingly, use of chiral Mo-based metathesis catalysts (S)-245 and (S)-246, which both contain the same chiral diol ligands but have different achiral imido ligands, afforded opposite enantiomers of seven-membered ring products 247 and 248 with good to excellent enantioselectivity. This opposite stereoinduction was rationalized with different reactive alkylidene geometrical isomers. The anti-alkylidene isomer was proposed to be favored with the catalyst (S)-245 as a result of the steric repulsion between the isopropyl groups and the alkylidene and the syn isomer for catalyst (S)-246 because of the less hindered adamantyl group. Minimized syn-pentane interactions also explained the sense of stereoinduction.

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Scheme 1.42 Desymmetrization of prochiral phosphinates and phosphine oxides using enantioselective RCM.

In 2010, Gouverneur and coworkers further reported the diastereoselective synthesis of P-stereogenic heterocycles in three steps from POCl3 via enyne RCM (Scheme 1.43) [64]. Desymmetrization of prochiral P-containing ene-diynes 249 in the presence of HG-II afforded six- and seven-membered P-heterocycles 250 with good diastereoselectivity and in excellent yield. Anomeric stabilization of the P=O bond and minimized syn-pentane interactions were used to rationalize the observed diastereoselectivity.

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Scheme 1.43 Diastereoselective synthesis of P-stereogenic heterocycles.

In 2010, Virieux and coworkers reported the efficient synthesis of new phosphorus heterocycles 253 and 254 using an RCM process employing allyl vinylphosphonates 251 or unsymmetrical allyl allylphosphonates 252 (Scheme 1.44) [65]. This method also facilitated the synthesis of the hydroxyphosphinate scaffolds 254d–f, with potential use for the generation of phosphosugar libraries.

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Scheme 1.44 RCM approaches to phosphorus heterocycles.

In 2005, Hanson and coworkers utilized an RCM strategy for the concise synthesis of an array of P-chiral, nonracemic phosphono sugars 260 (Scheme 1.45) [66]. The method relied on the stereoselective additions of the allylic alcohols 255 to the allyldiphenylphosphonate esters 256 to afford the P-chiral allylphosphonates 257. Subsequent RCM of 257 using the G-I catalyst generated the allylphostone building block 258. Further transformations utilized oxidation and base-mediated olefin transposition to generate the γ-hydroxy vinyl phosphonates 259, which were available for further stereoselective reactions en route to 260. In this method, the P(2) and C(6) stereogenic centers governed the stereoselective transformations. In addition, the exchangeable phosphonate ester was armed to attenuate the stereochemical environment at phosphorus.

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Scheme 1.45 Syntheses of P-heterocyclic analogs.

In 2006, Prestwich and coworkers reported a versatile and efficient RCM/dihydroxylation strategy for the synthesis of biologically active cyclic phosphonate analogs of lysophosphatidic acid (Scheme 1.45) [67]. RCM of phosphonate 261 with G-I provided the six-membered cyclic phosphonate 262 in excellent yield, and this product was further treated with catalytic dihydroxylation and esterification with palmitic acid to furnish dipalmitoyloxy-substituted cyclic phosphonate 263 and 4-palmitoyloxy-cyclic phosphonate 264 in 28 and 48% yields, respectively. Both phosphonates were converted into the corresponding phosphonic acids 265 and 266 by reductive cleavage (1 atm H2/PtO2 in MeOH).

In 2005, Hanson and coworkers [68] reported the desymmetrization of the C2-symmetric 1,3-anti-diol diene 267 by employing a diastereoselective RCM of the phosphate triester 268 in the presence of the G-II catalyst to enable the formation of the P-chiral bicyclo[4.3.1]phosphate (S,S,SP)-269 in good yield (Scheme 1.46). Treatment of phosphate 269 with LiAlH4 revealed the newly formed Z-allylic alcohol 270.

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Scheme 1.46 Desymmetrization of C2-symmetric 1,3-anti-diol dienes.

A series of synthetically useful transformations were developed by taking advantage of the inherent properties of the unique bicyclic phosphate (S,S,SP)-269 (or its enantiomeric (R,R,RP) counterpart). Specifically, a sequence consisting of chemoselective hydrogenation of the exocyclic olefin followed by diastereoselective cuprate addition provided the derivative 271 in good yield. Successful CM of type I and type II olefins with the exocyclic double bond in 269, followed by tether removal, led to the formation of intermediates with stereochemical arrays found in many polyketide natural products [69]. In 2012, Hanson and coworkers published a multistep, one-pot, sequential RCM/CM/H2 process to construct complex intermediates such as 274 and 275, en route to the total synthesis of natural products (Scheme 1.47) [70]. The chemo- and regioselective hydrogenation was made possible by the stereoelectronic properties inherent to phosphate tethers. Most importantly, this tandem RCM/CM/H2 process preserved the stereochemical integrity of the bicyclic phosphate, which is critical for the success of later transformations.

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Scheme 1.47 Polyketide stereochemical arrays from RCM/CM sequence.

In 2013, the Hanson group reported the importance of the ring size of the product and stereochemistry of the coupling partner in their phosphate tether-mediated RCM process for the preparation of complex 1,3-anti-diol-containing subunits (Scheme 1.48) [71]. Plausible metallacyclobutane RCM intermediates leading to bicyclo[4.3.1]- and bicyclo[5.3.1]-phosphates were proposed to rationalize the observed experimental findings. In the [4.3.1] series, for example, phosphate cis-276 reacted at a much faster rate and in better yield than trans-277, presumably due to an unfavorable 1,2-steric interaction in the metallacyclobutane intermediate trans-278, leading to formation of eight-membered Z-olefin trans-279. The importance of allylic stereochemistry in the formation of the eight-membered ring in the [5.3.1] series was demonstrated by a double diastereotopic differentiation experiment. RCM of triene 282 exclusively provided bicyclo[5.3.1]phosphate diastereomer 284 along with unreacted diastereomeric triene. The endo orientation of the allylic methyl group in trans-284 was confirmed with X-ray crystallography. Its configuration supported the proposed favorable metallacyclobutane intermediate exo,endo-283, and led to the conclusion that the exo-allylic methyl group in 285 is capable of impeding the formation of bicyclic phosphate trans-286. Finally, exclusive E RCM selectivity was observed in the bicyclo[7.3.1]phosphate series, such as in the conversion of trienes 287 and 288 to 10-membered products 289 and 290, respectively.

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Scheme 1.48 Plausible metallacyclobutane RCM intermediates and the formation of complex 1,3-anti-diol-containing subunits.

In 2013, Schmidt and coworkers reported a one-pot diastereoselective synthesis of conjugated dienyl phosphonates from allylphosphonates utilizing a RCM/ring-opening/alkylation sequence [72]. RCM of allylphosphonate 291 in the presence of 0.5 mol% of G-II furnished olefin 292, which was treated with sequential additions of NaH and Meerwein's reagent to afford (1Z,3E)-configured diene 294 in good yield (Scheme 1.49).

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Scheme 1.49 Synthesis of conjugated dienyl phosphonates.

In 2003, Nielsen and coworkers reported the synthesis of dinucleotides from nucleoside monomers containing 4′C-vinyl and 5′C-allyl groups using phosphate-tether mediated RCM (Scheme 1.50) [73]. Their efforts initially focused on the RCM of phosphate-tethered dinucleotide 295; however, RCM cyclization was not observed because of steric hindrance of the vinyl groups. In contrast, RCM of the 5′C-allyl substituted dinucleotide 296 readily occurred in the presence of G-II and afforded the product 297 as mixture of E- and Z-isomers in good yield. Mixed dinucleotide 298, containing 4′C-vinyl and 5′C-allyl groups, generated the RCM product 299 as the Z-isomer in 38% yield, along with 50% starting material.

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Scheme 1.50 RCM approach to dinucleotides.

1.4.3 S-Heterocycles

In 2006, Paquette and coworkers developed a practical synthesis of a doubly unsaturated bicyclo[4.2.1]nonanyl sultam 304 via RCM (Scheme 1.51) [74]. The synthesis was started with commercially available 1,3-propanesultone (300), which was converted in to the RCM precursor 301 in four steps. In the presence G-I, diene 301 gave the monocycle 302 in high yield. Subsequent base-promoted intramolecular alkylation afforded bicycle 303 which after a bromination–dehydrobromination sequence furnished bicyclo-diene 304. Direct 300-nm irradiation of bicyclic sultam 304 delivered endo-oriented cyclobutene 305 in low yield. Sultam 304 was also subjected to heating in the presence of endo-bornyltriazolinedione and underwent [2 + 2] cycloaddition followed by a vinylcyclobutane–cyclohexene rearrangement to provide a 1 : 1 mixture of 308 and its diastereomer.

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Scheme 1.51 Synthesis of a doubly unsaturated bicyclo[4.2.1] sultam.

In 2004, Liskamp and coworkers developed a convenient synthesis of cyclic peptidosulfonamides using RCM (Scheme 1.52) [75]. RCM cyclization of 309 in the presence of G-II in 1,1,2-trichloroethane (TCE) and α,α-dichlorotoluene (to enhance catalyst activity) unexpectedly gave the dimeric 18-membered ring 311 instead of the 9-membered 310. They did not observe the nine-membered ring even at lower concentrations because of to the cisoid conformation of the acrylamide bond. In contrast, allylated peptidosulfonamides 312a–c efficiently ring-closed under same conditions to afford the nine-membered 313a–c in good yields.

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Scheme 1.52 Synthesis of cyclic sulfonamides.

In 2005, Hanson reported the synthesis of 9-, 10-, and 11-membered cyclic sulfamoyl carbamates and nine-membered sulfamoyl ureas utilizing RCM (Scheme 1.52) [76]. A three-component coupling of chlorosulfonyl isocyanate (CSI), allyl alcohol, and N-allyl amino ester 314 was used to generate the corresponding sulfamoyl carbamate 315. Mitsunobu alkylation with benzyl alcohol furnished the intermediate 316 and limited the formation of sulfahydantoin. The desired nine-membered sulfamoyl carbamate 317 was generated using RCM with the G-II catalyst. A similar strategy was employed for the synthesis of sulfamoyl ureas 320, whereby the initial CSI coupling with 2.2 equiv of 314 was found to be optimal affording the acyclic sulfamoyl urea diene 318 in good yields. Benzylation followed by RCM with 6 mol% of G-II catalyst afforded the desired cyclic sulfamoyl ureas 320 in good yields (71–81%).

In 2006, Cossy et al. developed an efficient RCM route for the synthesis of sultones 324 from sulfonyl chloride 321 and secondary alkenols 322 (Scheme 1.53) [77]. Because of its instability, the crude sulfonylation product 323 was subjected to RCM in the presence of G-II (C6H6, 70 °C), affording a variety of substituted sultones 324 in good yields.

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Scheme 1.53 Sultone synthesis.

The aforementioned sulfur building blocks had different α-reactivities under various reaction conditions (Scheme 1.54) [78]. When LDA was used as the base and prior to the introduction of any electrophiles, a sulfene intermediate formed and underwent rapid self-dimerization via [2 + 2] cycloaddition to furnish 1,3-dithietane tetraoxide 325. The authors reported successful α-alkylation of sultone 327 with different alkyl halides in the presence of n-butyllithium, which furnished sultones 326 in excellent yields.

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Scheme 1.54 The chemistry of RCM-derived sultones.

Cossy and coworkers also reported the use of this chemistry