Diverse Natural Products from Dichlorocyclobutanones: An

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Diverse Natural Products from Dichlorocyclobutanones: An Evolutionary Tale Jean-Pierre Deprés, Philippe Delair, Jean-François Poisson, Alice Kanazawa, and Andrew E. Greene* SERCO, Département de Chimie Moléculaire, Univ. Grenoble Alpes, ICMG FR-2607, UMR-5250, 38041 Cedex 9 Grenoble, France CONSPECTUS: 11-Nor PGE2 was prepared in our laboratory several years ago and used to obtain the corresponding ringexpanded γ-butyrolactam, γ-butyrolactone, and cyclopentanone derivatives. The conversion of a cyclobutanone into a cyclopentanone had relatively little precedent and merited further study. It was soon found that the presence of a single chlorine adjacent to the carbonyl not only greatly accelerated the reaction with ethereal diazomethane, but also substantially enhanced its regioselectivity; not surprisingly, a second chlorine further increased both. The confluence of this finding and the discovery by Krepski and Hassner that the presence of phosphorus oxychloride significantly improved the Zn-mediated dehalogenation procedure for the preparation of α,α-dichlorocyclobutanones from olefins provided the starting point for decades’ worth of exciting adventures in natural product synthesis. A wide variety of naturally occurring 5membered carbocycles (e.g., hirsutanes, cuparenones, bakkanes, guaianolides, azulenes) could thus be prepared by using dichloroketene−olefin cycloaddition, followed by regioselective one-carbon ring expansion with diazomethane. Importantly, it was also found that natural γ-butyrolactones (e.g., β-oxygenated γ-butyrolactones, lactone fatty acids) could be secured through regioselective Baeyer−Villiger oxidation of cycloadducts with m-CPBA and that naturally occurring γ-butyrolactam derivatives (e.g., amino acids, pyrrolidines, pyrrolizidines, indolizidines) could be efficiently obtained by regioselective Beckmann ring expansion of the adducts with O-(mesitylenesulfonyl)hydroxylamine (Tamura’s reagent). These 5-membered carbocycles, γ-butyrolactones, and γ-butyrolactam derivatives were generally secured in enantiopure form through the use of either intrinsically chiral olefins or olefins bearing Stericol, a highly effective chiral auxiliary developed specifically for this “three-atom olefin annelation” approach. In addition, considerable useful chemistry has been developed in the context of this synthesis program. This includes new methods for olefin vicinal dicarboxylation, β-methylene-γ-butyrolactonization, γ-butyrolactone and δ-valerolactone α-methylenations, transesterification, angelic ester synthesis, chiral enol and ynol ether preparations, dichloroacetylene synthesis, and trans, trans hydroxy triad introduction. This versatile dichlorocyclobutanone-centered approach to natural product synthesis, together with the attendant new methods that have been developed, forms the basis of this Account, which is presented as an evolutionary tale. It is hoped that the Account will stimulate other research groups to seek to exploit the rich chemistry of dichlorocyclobutanones for possible solutions to problems in organic synthesis.

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INTRODUCTION A number of years ago, our laboratory investigated the synthesis of natural and modified prostaglandins.1 11-Nor PGE2 (1) was prepared2 for the first time in the context of this program and used to obtain the corresponding novel ringexpanded γ-butyrolactone, γ-butyrolactam, and cyclopentanone derivatives (Scheme 1).3 The conversion of a cyclobutanone into a cyclopentanone had at the time relatively little precedent,4 and, we felt, merited further study in light of its considerable potential in synthesis.5 The bicyclic cyclobutanones 6, 9 and 12 (Scheme 2) were immediately available to us, 6 and 12 having served as intermediates in the above syntheses. Exposure of these three substrates to diazomethane in ether-methanol at room temperature proved enlightening: the presence of a single chlorine adjacent © XXXX American Chemical Society

to the carbonyl not only greatly accelerated the reaction, but also substantially enhanced its regioselectivity; not surprisingly, a second chlorine further increased both.6 Dichlorocyclobutanones at the time were invariably prepared from olefins through cycloaddition with dichloroketene, which could be generated by dehydrohalogenation of dichloroacetyl chloride with triethylamine or by dehalogenation of trichloroacetyl chloride with zinc.7 While these procedures were effective with certain classes of olefins, others proved to be poor substrates for dichloroketene generated in either fashion. Fortuitously, Krepski and Hassner disclosed,8 almost concomiReceived: November 8, 2015

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DOI: 10.1021/acs.accounts.5b00493 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. Ring Expansions of 11-Nor PGE2

Scheme 3. Three-Carbon Annelation of Olefins

Scheme 2. Diazomethane Ring Expansions and elimination procedures, effected either alone or in combination, can be used to produce (methyl, chloro) cyclopentanones and cyclopentenones (Chart 1).11 The synthetic usefulness of these various conversions will be in evidence in the work described below. Chart 1. Dichlorocyclopentanone Conversions

tantly with our above study, that the presence of phosphorus oxychloride in the reaction medium served to broaden the scope of the Zn-mediated dehalogenation procedure so as to include previously untoward substrates (eq 1).9

This confluence of discoveries provided the starting point for decades’ worth of exciting adventures in natural product synthesis and in the development of new chemistry. These areas form the subject of this Account.

This three-carbon annelation procedure was first applied iteratively to access two members of the hirsutane family of cis, anti, cis-tricyclo[3.3.0.02,6]undecanes: hirsutene12 and hirsutic acid C.13 The efficient synthesis of hirsutic acid C (36) illustrates this conceptually simple iteration approach, which is well suited to the preparation of fused polycyclopentanoid systems (Scheme 4). The pro-angular methyl group of this triquinane could be introduced directly by cycloaddition with chloromethylketene, but this introduction was more effectively accomplished through methylation of the chlorocyclobutanone enolate (better than the chlorocyclopentanone enolate11). The good to excellent stereo- and regioselectivities with dichloroketene observed in this synthetic approach is an important and recurrent feature of the cycloadditions.

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FIVE- AND FOUR-MEMBERED CARBOCYCLES It was found at the outset that the ubiquitous 5-membered carbocycle could be reliably accessed with diazomethane from the corresponding α,α-dichlorocyclobutanones in high yield and with excellent regioselectivity (Scheme 3). This ring expansion, coupled with the dichloroketene cycloaddition, translates into a three-carbon olefin annelation, a transformation even today not readily accomplished through other approaches.5a,10 The resulting α,α-dichlorocyclopentanones, themselves, can undergo myriad transformations of synthetic interest. For example, partial or complete reductive dechlorination, α-methylation, B


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Accounts of Chemical Research Scheme 4. Iterative Three-Carbon Annelation: Synthesis of (±)-Hirsutic Acid Ca

a

LDC = lithium dimethylcuprate. THT = tetrahydrothiophene.

Scheme 5. Three-Carbon Annelation: Synthesis of (±)-Geigerin

provide the most general access available today to this important class of aromatics.18 Enantioenriched olefins, of course, can also be used in the cycloaddition reaction to generate ultimately enantioenriched, if not enantiopure, natural products.19 Intrinsically chiral olefins (rather than auxiliary-bearing olefins, discussed below) were initially employed in a broad program directed toward the bakkanes, a family of ca. 50 biologically active β-methylene-γbutyrolactone hydrindane sesquiterpenes.20 Easily prepared (S)-1,6-dimethyl-1-cyclohexene (>95% ee) was used to secure not only natural bakkenolide A, but also, subsequently, the densely functionalized bakkenolides, III, B, C, H, L, V, and X.21 The bakkenolide A synthesis showcases general vicinal dicarboxylation22 (50 → 52) and β-methylene-γ-butyrolactonization21a (53 → 54) transformations (Scheme 6). The preparation of bakkenolide B is representative of the complex bakkane syntheses developed in our laboratory (Scheme 7). The high efficiency of the approach results from the development of numerous new methods: a mild transesterification (→ 55), a

More recently, an extremely brief and efficient approach to the guaianolide geigerin (43) has been achieved,14 which clearly illustrates the role this three-carbon annelation can play in the synthesis of complex carbocycles (Scheme 5).15 A key transformation in the approach is the three-step conversion of methylcycloheptatriene 37 into chlorocyclopentenone 38; this provides an appropriately functionalized hydroazulene ring system for effectively accessing the natural product (8%, 8 steps overall). Similar chemistry has produced the hydroazulenes achalensolide, pechueloic acid, and 7-epi-pechueloic (purported to be rupestonic acid).16 Concomitant with this work on hydroazulenes, the use of readily accessible bicyclic chloroenones, such as 38, as pivotal intermediates in a new and concise route to azulenes was also examined. These intermediates, as had been hoped, could be readily modified through various carbonyl additions, couplings, and conjugate additions to provide a route to a wide variety of azulenes in high yield and with perfect regiocontrol (Chart 2).17 Overall, this flexible approach would seem to C


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Accounts of Chemical Research

Preliminary studies with relatively simple chiral enol ethers showed that reasonable to excellent facial selectivities could indeed be achieved on cycloaddition with dichloroketene, thus confirming the validity of the approach.23 The first synthetic application of this new approach to chiral cyclobutanones was for the enantioselective syntheses of (−)-α- and (+)-βcuparenones (64 and 65), seemingly simple cyclopentanones (Scheme 8).24 While the approach was successful, it was apparent that a more general enol ether preparation and a more flexible chiral auxiliary were desirable. At the time, there was a dearth of simple, general procedures to access enol ethers, particularly chiral ones. Since a greater availability of these useful, well-studied compounds would transcend our own needs, considerable effort was expended toward this end. An outstandingly simple and flexible procedure was eventually developed based on alkoxide addition to in situ generated dichloroacetylene25 and subsequent ynol ether reduction (eq 2).26 Recently, 35Cl labeling and theoretical

Chart 2. Three-Carbon Annelation: Azulenes

studies27 have led to a mechanistic understanding of this transformation of alcohols into ynol ethers (themselves valuable compounds28). It was clear that the possibility of ultimately cleaving the chiral control group to leave a hydroxyl group would provide additional synthetic options in our work; thus, benzylic alcohol inductors were examined.29 As can be seen in Chart 3, 1-(2,4,6triisopropylphenyl)ethanol was the best of the benzylic alcohols tested. Molecular mechanics calculations29 indicated that cycloaddition should in fact occur as observed, highly stereoselectively on the Cα-si face, the re face being obscured by an isopropyl group. This excellent inductor, now known as Stericol, can easily be prepared on a large scale in both enantiomeric forms,30 which are currently available commercially from several suppliers. The various enantiocontrolled syntheses described in the remainder of this review in large measure owe their success to the different synthetic options that are afforded by Stericol.31 Four-membered carbocycles are found in nature and serve as building blocks. Effective routes to cyclobutanes were relatively rare, however, and few were able to provide enantiomerically pure derivatives.32 The chiral enol ether−dichloroketene cycloaddition potentially offered flexible access to usefully functionalized, stereopure cyclobutanes, but the chlorines needed to be satisfactorily removed at some point from the dichlorocyclobutanones for the approach to be of broad value. This reduction was thus studied and a simple, one-pot procedure was devised for converting the Z-enol ethers into the desired reduced cis-disubstituted cyclobutanones in excellent yield and stereochemical purity (Table 1).33,34 Although E-enol ethers could be used to furnish the corresponding trans-disubstituted cyclobutanones, DBU−promoted cis → trans isomerization of the above cycloadducts proved more efficient (65% average overall yield from the Z-enol ethers). Clean cleavage of the chiral inductor is of course crucial for subsequent synthetic use of these molecules; fortunately, this can be accomplished smoothly with trifluoroacetic acid

Scheme 6. Selective Synthesis of (+)-Bakkenolide A

spiro β-methylene-γ-butyrolactonization (55 → 56), an epoxy ketone double reduction (→ 58), a retro aldol−aldol approach to low energy aldol isomers (58 → 59), and an improved procedure for angelic ester preparation (59 → 60).21 The conversion of the dechlorinated cyclobutanone from 51 into its cyclopentanone derivative is particularly noteworthy since it involves an insertion (81:19 selectivity) that is regio complementary to the diazomethane ring expansion of 18 (95:5, Scheme 3). Enantioenriched olefins that are chiral by virtue of an auxiliary, in particular enol ethers, offer a number of potential advantages over those that are intrinsically chiral: generally greater availability, enhanced reactivity, and cycloaddition products with additional useful functionality. Because of the large number of known, readily available chiral alcohols, attention was focused from the outset on enol ethers. D


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Accounts of Chemical Research Scheme 7. Diastereoselective Synthesis of (−)-Bakkenolide B

Scheme 8. Synthesis of Enantiopure α- and β-Cuparenonesa

a

Table 1. Chiral Cyclobutanone Synthesisa

TPC = (1S,2R)-2-phenylcyclohexyl.

Chart 3. Chiral Auxiliary

aR

StOH = (R)-Stericol; SStOH = (S)-Stericol.

The synthesis from cyclobutanone 77 of cyclobut-G (81, Lobucavir), a derivative of the highly potent anti-HIV natural product, oxetanocin A, showcases this cyclobutane approach (Scheme 9).33a Given the lack of useful routes to chiral cyclobutanes, this simple and efficient approach from readily available enol ethers, via dichlorocyclobutanones, would seem to be of particular value.

in methylene chloride at 0 °C (selectively in the presence of OTIPS (77), 90%). E


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Accounts of Chemical Research Scheme 9. Synthesis of (−)-Cyclobut-Ga

aR

Scheme 10. Asymmetric Lactone Synthesis: (+)-Blastmycinone and (+)-Antimycinonea

StOH = (R)-Stericol.

Significantly, ring expansion of the chiral enol ether− dichloroketene cycloadducts is not limited to methylene insertion.35 It was discovered relatively early in our work that Stericol-bearing dichlorocyclobutanones also partake smoothly and highly regioselectively in Baeyer−Villiger and Beckmann ring expansions to engender a variety of γ-butyrolactones and γ-butyrolactams, constituting, overall, lactone and lactam olefin annelations.

aS

StOH = (S)-Stericol. RI = C4H9I or C6H13I.

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γ-BUTYROLACTONES γ-Butyrolactones represent greater than 10% of structurally elucidated natural products; thus, new synthetic approaches, particularly asymmetric ones, are of real interest. Since Baeyer− Villiger oxidation had already been successfully applied to cyclobutanones (including dichloro-5a and 3-benzyloxysubstituted19a ones), it was with confidence that the Stericolbearing dichlorocyclobutanones were envisioned for enantioselective γ-butyrolactone synthesis. (+)-Blastmycinone (85), a hydrolysis product of antimycin A3, and (+)-antimycinone (86), a degradation product from antimycin A3, are representative of β-oxygenated γ-butyrolactones obtained from metabolites. Their synthesis, shown in Scheme 10, was efficient and afforded enantiopure material.29 Key to the success of the approach, in addition to the smooth Baeyer−Villiger reaction of the dichlorocyclobutanone, was the dechlorination, without β-elimination, in the transformation into 84. This reduction was in remarkable contrast to what had earlier been observed with similarly substituted cyclopentanones (e.g., 62 → 63, Scheme 8). The most likely explanation for this dichotomy is conformational: the relatively flexible cyclopentanones are better able to achieve the necessary alignment for elimination. The lack of elimination observed on reduction of the dichlorocyclobutanones (Table 1) supports this hypothesis. (−)-Methylenolactocin (88) and (−)-protolichesterinic acid (89) were similarly prepared, each for the first time (eq 3).36 These syntheses featured, in addition to asymmetric cycloadditions coupled with regioselective Baeyer−Villiger reactions of the derived dichlorocyclobutanones, an improved procedure for α-methylenation of γ-lactones, an important transformation in view of the ubiquity of α-methylene-γ-butyrolactones in nature and their biological activity. These fragile lactone fatty

acids could be secured in 66−68% yields through the use of this new procedure (eq 3).

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γ-BUTYROLACTAM DERIVATIVES The clean, regioselective ring expansion of cyclobutanone 1 with Tamura’s reagent37 suggested that the reagent might prove generally useful for effecting Beckmann reactions of 4-membered ring ketones. However, it was soon discovered that other cyclobutanones suffered expansions that were considerably less selective, with one exception: the α,αdichlorocyclobutanones. We and others38 found these substrates on exposure to Tamura’s reagent underwent ring expansion exclusively on the side opposite to that of the chlorines to generate α,α-dichloro γ-butyrolactams, compounds of considerable synthetic potential (eq 4).

The first use of dichloroketene-olefin asymmetric cycloaddition for an enantioselective synthesis of a γ-lactam was for the preparation of a key component of several acid protease inhibitors, (−)-statine (93, Scheme 11).39 The synthesis relied F


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Accounts of Chemical Research Scheme 11. Amino Acids from Pyrrolidinones: (−)-Statinea

aR

chlorine reduction that needed once again to proceed without elimination (→ 92). Recrystallization of pyrrolidinone 92, followed by treatment with acid, provided enantiopure (−)-statine. Two other β-hydroxy-γ-amino acids, (−)-AHPPA40 and (−)-detoxinine,41 have also been prepared in our laboratory by using these key transformations. The chiral pyrrolidinones were obviously also potential precursors of pyrrolidine natural products, such as (+)-preussin40 and (−)-anisomycin.42 Our short preparation of the former, summarized in Scheme 12, demonstrated this feasibility. (+)-Preussin (97), isolated from fermentation broths of Aspergillus ochraceus and found to possess a broad spectrum of potent antifugal activity against fungi and yeasts, has most often been prepared from (S)-phenylalanine. Our nonchiral pool approach, however, proved highly effective. The key dichlorocyclobutanone 94, obtained diastereomerically pure by recrystallization, was converted with total regioselectivity into the corresponding pyrrolidinone, which in turn could be transformed into pyrrolidine 96 with complete stereocontrol. (+)-Preussin was obtained in 15% overall yield (10 steps). It was also easily recognized that the pyrrolidinones and pyrrolidines might, in addition, provide direct access to pyrrolizidines43 and indolizidines44 through functionalized sidechain(s) cyclization. This approach has indeed proven over the past few years to be extremely versatile and has allowed us to prepare efficiently a large variety of naturally occurring pyrrolizidines ((+)-amphorogynines A and D,45 (+)-retronecine,45 and (+)-hyacinthacines A1, A2, A6, A7, B1 et B246) and indolizidines ((−)-slaframine,47 (+)-lentiginosine,48 (−)-2epilentiginosine,48 (−)-swainsonine,49 (+)-6-epicastanospermine,49 and (+)-castanospermine50). The first nonchiral pool synthesis of (+)-hyacinthacine B1 (104, Scheme 13) is representative of our approach to the pyrrolizidines. (+)-Hyacinthacine B1, a selective β-glucosidase inhibitor, is characterized by the presence of five stereogenic centers and two hydroxymethyl groups. These synthetically challenging features could be effectively addressed through an enantioselective preparation of lactam 98, highly stereoselective Bruylants-like reactions for the introduction of latent hydroxymethyl sub-


Scheme 12. Pyrrolidines from Pyrrolidinones: (+)-Preussina

aR


on the efficient, regioselective Beckmann ring expansion of the densely substituted dichlorocyclobutanone 91 and a subsequent

Scheme 13. Pyrrolizidines from Pyrrolidinones: (+)-Hyacinthacine B1a

aS

StOH = (S)-Stericol. G


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Accounts of Chemical Research Scheme 14. Indolizidines from Pyrrolidinones: (+)-Castanosperminea

aR


stituents, an endoselective reaction of olefin 101 with osmium tetroxide for dihydroxylation, and an unusual double TamaoFleming oxidation of disilyl derivative 103 to liberate in a single step the two requisite hydroxymethyl groups. The overall yield of enantiopure (+)-hyacinthacine B1 through this nonchiral pool approach was 6.5%. Diverse techniques, which allow for different subsequent synthetic transformations, can be used to achieve cyclization to form the pyrrolizidine and indolizidine skeletons.45−50 While lactamization (99 → 100) was a key step in the above pyrrolizidine synthesis, Grubbs ring-closing metathesis was crucial in our synthesis of the indolizidine (+)-castanospermine (111): it provided the necessary substrate 108 for stereoselective introduction on the six-membered ring of the required trans, trans hydroxy triad through hydroboration-oxidation (Scheme 14).50 Since the trans, trans hydroxy arrangement is common to several other natural products (inter alia, pancratistatin, siculinine, and calystegin B2), this novel enol ether metathesis-hydroboration/oxidation, developed for castanospermine, should find additional application.

with Prof. P. Crabbé at the same university in 1979. He was appointed assistant professor at the university in 1981 and then full professor in 1992. During 1980−1982, he was a visiting scholar at the University of California, Berkeley, with Prof. W. Dauben. Prof. Deprés, who has authored over 40 publications in the areas of natural product synthesis and development of new synthetic methods, retired from the university in 2014. He is currently a consultant with ERAS Labo, near Grenoble. Philippe Delair was born in Saint-Etienne, France, in 1963. He completed his undergraduate studies at the Université Joseph Fourier in Grenoble, where he also received his PhD degree in 1993 (Dr. J.-L. Luche). He then went to the University of Rochester for postdoctoral training under the guidance of Prof. A. S. Kende. In 1994, he returned to the university in Grenoble, where he was appointed Assistant Professor and joined the group of Dr. A. E. Greene. Jean-François Poisson was born in Brest on May 16, 1972. He studied chemistry at the Ecole Nationale Supérieure de Chimie de Paris (ENSCP) and obtained a Master’s Degree from the Université Pierre et Marie Curie (Prof. I. Marek) in 1995. He then spent 18 months at the University of Cambridge (Prof. S. V. Ley) as a visiting student. In 2000, he obtained his PhD from the Université Pierre et Marie Curie (Prof. J. Normant). After postdoctoral study in Zurich (ETH, Prof. A. Vasella), he joined the Département de Chimie Moléculaire at the Université Joseph Fourier in Grenoble in 2001 as a CNRS researcher and obtained his “habilitation à diriger les recherches” in 2007. He was promoted in September 2013 to Full Professor at the Université Joseph Fourier, where he is currently the head of the “Synthèse et Réactivité en Chimie Organique” group. His main research interest centers on the development of novel synthetic methods for natural product synthesis.

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CONCLUDING REMARKS A poorly selective diazomethane ring expansion of a cyclobutanone observed many years ago has led to the discovery of effective approaches to a variety of cyclobutane, cyclopentane, γ-butyrolactone, and γ-butyrolactam-derived natural products, with attendant development of considerable new chemistry. Recently, in an extension of the above work, the 8b-azaacenaphthylene tricyclic scaffold common to the dimeric ladybird alkaloids has been prepared.51 It is probable that this rich dichlorocyclobutanone-centered research will evolve yet further to provide novel solutions to other problems in organic synthesis.

Biographies

Alice Kanazawa was born in 1964 in Jacarei-SP, Brazil. She received her BSc degree in chemistry from the Federal University of Sao Carlos in 1986 and her MSc degree from the State University of Campinas in 1989. She then moved to France for her PhD studies (1990−1994) under the supervision of Dr. A. E. Greene at the Université Joseph Fourier in Grenoble. After postdoctoral studies at the University of Rochester in the group of Prof. R. Boeckman, Jr., and a temporary lecturer position (ATER) at the Université Joseph Fourier, she was appointed Assistant Professor at the latter university. Her research interests focus on the synthesis of bioactive compounds and the development of novel synthetic methodologies in organic chemistry.

Jean-Pierre Deprés was born on July 31, 1944 in Jura, France. He obtained his undergraduate degree at the Université Scientifique et Médicale de Grenoble in 1973 and his doctoral degree (Thèse d’Etat)

Andrew E. Greene was born in New York on July 3, 1944. He received his undergraduate degree from Princeton University in 1966 and his doctoral degree from Northwestern University

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

H


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(9) For reviews on dichloroketene, see: (a) Hyatt, J. A.; Raynolds, P. W. Ketene Cycloadditions. Org. React. 1994, 45, 159−646. (b) Tidwell, T. T. Ketenes; Wiley: New York, 1995. For a review on (chloro) cyclobutanone synthesis through intramolecular (chloro) ketene cycloaddition, see: (c) Snider, B. B. Intramolecular Cycloaddition Reactions of Ketenes and Keteiminium Salts with Alkenes. Chem. Rev. 1988, 88, 793−811. (10) Ramaiah, M. Cyclopentaannellation Reactions in Organic Synthesis. Synthesis 1984, 529−570. (11) Deprés, J.-P.; Greene, A. E. Transformations of α,αDichlorocyclopentanones Obtained by Three-Carbon Annelation. J. Org. Chem. 1980, 45, 2036−2037. (12) Greene, A. E. Iterative Three-Carbon Annelations. Synthesis of (±)-Hirsutene. Tetrahedron Lett. 1980, 21, 3059−3060. (13) Greene, A. E.; Luche, M.-J.; Deprés, J.-P. Iterative Three-Carbon Annelation. A Stereoselective Total Synthesis of (±)-Hirsutic Acid C. J. Am. Chem. Soc. 1983, 105, 2435−2439. (14) Carret, S.; Deprés, J.-P. Access to Guaianolides: Highly Efficient Stereocontrolled Total Synthesis of (±)-Geigerin. Angew. Chem., Int. Ed. 2007, 46, 6870−6873. (15) See: Zhuzbaev, B. T.; Adekenov, S. M.; Veselovsky, V. V. Approaches the Total Synthesis of Sesquiterpenoids of the Guaiane Series. Russ. Chem. Rev. 1995, 64, 187−200. (16) Sainte-Luce Banchelin, T.; Carret, S.; Giannini, A.; Deprés, J.-P. Short and Stereoselective Total Synthesis of Δ-11,13-Didehydroguaianes and -guaianolides: Synthesis of (±)-Achalensolide and (±)-Pechueloic Acid; Revision of the Structure of (+)-Rupestonic Acid. Eur. J. Org. Chem. 2009, 3678−3682. (17) Carret, S.; Blanc, A.; Coquerel, Y.; Berthod, M.; Greene, A. E.; Deprés, J.-P. Approach to the Blues: A Highly Flexible Route to the Azulenes. Angew. Chem., Int. Ed. 2005, 44, 5130−5133. (18) (a) For a review, see: Zeller, K.-P. Azulene. In Houben-Weyl; Methoden der Organischen Chemie, 4th ed.; Kropf, H., Ed.; Georg Thieme: Stuttgart, 1985; Vol. V/2c, pp 127−418. (b) For a more recent synthetic approach, see: Crombie, A. L.; Kane, J. L., Jr.; Shea, K. M.; Danheiser, R. L. Ring Expansion-Annulation Strategy for the Synthesis of Substituted Azulenes and Oligoazulenes. 2. Synthesis of Azulenyl Halides, Sulfonates, and Azulenylmetal Compounds and Their Application in Transition-Metal-Mediated Coupling Reactions. J. Org. Chem. 2004, 69, 8652−8667. (19) Alternatively, chiral ketene and chiral keteniminium salts can be used. See: (a) Fráter, G.; Müller, U.; Günther, W. [2 + 2] Cycloaddition of Optically Active Ketenes. Synthesis of (−)-Blastmycinone. Helv. Chim. Acta 1986, 69, 1858−1861. (b) Houge, C.; Frisque-Hesbain, A. M.; Mockel, A.; Ghosez, L.; Declercq, J. P.; Germain, G.; Van Meerssche, M. Models for Asymmetric [2 + 2] Cycloadditions. J. Am. Chem. Soc. 1982, 104, 2920−2921. (20) (a) Fischer, N. H.; Oliver, E. J.; Fischer, H. D. The Biogenesis and Chemistry of Sesquiterpene Lactones. In Progress in the Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer-Verlag: New York, 1979; Vol. 38, Chapter 2, pp 47− 320. (b) Silva, L. F. Total Synthesis of Bakkanes. Synthesis 2001, 671− 689. (21) (a) Brocksom, T. J.; Coelho, F.; Deprés, J.-P.; Greene, A. E.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.; Kanazawa, A. M.; Wang, Y. First Comprehensive Bakkane Approach: Stereoselective and Efficient Dichloroketene-Based Total Syntheses of (±)- and (−)-9Acetoxyfukinanolide, (±)- and (+)-Bakkenolide A, (−)-Bakkenolides III, B, C, H, L, V, and X, (±)- and (−)-Homogynolide A, (±)-Homogynolide B, and (±)-Palmosalide C. J. Am. Chem. Soc. 2002, 124, 15313−15325. (b) Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. The First Entry to Complex Bakkanes: A Highly Effective Retroaldol−Aldol-Based Approach to (−)-Bakkenolides III, B, C, and H. Angew. Chem., Int. Ed. 2000, 39, 4314−4316. (22) Deprés, J.-P.; Greene, A. E. Vicinal Dicarboxylation of an Alkene: cis-1-Methylcyclopentane-1,2-dicarboxylic Acid. Org. Synth. 1987, 68, 41−48. (23) It is important to recognize at this point that if the alcohol used to prepare an enol ether is enantiopure, the resulting diastereomers are

(Prof. J. A. Marshall) in 1971. After postdoctoral studies in Strasbourg (Prof. G. Ourisson) and a stint at Smith, Kline & French in Philadelphia, he returned to France in 1974 for additional postdoctoral studies at the Université Scientifique et Médicale de Grenoble (Prof. P. Crabbé), where he entered the CNRS in 1976. He continues to work in Grenoble and is currently an emeritus Directeur de Recherche with the CNRS. His main research interests continue to be in the areas of natural product synthesis and new synthetic methods.

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ACKNOWLEDGMENTS The authors thank the many talented staff members and undergraduate, doctoral, and postdoctoral students, whose names are cited in the references, for their invaluable contributions to this research. In addition, the referees are thanked for their many constructive comments. Research support from the CNRS, the Ministry of Research, the Université Joseph Fourier, RhônePoulenc Agro, Rhône-Poulenc Rorer, and Sanofi-Aventis is gratefully acknowledged.

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DEDICATION This Account is dedicated to the memory of Pierre Crabbé, an excellent chemist, mentor, and friend. REFERENCES

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(36) (a) M. B. de Azevedo, M.; Murta, M. M.; Greene, A. E. Novel, Enantioselective Lactone Construction. First Synthesis of Methylenolactocin, Antitumor Antibiotic from Penicillium sp. J. Org. Chem. 1992, 57, 4567−4569. (b) Murta, M. M.; M. B. de Azevedo, M.; Greene, A. E. Synthesis and Absolute Stereochemistry of (−)-Protolichesterinic acid, Antitumor Antibiotic Lactone from Cetraria islandica. J. Org. Chem. 1993, 58, 7537−7541. (37) Tamura, Y.; Minamikawa, J.; Ikeda, M. O-Mesitylenesulfonylhydroxylamine and Related Compounds  Powerful Aminating Reagents. Synthesis 1977, 1−17. (38) Luh, T.-Y.; Chow, H.-F.; Leung, W. Y.; Tam, S. W. On the Regioselectivity of the Beckmann Rearrangement of Cyclobutanones with O-Mesitylene-sulfonylhydroxylamine. A Convenient Synthesis of Substituted Octahydrocyclopenta[b]pyrroles. Tetrahedron 1985, 41, 519−525. (39) Nebois, P.; Greene, A. E. Novel Enantioselective Approach to γLactams from Chiral Enol Ethers: Synthesis of (−)-Statine. J. Org. Chem. 1996, 61, 5210−5211. (40) Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. Practical Asymmetric Approach to Pyrrolidinones: Efficient Synthesis of (+)-Preussin and (−)-AHPPA. J. Org. Chem. 1998, 63, 4660−4663. (41) Ceccon, J.; Poisson, J.-F.; Greene, A. E. Extending the Scope of the [2 + 2] Cycloaddition of Dichloroketene to Chiral Enol Ethers: Synthesis of (−)-Detoxinine. Synlett 2005, 1413−1416. (42) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. Formal Total Synthesis of Enantiopure (−)-Anisomycin, Antibiotic from Streptomyces. J. Org. Chem. 1999, 64, 1383−1386. (43) For a review, see: Robertson, J.; Stevens, K. Pyrrolizidine Alkaloids. Nat. Prod. Rep. 2014, 31, 1721−1788. (44) For a review, see: Michael, J. P. Indolizidine and Quinolizidine Alkaloids. Nat. Prod. Rep. 2008, 25, 139−165. (45) Roche, C.; Kadlecikova, K.; Veyron, A.; Delair, P.; Philouze, C.; Greene, A. E.; Flot, D.; Burghammer, M. New Asymmetric Approach to Natural Pyrrolizidines: Synthesis of (+)-Amphorogynine A, (+)-Amphorogynine D, and (+)-Retronecine. J. Org. Chem. 2005, 70, 8352−8363. (46) (a) Veyron, A.; Reddy, P. V.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Stereocontrolled Synthesis of Glycosidase Inhibitors (+)-Hyacinthacines A1 and A2. Tetrahedron: Asymmetry 2015, 26, 85−94. (b) Smith, J.; Kamath, A.; Greene, A. E.; Delair, P. Total Synthesis of (+)-Hyacinthacine A6 and (+)-Hyacinthacine A7. Synlett 2014, 25, 209−212. (c) Reddy, P. V.; Smith, J.; Kamath, A.; Jamet, H.; Veyron, A.; Koos, P.; Philouze, C.; Greene, A. E.; Delair, P. Asymmetric Approach to Hyacinthacines B1 and B2. J. Org. Chem. 2013, 78, 4840−4849. (47) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A. E. Highly Enantioselective Approach to Indolizidines: Preparation of (+)-(1S,8aS)-1-Hydroxyindolizidine and (−)-Slaframine. J. Org. Chem. 2000, 65, 6966−6972. (48) Rasmussen, M. O.; Delair, P.; Greene, A. E. Enantiocontrolled Preparation of Indolizidines: Synthesis of (−)-2-Epilentiginosine and (+)-Lentiginosine. J. Org. Chem. 2001, 66, 5438−5443. (49) Ceccon, J.; Greene, A. E.; Poisson, J.-F. Asymmetric [2 + 2] Cycloaddition: Total Synthesis of (−)-Swainsonine and (+)-6Epicastanospermine. Org. Lett. 2006, 8, 4739−4742. (50) (a) Ceccon, J.; Danoun, G.; Greene, A. E.; Poisson, J.-F. Asymmetric Synthesis of (+)-Castanospermine Through Enol Ether Metathesis−Hydroboration/Oxidation. Org. Biomol. Chem. 2009, 7, 2029−2031. (b) This strategy has also been used in an efficient synthesis of (+)-1-deoxynojirimycin. See: Danoun, G.; Ceccon, J.; Greene, A. E.; Poisson, J.-F. Stereocontrolled Total Synthesis of (+)-1Deoxynojirimycin. Eur. J. Org. Chem. 2009, 2009, 4221−4224. (51) Kamath, A.; Fabritius, C.-H.; Philouze, C.; Delair, P. A New Approach to the 8b-Azaacenaphthylene Ring System. Org. Biomol. Chem. 2015, 13, 9834−9843.

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