Table of Contents
Related Titles
Title Page
Copyright
List of Contributors
Chapter 1: Catalytic Enantioselective Alkylation of Prochiral Ketone Enolates
Background
Strategy and Results
Asymmetric Allylic Alkylation in Total Synthesis
Conclusions
CV of Corey M. Reeves
CV of Brian M. Stoltz
References
Chapter 2: Point-to-Planar Chirality Transfer in Total Synthesis: Scalable and Programmable Synthesis of Haouamine A and Its Atropisomer
Introduction
Synthetic Strategy Featuring Point-to-Planar Chirality Transfer
Programmable Synthesis of Haouamine A and Its Atropisomer
CV of Noah Z. Burns
CV of Phil S. Baran
References
Chapter 3: Tethered Aminohydroxylation
Introduction and Background
Tethered Aminohydroxylation
Amide-Based Reoxidants
Evidence for the Mechanism of the TA Reaction
Applications in Organic Synthesis
Conclusion and Future Work
CV of Timothy J. Donohoe
CV of Stefanie Mesch
References
Chapter 4: Organocatalyzed Transformations of α, β-Unsaturated Carbonyl Compounds through Iminium Ion Intermediates
CV of Nicholas C. O. Tomkinson
CV of Julian H. Rowley
References
Chapter 5: The Renaissance of Silicon-Stereogenic Silanes: A Personal Account
Background
Results
Conclusion
CV of Martin Oestreich
CV of Andreas Weickgenannt
References
Chapter 6: Asymmetric Dienamine Activation
Introduction
Historic Background
Results
Conclusion
CV of Mathias Christmann
References
Chapter 7: Asymmetric Brønsted Acid Catalysis
Introduction and Background
Strategy
Results
Summary
CV of Iuliana Atodiresei
CV of Uxue Uria
CV of Magnus Rueping
References
Chapter 8: Quaternary Stereogenic Centers by Enantioselective β-Carbon Eliminations from tert-Cyclobutanols
Background
Objective: Enantioselective Formation of Quaternary Stereogenic Centers in Combination with Reactive Alkyl-Rhodium Intermediates
Selective Generation of the Alkyl-Rhodium Species and Its Downstream Reactivities
CV of Nicolai Cramer
CV of Tobias Seiser
Chapter 9: Total Synthesis of Oseltamivir and ABT-341 Using One-Pot Technology
Introduction
Results
Conclusions
CV of Yujiro Hayashi
CV of Hayato Ishikawa
References
Chapter 10: Enantioselective Annulations with Chiral N-Mesityl N-Heterocyclic Carbenes
Introduction
Catalytic Generation of Chiral Enolate Equivalents
Catalytic Generation of Homoenolate Equivalents
Enantioselective Cascade Reactions Catalyzed by Chiral N-Heterocyclic Carbenes
Catalytic Annulations via α, β-Unsaturated Acyl Azoliums
Conclusions
CV of Jeffrey Bode
CV of Jessada Mahatthananchai
References
Chapter 11: Asymmetric Counteranion-Directed Catalysis (ACDC)
Concept
Application of ACDC to Organocatalysis
Application of ACDC to Transition Metal Catalysis
Application of ACDC to Lewis Acid Catalysis
CV of Manuel Mahlau
CV of Prof. Dr. Benjamin List
References
Chapter 12: Enantioselective Organo-SOMO Catalysis: a Novel Activation Mode for Asymmetric Synthesis
Background
Objective
Results
CV of David W.C. MacMillan
CV of Sebastian Rendler
References
Chapter 13: Enantioselective Passerini Reaction
Introduction
Background
Results
Conclusion and Perspective
CV of Qian Wang
CV of Jieping Zhu
CV of Mei-Xiang Wang
References
Chapter 14: Rapid Enantiomeric Excess Determination
CV of Oliver Trapp
References
Chapter 15: Asymmetric Catalysis of Reversible Reactions
Thermochemistry of Asymmetric Catalyses Close to the Equilibrium
Kinetic Modeling of a Reversible Asymmetric Catalytic Reaction
Case Study: a Reversible Asymmetric Organocatalytic Reaction
Conclusions
CV of Lukas Hintermann
References
Chapter 16: Exploiting Fluorine Conformational Effects in Organocatalyst Design: The Fluorine–Iminium Ion Gauche Effect
CV of C. Sparr
CV of L. Zimmer
CV of R. Gilmour
References
Chapter 17: Dutch Resolution
CV of Richard M. Kellogg
References
Chapter 18: Construction of anti-Me-OH Vicinal Relationships in Polyketides
Introduction
Marshall–Tamaru Reaction
Conclusions
CV of Vaidotas Navickas
CV of Martin E. Maier
References
Chapter 19: Photoswitchable General Base Catalysts
Introduction and Background
Strategy and Results
Outlook
CV of Philipp Viehmann
CV of Stefan Hecht
References
Chapter 20: Asymmetric Halonium Addition to Olefins
Introduction
Intramolecular Lactonizations, Etherifications, and Aminations
Polyene Cyclizations
Intermolecular Additions to Alkenes
Conclusion
CV of Scott A. Snyder
CV of Alexandria P. Brucks
References
Chapter 21: Catalytic Asymmetric Gosteli–Claisen Rearrangement (CAGC)
CV of Julia Rehbein
CV of Martin Hiersemann
References
Chapter 22: Biomimetic Total Synthesis of the Penifulvin Family
Introduction
The Penifulvin Family: Isolation and Biogenetic Origin
Total Syntheses of Penifulvins A, B, and C
Summary
CV of Prof. Johann Mulzer
CV of Tanja Gaich
References
Chapter 23: Catalyst-Controlled 1,3-Polyol Syntheses
CV of Stefan F. Kirsch
CV of Tobias Harschneck
References
Chapter 24: Enantioselective Carbonyl Allylation and Crotylation from the Alcohol Oxidation Level via C–C Bond Forming Transfer Hydrogenation
Introduction and Background
Strategy
Results
CV of Michael Krische
CV of Joseph Moran
References
Chapter 25: Stereoselective Synthesis with Hypervalent Iodine Reagents
CV of Umar Farid
CV of Thomas Wirth
References
Chapter 26: Asymmetric Gold-Catalyzed Reactions
Introduction
Diphosphine-Gold Complexes in Enantioselective Catalysis
Monophosphine-Gold Complexes in Enantioselective Catalysis
CV of Núria Huguet
CV of Antonio M. Echavarren
References
Chapter 27: Asymmetric Catalysis in the Total Synthesis of Lipids and Polyketides
Background
Tuberculostearic Acid: One Isolated Methyl Group
Ant Pheromones: Vicinal Methyl Branches
Deoxypropionates: 1,3-Methyl Arrays
Membrane-Spanning Lipids: 1,4-Dimethyl Units
Saturated Isoprenoids: 1,5-Methyl Arrays
CV of Santiago Barroso
CV of Adriaan J. Minnaard
References
Chapter 28: The Evolving Role of Biocatalysis in Asymmetric Synthesis
Background – First- and Second-Generation Biotransformations
Results–Third-Generation Biotransformations
Conclusions and Future Perspectives
CV of Mélanie Hall
CV of Wolfgang Kroutil
CV of Kurt Faber
References
Chapter 29: Bifunctional Thiourea Catalysts
Background
Results
CV of Yoshiji Takemoto
CV of Tsubasa Inokuma
References
Chapter 30: Catalytic Asymmetric (4 + 3) Cycloadditions Using Allenamides
Introduction and Background
Strategy
Results
Conclusion
CV of Yun-Fei Du
CV of Richard P. Hsung
References
Chapter 31: Application of the Achmatowicz Rearrangement for the Synthesis of Oligosaccharides
Introduction
De novo Approach to Carbohydrates
An Iterative Pd-Catalyzed Glycosylation and Bidirectional Postglycosylation
Application to the Synthesis of the Anthrax Tetrasaccharide
CV of Michael F. Cuccarese
CV of George A. O'Doherty
References
Chapter 32: Asymmetric C–C Bond Formation Using Chiral Phosphoric Acid
Background
Results
Conclusions and Future Perspectives
CV of Takahiko Akiyama
References
Chapter 33: Asymmetric C–H Bond Functionalization
Background
Results
Conclusions and Future Perspectives
CV of Masayuki Wasa
CV of Kelvin S. L. Chan
CV of Jin-Quan Yu
References
Chapter 34: Asymmetric C–C Bond Formation Using Chiral Guanidine Catalysts
Background
Catalyst Design and Results
CV of Masahiro Terada
References
Chapter 35: Enantioselective Synthesis of Lactones via Rh-Catalyzed Ketone Hydroacylation
Background and Introduction
Strategy and Results
Conclusions and Future Directions
CV of Vy M. Dong
CV of Matthew M. Coulter
References
Chapter 36: Radical Haloalkylation
CV of Armen Zakarian
References
Chapter 37: Asymmetric Hydrovinylation of Alkenes
Introduction
New Protocols for the Heterodimerization of Ethylene/Propylene and Vinylarenes, 1,3-Dienes, and Norbornene
Catalytic Asymmetric Hydrovinylation Reactions: Effects of Hemilabile Ligands
All-Carbon Quaternary Centers via Catalytic Asymmetric HV
Hydrovinylation (HV) of 1,3-Dienes and Asymmetric Variations
Asymmetric Hydrovinylation of Unactivated Linear 1,3-Dienes Using Co(II) Catalysis
Scope and Applications of Hydrovinylation Reactions: Exocyclic Stereocontrol
A Stereoselective Route to either Steroid-C20(S) or -C20(R) Derivatives
Asymmetric Hydrovinylation of Strained Alkenes
Conclusions and Future Perspectives
CV of T. V. (Babu) RajanBabu
References
Chapter 38: Heterocycle Construction via Asymmetric Rhodium-Catalyzed Cycloadditions
Background
Strategy
Results
Application to Other Reactions
Conclusion and Future Perspectives
CV of Tomislav Rovis
CV of Kevin M. Oberg
References
Chapter 39: N-Heterocyclic Carbene-Catalyzed Aldol Desymmetrizations
Introduction
Strategy and Results
Application to the Syntheses of Bakkenolides I, J, and S
Conclusion
CV of Karl A. Scheidt
CV of Eric M. Phillips
CV of Julien Dugal-Tessier
References
Chapter 40: Strategies for the Asymmetric Total Synthesis of Natural Products: “Chiral Pool” versus Chiral Catalysts
Introduction
Catalytic Stereoselective Total Synthesis
Natural Product Synthesis Starting from Chiral, Nonracemic Starting Materials
Conclusion
CV of Karl Gademann
References
Chapter 41: Dynamic Kinetic Asymmetric Transformations Involving Carbon–Carbon Bond Cleavage
Background
Donor–Acceptor Cyclopropanes as DYKAT Substrates
Lewis Acid Catalysis
Palladium Catalysis
Deracemization of Tertiary Propargyl-Allyl Alcohols via Rhodium-Catalyzed Sequential Rearrangement/Enantioselective Conjugate Addition
Conclusion
CV of Andrew Parsons
CV of Jeffrey Johnson
References
Chapter 42: Iron-Catalyzed Allylic Substitutions
Allylic Substitutions Catalyzed by the Hieber-Anion [Fe(CO)3(NO)]−
Allylic Substitutions Catalyzed by Fe2(CO)9
CV of Markus Jegelka
CV of Bernd Plietker
References
Chapter 43: Asymmetric Conia-Ene Carbocyclizations
Introduction and Background: the Conia-ene Reaction
Strategy: Organo/Metal Cooperative Catalysis
Results
CV of Filippo Sladojevich
CV of Darren J. Dixon
References
Chapter 44: Tactics and Strategies in the Total Synthesis of Chlorosulfolipids
Background
Stereoselective Synthesis of vic-Dichloride Fragments
Total Synthesis of Hexachlorosulfolipid
Conclusions
CV of Christian Nilewski
CV of Erick M. Carreira
References
Chapter 45: Linear Free Energy Relationships (LFERs) in Asymmetric Catalysis
Introduction and Background
Hammett Electronic Parameters and Their Application to (salen)Mn(III)-Catalyzed Asymmetric Epoxidation Reactions
Relating Brønsted Acidity to Enantiomeric Ratio in an Asymmetric Hydrogen-Bond-Catalyzed Diels-Alder Reaction
An LFER Describing the Influence of Steric Bulk in a Nozaki–Hiyama–Kishi Asymmetric Allylation of Acetophenone
Correlating Quadrupole Moment to Enantioselectivity in Cation-π-Mediated Asymmetric Polycyclization
Simultaneously Correlating Hammett and Charton Parameters to Enantioselectivity in Two-Dimensional Free Energy Relationships
Conclusions
CV of Elizabeth Bess
CV of Matt Sigman
References
Chapter 46: Asymmetric Diamination of Alkenes
Introduction and Background
Strategy
Results
CV of José Souto
CV of Kilian Muñiz
References
Chapter 47: Enzymatic Asymmetric Synthesis of Tertiary Alcohols
Introduction
YerE–a Unique ThDP-Dependent Enzyme
Hydroxynitrile Lyases
Conclusion
CV of Michael Richter
References
Chapter 48: Oxidative Dearomatization and Organocatalytic Desymmetrization
Introduction
Desymmetrization of Cyclohexadienones
A One-Pot Oxidative Dearomatization and Catalytic Desymmetrization
Oxo- and Aza-Michael Additions
Further One-Pot Methods for Oxidative Dearomatization and Catalytic Desymmetrization
Alkylative Dearomatization
Summary
CV of Matthew J. Gaunt
CV of Alice E. Williamson
References
Chapter 49: Total Synthesis of All (–)-Agelastatin Alkaloids
Introduction
Biosynthetically Inspired Plan for Total Synthesis
Total Synthesis of the Agelastatin Alkaloids
CV of Mohammad Movassaghi
CV of Sunkyu Han
References
Index
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The Editor
Prof. Dr. Mathias Christmann
Technische Universität
Organische Chemie
Otto-Hahn-Str. 6
44227 Dortmund
Germany
Prof. Dr. Stefan Bräse
Institut für Technologie (KIT)
Inst. f. Organische Chemie
Fritz-Haber-Weg 6
76131 Karlsruhe
Germany
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List of Contributors
Chapter 1
Catalytic Enantioselective Alkylation of Prochiral Ketone Enolates
The synthesis of stereogenic all-carbon quaternary centers remains a formidable challenge, notwithstanding the strides made by modern organic chemistry in this regard [1]. Contemporary advances in enolate alkylation have made it a fundamental strategy for the construction of C–C bonds [2]. Although methods for the reaction of a number of enolate types (e.g., ester, ketone, and propionimide) with a variety of alkylating agents exist, catalytic enantioselective variants of these transformations are relatively rare [3]. Of the catalytic asymmetric methods available, there have been few examples of general techniques for the asymmetric alkylation of carbocyclic systems and still fewer examples that have the capacity to deliver all-carbon quaternary stereocenters [4]. While the Merck phase transfer methylation and Koga alkylation of 2-alkyltetralone-derived silyl enol ethers represent notable exceptions [4], the breadth of application and utility of these reactions has been limited. In fact, at the outset of our investigations in this area, there were no examples of catalytic enantioselective alkylations of monocyclic 2-substituted cycloalkanone enolates in the absence of either α′-blocking groups or α-enolate-stabilizing groups (e.g., R = aryl, ester, etc.; Figure 1.1). Concurrent to our work in this area, Trost and coworkers [5] have published a series of papers that complement our studies. Jacobsen and coworkers, as well, have revealed a unique enantioselective method involving the chromium-catalyzed reaction of tin enolates with a variety of unactivated alkyl halides [4a]. Herein, we relate our development of Pd-catalyzed enantioselective functionalization reactions of prochiral enolates, specifically tetrasubstituted cyclic ketone enolates that give rise to quaternary stereogenicity [6]. The synthetic utility of the building blocks derived from these reactions is demonstrated by application in a number of total syntheses.
Figure 1.1 Enolate reactions: previous examples and our approach.
In 2003, we initiated a program aimed at the catalytic enantioselective synthesis of all-carbon quaternary stereocenters by allylic alkylation of prochiral cyclic ketone enolates [6]. We adapted a protocol originally developed by Tsuji and Minami [7] to incorporate a chiral ligand scaffold and found that the phosphinooxazoline (PHOX) ligands (e.g., 10) [8] were optimal for both chemical yields and enantioselectivity. The allylic alkylation protocol that we developed was robust enough to employ several different enolate precursors as substrates, namely, allyl enol carbonates (6), enol silanes (7), and β-ketoesters (8; Scheme 1.2) [6].
Scheme 1.1 Enantioselective alkylation methodology.
In addition, the reaction is highly tolerant of a broad range of functionality and substitution on both the enolate precursors and allyl fragments. Enolates derived from cyclic ketones [4], enones [4], vinylogous esters [9], vinylogous thioesters [10], tetralones [4], and dioxanones [11] function with similar levels of selectivity in the catalytic asymmetric chemistry. We have also developed a highly efficient large-scale protocol that employs reduced catalyst loading (2.5 mol% Pd) and allows access to greater than 10 of enantioenriched material.
Furthermore, we have been able to exploit seven-membered ring vinylogous ester substrates (11) by virtue of a unique trait that these molecules possess in contrast to their six-membered counterparts. While cyclohexanone products will readily eliminate to form cyclic enones under Stork–Danheiser conditions (reduction and treatment with acid) [13], cycloheptanones (12) form stable β-hydroxy ketone intermediates (13). Our efforts have uncovered a retro-aldol/aldol ring contraction strategy to access a number of functionalized acyl cyclopentenes (14) from this unusual and unexpected product [14] (Scheme 1.3).
Scheme 1.2 Ring contraction methodology.
In addition to the desirable properties of (S)-tBu-PHOX (10), the PHOX ligand scaffold was found to be highly modular, such that a range of steric and electronic properties could be investigated [15]. Our studies in this area were facilitated by the use of a copper-catalyzed coupling reaction of aryl halides (15) and phosphines (16) or phosphine oxides (17), originally developed by Buchwald [16] (Scheme 1.4). As with our enantioselective reaction itself, production of the ligand on a large scale is also feasible [17].
Scheme 1.3 Concise, scalable synthesis of phosphinooxazoline (PHOX) ligands.
We have intensely investigated the mechanism of these alkylation reactions in an effort to understand the elements controlling asymmetric induction so that we may design catalysts with greater reactivity and enantioselectivity. An intriguing picture of the general reaction mechanism has emerged from our experimental studies. Preliminary kinetics experiments demonstrate that the reactions are first order with respect to [Pd · PHOX] and zeroth order with respect to [substrate]. Furthermore, we have carried out Kagan-type nonlinear effect experiments and found a linear relationship between the enantiomeric excess of ligand and product [18]. Finally, we have been using NMR spectroscopy and single crystal X-ray analysis to characterize intermediates and resting states in the catalytic cycle [19].
We have confirmed that adduct 19, with an η2-coordinated dba ligand [20], is initially formed, but that in the presence of substrate, a highly unusual η1-allyl, η1-carboxylate Pd · PHOX complex (20) persists (Scheme 1.5) [21]. These complexes are the resting states of the catalytic cycle, depending on whether substrate is available (20) or not (19) and point to decarboxylation as the slow step of the catalytic cycle [19]. Because the enantiodetermining step is kinetically inaccessible to direct observation, we turned to computational modeling, in collaboration with Professor William Goddard at Caltech, to investigate the possible transition states for the allylation. While it is still premature to draw definitive conclusions, it appears that an inner-sphere mechanism is operative wherein attack of the derived enolate occurs first on Pd, followed by a reductive elimination pathway to produce the C–C bond (Scheme 1.5) [22].
Scheme 1.4 Isolated intermediates and comparison of inner- and outer-sphere pathways.
Although this mechanistic hypothesis contrasts the accepted mechanism for most asymmetric allylic alkylations (i.e., outer-sphere backside attack on the π-allyl-Pd complex) [23], an inner-sphere mechanism would more reasonably account for the high enolate enantiofacial preference and for the limitations on the size and substitution of the allylic fragment. Furthermore, reactions involving stabilized enolates (Scheme 1.2, R = aryl, CO2R, etc.) lead to low enantioselectivity under our conditions, pointing to the possibility of a mechanistic switch between inner-sphere (high selectivity) and outer-sphere (low selectivity) pathways depending on the substrate electronics.
In view of our mechanistic findings, we hypothesized potential interception of our putative chiral metal enolate species and subsequent trapping with alternative electrophiles. Indeed, via acidic trapping, we are able to generate an array of chiral α-tertiary cycloalkanones in high yield and enantioselectivity [24]. Benzylidene-malononitrile-derived conjugate acceptors may be coupled along with an allyl cation fragment to deliver highly functionalized, vicinal all-carbon quaternary and tertiary stereocenters neighboring an achiral quaternary center in good diastereo- and enantioselectivities [25].
Quaternary centers are present in thousands of natural products and are especially prominent in large numbers of terpenes and bioactive alkaloids [26]. The α-quaternary cycloalkanones produced by our asymmetric alkylation chemistry are highly useful chiral building blocks, containing at least two functional groups, a ketone and an olefin, for further manipulation. We have prepared a number of natural products by employing our technology as a critical means to build structural complexity and set absolute stereochemistry.
Our early efforts resulted in a rapid, protecting-group-free synthesis of (+)-dichroanone (25) via the intermediacy of bicyclic enone (24), a compound accessible by a two-step sequence from alkylation product 23 (Scheme 1.6) [27]. In addition, enone (24) could be recrystallized via the semicarbazone derivative to 97% ee. This same intermediate (24), in the enantiomeric series, was recently employed in the total synthesis of (+)-liphagal (27) [28–30]. Our unique synthesis [31] allows access to a variety of structural and functional liphagal congeners.
Scheme 1.5 Total syntheses of (+)-dichroanone and (+)-liphagal.
An enol carbonate substrate (28) was employed in the expedient formal synthesis of (+)-hamigeran B (31; Scheme 1.7) [32, 33]. Our approach rapidly builds the tricyclic core (33) in a highly enantioselective manner and ties into the Miesch synthesis of racemic hamigeran B [34], leading to enantioenriched hamigeran B (31) in only 10 steps from carbonate (28).
Scheme 1.6 Formal synthesis of (+)-hamigeran B.
In an effort to construct both quaternary stereocenters present in the cyathane diterpenoid natural products [35, 36] in a single transformation, we designed bis(β-ketoester) (32), which was employed in a stereoconvergent process that converted each of the three stereoisomeric starting materials (i.e., two C2 symmetric enantiomers and one meso diastereomer) to an enantioenriched product with excellent and amplified stereocontrol (e.g., 32 → 33; Scheme 1.8) [37]. The successful application of this double enantioselective decarboxylative allylation strategy led to the rapid total synthesis of cyanthiwigin F (35), as well as cyanthiwigins B (36) and G (37) [38].
Scheme 1.7 Total synthesis of (−)-cyanthiwigins F, B, and G.
We have developed an allylic alkylation reaction for the assembly of enantioenriched α-quaternary carbonyl compounds. This methodology has enabled the rapid construction of a number of natural products that feature all-carbon quaternary centers. In addition to cyclic ketones, we have expanded our asymmetric alkylation reaction substrate scope to include lactams, which undergo the chemistry in excellent yield and enantioselectivities [39]. Expansion of scope of this method and its application in total synthesis are ongoing areas of research in our group.
Corey M. Reeves was born in Santa Monica, CA, USA. Corey obtained a BS in Chemistry and BA in Sociology from Columbia University in New York City in 2009. During this time, he completed undergraduate research under the guidance of Professor Tristan Lambert. In 2010, he began doctoral studies at the California Institute of Technology, working in the laboratory of Professor Brian Stoltz.
Brian M. Stoltz was born in Philadelphia, PA, USA, in 1970. After spending a year at the Ludwig Maximilians Universität in München, Germany, he obtained his BS in Chemistry and BA in German from Indiana University of Pennsylvania in 1993. He then earned his Ph. D. in 1997 under the direction of Professor John L. Wood at Yale University. Following an NIH postdoctoral fellowship in the laboratories of Professor E. J. Corey at Harvard University (1998–2000), he joined the faculty at Caltech in 2000 where he is currently the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and a KAUST GRP Investigator. His research interests lie in the development of new methodology for general applications in synthetic chemistry.
References
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Chapter 2
Point-to-Planar Chirality Transfer in Total Synthesis: Scalable and Programmable Synthesis of Haouamine A and Its Atropisomer
Haouamine A (1; Figure 2.1) is a structurally unprecedented natural product that was isolated in 2003 by Zubía and coworkers [1] from a marine tunicate species (Aplidium haouarianum) collected off the southern coast of Spain and found to exist in solution as a mixture of two rapidly interconverting isomers (vide infra). Its most interesting structural feature is a 3-aza-[7]-paracyclophane macrocycle, the smallest paracyclophane yet encountered in any natural product, that significantly deforms the rightmost phenol out of planarity. The strain introduced herein has complicated the synthesis of 1, with the first solution arising through the use of a low-yielding pyrone-alkyne Diels–Alder reaction [2] that simultaneously formed the bent phenol as well as the cyclophane macrocycle.
Figure 2.1 Haouamine A and other natural products synthesized with a strategy of point-to-planar chirality transfer.
As depicted in Figure 2.1, haouamine A (1) exhibits planar chirality within the paracyclophane macrocycle. A second-generation synthesis sought to improve the overall efficiency of its production as well as to address this stereochemistry through the strategic point-to-planar chirality transfer. Such a strategy has found successful application in the total synthesis of a number of elegant natural products, with noteworthy examples shown in Figure 2.1. These include Evans' approach to vancomycin (2) [3], Shair's synthesis of longithorone A (3) [4], and Thomson's construction of bismurrayaquinone A (4) [5].
The original characterization of 1 was complicated by the fact that it exists in solution as a binary mixture of isomers. The origin of this isomerism was initially proposed [1] to be the result of either atropisomerism of the rightmost phenol or slowed pyramidal inversion at nitrogen. Recent computational work [6] supported a theory coupling the latter process with conformational reorganization of the tetrahydropyridine ring but could not unequivocally rule out atropisomerism.
In order to address this isomerism question, or specifically, whether haouamine A is a single atropisomer that does not equilibrate with atropisomeric 5 or if the natural product is represented by 1 and 5 (Scheme 2.1), a strategy was developed wherein the two atropisomers were retrosynthetically traced back onto diastereomeric cyclohexenone macrocycles 6 and 7. In light of the fact that these structures are epimeric at nonepimerizable sp3 stereocenters (labeled), it was assumed that no interconversion would take place between them. If 6 and 7 could then be synthesized and independently oxidized to the cyclophane, proof would be obtained of whether haouamine A is a single atropisomer. Feasibility of this strategy arose from examination of molecular models, suggesting that an sp2 to sp3 hybridization change of one of the carbons in the cyclophane might significantly reduce the strain present within the macrocycles and thus make for accessible intermediates.
Scheme 2.1 Haouamine A isomerism question and stereochemical strategy for addressing it.
The realization of the above strategy is delineated in Scheme 2.2 [7]. Racemic bromo-indeno-tetrahydropyridine (8) [8] was first cross-coupled with tosyloxy-iodocyclohexenone (9) in a straightforward procedure involving lithium-halogen exchange, reaction of the aryl lithium with B(OMe)3, addition of water, and direct transfer of the resulting boronic acid to 9 in the presence of catalytic palladium. The product 10 (77% yield on gram scale) was isolated as an inseparable mixture of diastereomers, which was converted to a mixture of primary iodides in high yield. N-Boc deprotection and heating of the unpurified amine-TFA salt (after azeotropic removal of excess TFA with benzene) in dilute acetonitrile with Hünig's base then delivered macrocycles 11 and 12111121