Steroids Cholesterol Progesterone Cortisone PGF 1 C 2 C 2 Prostaglandins C 2 PGE 1 PGA 1 C 2 Six-membered Rings Five-membered Rings Stereocontrol in Cyclic Systems Acyclic Diastereoselection Biomimetic Synthesis C 2 Five-membered Rings lefin Synthesis Acyclic Diastereoselection 2 rganic Synthesis via Examination of Selected atural Products PGF 2 PGE 2 Introduction-1 RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Introduction 3 Introduction-1 ne of my objectives is to provide a sense of the history of organic synthesis. 1 I am not a historian, so the reader should understand that this is only my perspective of the field. It is my own sense of this history, however, that leads me to select steroids as the first family of natural products for discussion (Introduction-1). These compounds were clearly of interest to early practitioners of organic synthesis because of their biological activity, structural complexity, and central role they played in the development of the field of biosynthesis. n the other hand, one might argue that steroids were early targets for synthesis because some steroids, such as equilinen and estrone (Steroids-2), were not too complex, and thus were achievable synthetic goals given the tools available at the time. ur discussion will begin with the Woodward synthesis of cholesterol (circa 1950; the steroid we all love to eat) because it is one of the earliest examples of complex natural products synthesis. It also introduces a number of strategies that are still widely used in carbocycle synthesis (synthesis of 6-membered rings, synthesis of 5-membered rings, stereocontrol in cyclic systems). This synthesis will also touch upon other topics, such as acyclic diastereoselection, that are still of contemporary interest. We will next move to the topic of biomimetic synthesis to see how thinking about a biosynthetic pathway to a natural product can influence the design of synthetic pathways to that natural product. It will also illustrate how persistence and attention to detail can play an important role in realizing a given synthetic strategy in the laboratory (see Introduction-1 for targets). The second broad topic for discussion will be prostaglandins (Introduction-1). Interest in this family of natural products was once again stimulated by their importance in biology. The focus here will be on methods for 5-membered ring synthesis, olefin synthesis, and once again we will encounter the topic of acyclic diastereoselection. Although steroids and prostaglandins have remarkably different structures, we will see that they have some structural features in common, and there are strategic parallels to be found in their synthesis when these structural features are addressed. RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
X 1 2 Y Return to Steroids: The Sidechain Stereochemistry Problem 20 C 20 of Cholesterol * C 2 Me * erythro R R C 15 of Prostaglandins The Juvabiones Difunctional Relationships 15 C 2 Me threo Pyrrolizidine Alkaloids X Y X X 4 1 3 1 1 Y * * 1 7 Y 5 4 rganic Synthesis via Examination of Selected atural Products 1,2-Difunctional Relationship 1,3-Difunctional Relationship Even Difunctional Relationship dd Difunctional Relationship Introduction-2 RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Introduction 5 Introduction-2 I will next move from a family of compounds to a general problem in organic synthesis that I call the terpenoid sidechain stereochemistry problem (Introduction-2). This is really a relatively simple example of a problem in acyclic diastereoselection. The central question here is: When a stereogenic center does not reside in a ring, how can one control stereochemistry at this center relative to other stereogenic centers in the molecule? Acyclic diastereoselection is a general problem presented to the synthetic chemist by many families of natural products. For example, it arises in the steroids at C 20, in the prostaglandins at C 15, and at the exocyclic carbon of the sesquiterpene ester juvabione. It arises, in a less obvious manner, at C 1 and C 7 of the pyrrolizidine alkaloids. We will revisit this problem again and again throughout this book. At this point we will examine a topic that can provide insight into strategies that have been adopted for the synthesis of a host of molecules. The topic here is that of difunctional relationships. For example, the juvabiones have three functional groups: ketone, ester and alkene. The central question here is: When two functional groups are present in a target, does their spatial relationship provide a clue as to what chemistry can be used to construct that relationship and/or the ease with which the relationship can be constructed? The ideas set forth in this section are derived entirely from a concept I learned as a postdoc in the laboratories of David Evans (then at the California Institute of Technology), although any misrepresentation of these ideas are my responsibility alone. RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Me Where to we start? C 3 Porantherine Difunctional Relationships Morphine 3 C Some Unnatural Products Twistane Triquinacene Alkaloids Me Luciduline Me Me Difunctional Relationships istrionicotoxin Me Me 6 rganic Synthesis via Examination of Selected atural Products Biomimetic Synthesis Introduction-3 RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Introduction 7 Introduction-3 Targets to be addressed in the next section are twistane and triquinacene (Introduction-3). These are unnatural products. Twistane consists of 6-membered rings and triquinacene of 5-membered rings. Both have low levels of functionality. ow can the concept of examining difunctional relationships be used to develop strategies (or analyze syntheses) of these compounds? We will also look at the alkaloids porantherine and luciduline with the same question in mind. I think that it is important that aspiring practioners of synthesis lose any fear of heteroatoms they might have early in the game. Thus we will next spend some time talking about alkaloids, nitrogen-containing natural products. We will already have seen such compounds (the pyrrolizidine alkaloids) earlier in the book, so this section will serve in part to revisit strategies within the context of new targets. For example we will revisit the notion of biomimetic synthesis with morphine (arguably the most important painkiller used in medicine) and the concept of difunctional relationships within the context of histrionicotoxin and pumiliotoxin-c, neurotoxins used as a defense secretion by a certain frog species. RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Me Pumiliotoxin-C Me Kinetics vs. Thermodynamics for Stereocontrol Me More Alkaloids Me 2 C Me Reserpine A Classic in Alkaloid Synthesis Me Me Me Gephyrotoxin Stereoelectronic Effects 8 rganic Synthesis via Examination of Selected atural Products Introduction-4 RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Introduction 9 Introduction-4 We will continue with alkaloids by discussing a personal favorite (gephyrotoxin) and a classical target (reserpine) (Introduction-4). As with all of the natural (and unnatural) product targets discussed in this book, numerous total syntheses of gephyrotoxin and reserpine have been reported. It is instructive to compare syntheses, and look for strategic differences and similarities, and this will be done here as well as throughout this book. RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Cecropia Juvenile ormone: Stereoselective lefin Synthesis Lasonolide A Cecropia J Me Synthesis and Structure Determination Claisen Rearrangements Fragmentations Methodology Driven Synthesis Sigmatropic Rearrangements Macrocyclic atural Products and Ionophores C 2 Calcimycin (A-23187) Me 10 rganic Synthesis via Examination of Selected atural Products Total Synthesis and Structure Determination lefin Synthesis Macrolide Synthesis Acyclic Diastereoselection Thermodynamics and Stereocontrol Introduction-5 RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Introduction 11 Introduction-5 We will then leave alkaloids and move back in time to a target that became important in the 1960 s, Cecropia juvenile hormone (Introduction-5). Approaches to this deceptively simple structure constitute a study in stereoselective tri-substituted olefin synthesis. Given the importance of olefins (both synthesis and chemistry of) to modern organic synthesis, I think that a visit to this old topic will be instructive, and will help set the stage for a discussion of targets of more contemporary interest. In addition, it will focus on the important role synthesis plays in structure determination, and the stimulus natural products can provide for the development of new synthetic methodology. We will continue with olefin chemistry by considering lasonolide A (Introduction-5). Lasonolide A is a target that will reinforce how synthesis is still an important tool for determining structure. This target will allow us to briefly look at some modern organometallic chemistry as applied to the problem of stereoselective olefin synthesis. In addition it will be used to introduce the topic of macrolide synthesis (macrocyclic lactones). We will move on to the ionophores, a large family of natural products that present many synthetic challenges. From the many targets one might discuss in this chapter, I have chosen the historically significant calcimycin (A23187). This target will provide us with a look at several strategies for synthesizing molecules with multiple stereogenic centers. RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Strategy = Plans Assembling Carbon Skeleton xidation States at Carbon Stereochemical Issues Tactical Flexibility A Polypropionate Target Me Erythromycin A Macrolide Synthesis Acyclic Diastereoselection Me 2 Strategy and Tactics Tactics = Execution of Strategy Reagent Selection Functional Group Compatibility Functional Group Interconversions Stereochemical Issues 12 rganic Synthesis via Examination of Selected atural Products Introduction-6 RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
Introduction 13 Introduction-6 Although macrolides are of contemporary interest, the first major steps toward successful macrolide syntheses were reported in the 1970 s. Thus, for historical reasons, we will look at two approaches to the classical target erythromycin A and its aglycone, erythronolide-a. The erythromycins are examples of polypropionates, natural products biosynthetically derived largely from propionic acid units via a series of condensation reactions. Many natural products, broadly called polyketides, share this biosynthetic origin. These compounds are decorated with multiple stereogenic centers, and acyclic diastereoselection problems that are much more complex than the terpenoid sidechain stereochemistry problem will surface with erythromycin, including the problem of asymmetric synthesis. Finally, throughout this book I will use the terms strategy and tactics when discussing syntheses. These terms are not new and, in fact, there is a series that bares the title Strategies and Tactics in rganic Synthesis. 2 In a broad sense what I will mean by strategy is the plan and by tactics I mean execution of the plan. Some of the general features of strategy and tactics are outlined on the slide (Introduction-6). Whereas there are some distinct differences between the two terms, there is also some overlap (for example both deal with stereochemical issues), so I feel it is important not to get too rigid with definitions here. onetheless I hope this will help the reader keep these issues clear when I begin to use these terms. Let s have a look at the steroids as targets for synthesis. RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS
14 rganic Synthesis via Examination of Selected atural Products References 1. For a retrospective view see: icolaou, K. C.; Vourloumis, D.; Winsdsinger,.; Baran, P. S. The art and science of total synthesis at the dawn of the twenty-first century Angew. Chem., Int. Ed. 2000, 39, 44 122. 2. Strategies and Tactics in rganic Synthesis, Lindberg, T., Ed.; Academic Press; 1984, Vol. 1 (370 pages). Strategies and Tactics in rganic Synthesis, Lindberg, T., Ed.; Academic Press; 1989, Vol. 2 (469 pages). Strategies and Tactics in rganic Synthesis, Lindberg, T., Ed.; Academic Press; 1991, Vol. 3 (544 pages). Strategies and Tactics in rganic Synthesis, armata, M. Ed.; Elsevier; 2004, Vol. 4 (415 pages). Strategies and Tactics in rganic Synthesis, armata, M. Ed.; Elsevier; 2004, Vol. 5 (486 pages). Strategies and Tactics in rganic Synthesis, armata, M. Ed.; Academic Press; 2007, Vol. 7 (532 pages). RGAIC SYTESIS VIA EXAMIATI F SELECTED ATURAL PRDUCTS