Discovering Stereoselectivity: Synthesis of Exo- and Endobrevicomin Using a Tunable Hydride Reduction A Program of Organic Synthesis Experiments for Advanced Undergraduate Students David P. Richardson? Whitnev Wilson. Rebecca J. Mattson, Dawn M. Powers, and Brian T. Dolan Williams College, Williamstown, MA 01267
Well-developed curricula for undergraduate chemical education frequently offer advanced-level courses in the major subdisciplines of chemistry In organic chemistry, advanced courses usually include modern synthesis theory and technique as centrailecture and laboratory topics, and a number of recent experiments have shown that multistep total synthesis experiments are ideal vehicles for exploring these topics ( I ) . With their low molecular weights and modest structural complexity, insect pheromones have proven to he especially fruitful targets for such synthesis experiments (2).However, none of these experiments has highlighted the special problems associated with efficiently svnthesizin~natural targets that contain chiral centers. &e the stereochemical structure of natural products is oRen of central importance to their biolokcal activity, up-to-date synthesis-experiments must demonstrate methods for huilding chiral centers into molecules in a controlled fashion. Insect pheromones also prove to be ideal targets for developing these more subtle synthetic concepts. Forexample, many serious North American timber pests produce aggregation pheromones that are based on the 6,8dioxabicyclo[3.2.11-octane skeleton and contain a small number of chiral centers. Such pheromones include multistriatin (I), the sex attractant of the European elm hark beetle, Scolytus multistriatus (31,and the exo (2) and endo (3) isomers of hrevicomin (4).Although 2 and 3 differ only with respect to the configuration of a single chiral center
synthetic pheromone (e.g. ,pheromone-baited traps) would reauire the svnthetic material to match the stereochemical stkcture of "the actual pheromone. Since the hrevicomin isomers contain only three chiral centers, they are perfect targets for presenting the fundamental concepts that make the controlled production of stereochemically complex synthetic materials possible. Our approach to 2 and 3, presented inFigure 1,pivots on the intermediate ethylketone 7 and is based upon the synthesis of Mundy (713We have modified this route into a series of experiments which can each be accomplished in 3 4 hour lab periods. Every step in this pathway highlights an important modem synthetic transformation requiring discussion of key mechanistic concepts and crucial elements of synthesis technique. Students characterize all synthetic products by IR and 'H NMR spectroscopy (GCMS analysis can also be performed), providina - opportuni.. ties to discuss the roles these techniqies play in synthesis. The central svnthetic conceot develooed in this series of experiments involves utilizing the inherent chirality of the C-1 center in intermediate ketone 7 to control the creation of the C-7 and C-5 chiral centers in the target pheromones 2 and 3. The process of influencing the creation of a new chiral center in the vicinity of a preexisting chiral center is known as stereoinduction. Any reaction that produces, exclusively or predominantly, one possible product stereoisomer is called a stereoselective reaction (8).Due to its chirality, the C-1 centerin 7shouldstereoinductively direct hydride reduction ofthe neighboring C-7 ketone center. For example, stereoselective hydride delivery to the "bottom" face of the ketone carbonyl in 7 would give syn-alcohol8, while the opposite process would yield anti-isomer 9 (Fig. I ) .Through ~ a systematic exploration ofreactions, students in our program discover the conditions for controlling this
(C-71, this stereochemical detail has a direct effect on the behavior of various beetles that use these isomers as pheromones. Thus, the aggregation pheromone of the westem pine beetle, Dendroctonus brevicomis, contains both 2 and 3 (51,while aggregation of the extremely destructive southe m pine beetle (D. frontalis) is inhibited by 3 (6).Any potential strategy for controlling such insect pests with a Presented at the Norlheast Organic Educators Symposium held at the Fourth National Conferenceon Undergraduate Research, Union College. Schenectady,New York, April 21, 1990. 'Corresponding author. 'AII structures presented refer to racemic material. Single enantiomers are shown for convenience. %vn and anti are assianed accordina to the recent definitions of S. detm ton ~ a s a m ~ neteal, (see ref 13) A com6lete y ~namo~g-om 01 there atlwestereocnem stry nlsomers8ana9WOL d be 8 11R,7R) 9 I R 75,
Figure 1. Synthetic pathway to exo- (2) and endo brevicomin (3) Volume 68 Number 11 November 1991
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reduction with either sense of stereoselectivitv. ARemard, in a final cyclization process, the common C-1 chirality in 8 - and - ~ - 9- also ~ ~ directs the creation ofthc C-5 chiral centers in t h e brevicomin isomers. Although several o t h e r stereoselective syntheses of 2 and 3 have been reported (91, the synthetic approach embodiedin our programis unusual because it allows for synthesis of either pheromone by "tuning" the stereoselective transformation of a common intermediate (10). The first step in the overall sequence is dimerization of methyl vinyl ketone (4) via DielsIAlder reaction. This process provides the framework for the targets and also for a discussion of electrocyclic reactions and heteroatomic variations on the DielsIAlder condensation. Purification of the dimer (5) provides exposure to the practical techniques involved in vacuum distillation, which may include use of either "short path" or Kugelrohr apparatus, depending .~ of upon equipment available to the i n s t ~ u c t o rCoverage 'H NMR spectroscopy begins with a comparison of spectra of 4 and 5. Students assign all proton signals in these spectra and are asked to track the changes in these signals a s the synthesis proceeds. The 'H NMR spectrum of 5 is sufficiently involved to allow for review of concepts like chemical shift and proton-proton coupling. The first reaction also reviews basic cyclohexane conformational concepts, which account for the preferred configuration of the first chiral center created in the synthesis (C-1). The second and third steps selectively homologate 5 to the ethylketone 7. This transformation provides for discussion of alkylation techniques a n d t h e concepts of regioselectivity and enolate formation. Removal of the more hindered methine proton a t the ring position in 5 is favored, even with bulky bases such a s LDA(7) andlithium isopropylcyclohexylamine ( l l ) , probably due to prior complexation of the base's counterion between the oxygen atoms of the ketone and ether groups. Fortunatelv. .. a n alternative approach, beginning with rapid and quantitative conversion b f 5 to the iyclohexylimine derivative 61, allows efficient and regioselect~vehomologation. ~ e ~ r o t o n a t i oofn 6 with excess ethylmagnesium bromide in refluxing tetrahydrofuran is regioselective. Alkylation with methyliodide provides a n 89%yield of 7 with less than 4% of the methylation regioisomer (GC-MS analysis). Unlike standard kinetic deprotonation approaches, these conditions allow for equilibration of the two regioisomeric enolate anions. For steric reasons, the anion leading to alkylation on the methyl group position is favored (12). This process leads into a discussion of reactions u n d e r kinetic versus thermodynamic control a n d demonstrates the flexibilty of modem synthetic methods. The failure of standard technology i n the preparation of 7 also gives a taste of the complexity involved in synthesis and the importance of resourcefulness in research. Preparation of 7 also exposes students to modem syringe and inert-eas-manifold techniques. The ethylketone produced in th;s manner is sufficiently pure to hiused dir&tly in the next step or, ifthe overall rxpcnment hegms with 5, 7 may be vaccum distilled todrmonstrate thehe techniques. Analvsis of the lH N M K spectrum of 7 also expl(~resNMR concepts that have ster~ochemicalbases. For example, students are surprised to observe a 14line pattern for the diastereotopic methylene hydrogens of 7, which can initiate a discussion of diastereotopicity, prochirality and non-firstorder coupling relationships. Ketone 7 is the common intermediate in synthetic routes to both target pheromones. I n the last two steps, hydride ~
~
~
41f time is a limitation, the instructor may prepare and purify 5 in advance and students can begin experiments with this as starting material.
952
Journal of Chemical Education
reduction of 7 produces a mixture of the secondary alcohols 8 and 9 and cyclization of these then leads to the target pheromones 2 and 3, respectively. The key discovery experiment in our program is a study of the stereoselectivity of the reduction a s determined by measurement of ratios for the alcohols 8 and9. Each student is assigned anindividual set of reductions to carry out and evaluate, and afterward all the student data are compiled in a single table. As a team, the students are then charged with the following tasks: (a)Determiningwhichconditions were most highly stereoselective far each of the isomeric alcohols. (b)Establishingtheproperstereochemicalconfiguration for the alcohols hy converting them to the brevieamin isomers, and finally (cl Farmulatine mechanistic models for the reduction which account f& their data. Since the reduction substrate (7) contains a single chiral center and only one new chiral center is produced, this reaction~rovidesanideal setting for exploring the concepts of s t e r e ~ ~ e l e c t i vand i t ~ stereoinhuction. Reduction of 7 is studied using u r a w-e of reagents and conditions to explore the effects of various reaction parameters on the overall stereoselectivity. Important parameters to consider are the steric bulk of the hydride reagent, the counterion in the hvdride reagent, the solvent, and temperature, as well a s the concepts of chelation and substrate confimnat~onalanalvsis. The data in the table gives a limited examination of these parameters. We consider this set of experiments to be the minimum needed to draw meaningful conclusions about the. stereoselectivity of the reduction. If many students are involved, experiments may be replicated or different reduction conditions may be examined. Yields for the reductions vary from 6&90%. Data in the table are expressed a s a ratio of the product alcohols syn-8: anti-9 (13)and lead to the following observations. First, the simple borohydride reagents (e.g., lithium, sodium, and potassium borohydride) display very weak selectivity for the syn-product 8 (57:43+2), and this selectivity does not vary with temperature or the counterion in the reagent. Second, zinc borohydride is selective for the opposite anti-alcohol 9, and this selectivity increases and r&hes the highest level observed a s temperature is lowered to -60 "C. Third, the Selectride reagents are all elective . .-. ~-- for - ~ 8 - and all show a n increase in svn-selectivitv a s temperature is lowered. Fourth, lithium Selectride a e 60 'C is most selective for the svn-alcohol, although no simple effect on stereoselectivity i"s apparent a s the series lithium-, sodium-, potassium-Selectride is traversed. Discussion of possible mechanistic models for the reduction should begin by placing the concepts of stereoselectivitv and stereoinduction on a firm footing. The simple chiral ketone 7 represents un ideal system for developing these ideas. Since thecarbonylgmup in 7 i s prcch~ral,this means that hvdride deliverv to this element will produce a new chiral center, with e i h e r R- or S-configura
