Alkenes, Important Synthetic Intermediates.

Transcription

1 UTLIE 535 SESSI 08 (2007) Page 73 Alkenes, Important Synthetic Intermediates. 1. We have discussed the synthesis of alkenes There are many more protocols than the ones we have discussed Some of these you will encounter in your working problems We will discuss more as the semester matures In the synthesis of alkenes one needs to worry about stereocontrol ften this is no small task We talked about stereocontrol in trisubstituted alkenes and 1,2- disubstituted alkenes. 2. The most important thing to remember regarding stereocontrol and alkene starting materials is: if you can control the stereochemistry in the alkene you can effect from stereocontrol in the product We saw some of this in the discussions of the 3,3-sigmatropic rearrangement, the aldol, the cyclizations, 2,3-sigmatropic rearrangement and the Diels-Alder reaction Keep this in mind as we talk about the reactions of alkenes. 3. Let s now discuss alkenes in the synthetic context in which they are starting materials Where can you go from here? You can go from flat land achiral to 3D space chiral and/ or polycyclic Many of these reactions should be familiar to you from your previous study of organic chemistry. 73

2 UTLIE 535 SESSI 08 (2007) Page 74 stereo & regiochem 2 1 regiochem 6 2 stereochem Br 2 Br Br stereochem We will refer to this figure throughout the text below. Br 2 nuc FIG etro 1 (FIG 1) can be accomplished via addition of borane followed by cleavage of the B-C bond with Your sophomore organic text would have listed this among the reactions that perform hydration (adding water to) of double bonds in an anti-markovnikov fashion. B TF B / - / ne of the friendliest procedures of the borane-mediated hydration of an alkene Borane addition and oxidation can be done in an asymmetric manner. 74

3 UTLIE 535 SESSI 08 (2007) Page 75 B 2 6 1) B ) (xidation) optically pure isosafrole (cheap and commercially available) B / 2 / a 1. TolS 2 Cl pyridine 2. amec 2 tbu 3. hydrolysis ypothetical path above should give ecstasy (-methyl- 3,4- methylenedioxyamphetamine Why should the hydration of the alkene occur with the regiochemistry indicated? The stereochemistry is difficult to predict emember that addition of borane to alkynes gives rise to ketones and aldehydes instead of alcohols. B Markovnikov addition of 2 is usually less problematic, etro 2 in the Figure egiochemical problems can arise when and 2 are similar If this is attempted with (+) carbocation rearrangement can dominate the product mixture. 75

4 UTLIE 535 SESSI 08 (2007) Page Sometimes rearrangement is a good thing. Perhaps you are smart enough to plan on the carbocation rearranging to your desired product Ts C Slightly changing the conditions to more aqueous would give rise to the hydrated material by trapping the carbocation--see below The cation that forms is the most stable, in this case benzylic and tertiary opefully in the near future we can talk about syntheses based on carbocation rearrangements. I find this topic fascinating ne of the most obvious side reactions of cation based chemistry is polymerization. Usually one can find reaction conditions in which the cation does not polymerize with the starting alkene Polymer in most of these reactions is usually a side product It happens most often when the cation is stable Polystyrene for example is a very easy polymer to make under acid catalyzed conditions Trifluoroacetic acid reacts with the plain vanilla alkene under fairly mild conditions. This followed by saponification under basic conditions results in net addition of 2 across the double bond. CF 3 CF 3 C 2 a/ Me 76

5 UTLIE 535 SESSI 08 (2007) Page xy-mercuration is ugly and out of respect for mother earth should only be planned on small scale when not other protocol meets the need. gac 2 2 gac gac ab etro 3 (FIG 1) is trivial and is discussed quite a bit in organic one and two Bromohydrins and 1,2-dibromoalkanes are readily available There is quite a bit of evidence for the epibromonium ion intermediate etro 4 (FIG 1) can be accomplished via peroxyacids This protocol gives rise to epoxides, as we have seen; these are important intermediates in organic synthesis. Cl 1.1 equiv C 2 Cl Why does one double get epoxidized preferentially? m-cpba % Alcohols tend to direct the delivery of the oxygen atom, the enbest effect Mechanism 77

6 UTLIE 535 SESSI 08 (2007) Page 78 Cl Cl transition state has no intermediates delivery of oxene We have discussed the chemistry of C,, carbene, nitrene and oxene. Isoelectronic ther reagents capable of epoxidizing alkenes are S K xone, potassium peroxyhydrogen sulfate and peroxytrifluoromethylacetic acid and dimethyldioxirane Using oxone and a chiral ketone subject to electron withdrawal alkene can be epoxidized Frohn, M.; Shi, Y. "Chiral ketone-catalyzed asymmetric epoxidation of olefins." Synthesis 2000, KS KS and/ or 2 are chirotopic D-fructose acetone Cl 4 53% 1) PCC C 2 Cl 2 rt. 93% 2) alkene S <catalytic intermediate> 78

7 UTLIE 535 SESSI 08 (2007) Page / MeC 1:1 p = mol% fructose derived ketone oxone 82% yield 95% ee 82% yield 95% ee (+) 82% yield TBS TBS (+) 95% ee Epoxides are important intermediates in the synthesis of complex organic molecules The nucleophilic ring opening in Figure 1 alludes to this utility Usually one needs a Lewis acid as well as a good nucleophile to open epoxides What are the advantages of using the ketone catalytically? Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, Atom economy (below from Wikipedia) Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved. In an ideal chemical process the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted. Atom economy can be written as: % atom economy = MW (desired products) / MW (all reactants)* 100% Think about the impact on % atom economy of the incorporation of a protecting group in the synthetic scheme Atom economy (below from Wikipedia) ote that atom economy can be poor even when chemical yield is 100%, see for instance the Cannizzaro reaction. A Diels-Alder reaction is an example of a potentially very atom efficient reaction. n the other 79

8 UTLIE 535 SESSI 08 (2007) Page 80 hand if the desired product has an enantiomer the reaction needs to be sufficiently stereoselective even when atom economy is 100% Atom economy can also be adjusted if a pendant group is recoverable, for example Evans auxiliary groups. owever, if this can be avoided it is more desirable, as recovery processes will never be 100% Atom economy can be improved upon by careful selection of starting materials and a catalyst system. Atom economy is just one way to evaluate a chemical process, other criteria can include energy consumption, pollutants released and/or price What is the definition of %ee? enantiomeric excess What percent or fraction is not optically pure? {[]-[S]}/{[]+[S]} A 1: 1 mixture of :S by this equation gives 0%ee likewise an 8:2 mixture of :S gives {8-2}/{8+2}=60%ee Same principle applies to diastereomeric excess. %de GEEAL PICIPLE Kinetic resolution imagine a racemic mixture of * * Do the two reactions above have the same rates when catalyzed by an optically pure chiral catalyst? remember our previous discussion of matched and mismatched pairs? Kinetic resolution procedure 80

9 UTLIE 535 SESSI 08 (2007) Page un the reaction on the racemic mixture until about 50-80% of the target enantiomer is consumed The better the selectivity and the less optically pure you need your product to be the further you can run the reaction and get an acceptable result Isolate the optically pure (enriched) product What would happen if you run the reaction to completion? 4.7. Another way to accomplish etro 4 (FIG 1) is via a variety of transition metal peroxo-catalysts 1 3 Mn Cl mol% acl There are a lot of these salen-derived catalysts etro 4 can be controlled stereochemically from allyl alcohol starting materials and Sharpless epoxidation cis or trans Sharpless epoxidation leads to enantioselective epoxide derivatives of allylalcohols Where do you suppose you might get these in a stereocontrolled fashion? ,2-disubstited (E) ,2-disubstited (Z) ,1,2-trisubstited 2 81

10 UTLIE 535 SESSI 08 (2007) Page Pfenniger, A. "Asymmetric Epoxidation of Allylic Alcohols: The Sharpless Epoxidation." Synthesis 1986, JACS JACS 1987, 109, Johnson,. A.; Sharpless, K. B. "Asymmetric xidation: Catalytic Asymmetric Epoxidation of Allylic Alcohols."In Catalytic Asymmetric Synthesis; jima, I., Ed.; VC: ew York, 1993; pp QD262.C The breath of asymmetry in Sharpless epoxidation comes from tartaric acid epoxidation with early transition metals Ti(IV), V(V), Mo(VI), W(VI) A B C ABC and the olefin and the C2 are all coplanar if you could add reagents (form bonds selectively from the α or the β face), you would create stereogenic centers and a chiral molecules The α and the β faces of the molecule are prochiral This is said of any sp2 center that would create chirotopic environment upon hybridization to sp 3. (D)-(-)-diethyltartrate A tbu A 20 C C 2 Cl 2, Ti(iPr) 4 B C B C Same proc with the (L)-(+)-DET give other enantiomer The alcohol function determines the enantioselectivity (facial selectivity of the reagent) Applications asymmetric epoxidation of prochiral allylic alcohols 82

11 UTLIE 535 SESSI 08 (2007) Page kinetic resolution of racemic allylic alcohols see above for an explanation of kinetic resolution 1 (L)-(+)-diethyltartrate Both are optically pure after separation with a achiral media Advantages of Sharpless Asymmetric Epoxidation: simple and cheap reliable (large C give unreliable results) greater than 95% ee predictable almost insensitive to preexisting stereogenicity 83

12 UTLIE 535 SESSI 08 (2007) Page 84 L M L L M tbu L M L L M M L M 84

13 UTLIE 535 SESSI 08 (2007) Page 85 C 2 Et C 2 Et C 2 Et Ti Ti C 2 Et Et Et The Tartrate-bound catalyst Et E Ti Ti E Et Et E Ti Ti E ' Et Upon chemical contact with the Tartrate-bound catalyst, the peroxide and the allylic alcohol exchange ligands with the isopropoxide Epoxides are important intermediates in synthesis etro 5 can be controlled stereochemically by using Sharpless dihydroxylation s s eductive insertion s(8) 5.1. s(6) 5.2. Criegee discovered that s 4, is reduced by alkenes eaction is usually run in neutral aq conditions The last product shown is an ester (an osmate ester) s(0) evolves upon stoichiometric reduction owever, in the presence of certain [] agents the reaction runs catalytic in s s 85

14 UTLIE 535 SESSI 08 (2007) Page 86 s 2 s s s s Accounting of electrons Two electron reduction of s. Upon reductive insertion of into the s-c bond after 2+2 addition The microscopic reverse of this mechanism from kinetic data is observed for e in the 7+ oxidation state--isoelectronic with s in the 8+ oxidation state The two electrons came from the alkene The organic substrate went up in oxidation state itrogen center goes from +1 to Thus two nitrogen oxides are needed. 86

15 UTLIE 535 SESSI 08 (2007) Page 87 Cl Me dihydroquinidine ester Cl.2-.4% s 4, acetone, water, M dihydroquinoline ester 40-95% ee Me We have discussed etro 6 in Figure 1 briefly, Simmons-Smith cyclopropanation. There is much more to say For a preview see: Transition Metal Carbene Complexes: Cyclopropanation. Doyle, M. P. In Comprehensive rganometallic Chemistry II: A eview of the Literature ; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: xford, UK, 1995; Vol. 12; pp