教学课件学术资源大全高等有机化学lecture 15

1、Lecture 16: Medium and Large RingsJ. Wzorek, D. A. EvansChem 106Conformational and Stereochemical Control of Medium to Large Rings Can a macrocycle be conformationally defined?MeMeMeMeJoseph S. Wzorek(Evans Group, Harvard University)OOOOMeOHOOHOMe O Me OHMeOOLecture OverviewOMe10 membered ringsMeH O

2、HOMeConformational Control ElementsOOMecyclooctanecyclodecaneMiyakolide macrocyclic precursorOMeAmphidinolide Xintramolecular reactionsMacrocyclic Stereocontrolintermolecular reactionsSSMeMeNNHelpful ReferencesHHOOOOMeMe OMeOHMeMeOHMeMe1. Classics tereoselective Synthesis. Carreira, Erick M.;DMDOKva

3、erno, Lisbet. Weinheim: Wiley-VCH, 2009. 1-16.MeMeMe2. Still, Clark W.; Galynker, I. Tetrahedron 1981, 37, 3981- 3996.O OHO OHSelectivity?Me12,13-Desoxyepothilone BDMDO =Me Epothilone B (anticancer)3. Deslongchamps, P. Pure and Appl. Chem. 1992, 64, 1831-1847.OMeOMeIntroductionJ. Wzorek, D. A. Evans

4、Chem 106 Before we begin our examination of medium and large rings, it is important we remain grounded in the principles that govern our science; for example the Curtin-Hammett Principle Consider the following kinetic scheme: So why can we apply conformational analysis (a ground state phenomenon) to

5、 study reactivity?MeOMe2CuLiOFastk2399% antiSlowk21Slowk34MeMe12A1A2A3A4k32Fast The above reaction (which we will return to) involves a selective, exothermic process The above equation describes two quickly interconvertingspecies (conformations of a single molecule for which react at different rates

6、 to form producttance)OO Me Me1-conf(a)1-conf(b)MeMeOO Me2 Me2-syn We must make an assumption that the relative position of ground state conformers also translates to the transition state Secondly, an “outside” attack of the ring is preferred This forms the basis for future arguments within this lec

7、ture The reaction with the lower absolute barrier, will lead to the major product under this scheme (thus A4 is preferred)IntroductionJ. Wzorek, D. A. EvansChem 106 How did chemists tackle these challenges for synthesis? Concavity/convexity was the dominant method of stereocontrol Often bicyclic sys

8、tems were used in this capacity, even if they were not present in the final targetnuc The discovery of pikromycin, the first macrolide antibiotic, introduced an additional level of complexity to synthetic organic chemistsOnucnucconvex face preferredHHMeMeHHOMe EtOHMe OOHHOHHMe Oconcave faceNMe2HO Th

9、is approach is exemplified by Woodward and coworkers synthesis of erythronolide AOOMeErythromycinHHOMeSSSS1) NaBH4MeMeMeMeOO2) MOMI, KHO OHMeMeOOMOMOBnOBnHOMe EtOHMe OHRMe EtOHMe OHOHMe OHSSstepsMe O1) OsO4Erythronolide A2) DMP, TsOHMOMOMeOOHOOHOOMePikromycinMeR = H, Erythronolide B R = OH, Erythron

10、olide AOBnMe Here, a single dithioacetal stereocenter is used to direct a reduction step, and oxidation step to secure the desired relative stereochemistry Related natural products erythromycin and aglycons known as the erythronolides became ambitious targets for synthesis“Erythromycin, with all of

11、our advantages, looks at present quite hopelessly complex, particularly in view of its plethora of asymmetric centers.”- R. B. Woodward, Perspectives in Org. Chem., 1956Clark Still: Peripheral Attack HypothesisJ. Wzorek, D. A. EvansChem 106 Peripheral attack: as initially proposed by Still, reagents

12、 prefer to attack medium-sized rings from the exterior rather than the interior Still and coworkers helped to deconvolute the seemingly intractable problems associated with medium and large ring stereocontrol Consider the following examples:MeMeOOLDA, MeI95% antiMeMeMeOOLDA, MeI98% synMe What sort o

13、f principles can we apply to these systems to explain the outcome? W. Clark Still 1946 - Born (Augusta, GA) 1972 - Ph.D. (Emory, Goldsmith) 1973 - Postdoc (Princeton, Wipke) 1974 - Postdoc (Columbia, Stork) We shall return to this example later, as the concept of conformationally defined medium and

14、large membered rings is considered Let us now consider the following rings and their canonical conformations: Career highlights: Flash chromatography (7400 citations), Macromodel (2700 citations), Solvation in molecular mechanics (1500 citations), Monte Carlo searching (650 citations), Still-Gennari

15、 modification of HWE (650 citations)cyclooctanecyclodecane“This principle of peripheral attack appears to be general as a strategy for stereochemical control in the synthesis and modification of germacranes and related medium-ring compounds. It does, however, require knowledge of the conformation of

16、 the starting oleftill, W. C. JACS, 1979, 101, 2493-2495.CyclooctaneJ. Wzorek, D. A. EvansChem 106boat-boatErel = 3.4 kcal/moloror Still argues that torsional effects contribute to the ca. 0.5 kcal/mol difference While torsional issues may contribute, ultimately both conformers are quite similar in

17、energy cyclooctanechairboatchair chairboat boatchair-boat!Grel = 0 kcal/molchair-boatdestabilizing transannular nonbonded interactions!chair-chair!Grel = 0.52 kcal/molchair-chairComputed energies and conformations: B3LYP/6-31G*“Cyclooctane is unquestionably the conformationally most complex cycloalk

18、ane owing to the existence of so many forms of comparable energy”-Hendrickson, J. B. JACS 1967, 89, 7036-7043.CyclooctaneJ. Wzorek, D. A. EvansChem 106 With our newfound understanding of the dominant conformations of cyclooctane, let us revisit one of the reactions presented earlierMeMeOLDA, MeIO95%

19、 antiMeLDAMeI MeHHMeOLi or13MeOLi13OLi(enantiomer forsimplicity) Placing the enolate within the boat relieves transannular nonbonded interactions For this reason, sp2 hybridized carbon atoms should generally be placed at position 3Enolate 1!Grel = 0.50 kcal/molComputed energies and conformations: B3

20、LYP/6-31G*Enolate 2!Grel = 0 kcal/mol Both enolates are very similar in energy, and they both lead to the same anti product Which conformer do you think will pass through a lower transition state when reacting with methyl iodide? A “thought experiment”: provide a rational for the depicted stereochem

21、ical outcomeHOHHg(OAc)2, H2OMeMeMeMe Hg OAc Step 1: consider the conformation of the substrate Both cis double bonds are placed in a position that relieves transannular strainH2OHHg(OAc)2HOHOAc HHHgMe Me OAcMe MeHgMe HHOAcMeCyclooctenoneJ. Wzorek, D. A. EvansChem 106 Cyclooctenone differs in conform

22、ation from what one might predict based upon the previous examples Consider the following reaction:MeNuc(exo-faceH Hattack)O Me2CuLi O H 65O99% antiMeMe4Me Placing unsaturation in the 2-3 positions relieves transannular nonbonded interactions, but contributes to poorp-overlap Now consider the hydrog

23、enation of an exocyclic enoneMeMeOH ORh, H2O6Me 291% antiMe453 Consider the relevant conformations:ufficient overlap of !-system Placing enone at the 4-5-6 positions affords proper overlapMeCH2HCH2OMeOHMeNuc(exo-face attack)MeO CH2OHCH2HHH 65O4Me Why does the relative stereochemistry of the product

24、predominate?Computed conformations: B3LYP/6-31G*CyclodecaneJ. Wzorek, D. A. EvansChem 106 Macrocyles tend to minimize transannular non-bonded interactions and high-energy torsional arrangementsor chair-chair-boatboatchairboatchairchair chaircyclodecane!G= 1.4 kcal/molrel While many conformations for

25、 cyclodecane exist, two commonly depicted ones are drawn aboveboat-chair-boat!Grel = 0 kcal/mol The boat-chair-boat conformation is decisively lower in energy than the other depicted conformationsLDA, MeIMe50% antiOOMeMe However, not all reactions are stereoselective, including enolate alkylation of

26、 2-methylcyclodecanoneHMeHMeMeOLiantiHOLisynLiOLiOchair-chair-chair!Grel = 6.5 kcal/molMesynHantieclipsed! (4-total) Drawn above are several reasonable conformers Placing substituents in either an axial or equatorial position at the corners of the ring has little energetic penaltyComputed energies a

27、nd conformations: B3LYP/6-31G*CyclodecenoneJ. Wzorek, D. A. EvansChem 106 Let us now consider the dimethyl cuprate addition into a cyclodecenone acceptorMeMe2CuLiMeO94% antiOOHMeMe Placement of an enone in the above locations clearly reduces transannular interactions (E-isomer shown for completeness

28、)OAxial Methyl!Grel= 0 kcal/mol A small difference in energy is associated with either the axial or equatorial conformation What potentially contributes to the high anti-selectivity?OZE Relief of transannular nonbonded interactions via introduction of sp2 hybridized atoms much like the 8-membered ca

29、se also holds for cyclodecaneMMMeOMeOorHHNucdeveloping A(1,2)-straindestabilizing steric effectsHO Two possible explanations include destabilizing steric effects, reducing Lewis acid activation of the carbonyl oxygen Developing A(1,2)-strain in the transition stateMeEquatorial Methyl!Grel = 0.38 kca

30、l/molComputed energies and conformations: B3LYP/6-31G*Macrocyclic StereocontrolynthesisJ. Wzorek, D. A. EvansChem 106O To this point, we have discussed the conformational control of 8 and 10-membered rings and the possibility of achieving high selectivity within the context of a given reaction What

31、about larger rings?OO OMe MeOMeOH H2CHMePeriplanone B (cockroach sex pheromone) Originally isolated in 1952OSSMeMeNNHHOOOHMeOOOHMeMeMeMe OMeOTBSDMDOO1)100%MeLiMeMeMe dr = 25:1MeMe2) KH, 18-C-6; TMSCl; m-CPBAO OHO OHMeMePgO3) TBSClanionic oxy-CopePgOPg =MeMe12,13-Desoxyepothilone BMe Epothilone B (an

32、ticancer)OEtOTBSHHHOOt-BuOOHMe OTBSMeTriton B 66%MePgOOHMePgOHOTBSOMeSMe75%HHOOMeMeOTBSPgOOMeN Me MeHMeMe PgOdiastereomeric toperiplanone!Triton B:OHBnComputed energies and conformations: B3LYP/6-31G* At this point, the synthesis needed to be reconsidered How might they obtain the desired stereochem

33、istry?olefinDanishefsky, S. J. Tet. Lett. 2001, 6785-6787.Still, W. C. JACS, 1979, 101, 2493-2495.Macrocyclic Conformational ControlJ. Wzorek, D. A. EvansChem 106 Two lowest energy conformations (result of semi-empirical PM3 Monte Carlo conformational search and further DFT Analysis of amphidinolide

34、 X and analogues also reveals that stereochemical components may stabilize a given conformationoptimization)A(1,3)-minimizedpseudo equat.MeMeMeOMeOOOMeOOAmphidinolide X (1) (anticancer)A(1,3)-minimizedMeseveral analogues synthesizedpseudo equat.Mepseudo equat.HHMeOMeMajor Conformation!Grel = 0 kcal/

35、molOOOMeMeOO2MeMeOMeMeHOOOOMeMeHpseudo axialOO3MeMeMeOOOH HOO4H HMinor ConformationIC50 (mg/mL)TypeCell linepseudo axial!Grel= 4.5 kcal/mol 12345.157.897.335.95101010103.708.58106.90104.291010HT29 LXFA 629LMAXF 401NLMEXF 462NLcolorectal lung breastmelanoma Indeed, larger rings may be conformationall

36、y defined if requisite controlling elements are presentFrstner, A. Chem. Eur. J. 2009, 15, 4030-4043.Computed energies and conformations: B3LYP/6-31G*Large Ring Conformational Control ElementsJ. Wzorek, D. A. EvansChem 106 If macrocycles can be conformationally defined, what types of conformational

37、control elements exist?H Amphidinolide B1 is a bioactive natural product that features a 26-membered macrolactoneMeMeMeRMeHHHOOMeRMeOHHOHHOH MeA(1,3)-strain minimizationA(1,2)-strain minimizationOHMeOMeHOOOHHOORRRHAmphidinolide B1(anticancer) The crystal structure of this compound reveals a transann

38、ular hydrogen bond that is present in the solid state Additionally, features include avoidance of a syn pentane interaction, and A(1,3) strain minimizationsyn pentane avoidedORRROHdipole minimizationhydrogen bondingstereoelectronic effectsMeMeHHMeHHHHHHMegaucheantiHRHHHRRHHRHHsyn pentane General con

39、formational control elements are listed above Empirically it can be shown that, in large rings especially, acyclic conformational analysis concepts generally hold Let us examine an X-ray crystal structure to visualize a few of these interactionsH-bond(X-ray)crystal structure: Bauer, I.; Maranda, L.;

40、 Shimizu, Y. JACS, 1994, 116, 2657-2658.A(1,3)-minimizedOleandolide and Transannular DirectionWzorek, Evans, KwanChem 106 Consider the following macrolide, which was a target for synthesis by Panek and coworkersOMeO Panek argues these results show the olefin is extremely shielded on one face by the

41、silyl protecting group Is there perhaps evidence for a directed reaction?pseudo equat.MeMeOHMe Opseudo equat.late-stage epoxidation?MeOHOOHMeOleandolideOTBSOTBSpseudo equat.pseudo equat.MeMeOMeMeMeMem-CPBAORMe OORMe OMeOMeOpseudo equat.MeMeMeMeOOOOMeMe This is an important conceptual example because

42、 there is a breakdown in one of our fundamental assumptions (peripheral attack)correct : epiyield (%)RHMe Bn100:0100:0na89280 peripheralattackn This example represents an exception, rather than the rule; nonetheless, beware that results of this nature existPanek, J. S. JACS, 2002, 124, 12806-12815.C

43、omputed conformation: B3LYP/6-31G*Intramolecular Reactions: Diels-AlderJ. Wzorek, D. A. EvansChem 106 Consider the following polycyclic natural productOO To this point, we have discussed intermolecular reactions involving medium and large ringsRing blocks face of functional groupNMe2MeHMeHHOOHMe*Me*

44、Nuc (or E+)Cassaine Deslongchamps has shown that tricyclic core structures of this type lend themselves to transannular Diels-Alder In the above reaction, a generic functional group (*) isreacted with a reagent to produce a new functional groupOreactionsOOMeOMeNMe*NMe OTBS!MeHMe76%OTBSHOMe MeOHM Now

45、 consider an intramolecular alternative, in which functional groups on the same molecule may react This approach uses conformational control much like the intermolecular cases already discussedMe How can we rationalize this outcome?eMeMeRHOMeHOMeMeRRMeRMeMeHOMeH RRMeMeOMeRRPreferred TSDeslongchamps,

46、 P. JACS, 2008, 130, 13989-13995.“Macrocycles have a high degree of conformational restriction and as a result, proximity effects become operative and very often, these effects will increase the rate of one reaction and slow down others which are normally competing.”-Pierre Deslongchamps, Pure and A

47、ppl. Chem. 1992, 64, 1831-1847.Intramolecular Reactions: Bis-MichaelJ. Wzorek, D. A. EvansChem 106 The salvinorin A caseO Both components may be combined to produce the macrocyclic precursorTBSOArOHCO2H OTBSHOfunctional groups in close proximityHHBOMOOOOOHHHHMeHAcO BOMO(OMe)2CHMeOOMeMe The elaborate

48、d macrocycleOOHMeMeO2C Salvinorin A(potent hallucinogen)OMe(MeO)2HCArOHHOMeHHOBOMOTBAFBOMOOOMeOOTBS MeOMeOMeMe(OMe) CHO2BOMOBOMO OOHOOTBSMeMeO(MeO)2HCCO2HO(MeO)2HCAcyclic precursor(MeO)2HC The macrocyclization event (acyclic stereocontrol)ArOTBS MeBOMOOHOTBSMeminimize A(1,3)- strainCO2H(enol)CH(OMe)

49、2minimize A(1,3)-MeHHOHArComputed conformation: B3LYP/6-31G* The low energy conformer predicts the correct face of attack Evans, D. A. JACS, 2007, 129, 8968 - 8969.strainTBSBOMOMeHOTBSH(MeO)2CHOCO2HHAn Atropisomeric MacrocycleJ. Wzorek, D. A. EvansChem 106Me In 2002, Shair disclosed a synthesis of longithorone AMePCy3ClRuMeOOTBS Hminimize A(1,3)-strainTBSOPhClOPCy3OHGrubbs IMeMeMeOMeOOTBSHH OHC20:1 atropdiastereoselectivityOTBSOMeLongithorone AMe The two chiral macrocycles were then employed in an intermolecular Diels-Alder reactionMeMeOOMeMeMeOOTBS+Me