教学课件学术资源大全高等有机化学lecture 18_h

1、Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106Key Questions:(1) Easy or hard?LiHeteroatom-Stabilized CarbanionsEugene E. KwanOctober 17, 2011.PhLiPh(2) Why this dichotomy?OCbOHiPrPhs-BuLi;Scope of Lecturemodel for Wittig selectivitybetaines?Phconfigurationally stable organolithiumsEt-B

2、-9-BBN91%, 98:299:1inversion barrierss-BuLi;heteroatom- stabilized carbanionsOCbiPrHOPhsparteinePh OB80%, 4:9699:1enantioselective deprotonationsONMR observations of oxaphosphetanesHoffmann tests(3) Is this the mechanism of the Wittig reaction? does E/Z selectivity come from?WhereWittig reactionHelp

3、ful References1. Configurational Stability and Transfer of Stereochemical Information in the Reactions of Enantioenriched Organolithium Reagents. Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed. 2002, 42, 716-738.2. Enantioselective Synthesis with Lithium/(-)-Sparteine Carbanion Pairs. Hoppe, D.; He

4、nse, T. Angew. Chem. Int. Ed. 1997 36 2282- 2316.HHR3PRR3PRbetaines+ORH OHRORH+PR3R P OR P O33+oxaphos- phetanesRHRRRR3. The Wittig Olefination Reaction. Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863-927.4. Stereochemistry and Mechanism of the Wittig Reaction. Vedejs, E.; Peterson, M.J. Topi

5、cstereochemistry, 1994, 21, 1-157.cis olefintrans olefinI think Professor David A. Evans (Harvard) for providing me with some useful material on the Wittig reaction.LiPhOOLecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106Configurationally Stable Organolithium Reagents Configurational Stabi

6、lity and Transfer of Stereochemical Information in the Reactions of Enantioenriched OrganolithiumReagents. Basu, A.; Thayumanavan, S. Angew. Chem. Int. Ed. 2002, 42, 716-738.In this section, we will consider the relative rates of performing enantioselective deprotonations of prochiral methylene grou

7、ps and subsequent substitution reactions:NNNN(-)-sparteine(+)-sparteineNNNNHRERretentionEStoltz literature seminar 6-13-02b-isosparteinea-isosparteineHRLiR*ROf these, only (-)-sparteine is naturally abundant (isolated from lupin plants). (+)-sparteine also occurs naturally, but it far less abundant.

8、 The isosparteines are only availablesynthetically. Efforts are underway to find cheap replacements for sparteine, but they need not concern us for now.Inversion BarriersWithout proximal heteroatom ligands or stoichiometric chelating ligands, organolithiums are not configurationally stable. For exam

9、ple, the barriers to the inversion of this norbornyllithium have been measured by NMR (Grutzner JACS 1980 102 4709):EERHRinversionH HRLiR*HRERRinversionE*RLiRHRdeprotonationepimerizationDG = +9.6 kcal/molDH = +6.7 kcal/molDS = -14 e.u.EPhLiERHRLiPhretention substitutionAs mentioned before, nucleophi

10、lic substitution reactions (SN2) generally occur via inversion of configuration, but electrophilic substitution reactions can proceed with inversion, retention, or even racemization depending on what the electrophile (E) is.The negative entropy of activation is consistent with formation of a solvent

11、-separated ion pair:- Ejection of a lithium atom will incur an entropic cost as solvent reorganizes.- This is a fast process compared to the desired substitution reactions.Ph+ LiSnWhat is the nature of the chiral ligand R*? (-)-Sparteine is a good bidentate ligand for lithium:Lecture 18 - Heteroatom

12、-Stabilized CarbanionsE. KwanChem 106Inversion Barriersa-heteroatoms are not particularly helpful in increasing the configurational stability:Unfortunately, the literature on this is completely chaotic. are some examples.HereDipole StabilizationLiMeLiLiHere are some barriers to inversion in lithiate

13、d sulfones:PhNMeMePhSePhPhSPhLiLiDG = +9.5 kcal/molDG = +10.0 kcal/molSO PhSO Ph22PhPhDG = +9.0 kcal/molPhDG = +9.6MeDG = +9.6MeOLi Evidently, the potential for chelate formation does not increase stability in this example.SePhLiLiSO2CF3SO2CF3PhPhDG= +9.3 kcal/molThe presence of adjacent heteroatoms

14、 gives an alternative to the solvent-stabilized ion pair mechanism: the conducted tour mechanism originally suggested by Cram (JACS 1964 86 2950). The idea is that the Lewis-basic heteroatom can coordinate the lithium, and then deliver it to the other enantioface via C-C bond rotation:PhDG = +16.0Me

15、DG = +17.8The difference has been attributed to increased nC to s*SC donation with the CF3 group (S and C have about the same electronegativity). However, if the inversion proceeds via a SSIP, then placing electron withdrawing groups should be expected to stabilize the solvent stabilized anion more

16、than it stabilizes the contact ion pair, so increased dipole or donor- acceptor stabilization should be expected to decrease the configurational stability.LiLiLiHPhMeMeHPhMeMeNNPhNAlternatively, C-C bond rotation could be rate-limiting. Indeed, increasing the size of the aryl group does increase the

17、 stability. In the top two cases, one could argue that resonance stabilization by phenyl decreases stability, while the increased size of phenyl increases stability by hindering rotation.ome cases, this has been corroborated by the finding of low entropies of activation, but I think its fair to say

18、that theres no real understanding of exactly how inversion happens.LiHMeMeHMeMePhNNNPhPhLiLiBridged species have been observed by NMR spectroscopy. ome cases, it is possible for bond rotation to be rate-determining.Remarkably a-alkoxyoganolithium reagents appear to be stable at relatively high tempe

19、ratures. Originally demonstrated byQ: What influences the inversion barrier?Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106Still (JACS 1980 102 1201), transmetallation from alkyltpeciesAfter four hours at 40 C, a remarkable 83% of the optical activity remained.s-BuLi, pentaneis stereosp

20、ecific and leads to configurationally stable organo-70 C; CO2SnBu3OCO2HHgBrPhO1. Bu3SnLi2. MOMClBuLi, THF 30 C Given the deleterious effects of donating solvents, these inversion barriers may not be as surprising:CHOPh3. MPLCSnBu3PhOOLiNLiPhPhSiSiSiSiLiOHDG = +11.2DG = +10.7PhOOPhOOacetoneOHLiLiLiOP

21、hOOPhOOPhPhPhSSiSSiconfigurationally stable!Why this works in THF at such a high temperature is a mystery. Donating solvents like THF are known to decrease the stability of these compounds. For example, here is an early example from Letsinger (JACS 1950 72 4842):s-BuLi, 94:6 pet ether/ether 70 C,DG

22、= +8.0DG = +10.0OLiOLiNPhPhSSiSSiICO2H2 min; CO2100% ee20% eeDG = +10.5DG = +9.3Generally, the ether is needed to increase the rate of lithium- halogen exchange. If ether is avoided, then the stability is substantially improved (Curtin JACS 1962 84 1967):s-BuLi, pentaneAs far as I can tell here, the

23、re is no correlation between the donor ability and the stability-these are just all low barriers.Interestingly, cyclopropyllithium reagents are very stable, even at 0 C in ether:40 C; CO2CO HHgBr2Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106Lithiation-Substitution Sequences: Reaction

24、Pathways and Synthetic Applications. Beak, P. et al. Acc. Chem. Res.1996, 29, 552-560.i-PrLi,94:6 petane:ether40 C; CO2HO2C99% ee95% eeThe second selectivity is even higher because it is double diastereodifferentiating. The success of this is surprising, given the many donating groups present. Nonet

25、heless, these reactions do work and are widely used.1. PDC1. CH I2 22. Ph P=CH 2. resolution Bu3SnOHBu3SnOH323. N2H2It is proposed that the presence of the carbamate increases the kinetic acidity of the adjacent protons in an effect named the complex-induced proximity effect. It is analogous to the

26、effect in ortho- and lateral lithations on aromatic rings. (See Snieckus and Beak, ACIE 2004 43 2206 for a review.)H2 equiv n-BuLi3 h, 0 C, THFBu3SnOTsLi+OHHThe diastereoselectivity is presumably controlled by the concave nature of this 3.2.0 system.Interestingly, the presence of an achiral bidentan

27、te amine reduces the configurational stability and reactivity (there is an error in the original report; see Clayden, page 188):s-BuLi / TMEDAOTsOHHTMSCl 78 C, Et2OLiSnBuNBocNBoc3Perhaps the most useful variant of this chemistry is the enantioselective deprotonation of alkoxycarbamates. Here are som

28、e leading reviews:Enantioselective Synthesis with Lithium/(-)-Sparteine Carbanion Pairs. Hoppe, D.; Hense, T. Angew. Chem. Int. Ed. 1997 36 2282- 2316.Regioselective, Diastereoselective, and Enantioselectivewith TMEDA: 36% yield, 74% eewithout TMEDA: 15% yield, 93% eeTMSNBocIf desired, the left over

29、 sparteine can be recovered by aqueous extraction.Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106Unfortunately, piperidines do not work as well (Wiberg et al.JACS 2002 124 1889):s-BuLi, ether/cyclohexane(Ordinarily, benzyllithiums are very configurationally unstable, but the presence of

30、 the carbamate is very stabilizing. Why that is true is unclear to me, but the fact is it works.) These secondary carbamates can be prepared by a variety of means: Noyori transfer hydrogenation, CBS reduction, etc. After lithiation, the resulting chiral carbenoid is treated with a borane:R78 C, 16 h

31、NNBocTMSOOLiB(OR)RB(OR)warm8%, 74% ee22MePhMePhOCbretentionOCbApparently, a-lithiation is very slow, allowing for competitive lithiation of the Boc group. The major products are condensation and addition products (i.e., of s-BuLi to the carbonyl group):RRH O2 2MePhMePhOHB(OR)2ONInterestingly, a ster

32、eochemical turnover to inversion occurs with trialkylboranes:LiOCbRB(R)2warm43%9%MePhMePhOCbinversionB(R)Aggarwal has demonstrated an interesting application of this2technology to the asymmetric synthesis of tertiary alcohols.The idea is that typically, one would try to do an enantioselective1,2-add

33、ition of an organometallic reagent to a ketone:RB(R)2H O2 2MePhMePhROHOOH MeLi cat*Aggarwal proposes the following explanation (Nature 2008 456 778). With boronates, prior coordination to lithium results in what is essentially a directed delivery of boron:The above example is completely made up, but

34、 illustrates the difficulty: beacuse the groups on either side are about the same size, it will be very difficult for a catalyst to discriminate between the two enantiofaces. Aggarwals solution is very clever. First, a carbamate-stabilized benzyllithium reagent is generated:OR OLiBLiOON(i-Pr)2 s-BuL

35、i, Et O278 C, 20 minMe ArMePhOCbON(i-Pr)2Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106With alkylboranes, deliever occurs opposite the lithium. One idea is that the carbanion will reside in a more p-like orbital soas to be better stabilized by the aromatic ring. Therefore, there will b

36、e more electron density opposite the lithium.LiOOCbOHEtPhs-BuLi;PhBEt391%, 99:199:1s-BuLi;OCbOHEtPhMe ArON(i-Pr)Ph OBO295%, 1:9999:1RB OBranching is allowed:OCbThis is bolstered by the fact that with alkyllithiums, addition of either alkylboranes or alkoxyboranes leads to retention:OHiPrPhs-BuLi;RPh

37、Et-B-9-BBNR/RO BR/RO91%, 98:299:1LiOs-BuLi;OCbiPrHOPhMe AlkylON(i-Pr)2Ph OThe idea is that with an alkyllithium, theres no possibility of resonance stabilization and therefore the anion sits in an orbital that is more sp3-like. Therefore, theres little electron density opposite the metal. Its a cute

38、 explanation, but I think its safe to say its speculation. Bents rule means that the anion should have a lot of s-character regardless of whats next to it.80%, 4:96B99:1OAryl groups are tolerated:OCbOHArPhs-BuLi;OPh BCl96%, 99:1Aggarwal makes two notes:(1) Arylboranes like Ph-9-BBN are not usable be

39、cause of proto- deboronation occurs during the oxidative workup. Butalkyl boronic esters are stable.(2) Another way to get to these tertiary alcohols is to add organozinc reagents to ketones with Ti catalysts. However, that method cannot make tertiary alchols with branched alkyl groups, vinyl, or he

40、teroaryl groups.99:1Os-BuLi;OHArPhOCbPh OOB94%, 98:299:1OHowever, in all of the cases reported, there is a phenyl ringat the secondary alcohol. p-OMe-Ph, p-Cl-Ph, and indanones are demonstrated, but no alkyl groups are listed (maybe those precursors are hard to access).Here are some entries from the

41、 substrate tables:Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106This can all be understood with energy diagrams. Suppose the barrier to inversion is low. In reaction (1), we have four possible pathways:Q: How can one determine if an organolithium reagent is configurationally stable?Cle

42、arly, if we want to design reactions on chiral organolithium reagents, we need to know what their inversion barriers are. Although one can sometimes measure the barriers directly via dynamic NMR methods, that is a laborious, complicated process that may well provide more information than is really n

43、eeded. What we really care about is how fast racemization is relative to substitution.The Hoffman test (Tetrahedron 1994 50 6049) involves two reactions:S,SR,RDDGS,RR,SSRorganolithium(1) take a racemic organolithium reagent and react it with a racemic, chiral electrophile; andproductsproductsThe R,R

44、 / S,S and R,S / S,R combinations are mirror images, so they appear at the same heights. The diastereoselectivityin the reaction will be determined by DDG; the enantioselectivity will be 0. With the enantiopure electrophile, we take away two of the pathways. Say we only have S electrophile:(2) take

45、a racemic organolithium reagent and react it with an enantiopure, chiral electrophile.This means four products are possible. With the first descriptor representing the configuration at the organolithium and the second descriptor representing the configuration at the chiral electrophile:S,SDDGE(R)E(S

46、)E(R)E(S)R,SRRRRRRRR(S,R)(S,S)(R,R)(R,S)Typically, the Reetz aldehyde is used as the electrophile:HOSRorganolithiumproductsproductsNNow we can only talk about diastereoselectivity. In this case, it will be the same as in reaction (1). Therefore, if r(reaction 1)= r(reaction 2), then the reagent is c

47、onfigurationally labile. Generally, for good results, r should be between at least 1.5. If its too low, then both reactions will give the same answerQ: What is the expected ratio in the first reaction?Lecture 18 - Heteroatom-Stabilized CarbanionsE. KwanChem 106regardless of how labile the reagent is

48、.A modified Hoffmann test exists for situations where a chiral ligand is present (e.g., sparteine). The two reactions are:Q: What happens if the reagent is configurationally stable?Now, we move from a Curtin-Hammett scenario to a kinetic quench scenario:(1) React a racemic organolithium with an exce

49、ss of enantio- pure electrophile.(2) React a racemeic organolithium with asub-stoichiometric amount of enantiopure electrophile.R,RS,SIf the reagent is configurationally stable, we have:racemization barriertrap S lithiumDDGS,RR,Swith R electrophiletrap R lithium with R electrophileSRRL*organolithium

50、productsproductsSL*In the first reaction, there is no difference. The low barrier in the last case only served to epimerize an already racemic mixture of organolithium reagent. In the second reaction, the diastereoselectivity will be 1:S,RR,RWith an excess of reagent, then the product ratio will ref

51、lect the ratio of the diastereomeric complexes (it wont be 1:1!). With a sub-stoichiometric amount of reagent/low conversion, the product ratio will reflect the difference in barrier heights; each diastereomeric complex is isolated from the other bythe high racemization barrier, and one can call thi

52、s two ground states.S,SR,SThese sorts of test has been applied to a variety of systems, and I direct you to the review by Basu for leading references.I turn now to an entirely different sort of carbanion: phosphorus ylides. I ask how Wittig reactions occur, and the origin of the stereochemical dichotomy b