Scope: 1. S N 2' Displacements. 2. Michael additions. Not Covered:

Transcription

1 Is There a "Crams's ule" for lefins? Part A C=C cleophile Additions cleophilic lefin Additions?! Any reaction which proceeds through electron donation (pair or radical) into the π* orbital of the olefin in the transition state. eviews -This may be it. -Cited papers with particularly elaborate / insightful discussion will be marked with a dot ( ). cope 1. 2' Displacements 2. Michael additions 3. Additions to acivated olefins (vinyl nitriles, vinyl sulfones, dithioketene acetals). 4. Diels Alder reactions (chiral dienophile) 5. [3 2] Dipolar additions (chiral dipolarophile) 6. Claisen and related [3,3] rearrangements (chiral allylic moiety) 7. Wittig [2,3] rearrangements (chiral allylic moiety) ot Covered s 4 Dihydroxylations ([2 2] or [3 2] mechanism), reviewed recently. ee Barrow, J. eminar otes, 1993, Joe Duffy 1 / 4 / /12/ PM

2 Transition tates (3-21G) Predictions from Computational tudies Predictions from Computational tudies Transition state assumption Attack angle of 9, 2 Å, relative energies calculated at T-3G (verified with single point calculations at MP2/4-31G level). * * * thylene vs. formaldehyde for C 3 addition. 3 9 ouk's ule "The tendency for staggering of vicinal bonds with respect to partially formed bonds is greater than for fully formed bonds." M thylene vs. formaldehyde for addition. LUM -thylene has a shorter -C bond length (less exothermic, later T ). -Potentially higher diastereoselectivity for olefins than carbonyls. "Felkin-ke" teric Analysis (T-3G) - ouk, K.. Von. chleyer, P. J. Am. Chem. oc. 1985, 17, 2821, and C 3-3 C M LUM Unfavorable C 3 FM aspects are somewhat vague. rel Avoid eclipsing interactions in the transition state. ouk, K.. et al., J. Am. Chem. oc. 1982, 14, 7162 ouk, K.. et al. J. Am. Chem. oc. 1981, 13, /12/ PM

3 The 2' eaction - Alkyl ubstitution The 2' eaction - Alkyl ubstitution L L Felkin like T For = For = CC 2 L (Z) - olefins Cl 'M TF, -7 C 'Cram" 'Anti-Cram" () - olefins Cl 'M TF, -7 C 'M 'Cram" atio 'Anti-Cram" 'M Bu 2 ZnCl ZnCl 2 88 atio Ketone equivelant Cl 'M TF, -7 C t t t Chex Chex Bu 2 Zn 2Cl Bu 2 ZnCl 2 Bu 2 Ti() 3 1 Bu BF 3 2 ZnCl 2 Bu 2 ZnCl 2 2 ZnCl ***Analogous Carbonyl Additions*** 'M Bu 2 ZnCl 2 2 ZnCl 2 'Cram" atio 'Anti-Cram" Chex MgI BuMgI Proposed chansim clophilic attack of the group, not the (I) to (III). 1 Catalytic I 2Cl added 2 Cram, D. J. et al. J. Am. Chem. oc. 1952, 74, 5828; Cram, D. J. et al., J. Am. Chem. oc. 1953, 75, 65. ' n ZnCl 2-n / Cl Added Lewis acid was required in all cases ( was unreactive, 2 gave only 2 products). () olefins afford higher diastereofacial selectivity than carbonyls with the same sense of induction akamura,. et al. J. rg. Chem. 1993, 58, J. Am. Chem. oc. 199, 112, /12/94 13 AM

4 The 2' eaction - Alkyl ubstitution The 2' eaction - Alkoxy ubstitution Proposed transition state () lefins L favored L P Felkin like T () olefins P For = P For = CC 2 Felkin like T P Bu 2 ZnCl 2 P P L disfavored L Cl TF, -7 C P atio Anti Felkin like T imilar 4-centered T for ia 2 B reduction of ketones favors anti-cram product (opposite steric contraints on reagent). Midland, M. et al. J. Am. Chem. oc. 1983, 15, ouk, K.. et al/ J. Am. Chem. oc. 1982, 14, tbu MM MM TIP MM (Z) lefins ame ratios observed using Bu 2 Zn / cat Br 2, Bu BF 3, BuTi() 3 / cat Br 2, and Bu 2 Zn 2Cl / 2 MPA (no copper). L Felkin like T L favored disfavored L L (Z) olefins Cl P tbu Bu 2 ZnCl 2 TF, -7 C P MM P 9 4 atio P 1 6 A-1,3 train T The "chelation control" product predominates in the absence of chelation! A-1,3 train may deminish stereoselectivity for (Z) lefins. The ratio is enhanced by larger "" for () olefins, decreased by larger "" for (Z) olefins /12/ PM

5 The 2' eaction - Alkoxy ubstitution The Michael eaction - Alkyl ubstitution Proposed transition state () lefins L P L P L Felkin like T L For = L C 2 For = CC Chelate like T () lefins o anchiomeric assistance from (since TIP gives ). TM Could be based on sterics as concluded from dialkyl cases (P = m ). Could be a definitive case of ouk's "inside alkoxy effect" which applies to electrophilic additions. WG DG favored over WG DG σ* C-C Lewis Acid Lewis Acid TM TiCl 4 TM BF 3 t 2 MgBr Br atio σ C-C ouk, K.. et al. J. Am. Chem. oc. 1984, 16, 388. eathcock, C.. et al. J. rg. Cem. 1984, 49, (Z) lefins C 2 t M C 2 t C 2 t P L L M atio A-1,3 train T A-1,3 train may deminish stereoselectivity for (Z) olefins. Larger L prefers A-1,3 model more. akamura,. et al. J. rg. Chem. oc. 1993,58, Bu 2 BF 3 Bu BF BF amamoto,, et al. J. Chem. oc. Chem. Comm. 1987, /12/ AM

6 (Z) lefins () lefins Both the Felkin and electron transfer models predict the same product for () olefins. (Z) lefins C 2 t amamoto's hypothesis organocopper species react as a nucleophile, cuprates via initial electron transfer, affording a semi-pyramidalized transition state. L L? t 2 C The Michael eaction - Alkyl ubstitution Felkin like T Felkin model violates A-1,3 strain for (Z) olefins. C 2 t M Felkin like T M Bu 2 BF 3 Bu BF BF lectron transfer T "Anti-Cram" atio - lectron transfer T (similar to product conformer) amamoto,, et al. J. Chem. oc. Chem. Comm. 1987, C 2 t t 2 C L C 2 t L C 2 t Disubstituted lefins Disubstituted lefins Added 1 eq. The "Michael" eaction - Alkyl ubstitution I Zn/I M t 2-78 C M t 2-78 C M M nbu Chex tbu imilar results to (Z) olefins, reagent based turnover is observed. C 2 t C 2 t 2 2 "Anti-Cram" atio rganocopper and cuprate reagents both give anti Cram diastereofacial selectivity. Diastereofacial selectivity for both can be reversed with an electron acceptor. C 2 t C 2 t atio "Anti-Cram" amamoto,. et al. J. Am. Chem. oc. 1988, 11, 617. Geise, B. et al. ynlett 1992, 441. C 2 t C 2 t 6.1 1/12/ AM

7 The "Michael" eaction amamoto's next generation hypothesis All reactions of dinitriles proceed via the electron transfer mechanism. C 2 t C 2 t ubstrate eduction Potentials ' C 2 t red vs C (V) >-2. Further claim 2 is an electrophilic radical, with an attack angle < 9. L Felkin like T attack angle >9 efuted by Morokuma calculated T at UF / 3-21G level - - ame as for C lectrophilic radical T attack angle <9 owever, copper may form the electrophilic π - complex at <9 which prefers "inside" hydrogen. nergy of complexation kcal / mol rel Morokuma's proposed T C /12/ AM Why does p-db shut down this mechanism? Morokuma, K. et al. J. Chem. oc. Chem. Comm. 1989, L A. Alkoxy substitution The Michael eaction - Alkoxy ubstitution Felkin like T For = For = CC () lefins P M TB TB TB In the synthesis of livomycin A P P C 2 t M P (2-methallyl) 2 BF 3 () BF 3 Bu BF 3 BF 3 2 BF 3 2 () 2 BF atio amamoto,. et al J. Am. Chem. oc. 1992, 114, t 2, 2, TF 98 2 P C 2 t oush, W.. et al. J. Am. Chem. oc. 1989, 111, P P C 2 C 2 t

8 The Michael eaction - Alkoxy ubstitution The Michael eaction - Alkoxy ubstitution TiCl 4 TM bservations on () olefins Anti Cram ("chelate") diastereomer is favored for cuprates. Cram diastereomer is favored for other nucleophiles. eathcock's proposal ' atio eathcock, C.. et al. J. rg. Chem. oc. 1984, 49, C P P C 2 In the synthesis of Leucomycin A 3 I C 2 C 2 TF, -4 C 93 7 Cram" Ac icolaou, K. C.,et al. J. Am. Chem. oc. 1981, 13, In the synthesis of β-lactams 2 C 2 t neat, -5 C C 2 t "exclusively" C 2 B amada,. et al. Tetrahedron Lett. 1983, 24, 39. "The stereostructures of the major isomers produced...are those predicted by the application of Felkin's model (Figure 2)." *** ote that figure 2 is incorrect in eathcock publication, read text carefully*** amamoto's revised next generation proposal rel P. kcal C 2 π - Complex involves electrophilic attack, governed by the "inside alkoxy effect." Computational support Transition structures located at F / 3-21G. C 3 vs. 3 C.6 kcal lectron donor should be antiperiplanar, electron acceptor should be out of conjugation. The two computed transition structures predict a ratio of for additions at r.t., amamoto found P C 2 Morokuma, K. et al. J. Am. Chem. oc. 1989, 111, /12/ AM

9 The Michael eaction - Alkoxy ubstitution The Michael eaction - Alkoxy ubstitution P P P C 2 Felkin like T For = For = CC on cuprate nucleophiles TiCl 4 TM (Z) lefins P C 2 t P P 1 1 eathcock, C.. et al. J. rg. Chem. oc. 1984, 49, P M TB TB TB M C 2 t (2-methallyl) 2 BF 3 () BF 3 Bu BF 3 BF 3 2 BF 3 2 () 2 BF atio C 2 t In the synthesis of β-lactams C 2 t 2 neat, -5 C "exclusively" amada,. et al. Tetrahedron Lett. 1983, 24, 39. eathcock observes a turnover in selectivity based on olefin geometrty, amada does not. C 2 t In the synthesis of livomycin A amamoto,. et al J. Am. Chem. oc. 1992, 114, t 2, 2, TF 96 4 "Chelate!!!" oush, W.. et al. J. Am. Chem. oc. 1989, 111, amamoto observes a turnover in selectivity based on olefin geometry, oush does not! C 2 t / Z = a C 2 t, 78 C 95 5 Mulzer, J. et al. Angew. Chem. Int. d. ng. 1984, 23, /12/ AM

10 The Michael eaction - Alkoxy ubstitution The Michael eaction - Alkoxy ubstitution Bis-activated lefins cleophiles without Lewis acid P C 2 t C 2 t M P C 2 t C 2 t P C 2 t C 2 t 2 C P Violates A-1,3 strain principles! P C 2 P M atio cleophiles with Lewis acid (eathcock proposal) TB TB TB (2-methallyl) 2 BF 3 Bu BF 3 BF 3 () () BF P TiCl n rganocuprate addition P amamoto,. et al J. Am. Chem. oc. 1992, 114, C 2 t P ame facial preference as (Z) olefins. bservations on (Z) and Bis-activated lefins P A-1,3 strain forces P to the outside position. C 2 Cram product favored for copper-based additions (except oush case which remains unexplained). Computational support Transition structures located at F / 3-21G, found same diastereofacial preference, but from a different rotamer. Anti-Cram (or "chelate") product favored for non-copper nucleophiles with added Lewis acid. Cram product favored for non-copper nucleophiles without added Lewis acid. 3 C vs. 3 C rel. kcal 4.7 kcal Morokuma, K. et al. J. Am. Chem. oc. 1989, 111, /12/ PM

11 () Vinyl sulfones Vinyl ulfone Additions Vinyl ulfone Additions MM TM 2 1) ', -78 C, t 2 2) KF, MM ' tbu tbu 2 96 >98 >98 >98 MM atio 2 4 <2 <2 <2 Carretero's proposal 2 TM Isobe's proposal MM 2 (Z) Vinyl sulfones P 2 TM Carretero, J. C. et al. Tetrahedron Lett. 1991, 32, ), -78 C, t 2 P P 2 2 2) KF, TM P 2 MM 2 P atio Both are similar, except Isobe recognizes the importance of A-1,3 strain. Utility C 2 C 2 C 2 MM MM TB "only" 97 > <1 5 Isobe, M. et al. Pure Appl. Chem. 199, 62, 27. Isobe, M. et al. Tetrahedron Lett. 198, 21, ame diastereofacial selectivity is observed with P = TB! Asymmetric variant P 2 t P t 2 1) ag 2) 3 P it 3 2 1) -Br 2) TBAF 2 TM 1) 2) ecl P 2 e TM xidize P 98 2 Isobe, M. et al. Tetrahedron Lett. 1988,29, Isobe, M. et al. Tetrahedron, 1986, 42, /12/ AM

12 Dithioketene Acetal Additions Vinyl ulfone Additions 2 TF/MPA t nbu 98 atio "Anti-Cram" 2 Carretero's proposal 2 TM Isobe's proposal MM 2 Transition state proposal LA TF/MPA Governed by A-1,3 interactions with directed nucleophilic attack. t nbu "Anti-Cram" atio Both are similar, except Isobe recognizes the importance of A-1,3 strain. ame diastereofacial selectivity is observed with P = TB! Asymmetric variant P TM 2 it 3 2 1) -Br 2) TBAF MM TB protected substrate decomposed, the role of chelation was not further tested. Isobe, M. et al. Tetrahedron Lett. 1988,29, Fujisawa, T. et al. Tetrahedron Lett. 1989, 3, /12/ PM

13 Ac ' ' Ac Ac Ac imilar proposal for each Diels Alder eactions - Alkoxy ubstitution Toluene Toluene only diastereomer (exo product!) Both Anti Cram dienophile diastereoface is prefered in each case. Ac 3 1 exo endo orton, D. et al. J. Chem. oc. Chem. Comm. 1981, 88. Diels Alder eactions - Amine ubstitution α-lectron donating substituents C 2 C C CBz CBz 2 C C 2 CBz only diastereomer chmidland, T. et al. elv. Chim. Act. 1983, 45. ehre's Proposal The Diels Alder results are expanded into a general rule for olefin attack with an asymmetric allylic center. syn anti C P Franck C P orton (no explanation for exo preference) lectron ich lectron Poor lectrophile yn Anti cleophile Anti yn This theory works well for all reactions covered except Michael additions. Makes no account for () vs (Z) olefins. ehre, W. J., Kahn,. D. J. Am. Chem. oc. 1987, 19, /12/ AM

14 [3 2] Additions [3 2] Additions δ P δ Felkin like T P Proposed chanism A genuine nucleophilic attack. Ac TM TM PdL 4 Ac- PdL 2 (-) PdL 2 A. Palladium catylized [32] C 2-2 C 2 C (-) (-) PdL 2 PdL 2 Ac TM 5% Pd(Ac) 2 25% () 3 P PdL 2 BM C(C 3 ) 2 i(tbu) 2 ' BM The steric environment of the protecting group is not a factor atio 2 C 2 C C 2 - PdL 2 atio eactions of () olefins are stereospecific, (Z) olefins are not (with recovery of isomerized starting material. Trost, B. M. et al. J. Am. Chem. oc. 1983, 15, Trost, B. M. et al. J. Am. Chem. oc. 1983, 15, C Dipole Model Trost claims the reaction is governed by the moecular dipole, not Felkin, based on independence of sterics of and '. Claims silicon acetonide provides higer dipole, resulting in higher stereoselectivity. Dipole model is similar to Kahn / ehre proposal. 2 C - - Felkin Model Trost, B. M. et al. Tetrahedron Lett. 1985, 26, /12/ AM

15 [3 2] Additions - Alkyl ubstitution [3 2] Additions - Alkoxy ubstitution m L - Felkin like T m P - P Felkin like T B. itrile xide [32] Ar - C 2 Cl 2, r.t. tbu TM atio Both authors invoke the Felkin like transition state above. Ar "Anti Cram" ouk, K.. et al. J. Am. Chem. oc. 1986, 18, 2754 rran, D. P. et al. ynthesis 1986, 312. Ar P Greater dependance on the size of "" than of "P." Ar C 2 Cl 2, r.t. Ar - tbu tbu - C 2 Cl 2, r.t. P P TM TB TM Ar <5 <5 atio >95 >95 ouk, K.. et al., J. Am. Chem. oc. 1984, 16, 388 ouk, K.. et al, J. Am. Chem. oc. 1986, 18, 2754 Kozikowski, A. P. et al., J. rg. Chem. 1984, 49, 2762 Ar atio P Ar Ar C() 2 Chex C= Kozikowski, A. P. et al. J. Am. Chem. oc. 1982, 14, 5788 ouk, K.. et al. J. Am. Chem. oc. 1984, 16, /12/ AM

16 [3 2] Additions - Alkoxy ubstitution 2,3-Wittig earrangement ouk claims the additions are more electrophilic in nature, and conform to the "inside alkoxy effect" rule. Computational evidence Base transition structure (propene) was found at the 3-21G level, then the substituted rotamers were minimized by MM2, with single point energy calculations at T-3G. P (-) Felkin like T P () lefins nbu 3 rel kcal Predicts Anti-Cram / Cram ratio of 6832 at room temperature (observed 6436). Larger group affords higher diastereoselectivity. (Z) lefins Bu -78 C 6 79 (isolated) C 2 LDA -78 C C 2 Proposed (only diastereomer, 4% y) (-) (-) () lefins (Z) lefins Violates the Kahn / ehre proposal. Bruckner,. et al, Angew. Chem. Int. d. ng. 1988, 27, /12/ AM

17 Claisen earrangements Claisen earrangements - The Aldol Analogy () lefins P Felkin like T M 1) LDA, TF - C 2) TMCl MM BM TM P atio M TM C vs. Proposed anti-felkin Caisen transition states Geometrically and electronically analogous to the acid diolate aldol reaction, which exhibits an exceptional Felkin diastereo-preference. L C Bu 2 B Bu 2 B C Anti Aldol TB Felkin Diastereomer Cha, J. K. et al. Tetrahedron Lett. 1984, 25, 5263 BBu 2 TB C vs. Claisen The Claisen (Z) enolate is analogous to the aldol () enolate. C L C M Aldol Bu 2 B L C Bu 2 B Bu 2 B ratio 93 7 TB yn Aldol Felkin Diastereomer This [3,3] sigmatropic rearrangement is isoelectronic with the aldol reaction. The inside alkoxy transition state aviods the syn-pentane interaction, but should only apply to electropphilic additions. vans, D. A.; Duffy, J. L. Unpublished results. Violates Kahn / ehre proposal. Dart, M., private communication /12/ AM

18 Claisen earrangements Claisen earrangements () lefin, methyl ketone enolate () lefin, methyl ketone enolate TP C(t) 3 cat 2 14 C TP TP TP C(t) 3 cat 2 14 C TP TP "Anti-Cram" "Anti-Cram" Takano,. et al. Tetrahedron Lett. 1985, 26, 865 Takano,. et al. Tetrahedron Lett. 1985, 26, 865 Thioester Claisen Thioester Claisen TB TB Cl Cl TB Cl Cl "Anti-Cram" TB TB TB "Anti-Cram" Cl Cl atio Cl Cl atio ttb <5 <5 <5 >95 >95 >95 ttb <5 <5 <5 >95 >95 >95 rnst, B.; Bellus, D. et al. Angew Chem. Int. d. ng. 1991, 3, rnst, B.; Bellus, D. et al. Angew Chem. Int. d. ng. 1991, 3, C or C C or C Case 1 =, =, "=t Case 2 =Cl, =, '= Again, anti-felkin or inside alkoxy transition states are proposed. Case 1 =, =, "=t Case 2 =Cl, =, '= Again, anti-felkin or inside alkoxy transition states are proposed /12/ PM

19 Conclusions??? Conclusions??? Alkoxy-ubstituted Additions Is there a "Cram's ule" for nucleophilic attack of olefins?... owever, application of Cram's rules in the following way predicts the favored product for everything except Michael additions P P Alkyl substituted olefins follow the Cram teric rule. Alkoxy substituted olefins follow the Cram Chelate rule. Alkyl-ubstituted Additions Cram Diastereoface Vinyl sulfone additions () and (Z) Michael additions () and (Z) except (Z) "charge transfer" Anti-Cram Diastereoface (Chelation Diastereoface) 2' additions () and (Z) Diels Alder reactions [3 2] Pd - C(C 2 ) 3 additions L L [3 2] itrone additions [2,3] Wittig rearrangements Claisen rearrangements Cram Diastereoface Anti-Cram Diastereoface (A-1,3 Diastereoface) Michael additions (Z) "charge transfer" 2' additions () and (Z) Michael additions () and (Z) except (Z) "charge transfer" [3 2] itrone additions () Michael addition (Z) "charge transfer" Michael - type additions follow Cram's (Felkin's) rule. All cycloadditions follow the Cram Chelate rule. ote added in proof A model was suggested which would explain all of the results presented (except Michael additions) m cleophilic attack on olefins always follows Cram's steric rule, where P = m for alkoxy substituted olefins. In the absence of "charge transfer" mechanisms, Cram's rule generally applies for nucleophiles and nucleophilic radicals. L This disregards any electronic component, but predicts the correct product. In no case does attack of the preferred A-1,3 strain conformer predominate. J. Leighton, private communication /12/ PM