Asymmetric Catalysis with Chiral Lewis Bases

Transcription

1 Asymmetric Catalysis with Chiral Lewis Bases I. Catalysis of the allylation of aldehydes A. osphoramides B. Formamides C. Amine-oxides II. Catalysis of the aldol reaction III. Kinetic resolutions of alcohols/amines A. osphines B. lanar-chiral DMA analogs Karl Scheidt Evans Group Friday Seminar March 9, 00 IV. Catalysis of the ring opening of meso-epoxides A. osphoramides B. Amine-oxides V. TMS-C additions and ketone reductions eviews: Denmark, S. E.; Stavenger,. A.; Su, X.; Wong, K.-T.; ishigaichi, Y. ure Appl. Chem. 998, 70, 9-7. Denmark, S. E.; Stavenger,. A. Acc. Chem. es. 000,, -0. Fu, G. C. Acc. Chem. es. 000,, -0. Buono, G.; Chiodi,.; Wills, M. Synlett 999, Title /8/0 9: AM

2 Seminal bservation: DMF romotes Allylations Genreal eaction: C Si. DMF, 0 C. : C /DMF as solvent provides product in 97% yield in h C = C, cinnamaldehyde, hydrocinnamaldehyde, cyclohexanecarboxaldehyde 9 Si M Chemical Shifts of (Z)-Crotyltrichlorosilane in Various Solvents d( ) (0. mol%) Si solvent CD CD C C D TF-d 8 DMF-d 7 MA chemical shift (ppm) Si h Si cat. Cu Et 0 min 7% >99: Z:E Si 89% >99: E:Z 00-DMF as promoter /7/0 0: AM Kobayashi, S.; ishio, K. Tetrahedron Lett. 99,, -. Kobayashi, S.; ishio, K. J. rg. Chem. 99, 9, 0-8.

3 roposed Transition State for Allylation Si C DMF Si E crotyltrichlorosilane gives >99: anti product Z crotyltricholorsilane gives >99: syn product Kobayashi invokes : DMF/allylsilane complex in transition state, but no kinetic data provided ne-ot rocedure from Allylic chloride:. Si, Et, cat. Cu. C, DMF >80% yields >9: dr 00-Si M data/t-states /7/0 0: AM

4 Why are pentacoordinate compounds more electrophilic? Slide taken from Forrest Michael's Seminar : ypercoordinate Main-Group Compounds 999 B.. = 0.8 All B.. = X X Si X X X X X X Si X X X B.. = 0.7 X X X Si X X X All B.. = / Formal charges: X = 0 Si = 0 Ab initio study: Formal charges: X ax = 0., X eq = 0.7, Si = 0 Formal charges: X = 0. Si = 0 Species Si Si Si F Si F Si charge Ligand charge (eq), 0.9(ax) 0.(), 0.7(F) 0.(), 0.7(F) This phenomenon is termed the "spillover effect", and is widely seen in donor-acceptor complexes. Although the formal charge does not change, the number of electronegative substituents increases upon increasing coordination. SiF SiF SiF (F, eq), 0.8(F, ax), 0.08( ) 0.(F), 0.9( ) 00-entacoordinate Si /7/0 0: AM Voronkov, M. Top. Curr. Chem. 98,, 99. Corriu,. et al. Chem. ev. 99, 9, 7.

5 Second on the Scene: Denmark e-examination of allylation promoters: additive, rt Si C solvent, M entry additive (equiv) solvent t / (min) conversion (time) yield MA superior to DMF DMF () MA () MA () MA () MA (0.) MA (0.) C D C D CD CD C C D TF-d 8 nd 8 nd nd (70 h) nd ( min) ( min) 0 ( h) 80 ( h) nd nd nd DMS and pyridine -oxide were "incompatible" with trichloroallylsilane In contrast to Kobayashi's observations: Si C solvent DMF: h, 90% yield MA: h, 8% yield 00-Denmarks Allylation I /7/0 0:7 AM Denmark, S. E.; Coe, D. M.; ratt,. E.; Griedel, B. D. J. rg. Chem. 99, 9, -.

6 Development of Asymmetric Allylation: Synthesis of Chiral osphoramides Catalyst structures screened be Denmark: General synthesis of chiral phosphoramides:. Et.. MCBA 0-9% yields () Syntheses of chiral phosphoramides: Denmark et al. J. rg. Chem. 999,, anessian et al. J. Am. Chem. Soc. 98, 0, 7-77; ormant et al. Synthesis 988, -7. For a review of,-diamines see Bennani, Y. L.; anessian, S. Chem. ev. 997, 97,. 00-Syn of osphoramides /7/0 0:7 AM

7 Asymmetric Allylation with Chiral osphoramides Si A (x equiv) C, 78 C M entry equiv A time yield % ee (config) 7 8 -C - -C -C - -C (E)-C=C h h h h h h h h () 7 () () () () 0 () () 8 () A A ( equiv) Si C C, 78 C >99: E:Z M, 7. h Si C same conditions >99: Z:E 8% yield 98: anti/syn % ee 7% yield 98: syn/anti 0% ee 007-Allyl w/phosphoramides /7/0 0:9 AM Denmark, S. E.; Coe, D. M.; ratt,. E.; Griedel, B. D. J. rg. Chem. 99, 9, -.

8 Asymmetric Allylation with Chiral Formamides C Si (. equiv) catalyst B, MA C C, 78 C catalyst B entry B (mol%) MA (mol%) time (weeks) yield (%) % ee (config) 7 8 cyclopentyl C C (C ) C (C ) C (C ) C =C(C ) -butynyl (S) catalyst recovered in >9% by chromatography >97: E:Z. equiv Si C 0 mol% B, 00 mol% MA C C, 78 C weeks = cyclohexyl: 9% yield, >99: anti/syn, 98% ee = C C : 97% yield, >99: anti/syn, 9% ee 008-Allylation with C's /8/0 9: AM Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron Lett. 998, 9,

9 Asymmetric Allenylation with Chiral Formamides catalyst B C Si Si catalyst B, MA C, 78 C (:) (. equiv) entry B MA time yield (%) / % ee (config) (mol%) (mol%) (days) 7 8 cyclohexyl cyclohexyl cyclohexyl C C (C ) C (C ) C (C ) / 98/ 98/ 99/ 9/ 9/ 9/7 9/ 79 (S) 79 (S) Allenylation /7/0 0: AM Iseki, K.; Kuroki, Y.; Kobayashi, Y. Tetrahedron: Asymmetry 998, 9,

10 Catalytic Asymmetric Allylation with Chiral osphoramides Si TF, 0 C (0 equiv) = = (Z)- =, = (E)- =, = catalyst C r r C entry mol% C silane time (h) yield (%) syn/anti % ee (config) -C -C -t-buc (Z)- (E)- (Z)- (Z) / /98 99/ 9/ 88 (S) a a eaction 78 C C catalyst D ( mol%) Si TF, 0 C (0 equiv) d 98%, 88% ee r r D 00-Cat Ent Allylation roos /7/0 0: AM Iseki et al. Tetrahedron Lett. 99, 7, 9-0. Iseki et al. Tetrahedron 997,, -.

11 Catalytic Asymmetric Allylation with yridine -xides C Si (. equiv) (S)-E (0 mol%) i-r Et ( equiv) C, 78 C, h () (S)-E entry yield (%) C -CF -C -C -naphthyl (E)-C 7 C=C (E)-C=C C C c-ex ee% a 8 a a rovided (S)-homoallylic alcohol i-r Et only amine that accelerates productive reaction- most likely promotes turnover since it does not influence enantioselection. 0--oxides /7/0 0: AM akajima, M.; Saito, M.; Shiro, M.; ashimoto, S.-i. J. Am. Chem. Soc. 998, 0, 9-0

12 Catalytic Asymmetric Allylation with yridine -xides C Si (. equiv) (S)-E (0 mol%) i-r Et ( equiv) C, 78 C, h (S)-E entry syn/anti yield (%) ee% C C C C C :97 99: na na proposed transition state Si 0--oxides DiastTstate /7/0 :0 AM akajima, M.; Saito, M.; Shiro, M.; ashimoto, S.-i. J. Am. Chem. Soc. 998, 0, 9-0

13 "Inventing" a ew Type of Aldol eaction "We set for ourselves the goal of inventing a new type of aldol addition reaction which involves the ordered preassembly of enolate, aldehyde and chiral agent for maximum asymmetric influence and which would be catalytic in the chiral reagent." Denmark et al. J. Am. Chem. Soc. 99, 8, C A B X C Si? A B X C Si Successful allylation strategy: Kobayashi, Iseki, Denmark, akajima Cautionary ote: MA catalyzed reaction, but background is a potential problem. Si t-bu solvent, 80 C t-bu entry solvent promoter (equiv) conversion time (min) toluene-d 8 CD TF-d 8 CD none none none MA (0.) < Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 99, 8, Inventing a new aldol /7/0 :0 AM

14 Trichlorosilyl Enolates: reparation st generation synthesis:. LDA, 78 C. n-bu Sn. Si ( equiv). 0 C Bu Sn 0% % Si Baukov and Lustenko et al. J. rganomet. Chem. 9,, 0-8. Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 99, 8, nd generation synthesis: TMS g(ac) ( mol%) Si, C Xg Denmark et al. J. rg. Chem. 998,, While many other chlorosilyl enolates were generated, only the trichlorosilyl variant was useful Si group i-r n-bu i-bu t-bu TBS-C C C >0% yield for most substrates 0-Si enolates bckgrnd /7/0 :0 AM

15 Asymmetric Aldol eaction with Trichlorosilyl Enolates Si promoter C, 78 C entry C promoter (equiv) config ee% yield 7 8 C C C C t-buc t-buc t-buc t-buc A (0.) F (0.) G (0.) F (.0) A (0.) F (0.) G (0.) G (.0) () (S) (S) (S) () (S) (S) (S) (,)-A (S,S)-F ()-G 0-Asym Aldol-Survey /7/0 : AM Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 99, 8,

16 Aldol eactions with Trichlorosilyl Enolsilanes Uncatalyzed reactions are syn selective (>:, max 0:): Si 0 C, Å sieves C C, > h >80% yield (S,S)-F eactions catalyzed by F are highly anti selective: Si C 0 mol% F, 78 C C, h entry syn/anti a ee% (anti) yield -naphthyl (E)-C=C (E)-C=C() C C- : <:99 <:99 <:99 : a Determined by M (00 Mz) analysis (?) 0-Aldol Si /7/0 :9 AM Denmark, S. E.; Wong, K.-T.; Stavenger,. A. J. Am. Chem. Soc. 997, 9, -.

17 Aldol eactions with ropiophenonetrichlorosilyl Enolsilanes Uncatalyzed reactions are slightly anti selective (~:): Si 0 C, Å sieves C C, >0 h eactions catalyzed by F are syn selective: dr=~: (S,S)-F Si C mol% F, 78 C C, h entry C syn/anti ee% (syn) yield C -Br-C -naphthyl (E)-C=C (E)-C=C C C 8: : : 9.: 7: : Aliphatic aldehydes did not react, presumably due to competitive enolization. 07-ropiophenone Addns /7/0 :0 AM Denmark, S. E.; Wong, K.-T.; Stavenger,. A. J. Am. Chem. Soc. 997, 9, -.

18 Early Analysis of Trichlorosilyl Enolate Aldol eactions Uncatalyzed reactions: Si Si boat-like transition states predominate pentacoordinate siliconates invoked Catalyzed reactions: Si or chair-like transition states predominate octahedral siliconates invoked "The lack of structural information about the coordination geometry at silicon makes the formulation of a sensible transition structure model tenuous at this stage." Denmark et al. J. Am. Chem. Soc. 997, 9, Early rationale /8/0 :0 M

19 Lewis Base-Catalyzed thyl Ketone Aldol eactions Uncatalyzed reaction: Si C C =, h, 9% = c-ex, 9 h, 9% (S,S)-F Catalyzed reaction: Si C mol% F, h C, 78 C >9% yield = alkyl, 80-8% ee =, 0% ee n-bu Si C x mol% F C, 78 C n-bu entry C mol% F time (h) %ee yield enolizable cinnamaldehyde α--cinnamaldehyde -naphthaldehyde --C c-hexc t-buc thylketone aldols /8/0 9: AM Denmark, S. E.; Stavenger,. A.; Wong, K.-T. J. Am. Chem. Soc. 998,,

20 Lewis Base-Catalyzed thyl Ketone Aldol eactions Uncatalyzed reaction: TMS. g(ac), Si. C, rt entry g(ac) (mol%) syn/anti yield TBS iv Bn /. /. / (S,S)-F Catalyzed reaction: mismatched TMS. g(ac) ( mol%) Si. C, 78 C mol% F entry catalyst syn/anti yield TBS iv Bn (S,S)-F (S,S)-F (S,S)-F././ / matched 7 TBS iv Bn TBS (E)-C=C (,)-F (,)-F (,)-F (,)-F 7/ 0/ /./ DD-thylketone aldols /7/0 :8 AM Denmark, S. E.; Stavenger,. A. J. Am. Chem. Soc. 998,, 9-97.

21 thyl Ketone Aldol eactions: ationale Uncatalyzed reaction: Si C, 78 C Si Bn "The low diastereoselectivities make proposals for transition structure arrangements speculative at best." Catalyzed reaction: Si C, 78 C mol% F Si L minimization of oxygen dipoles Model does not account for matched and mismatched cases. 0-thylketone aldol rational /7/0 :8 AM Denmark, S. E.; Stavenger,. A. J. Am. Chem. Soc. 998,, 9-97

22 chanistic Insights on Trichlorosilyl Enolate Aldols Intriguing switch of diastereoselectivity Si 0 mol% cat C C, 78 C Ee dependence of catalyst cat = F ( = ): anti/syn = 0/, (anti, 9%ee), 9% cat = ( = ): anti/syn = /97, (syn, %ee), 9% (S,S) F, = (S,S), = %ee of product = anti; = syn Anti diastereomer favored with less hindered catalysts as well as at higher loadings of achiral F analog Conclusion: Anti product arises from two catalyst molecules in transition state, while syn product arises from one catalyst molecule in the transition state ee% of F ( ) and ( ) 0-chanistic insights I /7/0 :7 AM

23 chanistic Insights on Trichlorosilyl Enolate Aldols (cont.) Intriguing switch of diastereoselectivity Si cat = F ( = ): anti/syn = 0/, (anti, 9%ee), 9% cat = ( = ): anti/syn = /97, (syn, %ee), 9% ositive nonlinear dependence on catalyst F 0 mol% cat C C, 78 C Magnitude of nonlinear effect not catalyst concentration dependent no reservoir effect (S,S) F, = (S,S), = Si syn Si anti cationic trigonal bipyramidal Favored for bulky catalyst Bu inhibits the reaction inhibits ionization of enolsilane-catalyst complex cationic octahedral Favored for smaller catalyst F Bu Tf accelerates the reaction by increasing the ionic strength of the medium 0-ch InsightII /7/0 :8 AM Lewis base promotion of ionization of allyltrichlorosilanes: Berrisford et al. Tetrahedron Lett. 997, 8, -. For a review of nonlinear effects see: Fenwick, D.; Kagan,. B. Top. Stereochem. 999,, 7.

24 Structural Insights of Trichlorosilyl Enolate Aldols Complexation between phosphoramides and Si or trichlorosilylenol silanes were very weak judged by and 9 Si M. Use Sn as a surrogate for Si ( 9 Sn M and X-ray) Sn 0. Sn (S,S)-F trigonal bipyramidal geometry Sn not linear piperdine almost sp octahedral geometry 0-Xray phosphoramides /7/0 :8 AM Denmark, S. E.; Su, X. Tetrahedron 999,,

25 Structural Insights on Trichlorosilyl Enolate Aldols Sn Sn C (S,S) 0-Xray phosphoramide II /7/0 : AM Denmark, S. E.; Su, X. Tetrahedron 999,,

26 Allyltrichlorosilane Additions evisited: ew and Improved Denmark 99 Si promoter C, 78 C entry promoter tether ( n) equiv yield (%) %ee A A A ositive nonlinear effect observed I I I I I I I % ee of product 0 J J a J a J a a.0 equiv of i-r Et added for turnover (C ) n 0-AllySi bisphoporamides /7/0 :9 AM I % ee of catalyst A J Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 000,, 0-0.

27 Kinetic esolutions: Theory and ractice Taken directly from Sih et. JACS, 98, 79 Basic math: ln[(-c)(-ee)] s = = ln[(-c)(ee)] s = selectivity c = conversion c = k fast-reacting enantiomer k slow-reacting enantiomer A B A 0 B 0 E = s ee = %ee of recovered substrate A 0 = initial amt. of fast-reacting enantiomer B 0 = intial amt. of slow-reacting enantiomer A = amt. of fast-reacting time T B = amt. of slow-reacting time T 07-Kinetic resolution /7/0 : AM For an excellent analysis of kinetic resolution, see: Sih et al. J. Am. Chem. Soc. 98, 0, For a review of kinetic resolutions, see: Kagan,. B.; Fiaud, J. C. Top. Stereochem. 998, 8, 9-0.

28 Enantioselective Acylations Catalyzed by Chiral osphines L entry substrate catalyst anhydride %ee (conv.) S b b b b a -0 mol% catalyst C a b a L Ac Ac Ac Ac Ac S 9 (0) (0) () (80) (0) L S selectivity (s) a n=0 b n=..... meso substrates (C )n C()tBu a a b a Ac Ac Bz Bz Bz -Bz 0 (0) 7 () () 8 (8) 8 (70) 8 () perdeuterated Ac give monoacetate without loss of deuterium: no ketene mechanism operative chiral phosphines: a, = b, = Et 08-Vedej Acylation /7/0 :7 M Vedejs, E.; Daugulis,.; Diver, T. S. J. rg. Chem. 99,, 0-.

29 Improved Chiral osphine for Kinetic esolutions ecall: racemic - mol% cat C 8% % conv. s = catalyst roblem: eaction is not general new chiral phosphine needed Li 8: dr C. LA. S ; u /ai S Tf specific ester necessary for diastereselectivity = or,-t-bu B.. BuLi. B X-ray (=) 09-Vedejs B acylation I /7/0 :9 M Vedejs, E.; Daugulis,. J. Am. Chem. Soc. 999,, 8-8.

30 Acylations Catalyzed by Chiral osphines U A racemic i-r i-r - mol% cat heptane 0 C U A U entry U A time (h) conv. (%) %ee product () cc 9 a - α-naphthyl b mesityl b n-bu i-bu i-r t-bu i-r A s c =,-t-bu catalyst a -cyclohexenyl, b reaction run in toluene, c s = 89 in duplicate run "The data in table underestimate catalyst reactivity because no special precautions were taken to exclude oxygen." 00-Vedejs B acyl II /7/0 :0 M Vedejs, E.; Daugulis,. J. Am. Chem. Soc. 999,, 8-8.

31 U A racemic Acylations Catalyzed by Chiral osphines i-r i-r mol% cat toluene 0 C U A i-r U A catalyst =,-t-bu alcohol time (h) conv. (%) %ee (/) s alcohol time (h) conv. (%) %ee (S.M./prod) s = -- 78/ /88 7 7/8 7 90/8 * 8 / 7 9/8 * 9 8 /7 7 99/9 * * = rxn in heptane 0-Vedejs B acylation III /7/0 : M Vedejs, E.; MacKay, J. rg. Lett. 00,, -.

32 Acylations Catalyzed by lanar-chiral DMA Analogs racemic mol% cat Et solvent, rt Ac Fe entry solvent % conv. after h selectivity entry solvent % conv. after h selectivity DMF C C C acetone TF EtAc toluene Et t-amyl alcohol catalyst Desymmetrizations: meso % cat, Ac Et, 0 C t-amyl alcohol Ac 99% ee 9% Ac Ac racemic 0-Fu acylation iam /9/0 0:09 AM % cat, Ac Et, 0 C t-amyl alcohol 98% ee % 99% ee 9% uble, J. C.; Tweddell, J.; Fu, G. C. J. rg. Chem. 998,,

33 Synthesis of lanar-chiral DMA Analogs C : $7 from Aldrich Fe. (C )Li resolve Fe. equiv Ac. AgSbF. Li 8 step synthesis (% overall yield) reparative chiral LC separation of catalyst necessary 0-Fu DMA synthesis /8/0 9: AM Catalyst prep: uble, J. C.; Fu, G. C. J. rg. Chem. 99,, X-ray: Tao, B.; uble, J. C.; oic, D. A.; Fu, G. C. J. Am. Chem. Soc. 999,,

34 Acylations Catalyzed by lanar-chiral DMA Analogs U A racemic entry U A - mol% cat Et, Et, rt U A U %ee of conversion (%) A selectivity (Et /t-amyl alcohol) Fe catalyst Et i-r t-bu C / 0/9 /87 /9 / 7 -F naphthyl cinnamyl α--cinnamyl / For a review on DMA, see: Steglich et al. Angew. Chem., Int. Ed. Engl. 978, 7, 9-9 For a resolution of alcohols using stoichiometric amounts of a chiral DMA analog, see: Vedejs, E.; Chen, X. J. Am. Soc. Chem. 99, 8, (s values 8- reported). 0-Fu Acylation /9/0 0:08 AM uble, J. C.; Latham,. A.; Fu, G. C. J. Am. Chem. Soc. 997, 9, 9-9.

35 Dynamic Kinetic esolutions of Azlactones with DMA Analogs The concept slow fast pka ~ 9 fast Fe catalyst = % cat. toluene, rt 0% C, 9% ee Et, % ee i-r, 78% ee Solvent study identified toluene as optimal solvent eaction with i-r too slow (t / ~ week) "We inadvertently discovered that the presence of benzoic acid leads to ring opening... at a faster rate." % cat. toluene, rt 0% C entry %ee yield (%) 7 C=C i-r c-ex C S Fu Azlactone DK /7/0 :7 M Liang, J.; uble, J. C.; Fu, G. C. J. rg. Chem. 998,, -. For a review on dynamic kinetic resolutions, see: Stecher,.; Faber, K. Synthesis 997, -9.

36 earrangements of -Acylated Azlactones X Steglich 970: DMA x=alkyl, X Fe Bn % catalyst, 0 C t-amyl alcohol, -h = -- Bn entry %ee yield (%) Et C allyl C C C C S roposed chanism Bn Bn fast catalyst Y* resting state Bn slow catalyst "Y*" zero order in substrate Crossover experiments provide evidence of ion pair 0-Fu-Ac Azlactones /7/0 :8 M uble, J. C.; Fu, G. C. J. Am. Chem. Soc. 998, 0, -.

37 Enantioselective Additions of Alcohols to Ketenes C 0% catalyst toluene, 78 C %,-t-bu-pyridinium-tf Fe TBS entry substrate %ee yield (%) = =Et C C roposed mechanism: C catalyst catalyst t-bu C 7 97 CAT S L CAT L S no nonlinear effects reaction has KIE of. ( vs. D) 07-Fu- addn to ketenes /7/0 :9 M odous, B. L.; uble, J. C.; Fu, G. C. J. Am. Chem. Soc. 999,, 7-8.

38 Kinetic esolutions of ropargylic Alcohols % catalyst Ac t-amyl alcohol, 0 C Ac Fe entry 7 = Et i-r t-bu = CF F unreacted (major enantiomer) s (%ee of unreacted ) 0 8% conv.) 8 8% conv.) % conv.).8 8% conv.) 0% conv.) 0 7% conv.) % conv.) catalyst acetic anhydride optimal anhydride added works, but omission of base gives highest s value 8 % conv.) % conv.) 08-Fu-ropargyl acylations /7/0 :0 M Tao, B.; uble, J. C.; oic, D. A.; Fu, G. C. J. Am. Chem. Soc. 999,,

39 Kinetic esolutions of Amines racemic t-bu =β-naphthyl 0% Y* C 0 C Fe catalyst "Y*" entry amine s entry amine s α-apth 7 F C 7 8 Et Cy 09-Fu-K of amines /7/0 : M ia, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 00, 0, -.

40 Asymmetric ing pening of meso-epoxides 0 mol% G Si (. equiv) C, 78 C entry substrate time (h) %ee yield (%) ()-G Si Bn Bn proposed transition state 00-Denmark Epoxide opening /7/0 : M "The origin of asymmetric induction is obscure at this time." Denmark, S. E.; Barsanti,. A., Wong, K.-T.; Stavenger,. A. J. rg. Chem. 998,, 8-9.

41 Asymmetric ing pening of meso-epoxides 0 mol% cat Si solvent, 78 C 0.- hours catalyst entry substrate solvent %ee yield (%) config TF 8 (,) C 8 (,) C 8 (,) C (,) X-ray (-) 7 Bn Bn C TF C (,) (,) (S,S) Si proposed transition state 0-Buono epoxide /8/0 9: AM Buono et al. Angew. Chem. Int. Ed. Engl. 000, 9, -7.

42 Asymmetric ing pening of meso-epoxides Si mol% cat Si i-r Et C, 8 C Fe entry yield (%) ee (%) -F- -- -CF - -naphthyl C Bn catalyst =,- C Increased steric demand of catalyst increases enantioselectivity dramatically: =, 0% ee vs. =,- C, 9% ee for opening of cis-stilbene oxide. ositive nonlinear effect. Zero-order in Si and i-r Et. and 9 Si M show interaction between Si and cat, but not between Si and epoxide or i-r Et 0-Fu-epoxide opeing /7/0 :0 M Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 00,, -.

43 Asymmetric Addition of TMS-C to Aldehydes TMS-C mol% cat. Et, 78 C TMS C Li catalyst entry %ee yield (%) time CF -naphthyl cinnamaldehyde n-hexyl c-hexyl t-bu decomp min min 0 min 0 min 8 h 0 min 8 h h < min h. h < min 0 min min *uc Si C proposed intermediate Li mono-lithio salt superior to di-lithio a, K, or Mg cation catalyzed reaction, but all were racemic Mono-lithio salt of (,)-( )-salen also competent catalyst, but enantioselectivity not much improved 0-Kagan TMSC addition /7/0 :0 M olmes, I..; Kagan,. B. Tetrahedron Lett. 000,, 7-7.

44 Asymmetric Catalytic eduction of Ketones Si() Li-amino-alcohol (0.00 equiv) TF, rt ote: () Si vapors cause blindness: bp = 9 C entry amino-alcohol yield (%) %ee Et (S)-enylalaninol (S)-rolinol (S)-enylalaninol osomi et al. Tetrahedron Lett. 988, 9, mol% cat. Si() 0: Et /TMEDA 0 C Li catalyst entry yield (%) %ee -aphthyl (E)-C=C i-bu () 77 () 8 () 7 (S) Si uc* Li 9 9 () proposed intermediate 0-osomi eduction /7/0 :0 M Schiffers,.; Kagan,. B Synlett 997, 7-78.

45 Conclusions Allylations with allyl and crotyl trichlorosilanes catalyzed by chiral Lewis bases provide high enantioselectivities and yields for unsaturated aldehydes. Aldol reactions of trichloro enolsilanes and aldehydes is exceptionally sensitive to the structures of the reacting partners and to small changes in catalyst structure. Kinetic resolutions of alcohols with chiral phosphines generally have excellent selectivity values and an increasing family of successful substrates from which to choose. lanar-chiral DMA analogs are good catalysts for kinetic resolutions of secondary alcohols, and amines as well as ketene additions, azlactone dynamic kinetic resolutions and the rearrangement of -acylated azlactones. Lewis base-catalyzed additions of Si to meso-epoxides is highly substrate dependent, but excellent enantioselectivities have been observed. Lewis base-catalyzed reductions have yet to be fully developed into a general reaction, but enantioselectivities are promising. While the selectivities of the reactions presented here are excellent in some cases, there remains the challenge to improve the existing reactions through a better understanding of the fundamental transformations the origins of asymmetric induction in many cases are not clear. 0-conclusions /9/0 0: AM