Update to 2011 Bode Research Group TOPIC: ENANTIOSELECTIVE ALDOL REACTIONS

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1 Update to 2011 ode esearch Group TPIC: EATIELECTIVE ALDL EACTI 1 ITDUCTI Formation of a new C-C bond with the possibility of forming two new stereocentersà 4 diastereomers. First described in 1848 by Kane and in 1872 Charles-Adolphe Wurtz would go on to describe such products as maintaining the properties of alcohol and aldehyde. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. 1.1 Types of Enolates Aldols thyl Ketone Aldol 1 1 hyl Ketone Aldol Acid and ase Catalysis Acid Catalyzed Aldol syn C 3 ase Catalyzed Aldol C 3 C anti C 2 2 C 3 Acetate Aldol 1.3 tereocontrol Elements - elative configuration: Configuration of the product is determined by enolate configuration. igh diastereoselectivity has been achieved through ordered 6-membered transition states. (E) tal C 1 C 1 C 2 1 Favored M 2 3 M C 3 2 M 3 C 3 Anti M 1 1 M Propionate Aldol 1 2 C 3 1 C 3 (Z) tal 3 yn C 1 C or Favored syn 2 M 3 2 M 1 3 C Anti anti yn M 1 1 M Absolute configuration is controlled by chirality within molecule from: (a) emovable chiral auxiliaries (b) Chiral enolates (c) Chiral catalysts (chiral ligand metal) (d) Chiral amine catalysis 1 M3 1 3 or 1 3 1

2 Update to 2011 ode esearch Group 2 CIAL AUXILIAIE 2.1 Diastereoselective Control yn Evans xazolidinones: ighly selective towards Z enolates. igh diastereoselectivity to yield a single yn product. terics often dominate the most preferred transition state. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. xazoldinones u 2 n-u 2 Tf, i-pr 2 C Evans, JAC 1981, 103, 2127 Effective only for chelating aldehydes. The second equivalent of titanium is necessary for the diastereoselective control. Chelation overrides steric control, but less as chelating group is further away from carbonyl. Aryl ulfonamide Indanyls p-tol Ti4 (2 equiv), i-pr 2 p-tol Ghosh, TL,1997, 38, Diastereoselective Control Anti Anti diastereoselectivity is achieved for the aryl sulfonamide indanyls when using one equivalent of titatanium. p-tol Ti 4 (1 equiv), i-pr 2 Ghosh, TL,1997, 38, 7171 Evans found that the generation of magnesium enolates with the oxazolidinone auxiliaries would give anti adducts. A closed T that does not follow the Zimmerman Traxler model is thought to be prevalent. TM does not catalyze the reaction but quenches the aldol adduct. u Ti 3 u 3 Ti Ti 2 p-tol 1 3Ti Ti % yield (C 2 )nc 51-84% yield Proposed T i-uc 83-92% yield Ti 2 Proposed T Li () >98:2 dr 3 Al =alkyl, phenyl p-tol p-tol :1 dr =alkyl, phenyll : dr =alkyl, phenyl C Mg 2 (10 mol%) 3, TM, ETAc 71-92% 7:1-32:1 dr =alkyl, aryl Evans, JAC, 2002, 124, 394 2

3 Update to 2011 ode esearch Group Asymmetric Propionate Aldols yn With the use of 2 equivalents of titanium, a non-evans is achieved. The second equivalent of titanium is thought to abstract a chloride that allows chelation to the thiazolidinethione. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. Ti 4 (2 equiv) i-pr 2 Ti 4 (1 equiv) parteine = parteine C C Ti Ti Crimmins JAC, 1997, 119, Asymmetric Propionate Aldols Anti orephedrines as auxiliaries- E-enolates are selectively formed and yield the anti products via six-membered T. Abiko JC, 2002, 67, 5250 A chelating substituent on the enolate provides a different mechanistic pathway for the thiazolidinethiones. Z enolate is formed but the anti product is obtained with the use of two equivalents of titanium. Crimmins L, 2003, 5, Asymmetric Acetate Aldols Asymmetric control with acetates is more challenging than with propionates. Increased bulk of thiazolidinethione auxiliary allows for moderate to high diastereoselectivity. This is not possible with Evans oxazoldinone auxiliaries % yield 75-95% yield 1. c-ex 2 Tf (2 equiv), 3, -78 o C 2. C 2 s 2 s >90% yield >95:5 dr =alkyl, alkenyl, phenyl 1. Ti 4 (1 equiv) parteine 2. C Ti Ti >97:3 dr =alkyl, phenyl non- Evan's yn 61-84% yield >94:6 dr =alkyl, phenyl Evan's yn 87:13 dr =alkyl 1. Ti 4 (1 equiv) (-)-sparteine, MP(1 equiv) C 2 2, 0o C Ti 2. C 77-90% yield >85:5 dr =alkyl, alkenyl, phenyl illips L, 2002, 4,

4 Update to 2011 ode esearch Group 3 CIAL ETE Enol oronates Zà syn aldol and Eà anti aldol. With the use of chiral alkyl boronates, moderate enantioselectivity can be afforded. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. Tf= ()-Ipc 2 Tf = ()-Ipc 2 Ipc 2 Ipc 2 80:20 E:Z selectivity Thus not effective for stereocontrol Ipc 2 Tf IPr 2 C 2 2 Paterson Tetrahedron, 1990, 46, MUKAIYAMA ALDL EACTI 4.1 ackground and chanism The crossed aldol reaction between a silyl enolate and a carbonyl compound in the presence of Lewis acid is referred to as a Mukaiyama aldol reaction. i 3 Mukaiyama Chem. Lett. 1973, 1011 chanism: - Diastereoselection. - tereochemical outcome is explained by open-transition model, based on steric- and dipolar effects. 1 i 3 2 MX 4 1 X Ti 4 T 2. 2 MX 3 3 i C Ipc 2 3 C Ti 4 T X TM 3 TM 3 TM 3 3 ix Ipc Ipc Ipc Ipc 75-99% >95:5 d.r % ee =Alkyl, alkenyl, phenyl Yields much lower for isopropyl aldehyde 80:20 d. r <20%ee for E isomer 63% 19% 63% 19% X 3 M 1 3 anti When 2 is small and 3 is large. transition state A is most favored and leads to anti-diastereomer. A C TM TM TM syn When 2 is large and 3 is small. transition state D is most favored and leads to syn-diastereomer. D E F 4

5 Update to 2011 ode esearch Group With an aldehyde capable of chelating to a Lewis acid, there is a reversal of the normal high anti-selectivity - syn-selectivity- was observed. 2 TM 3 2 TM 3 This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. syn (favored) Mahrwald Chem. ev. 1999, 99, Challenges to tal Catalytic Enantioselective Mukaiyama Aldol Addition - ackground silyl-catalyzed achiral aldol addition Chiral tal-catalyzed M*X n Achiral ilicon-catalyzed 3 ix M*X n i 3 - Anti vs yn (in aldol reaction with substituted silyl enolates) 4.3 istoric enantioselective Mukaiyama aldol addition The first enantioselective catalytic Mukaiyama aldol addition ynthetic route to monosaccharides from achiral compounds 3 C C i 3 n(tf) mol% n, AcC -78 o C ligand = ligand TM X i 3 i 3 3 C n(tf) mol% anti C 2 5 C, -78 o C M*X n 3 i! X ac i 3 i 3 MX n 3 ix 3 ix Carreira Tetrahedron Letters 1994, 35, osnich JAC 1995, 117, cat. s 4.M acetone- 2 / 0 o C dr = 97:3 92 %ee Tol Crotyl ctyl c-ex Yield Mukaiyama, Kobayashi Chem. Lett. 1990, 129, C MX n-1 3 i i 3!! syn : anti ac n Tf Tf 93 : 7 89 : : : : DIAL, DCM, -78 o C 2. Pd-C/ 2, 4 ee >98 >98 C 3 L-fucose Kobayashi ynlett 1993, 911 Guidelines for designing more recent catalysts: (1) Ligands with electron donors. (2) tabilizing aromatic stacking interactions. (3) eaction conditions minimize the silyl-catalyzed achiral aldol addition. 5

6 Update to 2011 ode esearch Group ilyl ketene acetals, thioester-derived silyl ketene acetals as nucleophiles yn - Chiral (acyloxy)borane (CA) complexes of tartrate-derived ligands by Yamamoto Pr i C 2 This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. 1 2 i 3 *L n 1 Yamamoto ynlett 1991, 439 α,β-unsaturated aldehydes reveal excellent diastereo- and enantioselective due to the π interaction. eaction with aliphatic aldehyde resulted in slight reduction of optical and chemical yields Anti - Chiral IL and Zr(IV) complexes by Kobayashi ynthesis of Khafrefungin 3 i 2 anti TM < *L n 1 3 i 2 syn 10 mol% n-pr, 2 2 I I Pr i 20 mol% 2 C Zr i-pr i-pr TM TM < TM 3 3 TM < TM 3 2 yn-adduct I 2 1 Anti-adduct C dr = 95:5 99 %ee dr = 93:7 98 %ee n-propyl n-pent-1-enyl yield (%) Kobayashi JAC 2000, 122, 5403 Kobayashi JAC 2002, 124, 3292 d.r 79:21 65:35 96:4 % ee The asymmetric environment around zirconium center is crowded with the bulky iodine on IL -> interaction between alkyl group of aldehyde and becomes more severe. Zr I TM 10 mol% n-pr, 2 I I dr = 80:20 99 %ee 3 C( 2 C) 9 Khafrefungin Kobayashi JC 2001, 66,

7 Update to 2011 ode esearch Group Acetate Mukaiyama aldol addition Like chiral auxiliaries, metal catalysts have also had difficulties in obtaining high enantioselectivity in acetate aldol additions (acetate derived nucleophiles). - Chiral oxazaborolidine complex generated from Cα-alkylated α-amino acids by Masamune This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. Ts ipr 20 mol% TM - IL and Ti(IV) complexes by Keck and Mikami TM Masamune JAC 1991, 113, 9365 IL/Ti x (Tf) y catalyzes acetate aldol addition with excellent yields and enantioselectivity. road scope of aldehydes including simple aldehydes and functionalized aldehydes such as trifluoroacetadehyde, chloroacetaldehyde, benzyloxyacetaldehyde, ethyl glycolate TM Mikami JAC 1993, 115, 7039, JAC 1994, 116, 4077 & ynlett 1995, Complex of Ti(IV), tridentate chiff base and di tert-butylsalicylic acid by Carreira F 3 C TM TM TM 2 mol% Ti 92 %ee >98 %ee ()-IL/Ti 2 (i-pr) 2 5 mol% ()-IL/Ti(i-Pr) 4 20 mol% ()-IL/Ti 2 (i-pr) mol% ()-IL/Ti 2 (i-pr) mol% then TAF r A 2 Ar C 2 ipr!,!'-disubstituted glycine F 3 C 96 %ee TM > 98%ee TM 96% ee TM 91 %ee 3 TF 98 %ee Ts ipr The carboxylate in the catalyst structure traps the electrophilic silyl group after the addition of the enoxy silane to aldehyde, thus precluding any silyl-catalyzed background reactions. The silyl carboxylate is then activated towards intramolecular silyl transfer. Ti L Ti 3 i L 3 3 i-trap i 3 i-shuttle i 3 TiL 3 Carreira JAC 1994, 116, 8837 Carreira, Kvaerno assics in stereoselective synthesis p

8 Update to 2011 ode esearch Group ynthesis of orboxazole A This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. PM TM A (2 mol%) PM TM 15 - Complex of chiral is(oxazolidine) (X) or bis(oxazoline) (PYX) and metals by Evans TM n Tf Tf 10 mol% mith JAC 2001, 123, Evans JAC 2000, 122, Evans ACIE 1997, 36, Ketones as electrophiles - Evans developed a family of chiral bis(oxazolidine) (X) and bis(oxazoline) (PYX) complexing with different metals as catalysts for enantioselective Mukaiyama aldol addition. Diverse stereo outcomes can be obtained based on the metal and ligand used in the complex. identate chelation leads to the formation of a square pyramidal complex and the re aldehyde enantioface is shielded -> igh level of diastereoselectivity and enantioselectivity. The requirement of chelation limits the scope of electrophiles ( α-alkoxyacetaldehydes, pyruvates, glycolates, α-diketones, 5-formyloxazoles). road range of nucleophiles: thioester-derived ketene acetals, ketene acetals, ketone-derived enolates. Chiral is(oxazolidine) (X) or bis(oxazoline) (PYX) and Cu(II) complexes TM Cu 0.5 mol% TM 99 %ee bf 6 r 94 %ee r 99 %ee 2 2Tf - Cu 10 mol% d.r = 94:6 96 %ee Ac orboxazole A orboxazole Cu u (si face) Ac 15 pongistatin 2 15 Evans JAC 1997, 119,

9 Update to 2011 ode esearch Group Chiral is(oxazolidine) (X) or bis(oxazoline) (PYX) and tin(ii) This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. Chiral is(oxazolidine) (X) or bis(oxazoline) (PYX) and scandium(iii) Evans JAC 1997, 119, Evans L 2002, Complex of Cu(I)fluoride and chiral Taniaphos ligand by hibasaki Examples of effective catalyzed enantioselective aldol addition involving simple ketone acceptors are scarce due to the attenuated reactivity of ketones and reversibity of their aldol addition. tereocontrol is also challenging. 4.5 Enol ethers as nucleophiles yn - Chiral (acyloxy)borane (CA) complex of tartrate-derived ligands by Yamamoto. ynthesis of cheimonophyllal TM Pr i TM TM Pr i n Tf Tf 10 mol% CuF(P 3 ) 3 2 (2.5 mol%) Pr i ligand 4 mol% 20 mol% C 2 C 2 c Tf Tf 10 mol% TM dr = 99:1 99 %ee yield = 94 % dr = 86:14 94 %ee TM dr = 92:8 93 %ee u 2 Fe Cy 2 P PCy 2 ligand hibasaki JAC 2006, 128, 7164 dr = 94:6 96 %ee dr = 93:7 94 %ee Yamamoto JAC 1991, 113, 1041 i-pr TM Pr i 20 mol% then z i-pr z C i-pr dr = 10:1 99 %ee ()-Cheimonophyllal Tadano JC 2002, 67,

10 Update to 2011 ode esearch Group - IL and Ti(IV) complexes by Keck and Mikami This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. C 2 C 2 2, 0 o C Ti 5 mol% i 3 road scope of enolates (esters, thio-esters, ketone-derived enolates) 58 % 54% i 3 Mikami JAC 1993, 115, Anti Enantioselective aldol addition of enolates to aldehyde catalyzed by IAP/ilver(I) complex by Yamamoto i() 3 i() 3 P * P 3 2 Ag 1 i() 3 F Yamamoto JC 2003, 68, Acetate Mukaiyama aldol aditions - Another class of amino acid derived -sulfonamide oxazaborolidines by Corey. Effective catalyst with a variety of aldehydes. The existence of hydrogen bonding between the catalyst and aldehyde contributes much to the significant facial differentiation. TM n-u E TM anti ()-IAP, AgTf, KF, 18-crown-6 ()-IAP, AgTf, KF, 18-crown-6 Ts n-u 20 mol % Ts n-u 20 mol % d.r 98:2 99 %ee d.r 98:2 99 %ee P * P 3 2 Ag i() 3 1 F Z syn n-u 90 %ee yield = 100% C 2 facial blocking ()-IL hydrogen bonding TFA ()-IAP PAr 2 PAr % yield 82 %ee Corey Tetrahedron Letters 1992, 33,

11 Update to 2011 ode esearch Group Dienolates as nucleophiles Addition reactions of dienolates and aldehydes lead to four-carbon subunits in one step, which facilitates the synthesis of polyketides. - Complex of Ti(IV), tridentate chiff base and di tert-butylsalicylic acid as catalyst This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. u 3 n - isphosphine Cu(I) complex TM TM TM TM 2 mol% then TFA ()-Tol-IAP Cu(Tf) 2 then TFA Ti ent-a A r u 3 n u 3 n A TM 7 TM %ee %ee Carreira JAC 1995, 117, ynthesis of Macrolactin A Carreira ACIE 1998, 37, 1261 Carreira JAC 1998, 120, 837 Carreira ACIE 1998, 37, 3124 ynthesis of Leucascandrolide Carreira JC 2003, 68, %ee n Tf Tf 10 mol% DCM, -78 o C dr >50:1 95 %ee 94%yield 99 %ee () azaspiracid-1 3 Macrolactin A Leucascandrolide A Evans JAC 2008, 130,

12 Update to 2011 ode esearch Group 5 LEWI AE TICLILYL EL A metalloenolate is activated by a chiral lewis base. This activated complex is much more reactive than the free enolate species. Association and activation of the aldehyde allows for a closed transition state. Enolate geometry is transferred directly to the diastereoselectivity of the products. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License.. osed 6-membered T Xn apid Turnover M * * MXn * * 5.1 Achiral thyl Ketone derived Trichlorosilyl Enols 5.2 Achiral hyl Ketone trichlorosilyl enols L i 3 i 3 Lewis ase Promoter Denmark JAC, 2000, 122, 8837 Denmark JC, 2003, 68, Chiral thyl Ketone derived trichlorosilyl enols Double diastereoselection with the use of chiral catalyst and chiral enolate. Matched case here involves the use of the (,) phosphoramide catalyst, whereas the (,) gives very low syn selectivity. T protection of alcohol is necessary to prevent chelation and lower diastereoselection. i 3 T L M Xn More reactive than free enolate 10 mol % P C 2 2 then sat. ac 3 92% yield 84% ee 10 mol % P C 2 2 L MXn 77% yield 11.5:1 syn/anti 94% ee for syn 5 mol % P C 2 2, -78 o C T MXn 85% yield 73:1 syn/anti Denmark, JAC, 2000, 122,

13 Update to 2011 ode esearch Group hyl Ketone trichlorosilyl enols Diastereoselectivity for these mostly dependent dependent on enolate configuration. The (,) and (,) phosphoramide catalysts give similar diastereoselectivities. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. i 3 T P C 2 2, -78 o C elative T 87% yield elative d.r. 16:1 syn/anti Internal Internal d.r. >50:1 syn/anti Denmark L, 2001, 3, DIECT CATALYTIC EATIELECTIVE ALDL These involve the in situ generation of enolates (donor) in the presence of an aldehyde (acceptor), circumventing the use of preformed enolates and decreasing waste. ften substoichiometric catalysts amounts of catalyst can be used. 6.1 Ito s Au(I) catalyst First example of a direct asymmetric catalysis by Ito and coworkers. Gold(I) catalyzed the reaction between α-cyanoacetate and an aldehyde to yield trans oxazolines. These lead trans products and do not have great scope beyond the use of α-cyanoacetate. C Ito JAC, 1986, 108, Lanthanum and arium inols as ifunctional Catalysts (Donor and Acceptor Activation) These catalysts serve as both lewis (lanthanum or barium) acid and bronsted base catalysts (lithium binaphthoxides or binols). Proceed with exogenous base. * 2 1 M AL 2 1 * Fe P L Au P L M C % yield M 2 1 =alkyl, alkenyl, aryl trans:cis= 54:46-93: % ee M hibasaki s first catalysts were barium and Lanthanum based and could provide moderate to high ee for methyl ketones. eaction times were long and large excess of ketone was necessary - 13

14 Update to 2011 ode esearch Group 20 mol% This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. Li Li Ln Li 43-90% 3-12 days = ()LL =alkyl, phenyl 52-91% ee hibasaki TL, 1998, 39, 5561 and hibasaki ACIE, 2003, 36, Lanthanum provides moderate anti and syn selectivity complimentary to enamine catalysis (favors anti adducts) 2 equiv 10 mol% ()LL 9% KMD 20 mol% 2-50 o C 78-92% hibasaki JAC, 2001, 123, Dinuclear Zinc Prophenols as ifunctional Direct aldols with acetone(enantioselectivity lower for alpha unbranched aldehydes) equiv Zn Zn Trost L, 2001, 3, Chelation of alpha hydroxyl ketone increases reactivity of donor and allows close to equimolar equivalents with respect to aldehyde(highly syn selective). 1.5 equiv Zn Zn 65-97% 48 h Trost JAC, 2001, 123, Mild conditions allow for use of ynones as substrates for aldol, used in the total synthesis of dephosphofostriecin. 4 A M, TF 5 o C 59-89% 48 h 4 A M, TF, o C =alkyl, phenyl 2:1-5:1 anti:syn 90-95% ee anti =alkyl, phenyl 4:1-100:0 syn:anti 86-98% ee =alkyl, phenyl 78-94% ee Ar 5 mol% X=inol- X a X DME, -20oC 77-99% Zn Zn =()a-m =alkyl, phenyl 50-70% ee 3 mol% Zn Zn T light excess 58-67% 4-17 h 4 A M, TF T 99% ee dephosphofostriecin Trost, JAC, 2004, 126,

15 Update to 2011 ode esearch Group 7 CIAL AMIE CATALYI In ature: P Lys 229 type I aldolase P This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. er 271 P er 271 P Early 1970s, ajos-parrish-eder-auer-wiechert reaction 3 C Trost Chem. oc. ev. 2010, 39, 1600 Eder ACIE 1971, 83, 496 & ajos JC 1974, 39, 1615 Pioneering findings by List, arbas III: Proline-catalyzed enantioselective intermolecular aldol addition 3 C C 3 chanism of Proline-catalyzed aldol addition Different proposed mechanisms and models for transition state Lys 229 C 2 3 mol% ajos-parish 3 C DMF, 20h C 2 30 mol% 3 C C n 3 P Lys C er 271 P Lys 229 = P 3 2- C 2 3 mol% DMF, 72h P Lys %ee 74 %ee DM 3 C ()-Proline ()-Proline ()-Proline 3 C 1 n 3 Ender-auer-Wiechert phenyl p-nitrophenyl o-chlorophenyl naphthyl isopropyl 2-2 % yield %ee arbas III JAC 2000, 122, 2395 n - 2 C C - 2 (crystal surface) intramolecular C 3 intermolecular ajos Model Agami model (two-proline mech.) waminathan Model ouk Model 15

16 Update to 2011 ode esearch Group C 3 C 2 3 C C 3 Electrophile C 3 C 2 3 C C This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. C 2 C 3 Discussion on mechanism: ouk ACIE 2004, 43, 5766 List PA 2004, 101, 5839 lackmond ioorg. d. Chem. Lett. 2009, 19, 3934 Trost Chem. oc. ev. 2010, 39, Progress Aldehyde electrophiles chanism proposed by List et al. 3 C C 3 20 mol% 3 C C 3 3 C C 3 C 3 C 3 C 2 E (L)-Proline mol% ()-Ipsenol (L)-Proline 20 mol% C 3 3 C 20 mol% 3 C E C 2 - Electrophile C 3 C 2 3 C chanism proposed by eebach et al ajos JC 1974, 39, 1615 Agami JAC 1986, 108, 2353 waminathan Tetrahedron Asymmetry 1999, 10, 1631 ouk JAC 2003, 125, 2475 List Acc. Chem. es. 2004, 37, 548 eebach&eschenmoser elv. Chim. Acta 2007, 90, 425 Limitations of Proline-catalyzed aldol addition - elatively large amount of proline (20-30mol%) - Large amount of ketones - Low enantioselectivity with aromatic aldehydes C 3 34 %yield 73 %ee C 3 C 3 C 3 anti C 3 1. T, imidazole 2. KMD TAF, TF r 4-2- naphthyl c-hexyl isopropyl phenyl naphthyl Tf Tf % yield % yield Tf C 3 C 2 - TC 3 nu 3 Pd(P 3 ) 4 TC 3 C 3 C 3 List L 2001, 3, 573 %ee Wu JAC 2003, 125, 5262 dr >20:1 >20:1 1:1 3:1 %ee >99 > C C 3 arbas III JAC 2001, 123, 5260 anti (favored) syn 16

17 Update to 2011 ode esearch Group Cross-aldol of aldehydes This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. C 3 Cross-trimerizations Two-step polyketide synthesis 1 ugar synthesis C 3 C 2 DMF, 40h, 5 o C TIP PM Activated Ketone electrophiles 2 C 2 C 2 C 2 10 mol% C 2 C 2 10 mol% 2 C mol% DMF, 40h, 5 o C TIPTIP % dr 4:1 98 %ee 3 C C 3 ketone donor C 3 aldehyde donor 3 C MacMillan ACIE 2008, 47, 3568 Cordova ACIE 2005, 44, 1343 & MacMillan cience 2004, 1752 Zhao Tetrahedron Letters 2006, 47, 3383 & Jorgensen Chem. Comm. 2002, ther asses of Aldols 8.1 eformatsky eaction dr 12:1 48 %yeild Felkin:anti Felkin >19:1 99 %ee 3 C C TIP C 3 C 2 10 mol% C 3 C 2 C PM 41 % 98 %ee 2 3 C 3 C 3 C T Ch 3 3 C C 2 3 C C callipeltoside C 1 2 C 2 C 2 C C 3 C 3 C 3 2 c-hexyl 79 % yield 75 %ee 90 % yield 90 %ee % yield % ee 99 >99 >99 assical eformatsky 1 2 X 3 M olvent X=, r, I M= Zn, In, mii, TiIII, Fe, Co, n... eformatsky erichte der Deutschen Chemischen Gesellschaft, 1887, 20,

18 Update to 2011 ode esearch Group Enolates with a CF 3 α to an ester or amide are often unstable, but they work well in eformatsky reactions. CF 3 r Zn Al % yield CF 3 CF 3 96% d.r. This work is licensed under a Creative Commons Attribution-onCommercial-hareAlike 4.0 International License. Ishihara TL, 2006, 8, The Indium tends to yield E enolates and can provide high diastereoselectivity in the formation of β-lactones. r In Toluene 67% yield aba L, 2006, 8, Ketene Aldehyde Cycloadditions Acyl halides can be transformed to the corresponding ketenes in the presence of base. With a chiral lewis base and a lewis acid, asymmetric aldols can be mediated to give β-lactones. TMq TM 96% d.r. 99%ee 10 mol% TMq 30 mol% Li % yield 3 3 * 3 2 M 3 * 10 mol% TMQ 30 mol% Li % yield M 99% d.r. 96% d.r. 99% ee M 3 2 M 3 * TM TMQ elson JAC, 2004, 126,