1 the Selective Aldol Reaction

The Selective Aldol Reaction

O O OH O R3 1 2 1 R R X R X R2 R4 4 R3 R

Alan B. Northrup

MacMillan Group Meeting

September 18, 2002

A Brief Recent General Review: Palomo, C.; Oiarbide, M.; García, J. M. "The Aldol Addition Reaction: An Old Transformation at Constant Rebirth" Chem. Eur. J. 2002, 8, 36. Review Focusing on Enzymatic and other Catalytic Aldols: Machajewski, T. D.; Wong, C.- H. "The Catalytic Asymmetric Aldol Reaction" Angew. Chem. Int. Ed. 2000, 39, 1352.

Classic Reviews Evans, D. A.; Nelson, J. V.; Taber, T. R. "Stereoselective Aldol Condensations," in Topics in Stereochemistry, New York, 1982; Vol. 13, p. 2. Mukaiyama, T. "The Directed Aldol Reaction," in Organic Reactions, New York, 1982; Vol. 28, p 203. Heathcock, C. H. Asymmetric Synthesis; Morrion, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, part B, p 111.

Aldol Reaction Time-Line

OTMS O OH OTMS O OH O OH O H 20 mol% cat 2 NaOH TiCl4 Ph Me H rt EtS RCHO EtS R Me H PhCHO 50% yield Me Me 82%, 3:1 syn:anti ! 93:7 dr Aldol Reaction ! 91% ee Discovered Independently Mukaiyama Publishes Mukaiyama Describes By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction 1957 1981 1997

1864 1973 1990 Zimmerman Proposed Evans Oxazolidone Shibasaki Claims Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic Led to Zimmerman-Traxler Models Described Enantioselective X Catalytic Direct Aldol H OBR2 M OH O O N O R X O LLB O OH R R' O R' O Ph Me RCHO Ph R (Z)-Enolate syn - Aldol X PhCHO up to 94% ee H OH O M O R' O R X O OH R R' N Ph (E)-Enolate anti - Aldol O Me O 88%, > 500 : 1

1 Racemic Aldol Technology

1864 1973 1990 Zimmerman Proposed Evans Oxazolidone Kobayashi Claims Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic Led to Zimmerman-Traxler Models Described Enantioselective X Catalytic Direct Aldol H OBR2 M OH O O N O R X O LLB O OH R R' O R' O Ph Me RCHO Ph R (Z)-Enolate syn - Aldol X PhCHO up to 94% ee H OH O M O R' O R X O OH R R' N Ph (E)-Enolate anti - Aldol O Me O 88%, > 500 : 1

Enolate Geometry Correlates with Product Diastereoselectivity Under Kinetic Control

! The anti - Aldol Stereochemistry is Thermodynamically Favored:

OLi OH O OH O PhCHO Subsequent cross-over experiments implicate aldol-retro-aldol equilibration Ph Ph OH OLi 25 ºC, 3d Ph OH rather than epimerization Ph Ph

8% 92% Mulzer, et al. Tet. Lett., 1977, 4651.

! Zimmerman Proposed a Chair Transition State for Kinetic Selectivity of the Ivanov Reaction:

OMgBr OMgBr OMgBr PhCHO H H OH O Ph MgBr MgBr O O OMgBr - 78 ºC Ph O O Ph OH Ph Ph Ph Ph diequatorial favored 3:1 anti:syn should lead to anti-aldol Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. ! Model Holds for a Variety of Enolates Both E and Z X OH O H OM M OH O PhCHO O Me X R' X O R X R Me R' R' M X Z:E anti:syn (Z)-Enolate syn - Aldol X Li i-Pr >98:2 90:10 H OH O Li Mesityl 5:95 8:92 M O B >97:3 R' i-Pr >99:1 O R X B St-Bu 5:95 5:95 R R' Mg t-Bu >99:1 >97:3 (E)-Enolate anti - Aldol

2 Selective Enolization Can Be Achieved

! Kinteic vs. Thermodynamic Acidity:

OLi OLi O OLi OLi

Me Me LDA Me Ph3CLi Me Me – 78 ºC !

99% 1% 10% 90% For other examples, see Evans 206 Kinetic Acidity

! Structure of Carbonyl Compound Can Influence Ratio of Enolates Formed under Kinetic Control:

These result can be rationalized with the Ireland model: OLi O LDA OLi R Me Me O R THF R R H Me Li (E) Me R H (E)-enolate (Z)-enolate O N R R Me O R E : Z R Me H Li (Z) OR, SR 95 : 5 R N H Et 77: 23 R t-Bu 0 : 100 NR2 0 : 100 Ireland et al. J. Am. Chem. Soc., 1976, 98, 2868 Ireland, J. Org. Chem. 1991, 56, 650 ! Solvent Can Impact Enolate Ratios:

R Solvent E : Z

OMe THF 95 : 5 Difference due to Enolate Equilibration OMe THF/HMPA 16 : 84

The Mukaiyama Aldol Reaction

! Mukaiyama's Report of a New Aldol-Type Process:

O OTMS O OH H • Broad Range of Ketone Nucleophiles 1.02 eq TiCl • Range of Aldehyde + Ketone Electrophiles LDA, TMSCl 4 Ph • 50-93% yield 1.0 eq PhCHO • 1:1 to 3:1 syn:anti – 78 ºC, CH Cl • Open Transition State 1.0 eq 2 2 • Use of SKA or thio-SKA can increase the dr aq. TsOH workup Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011 Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503 ! Reaction is syn-Selective Regardless of Enolsilane Geometry

OTMS O OH OTMS O OH TiCl4 TiCl4 Me PhCHO PhCHO EtO – 78 ºC EtO Ph EtO – 78 ºC EtO Ph Me Me Me 3:1 syn:anti 2:1 syn:anti

! Attractive Prospects for Catalysis...More on this Later

R3Si O OMLn silyl transfer O OSiR3 R + ML n X catalyst turnover R n ML X A OSiR3 O Path R X H ML n R Si LnM Path 3 O OSiR OMLn O 3 B R R X H X metal readily transmetalation dissociates from product

3 Chiral Auxiliary Technology

The Evans Aldol Reaction

! Chelate Organization Allowed for Highly Diastereoselective Alkylations of Imide Enolates

Li O O O O O O LDA R'–Br Me Me R' O N O N O N R'–Br must be Re-face reactive, R' " i-Pr Me R R R ! 99 : 1 dr all cases

Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737

! Chelate Organization Precluded in Aldol Process

Bu Bu H O O OH B O O O R Re-face O N R Me O N Me Bu Bu B R O O R RCHO free rotation Me O N

Bu Bu H R R O OH B R O O R Si-face N R Me N O Me O O O

! Will this Reaction be Selective Given Lack of Chelate Control?

4 The Evans Aldol Reaction ! Surprisingly, This Reaction is Highly Enolate Face-Selective:

Bu Bu Bu Bu B B O O i-Pr O OH O O Me O OH RCHO RCHO Me Me Ph O N N R O N N R O Me O Me

i-Pr O Ph Me O Evans, D. A.; Bartroli, J.; Shih, T. L. ! Reaction is Highly Diastereoselective in all propionate cases (141 : 1 to > 500 : 1) J. Am. Chem. Soc. 1981, 103, 2127 ! Reaction is Tolerant of a Broad Range of Aldehydes; R = Alkyl, Aryl, hindered, unhindered ! Acetyl-done provides poor selectivity—1 : 1 for the two diastereomers; Acetate aldol product via desulfurization ! One of the most reliable and predictable reactions in organic synthesis; industrially useful ! Possible Model for Asymmetric Induction: O BR2 O O OH O O H O R Si-face i-Pr N disfavored Me B O N R O N R O R dipole maximized O Me i-Pr i-Pr Me O

O i-Pr BR2 N R i-Pr O OH i-Pr O Re-face H B favored Me O N R N R dipole minimized O O O R Me Me O O ! Model does not account for the impact of the acyl-done !-substituent on diastereoselectivity. Perhaps a boat TS should be considered for smaller acyl donors as a competitive pathway

Heathcock's Modification to the Evans Aldol

! Chelated S-imides give Re-face attack and Non-Chelated Imides give Si-Face Attack

Li Bu Bu H O O O O B R'–Br R O OH Me R' R O O R' O N O N Si-face Re-face Me N R' Me N O Me R R O ! 99 : 1 dr all cases O O "Evans" syn

! Based on that Observation, Heathcock Developed a "non-Evans" syn or anti Aldol: J. Org. Chem. 1991, 56, 5747

Bu Bu Bu Bu O O OH O O OH B B O O O O O N R' H R' O N R' Me Me O N LA O N Me Me R' O H O R H H R LA "non-Evans" syn R R "non-Evans" anti

Method R R' Lewis Acid equiv. syn: anti "non-Evans" : "Evans"

A or C t-Bu i-Pr TiCl4 2.0 94 : 6 100 : 0

B t-Bu i-Pr SnCl4 2.0 93 : 7 100 : 0

C i-Pr i-Pr Et2AlCl 3.0 5 : 95 100 : 0

Method A: Lewis acid added to enolate at – 78ºC followed by slow addition of isobutyraldehyde Method B: Aldehyde added to enolate at – 78ºC followed by slow addition of Lewis acid Method C: Precomplexed aldehyde and Lewis acid cannulated into solution of enolate at – 78ºC

! "Size" of Lewis acid affects selectivity; propionaldehyde, isovaleraldehyde work well, benzaldehyde syn-only

5 Crimmins's Modification of the Evans Aldol

! Crimmins's Hypothesis for Observed Lower Selectivies with Titanium Imide Enolates (88-96% de):

O Bn N Bn O OH Ti has a higher affinity for S than O e.g.: Cl Cl H "Evans" syn Ti TiL O Cl N R TiLn n O Cl O S R O Me Me O - - + Cl – Cl S O Fowles, et al. J. Chem. Soc. 1971, 1920. O O O OH H X Bn N Cl "non-Evans" syn Ti O N R If X = S, then Ti chelate prefered R O Cl O Cl Me Me Bn ! Evans vs non-Evans Path Dictated by Auxiliary and Stoichiometry of Amine Base: J. Org. Chem. 2001, 66, 894.

X O Rc O OH X O OH Me 1. 1-2 eq TiCl4, Base Y N N R Y N R + anti isomers 2. 1-1.1 eq RCHO Y Me Me X Rc A: "Evans" Rc B: "Non-Evans"

X, Y = S; Rc = i-Bu (X = S, Y = O, Rc = Bn gave similar) X, Y = O; Rc = Bn Base equiv. R yield A : B : anti T (ºC) R yield A : B : anti DIEA 2.5 i-Pr 86 86 : 14 : 0.3 0 Et 84 99 : 1 : 0 DIEA 1.1 i-Pr 75 5 : 95 : n.a. 89 0 MeCH=CH 97 : 3 : 0 TMEDA 2.5 i-Pr 57 96 : 4 : n.a. 0 i-Pr 89 98 : 2 : 0 TMEDA 1.1 i-Pr 50 <1 : >99 : n.a. 0 t-Bu 87 97 : 3 : 0 Sparteine 2.5 i-Pr 84 95 : 5 : 0 98 – 78 i-Pr 98 : 2 : 0 Sparteine 1.1 i-Pr 63 5 : 95 : n.a.

Summary of Aldols with Imide Auxiliaries

! Syn Aldols: R O OH i-Bu O OH

N R N R RCHO 4 BOTf O Me ! 98% de syn S Me Bu 2 TiCl O O O ! 99:1 syn:anti S O S N, RCHO ! 90% de syn 3 Me Et Evans, J. Am. Chem. Soc. 1981, 103, 2127 Me 2.5 eq Sparteine ! 99:1 syn:anti O N S N 1. Bu TiCl 2 BOTf, Et 2. TiCl 4 RCHO i-Bu 1.1 eq Sparteine R O O OH S O OH 4 •RCHO 3 N O N R S N R Me ! 98% de syn Me R ! 87:13 syn:anti i-Bu ! 90% de syn ! 99:1 syn:anti Heathcock J. Org. Chem. 1991, 56, 5747 Crimmins J. Org. Chem. 2001, 66, 894.

! Anti Aldols:

Bu Bu O O OH O O B 1. Bu BOTf, NEt O O Me 2 3 R' O N R' O N Me 2. Et AlCl•RCHO O N Me 2 H O ! 98% de anti R ! 86:14 anti:syn R H AlEt2 R "non-Evans" anti

Heathcock J. Org. Chem. 1991, 56, 5747

! Auxiliary can be converted to the corresponding alcohols, aldehydes, acids, esters, thioesters, Weinreb amides

6 Other Useful Chiral Auxiliaries

! Oppolzer's Sultam: Both Propionate and Acetate Aldols Possible

Me Me Me Me O OH OBR O R2BOTf 2 RCHO X R ! 95% de Me Me c N N bottom face Et3N Me SO2 SO2 attack Oppolzer, J. Am. Chem. Soc. 1990, 112, 2767 Me Me Me Me TBS O OH O LDA LnTi N N O X R 90 to 95% de TBS-Cl O c SO2 SO2 H Oppolzer, Tet. Lett. 1992, 33, 2442 R ! Abiko and Masamune's Norephedrine-Derived Auxiliary Gives anti Aldols

Ph O Ph BR 2 O OH (c-Hex)2BOTf RCHO Me Me Me ! 90% de anti O O Et3N closed TS XcO R ! 98:2 anti:syn BnN BnN Me Me SO2Mes SO2Mes Abiko, A.; Liu, J.- F.; Masamune, S. E - enolate J. Am. Chem. Soc. 1997, 119, 2586 ! Masamune/Reetz Chiral Boron Enolates Give anti Aldols

95% ee DIEA Me O OH O Me H R' Me 1. B Me SR O OTf B R R O O t-BuS R' t-BuS RR' B O H 2. R'CHO Me SR R R = Me, H Me R = Me, 93-96% ee disfavored favored R = H, 87-94% ee

Masamune, J. Am. Chem. Soc. 1986, 108, 8279 Reetz, Tet. Lett. 1986, 4721

Chiral Ethyl Ketone Aldol Reactions (Z)-Enolates

! Even Simple !-Chiral (Z)-Ethyl Ketone Enolates Give High dr's: R dr

O O OH O OP Ph 97 : 3 Bu2BOTf, Et3N Et 98 : 2 R HO R BnOCH2CH2 96 : 4 RCHO i-Pr >99 : <1 OTBS TBSO Me Me Masamune J. Am. Che. Soc. 1981, 103, 1566 ! A "-Stereocenter Usually has Little Impact: OTBS O OTBS O OH TiCl4, Et3N Me Me Me Me i-PrCHO Me Me Me Me Me Me both 95:5 dr OTBS O OTBS O OH Me Me TiCl4, Et3N Me Me i-PrCHO Me Me Me Me Me Me Evans J. Am. Chem. Soc. 1991, 113, 1047 ! Stereochemical Model: Me R O O OH L O H M RL H R RM L H RM Me OM Favored RL RCHO major RL Me

Me RM O OH R O RL H O L R M H RL RM Me H L R minor M Disfavored

7 Chiral Ethyl Ketone Aldol Reactions (E)-Enolates

! Simple !-Chiral (E)-Ethyl Ketone Enolates also Give High dr's:

OTBS O OTBS O OH (c-Hex)2BCl, Et3N Me Me Me Me i-PrCHO 94:6 dr Me Me Me Me Me Me

OTBS O OTBS O OH Me Me (c-Hex)2BCl, Et3N Me Me 96:4 dr i-PrCHO Me Me Me Me Me Me ! Stereochemical Model: H H R R O OH OM O O Me Me RCHO L O O L RL RL M M R H H H H L L RM Me R Me RL 1,3 RM M R avoid A R M L major Disfavored Favored

Evans, J. Am. Chem. Soc. 1991, 113, 1047 ! However, not all (E)-enolates are well-behaved

O O OH (c-Hex) BCl, Et N 2 3 Me BnO BnO i-PrCHO Me Me Me Me 95:5 dr

Patterson, I.; Goodman, J. M.; Isaka, M. Tet. Lett. 1989, 30, 7121

Chiral Ethyl Ketone Aldol Reactions—!-Keto Imides ! Diastereomer Depends on Enolate Geometry and Lewis Acid

Xp Me O Cl O O O OH H TiCl4 H Ti O Cl O N R Cl DIEA O R Me Me Me Bn Z-Enolate Chelation Control 96:4 to 99:1 dr Xp Me O O O OH L O Sn(OTf)2 H Sn H O N R O Et3N L O Me Me O O O R Bn Me 89:11 to 95:5 dr Z-Enolate Dipole Minimized O N Xp Me Me O O O OH Bn (c-Hex)2BCl L O H O B H N R EtNMe O 2 L Me Me Me O R Bn H 84:16 to 97:3 dr E-Enolate Dipole Minimized X p O O O OH Me ? O O N R H H MLn Me O Me Me O Bn R unknown H Evans, J. Am. Chem. Soc. 1990, 112, 866 ABN: E-Enolate Chelation Control? Evans, Tetrahedron, 1992, 48, 2127 Open TS (Z)-enolate in anaolgy to Heathcock?

8 Chiral Ketone Aldol Reactions–1,5 Induction

! Evans and Patterson Independently Observed this Phenomenon:

OR OM RCHO OR O OH Evans J. Org. Chem. 1997, 62, 788 R R R Patterson Tet. Lett. 1996, 8585

1,5 anti ! Levels of Induction Strongly Dependent on Metal, Protecting Group and Solvent: anti:syn PMBO OM CHO PMBO O OH Ph TBSO OBBu2 Bn Bn Bn 40:60 Solvent – 78 ºC Bn

M solvent yield anti:syn Ph Li THF 79 40:60 O O OBBu TMS/BF3•Et2O CH2Cl2 85 50:50 2 >95:5 Cy2B CH2Cl2 85 82:18 TrO Bu2B CH2Cl2 80 87:13 Bu2B Et2O 85 98:02

! Chiral Ethyl Ketones Exhibit 1,5-Syn Induction:

t-Bu t-Bu t-Bu t-Bu Si Si O O OBPhCl O O O OH i-PrCHO Me Me Me >99:1 syn:anti i-Pr CH2Cl2, – 78 ºC Me 72% yield Me Me

1,5 syn ! No Good Models have been Presented to Account for the Observed Selectivities

Chiral Methyl Ketone Aldol Reactions–1,5 Induction in Synthesis

Long-Range Transmission of Stereochemical Information: 10 O OH No proposed model to account for the sense of diastereocontrol O HO 29 For a detailed investigation, see Evans J. Org. Chem. 1997, 62, 788 15 25 21

Patterson Roxaticin Synthesis: C-10 to C-29 Fragment OH OH OH OH OH (+) Roxaticin

OTBS 1,5 anti 29 OTBS 21 OTBS (c-Hex)2BCl 25 H 29 Et N, Et O 25 21 OTBS O OPMB 3 2 O 86% OH O OPMB 95 : 5 dr OTBS 29 25 21 O 10 OTIPS O O OPMB I

(c-Hex)2BCl OTBS PMBO 29 15 Et3N, Et2O 25 21

10 75% 15 O O OPMB OH O 1,5 anti I O OPMB OTIPS 75 : 25 dr

Paterson, I.; Collett, L. A.; Tet. Lett., 2001, 42, 1187 ! The analogous ethyl ketone enolates give 1,5-syn selectivity

9 Chiral Aldehyde Aldol Reactions–!-Chiral Aldeyhdes

! (E) Enolates Give the Felkin Product Me H O OH ORL H R Favored L O Me R L M n H Me Me R Felkin OMLn O Felkin Attack

RL R H syn-pentane Me Me H H O OH Me RL O Disfavored R Me O L ML R H n R Me Me Anti-Felkin Attack Anti-Felkin

Evans Topics in Stereochemistry, 1982, 13, 1-115 Roush J. Org. Chem. 1991, 56, 4151 ! A Complex Case: Woodward's Erythromycin Synthesis

Me Me Me Me Me Me Me Me

OLi O O OAc O OMOM O OH O OAc O OMOM O O 85% yield O O Me Me t-BuS t-BuS H one isomer Me Me Me Me Me Me Me Me Me Me Me Me Felkin anti-aldol product

Woodward, et al. J. Am. Chem. Soc., 1981, 103, 3210

Chiral Aldehyde Aldol Reactions–!-Chiral Aldeyhdes ! (Z) Enolates Give the Anti-Felkin Product: Li OLi O OBn O OH OBn Me Me Me H Me Me Me Me Me

Initially rationalized via a Cram-Chelate Model... Anti-Felkin 98:2 dr Masamune J. Am. Chem. Soc. 1982, 104, 5526 However... O OH OTBS OLi O OTBS TMSO TMSO Me Me Me H Me Me Me Me Me Me Me Me Me Anti-Felkin 73:27 dr Brooks Tet. Lett. 1982, 23, 4991 ! Stereochemical Model: syn-pentane Me O OH Me R R L O L H R Disfavored O H L M Me Me n H R Felkin OMLn O Felkin Attack Me RL R H Me H Me O OH Favored Me RL O R H O L ML R H n R Me Me Anti-Felkin Attack Anti-Felkin

10 Chiral Aldehyde Aldol Reactions–1,3 Induction

! Modest Levels of 1,3 anti Induction can be achieved with !-Polar Aldehyde Substituents: OTMS X Yield anti:syn O X O OH X Me SnCl4 or BF3•Et2O Me OPMB 79 95 : 5 H Ph Ph OTBS 90 73 : 27 Me OAc 85 89 : 11 Me Cl 84 83 : 17 ! All Alkyl Cases Do Not Give Useful Levels of 1,3 Induction

O OH Me OTMS O Me Me SnCl4 or BF3•Et2O Me H Me Me Me Me Me Me 58 : 42 anti:syn ! Stereochemical Model for 1,3 Induction: Evans Polar Model vs Reetz/Cram Model eclipsing interaction Nu: X H H H R! Nu: H O M OH X C M O H H favored C Nu R! H X H :Nu R! 1,3-Anti Product O X Evans Polar Model Reetz/Cram Polar Model H R! Nu: Nu:

H H OH X H H Nu: M O H M O H diopole maximized disfavored C Nu R! C H R ! 1,3-Syn Product X H X R! R –CO Gauche ! Reetz, Tet. Lett. 1984, 25, 729. Cram J. Am. Chem. Soc. 1968, 4011-4026. Evans Tet. Lett. 1994, 35, 8537. Evans J. Am. Chem. Soc. 1996, 118, 4322.

Chiral Aldehyde Aldol Reactions–Merged 1,2- and 1,3-Induction

! An Interesting Observation About !,"-Substituted Aldehydes (J. Am. Chem. Soc. 1996, 118, 4327)

Matched Case: Large Nucleophile Mismatched Case: Large Nucleophile O OPMB OH OPMB OH OPMB OTMS BF •Et O OTMS O OPMB 3 2 BF3•Et2O t-Bu H i-Pr Nu i-Pr Nu i-Pr t-Bu H i-Pr Me Me Me Me 99 : 1 Felkin : Anti-Felkin 96 : 4 Felkin : Anti-Felkin

Matched Case: Small Nucleophile Mismatched Case: Small Nucleophile OTMS O OPMB OH OPMB OH OPMB BF3•Et2O OTMS O OPMB BF3•Et2O H i-Pr Nu i-Pr Nu i-Pr Me Me H i-Pr Me Me Me Me 97 : 3 Felkin : Anti-Felkin 6 : 94 Felkin : Anti-Felkin

For sterically large nucleophiles, Felkin control is more important than 1,3-anti induction. However, the "-stereocenter (if bearing a polar group) can be the dominant control element.

Analysis of Mismatched Cases Analysis of Matched Case

Nu: Favored for Large Nucleophiles Favored for Small Nucleophiles Nu: Nu: H Me H O M Me H Me H C M O H H O M X H R" C C X H X H Felkin and Evans Polar Model R" R" both predict same face of attack Felkin Attack, 1,3-syn Anti-Felkin Attack, 1,3-anti

11 Chiral Aldehyde Aldol Reactions–Merged 1,2- and 1,3-Induction

! Propionate Mukaiyama Aldols Also Function Well (J. Am. Chem. Soc. 1995, 117, 9598) - (E) Propionate nucleophiles give high levels of Felkin Selectivity even in Mismatched cases: - (Z) Enolates generally less selective

Matched Case:

OTMS O OTBS O OH OTBS BF3•Et2O i-Pr i-Pr i-Pr H i-Pr 95% yield Me Me Me Me 95: 5 syn:anti Mismatched Case: > 99 : 1 Felkin : Anti-Felkin

OTMS O OTBS O OH OTBS BF3•Et2O

i-Pr H i-Pr 89% yield i-Pr i-Pr Me Me Me Me 70 : 30 syn:anti 99 : 1 Felkin : Anti-Felkin ! Summary of Stereochemical Relationships: Matched Case Mismatched Cases 1,3-syn 1,3-anti 1,3-anti

OH X OH X OH X

Nu i-Pr Nu i-Pr Nu i-Pr Me Me Me

Felkin Felkin Anti-Felkin Good selectivity for both large Favored for large Nu for Felkin Favored for small Nu for 1,3 anti and small Nu to dominate 1,3 anti effect to dominate Felkin control

Analysis of a Recent Complex Aldol Reaction

! A Key Disconnection in Crimmins's Recent Synthesis of the Spongistatins: J. Am. Chem. Soc., 2002, 5661.

OBn Me OBn H H Cy BCl, Et N, pentane O Me 2 3 O

Me O OH OTES OBn O Me Me H OTES OTES O OTES OBn 93% yield, >98:2 dr

Analysis of the Product's Stereochemical Relationships:

! 3 of the 4 Known Control Elements are reinforcing

1,4 anti Felkin ! For Large Nucleophiles, Felkin beats 1,3 anti 1,5 anti OBn Me H ! 1,3 anti Least Effective if 3 PG is Silyl O

O OH OTES OBn ! For the 1,4 anti Effect, see: Patterson Tet. Lett. 1994, Me 9083, 9087. Propionates give 1,4 syn. 1,3-syn OTES ! Effect of other 2 Stereocenters is Unknown

! Complex Aldol Reactions Generally Require Significant Optimization of Enolization Conditions, Solvent, and PG's

12 Enantioselective Catalysis of the Mukaiyama Aldol Reaction

Catalysis of the Aldol Reaction

! Challenges to Metal-Catalysis of the Aldol Reaction: The Direct Aldol

O O OM O M Base O O R H R X X H R X

i-PrOH pKa = 29 (DMSO) X DMSO pKa Aldol Acceptor More Acidic Product More Basic than SM Me 27 Ph 25 Ot-Bu 30 Turnover Problem NMe2 33 (est) Chemoselectivity Problem H 21-24 (est)

! Catalysis of the Mukaiyama Aldol Reaction:

R3Si O OMLn silyl transfer O OSiR3 R + ML X catalyst turnover R n n X ML A OSiR3 O Path R X H ML n Path R Si LnM 3 O OSiR B OMLn O 3 R R X H X metal readily transmetalation dissociates from product

13 The First Catalytic Mukaiyama Aldol Reaction

! Bergman and Heathcock J. Am. Chem. Soc., 1989,111, 938. – An excellent paper to read for its brilliant logic

! Enolate Equilibration Discovered:

Me P CO Me3P CO 3 Rh TMS DMSO Rh TMS O O O O PMe3 PMe3 Me Keq = 0.3 Me Ph Ph Ph Ph

! Stoichiometric Process: TMSO O CO TMSCl R P Rh PR CO Ph t-Bu 3 3 Me3P CO OC PMe3 Me Cl R3P Rh PR3 Rh Rh OK O O O Cl PMe3 PhCHO Me3P TMS Me Me O t-Bu t-Bu 5d, – 20 Ph t-Bu TMSO O Me3P CO toluene Rh > 90% yield Me Ph O PMe recrystallized 79% recryst. 1 isomer Ph t-Bu 3 16 e- sq. planar structure Me Ph assigned by CO IR stretch enolsilane is an effective ! Catalytic Process is Efficient silylating agent

1 mol% CO • Reaction scope limited to OTMS R3P Rh PR3 OH O OH O non-enolizable aldehyde Aldol Me Cl acceptors due to basicity of Rh t-Bu Ph t-Bu Ph t-Bu enolate PhCHO, DMSO Me Me • No crossover experiments 83% yield preformed to determine origin of 86 : 14 syn : anti loss in dr ! No Reports of Enantioselective Catalysis with this Reaction

Enantioselective Catalysis of the Mukaiyama Aldol Reaction–Syn Aldols

! The First Enantioselective Catalytic Mukaiyama Aldol: Mukaiyama and Kobayashi Chem Lett. 1990, 129, 1455. R Yield syn:anti ee OTMS NH!-Nap O OH O Sn(OTf)2 + Ph 77 93 : 7 90 N Tol 75 89 : 11 91 EtS 10-20 mol% Me R H EtS R Crotyl 76 96 : 4 93 Me Octyl 80 100 : 0 >98 C2H5CN, – 78ºC Me c-Hex 71 100 : 0 >98 A ! Proposed Catalytic Cycle: * N N Sn RCHO TfO OTf Stereochemical Model: + A

OTMS H N N EtS Sn OTf * Me L H Me N N O Sn TMSOTf O O OTf Nu: R EtS R Me ! State of the Art in Syn-Selective Enantioselective Mukaiyama Aldol Reactions:

OTMS OH O O [Cu(pybox)](SbF6)2 BnO BnO XR1 XR H 0.5 – 10 mol% R X = O, S R ! 96 : 4 syn:anti ! 92% ee pyruvate esters function with similar efficiency Evans J. Am. Chem. Soc. 1996, 118, 5814 R = H, Me Evans J. Am. Chem. Soc. 1997, 119, 7893 Evans J. Am. Chem. Soc. 1999, 121, 686

14 Enantioselective Catalysis of the Mukaiyama Aldol Reaction–Anti Aldols

! The First Efficient Anti-Selective Enantioselective Catalytic Mukaiyama Aldol Reaction:

O OTMS HO Me O MeO 10 mol% [Sn(Ph-pybox)](OTf)2 MeO Me St-Bu St-Bu o CH2Cl2, –78 C O R O R gloxalates also R = Me, Et, i-Bu anti:syn ! 98 : 2 efficient ee ! 96% O Me OTMS OMe tBuS Me O

anti adduct

d (H–Me) 2.18 Å O Me OTMS E = 0 kcal/mol OMe tBuS E = +5 kcal/mol Me O syn adduct Evans, D. A.; MacMillan, D. W.C. J. Am. Chem. Soc. 1997, 119, 10859 ! Kobayashi's Zirconium-Based Anti-Aldol I

OTMS O OH O O 10 mol% Zr(Ot-Bu)n yield 61 – 94% O ee generally ! 92% X R X (R = alkyl ee 80 – 89%) R H Me I Me anti:syn 85 : 15 – 96 : 4 R = Aryl, Crotyl, X = OR, SR EtOH, H O, toluene, 0 ºC Alkyl less selective 2 Acetate Aldols also Formed in Good ee Note: Non-Linear Effect Observed Uncertain TS Dimeric Catalyst Proposed Kobayashi, J. Am. Chem. Soc. 2002, 124, 3292

Enantioselective Catalysis of the Mukaiyama Aldol Reaction–Acetate Aldols

! Carreira Offered the Most General Solution to this Problem: t-Bu

N Ti(Oi-Pr)4 t-Bu O Catalyst 1 N O Ti Br CO2H O OH HO HO O O Br t-Bu t-Bu t-Bu

t-Bu J. Am. Chem. Soc. 1994, 116, 8837 J. Am. Chem. Soc. 1995, 117, 3649 Me O OTMS 2–5 mol% 1 OH O O 2–10 mol% 1 OH O neat, rt OMe Et2O, – 10ºC R OMe R H OMe R CH R H H O+ workup 3 72-98% yield 3 77-99% yield Aldehyde ee Aldehyde ee

CHO 97 CHO Me Ph 90

CHO 95 o-MePhCHO 75 Me

95 TBSOCH CHO c-HexCHO 2 93

PhCHO 96 Ph CHO 91

TIPS CHO 97 Ph(CH2)3 CHO 98 Methyl ester product can be obtained by ozonolysis workup

15 Chiral Lewis Base Catalysis of the Mukaiyama Aldol

An Organocatalytic Approach to the Aldol Reaction: see Denmark Acc. Chem. Res. 2000, 33, 432. Mechanistic Proposal: LB:

SiR3 O ! Only trichlorosilylenol ethers are substrates O OSiR3

! There is a background reaction with trichlorosilylenolates R R R

OSiR3 not Lewis Acidic ! Ketone & Aldeyhde enolates work well due to low bkgrd LB R LB R ! Phosphoramides and N-oxides are effective catalysts Si R Si R O O H R R O ! Reaction is stereospecific—Z-enolates give syn, R E-enolates give anti products, implicating a closed TS R R unlike most Mukaiyama-Type processes Lewis Base Adduct More Lewis Acidic ! Non-linear effects observed, complicates analysis

Ph Me Acetate Aldol: N O Propionate Aldol: P Me N N Ph O OSiCl3 O Ph Me O OH N 10 mol% P O Ph N N n-Bu H R n-Bu R OSiCl3 Me O OH CH2Cl2, rt Me 15 mol% R time (h) yield ee Ph H R Ph R CH2Cl2, – 78ºC Cinnamyl 2 94 84 Me R yield syn:anti ee !-Nap 2 92 86 Ph 95 18 : 1 95 p-Biphenyl 2 95 86 !-Nap 96 3 : 1 84 c-Hex 6 79 89 Cinnamyl 97 9 : 1 92 t-Bu 6 81 92 Denmark J. Org. Chem. 1998, 63, 918 Denmark Acc. Chem. Res. 2000, 33, 432.

Enantioselective Catalytic Direct Aldol Reactions

16 Catalysis of the Direct Aldol Reaction

! Challenges to Metal-Catalysis of the Aldol Reaction: The Direct Aldol

O Product More Basic than SM O OM O M Base O O R H R X X H R X Turnover Problem

! Approaches to the Direct Aldol Problem. Or, How to Quench an Alkoxide.

! Build an intramolecular trap for the nascent alkoxide (i.e. the Ito–Hayashi Gold Aldol) M O O O XOC R base, MLn + ML X R n R n LG RCHO O LG n

! Incorporate a proton shuttle on the catalyst (e.g., Shibasaki, and Trost)

+ O MLn–BH MLnBH MLnB O O O O O HO B–MLn

X X H R X R X R

! Silylate the aldolate (e.g., Evans catalytic aldol)

M M O O TMS–X O OTMS

X R X R Me O N • HX ! Avoid alkoxides altogether by using 2º amine catalysts (e.g., enzymes, proline, t-Bu-Bn-Im) Bn t-Bu N H

The First Catalytic Aldol Reaction

! The First Catalytic Aldol-Type Process: Ito and Hayashi J. Am. Chem. Soc., 1986, 108, 6405.

Solution to the Catalytic Aldol Problem — Intramolecular Trap for Alkoxide

NMeCH2CH2NEt2 PPh2 O O Fe C R COOMe R COOMe N 1 mol% H R OMe PPh2 yields 83 to 100% cis:trans = 89 : 11 to >99 : 1 O N + – O N ee generally ! 95% R = Ph, Crotyl, Me, i-Pr, c-Hex, t-Bu 1 mol% [Au(c-HexNC)2] BF CH2Cl2, rt

This is a direct, enantioselective catalytic aldol reaction 11 years before the reports of Shibasaki, and Trost!

Limitation/Adantage of this process is the !-amino acid functionality. Not applicable to acetate and propionate synthesis, but highly useful for the synthesis of serine derivatives and aminosugars.

! Ito and Hayashi Invoke the Following Mechanism for their Bifunctional Catalyst:

H P H P P R O R O R O Au O Au O L * C * C Au N * L N N N N COOMe OMe P OMe N P P NHR H NHR2 H 2 NHR2 Catalyst Amine Deprotonates Ester Aldol Reaction Alkoxide Trapped By Isocyanide, Catalyst Turnover

17 The Direct Aldol Reaction—Proton Shuttle # 1 LnLB ! Shibasaki Claims the First Direct Catalytic Aldol Reaction:

Proposed Catalytic Cycle: R1 O O M–O O H 1 * 2 Li R O–LA H R O R1 O O Li Ln O–M O M–O O O H H O * * Li O–LA O–LA O R1 R2 O O OH O M H O R1 R2 * (R)-LnLB O–LA R2

The Methyl Ketone Aldol More Acidic Ketones Give Better Results O O O O O OH 20% LnLB O OH 10% LnLB OH 1 2 THF – 50 ºC Ph R R Me H R THF – 20 ºC R1 R2 Ph H R 24-40h OH R1 R2 Ketone Equiv t (h) yield ee R Ketone Equiv yield syn:anti ee Ph t-Bu 5 88 76 88 i-Bu 2 86 2 : 1 90 Ph PhCH2C(CH3)2 7.4 87 90 69 Ph c-Hex 8 169 72 44 n-Hex 2 84 3 : 1 94 Ph i-Pr 8 277 59 54 Ph(CH2)2 2 84 5 : 1 95 Ph Ph(CH2)2 10 72 28 52 !-Nap t-Bu 8 253 55 76 c-Hexa 2 89 1 : 6 85 Me t-Bu 10 100 53 73 a Et PhCH2C(CH3)2 50 185 71 94 i-Pr 2 92 1 : 5 86 ausing a modified LnLB ligand

Shibasaki J. Am. Chem. Soc. 1999, 121, 4168 Shibasaki J. Am. Chem. Soc. 2001, 123, 2467

The Direct Aldol Reaction—Proton Shuttle # 2 Trost Ligand ! Trost's Design Closely Follows Shibasaki's Catalyst

O Proposed Catalytic Cycle: + precatalyst Ph O Et O Ph Zn Zn - ethane Ph Me Ph Ph OH O Ph N O N O R Ph Ph O O Ph R Zn RCHO Ph Zn Ph Ph H Me N O N O O Ph O O Ph Zn Ph P Ph Zn Ph Me O O precatalyst Ph O O Ph N O N Zn Zn Ph Ph Me R O N O N Acetone Functions Surprisingly Well: O Ph Ph O O Ph Me 5-10% precatalyst Zn O O O OH Ph Zn Ph Me O N O N aldol Me Me H R Ph3P=S, 4Å mol sievesMe R Ph Me THF, + 5 ºC R yield ee Me c-Hex 85 93 Acetophenone Works With Modest Efficiency i-Pr 89 91 t-Bu 72 94 O 5% precatalyst O OH RCHO i-Bu 59 84 Ph(CH ) 59 89 Ph Me Ph R 2 2 Ph3P=S, 4Å mol sieves n-Bu 56 84 THF, 2d, – 5 ºC Ph 55 88

R = unbranched alkyl yield 24-49% ee 56-68 OH O OH R = i-Pr or larger yield 60-79% ee 93-99% no reported, elimination major side-product R = aromatic unreactive R R

J. Am. Chem. Soc. 2000, 122, 12003 Added Ph3P=S aids in catalyst turnover by reversible competition with product

18 The Direct Aldol Reaction—Alkoxide Silylation for Turnover ! Evans et al. Developed A Catalytic Aldol Based on Silylation of the Aldolate:

O O O O OH O O O O OH O O 10 mol% MgCl2 10-20 mol% MgCl2 O N O N Ph O N O N R H Ph Et3N, TMSCl H R Et3N, TMSCl R EtOAc, rt, 24h R Me EtOAc, rt, 24h Me Bn Bn Bn Bn

R dr yield Aldehyde Procedure dr yield X = Me A 24 : 1 - Me 32 : 1 91 X Et 32 : 1 88 X = OMe A 32 : 1 91 Bn 26 : 1 94 X = NO2 B 7 : 1 71 i-Bu 32 : 1 91 CHO Allyl 28 : 1 91 Y X = Ph, Y = H B 21 : 1 92 i-Pr 3.5 : 1 36 (conv) X X = Ph, Y = Me A 28 : 1 92 CHO dr = major : ! isomers X = H, Y = Me B 16 : 1 77 doesn't indicate if dr is mostly due to anti:syn or anti dr A : 20 mol % MgCl2, B : 10 mol % MgCl2 30 mol% NaSBF6

! Crossover Experiments Show Delicate Balance Between Retro-Aldol and Product Silylation:

O O OTMS

O N O OH O O Me 20 mol% MgCl2 OMe H Bn O N 83% (65 : 1 dr) Et N, TMSCl Me 3 OMe Me EtOAc, rt O O OTMS Bn > 100 : 1 dr O N Me Me Note: Rate of Reaction with Tolualdehyde ! 2x faster than Anisaldehyde Bn 17% (25 : 1 dr)

Evans J. Am. Chem. Soc. 2002, 124, 392

The Direct Aldol Reaction—Alkoxide Silylation for Turnover

! In Analogy to Crimmins's Work, Thiazolidinthiones Give the Opposite Enantioseries:

O O O O OH S O S O OH O O 10 mol% MgCl2 10 mol% MgBr2•Et2O O N O N Ph S N S N R H Ph Et3N, TMSCl H R Et3N, TMSCl R EtOAc, rt, 24h R Me EtOAc, rt, 24h Me Bn Bn Bn dr = 7 to 19 : 1 Bn scope similar to oxy-done cases ! Retroaldol Seems to be Faster than Silylation for this Auxiliary:

Initial Isomer Product dr

S O OH S O OTMS

S N Ph S N Ph 9 : 1 Me Me Me Me Bn Bn

S O OH S O OTMS 10 mol% MgBr2•Et2O 7 : 1 S N Ph S N Ph Et3N, TMSCl Me Me EtOAc, rt, 24h Me Me Bn Bn

S O OH S O OTMS 16 : 1 S N Ph S N Ph Me Me Me Me Bn Bn

...Although Reaction not necessarily under Thermodynamic Control Evans Org. Lett. 2002, 4, 1127

19 The "Jake Aldol" Enantioselective Catalysis of the Direct Aldol Reaction

! Acidic Bidentate Thioesters, Non-Enolizeable Aldehydes and Small Amine Bases Function Well

O O OTMS O 20 mol% [t-BuMgPybox]Br 2 84% ee anti OBn H PhS 5 eq. Et3N, 10 eq TMS-Br PhS 82:18 anti:syn CH2Cl2, – 5 ºC OBn 80% yield

! Mechanistic Investigations Support it not beign a Mukaiyama Aldol:

O Amine Base Size Critical in Formation product OBn of Silyloxycarbenium ion PhS MLn O R3N R3N OTMS LnM O OTMS R H TMSBr R H MLn O 1 PhS R H NMR OBn OBn PhS SiMe3 R3N OTMS O

R H R H SiMe3 ML O O n O Bn Et N gives high ee and observable aminol Et3N 3 R H PhS Hünig's Base gives low ee and no aminol

! Reaction Scope Yet to be Determined

Wiener, MacMillan, Unpublished Results.

Enzymatic Aldol Reactions—A Summary

! The Original Organic Catalysts: For an excellent review, see: Wong, Angew. Chem. Int. Ed. 2000, 39, 1352. Two Types of Aldolases:

Type I: Type II: –O C His 2 O B Zn His H NH2 O Zinc enolate observed crystallographically. Enzymes found in –O PO enamine intermediate 3 prokaryotes presumed. Enzymes found in animals

! Synthesis of D-Fructose and L-Fructose With Type II DHAP Dependant Aldolases:

O O O OH O OH H OH O H OH HO OH – OH HO OH O3PO OH OH OH OH Rha aldolase, FDP aldolase, phosphatase DHAP phosphatase OH OH L-Fructose D-Fructose

Wong J. Org. Chem. 1995, 60, 4294

! The Type I Enzyme 2-Deoxyribose-5-Phosphate Aldolase (DERA) Catalyzes an Interesting Aldol Trimerization:

O O DERA O OH MOMO MOMO H Me H 6 days

OH DERA is an acetaldehyde dependant aldolase. While many aldehydes are good aceptors, only acetaldehyde is an efficient aldol donor

Wong, J. Am. Chem. Soc. 1995, 117, 3333

20 Antibody Catalyzed Aldol Reactions—A Summary

! Antibodies Raised with Haptens Designed to Place an Amine at the Binding/Active Site (Type I Mimic):

O O RHN O NR2 O H H RNH2 N N protein Linker similar to R H O O !max = 318 nm aldol TS

Lerner, Barbas Science 1995, 270, 1797 ! 2 of 20 generated antibodies showed Strong UV abs. at 316 nm, 38C2 and 33F12:

O O OH 0.2 mol% Ab yields listed for 2 of >20 examples X RCHO 67, 82% yields pH = 7 buffer R Lerner, Barbas J. Am. Chem. Soc. 1998, 120, 2768 7 days X

! Antibody 38C2 available through Aldrich Substrates ee 10mg $108.70 (MW = 150,000) should give 0.03mmol X R 38C2 33F12 ! Retroaldol kinetic resolution possible krel 2 – >200 with H Ph >99 >99 similar substrate types: Lerner, Barbas Angew. Chem. Int. Ed. H p-NO2Ph 98 99 1998, 37, 2481 H p-NO2Cinnamyl 99 98 ! New Hapten raises antibodies (93F3) giving opposite sense H AcHN 20 3 of induction and similar scope: OH n-Bu >98* 89* O O AbNH O AbNH Ab-NH2 ! 77* 70* OH AcHN S R S R R *syn:anti >99:1; opposite enantioseries! O O H O O O–

Lerner, Barbas Angew. Chem. Int. Ed. 1999, 38, 3738

Proline Catalyzed Aldol Reactions

! The Eder-Sauer-Wiechert-Hajos-Parrish Reaction: O Me O Me O 3 mol% L-Proline Me Eder, Sauer, Wiechert Angew. Chem. Int. Ed. 1971, 10, 496 Hajos, Parrish J. Org. Chem. 1974, 39, 1615 DMF, rt 20h O O 84% yield, 96% ee ! Barbas (with List and Lerner) became Interested Based on Ab Catalysis and Extended to Intermolecular Cases:

O OH ! Uses 20 mol% cat, 20 vol% acetone, O OH 24 – 48h at +4 ºC or rt 68% yield 97% yield Me Me 76% ee Me 96% ee ! Cyclic and Acyclic Ketones good Me NO2 ! Linear unbranched aldehydes low yield

List, Lerner, Barbas J. Am. Chem. Soc. 2000, 122, 2395 ! Hydroxyacetone Requires Harsher Conditions to Give the Anti-Aldol Product:

O O O OH 6 examples 30 mol% L-Proline 62% yield Me DMSO Me yields 38-62% Me H Me 99% ee 67 to >99%ee >95:5 anti:syn OH Me rt, 3 days OH Me 1.5:1 to >95:5 anti:syn 20 vol % List J. Am. Chem. Soc. 2000, 122, 7386 ! Aldehydes also Function Chemoselectively as Aldol Donors in High ee and Modest to Good Anti Selectivity

O OH Me O O Me 88% yield 10 mol% L-Proline 97% ee Me H Me 3:1 anti:syn H H Me DMF, + 4 ºC, 11h Me one regioisomer reaction tolerates a range of alkyl and !-oxy aldehyde donors and both alkyl and aromatic aldol acceptors Northrup, MacMillan J. Am. Chem. Soc. 2002, 124, 6798

21 A Brief Survey of Other Methods to Produce !-Hydroxy Carbonyl Compounds

! Allylation/Crotylation–Ozonolysis Sequence:

OH O OH L2B Me O OH O OH O3 Me BL2 O3 R OH R H2O2 H R R HO R Me Me H2O2 Me Me Review: Bubnov Pure Appl. Chem. 1987, 21, 895 ! Nelson's Acyl Halide–Aldehyde Cyclocondensation: Bn i-Pr i-Pr O O N O O O 78-90% yield TfN Al NTf • Me Me O R !90% ee Br H R H R H Me 87:13 – >99:1 syn:anti DIEA, CH2Cl2, –50 ºC Me

R = aromatic, CH2OBn, mostly alkynyl Nelson Org. Lett. 2000, 2, 1883 ! Calter's Enantioselective, Catalytic Ketene Dimerization/Aldol Sequence:

Me O OLi O O OH O 0.3 mol% quinidine O LiNMe(OMe) i-PrCHO O Me Me • N R2N i-Pr CH2Cl2, – 78 ºC CH2Cl2 OMe Me Me Me H Me Me 99% ee can be trapped with TMSCl 52% overall 10 mmol/hr 95:5 dr ! Leighton's Hydroformylation of Enol Ethers Builds Polyacetates in Opposite Direction: Calter Org. Lett. 2001, 3, 1499

t-Bu t-Bu 1 mol% Rh(acac)(CO)2 4 mol% PPh3 O O O O O 72% yield 800 psi 1:1 H2/CO 13:1 syn:anti Me THF, 75 ºC Me H See CJB Strained Cyclosilane Grp. Meeting for More Leighton Chemistry Leighton J. Am. Chem. Soc. 1997, 119, 11118

Summary

O O OH O R3 1 2 X 1 R R R X R2 R4 4 R3 R

! The Aldol Reaction is a Fundamental C-C Bond Forming Technology

! Enolate Geometry Dictates Syn:Anti Selectivity except for Mukaiyama Aldols

! Chiral Auxiliary Still Most Common Method for Inducing Chirality in the Aldol Reaction

! Many Predicitve Models Available for Diastereoselective Aldol Reactions—Beware! Very Case-Specific

! Several Good Enantioselective Catalytic Mukaiyama Aldols (both Syn and Anti) Available

! Direct, Enantioselective Catalytic Aldol Reactions Generally Not Amenable to an Itterative Aldol Sequence due to Reliance on Ketone Aldol Donors to solve pKa Problem