Enolates: Z(O,R)- and E(O,R)-enolates

Regardless of other groups the encircled R' and O- determine whether one is Z(O,R)- or E(O,R)- enolate.

R R O- O- R' H H R'

(E)-enolate (Z)-enolate

Enolates: deprotonation

90°

R R H O H O 30° R O R' H H R' H O H Heq π π R' R *C=O R *C=O H H σ O σ O Hax Most stable C-H C-H conformation R' H H R' -12 ° H O

H 104 ° R R - O O- R' H H R'

(E)-enolate (Z)-enolate

Corey, E.J.; Sneen, R.A. J. Am. Chem. Soc. 1956, 78, 6269. Effect of base on enolisation

! Base must be large and hard. ! Thus functions only as a base and not as a nucleophile.

Ph Ph

Si Si Si Si - + N N N N O K Li Li M M

LDA LiTMP MHMDS ((Me2Ph)2Si)NLi t-BuOK M = Li, Na, K pKa 36 37 26 25 18-20

Selective formation of E/Z- enolates O base TMSCl OTMS OTMS

R R R

Z(O,R) E(O,R)

RbaseZE Et LDA 30 70 (Me3Si)2NLi 70 30 (Et3Si)2NLi 99 1 (Me2PhSi)2NLi >100 <1

cC6H11 LDA 61 39 (Me3Si)2NLi 85 15 (Et3Si)2NLi 94 6 (Me2PhSi)2NLi 99 1

Masamune, S. Aldrichimica Acta 1982, 15, 47. Enolisation: Ireland-mechanism

! According to the Ireland-mechanism an (E)-enolate is formed via a chair form transition state (R = large alkyl group) ! If also R’ is large, a (Z)-enolate is formed! ! Note the actual proton abstractor and the role of the metal!

R , LiBr N N Li R H R R R + Li - 78 °C - - O O O H R' O R = Et 50 : 1 "R R = i-Pr 21 : 1 R= t-Bu 1 : >20

Ireland, R.E. J. Am. Chem. Soc. 1976, 98, 2868. Collum, D.B. J. Am. Chem. Soc. 1991, 113, 9571. Collum, D.B. J. Am. Chem. Soc. 1997, 119, 4765.

Dimeric Li-enolate - LDA complex

! First X-ray structure for a dimeric complex.

R Si O O 3 200 mol-% LDA Li O Li N O Si Li Li N O O SiR3

STEREO STRUCTURE: CCSD-code FOGRIC

Willard, P.G. J. Am. Chem. Soc. 1987, 109, 5539. Application: Taxol

D O O K O

t-BuOK D2O

O O O O O O

Ketoni Enolaatti

Stork, G. 1995.

Approach of the electrophile

o Houk: 106 (compare: NB! This angle is similar to Burgi-Dunitz angle) the Flippin-Lodge angle!

E E Agami, C. Tetrahedron Lett. 1977, 2801-2804. O R Tetrahedron Lett. 1979, 1855-1858. - RR Tetrahedron 1979, 35, 961-967. R OH Houk, K.N. J. Am. Chem. Soc. 1986,108, 2659-2662.

side view end view

Si O equatorial axial E attack attack

O- O E Re Asymmetric Induction in Enolate and Azaenolate Alkylations Intraligand asymmetric induction

intraannular extraannular chelate-mediated intraannular OM OM OM O M * R1 R M * R1 OO * O R OM R2 R2 * * * R R 1,3- 1,4- 1,2-1,3- 1,2- 1,3-

Interligand asymmetric induction

M* ML * O O n

Evans, D.A. Asymmetric Synthesis 1984, 3, 1-110.

Controlling Face Selectivity

CO2tBu MeI L = HMPA tBuO N H 1) LDA O 2) MeI CO Me L 2 Li NO OtBu N Li O OMe O tBuO L

MeI L = THF

hydrolysis

O O

CO2Me CO2Me

Tomioka, K.; Koga, K. J. Am. Chem. Soc. 1984, 106, 2718. Tomioka, K.; Koga, K. Tetrahedron Lett. 1984, 5677. SAMP-Hydrazones in Ketone Alkylation

O N Li N OMe SAMP N LDA N N

NH2 OMe OMe SAMP Enders, 1976

Me Me O O O + H3O Me-X Me N Li N N N or O 3 Me

X = I 67 %ee 99 %ee X = OSO2Me

Enders, D. Asymmetric Synthesis, vol. 3.

Chiral Bicyclic Lactam Enolates

OH O . KMnO4 NH2OH HCl N acetone Oxidation of pinene: OH OH Carlson, R.G.; Pierce, J.K. J. Org. Chem. 1971, 36, 2319-2324. LiAlH4 Reduction of oxime: O Masui, M.; Shioiri, T. Tetrahedron 1995, 51, R1 OH O R1 8363-8370. NH2 O N H O OH p-TsOH, toluene

Me O N H O

Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711. Chiral Bicyclic Lactam Enolates

R1 R1 R1 O O R X O s-BuLi 2 R2 N N repeat: N R3 H O H OLi s-BuLi; R3X H O

R1 = H, Me, Ph exo:endo selectivities typically > 98:2 R2 = Me, Bn, allyl (except: H, Me, H 2:1 R3 = H, Me, Bn

Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711.

Aldol Reaction

O OH O OH O O + + R R HR

syn anti

Chirality can reside in:

•nuclephile •electrophile •catalyst

One of the most extensively studied reactions

Review: Heathcock, C.H. Science 1981, 214, 395. Aldol Reaction

O OH O OH O O + + RPh RPh R HPh

syn anti

R Enolate syn anti

HZ 50 50

E6535 iPr Z 90 10 Bulky R - high selectivity

E4555 Z-enolate -> syn tBu Z 98 2 E-enolate -> anti

E892

Heathcock, C.H. J. Org. Chem. 1980, 45, 1066.

Generation of E/Z-enolates

O base TMSCl OTMS OTMS

R R R

Z(O,R) E(O,R)

R base ZE Et LDA 30 70 (Me3Si)2NLi 70 30 (Et3Si)2NLi 99 1 (Me2PhSi)2NLi >100 <1

cC6H11 LDA 61 39 (Me3Si)2NLi 85 15 (Et3Si)2NLi 94 6 (Me2PhSi)2NLi 99 1

Masamune, S. Aldrichimica Acta 1982, 15, 47. Aldol Reaction

OOH O- O + * R2 R1 * R3 R1 R3 H R2

R1 L R1 H H M RE O L O RE O R3 O Possible Transition States: ML R3 RZ n RZ

Cyclic (chelated) TS Open TS

Reviews: Heathcock, C.H. Science 1981, 214, 395. Heathcock, C.H. Aldrichimica Acta 1990, 23, 99. Hoffmann, R.W. Angew. Chem. Int. Ed., Engl. 1987, 26, 488. Mukaiyama, T. Org. React. 1982, 28, 203.

Classification of aldols

! Type I – follow Zimmermann-Traxler TS ! Type II – open TS; syn-selective – enol silanes, stannanes, borates, zirconates ! Type III – open TS; anti-selective – ketene acetals and thioacetals Aldol - Zimmermann-Traxler TS

R1 L OOH H OLM R2 O R1 R3 R H 3 R2 anti ML O n H R1 R2 E(O,R)-enolate R1 L OOH R3 OLM R2 O R1 R3 H H R2 syn

Aldol - Zimmermann-Traxler TS

R1 L OOH H OLM H O R1 R3 R3 R R2 2 syn ML O n

R2 R1 H Z(O,R)-enolate R1 L OOH R3 OLM H O R1 R3 H R R2 2 anti

Li-O 1.92-2.00 Å Mg-O 2.01-2.03 Å Zn-O 1.92-2.16 Å Diastereoselectivity maximized when R1 and R3 large Al-O 1.92 Å Diastereoselectivity: B > Li > Na > K B-O 1.36-1.47 Å Ti-O 1.62-1.73 Å Zr-O 2.15 Å Aldol - Open TS

O OOH O R2 H HR2

R3 H R1 R3 H R3 R OM R1 OM R2 1

E(O,R)-enolate anti Z(O,R)-enolate

O OOH O R2 H HR2 R1 R3 H R3 R3 H R2 R1 OM R1 OM E(O,R)-enolate syn Z(O,R)-enolate

Boron Enolates

BR OTf O 2 OBR O 2 R1 R1 X R1 X X

H Re OBR BR 2 X O 2 R Z(O,R)-enolate typical outcome X 1 HSi R1

OBR HSi 2 E(O,R)-enolate can be favored: X O X R = cC H R H BR2 6 11 1 Re R1 X = tBuS

Evans, D.A. J. Am. Chem. Soc. 1981, 103, 3099-3111. Boron Enolate Mediated Aldol

B RCHO OH O O OTf B O - 78 C DIPEA R SCEt3 SCEt3 SCEt3 anti:syn 33:1 98-99.9 %ee

For a similar example, see also: Reetz, M.T. Tetrahedron Lett. 1986, 27, 4721.

Masamune, S. J. Am. Chem. Soc. 1986, 108, 8279.

Evans Aldol: Non-Coordinating Metal

L2 B O O OH O O OR ORN O N α-attack L L O O B O O O N O N

L2 B OOH O OR N R Bu N Me β-attack O O O R B O O O H Bu H N O O Explanation: opposing dipoles!

Evans, D.A. J. Am. Chem. Soc. 1981, 103, 2127. Evans Aldol - Coordinating Metal

M O O O O E+ O N O N E Si attack

Chelated Z(O,R)-enolate

O OM O OM O E+ O N N O N O Re attack E O

Non-chelated Z(O,R)-enolate

Evans, D.A. J. Am. Chem. Soc. 1982, 104, 1737.

Evans Aldol

M O O O O O O + o LDA E , 0 C O N O N O N NaHMDS E+, -78 oC E

O O O O

O N O N E Ph Ph

E = MeI, EtI, BnBr, allylBr

kinetic ratio > 94 : 6

Evans, D.A. J. Am. Chem. Soc. 1982, 104, 1737. Synthesis of MeBMT, Amino Acid in Cyclosporine

O O 1) NaHMDS 2) MeI O O N 3) LAH H O NCS 4) Swern Bn O N O

Bn

Sn(OTf)2

+ - 1) Me3O BF4 S NHMe NCS 2) H2O HN HO X*N X*N O 3) KOH O OH + O OSnL 4) H3O O

Evans, D.A. J. Am. Chem. Soc. 1986, 108, 6757.

Non-Evans syn-Aldol: Ti Enolates

L4 O O Ti O O O O N H R ON

L3 O Ti O OOH O O H R ORN ON GOMLUP

Thornton, E.R. J. Org. Chem. 1991, 56, 2489. X-ray: Hinterman, T.; Deebach, D. Helv. Chim. Acta 1998, 81, 2093. Open Transition State: Effect of Lewis Acid

LL B O O O H OOH Me O N LA ON R R O H Me

small Lewis acids syn

LL B O O R O OOH Me O N H O ON R H LA Me

large Lewis acids anti

Heathcock, C.H. J. Org. Chem. 1990, 55, 173. Heathcock, C.H. J. Org. Chem. 1991, 56, 5747. Shioiri, T. Tetrahedron Lett. 1991, 32, 7287.

All Four Aldols from a Single Precursor: Heathcock OOH Li t-Bu

TBSO

OOH B t-Bu O TBSO t-Bu

TBSO OOH Mg t-Bu

TBSO

OOH Ti t-Bu

TBSO Heathcock, C.H. J. Org. Chem. 1991, 56, 2499. Heathcock, C.H. Aldrichimica Acta 1990, 23, 99. Summary of Best Aldols

O O B-enolate syn (S1) Evans O N Ti enolate syn (S2) Thornton B-enolate + LA anti Heatcock

Ph

O B-enolate syn Oppolzer N Si-enol ether anti Oppolzer S O O

Chiral Catalysis in Aldol: Corey

OH O O H OBR * R2*BBr 2 R-CHO R O O Me OtBu Me

R2*BBr tBu Et3N SO2 O Me Ar R O+ O N R *B Me CF3 CF3 2 Ph Ph OB Ph Br H H N N N CF3 SO2 B SO2 CF3 S Br Ph Ph Ar SO2 R2*BBr

Ester enolates: anti products; thioesters: syn products

Corey, E.J. J. Am. Chem. Soc. 1990, 112, 4976. Chiral Acyloxyborolidines

"Anomeric" O

H OOH H O OSiMe anti-coordination 3 CAB B + R"CHO R' OO R' R R" O CO2H R R R' Me ROCO

OOCO H 2 O OH CO H O 2 + BH3 RR' OH O

CAB

Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 1041. X-ray HASVOM: Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 10412.

syn-Selective Boron Aldol

Bu OBBu 2 B O RO R Bu N H H H N O O approach from least O O hindered enolate dipoles? diastereoface

Bu OH O OH O O O R R B R N H H Bu O H N H N iPr O O O O Acetate aldol

o O OSiMe3 2.5 mol-% cat., -10 C OH O + RH OMe then TBAF R OMe

Aldehyde %ee: t Bu CHO Me 97 CHO 95 N Me TiO t O Bu CHO 97 O Ph CHO O O Ph 94 But CHO 95 C6H11 t Bu CHO 96 Ph

Carreira, E. J. Am. Chem. Soc. 1994, 116, 8837.

Acetate aldol

Smith, A.B. Org. Lett. 1999, 1, 909-912. Acetate aldol

o O OSiMe3 10 mol-% cat., -10 C R OH O + 2 R1O t R1O t R2 S Bu then 1 M HCl S Bu O O

R1 R2 %ee: Me O O Me 99 Bn Me 99 N N t Cu Bu Me 99 ButtBu Me Et 94 i Me Bu 94 - i 2 OTf Et Bu 36

Evans, D.A. J. Am. Chem. Soc. 1997, 119, 7893.

Cyclic enolates: anti-Selective Aldols

S S S

H OOH O OMLn OOH

MLn yield anti:syn

O B 57 19:1 H O O SnPh 3 85 10:1 O LnM SnMe3 86 24:1

i Ti(O Pr)3 84 99:1

Hayashi, T. Tetrahedron Lett. 1991, 32, 5369. Amphotericin

OH O R O MeO N H Me2N OH N

S (HO)2PO2 O S CN OH O R O R O O R OP OP O OH OH OH OH OMe O O OH

NH2 Calyculin C HO OH S S

O OOMe Me O O O

Me COOH HO O OH OH OH OH O

Me O OH OH OH

Amphotericin B

Alkylation – Towards Amphotericin B

S S S LDA, TMSCl TiCl4, PhCHO O O o o O -78 C, THF CH2Cl2, -78 C O O O OSiMe H 64 % 3 OOHO

Major product

Karisalmi, K. Tetrahedron 2003, 59, 1421-1427 Final steps

S Raney Nickel (W-2) O O EtOH, 20-70 oC H O HO OH 50 % O OH OH 6 7

Karisalmi, K. Tetrahedron 2003, 59, 1421-1427

Syn-aldol from Z-enolate

weakly 17S-directing

OMe OMe o CH2Cl2, -78 to -26 C, 16 h OBn + OBn OOOBBu2 69 %, 82 %ds OOOOH OTBDMS OOTBDMS

weakly 17S-directing

OMe OH HO

O OH O

O OH OMe

Bafilomycin A

Paterson, I. Tetrahedron Lett. 1995, 36, 175. Anti-aldols from E-enolates

t Bu OMe t O LiO Bu OMe aldol OH O + O 55 %; 19:1 ds O tBu tBu

1. Hg(OCOCF3)2 2. PdCl2, CO, MeOH, CuCl2 100 % Me Me Me Me O N O Me O O O Me AcO CO2Me O O Me O Me C1-C8 sequence of pamamycins Me

Pamamycin

Walkup, R.D.; Kim, Y.S. Tetrahedron Lett. 1995, 36, 3091.

Anti-aldol from E-enolate

t O Bu t LiO Bu OMe aldol OH O + O 64 %; 2:1 ds O tBu tBu Heathcock TH 1981, 37, 4087.

But OMe OH O Me O Me H O H tBu O Me H O Felkin-Anh H Li ArO H

Pilli, R.A.; Murta, M.M. J. Org. Chem. 1993, 58, 338. Anti-aldol for macrolide synthesis

O O O LiO OMe aldol O O OH O + O 50 % O

Me Felkin-Anh H H H H O H Me O O Me O Me Li O Me O O ArO H

Tamm, C. Synthesis 1991, 435.