Chemistry 206 Advanced Organic Chemistry Handout–23A Enolate Acylation Matthew D. Shair Monday , November 11, 2002 Tet Let . 1990 , 31 , 1401-4 JOC . 1991 , 56 , 5301-7 Chem 206 Enolate Acylation Acylation & Carboxylation D. A. Evans The Reaction: + Acylation Carboalkoxylation + Situations where the reaction is employed: a73 Acyl moiety is a constituent of the target structure: ++ (–) (+) (–) (+) a73 Acyl moiety employed in assisting bond construction but not part of the target structure: + R–X Deacylation: When an acyl residue is employed in the one of the illustrated bond constructions, it may then be removed by nucleophilic deacylation: Several examples are provided. Deformylation: HCO 3 – competitive ring cleavage not a problem due to more electrophilic formyl C=O Decarboxylation in this system is a sigmatropic rearrangement involving C=O participation Decarboxylation: a73 Alkyl-Oxygen Cleavage: tert -butyl esters NaH, DMF R–Br CF 3 CO 2 H ? –CO 2 representative procedure: Henderson, Synthesis 1983 , 996 a73 Alkyl-Oxygen Cleavage: Methyl esters Li–I/H 2 O ? H 3 O + CO 2 R = H HO – Acylketeneintermediate leading references OM R 1 R 2 XR 3 O R 2 R 1 O R 3 OO OR 3 O R 1 R 2 O OR 3 X R 2 R 1 OM R 2 R 1 OH OR 3 O O OR 3 O R 1 R 2 R 2 R 1 O XO R 3 O O O OR 3 O H R 2 X R 1 O R R H O O O O Me CO 2 Me CO 2 Me Me O Me R 2 CO 2 Me R 1 O OR 3 O O Me Me Me Me O O Me CO 2 Me Me O CHO O Me Me Me Me O O CO 2 -t-Bu CO 2 -t-Bu O R R O O OO H H O R O CO 2 -Me N Me Me CO 2 – O R O R O O– OR CO O H23-01-Acylation Intro 11/5/00 8:20 PM LDA Chem 206 Claisen Condensation & Related Processes D. A. Evansa73 Claisen Condensation: Condensation of 2 esters + RO – H 3 O + a73 Intramolecular Variant: Dieckmann Condensation H 3 O + RO – Strictly speaking, the Claisen and Dieckmann condensations are defined as condensations between ester enolates & ester electrophiles. In this discussion, we choose to liberalize the classifcation to include ketone enolates as well. a73 Reaction Thermodynamics: Overall Keq ~ 1 RO – 2 + + + RO – ROH + a73 Final enolization Step: Keq ~ 10 +4 Contrary to popular belief, final enolization step does not render the process irreversible pKa 12 pKa 16 Reaction Control Elements: NaH kinetic product Thermodynamic product -78 °C 0 °C a73 Analysis of the two processes: Conventional Carbomethoxylation: Equilibrium achieved between all species Me 2 CO 3 + MeO – + MeOH Keq ~ 10 -2 Keq ~ 10 +4 Me 2 CO 3 Keq > 10 +4 Critical issue: Product enolate A is significantly destabilized by peri-interaction with aromatic ring disrupting the required planarity of the delocalized enolate.Hence, the greater stability of B dictates the product. A B Keq >> 1 A B a73 This type of control is general: HCO 2 Et KO t Bu Meyers, JOC 1976 , 41 , 1976 Piers, Tet. Let 1968 , 583 MeO – HCO 2 Et benzene benzene HCO 2 Et MeO – JACS 1965 , 87, 5728 These reactions can be manipulated to give either kinetic or thermodynamic control: CO 2 Me R Me CO 2 Me OR O O OR R O OR O R R O Me CO 2 Me R R O OR O R R O OR R O OR O O OR O– R R O NC OMe O O CO 2 Me O OMe MeO CO 2 Me O Me CO 2 Et O OH Me Me OH O CO 2 Et Me O– O CO 2 Me CO 2 Me O– O– CO 2 Me O O–CO 2 Me O– O MeOH CO 2 Me O– O Me O Me Me O Me O Me Me OH RO – H23-02-Claisen Condensation 11/5/00 8:17 PM -78 °C fast D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 a73 Kinetic Acylation: Methyl Cyanoformate ( 1): + slow + LiCN 1 Enolate acylation with 1 is fast Intermediate 2 breaks down to product more slowly than the acylation step 2 Under these conditions, proton transferfrom product to enolate does not occur. Mander Tet. Lett. 1983 , 24 , 5425 a73 Examples: LDA 1 84% 1 LDA 65% 75% LDA 1 1 Me-Li + isomer 7% Mander, SynLett. 1990 , 169 1 R 2 Cu(CN) 2 Li 2 82% Hashimoto, Chem. Lett. 1989 , 1063 a73 The Tetrahedral Intermediate 2; Why is it so stable? 2 slow + LiCN Consider this process in the broader context of elimination reactionsof the E1cb classification where: Y might be either C or some heteroatomX might be various leaving groups such as CN, OR etc. base – slow + X – + X – slow – base Data is available for the case where X = CN, OR & Y = carbanion: Stirling, Chem. Commun . 1975 , 940-941 leaving grp (X) pKaH–X log k X k OPh –OPh 10 1<-7 9.5 –CN –C(Me) 2 -NO 2 ~10 <-9-3.9 16 –OMe + LiCN + LiOMe 2 Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! O Li OCN OMe R 1 R 2 R 2 O R 1 OMe O X FG H R FG X FG Y XY R YH X R R R 2 R R O R 1 OMe OCN Li O OMe R 1 O R 2 R 2 O R 1 CN O OO NC OMe O R 2 O R 1 OMe OCN Li CO 2 Me Me OTMS Me CMe 3 Me 3 C H R 1 OLi R 2 O OMe R 1 O R 2 Me O Me CO 2 Me O Me O CO 2 Me O Me Me O Me CO 2 Me O OTBS O CO 2 Me H23-03-Mander Reagent 11/5/00 8:21 PM Acylating agents can be desiged where the tetrahedral intermediate exhibits exceptional stability: Chem 206 D. Evans and S. MillerJ. Org. Chem. 1993 , 58 , 471. 95% THF, -78 °C DIBAl-H M. Angelastro, N. Peet and P. BeyJ. Org. Chem. 1989 , 54 , 3913. THF, -78 °C 73% P. Thiesen and C. HeathcockJ. Org. Chem. 1988 , 53 , 2374. THF/Et 2 O -110 °C to -80 °C 62% Several other examples reported. J. Prasad and L. LiebeskindTetrahedron Lett. 1987 , 28 , 1857. THF, 0 °C 99% MeMgBr R- Li or R- MgBr THF, 0 °C R = Me, n-Bu, or Ph; yields > 90% Carbon Acylation with N -Methoxy- N -methylamides J. L. Leighton, D. A. Evans Nu(-) H 3 O + Weinreb Tet. Lett. 1981 , 22 , 3815. Nucleophiles: R–Li, R–MgX Acceptable DIBAL LiAlH 4 LiB(R) 3 H Weak hydride reagents: NaBH 4 Unacceptable R–ZnX & other colalent metal alkyls other colalent metal enolates An excellent review on all aspects of Weinreb amide chemistry: M. Sibi, Organic Preparations and Procedures Int. , 1993 , 25 (1) , 15-40. Representative Organometals: H 3 O + Hydride Reductions: R 1 –M H 3 O + H 3 O + R 2 –M W. Wipple, H. ReichJ. Org. Chem. 1991 , 56 , 2911-2. THF, -78 °C THF, -78 °C to R. T. J. Org. Chem. 1989 , 54 , 4229. Enolates and Metalloenamines: 83% 47% R L i(MgX) RO OLi R' N O Me OMe LiN R Li Ar S O R' R O O CH 2 Li OEt BrMg NOMe O N MeO Me OLi R Me NOMe O N O Li Nu RN O Me OMe R Me Me R Nu O N O Me OTBS N O OMe Me Ar N O Me OTBS Me O O R 1 Ar MeO 2 C N Me O OR OMe MeO 2 C P (OMe) 2 O OR O Li P(OMe) 2 O CbzHN N Me Bn O OMe CbzHN OEt Bn O Me N OMe Me OMe Me TBSO Me O 2 N OMeOMe Me O OMe OMe Me H OMe Me OMe Me TBSO Me O 2 N OMeOMe Me O OMe O t -Bu OLi O O t -Bu O R 1 R 2 O N O Me OMe OLi Me OO Me H23-04 Weinreb Amides-1 11/5/00 8:22 PM tetrahedral intermediate stable for hours at 0°C Problem is to control C=O reactivity on central D-fragment 35 30 28 21 F D 29 21 D F 17 28 Evans, Rieger, Jones, Kaldor, JOC , 1990 , 55 , 6260-6268 C 28 –C 29 C 20 –C 21 29 29 29 The Rutamycin B Synthesis, H. Ng, Ph. D. Thesis, Harvard University, 1993 Evans, Bender, Morris J. Am. Chem. Soc. 1988 , 110 , 2506. The Solution: Et 2 O, -78 °C LDA, 0 °C 83% The X-206 Synthesis, S. L. Bender, Ph. D. Thesis, Harvard University, 1986 MOP = 1 A + 7 16 17 21 C 1 -C 16 Subunit C 17 -C 37 Subunit A B C D E F 1 7 15 21 27 35 A D F 35 27 F E D 12 15 21 27 30 35 7 11 11 1 Carbon Acylation with N -Methoxy- N -methylamides-2 J. L. Leighton, D. A. Evans Chem 206 several steps 25 5 1 8 17 12 33 20 HF MeCN-H 2 O 80% 23 32 26 20 LDA 23 20 26 32 97% 26 20 26 32 80% 32 Me N NMe 2 Li Me Me H OMOP Me Me Me O O O O X O Me OBn H Me Me O N NMe 2 Me O H Et O H M Me O OH Me OH Me Me Me Et PMBO Me TESO O N Et OMe Me Et PMBO N NMe 2 H Me Me OO Me O O H O Me OH O O Me OH Me TESO Me O O O OO O Me OH Me Me Me HO Et Me OH Me OH OH Me Me OH Me Me OH O Me Me OMe Me H Me OH Et O O O O OH OR O Me OR Me Me OR Me Me O H O O Me Me OO O O OH Me Me Me OH Me Me O Me OH OH OH O O Et OH Me H Me OH Me Me H H Li O Me Me H H Me H O Me HO Me OH Me Me Et HO H Me Et PMBO Me O H Me I Me O Me O Me Me O O H H Me Me CH 2 Me N Me O O N MeNMe 2 MeO OMOP H Me H Me Me CH 2 Me O Li O O N MeNMe 2 MeN OMOP H Me H Me Me CH 2 Me O O O O OMOP H Me Et Me H Me Me NH OBn NMe 2 O Et Me H OBn Me O Me C MeMe OMe HO Me Me Me O O O O H H23-05-Weinreb Amides-2 11/5/00 8:25 PM E. Knott J. Chem. Soc. 916 (1955) The Thioamide component: Reagents P 4 S 10 JOC 46, 3558 (1981), Synthesis 149 (1973) Lawesson's Reagent Bull. Chim. Soc. Belg. 87, 229 & 293 (1978) P 4 S 10 , Et 3 N or NaHCO 3 Indian J. Chem., Sect. B 14, 999, (1976)JACS 102, 2392 (1980) RCS 2 R' + R 2 NH Thioamide Imidate +H 2 S Thioamide Chem. Ind. (London) 803 (1974)Angew. Chem. 79, 865 (1967) R 3 P=S R 3 P The Solution: ? (+) (–) The Problem: ?? (–) (+) (–) (+) (–) (+) ?? A. Eschenmoser Science 196 , 1410 (1977) Key Bond Construction Needed for the B12 Synthesis: ? Key papers: Review: Trost Comp. Org. Synth. Vol. 2, Ch. 3.7 (1991) A. Eschenmoser Helv. Chim. Acta. 54 , 710 (1971) A. Eschenmoser Angew. Chem., Int. Ed. Engl. 6 , 866 (1967) A. Eschenmoser Angew. Chem., Int. Ed. Engl. 8 , 343 (1969) Base, Thiophile The General Reaction: Acylation of an Amide C=O D. H. Ripin, D. A. Evans Chem 206 The Eschenmoser Coupling Reaction RN X R 3 S R’ R” O N R” R’ R R 3 O N N H N O OMe Me (CH 2 ) 2 CO 2 Me O Me N H N HO N H (CH 2 ) 2 CO 2 Me Me Me O O NH O RN O R’ R” N R” R’ S (CH 2 ) 2 CO 2 Me R P S P Me Me O N Me H (CH 2 ) 2 CO 2 Me (CH 2 ) 2 CO 2 Me Me Me O N R Me Me O N O H N H N O OMe Me R 3 Me Me R 3 Me R 2 Me R 3 O R 2 Me R 2 N NH N H N O N H N H N N H S NHN Me MeO 2 CCH 2 Me MeO 2 CCH 2 O (CH 2 ) 2 CO 2 Me Me MeO 2 CCH 2 C S N Me N H N S N X S S S p-MeOPh PhOMe H H23-06-Eschenmoser-1 11/5/00 8:27 PM Under equilibrating conditions (B1) appears to be preferred over (B2) Not observed Enolates (B1) and (B2) both more stable than enolate (A) Enolization at (A) preferred on basis of inductive effects. Hence,Path A preferred in kinetically controlled situation Explanation: Thermodynamic Control? Kinetic Control? B B 2 NaOEt/EtOH NaOEt/EtOH A NaH/C 6 H 6 Davis & Garratt, Comprehensive Organic Synthesis 1991 , 2 , 806-829 AB 1 ( ) n Reviews: The Dieckmann Condensation Regioselectivity: Chem 206 Intramolecular Enolate Acylation–Dieckmann Condensation D. A. Evans and P.H. Carter Schaefer, Bloomfield, Organic Reactions 1967 , 15 , 1. ( ) n not viable excellent excellent acceptable situation dependent high dilution required Accesible Ring SizesThe individual steps: + EtO – Enolization: + base + base-H A variety of bases may be considered for the enolization step. Either alkoxide or a non-nucleophilic base such as NaH are commonly used. Choice of base can be important (Vide infra). Ring Closure: + EtOH Keq (enoliz) Keq (cycliz) ~ 1 Keq (enoliz) ~ 10 +4 Statements claiming that the final enolization step renders the process irreversible are simply incorrect. NaOEt EtOH ? KOtBu / PhH R.H. Schlessinger, et al. Heterocycles 1987 , 25 , 315. NaOEt / EtOH The effect of beta heteroatoms: classical kinetic vs. thermodynamic control ?? EtO 2 C CH 2 CO 2 Et ONa N ONa CO 2 Et MeOMeO CO 2 Et CO 2 Et CO 2 Et N OH N OH CO 2 Et EtO O – OEt O O OEt O – EtO O – O CO 2 R O CO 2 R O CO 2 R O CO 2 R O CO 2 R CO 2 R O CO 2 RC O 2 R CO 2 Et CO 2 Et EtO 2 C CO 2 Et ONa CO 2 Et CO 2 Et EtO 2 C O OEt O EtO 2 C EtO CO 2 Et O CO 2 Et CO 2 Et H23-07-Dieckmann-1 11/5/00 8:29 PM S-Ylids Thioethers carbenes + : –+ ? Ra-Ni, 68% Rh(OAc) 2 + ii NaOH S. Danishefsky Tet. Lett. 30 , 3625 (1989) 99% * 79% DBU NaHCuBr T. Kametani J. Chem. Soc., Perkin Trans. I 1607 (1980) mix Et 3 N, PPh 3 H. Rapoport J. Org. Chem. 46 , 3230 (1981) 64% t -BuOK t -BuOH, 25 °C P(CH 2 CH 2 CN) 3 , TFA, sulfolane A. Eschenmoser Science 196 , 1410 (1977) This center readilyepimerizes to a 2:1mix of diaster. in favor of the shown. b) P(OEt) 3 , Xylene, ? a) 1.05 eqiv. (PhCOO) 284% (+) H. Rapoport J. Org. Chem. 46 , 3230 (1981) A. Eschenmoser Helv. Chim. Acta. 54 , 710 (1971) Bases:Inorganic: MHCO 3 , MOH, MH, MOR Organic: R 3 N, N-methylmorpholine, buffered solutions Thiophiles: Ar 3 P, R 3 P, (RO) 3 P Combination: 22 The Eschenmoser Coupling Reaction-2 Chem 206 D. H. Ripin, D. A. Evans Reagents for the Reaction: PhP NMe 2 N PhP O NBn t -BuO 2 CS TfO Me CO 2 Bn O O t -BuO 2 C NBn Me OO CO 2 Bn NH MeN OAc S Br CO 2 Me Ar CO 2 Et MeN CO 2 Et OAc NH CO 2 Me Br OMe Me N MeO Me CO 2 Me OAc NMe EtO 2 C N 2 HN O S CO 2 t -Bu N CO 2 t -Bu O CO 2 t -Bu N S O N 2 S N –O CO 2 t -Bu O CO 2 t -Bu N S S R S R N H N O OMe Me (CH 2 ) 2 CO 2 Me O Me (CH 2 ) 2 CO 2 Me Me Me O S NH O (CH 2 ) 2 CO 2 Me Me Me O N Me H (CH 2 ) 2 CO 2 Me (CH 2 ) 2 CO 2 Me Me Me S N R Me O N O H N H N O OMe Me R 3 Me Me R 3 Me R 2 Me R 3 O R 2 Me R 2 N NH NHN MeO 2 CCH 2 Me MeO 2 CCH 2 O (CH 2 ) 2 CO 2 Me Me MeO 2 CCH 2 Me Br R R R C RRR H23-08-Eschenmoser-2 11/5/00 8:27 PM Kocienski and Co-workers, Tet. 1990 , 46 , 1716 -78 °C LDA D. A. Evans and P.H. Carter Intramolecular Enolate Acylation–Dieckmann Condensation Chem 206 8:1 mixture Peterset, Recl.Trav.Chim.Pays-Bas 1977 , 96 , 219. R.Danieli, J.Org.Chem. 1983 , 48 , 123. J.L. Adams, J.Org.Chem. 1985 , 50 , 2730. tBuOK / PhH LDA NaH DMSO Miscellaneous Dieckmann Reactions of Potential Interest G.Stork and Co-workers, J.Am.Chem.Soc. 1960 , 82 , 4315. NaOEt Et 2 O Deduce the mechanism of this multistep process. T.M. Harris and Co-workers, J.Org.Chem. 1984 , 49 , 3681. no loss ofstereochemicalintegrity H.-J. Liu and Co-workers, Tet.Lett. 1982 , 23 , 295. KH, THF NaH Intramolecular Ketone Acylation S.Brandawge and Co-workers, Tet.Lett. 1992 , 33 , 3025. When X = NR 2 , this is a good reaction, but when X = OR, it is a poor reaction. (TMS) 2 NLi THF, -78 o C EtO 2 CR CO 2 Et SEt O R CO 2 Et EtS CO 2 Et SC O 2 Et N TMS tBOC S OTMS OEt (tBOC)HN CO 2 Et X X Me CO 2 Et CO 2 Et Me Cl O CO 2 Et Me O CO 2 Et H Me O CO 2 Et O Me Me Me CO 2 Et O Me O Me Me Me O O H N O Me TsHN CO 2 Et H HN TsHN OO R O Cl O Me O Me O Me O X O Me Me O HO OMe Me O Me O O OMe OMe H23-09-Dieckmann-2 11/5/00 8:30 PM D. A. Evans and P.H. Carter Intramolecular Enolate Acylation–Dieckmann Condensation Chem 206 Kinetically controlled Cyclizations LDA Heterocycles , 1987 , 25 , 315 Li-TMP 60-70% JACS , 1979 , 101 , 5060 Li-NTMS 2 Tet. Let , 1981 , 22 , 3883 Li-NTMS 2 3 equiv Hatanaka, Tet. Let , 1983 , 24 , 4837 NaH MeOH 6-demethyl-6-deoxy-tetracycline Woodward, JACS , 1962 , 84 , 3222 78% Li-NTMS 2 3 equiv Brandange, JOC , 1984 , 49 , 927 DMSO – 41% Danishefsky, JACS , 1973 , 95 , 2410 41% EtO – Prostaglandin E2 Sih, JACS , 1975 , 97 , 865 Multistep Condensations CO 2 Me OMe N CO 2 Me N CO 2 Me Me CO 2 t Bu CO 2 Me Me R CO 2 Me CO 2 Me R Me O CO 2 Me N N O CO 2 Bn O H COSPh H O CO 2 Bn CO 2 t Bu N O H PhOCH 2 CONH H COSPh H PhOCH 2 CONH N H O CO 2 t Bu OH O MeO 2 C O CO 2 Me MeO 2 C CO 2 Me O Cl MeO O Cl MeO O CO 2 Me OH OH CO 2 Me MeO 2 CC O 2 Me O OH OH O OH NMe 2 OHCONH 2 O HO CO 2 Me HO O OLi O C OMe O CCCO 2 Me H LiO H CH HO C O COMe H CO 2 Me CO 2 Me MeO 2 C OO O CO 2 Me CO 2 Me HO O OH CO 2 Me EtO 2 CC O 2 Et O Me H23-10-Dieckmann-3 11/5/00 8:31 PM tetrahedral intermediate stable for hours at 0°C Problem is to control C=O reactivity on central D-fragment 35 30 28 21 F D 29 21 D F 17 28 Evans, Rieger, Jones, Kaldor, JOC , 1990 , 55 , 6260-6268 C 28 –C 29 C 20 –C 21 29 29 29 The Rutamycin B Synthesis, H. Ng, Ph. D. Thesis, Harvard University, 1993 JACS 1993 , 115, 11446-11459. Evans, Bender, Morris J. Am. Chem. Soc. 1988 , 110 , 2506. The Solution: Et 2 O, -78 °C LDA, 0 °C 83% The X-206 Synthesis, S. L. Bender, Ph. D. Thesis, Harvard University, 1986 MOP = 1 A + 7 16 17 21 C 1 -C 16 Subunit C 17 -C 37 Subunit A B C D E F 1 7 15 21 27 35 A D F 35 27 F E D 12 15 21 27 30 35 7 11 11 1 Synthetic Applications of Metalloenamine Nucleophiles D. A. Evans Chem 206 several steps 25 5 1 8 17 12 33 20 HF MeCN-H 2 O 80% 23 32 26 20 LDA 23 20 26 32 97% 26 20 26 32 80% 32 Me N NMe 2 Li Me Me H OMOP Me Me Me O O O O X O Me OBn H Me Me O N NMe 2 Me O H Et O H M Me O OH Me OH Me Me Me Et PMBO Me TESO O N Et OMe Me Et PMBO N NMe 2 H Me Me OO Me O O H O Me OH O O Me OH Me TESO Me O O O OO O Me OH Me Me Me HO Et Me OH Me OH OH Me Me OH Me Me OH O Me Me OMe Me H Me OH Et O O O O OH OR O Me OR Me Me OR Me Me O H O O Me Me OO O O OH Me Me Me OH Me Me O Me OH OH OH O O Et OH Me H Me OH Me Me H H Li O Me Me H H Me H O Me HO Me OH Me Me Et HO H Me Et PMBO Me O H Me I Me O Me O Me Me O O H H Me Me CH 2 Me N Me O O N MeNMe 2 MeO OMOP H Me H Me Me CH 2 Me O Li O O N MeNMe 2 MeN OMOP H Me H Me Me CH 2 Me O O O O OMOP H Me Et Me H Me Me NH OBn NMe 2 O Et Me H OBn Me O Me C MeMe OMe HO Me Me Me O O O O H H23-11-met-enamine acylation 11/4/01 10:08 PM a73 The Ferensimycin B Synthesis, JACS 1991 , 113, 7613-7630 Synthetic Applications of Metalloenamine Nucleophiles D. A. Evans Chem 206 Ferensimycin B A C B A BC HO O Me OH H MeMe Me O OH O Me O Et O Me Me Me OH Et Et OH H O Me Me OO Et HO O Me OH H Me OH Me OH Me OH Me Et Me HE t O a73 The B–C Fragment ( C 10 -C 23 Synthon ) C 10 -C 23 Synthon 18 18 B B B C (–) 18 H OH Et Et OH Me Me Me O Et O Me O O Me O Et Me Me O Me Et Et OH OH H H O Me X Me Me Et O Me O Et Et OH 11 11 11 The C-11 ketone must be protected during the C-18C-19 bond construction Et 2 O Et-Li 17 B THF Et 2 NLi 21 21 11 18 C B BC 18 11 21 NaHSO 4 H 2 O C 18 diastereoselection 9 : 1 (48%) 21 11 18 C B B 18 BC C Bepi-C 18 6 PPTS MeOH PPTS MeOH 18 18 N NMe 2 O Me Me–N Li O H Me Me Me Et O Me O O Et Et Mg Br NMe 2 NH O Me O Et O Me Me Me Et Et OH H Me H OH Et Et OH Me Me Me O Et O Me OO Me O Et O Me Me Me OH Et Et OH H O O Et Me Me N Me H Li O Me–N Me NMe 2 O Et Me O Et Me O Me Et Me H O O O H Me Et Me O Me Et Me Et O Li 18 B H Me N Me Me Et O NMe O 11 a73 The In situ protection of the C–11 Carbonyl MeO NMe 2 R–M 17 B N NMe 2 O Me Me–N Li O H Me Me Me Et O R carbonyl-protected intermediate 18 B H Me N Me Me Et O NMe O 11 MeO NMe 2 H23-12-Ferensimycin construct 11/4/01 3:32 PM