Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020 Malonate Enolates : Oldest reported enolate alkylation of epoxides: - well established nucleophiles - some consider one of the “backbones of organic synthesis” O O CO Et Epoxides: EtO OEt 2 - well established electrophiles (polar, strained ring) O Na / EtOH CO2Et - many ways to make enantioselectively (Sharpless, Shi, Jacobsen, etc.) reflux OH And yet… 70-75% yield

J. Am. Chem. Soc. 1942, 64, 11, 2606–2610 “In spite of their intrinsic synthetic potential, addition reactions of metal enolates of non-stabilized esters, amides, and ketones to O O epoxides are not widely used in the synthesis of complex molecules.” H CO2Et EtO OEt H - Paolo Crotti and Mauro Pineschi Na / EtOH CO Et Aziridines and Epoxides in Organic Synthesis O 2 reflux OH H H Things to keep in mind: 94% yield

- Ketone and ester enolate alkylations of epoxides often require J. Am. Chem. Soc. 1961, 83, 3, 606–614 various additives, whereas standard amide enolates (more stable, more nucleophilic) and malonic enolates tend to readily Cyclobutane formation: undergo alkylation. O OMe Pd(dppe) - Ketone enolates can equilibrate, and ester enolates can O 2 CO2Me CO2Me fragment to ketenes/alkoxides. OMe CO2Me CO2Me - Stable enolate = good alkylation O HO HO

4:1 syn:anti General Scheme 70% yield O OM OH R3 Tet. Lett. 1995, 36, 14, 2487–2490 O S 2 O N O Lactam formation: OR4 R1 R R R 3 EtO O C H OH R 2 2 cat. NaOEt 6 13 1 R3 R2 OR4 R3 O R N O EtOH EtO2C rt, overnight N O EtO2C C6H13 O OEt R Some good reviews: Tetrahedron, 2000, 56, 9, 1149-1163. R = H 78% yield Aziridines and Epoxides in Organic Synthesis See also: Chem. Lett. 1983, 169-172 R = Me 93% yield edited by Andrei K. Yudin Bul. Chem. Soc. Jap. 1984, 57, 8, 2135-2139. Tetrahedron 1996, 52, 29, 9909–9924 1 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Industry Adventures with Malonates

O 1. Me3SiCH2MgCl O 2. BF3·OEt2 O O 3. Boc2O O BocHN 4. mCPBA or MMPP BocHN BocHN R BocHN H R R Ar Ar 4:1 d.r. OH R Peptide analog synthesis: H O O - can access all 8 stereoisomers N 5 2 - facile R group variability EtO OEt R O Na/EtOH

O O SMe Epoxide Synthesis BocHN H2C 2 BocHN O O H - retention of stereo. -separable diast. O O RX Bn Bn CO2Et BocHN BocHN CO Et R 2 Merck: J. Org. Chem. 1985, 50, 23, 4615–4625 Ar Ar

Merck L-685,434 Analogs LiOH HIV protease inhibitors R2

OH OH H BocHN N O O O Δ O O CO2H BocHN BocHN R R R 1 Ar Ar

O OPG R can equilibrate undesired O diastereomer with base L-685,434 BocHN OH Analogs BocHN R O Ar Ar J. Med. Chem. 1992, 35, 10, 1685–1701 J. Med. Chem. 1992, 35, 10, 1702–1709 2 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Ketones Abbott A-792611 HIV Protease Inhibitor Early work: imine salt workaround N O OTMS OM Me O OH O tBu OH O

NHCO2Me Me N N BnN H O tBu M = Li, MgBr “low to moderate yields”

O O M O O Me O O EtO OEt N O Cy N OH BocHN NaOEt Cy then BocHN CO Et EtOH, 0 °C 2 HOAc Me Bn Bn commercial M = Li, MgBr 75% yield enantiopure 78% yield 1:1 d.r. J. Org. Chem. 1975, 40, 20, 2963–2965 Br Seminal report: Schreiber’s total synthesis of (±)-recifeiolide

N LDA NaOEt O Me EtOH, 0 °C , AlMe3 N OH O Et2O,—78°C O O 80% yield 96% brsm O O LiOH, CO2Et O then AcOH BocHN BocHN Bn Bn

O 82% yield over 2 steps N 5:1 d.r. Me O recrystallization (±)-recifeiolide 97:3 d.r. J. Org. Chem. 2006, 71, 5369-5372 J. Am. Chem. Soc. 1980, 102, 6163-6165 3 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020 First published method: Paolo Crotti’s time to shine “But wait - there’s more!” -Crotti, probably Li O LHMDS O O LHMDS LiO R2 THF R Me R1 1 R2 O R1 R1 R3 Li O O

R1 OH [M] cat. Me O LiClO 4 R1 [M] cat. R2 R2 THF O 24-72 h, 25-50°C O OH R2

Me R1 Epoxide R1 Additive α attack % β attack % Yield % Ph

R1 OH O O tBu LiClO4 <1 >99 98

Me Ph LiClO4 <1 >99 86 O OH R2

Me R1 LiClO Ph O tBu 4 80 tBu — 17 R1 OH O

Ph LiClO4 95 Ph — 12 Superier catalyst was determined to be 10 mol % Sc(OTf)3 (78-95% yield). Unfortunately, method has poor diastereoselectivity. <1 >99 90 Slight syn preference - best syn:anti w/ Y(OTf) 60:40. tBu LiClO4 3 <1 >99 Other catalysts screened: O tBu — 30 Y(OTf)3, Ti(Cp2)(OTf)2, Zr(Cp)2(OTf)2, Ph4SbOTf, Yb(camph)3 PhO <1 >99 Moral of the story: Ph LiClO 76 4 Lewis acids allow for milder epoxide enolate alkylation conditions. <1 >99 Ph — 15

tBu LiClO4 9 91 95 O tBu — 9 91 30

Ph Ph LiClO4 12 88 80 Ph — 0 Tet. Lett. 1991, 32, 51, 7583-7586

Crotti later discovers that Y(OTf)3 promotes reaction in almost quantitative yields with milder, shorter reaction conditions (0°C - r.t., 18 hr). - Same substrate scope has yields (80-99%), * Worse α:β selectivity observed w/ styrene oxide R1 = tBu - 40:60, R1 = Ph - 85:15 Tet. Lett. 1994, 35, 29, 6537-6540 J. Org. Chem. 1996, 61, 9548-9552 4 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Intramolecular Ketone Enolate Alkylation Stereochemical studies:

4,5-epoxy ketone O O OLi Sc(OTf)3 LHMDS 20 mol% Ph Ph Ph O O R R R OH R Yield

H 94% Me 86%

6,7-epoxy ketone O LHMDS, O OH Sc(OTf)3 OH O Ph Ph Syn diastereomer = kinetic product. Equilibrating pure syn or anti product with KOH at r.t. for 2 days O R Ph R R gives 2:3 ratio of syn:anti diastereomers. Use of NaHMDS instead of LHMDS increases yield but severely A B diminishes diastereoselectivity.

*with 5,6 epoxy ketones, reaction R Yield A:B described as “unexpectedly Use of enones over ketones improves stereoselectivity. inefficient” yielding only a H 98% 84:12 complex mixture of products Me 92% 80:0

Tetrahedron. 1999, 55, 18, 5853-5866

A modern building block H O HO O 1. LiHMDS, THF, DME H

2. , BF ·OEt O 3 2 H

–78 °C, 0.5 hr 80% yield 89:11 dr

Tet. Lett. 2000, 41, 49, 9655-9659 J. Org. Chem. 2003, 68, 8, 3049-3054 5 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Enones Esters

H Aluminum enolates enable this transformation. O HO O O OtBu 1. LiSnMe H 3 O OLi OH 2. , BF ·OEt O 3 2 H SnMe OtBu PhMe, r.t. 3 12 hr –78 °C, 5 min 8% yield

O OtBu O OLi OH H Et2AlCl O H O HO O Pb(OAc)4, CaCO3 OtBu PhMe, –40 °C to r.t. 6 hr C H , reflux 68% yield H 6 6 H J. Org. Chem. 1976, 41, 9, 1669–1671 SnMe3 50% overall yield Monocyclic epoxides - Stephen Taylor

O 1. Li base R OH Method works for both 1- and 1,2 substituted epoxides and 2. Et2AlCl 3. O 6- and 7-membered enones. tBuO R’ Substrate scope yields range from 31 to 51%. O Synthetic equivalent of n+3 homologous Baeyer–Villiger oxidation R OtBu R'

Three Step Total Synthesis of (±)-Phoracantholide

O O Me O Me H2 1. LiSnMe3 (Ph3P)3RhCl O O then O

Me (±)-phoracantholide BF ·OEt 3 2 45% yield –78 °C, 1 hr 2. Pb(OAc)4, CaCO3

*<1% product w/o Et2AlCl 6 Tet. Lett. 2000, 41, 49, 9655-9659 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Monocyclic epoxides cont. Failure of the ester-enolate alkylation:

Other lessons learned: Total synthesis of marine diterpenoids (+)-dictyoxetane and (+)-dolabellane V R' H - Low temp. minimizes Claisen condenation pdts HO Me - Al NOT activating epoxide (no Markovnikov pdt) Me Me - N of LHMDS coordinates less strongly to Al as LDA Me Me H - HMPA cosolvent presumed to coordinate with Al; does biosynthesis O H H not improve selectivity with LHMDS O Et2AlO OtBu - α-substitution of ester has higher yields w/ LDA, but no α-substitution has higher yields w/ LHMDS HO H O HO H Me Me Me Me E enolate predominates Me Me syn preference J. Org. Chem. 1989, 54, 2039-2040 J. Org. Chem. 1993,58, 7304-7307 (+)-dolabellane V (+)-dictyoxetane Oxazolidinones O O Ph Ph Paternó-Büchi 1. KHMDS O O 2. Lewis acid N 3. N Me O HO Me H Alloc tBu Alloc tBu Me Me OR 82% yield O Lewis Acid Equiv Yield H O H O HO H TiCl4 3.3 0% CO2Me Me Me Me Bu2BOTf 2.2 0%

BF3·OEt2 2.2 29% Me Al 46% 3 2.1 OTBDPS Et AlCl 36% Me Me 2 1.1 Me Me H conditions Et2AlCl 2.1 69% O Et AlCl O 2 3.1 49% Tet. Lett. 1994, 35, 48, 8977-8980 H OMe OTBDPS O Spirocyclic Lactone Synthesis O

OAlEt2 O O O Bases: LHMDS, KHMDS, LDA, NaH, KH, OtBu HO OtBu TsOH O Lewis Acids: TMSCl, Ti(OiPr)4, Et2AlCl, AlCl3, TiCl4

n Only product (trace) was intermolecular Claisen condensation product. n n Halohydrin formation observed with AlCl3 and TiCl4. n = 1-4 62-76% yield 81-99% yield Synthesis 1988, 1009 Chem. Eur. J. 2016, 22, 15125-15136 7 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020 in situ lactonization ‘Activated’ amides with HMPA Amides 4 M HCl Li, HNEt , Early reports 2 80-90% yield then O O R O O O R1 O 1 1. NaNH2/NH3 R2 Me HO Me Me HO Me R2 O Et N N Me N N 2. O HMPA, C H 6 6 R R Me R R R Me Me Me 1 2 Me Me Me R R = H, 56% yield R = Me, 35% yield R1 R2 Amide Lactone H Me 72% yield 22% yield Me Me 51% yield 5% yield O O 1. NaNH2/NH3 OH Can. J. Chem. 1977, 55, 266-273 Me N 2. O Me N Secondary amides and a Lewis acid assist O 54% yield O OLi Me O Ph nBuLi Ph Lewis Acid HO Ph Me N N N Chem. Ber. 1972, 105, 1621-1633. H Li Me H

O LDA O Lewis Acid BF3·OEt2 SnCl4 TiCl4 Et2AlCl none O then HOAc Me Me Me Me N N Yield 80% 64% 61% 53% 10% Me THF, reflux Me OH Me Synth. Commun. 1988, 18, 1159-1165 85% yield Diastereoselctivity improves with bulky epoxides and amides. …and a very quick solvent “screen.”

O LDA OH O O O O then HOAc R nBuLi R R Me Me 2 1 2 Me N O Et N N THF, reflux N R1 R OH Me R Me Me 2 2 57% yield R1 R2 Solvent syn:anti Me iPr THF 63:37 J. Org. Chem. 1977, 42, 10, 1688–1690 Me iPr Et2O 74:26

Ph iPr Et2O 90:10 Best yields observed with 1- and 1,1-substituted epoxides. J. Org. Chem. 1981, 46, 2831-2833 8 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Myers: diastereoselectivity with pseudoephedrine amide enolates

O H

R RM RL RS “matched” case simplified Syn product formation is highly selective, J. Org. Chem. 1996, 61, 2428-2440 wheras anti product formation is not. Further reading on enolate facial selectivity: Tet. Lett. 1988, 29, 4245 Tet. Lett. 1994, 35, 673 Carboxylic Acids

OH OMe O O O CO2Me O + + + O O H H O TMSO OH O vernolepin vernomenin First time the ‘Danishefsky diene’ was used by the group.

OLi O OH O OH OLi O Nu O O O O O O OH Nu then CH2N2 O H O H O OH CO2Me O O axial attack from OH 56% yield concave face

J. Am. Chem. Soc. 1976, 98, 10, 3028–3030 J. Am. Chem. Soc. 1977, 99, 18, 6066–6075 9 Ciara M. Ordner Enolate Alkylation of Epoxides June 5, 2020

Danishefsky cont. - oxygen directing groups Spirocyclic lactone synthesis

Syn oxy-functionality OLi Model System OLi OR OR Me OR OLi O ONa OH Me Me Me OH 55 °C, 15 hr O THF O O O 40°C, 18 hr O O A B 91% yield

R A : B - HMPA did not improve yields or reaction homogenatiy - acidic workup yields lactone H 3 : 1 - dianions can have solubility problems (large excess often used) TMS 1 : 3.2

Anti oxy-functionality OLi O Me O OLi OR OR Me Me ONa O Me OR Me OLi Me O 55 °C, 15 hr THF O O 40°C, 18 hr O O MeO MeO A B 82% yield

R A : B O H 3.2 : 1 OLi Me O Me TMS 1 : 4.5 Me Me ONa Me O Me

O THF Dianion openings are affected by alpha-oxy-functionality, 40°C, 18 hr not by relative stereochemistry. O O O 73% yield J. Org. Chem. 1977, 42, 2, 394–396 10