Total Synthesis of (+)-Pleuromutilin

Neal J. Fazakerley, Matthew D. Helm

and David J. Procter

University of Manchester UK Chem. Eur. J. 2013, 19, 6718–6723

O

OH

OO

OH

H

2

Introduction – Pleuromutilin

3

•  Fungal secondary metabolite (+)-Pleuromutilin was first

isolated from Clitopilus passeckerianus in 1951 by

Kavangh and co-workers

•  Antibacterial acitivity through a novel mode of action

involving binding to the prokaryotic ribosome

•  First enantiospecific total synthesis of natural compound

by David Procter

•  Two racemic synthesis by Gibbons (JACS 1982) and

Boekman (JACS 1989)

•  Two elegant routes to the trycyclic core by Zard (Org.

Lett. 2003) and Sorensen (Chem. Commun. 2011)

Introduction – Pleuromutilin Analogues

4

•  Analogues derived by semi-synthesis from pleuromutilin, including tiamulin (2; Denegard® by Novartis Animal Health) and retapamulin (3; Altargo® by GlaxoSmithKline)

O

OH

OO

R

H

1, R = OH

3, R =

2, R =S

N

N

S

à Abstract of INN register (International Nonproprietary Names) by WHO

Key Step of Racemic Total Synthesis by Boeckman and co-workers

5

Sterically demanding oxy-Cope re-arrangement of tricyclic vinyl carbinol which could arise via a stereoelec- tronically controlled 1,6-addition/alkylation of a suitable derivative of dienone

R. K. Boeckman et al. J. Am. Chem. Soc. 1989, 111, 8284.

OHbase O- O- O

99%

racemic Pleuromutilin

O

OTs

Route to Tricyclic Core of Pleuromutilin by Samir Z. Zard

6

CO2H

CO2Et CO2Et

O SePh Radical InitiatorSnBu3

H

CO2Et

O

OO

OS

S

OEt

Radical Initiator

OO

O

SS

EtO

O

OH

OO

OH

H

O

OOH

OHO

Org. Lett. 2003, 5, 325-328.

Retrosynthetic Analysis

7

O

OH

OO

OH

HORHRO

O

MeO2COHHHO

OR

CO2MeO

ORO

O

1

3

911

12

14

65

Synthesis of the Cascade Cyclisation Substrate

8

(a) S. L. Schreiber J. Am. Chem. Soc. 1980, 102, 6163.

O

ref. (a)

O

1) TBSO MgBrCuCN 2LiClthen TMSCl

2) Pd(OAc)2, O2

85% (95% ee, chiral HPLC)

OTBSO

TBSO

TMS

3) CuI then Comins' reagent 85%

MgBrTMS

4) Pd(OAc)2, PPh3, Et3N, MeOH, DMF, CO 85%

CO2Me

d.r. 2.5:1TBSO O

BF3 Et2O

TBSOCO2Me

TBSO OH

d.r. 1:1

OCO2Me

OPivO5) PivCl, DMAP6) HF7) DMP

88% for 3 steps73%

d.r. 2.5:2.5:1:1

4)

SmI2-mediated Cyclisation Cascade

9

OCO2Me

OPivO

SmI2 (2.5 equivalent)

88%

MeO2C OHHHO

OPiv

HO

OMe

OPivO

O

H

SmIIIO

OPivO

OOMe

SmIII SmIIIO O

OPiv

H

O OMeSmIII

anti radical cyclisation selective enolate formation chelation-controlledaldol-cyclisation

Procter et al. ACIE 2009, 48, 9315.

Protection/Deprotection, Reduction of Double Bond

10

MeO2C OHHHO

OPiv1) TBSOTf

MeO2C OTBSHTBSO

OPiv

76%

d.r. 2.5:2.5:1:1

2) LiAlH4, rt3) DMP

63%

MeO2C OTBSHTBSO

O

(> 98% ee, chiral HPLC)

4) Pd/C, H2

MeO2C OTBSHTBSO

O

d.r. 3:1, but major was isolatedin 75% yield

Reduction of C5 Methyl Ester

11

Reduction of hind. esters with SmI2: D. J. Procter Chem Commun 2011, 47, 10254.

MeO2C OTBSHTBSO

O

MeO2C OTBSHTBSO

O

O ethanediol, HC(OCH3)3, amberlyst 15 (cat.)

99%

1)

2)LiAlH4reflux

OHHHO

O

O

HOOTBSHHO

O

O

HO

3)MeO OMe

, CSA4) TBSOTf5) PPTS

54% for 4 steps

1st generationMeO2C OTBSHTBSO

O

MeO2C OTBSHTBSO

O

O ethanediol, HC(OCH3)3, amberlyst 15 (cat.)

99%

1)

2)LiAlH4reflux

OHHHO

O

O

HOOTBSHHO

O

O

HO

3)MeO OMe

, CSA4) TBSOTf5) PPTS

54% for 4 steps

MeO2C OTBSHHO

O

O

6) ethanediol, HC(OCH3)3, amberlyst 15 (excess)

96%

7) SmI2/pyrrolidine/H2O95%

1st generation 2nd generation

8) LDAthen MBzCl

OTBSHR1O

O

O

R2OR1 = MBz, R2 = H, 77%R1 = H, R2 = MBz, 20%

9) NaOMe99% OTBSHMBzO

O

O10) TCDI11) nBu3SnH, AIBN

66%

S

NNNN

TCDI = 1,1'-Thiocarbonyldiimidazole

Elaboration of the Eight-Membered Ring

12

OTBSHMBzO

O

O

OTBSHMBzO

O1) FeCl3 SiO2

99%

2) HMDS, TMSI3) NaHCO3, mCPBA4) TBAF

94 %

OTBSHMBzO

OOH

5) HF(aq)

OHHMBzO

OOH

78%6) MOMCl

75%

OMOMHMBzO

OOMOM

OMOMHMBzO

OMOM

OH

7) SnBu3EtO

nBuli, then addition of ketone

8) FeCl3 SiO29) NaBH4

63% for 3 steps

10) NCS, DMS97%

OMOMHMBzO

OMOM

Cl 11) CuCN, ZnMe271%

OMOMHMBzO

OMOM

single diastereoisomer at C12

12

OHHO

OH12) LiAlH413) DMP14) AcCl

69% for 3 steps

(+)-mutilin

Completion of the Synthesis

13

OHHO

OH

(+)-mutilin

O

OHO

OF

FFN

HN

O

F F

F

OHHO

O

CF3O

EDCI, DMAP

then MeOH, Et3N

OHO

OH

O

OH

(+)-Pleuromutilin

75% for 2 steps

Conclusion

14

•  First entantiospecific total synthesis (but long)

•  Key Steps including SmI2: 1)  SmI2-mediated cyclisation cascade 2)  SmI2/pyrrolidine/H2O-based ester reduction

•  Efficient conversion of (+)-mutilin to (+)-pleuromutilin

•  This approach is currently being used to expand the pleuromutilin class of antibiotics through the synthesis of novel analogues that are inaccessible from the natural compound

Preparation of Starting Carboxylic Acid (Zard Synthesis)

15

S. L. Schreiber J. Am. Chem. Soc. 1980, 102, 6163.

16

i)Transfer of an electron from Fe2+to peroxide to form oxy-radical ii) Fragmentation to form carbon-radical iii) Oxidative coupling with Cu(OAc)2 iv) β-elimination

O OO

OOHMeOO3, MeOH Cu(OAc)2, FeSO4

Fe2+

Fe3+

O

OMeO

O O

[Cu]

i)

ii) iii)

iv)

Reduction of Ester with SmI2/amine/H2O by Procter (proposed Mechanism)

17