yassir el-azizi literature meeting a. charette group 15 feb. 2005

Yassir EL-AZIZI

Literature meeting A. Charette group

15 Feb. 2005

Statins Family: Cholesterol-Lowering Drugs

• Statin drugs constituted 6% of the total annual sale of the top 200 drugs in

1999, worth $125 billion in the USA.


MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, 2004, 82, Number 24, 47-62

http://pubs.acs.org/cen/staff/bioamr.html

•Introduction

•Cholesterol biosynthesis

•The missing members of the family

•Merck reduction of complexity of natural statins

•Synthetic Statins

• Exemple of industrail synthesis: Lescol


OUTLINE

OH

O

OHO

O

Lovastatinmevinolin, monacolin K, Mevacor®, Merck

First to be marketed in 1987

OH

O

OHO

O

O

HO

H

OH

HO

O

O O-, Na+

Pravastatineptastatin, Pravachol®,

Bristol-Myers Squibb/Sankyo

SimvastatinSynvinolin, Zocor®, Merck

OH

O

OHO

O

Mevastatincompactin, ML-236B, CS-500

METKINEN OYBalkanpharma-Razgrad AD

OHH

O

OHO

Monacolin J

H

O

OHO

Monacolin L

OH

O

OHO

OO

Monacolin X

OH

O

OHO

OOH

Monacolin M

H

H


O

ONa

N

F

OH OH

Lescol® (fluvastatin sodium)

NOVARTIS

O

OH

O

N

OHN

F

Lipitor®Atovarstatin

Pfizer

O

OH

O

N

N

F

NSO

O

CO2NaOHOH

N

H3CO

F

Baycol®Cerivastatin sodium

Bayer

Crestor®RosuvastatinAstraZeneka

FDA approval in Aug. 2003

CO2-

OHOH

N

F

2

Ca2+

pitavastatin (NK 104)

phase III clinical trials

OH

O

OHO

O


First to be marketed in 1987$389.5m

FERMENTATION

OH

O

OHO

OO

HO

H

OH

HO

O

O O-, Na+


Bristol-Myers Squibb/SankyoFDA approval in 1996

$1.18bOXIDATION FROM Mevastatin


FDA approval in 1998$2.3b

ESTER MODIFICATION FROM LOVASTATIN

OH

O

OHO

O

MevastatinCompactin®, ML-236B, CS-500

SANKYOMETKINEN OY

Balkanpharma-Razgrad AD

OHH

O

OHO

Monacolin J

H

O

OHO

Monacolin L

OH

O

OHO

OO

Monacolin X

OH

O

OHO

OOH

Monacolin M

H

H

FERMENTATION

Statins : Natural and Natural-like structures

R1

R2

H

O

OHO

common main polyketide portion

hexahydro naphthalene ring system

R1= H, OH, O

O

O

O

O

OO

O

OOH

, , ,

R2= H, CH3, OH

‘…the mechanism involved in the control of endogenous cholesterol levels by statins makes these molecules suitable for therapeutic use…, Different

types of statins are currently available: the natural statins obtained directly by fermentation, and the semi-synthetic and synthetic statins . Cerivastatin,

a fully synthesized statin approved in the United States in 1997, has been employed until the recent withdrawal from the market. ’ *

Mini reviewManzoni* M, Rollini M., ‘Biosynthesis and biotechnological production of statins

by filamentous fungi and application of these cholesterol-lowering drugs’, Appl. Microbiol. Biotechnol. 2002 Apr.;58(5):555-64.

Statins : Natural and Natural-like structures

•Introduction







OUTLINE

+ HSCoA

H2CC

CH3HO

CH2C

O O

C SCoA

O

H2CC

CH3HO

CH2C

O O

H2C OH

2NADP+

2NADPHHMG-CoA

mevalonate

HMG-CoA Reductase

5-pyrophosphomevalonateisopentenyl pyrophosphate

geranyl pyrophosphatefarnesyl pyrophosphate

squalene 2,3-oxidosqualene

The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)

The Mevanolate Pathway: Cholesterol Biogenesis

HOHO

19 steps

Lanosterol Cholesterol

OH

HO

O O-

Binding site of the enzyme

HMG-CoA Reductase like inhibior

OH

O

OHO

O


OH

O

OHO

O

O

HO

H

OH

HO

O

O O-, Na+


Bristol-Myers Squibb/Sankyo


OH

O

OHO

O

Mevastatincompactin, ML-236B, CS-500

METKINEN OYBalkanpharma-Razgrad AD

OHH

O

OHO

Monacolin J

H

O

OHO

Monacolin L

OH

O

OHO

OO

Monacolin X

OH

O

OHO

OOH

Monacolin M

H

H

Manzoni M, Rollini M., ‘Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs’, Appl. Microbiol. Biotechnol. 2002 Apr.;58(5):555-564.

Natural statins

•Introduction and problematic







OUTLINE

Total synthesis of natural and natural-like statins

R1

R2

H

O

OHOcommon main polyketide portion

Hexahydro or Octahydro naphthalene ring system Hexaline or octaline

R1= H, OH, O

O

O

O

O

OO

O

OOH

, , ,

R2= H, CH3, OH

Synthetic statins, The missing members of the family…

Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51.

Synthetic studies

1. Danishefsky, S.; Kerwin, J. F., Jr.; Kobayashi, S. J. Am. Chem. Soc. 1982, 204, 358.2. Funk, R. L.; Zeller, W. E. J. Org. Chem. 1982,47, 180. 3. Deutsch, E. A.; Snider, B. B. J. Org. Chem. 1982, 47, 2682.4. Prugh, J. D.; Deana, A. A. Tetrhedron Lett. 1982,23, 281.5. Yang, Y.-L.; Falck, J. R. Tetrahedron Lett. 1982, 23,4305.6. Heathcock, C. H.; Taschner, M. J.; R a n , T.; Thomas, J. A.; Hadley, C. R.; Popjak, G. Tetrahedron Lett.

1982, 23,4747. 7. Lee, T.-J.; Holtz, W. J.; Smith, R. L. J. Org. Chem. 1982,47,4750. MERCK8. Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24, 1373. 9. Kuo, C. H.; Patchett, A. A,; Wendler, N. L. J. Org. Chem. 1983, 48, 1991. 10. Deutsch, E. A,; Snider, B. B. Tetrahedron Lett. 1983, 24, 3701. 11. Funk, R. L.; Mossman, C. J.; Zeller, W. E. Tetrahedron Lett. 1984, 25, 1655. 12. Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lett. 1984, 25, 2101. 13. Prasad, K.; Repic,O. Tetrahedron Lett. 1984,25, 2435. NOVARTIS14. R a n , T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1984, 49, 3994. 15. Rosen, T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1985, 50, 1190. 16. Burke, S. D.; Saunders, J. 0.; Oplinger, J. A.; Murtiashaw, C. W. Tetrahedron Lett. 1985, 26, 1131. 17. Guindon, Y.; Yoakim, C.; Bernstein, M. A,; Morton, H. E. Tetrahedron Lett. 1985, 26, 1185. 18. Kozikowski, A. P.; Li, C.3. J. Org. Chem. 1985, 50, 778.

Deutsh and Sinder approach to Hexaline system

O

O

.

O

O

OEtEtO

0.5% BHT, benzene, sealed tube.150°C-2h

Excusively

O

O

.

EtO

OH

O OEt

OO OEt

BrPGO

1-Base-catalyzed isomerizationgKOtBu,tBuOH, 12 h, 40 °C, 50%2-[O]

Deutsch, E. A.; Snider, B. B., J. Org. Chem. 1982, 47, 2682.

OH

O

OHO

O

(+) Compactin

Heatcock approach to the Octaline system, Total synthesis of (+) Dihydromevinolin

OH OOAlkylation DA

OO

OCl

Zeller intermediate

OO

3Endo

2Exo

OH

O

OHO

O

(+)Dihydro Mevinolin

OH OOAlkylation DA

OO

OCl

Zeller intermediate

OO

6Endo

1Exo

Re Face of the dienophile

Hecker,S.; Heathcock, C. H. J. Am. Chem. Soc. 1986, 108, 45861.

Heatcock approach to Octaline system, Total synthesis of (+) Dihydromevinolin

OO

OO

1-DA2-MethylCuprate

O O

MeCuprate Axial attack

OO 1-TsNHNH2

2-BuLi

Shapiro reaction

OH1-H2/ Lindlar

2-Ac2O3-m-CPBA4-BF3

OAc

HO

O3

OAc O

HO

OAc O

HO

DBU

OAcOH

HO

LiAl(tBuO)3OH

OH

H

1-TsNHNH22-BuLi

Shapiro reaction

OHO

H

OMe

PhO

1-Acylation

2- separation

O O

H

O

1-Acylation2- selective saponification3- swern oxydation

O

H

OO

O OH

(+) dihydro-mevanolin1-Wittig2- 3,4 hydrogenation with Et3SiH, (PPH3)3RhCl3- desillylation4-cetone reduction5-Lactonisation

MeO2CO

OSiR3

(MeO)3P

95:5

Heatcock approach to Octaline system

Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51.


•Cholesterol biosynthesis (what can we learn from a biochemical process?)






OUTLINE

• New drug design approaches are geared towards making lovastatin analogs that will have longer interaction with the enzyme –increase duration of drug occupancy of active site.

• Structural modification: (Lee, et. al. 1982, Merck & Co)

• Structural modification and simplification: (Hoffman*, Stokker**, et. al. 1985, Merck & Co)

• suppression of the hexahydro-naphtaline system

• Progress toward the introduction of the (3 ,5-Disubstituted [ l, l’-biphenyl] system

Semi- synthetic statins, Modifications of Lovastatin

ClCl

F

O

HO O

HO

O

H

OO

O OH

LOVASTATIN

Synthetic statins, Hoffman- Stokker Modifications I

Cl

Cl

O

OHO

Hoffman, Stokker et al, J. Med. Chem. 1986, 28, 347-358

Synthetic statins, Hoffman- Stokker Modifications II

Hoffman, Stokker, J. Med. Chem. 1986,29, 170-181

ClCl

F

O

HO O

100 (+)








OUTLINE

Semi- synthetic statins

O

ONa

N

F

OH OH

Lescol® (fluvastatin sodium)

NOVARTIS

O

OH

O

N

OHN

F

Lipitor®Atovarstatin

Pfizer

O

OH

O

N

N

F

NSO

O

CO2NaOHOH

N

H3CO

F

Baycol®Cerivastatin sodium

Bayer

Crestor®RosuvastatinAstraZeneka

FDA approval in Aug. 2003

F

Cl

Cl

O

OHO

O

OHO

O

OHO

Cl

Cl

O

OHO

O

OHO

2 145 3

Statins Family: Common side chain

R

O

OHO

OH

OOHOHR

1,3 syn diolAbsolute configuration

(3R, 5S)

Enzymatic and chemo-enzymatic approach

OH

OOOHR

Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols

Chemo and stereoselective epoxyde reduction

OH

OOHR

O

OHIodolactonization

(...)

R H

O+

BR

OH

R

O

O

R

O

O

R

O

O

OR

O

O

OH

(PhSe)2/ NaBH4

AcOH/ EtOH

H2O2/NaOH

MeOH

Grubbs cat.,Ist generation

Acylation

92-96% ee

[O]

R= PhCH2CH2- PhCH=CH- PhCH2OCH2-

O

H

R

H

HO

O

OH

Statins side chain, H. C. Brown approach

Yields:

•Allylboration with (-)-B-allyldiisopinacocamphenylborane 71-76%•Esterification 80% •RCM up to 84%•Epoxydation 86%•1,3-reduction of the epoxyde 87% (Miyashita conditions,ee up to 92%, 99% after recrystallization)

‘It is believed that this reduction proceeds via the formation of PhSeH’

(a) M. Venkat Ram Reddy, Herbert C. Brown*, P. Veeraraghavan Ramachandran*, J. Organomet. Chem. 624 (2001) 239–243.(b) P. Veeraraghavan Ramachandran*, Kamlesh J. Padiya, Vivek Rauniyar, M. Venkat Ram Reddy, Herbert C. Brown*, J. Fluorine Chem. 125 (2004) 615–620.

O

O

OHHO

Regioselective 1,3 reduction of epoxyde

R

O

O

O

Na+,Ph(BR3)Se-

R

O

O

OB(R3)-, Na+

SePh

Na+,Ph(BR3)Se-

R

O

OB(R3)-, Na+

OB(R3)-, Na+

2 EtOH

2 Na+,[BR3(EtO)]-

R

O

O

OH

M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikishi, Tetahedron, 53, 12469


R

O

OHO

OH

OOHOHR


(3R, 5S)


OH

OOOHR



OH

OOHR

O

OHIodolactonization

(...)

Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach

O

O

OHHO

OO

CHO+

NO2

OTIPS

NO2

OH

OO OTIPS

OTIPSNO2O

O

1-DBU, CH3CN, 83%;2-CuCl, DCC, CH3CN, 87%;

OTIPS

OO

O

1-Zn, HOAc, THF 2-NaHSO3, EtOH-H2O 90%

OTIPSOHO

O

LiI, LAH, Et2O, -78°C

yield 93%syn: anti > 99:1

OHOBnO

O

OOO

OH

OH

1- NaH, BnBr, TBAI, THF2-TBAF, THF, 76%3-NaIO4, RuCl3.3H2O, CCl4-CH3CN-H2O,

1-p-TsOH, CH2Cl2, 65%

2-H2, Pd(OH)2,, EtOAc, 85%

(a) Arun K. Ghosh* and Hui Lei, ‘Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols and Synthesis of Compactin and Mevinolin Lactone’, J. Org. Chem., 2002, 67, 8783-8788.

(b) Narasaka*, K.; Pai, F., Tetrahedron 1984, 40, 2223.(c) Chen, K.-M.; Hardtmann, G. E.; Prasad*, K.; Repic*, O.; Shapiro, M., Tetrahedron Lett. 1987, 28, 155. (Novartis)

,

Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach

OTIPS

OO

O

Li H

OR

OO

O

Li

R= Bn, CHPh2, Tr, TIPS

OROO

O

Li Li

Li

syn:anti= 2.4:1; 7.5:1;11.5:1;99:1

OBnOO

O

Li

OBn

OO

O

Li

syn:anti= 2.4:1

Arun K. Ghosh* and Hui Lei, , J. Org. Chem., 2002, 67, 8783-8788.

,


R

O

OHO

OH

OOHOHR


(3R, 5S)


OH

OOOHR



OH

OOHR

O

OHIodolactonization

(...)

Statins side chain, Via IodolactonizationSubstarte controlled

O

OOONC

(a) Stanislav Ràdl,* Jan Stach and Josef Hajicek, Tetrahedron Letters, 43 (2002) 2087–2090(b) Butler, D. E.; Deering, C. F.; Millar, A.; Nanninga, T. N.; Roth, B. D. (Warner-Lambert Co.) US Patent 5,245,047.

OH OI

O

O

OONC

O

OONC

O

(i) BuLi/THF(ii) CO2 (iii) I2

(iv) p-TsOH, acetone, rt;

(v) KCN/DMSO, 40°C;

(vi) OsO4–NaIO4/dioxane–H2O; or (vii) O3; then (viii) Me2S;(ix) CrO3–H2SO4

acetone, 0°C

90%

75-80%

70%

OOI

OONC

91%

65%-70%

OH

OONC

O

X (x) mCPBA/CH2Cl2, rt;(xi) H5IO6/Et2O, rt;

86%60%

(xii) CrO3, H5IO6, acetone.

Cis-Racemate

Reagent Controlled Iodolactonizations are rare…

R1 CO2H

R1 = para-substituted aryl groups

NH2

ICl (1 eq.)

(2 eq.)

-78 oCCH2Cl2

OOR1

I

approx. 5 - 25 % ee

O

R1

OH

R1 = aryl groups

N

R3

R2OH

X

(30 mol %)

CH2Cl2, NaHCO3 aq, I2, 0 oC OR1

I

O O O

I

R1+

yield = 37 - 93 % (combined, though typically 5-exo products are

heavily favoured))

approx. 6 - 28 % ee

Haas, J.; Piguel, S.; Wirth*, T. Org. Lett. 2002, 2, 297 – 300.

Wang, M.; Gao*, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874 – 2876.

Reagent Controlled Iodolactonizations are rare…

2. I2, -78 oC, CH2Cl2

1. 30 mol % salen-Co, NCS. PhMe, rt, 30 min,

N N

t-Bu

t-Bu t-Bu

t-BuO OCo

R1

HO

R1 = alkyl groups

OR1

I

yield = 83 - 94 %approx. 67 - 90 % ee

Kang, S. H.; Lee, S. B.; Park, C. H. J. Am. Chem. Soc. 2003, 125, 15748 – 15749.


R

O

OHO

OH

OOHOHR


(3R, 5S)


OH

OOOHR



OH

OOHR

O

OHIodolactonization

(...)

OH

OH

C3 symmetryinternal plan of symmetry

HO OH

OHOH

OH

HO OH

OH

HO OH

Rh/CH2H2O

OTBDPS

TBDPSO OH

TBDPSiCl (2 eq)DMF Imidazole

PCC

OTBDPS

TBDPSO O

mCPBA

O

TBDPSO

TBDPSOO

1-EtOH/TFA2-PCC

OEt

OOPGOPG

O

Mixture of cis- cis and cis- trans

Statins side chain, Other methods…

O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519


R

O

OHO

OH

OOHOHR


(3R, 5S)


OH

OOOHR



OH

OOHR

O

OHIodolactonization

(...)

MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, June 14, 2004, Volume 82, Number 24, p. 47-62

‘Despite the unrelenting pace of research in catalytic asymmetric chemistry, relatively few catalytic

enantioselective processes are currently operated on a commercial scale.

Until more bio- and chemocatalytic chiral routes are developed that are robust and cost-effective for

large-scale production, the bulk of optically pure compounds will have to be prepared through traditional chemistry, including conventional

syntheses based on chiral substrates or stoichiometric chiral induction and separations, such

as chromatographic resolutions’.

MAUREEN ROUHI

Stereoselective synthesis vs. traditional chemistry



Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365

Statins side chain, Chemo-Enzymatic approach

DERA

After 15 h, product isolated in 96% yield (98.5%ee), 619 g.L-1d-1.


R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)

(α-Chymotrypsine-BioFac)

Highly scalable process (400g in one batch)

Cl O

OORO


R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)

PLE: Pig liver esterase

‘This so called ‘aza’-W ittig reaction, whichproceeds via an imine intermediate is promoted by a

phosphine reagent and a weak, sterically hindered acid’.R. Öhrlein

Cl O

OORO

Cl OEt

OO O(CH2Cl)2, 0°C, ethylene, AlCl3

89%OEt

OO O

Cl OEt

OO OH

Cl

PLE, pH7, 76%

OEt

OO O

N3

1- BEt3, NaBH4, 91%2-Dimetoxypropane, H+, 99%3-NaN3, DMF, 94%, ee 98.1%, de 98.8%

O OMe O OMe



DERA

Statins side chain, Total- Enzymatic approach

~‘Absolute’ stereo control>99.9% ee, >96.6% de

(a) Junjie Liu, Che-Chang Hsu and Chi-Huey Wong* , Tetrahedron Letters, 45 (2004) 2439–2441. Scripps RI, La Jolla. 10 dec 2003 (Early work since 1994)(b) W. A. Greenberg*, A. Varvak, S. R. Hanson, K. Wong, H. Huang, P. Chen, and M. J. Burk*, PNAS, April 20, 2004 vol. 101 no. 16,5788–5793. Diversa Co.14 Nov. 2003

O

OOO

N3

Statins side chain, Total -Enzymatic approach

(b) W. A. Greenberg*, A. Varvak, S. R. Hanson, K. Wong, H. Huang, P. Chen, and M. J. Burk*, PNAS, April 20, 2004 vol. 101 no. 16,5788–5793. Diversa Co.

O

OOO

N3

Statins side chain, Direct Cross Aldol approach

XH H

O O+ 2

Asymmetic catalyst O

OH

OHX

Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799

Statins side chain, Direct Cross Aldol approach

Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799

Statins side chain, Direct Aldol approach

XH H

O O+ 2

Asymetic catalyst O

OH

OHX

Alan B. Northrup, Ian K. Mangion, Frank Hettche, and David W. C. MacMillan* ,Angew. Chem. Int. Ed. 2004, 43, 2152 –2154

Statins side chain, Direct Aldol approach

Alan B. Northrup, Ian K. Mangion, Frank Hettche, and David W. C. MacMillan* ,Angew. Chem. Int. Ed. 2004, 43, 2152 –2154

Statins side chain, Direct Aldol approach (…)

Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579

N

RO

R H

O

OH

Houk/ List Model for Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions…

Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475 – 2479.

Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579

Statins side chain, Direct Aldol approach (…)






• Exemple of industrial synthesis: Lescol


OUTLINE

The story of Lescol®

O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519

O

ONa

N

F

OH OH

yassir el-azizi literature meeting a. charette group 15 feb. 2005

Documents

natural statins introduction

octalinesynthetic statins

biosynthesis of cholesterol

cholesterol biogenesis

different types of statins

lescolstatins family

family review

drugsoutlinestatins