Statins Family: Cholesterol-Lowering Drugs
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
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
•Introduction
•Cholesterol biosynthesis
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
HO
O
HO
O
O
O
O
HO
O
O
O
O
OH
H
H
HO
O
Mevastatin
compactin, ML-236B, CS-500
METKINEN OY
Balkanpharma-Razgrad AD
Monacolin J
O
Monacolin L
N
O
O
O
S
O
O
O
OH O
O
H
H
Monacolin M
F
O
N
N
O
O
HO
F
O
OH OH ONa
O
Monacolin X
O
F
Pravastatin
eptastatin, Pravachol®,
Bristol-Myers Squibb/Sankyo
O
H
H
HO
HO
O
H
H
O
H
Simvastatin
Synvinolin, Zocor®, Merck
O
OH
O
O
Lovastatin
mevinolin, monacolin K, Mevacor®, Merck
First to be marketed in 1987
HO
O
O
H
HO
O
O-, Na+
O
N
OH
N
HN
F
F
OH OH
OH OH
CO2Na
OH
CO2- Ca2+
H3CO
O
N
N
2
Lescol®
(fluvastatin sodium)
NOVARTIS
Crestor®
Rosuvastatin
AstraZeneka
FDA approval in Aug. 2003
Lipitor®
Atovarstatin
Pfizer
Baycol®
Cerivastatin sodium
Bayer
pitavastatin
(NK 104)
phase III clinical trials
Statins : Natural and Natural-like structures
O
HO
HO
O
HO
O
O
O
O-, Na+
O
O
OH
O
O
O
O
H
H
H
HO
Pravastatin
eptastatin, Pravachol®,
Bristol-Myers Squibb/Sankyo
FDA approval in 1996
$1.18b
OXIDATION FROM Mevastatin
Simvastatin
Lovastatin
Synvinolin, Zocor®, Merck
mevinolin, monacolin K, Mevacor®, Merck
FDA approval in 1998
First to be marketed in 1987
$2.3b
$389.5m
ESTER MODIFICATION FROM LOVASTATIN
FERMENTATION
HO
O
HO
O
O
O
H
O
HO
O
OH
H
H
Mevastatin
Monacolin J
Compactin®, ML-236B, CS-500
SANKYO
METKINEN OY
Balkanpharma-Razgrad AD
O
O
H
HO
O
O
O
O
H
Monacolin L
O
H
Monacolin X
FERMENTATION
HO
O
O
OH O
O
H
Monacolin M
Statins : Natural and Natural-like structures
HO
O
common main polyketide portion
O
R1
H
hexahydro naphthalene ring system
R2
R1= H, OH,
O
O
O
O ,
O ,
OH O
O
O,
O
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 review
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):555-64.
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
•Introduction
•Cholesterol biosynthesis
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
The Mevanolate Pathway: Cholesterol Biogenesis
The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)
HO
C
H2C
CH3
CH2
C

O
2NADP
+ HSCoA
HO
C
H2C
O
O
5-pyrophosphomevalonate
isopentenyl pyrophosphate
HMG-CoA
HMG-CoA
Reductase
+

SCoA
O
O
2NADPH
C
O
farnesyl pyrophosphate
CH3
CH2
C
geranyl pyrophosphate
H2
C OH
mevalonate
squalene
2,3-oxidosqualene
O-
HO
OH
HMG-CoA Reductase like inhibior
19 steps
Binding site of the enzyme
HO
HO
Lanosterol
Cholesterol
Natural statins
O-, Na+
O
HO
O
HO
O
O
O
O
HO
O
O
O
H
O
OH
H
H
Mevastatin
compactin, ML-236B, CS-500
METKINEN OY
Balkanpharma-Razgrad AD
Monacolin J
O
H
HO
O
O
H
H
Monacolin L
Pravastatin
eptastatin, Pravachol®,
Bristol-Myers Squibb/Sankyo
HO
O
H
HO
Simvastatin
Synvinolin, Zocor®, Merck
O
OH
O
O
Lovastatin
mevinolin, monacolin K, Mevacor®, Merck
HO
O
O
H
HO
O
O
O
O
O
H
Monacolin X
HO
O
O
OH O
O
H
Monacolin M
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.
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
•Introduction and problematic
•Cholesterol biosynthesis
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Total synthesis of natural and natural-like statins
HO
O
common main polyketide portion
O
R1
Hexahydro or Octahydro naphthalene ring system
H
Hexaline or octaline
R2
R2= H, CH3, OH
R1= H, OH,
O
O
O
O ,
O ,
OH O
O
O,
O
Synthetic statins, The missing members of the family…
Synthetic studies
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Danishefsky, S.; Kerwin, J. F., Jr.; Kobayashi, S. J. Am. Chem. Soc. 1982, 204, 358.
Funk, R. L.; Zeller, W. E. J. Org. Chem. 1982,47, 180.
Deutsch, E. A.; Snider, B. B. J. Org. Chem. 1982, 47, 2682.
Prugh, J. D.; Deana, A. A. Tetrhedron Lett. 1982,23, 281.
Yang, Y.-L.; Falck, J. R. Tetrahedron Lett. 1982, 23,4305.
Heathcock, C. H.; Taschner, M. J.; R a n , T.; Thomas, J. A.; Hadley, C. R.; Popjak, G. Tetrahedron Lett.
1982, 23,4747.
Lee, T.-J.; Holtz, W. J.; Smith, R. L. J. Org. Chem. 1982,47,4750.
MERCK
Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24, 1373.
Kuo, C. H.; Patchett, A. A,; Wendler, N. L. J. Org. Chem. 1983, 48, 1991.
Deutsch, E. A,; Snider, B. B. Tetrahedron Lett. 1983, 24, 3701.
Funk, R. L.; Mossman, C. J.; Zeller, W. E. Tetrahedron Lett. 1984, 25, 1655.
Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lett. 1984, 25, 2101.
Prasad, K.; Repic,O. Tetrahedron Lett. 1984,25, 2435.
NOVARTIS
R a n , T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1984, 49, 3994.
Rosen, T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1985, 50, 1190.
Burke, S. D.; Saunders, J. 0.; Oplinger, J. A.; Murtiashaw, C. W. Tetrahedron Lett. 1985, 26, 1131.
Guindon, Y.; Yoakim, C.; Bernstein, M. A,; Morton, H. E. Tetrahedron Lett. 1985, 26, 1185.
Kozikowski, A. P.; Li, C.3. J. Org. Chem. 1985, 50, 778.
Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’.
Tetrahedron (1986), 42(18), 4909-51.
HO
Deutsh and Sinder approach to Hexaline system
O
O
O
OEt
O
H
EtO
O
(+) Compactin
O
O
0.5% BHT, benzene,
sealed tube.150°C-2h
.
O
Excusively
EtO
O
O
OH
O
O
OEt
.
O
1-Base-catalyzed isomerizationg
KOtBu,tBuOH, 12 h, 40 °C, 50%
2-[O]
PGO
Br
Deutsch, E. A.; Snider, B. B., J. Org. Chem. 1982, 47, 2682.
OEt
Heatcock approach to the Octaline system, Total synthesis of (+) Dihydromevinolin
HO
O
O
O
OH
O
O
Alkylation
O
O
O
O
DA
H
(+)Dihydro Mevinolin
Cl
2
Exo
3
Endo
O
Zeller intermediate
Re Face of the dienophile
OH
Cl
Zeller intermediate
O
O
O
O
Alkylation
O
O
O
O
DA
6
Endo
Hecker,S.; Heathcock, C. H. J. Am. Chem. Soc. 1986, 108, 45861.
1
Exo
Heatcock approach to Octaline system, Total synthesis of (+) Dihydromevinolin
O
O
1-DA
2-MethylCuprate
O
MeCuprate Axial attack
O
O
O
Heatcock approach to Octaline system
O
O
OAc
OH
1-TsNHNH2
2-BuLi
1-H2/ Lindlar
O3
2-Ac2O
3-m-CPBA
4-BF3
Shapiro reaction
O
OAc
H
H
O
O
OMe
DBU
O
Ph
O
OH
OH
H
1-Acylation
1-TsNHNH2
2-BuLi
2- separation
Shapiro reaction
MeO2C
H
OSiR3
O
O
O
O
H
OAc
LiAl(tBuO)3
H
1-Acylation
2- selective saponification
3- swern oxydation
OH
OAc
OH
H
O
O
95:5
O
O
O
(MeO)3P
1-Wittig
2- 3,4 hydrogenation with Et3SiH, (PPH3)3RhCl
3- desillylation
4-cetone reduction
5-Lactonisation
Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’.
OH
O
H
(+) dihydro-mevanolin
Tetrahedron (1986), 42(18), 4909-51.
O
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
•Introduction and problematic
•Cholesterol biosynthesis (what can we learn from a biochemical process?)
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Semi- synthetic statins, Modifications of Lovastatin
•
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
HO
O
O
O
O
O
F
OH
O
HO
Cl
Cl
H
LOVASTATIN
Synthetic statins, Hoffman- Stokker Modifications I
HO
O
O
Cl
Cl
Hoffman, Stokker et al, J. Med. Chem. 1986, 28, 347-358
HO
Synthetic statins, Hoffman- Stokker Modifications II
O
O
F
Cl
Cl
100 (+)
Hoffman, Stokker, J. Med. Chem. 1986,29, 170-181
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
•Introduction and problematic
•Cholesterol biosynthesis (what can we learn from a biochemical process?)
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Semi- synthetic statins
HO
O
HO
O
O
HO
O
O
HO
O
O
HO
O
O
O
F
Cl
5
Cl
4
Cl
2
1
3
Cl
F
O
O
F
O
O
OH OH ONa
N
O
O
O
S
N
N
N
OH
N
HN
F
Lescol®
(fluvastatin sodium)
NOVARTIS
F
Crestor®
Rosuvastatin
AstraZeneka
FDA approval in Aug. 2003
OH OH
CO2Na
OH
H3CO
O
Lipitor®
Atovarstatin
Pfizer
N
Baycol®
Cerivastatin sodium
Bayer
Statins Family: Common side chain
OH O
R
O
OH
Chelation-Controlled Reduction:
Stereoselective Formation of syn-1,3-Diols
HO
O
Chemo and stereoselective
epoxyde reduction
OH OH O
O
R
R
OH
R
(...)
O O
OH
1,3 syn diol
Absolute configuration
(3R, 5S)
Iodolactonization
Enzymatic and chemoenzymatic approach
OH
OH
Statins side chain, H. C. Brown approach
O
O
HO
O
R
O
OH
H
B
+
OH
[O]
O
R
R
Acylation
R= PhCH2CH2PhCH=CHPhCH2OCH2-
Grubbs cat.,
Ist generation
O
O
O
R
O
(PhSe)2/ NaBH4
OH
AcOH/ EtOH
O
H2O2/NaOH
O
O
MeOH
R
R
92-96% ee
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’
H
H
O
O
H
R
O
H
O
(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.
Regioselective 1,3 reduction of epoxyde
Na+,Ph(BR3)Se-
Na+,Ph(BR3)Se-
O
R
OB(R3)-, Na+
O
O
O
O
R
SePh
O
R
OB(R3)-, Na+
OB(R3)-, Na+
2 EtOH
2 Na+,[BR3(EtO)]-
O
O
R
M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikishi, Tetahedron, 53, 12469
OH
Statins Family: Common side chain
OH O
R
O
OH
Chelation-Controlled Reduction:
Stereoselective Formation of syn-1,3-Diols
HO
O
Chemo and stereoselective
epoxyde reduction
OH OH O
O
R
R
OH
R
(...)
O O
OH
1,3 syn diol
Absolute configuration
(3R, 5S)
Iodolactonization
Enzymatic and chemoenzymatic approach
OH
OH
Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach
O
O
HO
OH
O
O
O
O
+
CHO
NO2
NO2 OTIPS
O
OH
O
OTIPS
NO2 OTIPS
O
O
OTIP
S
O
1-Zn, HOAc, THF
2-NaHSO3, EtOH-H2O
90%
LiI, LAH, Et2O,
-78°C
yield 93%
syn: anti > 99:1
1-DBU, CH3CN, 83%;
2-CuCl, DCC, CH3CN, 87%;
OH
O
O
O
OH 1-p-TsOH, CH Cl 65%
2 2,
O
2-H2, Pd(OH)2,, EtOAc, 85%
(a)
(b)
(c)
OBn OH
O
1- NaH, BnBr, TBAI, THF
2-TBAF, THF, 76%
3-NaIO4, RuCl3.3H2O,
CCl4-CH3CN-H2O,
O
OH OTIPS
O
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.
Narasaka*, K.; Pai, F., Tetrahedron 1984, 40, 2223.
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
Li
O
O
O
O
Li
Li
Li
O
O
OR
O
O
O
OR
H
OTIPS
Li
R= Bn, CHPh2, Tr, TIPS
syn:anti= 2.4:1; 7.5:1;11.5:1;99:1
Li
O
Li
O
O
O
OBn
O
Arun K. Ghosh* and Hui Lei, , J. Org. Chem., 2002, 67, 8783-8788.
O
OBn
syn:anti= 2.4:1
Statins Family: Common side chain
OH O
R
O
OH
Chelation-Controlled Reduction:
Stereoselective Formation of syn-1,3-Diols
HO
O
Chemo and stereoselective
epoxyde reduction
OH OH O
O
R
R
OH
R
(...)
O O
OH
1,3 syn diol
Absolute configuration
(3R, 5S)
Iodolactonization
Enzymatic and chemoenzymatic approach
OH
OH
Statins side chain, Via Iodolactonization
Substarte controlled
O
O
O
NC
(i) BuLi/THF
(ii) CO2
(iii) I2
OH
91%
O
O
O
(iv) p-TsOH, acetone, rt;
O
I
O
O
I
90%
75-80% (v) KCN/DMSO, 40°C;
O
O
NC
OH
O
(ix) CrO3–H2SO4
acetone, 0°C
NC
70%
O
O
(vi) OsO4–NaIO4/dioxane–H2O;
or (vii) O3; then (viii) Me2S;
O
O
NC
O
65%-70%
Cis-Racemate
60%
(xi) H5IO6/Et2O, rt;
X
(xii) CrO3, H5IO6, acetone.
O
NC
O
86%
(x) mCPBA/CH2Cl2, rt;
O
(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.
Reagent Controlled Iodolactonizations are rare…
NH2
I
O
(2 eq.)
R1
CO2H
1
R
ICl (1 eq.)
-78 oC
CH2Cl2
R1 = para-substituted
aryl groups
O
approx. 5 - 25 % ee
Haas, J.; Piguel, S.; Wirth*, T. Org. Lett. 2002, 2, 297 – 300.
X
H
R2O
N
R3
(30 mol %)
1
R
O
o
CH2Cl2, NaHCO3 aq, I2, 0 C
OH
1
I
I
R = aryl groups
R1
O
+
O
R1
O
O
yield = 37 - 93 %
(combined, though typically 5-exo products are
heavily favoured))
approx. 6 - 28 % ee
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…
N
N
Co
t-Bu
O
O
t-Bu
HO
t-Bu
t-Bu
1. 30 mol % salen-Co, NCS.
PhMe, rt, 30 min,
o
1
2. I2, -78 C, CH2Cl2
R
R1 = alkyl groups
I
1
R
O
yield = 83 - 94 %
approx. 67 - 90 % ee
Kang, S. H.; Lee, S. B.; Park, C. H. J. Am. Chem. Soc. 2003, 125, 15748 – 15749.
Statins Family: Common side chain
OH O
R
O
OH
Chelation-Controlled Reduction:
Stereoselective Formation of syn-1,3-Diols
HO
O
Chemo and stereoselective
epoxyde reduction
OH OH O
O
R
R
OH
R
(...)
O O
OH
1,3 syn diol
Absolute configuration
(3R, 5S)
Iodolactonization
Enzymatic and chemoenzymatic approach
OH
OH
Statins side chain, Other methods…
Rh/C
H2
H2O
OH
HO
OH
TBDPSiCl (2 eq)
DMF Imidazole
OH
HO
TBDPSO
OH
OTBDPS
OH
Mixture of cis- cis and cis- trans
PCC
OPG OPG O
1-EtOH/TFA
2-PCC
TBDPSO
OTBDPS
mCPBA
OEt
O
O
O
TBDPSO
TBDPSO
OH
OH
OH
internal plan of symmetry
HO
OH
C3 symmetry
OH
O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519
O
Statins Family: Common side chain
OH O
R
O
OH
Chelation-Controlled Reduction:
Stereoselective Formation of syn-1,3-Diols
HO
O
Chemo and stereoselective
epoxyde reduction
OH OH O
O
R
R
OH
R
(...)
O O
OH
1,3 syn diol
Absolute configuration
(3R, 5S)
Iodolactonization
Enzymatic and chemoenzymatic approach
OH
OH
Stereoselective synthesis vs. traditional chemistry
‘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
MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, June 14, 2004, Volume 82, Number 24, p. 47-62
Statins side chain, Chemo-Enzymatic approach
DERA
After 15 h, product isolated in 96%
yield (98.5%ee), 619 g.L-1d-1.
Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365
Statins side chain, Chemo-Enzymatic approach
Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365
Statins side chain, Chemo-Enzymatic approach
O
Cl
OR O
O
(α-Chymotrypsine-BioFac)
Highly scalable process
(400g in one batch)
R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)
Statins side chain, Chemo-Enzymatic approach
O
OR O
Cl
O
O
Cl
O
O
OMe
(CH2Cl)2, 0°C, ethylene, AlCl3
89%
O
OEt
O
Cl
O
O
OMe
O
O
PLE, pH7, 76%
OEt
OH O
Cl
OEt
PLE: Pig liver esterase
O
N3
1- BEt3, NaBH4, 91%
2-Dimetoxypropane, H+, 99%
3-NaN3, DMF,
94%, ee 98.1%, de 98.8%
O
O
OEt
‘This so called ‘aza’-W ittig reaction, which
proceeds via an imine intermediate is promoted by a
phosphine reagent and a weak, sterically hindered acid’.
R. Öhrlein
R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)
Statins side chain, Chemo-Enzymatic approach
DERA
Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365
Statins side chain, Total- Enzymatic approach
O
N3
O
O
O
~‘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
Statins side chain, Total -Enzymatic approach
O
N3
O
O
O
(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.
Statins side chain, Direct Cross Aldol approach
OH
O
X
O
H
+
2
Asymmetic catalyst
H
O
X
Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799
OH
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
OH
O
X
O
H
+
2
Asymetic catalyst
H
O
X
OH
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
Statins side chain, Direct Aldol approach (…)
Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579
Houk/ List Model for Proline-Catalyzed Asymmetric Intermolecular
Aldol Reactions…
O
 
N H
O
 O
R
R
H
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475 – 2479.
Statins side chain, Direct Aldol approach (…)
Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
•Introduction and problematic
•Cholesterol biosynthesis (what can we learn from a biochemical process?)
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrial synthesis: Lescol
F
The story of Lescol®
OH OH ONa
N
O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519
O