Life (& Death)

25 May 2005

T

Difficult Definitions: Water

• Impossible to define in a complete way.• Incomplete Definition: H2O• What is hydrogen? What is oxygen?• Water as a substance: Something we drink?• Operational definition: Something that boils at

100 °C, freezes at 0 °C?• Still not enough…

• What about something more complex…

What is Life?

• Why define life?– Space exploration– Terrean problems (prions, etc.)

• “A [self-sustaining] chemical system capable ofDarwinian evolution.” (NASA)

• Quiz time…

S. A. Benner, A. Ricardo, and M. A. Carrigan, “Is there a common chemical modelfor life in the universe?”, Curr. Opin. Chem. Biol., 2004, 8, 672-689.

Is this “Life”?

• Problem with confusing “being alive” with “life”.• Ability to move, eat, metabolize or reproduce may not be

enough.• A single male rabbit that is alive cannot (alone) support

Darwinian evolution.• Therefore, not life.

Is this “Life”?

• Sodium chlorate (NaClO3)• Can “reproduce”• Create exact copies of itself• Features (chirality) can be

passed onto descendents• Sometimes imperfect

crystallization (defects)

• Information in these defects is NOT inheritable.• Therefore, crystals do not support Darwinian evolution.• Therefore, not Life.• Nevertheless, the origin and propagation of crystalline

order (Entropy) has become a guiding theoretical concept.G. Arrhenius, “Crystals and Life”, Helv. Chim. Acta. 2003, 86, 1569-1586.

Systems (non chemical) capable ofDarwinian evolution (what would the

Federation say?)

• The nanites (“Evolution” on ST:TNG): evolution is nottied to an informational molecule like DNA.

• The calamarain (“Déjà Q”): Pure energy (no matter).• Q: neither matter nor energy.• Data: Artificial Life; biosignature/Alive?

What is necessary for Life?• Thermodynamic disequilibrium

– “High energy molecules”– Nuclear fusion reactor

• Bonding– Depends on the environment

• Isolation within the environment– Altruism/parasitism and Darwinian evolution

• Carbon-like scaffolding (covalent)– carbon vs. silicon

• Energetic patterns in metabolism– Disequilibrium– Multistep pathways

• Solvent– Affects outcome of the reactions– Water is often regarded as being antithetical to Life

Solvent and reactions

• On Earth:

• On Icy moons/Gas giants:

• On Venus:

OO

HHO H H2O

H3O+ (pKa -1)

HO- (pKa 15)

OOH

NHN

H

+H3N H NH3

NH4+ (pKa 9)

NH2- (pKa 30)

NHNH2

H

CH2

CH

H+ H2SO4

H2SO4 (pKa -10)

HSO4- (pKa 2)

CH2CH3

HH

Origins of Life

N

N

N

R

O

N N

NN

R

N

OH H

H

HHN

N

O

R

O

N N

NN

RN

H

H

H

donor

acceptor

acceptor

acceptor

donor

acceptor

acceptor

donor

donor

donor

acceptor

donor

pyDAA pyADA

puADD puDA_

Cytosine

Guanine

Thymine

Adenine

N

N

N

R

O

N N

NN

R

N

OH H

H

HHN

N

O

R

O

N N

NN

R

N

N

HH

H

H

H

donor

acceptor

acceptor

acceptor

donor

acceptor

acceptor

donor

donor

donor

acceptor

donor

pyDAA pyADA

puADD puDAD

Cytosine

Guanine

Thymine

2-amino-Adenine

N

N

O

R

N

N N

NN

R

O

NH

H

H

H

H

N N

R

NH

H

NH H

N N

N

N

R

O

O

H H

N

N

R

O

NH H

N N

N N R

N

O

H

HH

N

N

R

NH

H

O N N

NN

R

O

N

H

H

H

H

acceptor

acceptor

donor

donor

donor

acceptor

donor

acceptor

donor

donor

donor

acceptor

acceptor

donor

donor

acceptor

donor

acceptor

acceptor

acceptor

donor

donor

acceptor

acceptor

pyAAD

puDDA

pyDAD pyDDA

pyADD

puADA puAAD

puDAA

Prebiotic Starting Materials

C O H C N O C OO C S H

OH

O

CHH

H

NHH

S

CHH

C C HH

HN C O

HN C S

NH

CHH

O

CHHO

H C C N C

H C C C NH C C C C H

C C

H

HH

HN

C

CH HH

C

N

CH HH

O

HNH

H

O

HH

H H

Prebiotic Synthesis of DNA/RNA Bases• Adenine from HCN:

C NH

NC NH2

NH2NC

NC NH2

CNH2N

h!NC

H2NN

H

N N

N N

H

N

NH

TAUT. N

N N

H

N

NH H

H

C NH

N C

H+

N

H

NC

H

N CH+

NH2C

NC

NN C

H+

NH2C

NC

NH

NC

H

H+

NC NH2

NH2NC

NC NH2

CNH2N

h!C

H2NNH

NN

C

N

H

H+

N

N NH

N

NH

TAUT. N

N NH

N

NH H

H

(nobodyknows)

J. Orò, “Synthesis of adenine from ammonium cyanide”, Biochem. Biophys.Res. Commun. 1960, 2, 407-412

DISCLAIMER*

Organic Reactions & Rube Goldberg

See R. Hoffmann, V. I. Minkin, B. K. Carpenter, “Ockham’s Razor andchemistry” Bull. Soc. Chim. Fr. 1996, 133, 117-130.

Prebiotic Synthesis of DNA/RNA Bases• Purine acetic acids from HCN and glycine:

K. E. Nelson, M. Levy, S. L. Miller, “Peptide nucleic acids rather than RNA mayhave been the first genetic molecule”, Proc. Nat. Acad. Sci., 2000, 97, 3868-3871

“… 0.0062% adenine-N9-acetic acid, 0.0013% adenine-N6-acetic acid, and 0.0051%adenine […] guanine-N9-acetic acid […] in 0.11% [and] 0.0004% guanine.”

NC

NH2NC

NH2

HCN

HCN

H2N CO2H

+

NH

NH

CO2H

XH2

X = O, NHN

N

CO2H

H2N

H2N

XX = NH

X = O

NH

H2N

NC CN

N

N

CO2H

N

N

NH2

N

N

CO2H

N

HN

X

H2N

NC

NH2NC

NH2

HCN

HCN

H2N CO2H

+

NH

NH

CO2H

NC

NNC

NH2

NH

CO2H

N

N

CO2H

HN

NC

NH2

XH2

X = O, NHN

N

CO2H

H2N

NC

NH2HX

N

N

CO2H

HCN

H2N

H2N

XX = NH

X = O

NH

H2N

NC CN

N

N

CO2H

N

N

NH2

N

N

CO2H

N

HN

X

H2N

Prebiotic Synthesis of DNA/RNA Bases

• Pyrimidine Acetic Acids from cyanoacetaldehyde andhydantoic acid

K. E. Nelson, M. Levy, S. L. Miller, “Peptide nucleic acids rather than RNA mayhave been the first genetic molecule”, Proc. Nat. Acad. Sci., 2000, 97, 3868-3871

HN

HNO

O

H2O

hydantoin

NH2

NH

O CO2H

H

O

CN

cyanoacetaldehydeHO

H

CN

H2N

NO

CO2H

CN

N

NO

NH2

CO2H

HN

NO

O

CO2H

Cytosine-N1-

acetic acid

Uracil-N1-

acetic acid

“…18% of cytosine-N1-acetic acid and 1.8% for uracil-N1-acetic acid […]14% cytosine-N3-acetic acid…”

Ribose: BIG hole in RNA world hypothesis• The Problem:

• The Solution: borate

Ricardo, M. A. Carrigan, A. N. Olcott, S. A. Benner, “Borate minerals stabilizeribose”, Science, 2004, 303, 196-196

O

HHO

glycolaldehyde

Ca(OH)2

O

O

2+Ca

H

O

H

H

O

H

OH

OH O

O

2+Ca

H

OH

TAR

DL-glyceraldehyde

O

H

OH

BorateHO

HO

HO OH

HO OH

O

O

2+Ca

H

O

H

OH

OHO

H

OH

Borate

O

B

O

O

OH

OH

H

OH

HO

HHO

OH

pentoses

OHO OH

OBO

O O

Can we hear something interesting?

http://www.rxlist.com/top200.htm

N

OH OH

O

O

NH

O

F 2

Ca2+

*3 H2O

Lipitor (a.k.a., Atorvastatin)65.5 million prescriptions (2003); No. 2

S

HO2C

Cl

HN

O

H2N

O O

Furosemide (Lasix)

NH

NHS

OO

S

Cl

H2N

OO

Hydrochlorothiazide

N

N

NN

Cl

Alprazolam (Xanax)

NHCl

Cl

H

Cl

ZOLOFT® (sertraline hydrochloride)

O OH

O

N

N

Cl

Cl

Cl

Zyrtec (Cetirizine HCl)

racemic

H

H

SO

OH2N

N

N

FF

F

Celebrex

N

N

S OO

O

N

HNN

N

O

OH

O

OH

O

OH

O

OH

Viagra (Sildenafil citrate)

N

N

O Cl

Valium

N

N

NHN

Me

HN

O

N

N

CH2SO3H

Gleevec

Hydrocodone / APAP = 85.1 million prescriptionsLipitor = 65.5 million prescriptionsSynthroid = 47.2 million prescriptionsAtenolol = 40.9 million prescriptionsZithromax = 39.5 million prescriptions

N

OH OH

O

O

NH

O

F 2

Ca2+

*3 H2O

Lipitor (a.k.a., Atorvastatin)65.5 million prescriptions (2003); No. 2

S

HO2C

Cl

HN

O

H2N

O O

Furosemide (Lasix)

NH

NHS

OO

S

Cl

H2N

OO

Hydrochlorothiazide

N

N

NN

Cl

Alprazolam (Xanax)

NHCl

Cl

H

Cl

ZOLOFT® (sertraline hydrochloride)

O OH

O

N

N

Cl

Cl

Cl

Zyrtec (Cetirizine HCl)

racemic

H

H

SO

OH2N

N

N

FF

F

Celebrex

N

N

S OO

O

N

HNN

N

O

OH

O

OH

O

OH

O

OH

Viagra (Sildenafil citrate)

N

N

O Cl

Valium

N

N

NHN

Me

HN

O

N

N

CH2SO3H

Gleevec

Hydrocodone / APAP = 85.1 million prescriptionsLipitor = 65.5 million prescriptionsSynthroid = 47.2 million prescriptionsAtenolol = 40.9 million prescriptionsZithromax = 39.5 million prescriptions

N

OH OH

O

O

NH

O

F 2

Ca2+

*3 H2O

Lipitor (a.k.a., Atorvastatin)65.5 million prescriptions (2003); No. 2

S

HO2C

Cl

HN

O

H2N

O O

Furosemide (Lasix)

NH

NHS

OO

S

Cl

H2N

OO

Hydrochlorothiazide

N

N

NN

Cl

Alprazolam (Xanax)

NHCl

Cl

H

Cl

ZOLOFT® (sertraline hydrochloride)

O OH

O

N

N

Cl

Cl

Cl

Zyrtec (Cetirizine HCl)

racemic

H

H

SO

OH2N

N

N

FF

F

Celebrex

N

N

S OO

O

N

HNN

N

O

OH

O

OH

O

OH

O

OH

Viagra (Sildenafil citrate)

N

N

O Cl

Valium

N

N

NHN

Me

HN

O

N

N

CH2SO3H

Gleevec

Hydrocodone / APAP = 85.1 million prescriptionsLipitor = 65.5 million prescriptionsSynthroid = 47.2 million prescriptionsAtenolol = 40.9 million prescriptionsZithromax = 39.5 million prescriptions

N

OH OH

O

O

NH

O

F 2

Ca2+

*3 H2O

Lipitor (a.k.a., Atorvastatin)65.5 million prescriptions (2003); No. 2

S

HO2C

Cl

HN

O

H2N

O O

Furosemide (Lasix)

NH

NHS

OO

S

Cl

H2N

OO

Hydrochlorothiazide

N

N

NN

Cl

Alprazolam (Xanax)

NHCl

Cl

H

Cl

ZOLOFT® (sertraline hydrochloride)

O OH

O

N

N

Cl

Cl

Cl

Zyrtec (Cetirizine HCl)

racemic

H

H

SO

OH2N

N

N

FF

F

Celebrex

N

N

S OO

O

N

HNN

N

O

OH

O

OH

O

OH

O

OH

Viagra (Sildenafil citrate)

N

N

O Cl

Valium

N

N

NHN

Me

HN

O

N

N

CH2SO3H

Gleevec

Hydrocodone / APAP = 85.1 million prescriptionsLipitor = 65.5 million prescriptionsSynthroid = 47.2 million prescriptionsAtenolol = 40.9 million prescriptionsZithromax = 39.5 million prescriptions

N

OH OH

O

O

NH

O

F 2

Ca2+

*3 H2O

Lipitor (a.k.a., Atorvastatin)65.5 million prescriptions (2003); No. 2

S

HO2C

Cl

HN

O

H2N

O O

Furosemide (Lasix)

NH

NHS

OO

S

Cl

H2N

OO

Hydrochlorothiazide

N

N

NN

Cl

Alprazolam (Xanax)

NHCl

Cl

H

Cl

ZOLOFT® (sertraline hydrochloride)

O OH

O

N

N

Cl

Cl

Cl

Zyrtec (Cetirizine HCl)

racemic

H

H

SO

OH2N

N

N

FF

F

Celebrex

N

N

S OO

O

N

HNN

N

O

OH

O

OH

O

OH

O

OH

Viagra (Sildenafil citrate)

N

N

O Cl

Valium

N

N

NHN

Me

HN

O

N

N

CH2SO3H

Gleevec

Hydrocodone / APAP = 85.1 million prescriptionsLipitor = 65.5 million prescriptionsSynthroid = 47.2 million prescriptionsAtenolol = 40.9 million prescriptionsZithromax = 39.5 million prescriptions

• Top Pharmaceutical Drugs

Lipitor (U.S. Pat. No. 5,273,995 (12/28/1993)

• No purification other than crystallization (even for Aldol)• More recent patent (Int. Pat. No. 2004/89894 A1) uses

RCM to generate the cyclic intermediate

N H

O

HN

O

Ph

Ph

F

O

O

Ph

O

PhPh

Mg2+

N

OH

HN

O

Ph

Ph

F

O

O Ph

OH

PhPhthen HOAc

73% yield

NaOMe/MeOH75 % yield

Ar

OH

OMe

O

78 % yield

O

OtBu

(8 eq.)

Ar

OH O

OtBu

O

Ar

O

1. B(Et)3, NaBH4

then H2O2(83 %)

2. NaOH, Tol. (83 %)

O

OH

1. NaOH (0.98 eq.)

2. CaCl2, H2ON

OH OH

O

O

Ph

PhHNOC

F 2

Ca2+

*3 H2O

J. Med. Chem. 1991, 34, 1, 357-366

Lipitor Starting Material

F

Br

OEtO

H2N O

O

Et3N, CH3CN

RT

82%

F

N

OEtO

H

OO

1. (Me)2CHCOCl

Et3N, CH2Cl22. NaOH

97%

F

N

OO

HO2C O

Ph CONHPh

Ac2O, 90°C

43%

N

OO

F

Ph CONHPh

1. HCl, EtOH reflux2. pTsOH acetone/water reflux 87%

N H

O

HN

O

Ph

Ph

F

B. D. Roth et al., “Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one Inhibors of HMG-CoAReductase. 2. Effects of Introducing Substituents at Positions Three and fourof the Pyrrole Nucleus”, J. Med. Chem., 1991, 34, 357-366.

Gleevec (imatinib; EP Pat. No. 0564409;U.S. Pat. 55211584)

Me

NH2

NO2

HNO3

then

20-25%

NH2CN

Me HN

NO2

NH

NH2 NaOH50%

N

O NMe2

Me HN

NH2

N

N

N

1.

2. H2, Pd/C

Me

CO2H

1. MeOH, H+

2. NBS

3. N-Me-piperazine

CO2Me

N

N

1. KOH/H2O

2. SOCl2

CO2Cl

N

N

Py

N

N

NHN

Me

NH

O

N

N

• “Improved” process published in Int. Pat. 2004/108699 A1• How are these drugs discovered?

Viagra (sildenafil; U.S. Pat. No. 6,066,735)

D. J. Pale et al. “The Chemical Development of the Commercial Route toSildenafil: A Case History”, Org. Proc. Res. Dev. 2000, 4, 17-22

O

PrMe(CO2Et)2

NaOEt

O

PrNaO

OEtOH2NNHMe

NN

Pr

HO

O Me

1. HNO3/H2SO4

2. SOCl2/NH3

NN

Pr

H2N

O Me

O2N

OEt

OH

O ClSO3H

SOCl2H2O quench

Problem with using dry thionyl chloride

OEt

OH

O

SO2Cl

HN

NMe

NaOH/H2O

OEt

OH

O

O2SN

N

NN

Pr

H2N

O Me

O2N

H2, Pd/C

Med. Chem.

used SnCl2/HCl

NN

Pr

H2N

O Me

H2N

OEt

OH

O

O2SN

N

O

NNNN

OEt

N

O

O2SN

N

N

OEt

NH

O

O2SN

N

N

NH2NOC

Me

Pr

EtO

N

HN

O2SN

N

O

N

N

Me

Pr

KOtBu

tBuOH

then HCl

Requirements for a good process

• Process safety– Exothermicity of reaction(s)– Reagents used– Order of steps

• Environmental assessment/impact– Byproducts– Solvent waste/recovery

• Approach– Convergent/Linear

• Yield– Throughput– Purification