Artificial Photosynthesis: a synthetic organic perspective

Wei LiuMacMillan group meeting

Mar. 11th, 2020

image credit: Wiley-VCH

Photosynthesis: a brief overview

Net reaction

6 CO2 6 H2O+ + 6 O2sunlight O

OH

H

OH

H

H

OHOH

H H

HO

Water-splitting reaction (Light-dependent)

2 H2O +sunlight

O2 4 H+ + 4 e-

(stored in NADPH and ATP)

CO2 fixation (Light-independent)

3 CO2

RuBisCO-O3PO

CHO

OH

(G3P)

Jack Twilton, MacMillan group meeting, “Photosynthesis – An Organic Chemists Guide”

��Complex organic molecules

��Socioeconomic considerations

��Progress in synthetic biology

Artificial photosynthesis: a brief overview

Artificial photosynthesis

2 H2O +sunlight

O2 2 H2

CO2

chemical

Representative review: Chem. Rev. 2013, 113, 6621; Acc. Chem. Res. 2017, 50, 476

+ H2biological

CO CH4 CH3OH

and more…C4H9OH

OOH

H

OH

H

H

OHOH

H H

HO

Outlook

CO2 Conversion Challenge

Started by NASA in 2019 (now in Phase II)

Space exploration to Mars

CO2 recycling (life support system)

Why NASA wants glucose?

Energy sources for microbial fermentation

C6 sugar is preferred in microbial system

https://www.co2conversionchallenge.org

CO2 fixation (availabe SM on Mars)

Total synthesis of glucose on Mars?

What about earthly synthesis of glucose?

POO

OP

OH

OH RuBisCO

CO2, H2O

OHPO OH

O

Nature’s approach: Calvin-Benson cycle

RuBisCO (ribulose-1,5-bisphosphate carboxylase/oxygenase)

responsible for more than 90% carbon fixation

one of the most abdundant enzyme on earth

Erb, T. J.; Zarzycki, J. Curr. Opin. Biotech. 2018, 49, 100

low turnover frequency (1 to 10 s-1)

3 to 10 molecules of CO2 fixed per second per enzyme

low specificity (CO2 vs O2)

Bar-Even, A.; Noor, E.; Lewis, N. E.; Milo, R. Proc. Natl. Acad. Sci. USA 2010, 107, 8889Schwander T.; Schada, v. B. L.; Burgener, S.; Cortina, N. S.; Erb, T. J. Science, 2016, 354, 900

targets for synthetic biology

POO

OP

OH

OH

Nature’s approach: Calvin-Benson cycle

Erb, T. J.; Zarzycki, J. Curr. Opin. Biotech. 2018, 49, 100

POOH

OP

OH

OHenolization

Mg2+

CO2 PO OP

O

OHOH

–OOC

H2OPO OP

OH

OHOH

HOOC OH

retro-Claisen OHPO OH

O

OHPO H

O

[H]

G3P

Ribulose-1,5-BP

Mechanism of RuBisCO

Economics of RuBisCO

3 Ribulose-1,5-BP + 3 CO2 5 G3P3 x C5 5 x C33 x C1

CO2 to C6 sugarOH

PO H

O

+O

HO OHPO

OHO

OH

OH

OH

tautomerization

1 G3P1 x C3

Fructose-6-P

cross Aldol

POO

OP

OH

OH

Nature’s approach: Calvin-Benson cycle

Erb, T. J.; Zarzycki, J. Curr. Opin. Biotech. 2018, 49, 100

POOH

OP

OH

OHenolization

Mg2+

Ribulose-1,5-BP

Mechanism of RuBisCO

Economics of RuBisCO

3 Ribulose-1,5-BP + 3 CO2 5 G3P3 x C5 5 x C33 x C1

CO2 to C6 sugarOH

PO H

O

+O

HO OHPO

OHO

OH

OH

OH

tautomerization

1 G3P1 x C3

Fructose-6-P

O2

OHPO OH

O

O

OHPO

recycle+

De novo synthesis of Hexose

Masamune & Sharpless, Science 1983, 220, 949

HOOH

HOO

H

OH

OH

OH

OH

asymmetric epoxidation

MeO

OO

OR

OBn

OAc

+

OHO

OBn

OAcOR

R1

[4+2] cycloaddition

H

O

OR

organocatalytic

“trimerization”

OTIPSO

OH

OAcOH

TIPSO3 X

Boger, J. Org. Chem. 1988, 53, 5793

MacMillan, Science 2004, 305, 1752

De novo synthesis of Hexose

Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, 949

OHRO

OHRO

O

Ti(OiPr)4, tBuOOH

(+)-diisopropyl tartrate

PhSH, NaOH

tBuOHSPh

ROOH

OH

SPhRO

O

OMe Me

MeO OMe

POCl3

1. mCPBA

2. Ac2O, NaOAcSPh

ROO

O

OAc

DIBAL

CHOROO

O H

OPh3P1.

2. NaBH4 ROO

OOH

ROO

OOH

O

(-)-AE

ROO

OSPh

PhSH, NaOH

tBuOHOH

OH1. Diol protection

2. Pummerer

3. K2CO3, MeOH4. deprotection

HOOH

OHO

OH

OH

L-glucose

De novo synthesis of Hexose

Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, 949

OHRO

OHRO

O

Ti(OiPr)4, tBuOOH

(+)-diisopropyl tartrate

PhSH, NaOH

tBuOHSPh

ROOH

OH

OHRO

O

OH-

Payne rearrangement

ROOH

O PhS-SPh

ROOH

OH

avoids unprotected triol

De novo synthesis of Hexose

Masamune & Sharpless, Science 1983, 220, 949

HOOH

HOO

H

OH

OH

OH

OH

asymmetric epoxidation

MeO

OO

OR

OBn

OAc

+

OHO

OBn

OAcOR

R1

[4+2] cycloaddition

H

O

OR

organocatalytic

“trimerization”

OTIPSO

OH

OAcOH

TIPSO3 X

Boger, J. Org. Chem. 1988, 53, 5793

MacMillan, Science 2004, 305, 1752

De novo synthesis of Hexose

Boger, D. L.; Robarge, K. D. J. Org. Chem. 1988, 53, 5793

Inverse electron demand [4+2] cycloaddition

H3CO

OO

OCH3

OEt+

O OEt

OCH3

H3CO

O

Condition Result

neat, 13 kbar 82% yield (6:1 endo:exo)

CH2Cl2, 6 kbar 75% yield (6:1 endo:exo)

EtAlCl2 or TiCl4 complex mixture

Toluene, 110oC 48% yield (2:1 endo:exo)

H3CO

OO

OCH3

OEt+

O OEt

OCH3

H3CO

O

OAcOAc

13 kbar

CH2Cl2

49% yield (>45:1 endo:exo)

De novo synthesis of Hexose

Boger, D. L.; Robarge, K. D. J. Org. Chem. 1988, 53, 5793

H3CO

OO

OCH3

OEt

OEt

OAc

13 kbar

O OEt

OCH3

HO

O OEt

OCH3

HO

O OEt

OCH3

HO

O OEt

OCH3

HO

HO

HO

OAc

OAc

O OEt

OCH3

MeO2C

O OEt

OCH3

AcO

O OEt

OCH3

MeO2C

O OEt

OCH3

AcO

OAc

OAc

O OEt

OCH3

H3CO

O

O OEt

OCH3

H3CO

O

OAc13 kbar

H2

LAH;

Ac2O

H2

LAH;

Ac2O

LAH

LAH

BH3

[O]

BH3

[O]

De novo synthesis of Hexose

Masamune & Sharpless, Science 1983, 220, 949

HOOH

HOO

H

OH

OH

OH

OH

asymmetric epoxidation

MeO

OO

OR

OBn

OAc

+

OHO

OBn

OAcOR

R1

[4+2] cycloaddition

H

O

OR

organocatalytic

“trimerization”

OTIPSO

OH

OAcOH

TIPSO3 X

Boger, J. Org. Chem. 1988, 53, 5793

MacMillan, Science 2004, 305, 1752

L-allose97% yield>19:1 dr95% ee

L-mannose87% yield>19:1 dr95% ee

L-glucose

De novo synthesis of Hexose

Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152

H

O

OR

L-proline N

OR

COOH H

OOR

enantioselectivealdol

H

O

OR

OH

OR

92% yield, 4:1 anti:syn, 95% ee (R = TIPS)78% yield, 4:1 anti:syn, 98% ee (R = Bn)

H

O

TIPSO

OH

OTIPSH

OTMSOAc+

O

OHTIPSO OAc

OHTIPSO

O

OHTIPSO OAc

OHTIPSO

O

OHTIPSO OAc

OHTIPSO

MgBr2

Et2O

MgBr2

CH2Cl2

TiCl4CH2Cl2

79% yield10:1 dr95% ee

https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19850008164.pdf

NASA’s approach

https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19850008164.pdf

NASA’s approach

page 49

Formose reaction

Discovered by Aleksandr Butlerow in 1861

Now accepted mechanism proposed by Breslow in 1959

Considered by NASA as a way to synthesize glycerol

Breslow, R. Tetrahedron Lett. 1959, 21, 22

Autocatalytic: long induction period, followed by fast reaction

H H

O aq. Ca(OH)2HO

OH

OHOH

nHO

OH

OHOH

n

O HOH2C

HO OH

O OHO

HOH2C

OH

OH

OH

OH

a mixture of sugars: “formose sugar”

Butlerow, A. Justus Liebigs Annalen der Chemie, 1861, 120, 295

Addition of intermediates removes induction, but doesn’t increase rate

H

O

OHH

O

OHHO OH

OHO

Formose reaction

Breslow, R. Tetrahedron Lett. 1959, 21, 22

Autocatalytic cycle

H H

O

H H

O+

slowhv? H

OOH

H

O

OHOH

HOO

OH

OOH

HOOH

OHO

HOOH

H H

O

Ca(OH)2Aldol

Tautomerization Ca(OH)2

H H

OCa(OH)2

Aldol

TautomerizationCa(OH)2

retro-AldolCa(OH)2

Formose reaction

Breslow, R. Tetrahedron Lett. 1959, 21, 22

Product-forming pathway

H H

O

H

OOH

H

O

OHOH

HOO

OHO

OHHO

OH

H

O

OHOH

Cross Aldol reaction

H

OOH

H

O

OH

OH

OHOH

HOH2C

HO OH

O OH

HOO

OHH

O

OHOH

HOO

OH

OH

OHOH

HOH2C

HO OH

O OH

CH2OH

Cannizzaro reaction

H

O

OHOH H H

OHO

OHOH

H OH

OOH-

Formose reaction

Decker, P.; Schweer, H.; Pohlmann, R. J. Chromatogr. A 1982, 244, 281

The reality

H H

O aq. Ca(OH)2H

O

OHOH HO

OHOH HO

OOH

HOOH

OH

HO

OHO

HOOH

OHO

OH

HOOH

OHOH

HOO

OHO

HOOH

HO OOH

OH

HOOH

OH

OH

HOOH

OHH

O

and all the diastereomers…

Formose reaction

Decker, P.; Schweer, H.; Pohlmann, R. J. Chromatogr. A 1982, 244, 281

The reality

“the formose product can be regarded as a carbohydrate analog of petroleum, in that it contains so many carbohydrates of varying molecular weight and isomeric structure” (Weiss et al., 1970)

Selective Formose reaction

H

OHO H

O

OHHO H

O

HOOH

OH

OH

C5 pentoseglycoaldehyde(donor)

glyceraldehyde(acceptor)

Na2B4O7

borate minerals H

HOH2C

O O

O

BO O

H

OH

stabilized by borate complex

H

OHO

H

OHO

glycoaldehyde glycoaldehyde

Na2SiO3H

OHO

OH

OH

C4 sugarstabilized by silicate complex

O

H

HO O

O

H

H

SiHO

O

O

Ricardo, A.; Carrigan, M. A.; Olcott, A. N. Benner, S. A. Science 2004, 303, 196Lambert, J. B.; Gurusamy-Thangavelu, S. A.; Ma, K. Science 2010, 327, 984Matsumoto, T.; Yamamoto, H.; Inoue, S. J. Am. Chem. Soc. 1984, 106, 4829

H H

O

formaldehyde dihydroxyacetone

thiazolium catalyst3 X

OOHHO

17% IY

N

S

Et

Br–

catalyst

Selective Formose reaction

H

OHO H

O

OHHO H

O

HOOH

OH

OH

Ca(OH)2

Ricardo, A.; Carrigan, M. A.; Olcott, A. N. Benner, S. A. Science 2004, 303, 196

45oC

pentose detected after 20 mins

pentose disappeared after 1 hour

reaction turned brown

Original Formose condition

pentose is the majority of total carbon

ribose remains stable for days

suggest prebiotic ribose synthesis

Borate mineral condition

H

O

OB OH

O

OHHO

OO

H

OH

OHHO

enediol

decomp.

Selective Formose reaction

H

OHO H

OHO

OH

OHNa2SiO3

Lambert, J. B.; Gurusamy-Thangavelu, S. A.; Ma, K. Science 2010, 327, 984

25oC

major C4 with some C6 product after 20 mins

C6 becomes major product after 12 hours

product decomposes or oligomerizes if it can’t form silicate

H

OHO

O

H

HO O

O

H

H

SiHO

O

O

H

ONa2SiO3

25oCH

O

OHHO HO

OH

C6 sugar silicate

Selective Formose reaction

H

OHO H

OHO

OH

OHNa2SiO3

Lambert, J. B.; Gurusamy-Thangavelu, S. A.; Ma, K. Science 2010, 327, 984

25oCH

OHO

silicate, 30 mins

silicate, 12 hours

NaOH, 30 mins

NaOH, 12 hours

Selective Formose reaction

Matsumoto, T.; Yamamoto, H.; Inoue, S. J. Am. Chem. Soc. 1984, 106, 4829

H H

O

formaldehyde dihydroxyacetone

thiazolium (5 %)3 X

OOHHO

N

S

Et

Br–

catalyst

Et3N (5%), EtOH30 mins, 100oC

S

NEt

H H

O

S

NEt

COH

H S

NEt

CHOH

H H

O

S

NEt

CHOH

CH2O

S

NEt

CHOCH2

HOH H

O

S

NEt

CO

HO

HO

S

NEt

OOHHO

Selective Formose reaction

Matsumoto, T.; Yamamoto, H.; Inoue, S. J. Am. Chem. Soc. 1984, 106, 4829

H H

O

formaldehyde dihydroxyacetone

thiazolium (5 %)3 X

OOHHO

N

S

Et

Br–

catalyst

Et3N (5%), EtOH30 mins, 100oC

S

NEt

H H

O

S

NEt

COH

H S

NEt

CHOH

H H

O

S

NEt

CHOH

CH2O

S

NEt

CHOCH2

HOH H

O

S

NEt

CO

HO

HO

S

NEt

OOHHO

Selective Formose reaction

Matsumoto, T.; Yamamoto, H.; Inoue, S. J. Am. Chem. Soc. 1984, 106, 4829

H H

O

formaldehyde dihydroxyacetone

thiazolium (5 %)3 X

OOHHO

Et3N (5%), EtOH30 mins, 100oC

OHO

CHO

OHHO

H

not detected

Reactivity with thiazolium:

OHO

H H H

O

CHO

OHHO> >

Control experiments:

OHO

H

thiazolium (5 %)

Et3N (5%), EtOHno conversion

OHHO

CHO

thiazolium (5 %)

Et3N (5%), EtOHno conversion

Selective Formose reaction

Matsumoto, T.; Yamamoto, H.; Inoue, S. J. Am. Chem. Soc. 1984, 106, 4829

H H

O

formaldehyde dihydroxyacetone

thiazolium (5 %)3 X

OOHHO

Et3N (5%), EtOH30 mins, 100oC

OHO

CHO

OHHO

H

not detected

Reactivity with thiazolium:

OHO

H H H

O

CHO

OHHO> >

Control experiments:

OHO

H

thiazolium (5 %)

Et3N (5%), EtOH

OHHO

CHO

thiazolium (5 %)

Et3N (5%), EtOH

H H

O

H H

O

+O

OHHO

+O

OHHO

OHHO

CHO+

fully recovered

Selective Formose reaction

Matsumoto, T.; Yamamoto, H.; Inoue, S. J. Am. Chem. Soc. 1984, 106, 4829

H H

O

formaldehyde dihydroxyacetone

thiazolium (5 %)3 X

OOHHO

Et3N (5%), EtOH30 mins, 100oC

OHO

CHO

OHHO

H

not detected

Reactivity with thiazolium:

OHO

H H H

O

CHO

OHHO> >

Control experiments:

OHO

H

thiazolium (5 %)

Et3N (5%), EtOHH H

O+

OOHHO

If formaldehyde reacts first:

S

NEt

CHOH

OHO

H

S

NEt

CHO H

HO

O

S

NEt

CO

HO

HO

HCHO

OHHO

S

NEt

not detected