Artificial Photosynthesis: a synthetic organic perspective

Wei Liu
MacMillan group meeting
Mar. 11th, 2020

image credit: Wiley-VCH

 Photosynthesis: a brief overview

Net reaction
OH
HO H O
sunlight
6 CO2 + 6 H2O H + 6 O2
H H
H
OH
OH OH

Water-splitting reaction (Light-dependent)

sunlight
2 H2O O2 + 4 H+ + 4 e-

(stored in NADPH and ATP)

CO2 fixation (Light-independent)

RuBisCO OH
-O PO
3 CO2 3
CHO

(G3P)

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

 Artificial photosynthesis: a brief overview

Artificial photosynthesis Outlook

sunlight
2 H2O O2 + 2 H2
OH
HO H O
H
H H
chemical CO CH4 CH3OH H
OH
CO2 + H2 OH OH
biological C4H9OH and more…

Complex organic molecules

Socioeconomic considerations

Progress in synthetic biology

Representative review: Chem. Rev. 2013, 113, 6621; Acc. Chem. Res. 2017, 50, 476
 CO2 Conversion Challenge

Started by NASA in 2019 (now in Phase II)

Space exploration to Mars

CO2 recycling (life support system)

CO2 fixation (availabe SM on Mars)

Why NASA wants glucose?

Energy sources for microbial fermentation

C6 sugar is preferred in microbial system

Total synthesis of glucose on Mars?

What about earthly synthesis of glucose?

https://www.co2conversionchallenge.org
 Nature’s approach: Calvin-Benson cycle

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

O OH OH
RuBisCO
PO OP PO OH
CO2, H2O
OH O

responsible for more than 90% carbon fixation

one of the most abdundant enzyme on earth

low turnover frequency (1 to 10 s-1)

3 to 10 molecules of CO2 fixed per second per enzyme

low specificity (CO2 vs O2)

targets for synthetic biology

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

Bar-Even, A.; Noor, E.; Lewis, N. E.; Milo, R. Proc. Natl. Acad. Sci. USA 2010, 107, 8889
Schwander T.; Schada, v. B. L.; Burgener, S.; Cortina, N. S.; Erb, T. J. Science, 2016, 354, 900
 Nature’s approach: Calvin-Benson cycle

Mechanism of RuBisCO

O OH OH OH OH OH
enolization CO2
PO OP PO OP PO OP
Mg2+ –OOC
OH OH O
Ribulose-1,5-BP

OH OH OH [H] OH
H 2O retro-Claisen
PO OP PO OH PO H

HOOC OH
OH O O
G3P
CO2 to C6 sugar
OH OH
OH O cross Aldol
+ PO
PO H OH
HO OH
OH O
O
tautomerization
Fructose-6-P

Economics of RuBisCO

3 Ribulose-1,5-BP + 3 CO2 5 G3P 1 G3P

3 x C5 3 x C1 5 x C3 1 x C3

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

 Nature’s approach: Calvin-Benson cycle

Mechanism of RuBisCO
OH
O OH OH OH
enolization O2 PO OH
PO OP PO OP
Mg2+ O
OH OH
Ribulose-1,5-BP + recycle
OH
PO
O

CO2 to C6 sugar
OH OH
OH O
+ PO
PO H OH
HO OH
OH O
O
tautomerization
Fructose-6-P

Economics of RuBisCO

3 Ribulose-1,5-BP + 3 CO2 5 G3P 1 G3P

3 x C5 3 x C1 5 x C3 1 x C3

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

 De novo synthesis of Hexose

asymmetric epoxidation OH OH
OH O
HO HO
OH OH H

Masamune & Sharpless, Science 1983, 220, 949

O
O OBn
O OBn [4+2] cycloaddition HO
MeO
+
R1 OAc
OAc
OR
OR
Boger, J. Org. Chem. 1988, 53, 5793

O O OH
organocatalytic TIPSO

3X H TIPSO OAc
OR “trimerization”
OH

MacMillan, Science 2004, 305, 1752

 De novo synthesis of Hexose

OH
Ti(OiPr)4, tBuOOH OH PhSH, NaOH
OH RO SPh
RO O RO
(+)-diisopropyl tartrate tBuOH
OH

MeO OMe
O O
Me Me 1. mCPBA DIBAL
SPh SPh
RO RO
POCl3 2. Ac2O, NaOAc
O O OAc

O
1. Ph3P
O O
H (-)-AE
OH OH
RO CHO 2. NaBH4 RO RO
O
O O O

1. Diol protection
O OH OH OH
PhSH, NaOH 2. Pummerer
SPh O
RO HO L-glucose
tBuOH 3. K2CO3, MeOH
O OH OH OH
4. deprotection

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

OH
Ti(OiPr)4, tBuOOH OH PhSH, NaOH
OH RO SPh
RO O RO
(+)-diisopropyl tartrate tBuOH
OH

OH
OH- O
PhS-
OH SPh
RO RO RO
O
OH OH

Payne rearrangement avoids unprotected triol

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

asymmetric epoxidation OH OH
OH O
HO HO
OH OH H

Masamune & Sharpless, Science 1983, 220, 949

O
O OBn
O OBn [4+2] cycloaddition HO
MeO
+
R1 OAc
OAc
OR
OR
Boger, J. Org. Chem. 1988, 53, 5793

O O OH
organocatalytic TIPSO

3X H TIPSO OAc
OR “trimerization”
OH

MacMillan, Science 2004, 305, 1752

 De novo synthesis of Hexose

Inverse electron demand [4+2] cycloaddition

O
O
O OEt
O OEt H3CO
H3CO
+

OCH3
OCH3

Condition Result

EtAlCl2 or TiCl4 complex mixture

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

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

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

O
O
O OEt
O OEt 13 kbar H3CO
H3CO
+
OAc
CH2Cl2 OAc
OCH3
OCH3

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

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

 De novo synthesis of Hexose

O OEt
MeO2C O OEt HO
H2 LAH

OEt O
OCH3
O OEt OCH3
H3CO

13 kbar
O OEt
OCH3 HO
LAH; O OEt BH3
AcO
[O] HO
Ac2O
O OCH3
OCH3
O
H3CO

OCH3 MeO2C O OEt O OEt

HO
H2 LAH
OEt OAc OAc
O
OCH3 OCH3
O OEt
OAc H3CO

13 kbar OAc
OCH3 O OEt O OEt
LAH; AcO BH3 HO

Ac2O OAc [O] HO OAc

OCH3 OCH3

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

 De novo synthesis of Hexose

asymmetric epoxidation OH OH
OH O
HO HO
OH OH H

Masamune & Sharpless, Science 1983, 220, 949

O
O OBn
O OBn [4+2] cycloaddition HO
MeO
+
R1 OAc
OAc
OR
OR
Boger, J. Org. Chem. 1988, 53, 5793

O O OH
organocatalytic TIPSO

3X H TIPSO OAc
OR “trimerization”
OH

MacMillan, Science 2004, 305, 1752

 De novo synthesis of Hexose

O
O OR O OH
L-proline N COOH H
H H
enantioselective
OR aldol OR OR
OR

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

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

O OH L-glucose
MgBr2 TIPSO
79% yield
Et2O TIPSO OAc 10:1 dr
OH 95% ee

O OH O OH L-mannose
OTMS MgBr2 TIPSO
+ 87% yield
H OAc
H CH2Cl2 TIPSO OAc >19:1 dr
TIPSO OTIPS
OH 95% ee

O OH L-allose
TiCl4 TIPSO
97% yield
CH2Cl2 TIPSO OAc >19:1 dr
OH 95% ee

Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752

Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152
 NASA’s approach

https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19850008164.pdf
 NASA’s approach

page 49

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

HOH2C
OH O OH HOH2C OH
O O OH
O aq. Ca(OH)2
OH OH OH
HO HO
H H
OH n OH n HO OH OH
OH

a mixture of sugars: “formose sugar”

Discovered by Aleksandr Butlerow in 1861

Considered by NASA as a way to synthesize glycerol

Now accepted mechanism proposed by Breslow in 1959

Autocatalytic: long induction period, followed by fast reaction

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

O O

H HO H HO OH
OH OH O

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

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

Autocatalytic cycle
O
O O slow O
+ H H
OH
H H H H hv? H
Ca(OH)2
Ca(OH)2 retro-Aldol Aldol

OH O
HO
O H OH
OH OH

Ca(OH)2 Tautomerization Tautomerization Ca(OH)2

OH
HO HO OH
OH
O
O
Aldol

Ca(OH)2 O

H H

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

 Formose reaction

Product-forming pathway

O O O O O
OH HO OH OH
H H H H OH HO
OH OH

Cross Aldol reaction

HOH2C OH
O O O OH O

OH
H H OH H OH
HO OH
OH OH OH

HOH2C OH
O O O OH O
HO OH HO
H OH OH CH2OH
OH OH OH HO OH

Cannizzaro reaction
O O O
OH- HO OH
H OH H H H OH
OH
OH

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

 Formose reaction

The reality
O O
O aq. Ca(OH)2
H OH HO OH HO OH
H H
OH OH

HO
OH O
HO HO
HO OH O OH
OH OH OH

OH OH OH
HO
HO O O HO OH
OH OH HO OH OH O

OH OH
H
HO and all the diastereomers…
OH OH O

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

 Formose reaction

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)

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

 Selective Formose reaction

O HOH2C OH
O OH O O
Na2B4O7
HO HO H
H borate minerals HO H H
OH H
OH OH O O
glycoaldehyde glyceraldehyde B
C5 pentose O O
(donor) (acceptor)
stabilized by borate complex

H H
OH O O
O O
Na2SiO3 HO
HO HO H H
H H O
OH HO O O
glycoaldehyde glycoaldehyde Si
C4 sugar HO O

stabilized by silicate complex

Et
O thiazolium catalyst O N
HO OH Br–
3X H H 17% IY S

formaldehyde dihydroxyacetone catalyst

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

O
O OH O
Ca(OH)2
HO HO H
H 45oC HO H
OH OH OH

Original Formose condition

O
pentose detected after 20 mins O
O H
pentose disappeared after 1 hour HO H
B O
O
OH
reaction turned brown O

Borate mineral condition

pentose is the majority of total carbon OH

HO H
decomp.
ribose remains stable for days
OH
suggest prebiotic ribose synthesis
enediol

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

O O OH O
Na2SiO3
HO HO HO
H
H H 25oC
OH

H H
O
major C4 with some C6 product after 20 mins
H
O
C6 becomes major product after 12 hours O O
HO
Si
product decomposes or oligomerizes if it can’t form silicate HO O

O O
Na2SiO3
HO H HO H C6 sugar silicate
25oC
OH OH

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

 Selective Formose reaction

O O OH O
Na2SiO3
HO HO HO
H
H H 25oC
OH

silicate, 30 mins

silicate, 12 hours

NaOH, 30 mins

NaOH, 12 hours

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

 Selective Formose reaction

Et
O thiazolium (5 %) O N
HO OH Br–
3X H H Et3N (5%), EtOH S
30 mins, 100oC
formaldehyde dihydroxyacetone catalyst

O O
Et Et Et O Et
N H H H N N H H CH2 N
O C HO C HO C
S H S H S H S
Et
N
O
HO Et HO Et
S
CH2 N N O
H H
HO C O C HO OH
S S
HO

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

Et
O thiazolium (5 %) O N
HO OH Br–
3X H H Et3N (5%), EtOH S
30 mins, 100oC
formaldehyde dihydroxyacetone catalyst

O O
Et Et Et O Et
N H H H N N H H CH2 N
O C HO C HO C
S H S H S H S
Et
N
O
HO Et HO Et
S
CH2 N N O
H H
HO C O C HO OH
S S
HO

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

O thiazolium (5 %) O O OH
HO OH HO HO
3X H H Et3N (5%), EtOH H CHO
30 mins, 100oC
formaldehyde dihydroxyacetone not detected

Reactivity with thiazolium:

O O OH
HO > > HO
H H H CHO

Control experiments:

O thiazolium (5 %)
HO no conversion
H Et3N (5%), EtOH

OH thiazolium (5 %)
HO no conversion
CHO Et3N (5%), EtOH

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

O thiazolium (5 %) O O OH
HO OH HO HO
3X H H Et3N (5%), EtOH H CHO
30 mins, 100oC
formaldehyde dihydroxyacetone not detected

Reactivity with thiazolium:

O O OH
HO > > HO
H H H CHO

Control experiments:

O O thiazolium (5 %) O
+ HO HO OH
H H H Et3N (5%), EtOH

O OH
O OH thiazolium (5 %)
+ HO HO OH + HO
CHO
H H CHO Et3N (5%), EtOH
fully recovered

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

O thiazolium (5 %) O O OH
HO OH HO HO
3X H H Et3N (5%), EtOH H CHO
30 mins, 100oC
formaldehyde dihydroxyacetone not detected

Reactivity with thiazolium:

O O OH
HO > > HO
H H H CHO

Control experiments:

O O thiazolium (5 %) O
+ HO HO OH
H H H Et3N (5%), EtOH
Et
If formaldehyde reacts first: N

HO HO
O S
Et Et Et
HO OH
N H O N HO N
HO C HO
C C CHO
S HO S O S
H H H
not detected

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