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
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