1. Circularly polarized light 2. Solid-phase 3. Solution-phase • Covalently-bound chiral auxilliaries • Chiral complexing agents • Chiral sensitizer Asymmetric Photochemistry MacMillan Group Meeting October 18, 2000 Tehshik Yoon Inoue, Y., in Organic Molecular Photochemistry, Ramamurthy, V., Schanze, K. S., Eds.; Dekker: New York, 1999, pp 71-130. Inoue, Y. Chem. Rev. 1992, 92, 741-770. Rau, H. Chem. Rev. 1983, 83, 535-547. Reviews: Why Study Asymmetric Photochemistry? ! Prebiotic photochemistry –– enantiomeric excess of biomolecules may have been generated by circularly polarized light (CPL) ! Environmentally benign processes –– light requires no workup, generates no waste ! Different mode of reactivity –– access to novel, strained compounds which are thermally inaccessible or difficult to synthesize
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1. Circularly polarized light
2. Solid-phase
3. Solution-phase • Covalently-bound chiral auxilliaries • Chiral complexing agents • Chiral sensitizer
Asymmetric Photochemistry
MacMillan Group MeetingOctober 18, 2000
Tehshik Yoon
Inoue, Y., in Organic Molecular Photochemistry, Ramamurthy, V., Schanze, K. S., Eds.; Dekker: New York, 1999, pp 71-130.Inoue, Y. Chem. Rev. 1992, 92, 741-770.Rau, H. Chem. Rev. 1983, 83, 535-547.
Reviews:
Why Study Asymmetric Photochemistry?
! Prebiotic photochemistry –– enantiomeric excess of biomolecules may have been
generated by circularly polarized light (CPL)
! Environmentally benign processes –– light requires no workup, generates no waste
! Different mode of reactivity –– access to novel, strained compounds which are
thermally inaccessible or difficult to synthesize
S0
S1
S2
T1
S0
T1absorption fluorescence
intersystemcrossing
vibrational relaxation
radiationlessdecay
radiative process
nonradiative process
sensitization(quenching)
Photophysical processes
E
! Generalized Jablonski diagram
• Photochemistry can happen from either S1 or T1 state, but normally T1
• Spin-allowed processes (S to S, T to T) tend to be faster, so T1 is usually longer-lived (kd ~ 0.4 s-1)
• E(T1/S1) ~ 102 kcal/mol for most useful organic photochemistry
phosphorescence
see, e.g., Carroll, Structure and Mechanism inOrganic Chemistry, Pacific Grove, CA: Brooks/ColeCh. 12.
Asymmetric photodestruction with CPL
! Kuhn and Braun (1929)
MeEtO
O
Br
R-CPL
50% conv
MeEtO
O
Br
!D = +0.5 °(±) *
! Kuhn and Knopf (1930)
MeMe2N
O
N3
R-CPL
40% conv
MeMe2N
O
N3
[!]D = +0.78 °0.5% ee(±) *
Me
Me Me
O
! Kagan (1974)
(±)R-CPL
99% convMe
Me Me
O
20% ee
Naturwissenschaften, 1929, 17, 227
Naturwissenschaften, 1930, 19, 183
JACS, 1974, 96, 5152
! van't Hoff first suggested the possibility of asymmetric photochemistry with CPL in 1897
Photoresolution using CPL
Sh!, k1
h!, k-1
! enantiomers absorb nonpolarized or linearly polarized light with equal intensity
! enantiomers can absorb circularly polarized light with different intensities; the rate of reaction is proportional to the absorption coefficients ("R and "S)
! a photostationary state (pss) is achieved when k1[R] = k-1[S]
optical purity = ([R]-[S])/([R]+[S]) = g/2
where g = ("R - "S)/"; " = ("R + "s)/2
"R[R] = "S[S]
! g depends on wavelength of irradiation
Stevenson JACS 1978, 90, 2974
Photoresolution using CPL
O
PhH
O
H
Ph
O
HPh
h!
h!
! Schuster (1995): g313 = 0.0502
CPL induces observed 1.6% ee
JOC, 1995, 60, 7192
Cr
O
O O
O
O
O
O
O
O
O
O
O
Cr
O
OO
O
O
O
O
O
O
O
O
O
h!
! Stevenson and Verdieck, JACS 1968, 90, 2974
3- 3-
R
Photochemistry with CPL—prebiotic origin of optical activity?
! Bonner (1977)
O
HO
NH2
(±)L-CPL
75% conv
O
HO
NH2
2.5% ee
! Chiral amplification by autocatalysis (Soai)
N
NMe
CHO
i-Pr2Zn2% chiral initiator
toluene, 0 °C
N
NMe
OH
Me Me
Me
Me Me
Me
initiator
L-valine (2% ee)
yield
82%
ee
21%
JACS, 1977, 99, 3622
Ph CO2Me
OH
Ph Me
NHMe
(0.5% ee)
(0.1% ee)
89% 54%
notgiven 79%
JACS 1998, 120, 12157
Enantioselective photofixation using CPL
AS
PR
PS
!
h"
h"
Asymmetric photofixation possible by preferential photoexcitation of one of a pair ofrapidly equilibrating enantiomeric confomers
! Helicenes (Kagan)
CPL
fast
0.5% ee
Tetrahedron, 1975, 31, 2139)
Large g values are required for appreciable ee's; however, conformational flexibility
allows averaging of CD spectra with opposite signs.
AR
Enantioselective solid-phase photochemistry
i-PrO2C
CO2i-Pr
i-PrO2C CO2i-Pr
! Achiral compounds can crystallize into chiral point groups
h!
21%
>95% eeP212121
Scheffer JACS 1989, 111, 4985
! Introduction of chiral "handles" induces chiral crystals
–O2C
CO2i-Pr
CO2i-Pr
1. h! (20-40% conv)
2. CH2N2
>95% ee
Scheffer, Acc. Chem. Res. 1996, 29, 203
NH2+
CO2t-Bu
MeO2C
the solution-phase reaction gives racemic product and 1:1 regioselectivity
The di-"-methane rearrangement
Me Me Me MeMe
Me
———
General mechanism:
• olefin-arene rearrangement
h!
O O O
• olefin-carbonyl rearrangement
Enantioselective solid-phase photochemistry
O
OPh
! Modified zeolites as hosts
OO
H
Ph
h!, 10 min
69% ee, hexane slurry
Ramamurthy, Org. Lett. 2000, 2, 119
NaY•ephedrine
O
OPh
! Cyclodextrin hosts:
OO
H
Ph
"-cyclodextrin
h!, 15 min
33% ee solid phase4% ee aqueous phase
Ramamurthy, Tetrahedron 2000, 56, 7005
rigid environment essential?
Meyers' chiral lactam auxilliary
Meyers, A. I. JACS, 1986, 108, 306
N
O
O
Me
N
O
O
Me
Me
Me
Me
MeMe
MeO2C
Me
O
Me
MeO2C
Me
O
Me
MeN
O
O
Me
Me
Me
ethylene,acetophenone
h!, -78 °C
93% yield84-86% de
H2SO4/MeOH(56%)
H2SO4
+
~ 1:1
Me
HOMe
H
(–)-grandisol
No other examples reported
9 steps
Menthone-derived spirodioxinone
Me
HOMe
H
(+)-grandisol
5 steps
O O
O
i-Pr
Me
Me
tBu
O
O
O
i-Pr
Me
tBu
O
O
O
i-Pr
Me
O
O
O
i-Pr
MeMe
Me
H
Me
H
Me
H Me
H
H
H
+h!
h!
h!
O
Me
HO2C
Me
H
33% yield
3:1 r.s.
8:1 d.s.
70% yield
10:1 d.s.
55% yield
7:1 r.s.
5:1 d.s.
HCO2HH2O : acetone
80%
Demuth ACIEE 1986, 25, 1117
2 diastereomersseparated by crystallization
Menthone-derived spirodioxinone
O O
O
i-Pr
Me
MeO
O
O
i-Pr
MeMe
H
H
H
h!
70% yield
10:1 d.s.
Sato and Kaneko, Chem. Pharm. Bull. 1987, 35, 3971
+
O
OO
Me
Me
O
O
Me
Me
O
a
b
"Though the b-side attack of the alkene on A is not completely denied, it is morereasonable to assume that the minor adduct... may be formed via the less stableconfomer (B) by the attack of the alkene from the b-side."
major product minor product
[2+2] cycloadditions with tartarate auxilliary
OO
i-PrO2C CO2i-PrO
MeO2C
OO
O
i-PrO2CCO2i-Pr
CO2Me
H
O
MeO2C
OO
i-PrO2CCO2i-Pr
CO2Me
H O
84% deh!
benzene
h!
benzene 43% de
2-fold excess of ketal — isolated yields only 30-45%
Lange, TL, 1988, 29, 2613
! Chiral auxilliaries on the alkene component of alkene-enone photocycloadditions as much rarer
Chiral allene-enone [2+2] photocycloadditions
Carreira JACS, 1994, 116, 6622JACS, 1997, 119, 2597
O
O
C
tBuHO
O
H
tBu O
O
HO
h! O3
(92% ee)89% yield, 1.2:1 Z : E
(92% and 91% ee)
O
O
C
SiMe3HO
O
H
SiMe3 O
O
H
h!
(99% ee)89% yield, 1.3:1 Z : E
(92% and 86% ee)
1:2TBAF:AcOH
Chiral allene-enone [2+2] photocycloadditions
Carreira JACS, 1994, 116, 6622JACS, 1997, 119, 2597
O
O
C
tBu
H
O
O
C
tBu
H
O
tBu
O
H
• exo approach of allene: ring ! H vs ring ! tether
• enone approaches opposite t-Bu group
• free bond rotation at 1,4-diradical; cycloreversion is not competitive with ring closure (kr << kc)
kckf
kr
The Paterno-Buchi Reaction
Me
Me
Me
PhO
O
O
PhO
O Me
Me
MeO OMe
8-phenylmenthol auxilliary control
O
OOMe
Me
H
H
CO2R*
Ph
O
Ph
CO2R*
H
H
O
Ph
CO2R*
MeO
MeO
O
Ph
CO2R*MeO
MeO
h!
h!
h!
>96% de+
92% de
OO
H
H
CO2R*
Ph
h!>96% de
O
590% de
176% de
:
Scharf, ACIEE 1991, 30, 477
77%
99%
Asymmetric meta-arene-alkene photocycloaddition
O O
Me Me
O
O
OO
Me
Me
Me
Me
O
O
Me
Me
h!
pentane 55%
73 : 27
! C2-symmetric diol tether gives excellent facial selectivity
O O
Me Me
OO
Me
Me
h!
pentane
! Selectivity of the cyclopropane closure can be achieved by adjusting the tether
70% yieldonly isomer
• substrate synthesis was not discussed
• tether cleavage requires 3 steps, consumes the diol, and destroys 2 stereocenters
Sugimura, Tai Tet. Asymm. 1994, 5, 1163
Asymmetric photoinduced radical cyclization
Ph N
O
Ts O
N
OO
O
O
Ph
PhN
X*
O
OHPh
Ts
h!
cyclohexanebenzene
70% yieldone isomer
Ph N
OH
Ts O
X*
OH
PhH
N
Ts O
N
OO
O
O
minimize Ph — auxilliary
interaction
! Synthesis of 3-hydroxyproline derivatives
Wessig, Helv. Chim. Acta 1994, 77, 829
1,5-Habstraction
Photodeconjugation of esters with chiral auxilliaries
O
O
O
Me
Me
Me
Me
O
Me
OR*
OH
OR*
Me
Me
Me OH
OR*
Me
Me Me
Me
Me
O
Me
OR*
O
OO
H
Me Me
OR* =
h!, -60 °Chexane
h!
h!
73 % yield98% de
enantiodifferentiating step is protonation of the enol—not a photoprocess
MeO
O
c-Hex
Me Me
0.1 eq AHOR* =
AH
i-Pr2NH
(+)-ephedrine
(–)-ephedrine
yield
71%
65%
69%
dr
94%
52%
48%
Pete, Tet. Asym. 1991, 2, 1101
Me
Me
O
Et
OR*Me
Me
O
Et
OR*
h!, -60 °Chexane
0.1 eq AH
Piva, Tet. Asym. 1992, 3, 759
Asymmetric photodeconjugation of achiral esters
O
BnOMe
MeMe
NH
OH
PhMe
MeMe
O
BnOMe
MeMeh!, CH2CH2
-40 °C
(0.1 eq)70% ee
65% yield
! High levels of enantioselectivity can be achieved with catalytic amounts of addititve
! Selectivity is highly substrate-dependent
O
EtOMe
MeMe
O
EtOEt
EtMe
O
BnO
Me
O
EtO
Me
O
i-PrOMe
MeMe
O
OMe
MeMe
c-Hex
40% ee84% yield
52% ee60% yield
68% ee76% yield
25% ee65% yield
10% ee56% yield
43% ee74% yield
Piva, JACS, 1990, 112, 9263
Cycloadditions using chiral complexing agents
! 2:1 host:guest complexes
O
O
OH
OH
Ph
Ph
Ph
Ph
O
O
NBn
NBn
O
O
h!
wateralkyl sulfate
90% yield> 99% ee
O
O
OH
OH
Ph
Ph
Ph
Ph
O
O
NEt
NEt
O
O
h!
wateralkyl sulfate
40% yield
14% ee
• N-benzyl groups work well; N-alkyl, N-aryl, and N-allyl give poorer results
O
O
OH
OH
Ph
Ph
Ph
Ph
O
O
NMe
NMe
O
O
h!
wateralkyl sulfate
69% yield97% ee
• Aqueous suspensions made from powdered 2:1 host:guest co-crystals. Is this really a solution-phase reaction?
Toda, JCS, Chem. Comm. 1995, 621
Cycloadditions using chiral complexing agents
O
Me Me
Me
NO
NH
NH
O
O
NH
O
O
H
H
h!, 2.6 eq sens*
toluene, -60 °C
77% yield93% ee
sens*:
NH
O
O
h!, 1.2 eq sens*
toluene, -15 °CNH
O
O
H 88% yield88% ee
! Stereoselectivity based host-guest recognition: amide–amide interaction
! Best enantioselectivity in a solution-phase photochemical reaction to date
Bach, ACIEE, 2000, 39, 2302
Enantioselective sensitized photodestruction
RuN
NN
N
N
N
R
R
R
RR
R
R =
Me
Me Me
O
O
EtOH
MeCHO !-[Ru(Menbpy)3]2+ [!-[Ru(Menbpy)3]2+]*
!-[Ru(Menbpy)3]3+
h"
!-[Co(acac)3]
#-[Co(acac)3]
Co(acac)2 + acac–
! Inorganic systems can work well
k!
k#
!-[Ru(Menbpy)3]2+ =
! 1.3 mol% sensitizer used
! k!/k# = 14.7 (94% ee) in
9:1 EtOH:water at 30% conversion
! Enantioselectivity is critically
solvent-dependant: k!/k# = 8.7
in 8:1 EtOH:water
Inoue JCS, Chem. Comm. 1993, 1423
2+
Enantioselective organic photosensitized reactions
! Organic systems work less well
(±)O
H
H
h", -78 °CO
O
H
H
• 10% ee at 44% conv.
• sensitizer loading not given
Demuth Helv. Chim. Acta 1980, 63, 2434
• Di-$-methane rearrangement
• Sulfoxide isomerization
Me
SMe
O
Me
SMe
O
Me NHAc
h"• 20 mol% sensitizer
• 4.1% ee at pss
Kagan TL 1973, 42, 4159
Enantioselective photosensitized polar addition
! Photosensitized ant-Markovnikov methanol addition to 1,1-diphenylpropene
Ph
PhMe
Ph
PhMe
OMe
CO2R CO2R
Me
Ph Ph
15% sensitizerh!, 25°C
+ MeOH
R =
27% ee1.9% yield8.5 days
• The intermediacy of an electron-transfer exiplex is invoked
• Addition occurs to the radical cation intermediate
• Increasing concentration of MeOH lowers ee, indicating that polar effects are
important in the symmetry-breaking step
benzene
Inoue JCS, Chem Comm 1993, 718
Enantioselective photosensitized [4+2] cycloaddition
Ph
MeMe
Ph
hn (2.5% sens*)
toluene, -65 °C
CN
CN
CN
CN
15% ee
• No yields given
• Reaction of electron-rich diene with electron-rich dienophile
• Enantioselectivty presumably arises from selective capture of
diastereomeric exciplexes
Schuster JACS 1990, 112, 9635
! Photochemistry with circularly-polarized light gives poor enantiomeric
excesses, but CPL can't be ruled out as the prebiotic origin of biological
homochirality
! Solid-phase asymmetric photochemistry can work very well, but has limited
range
! Solution-phase photochemistry can have good enantioselectivity, particularly
with [2+2] photocycloadditions using chiral auxilliaries
! Asymmetric photochemistry using chiral sensitizers is usually poorly
selective
Conclusions
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