Memory of chirality
Baran Group Meeting
6/21/2008
Florina Voica
The concept of memory of chirality describes a phenomenon in which the "the chirality of a starting material having a chiral sp3
carbon is preserved in the reaction product even though the reaction proceeds at the chiral carbon as a reaction center through
reactive intermediates such as carbanions, singlet monoradicals, biradicals, or carbenium ions".
OL, 2002, 4, 1875.
We all know that:
Requirements for memory of chirality:
Y
X
R1
R2
R2
R1
H
chiral
Y-
R1
H
R1
achiral
intermediate
+
R2
- enantioselective formation of a conformationally chiral intermediate
from a chiral starting material
- slow rate of racemization of the conformationally chiral intermediate
- enhanced reactivity of the chiral intermediate toward product formation
R2
H
H
Y
racemic
Furthermore:
H
Ph
(R)-A-H
H
NH2
Ph
CO2H
static chirality
H
very
slow
CO2H
achiral
H
Ph
CO2H
H
chirality
transfer
chirality
transfer
base
fast
(M)-Avery
slow
ΔG‡
(P)-AHO2C
Ph
H
H
gauche conformers with transient chirality
(dynamic chirality)
Therefore, we can hypothesize that upon erosion of
an unique chiral center, a non-racemic product mixture
may arise from a "chiral" intermediate.
MeI
fast
(R)-A-Me
very
slow
(S)-A-Me
What would be the ideal characteristics of a conformationally chiral
intermediate in order to generate enantioenriched products?
No limitations on the type of the intermediate as long as it resits the forces of
racemization:
- assuming the racemization process to be an unimolecular phenomenon, the
racemization rate constant can be calculated using the Eyring equation
- best scenario: at -78 °C, for ΔG‡= 16 kcal/mol, t1/2 = 20h
- chiral intermediates containing sp2-sp2 bonds which commonly have barriers to rotation
higher that 16 kcal/mol, could be successfully used to achieve memory of chirality.
for a review see: Synthesis 2005, 1.
1
Memory of chirality
Baran Group Meeting
6/21/2008
Florina Voica
1. Enolate chemistry
1.1 Enantioselective alkylation of ketones
Principle:
O
R1
Application: JACS 1991, 113, 9694
OM
base
R2
R2
R3
H
Ph
Ph
R3
KO
O
MeO
R1
OEt
achiral-no static chirality
R1
R2
OM
A
MO
A
B
R1
R2
B
dynamic chirality - axial chirality
ii.
M
M
R1
O
O
R1
R2
R3
R3
R2
KH,18-crown-6
THF, -78 °C to -20 °C
EtO
OMe
1'
O
MeI
OEt
EtO
OEt
However, under specific conditions:
i.
1
Ph
Me
MeO
93% ee
OEt
chiral enolate with axial chirality
48% (66% ee)
Experimental support for the formation of observed product via the supposed chiral
enolate:
Ph
Ph
Ph
1.
2.
Me
MeO
O
O
OMe
MeO
KH,18-crown-6
MeO
EtO
OEt THF, -78 °C to -20 °C
OEt
EtO
OEt
OEt
96% ee
isolated byproduct
(optically active)
dynamic chirality - planar chirality
then MeI
51% (0% ee)
3. barrier to rotation across the 1,1' bond calculated to be 22. 6 kcal/mol at 21 °C.
1.2 α-Alkylation of amino-acids
Principle:
Chem-Eur. J. 1998, 4, 373
H
R
CO2R1
N
R3
R2
base
Dynamic chirality of the enolate:
R1O
R
R1O
MO
MO
NR2R3
achiral enolate
R3 M
R
N
R3
R2
axial chirality
R2
M
R1O
N
O
R
OR1
planar chirality
O
N
R
R2
R3
central chirality
2
Memory of chirality
Baran Group Meeting
6/21/2008
Applications:
* To rule out the formation of aggregates:
A. Intermolecular alkylation
Bn
a) KHMDS
CO2Et
R
H
Boc
R
b) MeI, THF:toluene (1:4)
- 78 °C
N MOM
Entry
CO2Et
Me
Boc
Yield (%)
R
N
Boc
2
N
N MOM
CO2Et
93
N
94
CH2
MeO
N
Me
Me
b. MeI
80
80
Bn
CO2Et
Me
+
N Boc
Boc
a. LiTMP, THF
-78 °C
b. MeI
(±)
30 % yield
(S)
Bn
CO2Et
Me
N Boc
Me
Bn
Me
CO2nBu
Me
(S), 74% ee
26% yield
CO2nBu
+
Bn
N Boc
+
CO2nBu
Me
N Boc
Me
(±)
17% yield
JACS 1994, 116, 10809
CH2
3
Boc
Bn
(±)
79
Boc
a. LiTMP, THF
-78 °C
(±)
(S)
Me
MOMO
N
Me
ee (%)
83
CO2nBu
+
Boc
Bn
CH2
Bn
CO2Et
Me
N
1
Florina Voica
(S), 71% ee
24% yield
* To explain the retained streochemistry of the product:
MeO
CH2
4
88
O
O
76
N
N
Boc
H
AGIE 2000, 39, 2155
Mechanistic studies:
* Possible sources of asymmetric induction:
OtBu
OEt
Ph
O
Me
N
O
OtBu
Li
O
N
EtO
Me
O
N
Ph
OEt
SM/enolate aggregates
O
Li
Ph
Me
Boc
EtO
Boc
N
Ph
base
EtO
N
O
Ph
O
CH2OMe
MeI
CO2tBu
R
Me
Boc
CO2Et
N MOM
chiral enolate
product (S)
most stable conformer (S)
(molecular models
ΔGrot(C-N bond) = 16 kcal/mol ( at -78 °C)
calculations)
AGIE 2000, 39, 2155
Li
O
OK
O
Me
chiral enolate
chiral enolate
with central chirality with axial chirality
* To certify the implication of an axially chiral enolate:
same
O
CO2Et
Bn
CO2Et
conditions Bn
Bn
and
and
Me
N
H
Boc
N Boc
H
BocN
Synthesis, 2005, 1368
O
Boc
Boc
O
Bn
Me
BocN
O
racemic mixtures
3
Memory of chirality
Baran Group Meeting
6/21/2008
B. Intramolecular α-alkylation
RO2C
R
H
RO2C
NH2
R
H
Mechanistic considerations:
X
base
RO2C
R
NH
NH
O
O
O
O
R
Boc
KHMDS or NaHMDS
CO2Et
N
(CH)2-Br
Entry
1
2
3
4
5
6
7
DMF
-60 °C, 30 min
R
PhCH2
MeSCH2CH2
Me2CH
Me
PhCH2
PhCH2
PhCH2
n
3
3
3
3
2
4
5
Florina Voica
EtO2C
R
M+R2N-
N
Ph
Boc
N
(CH)3-Br
OEt
Ph
O
H
Br
R
Br
N
OK
A
N
Br
R
retention
Br
Yield (%)
94
92
78
91
61
84
31
ee (%)
98 (S)
97
94
95 (R)
95
97
83 (S)
Ph
O
H
N
Boc
Br
O
M+R2N(M = Li)
THF, various temp
EtO2C
R
Boc
OEt
Ph
N
O
O O
H
Ph
M
N
For the same R substituents, the yields are comparable
with the ones observed in the previous study. The ees for
are the inverted product in the 81--91% range.
JACS 2006, 128, 15394
O
OEt
N
OK
ent-A
OtBu
R
JACS 2006, 128, 15394
N
inversion
N
retention
Br
O
R
LiTMP
CO2Et
O
Alternatively,
CO2Et
N
OtBu
M
(CH2)n
JACS 2003, 125, 13012
R
O
OEt
(M = Na, K)
H
NH
Boc
OtBu
O
Ph
For improved conditions for the intramolecular
alkylation with retention of configuration,
see JACS 2008, 130, 4153.
CO2Et
Boc
N
inversion
4
Memory of chirality
Baran Group Meeting
6/21/2008
Florina Voica
1.3 Alkylation of benzodiazepines
2. Radical chemistry
1,4-Benzodiazepin-2-ones are chiral, existing as (M)- or
(P)-conformational isomers,
2.1 Memory of chirality due to spinisomers
CO2Me
Cl
R
O
ΔG‡
R'
N
O
R
N Ph
R1
O N
Ph
R1
N
Me
MeO2C
OEt
N
Ts
Cl
naphtalene*
PhH
O
(P)
OEt
N
Ts
ΔG‡
(kcal/mol)
12.3
18
21.1
> 24
Ph
Cl
N
Me
N
R1
R1=Me
R1=iPr
CO2Et
N
For R or R'≠ H, the pseudoequatorial
conformer is favored!
1. 1.2 eq. LDA
6 eq. HMPA,
THF, -78 °C, 15min;
1.2 eq. nBuLi, 15 min
2. 10 eq. BnBr, -78°C
3. NH4Cl (aq.)
OH
MeO2C OH
For R=R'=H, the equilibrium is influenced by the nature of R:
O
hν
O
R'
(M)
R1
H
Me
iPr
tBu
OH
Me
Me
+
N
Ts
7% (94% ee)
*
Proposed mechanism:
β
Ph
Cl
N
Bn
Me
O
CO2Me
OH
Me
OEt
γ
N
Ts
72% (0% ee)
74% (97% ee)
High enantioselectivities observed when other electrophiles
(MeI, allylBr, 4-MeC6H4CH2Br) are used
JACS 2003, 125, 11482
OL 2005, 7, 5305
(M)
racemization
N
R1
O
ΔG‡
MeO2C OH
CO2Et
N
ΔGrot-β bond‡ = 5 kcal/mol
B
ΔG‡ = 2 kcal/mol
CO2Et
N
O
Me
Ts
HO
Me
EtO
naphtalene is a triplet quencher
MeO2C OH
MeO2C
Me
Ts
40% (92% ee)
α
CO2Me
CO2Et
Ts
(P)
N
Ts
Me
ent-B
The observed ees are due to a slow racemization
compared to the cyclization of the singlet diradical.
AGIE 1999, 38, 2586
5
Memory of chirality
Baran Group Meeting
6/21/2008
2.2 Memory of chirality due to radical conformers
B. Intramolecular radical cyclization
1. oxalyl chloride
2. S
OH
N
, DMAP
A. Enantioselective radical quenching
S
Ph
i. DIPDI, DMAP,
N
OH
O
ring inversion
(racemization)
> 97% ee
O
Ph
ii. hν, 1M PhSH, -78 °C
ΔG‡
PhSH
5 < ΔG‡ < 10 kcal/mol
93
7
O
O
Ph
HO
H
Ph
BnO2C
H
O
Ph
CN
THF
-78 °C
JACS 1998, 120, 5589
JACS 2000, 122, 9386
e-, H+
CO2Bn
PhMe, hν, -15 °C
Ph
H
CO2Bn
H
CO2Bn
racemization
(chair-boat
interconversion)
CO2Bn
CO2Bn
H
ΔG‡ = 15.5 kcal/mol
H
O
CO2Bn
Proposed mechanism:
- Bu2SnH reacts slowly as a proton donor, leading to racemic mixtures
- dilute concentrations of tBuSH or PhSH determine a decrease in ees
- an increase in the temperature leads to low enantiomeric excess
[R ]
N
51% yield (68% ee)
92% yield (83% ee)
Li (6.4M)/NH3
S
H
CO2Bn
PhSH
O
CO2H
Florina Voica
H
BnO2C
CO2Bn
Ph
H
CO2Bn
80% yield (90% ee)
CO2Bn
H
H
SPyr
H
SPyr
CO2Bn
H
CO2Bn
CO2Bn
CO2Bn
H
H
OL 2004, 6, 2713
6
Memory of chirality
Baran Group Meeting
6/21/2008
3. Memory of chirality via carbocation intermediates
C. Umpolung benzylic substitution via chiral organometallic
intermediates
EtO
EtO
Me
Me
Cr(CO)6
Cr(CO)3
THF, 145 °C
Me
i. LiDBB
THF, -78 °C,
then RX
ii. air, sunlight
(99% yield)
Me
RX: TMSCl
BnBr
Me2NC(O)Cl
Initial result:
O
R
N
72% yield (87% ee)
37% yield (87% ee)
67% yield (86% ee)
O
2 F/mol
NaOMe
(OC)3Cr
Me
Me
(17 VE)
O
N
CO2H
O
Me
R-X
O
Ph
80% ee
O
Proposed mechanism:
Cr(CO)3
ΔG‡ = 13. 2 kcal/mol
+ e-
OMe
N
H
H
Cr(CO)3
R
ΔG‡
69% yield, 39% ee
O
Pt cathode
graphite anode
MeOH
Ph
+ e- OEt-
O
OL 2000, 2, 1689
CO2H
O
Me
OMe
N
Improvement:
N
OEt
O
Pt cathode
graphite anode
MeOH
O
Me
2 F/mol
NaOMe
CO2H
Me
Mechanism:
Florina Voica
Nu
N
O
Nu-
O
90%
N
O
retention
Me
H
Cr(CO)3
Cr(CO)3
(18 VE)
O
NuOL 2002, 4, 1875
N
O
Nu
10%
AGIE 1999, 38, 1620
inversion
7