Powdered KOH in DMSO: An Efficient Base for Asymmetric Cyclization via Memory of Chirality at Ambient Temperature
Wipf Group Saturday Morning Meeting
Current Literature Abstracts & Reports
Rob Lettan March 29th, 2008
Takeo Kawabata,* Katsuhiko Moriyama, Shimpei Kawkami, and Kazunori Tsubaki
Journal of the American Chemical Society, 2008, 130, 4153-4157.
Institute for Chemical Research, Kyoto University Uji, Kyoto, Japan
CO2EtR
N(CH2)nBoc X
EtO
OK
R
N(CH2)nX
CO2tBu N
CO2Et
R
Boc
(CH2)n
powdered KOH
DMSO, 20 °C
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Memory of Chirality
E
EWGR1
R2
H
EWGR1
R2
EWG
R1
R2
sp3
tetrahedralsp3
tetrahedral
sp2
trigonal planar
DeprotonationElectrophile
Addition
Retentionof
Chirality
ChiralStartingMaterial
Dynamically Chiral
Intermediate
“A formal substitution at an sp3 stereogenic center that proceeds
stereospecifically, even though the reaction proceeds by trigonalization of that
center, and despite the fact that no other permanently chiral elements are present
in the system.” -T. Kawabata
Defined As:
Fuji, K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373-376.
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First Reported Observation of Chiral Memory
tBuO2CCO2tBu
NHCHO
CO2tBu
N
OLi
OLi
tBuO
tBuO2C
N
OLi
OtBu
OLi
tBuO2CCO2tBu
NHCHO
tBuO2CCO2tBu
NHCHO
Me
Me
55% yield
15% yield60% ee
LiNEt2 MeI
MeI
Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 971.
Postulated Origins of selectivity:
1) "The achiral enolate intermediate B forms mixed aggregates with the chiral dilithio derivative A."
A
B
2) "The 6-atom-8-electron !-system is axially chiral... If this interpretation should turn out to be valid, simple amino acids may also be alkylate via derivatives of type B (R instead of CH2CO2tBu) without racemization.
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The First Rationally Designed MOC Process
O
Ph
MeO
OEt
OEt
OK
Ph
MeO
OEt
OEt
O
OEt
OEt
Ph
MeOMe
93% ee "chiral" intermediate
KH MeI
66% ee
OMe
OEt
OEt
Ph
! 65% ee
MeO
O
Ph
MeO
OEt
OEt
1. KH
2. MeI
O
OEt
OEt
Ph
MeMeO
96% ee 0% ee
Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694-9696.
O
Ph
MeO
OEt
OEt
K O
Ph
O
EtO OEt
Me
Possible Alternative Stereochemical Origination
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The First Rationally Designed MOC Process
H
BnN
OOEt
Boc
MOMR
BnN
OOEt
Boc
MOM
OKEtO
Bn
N
Boc
Mom
KHMDS
THF/Toluene (1:4)-78 °C
RX
16-17 hup to 93% ee
Experimental Support for MOC
Variation in reaction time enolate intermediate of prior to MeI quench:
Kawabata, T.; Suzuki, T.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155-2157.
Barrier of Rotation = 16.0 kcal·mol-1
OTBSEtO
Bn
N
Boc
MOM
Z:E = 2:1
Barrier of Rotation = 16.8 kcal·mol-1
(AB quartets from CH2 of MOM)
Half-Life =
VT NMR experimentation:
5 x 10-4 at 365 K7 days @ -78 °C
Comparable substrates:
PhCO2Et
NR
Boc
BocPh O
N
O
Boc
R
1: R = H3: R = Me
2: R = H4: R = Me
Alkylation of 1 or 2 led to racemic 3 or 4.
energy minimized orientation for deprotonation
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Intramolecular MOC ApproachesAlkylations:
BocN
EtO2C
Bn
Kawabata et al.J. Am. Chem. Soc. 2003, 125, 13012-13013.
cyclic amino acids 2-azetidinones
N
O R2
R1
CO2Et
González-Muñiz, R. et al.Tetrahedron 2006, 62, 130-138.
Michael Additions:
BocN
CO2EtPh
CO2tBu
n
n = 1, 2, 3
BocN
EtO2C
Me
CO2tBu
Enolate Additions to Diazoacetals:
98% ee 82% ee
up to98% ee 95% ee
N
N
HN
S
MeO2C
O
Me
O
> 99% ee
Kawabata et al.Org. Biomol. Chem. 2005, 125, 1609-1611.
Stoodley et al.J. Chem. Soc., Perkin Trans. 1, 1993, 1761-1770.
N
O
Me
O
X
CO2iPr
N
X
CO2iPr
OH
MeO
N
X
CO2iPr
Me
OHO
N
X
O O
HO Me18 19 20
3 : 1 minor
Base
X = O, CH2
> 99% ee
Aldol Cyclizations:
Stoodley et al. Tetrahedron Lett. 2002, 43, 3919-3922.
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Asymmetric MOC Cyclization at Ambient Temperature
Overcoming Racemization
EtO
OK
R
NCH2OMe
CO2tBu
!G = 16 kcal/mol
t1/2 (-78 °C) = 22 h
t1/2 (20 °C) = < 0.1 sec
Possibility of an intramolecular MOC reactionin which "the chiral enolate intermediate reacts very rapidly within the time-scale of theirracemization."
N N N
CO2R2R1
N(CH2)nBoc X
CO2R2
R1
CO2R2 CO2R2
R1R1
Boc Boc Boc
Base
Reactivity vs Racemization?
Enantioselective approaches to rigified cyclic amino acids have played an important role in drug design and development, and in the design of novel peptides.
Revied on cyclic amino acids: Park, K.-H.; Kurth, M. J. Tetrahedron, 2002, 58, 8629-8659.
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Base/Solvent Screening
entry base (mol equiv) solvent temp, time (h) yield ee
PhCo2Et
NBoc
Br
1
base, solvent
temp N
Co2EtPh
Boc
2
1
2
5
6
11
LiOH was uneffective, NaOH and CsOH had inferior results
Increased amounts of H2O led to decreased reactivity
Solvents: CH2Cl2 proved uneffective, THF was inferior, and EtOH gives saponification.
KHMDS (1.2)
KHMDS (1.2)
KOH (3.0)
KOH (3.0)
KOH (3.0)
DMF
DMF
DMF
DMSO
1% H2O DMSO
60°C, 0.5-0°C, 0.2
20°C, 0.2
20°C, 0.2
20°C, 0.2
94
97
89
91
98
98
93
98
99
99
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Substrate Scope
entry n time (h) yield ee
powdered KOH
DMSO, 20 °C
1
4
7
10
2 Br 2
2
12
2
82
91
73
97
99
99
90
97
CO2Et
N(CH2)nBoc X
N
CO2Et
Boc
(CH2)n
PhPh
3
4
4
X
Br
Br
I
footnote 17 ? 25 495 X
Similar trend also observed with valine and methionine derived substrates.
Me CO2Et
N BrBoc
Me
N
Me
MeCO2Et
BocN
Me
MeCO2H
Fmoc
powdered KOH
DMSO, 20 °C
1) 4 M HCl
2) Fmoc-Cl
3) conc. HCl94%
single diastereomer53%
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Mechanistic Investigation
powdered KOH
DMSO, 20 °C
CO2Et
N(CH2)nBoc X
N
CO2Et
Boc
(CH2)n
PhPh
EtO
OK
R
N(CH2)nX
CO2tBu
Dynamic Chirality
CO2EtPh
CO2tBu
X
K
HO
H
Concerted SEi Process
CO2Et
N
Ph
Br BrN
Ph
CO2Et
Br
racemic
Concerted SEi Process is not plausible reaction pathway
vs
powdered KOH
DMSO, 20 °C
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Barrier of Racemizationpowdered KOH
DMSO, 20 °C
CO2Et
NBoc
Ph
Br N
Ph
CO2Et
Boc
Difficult to determine barrier of rotation b/c of relative rate of intramolecular cyclization.
Analogous Substrate:
Barrier of Racemization = 15.5 kcal/mol at -78 °C ffrom the slope, 2k = 1.99 x 10-3 min-1
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Relative Rate of Cyclization
entry n time (h) yield ee
powdered KOH
DMSO, 20 °C
1 (4 5)
7 (14 15)
2 Br 2
12
82
73
99
90
CO2Et
N(CH2)nBoc X
N
CO2Et
Boc
(CH2)n
PhPh
4
X
Br
Suggested Reasoning:
Inductive effects of bromide could slightly increase the acidity of ! proton
or
chelation assisted deprotonation
Rob Lettan @ Wipf Group Page 12 of 13 6/25/2008
Summary
CO2EtR
N(CH2)nBoc X
EtO
OK
R
N(CH2)nX
CO2tBu N
CO2Et
R
Boc
(CH2)n
powdered KOH
DMSO, 20 °C
Kawabata and coworkers demonstrated a highly enantioselective memory of chirality cyclization at ambient temperature.
The obtained cyclic amino acids are important role motifs in drug design and development, and in the design of novel peptides.
Interestingly, the cyclization of 4-membered ring systems occurs 2 to 3 times faster than the corresponding 6-membered variants.
The use of KOH in DMSO in the generation of highly reactive enolates under relatively mild conditionsfor enantioselective reactions has had little to no previous precedence, and could prove useful in thefuture for C-C bond forming processes.
Rob Lettan @ Wipf Group Page 13 of 13 6/25/2008