Memory of Chirality: A Strategy for Asymmetric Synthesisorggroup/supergroup_pdf/DJRSGPresent... ·...
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Memory of Chirality: A Strategy for Asymmetric Synthesis David J. Richard September 14, 2005
Transcript of Memory of Chirality: A Strategy for Asymmetric Synthesisorggroup/supergroup_pdf/DJRSGPresent... ·...
Memory of Chirality:A Strategy for Asymmetric
Synthesis
David J. Richard
September 14, 2005
Two Forms of Chirality
Ph
O
OHNH2H
Absolute (Static) Chirality
Ph
O
OHHH
PhH
CO2HHPh
H
HHO2C
Dynamic (Conformational) Chirality
- Dynamic chirality - chirality present only when C-C single bond rotation is restricted
- Absolute chirality - orientation of functional groups at a stereocenter
H3C
CH3 H3C
CH3
Barrier of rotation = 18 kcal/mol
Memory of Chirality in Enolate Chemistry
- In 1981, Seebach and Wasmuth made the following observation:
O
t-BuO
O
Ot-Bu
HN
O
O
t-BuOOLi
N
OLi
Ot-Bu
O
t-BuO
O
Ot-BuHN CH3
O
LDA
then MeI
THF,
15%, 60% ee
Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 971.Seebach, D.; Sting, A. R.; Hoffman, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708.
- No mechanism was established; however, one hypothesis was that reaction occurred through an axially chiral intermediate - Mixed aggregates involving the chiral enolate below were later implicated
OLi
t-BuOOt-Bu
HN
O
O
Memory of Chirality: Definition
Problem: Can stereochemical information be retained during a process in which the sole stereogenic center of a substrate is destroyed?
Ph
O
OCH3
NHR1HPh
OM
OCH3 *
NHR1Ph
O
OCH3
NHR1R
> 0% ee
"the chirality of the starting material is preserved in a reactive intermediate for a limited time"
Memory of chirality (MOC) has been defined as a process in which:
"A 'memory of chirality' reaction can be defined as 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."
This process has also been described as follows:
Fuji, K.; Kawabata, T. Chem.-Eur. J. 1998, 4, 373-378.
Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1-17.
Additional Review: Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, 175-205.
Enolate Alkylation: Design of a Memory of Chirality System
R1 R3
O
H R2
R1 R3
OM
R2
Base
R1
R2
OMA
B
MO
R2
R1A
B
R1
R2
O
R3
O
R3 R2
R1
M M
Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694.
- Fuji and co-workers proposed two strategies for the establishment of conformationally chiral enolates - axially chiral enolates or planar chiral enolates
Stereoselectivity by Memory of Chirality: General Considerations
Substrate* (M)-Intermediate
(P)-Intermediate
(R)-Product
(S)-Product
A
B
C
Fast
Very Slow
A Reaction at stereogenic center (e.g., enolate formation) generates conformationallychiral intermediate
BVery Slow
C
Conformationally chiral intermediate must not readily racemize
Fast
Fast
Very Slow
Reaction must occur with high stereospecificity
- Critical issue: reaction kinetics
Enolate Alkylation Utilizing Memory of Chirality (MOC)
EtO
EtO
OOCH3
93% ee
KO
Ph
OCH3
EtO
EtO
KH
18-crown-6
Toluene
MeIEtO
EtO
OOCH3
CH3
54%, 73% ee
Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991, 113, 9694.
EtO
EtO
OOCH3
Et
65% ee
EtO
EtO
OOCH3
CH2Ph
67% ee
EtO
EtO
OOCH3
48% ee
EtO
EtO
OOCH3
70% ee
OH3C
- O-methylated product also isolated in 65% ee by chiral HPLC
- Half-life of racemization determined to be 53 minutes at room temperature
Asymmetric Syntheses of Amino Acid Derivatives
R1OR4
O
H N
R1 OR4
OM
N
Base
R1
N
OM
OR4
R2
R3R2 R3
R2
R3
Axial Chirality
N
R1
O
OR4
Planar Chirality
MR3
R2
N
R1
O
OR4
Central Chirality
M
R3
R2
Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem. Soc. 1994, 116, 10809.
Ph
NBocH3C
O
OEt
Asymmetric Alkylation of Amino Acid Esters
Ph
O
OEtN CH3H3C
Boc
LiTMP
THF
- 78 C,
then CH3I
40%, 82% ee
Ph
NBoc
O
OEt
OH3C
KHMDS
Toluene-THF (4:1)
- 78 C,
then CH3I
Ph
O
OEtCH3NMOM
Boc
96 %, 81% ee
O
OEtCH3N
Boc
83%, 93% ee
O
OEtCH3N
Boc
88%, 76% ee
O
OEtCH3N
Boc
78%, 78% ee
MOM
BocN
NMOM
MOMN
Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem. Soc. 1994, 116, 10809.Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.
MOM
Mechanism of Memory of Chirality Effect
- One possibility - mixed aggregate mechanism
N
Ph
MOM
O
OEt
O
Ot-Bu
KO
O
OEt
Ph
N
Ot-Bu
MOM
- Ruled out by competition experiments
N
Ph
MOM
OTBS
OEt
O
Ot-Bu
- Silyl enol ether prepared - exhibits rotational barrier of 16.8 kcal/mol by VT NMR experiments
N
Ph
MOM
OTBS
OEt
O
Ot-Bu
- Half-life of approximately 7 days at -78 C
- Variable reaction times explored for enolate deprotonation - rotational barrier calculated as 16.0 kcal/mol
Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.
Mechanism of Memory of Chirality Effect
OO
N
HO
OO
OO
N
HOO
O
OO
H
NPh
O K
NTMS TMS
Ot-BuO
OK
OEt
N
O Ot-Bu
O
Ph
CH3I
OO
CH3
NPh
Ot-BuO
O
OO
H
NPh
K
NTMS TMS
O
OK
OEt
N
O
Ot-Bu
Ph
CH3I
Major product
Ot-BuO O
OO
N
H3CPh
Minor productO
t-BuO O
Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.
- Additional evidence: di-Boc and oxazolidinone analogs showed no enantioselectivity
Effect of Adjacent Stereocenters
O
OEt
NMOMBoc
O
OEt
NMOMBoc
KHMDS
-78 C
EtOOK
NCH2OCH3
CO2t-Bu
EtOOK
NCO2t-Bu
CH2OCH3
CH3I
O
OEt
O
OEtNMOM
BocN
Boc
MOM
93%, 93% de 91%, 86% de
Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.
Asymmetric Alkylation - Intramolecular Cyclization
Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem. Soc. 2003, 125, 13012.
Ph
N
O
OEt
Boc
KHMDS
DMF
-60 CBr
BocN
EtO2C
Ph
94%, 98% ee
BocN
EtO2C
Ph
84%, 97% ee
BocN
EtO2C
Ph
61%, 95% ee
BocN
EtO2CPh
31%, 83% ee
- Other six-membered rings were produced in excellent ee (94-97%)
H
NO O
O Ot-Bu
Br
N OKOEtPh
Br
Ot-BuO
BocN
EtO2C
Ph
Favored conformation
Beagley, B.; Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S. J. Chem. Soc., Perkin Trans. I 1993, 1761-1770.
S
NCO2CH3O
N2
S
NO
NNH
CO2CH3
NaOCH3
CH3OH
35%
Additional Applications of Memory of Chirality Strategy
Et3N, CH3OH = 65%
O O
ONN
ON
S
H
ONN
ON
S
OH3COON
N
ON
S
OH3CO
ONN
ON
SH
CO2Me
OMeO
- NMR studies of SM indicate presence of three rotamers
S
NO
NNH
CO2CH3
O
S
NO
NNH
CO2CH3
O
Not observed
Observed
Extension of Methodology: Cyclization of Sulfoxides
Betts, M. J.; Pritchard, R. G.; Schofield, A.; Stoodley, R. J.; Vohra, S. J. Chem. Soc., Perkin Trans. I, 1999, 1067-1072.
S
NCO2CH3O
N2
S
NO
N2
Et3N
CH3OH
61%
O
O
O
O
CO2CH3
Et3N
CH3OH
S
NO
NNH
CO2CH3
O
O
S
NCO2CH3O
N2O
O
+
63%
S
NO
NNH
CO2CH3
O
O
37%
S
NO
NNH
CO2CH3
O
O
65% 35%
Brewster, A. G.; Frampton, C. S.; Jayatissa, J.; Mitchell, M. B.; Stoodley, R. J. Chem. Commun. 1998, 299.Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garcia-Lopez, M. T.; Gonzalez-Muniz, R. J. Org. Chem. 2001, 66, 3538.
S
NCO2i-PrO
O
KCN
MeOH
S
N CO2iPrOH
O
S
N CO2iPr
OHO
+
49% 19%
Additional Applications - Aldol Cyclization and Azetidinone Closure
ClN
O
PMB
PhCO2t-Bu
Cs2CO3
CH3CN NO PMB
Ph
CO2t-Bu
53%, 56% ee
- Enantioselectivity highly substrate dependent (0-50% ee)
- No specific models proposed - however, existence of axial chirality proposed
Memory of Chirality in Benzodiazepines
Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P.C.-H. J. Am. Chem. Soc. 2003, 125, 11482.
N
Ni-Pr
O
ClPh LDA
HMPA
n-BuLi,N
Ni-Pr
O
ClPh
then BnBr
74%, 97% ee
- With N-Me amide: 0% ee
Ph
- Alkylation with other electrophiles (Me, allyl, 2- PhC6H4CH2, 4-MeC6H4CH2) all proceed with 94- 99% ee
NN
H
H3C
O i-Pr
Cl
NO
Ni-Pr
Ph
CH3
H
NN
O i-Pr
Cl
H3C
N
Ni-Pr
Ph
H3C
0.0 kcal/mol
+ 17.5 kcal/mol
- Factors which lead to attack of electrophile on concave face yet to be determined
t1/2(inversion) = 970 hours @ -78 C
-78 C
Cr(CO)3
OEt LiDBB
- 78 C
THF, then
RXCr(CO)3
R
R = TMSCl; 72%, 87% eeR = PhCH2Br; 37%, 87% eeR = CH3OC(O)Cl; 67%, 86% eeR = (CH3)2NC(O)Cl; 57%, 84% ee
Memory of Chirality in Radical Chemistry
Schmalz, H.-G.; Koning, C. B. D.; Bernicke, D.; Siegel, S.; Pfletschinger, A. Angew. Chem. Int. Ed. 1999, 38, 1620.
Cr(CO)3
OEt
+ 1 e
Cr(CO)3
CH3
Cr(CO)3
CH3
HFast Fast
Slow
Cr(CO)3
H
CH3
Cr(CO)3
CH3
H
Configurationally Stable
Cr(CO)3
R
Reaction of Pyranyl Radicals
Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D. J. Am. Chem. Soc. 2000, 122, 9386.
O Ph O Ph
HO O
NS
hv
1M PhSH
-78 C
92%, 88% ee
O Ph
CN
LiDBB
THF
-78 C,
then CO2
O Ph
CO2H
48% ee
O Ph
CN
Li (6.4M)/NH3
THF
-78 C,
then NH4Cl
O Ph
H
90% ee
- Memory of original chiral center retained due to ring conformational preference
- Furanyl radicals exhibit no enantioselectivity
OBnO2C CO2Bn
O
O
O
N
S Toluene
hvH
H
S N
CO2Bn
CO2Bn-15 C
Radical Cyclization of Cyclodecenyl Systems
CO2Bn
CO2BnCO2Bn
CO2Bn
CO2Bn
CO2BnH
CO2Bn
CO2Bn
H
HH
H
H
S N
CO2Bn
CO2Bn
H
H
S N
CO2Bn
CO2Bn
H H
Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2713-2716.
- Barrier to ring inversion provides stereocontrol
51%, 68% ee
- Lower temp. provides no improvement of ee
N
O
I
Bu3SnHEt3B
O2
rt
NCH3
O
84% ee
N
O
I
Bu3SnHEt3B
O2
rt
NCH3
O
82% ee
Curran, D. P.; Liu, W.; Chen, C. H.-T. J. Am. Chem. Soc. 1999, 121, 11012-11013.
Radical Cyclization of Haloacrylanilides
- Chirality of atropisomer is maintained in radical - cylization proceeds faster than isomerization
H3CO2C
O
NTs
O
OEt
hv
Benzene
NTs CO2Et
OHCO2CH3
+
NTs CO2Et
OHCO2CH3
Radical Cyclization to Substituted Pyrrolidines
40%, 96% ee 7%, 94% ee
- When reaction is performed in the presence of a triplet sensitizer, no diastereoselectivity or enantionselectivity is observed
Giese, B.; Wettstein, P.; Stahelin, C.; Barbosa, F.; Neuburger, M.; Zehnder, M.; Wessig, P. Angew. Chem. Int. Ed. 1999, 38, 2586-2587.Sinicropi, A.; Barbosa, F.; Basosi, R.; Giese, B.; Olivucci, M. Angew. Chem. Int. Ed. 2005, 44, 2390-2393.
N
Ts O
OEtOH
CO2CH3
EtO
ON
Ts
HO
H3CO2C
NTs CO2Et
OHCO2CH3
Helically chiral diradicals
5 kcal/mol
Cyclization via Photodecarboxylation
Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem. Int. Ed. 2001, 40, 577.
N
N
O
O
O
CO2K
N
N
O
OHH
O
45%, 86% ee
hv
Acetone
H2O
13 kcal/mol
- Via triplet diradical
MOC via a Carbocationic IntermediateO
N
O
CO2H
O
N
O
Pt cathode
Graphite anode
69%, 39% ee
O
N
O
CO2H
O
N
O
OCH3
NaOCH3
CH3OH
Pt cathode
Graphite anode
69%, 39% ee
Ph Ph
OCH3
Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka, T.; Maki, T.; Onomura, O. Org. Lett. 2000, 2, 1689.
NOCO2H
O
NO
O
CH3OH
NaOCH3
CH3OH
O
N
O
OCH3
Ph
Conclusions
- Memory of chirality represents an emerging strategy in the field of stereoselective synthesis
- This method takes advantage of the dynamic, conformational chirality present in systems with restricted rotation about single bonds
- Requires no external sources of chirailty
- Highly time, temperature, and substrate dependent
- Primary application has been in the area of enolate chemistry - limited number of examples involving radical and carbocationic intermediates
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