Transcript CHIRAL OXAZOLINES- THEIR LEGACY IN ASYMMETRIC C-C BOND FORMATION A.I. MEYERS O R N DEPARTMENT OF CHEMISTRY R* COLORADO STATE UNIVERSITY Spring 2006

CHIRAL OXAZOLINES- THEIR LEGACY IN ASYMMETRIC C-C BOND FORMATION
A.I. MEYERS
O
R
N
DEPARTMENT OF CHEMISTRY
R*
COLORADO STATE UNIVERSITY
Spring 2006
ASYMMETRIC SYNTHESIS - HISTORICAL EVENTS
PRIOR TO 1960
McKenzie, Prelog, Mislow, Horeau, Cram, Berson,
Mosher, Doering, Yamada, Walborsky, Wynberg
set forth principles and guidelines even
though high ee's were not achieved in practice.
1960 - 1973
Progress was excellent in C-H bond forming reactions
(REDUCTIONS).
H.C. Brown(1964)- Pinene +Borane
*
CH-CH2OH
Ipc2BH + C=C
E.J. Corey (1970) - Amino Acid Synthesis
H.B. Kagan (1972) - DIOP-Chiral Phosphines
C N
C C
W.S. Knowles, M.J. Sabacky (1972) - Chiral Phosphines C C
*
CH—NH
*
CH—CH
*
CH—CH
1972
An Explosion of Information
Occurred in Asymmetric
C-C, C-O, C-H Bond Forming
Reactions
2005
All Products > 90% ee
C-C Bonds
STOICHIOMETRIC
Chiral Enolates
Chiral Nucleophiles
Chiral Electrophiles
Cycloadditions
Rearrangements
C-O
Chiral Oxaziridines
Chiral Osmium
Chiral Boranes
C-H
Chiral NaDH-Mimics
Chiral Boranes
Chiral Silanes
C-N
Chiral Hydrides
Chiral Epoxides + N3–
CATALYTIC
Coupling Rxn's
Nucleophilic
Additions
Cycloadditions
Ene Rxns
Hydroformylations
Carbometallations
Chiral Titanium
Chiral Osmium
Chiral Manganese
Chiral Dioxiranes
Chiral Rh, Ru,
B, Co, Ti, Zr
Chiral Cu, Mn, Fe,
Ru, Cr
Early Asymmetric M-P-V Reductions A Self Immolative Process
(Comm. Ed., JACS)
OH
O
(+)
O
36 °C
Al +
H
(6% ee)
3
(+)
O
H
36 °C
+
Al
(22% ee)
3
O
OH
Doering (1950)
(+)
Me
H
O
O
Al
+
200 °C
Hex
3
Jackman (1950)
OH
H
Hex
(<1 % ee)
Two Classic Determinations of Enantiomeric Purity
Pirkle
(1980)
O
Si O
OMe
O
O
C N
H
N Ph
H
O2N
Enantiomeric mixture
+
R
i.e.
MeO
NO2
%R
N
+ %S
(±1%)
O
Chiral Chrom'y Column
R
Mosher
(1969)
MeO
CF3
Ph
C
O
H2N
Cl
R1
Amides
(19F integration of dias'ms)
+
R
HO
R1
Esters
(19F integration of dias'ms)
W.H. Pirkle, J. Chromatography 1980, 192, 143; JACS, 1981, 103, 3964
H.S. Mosher, J. Org. Chem. 1969, 34, 2543
"Asymmetric Organic Reactions" J.D. Morrison, H.S. Mosher, 1971 Prentice Hall
J.W. Scott, D. Valentine, Science 1974, 184, 943
Oxazolines (1884)
RCO2H
HO
H2N
or
O
H+
RCO2H
R
, H+, M++
N
RC N
MeX
H–
Reviews
R—CHO
H+
Wiley, Chem. Rev. 1949, 447
Frump, Chem. Rev. 1971, 483
Mihelich; Meyers, Angew. Chem. Int. Ed. 1975
Reuman; Meyers, Tetrahedron 1985, 837
Gant; Meyers, Tetrahedron 1994, 2297
Wong,"Chemistry Heterocyclic Compounds" Vol 60 Part B 2005
Oxazolines as Acid (Ester) Enolate Equivalents
O
BuLi
H
O
N
-78 °C
R
N
Li
RCH2
E
E
E = RX, X
X,
O
CO2H
R
H3O+
+
AOH2
E
O
R
N
Stable to: RMgX
LiAlH4
NaBH4
(except t-Bu)
E
CO2A
R
E=H
A = t-Bu
R° H
Meyers JACS 1970
LiCA
E = Alkyl
Review - ACIE (1975)
Rathke, JACS (1971)
CHELATE CONTROL
(1974 - 1976)
95:5
O
Ph
CH3CH2
N
• BLi
•
H3C
O
–BH
H
N
+
Li
OMe
(+)
RX
O
Ph
N
CH3
CH3CH2
H
Ph
• BLi
•
10-13% ee
(+)
OMe
H+
G† = 1.3 Kcal
H3C
CO2H
HR
76-80% ee
No chelate possible
H3C
Chelate Enforced Stereoselectivity
H3C
O
H3C
O
Ph
N
O
OMe
C6H5Li
or
C6H5MgBr
10% ee
G† = 0.24 kCal
99% ee
G† = 2.9 kCal
H3C
CO2H
C6H5 H
Walborsky (1962)
Meyers (1975)
R
O
Ph
H
N
Li
O
H
E+
N
S
Ph
H
S
S
OMe
A (Nucleophilic Addition)
(1974)
R
Li
OMe
B (Electrophilic Addition)
(1974)
ACS National Organic Symposium, Morgantown, W. Virginia, 1977
IUPAC - Organic Synthesis, Jerusalem, 1978
Perspective Article, J.Org Chem. 70 6137 (2005)
Early Attempts at Asymmetric Alkylations
O
N
H2N—R*
R*
R* = norbornyl
LDA or RMgX
phenethyl
2-butyl
E
N
R*
Li
NR*
O
E+
etc.
E
E
(10-30% ee's)
N
Horeau (1969)
Yamada (1972 - 1974)
Li
R*
E
Chiral Amino Alcohols – Various Reductions
CO2H
CF3
[H]
H NH
H NH
2
OH
2
(S)
[H]
O
Cl
(Mosher, 1969)
[]D
+4.89, +1.22
BH3•Me2S•THF
NaBH4•EtOH, H+ -1.23, +1..36
-1.22,+2.48
LiAlH4•Et2O
4.80, 1.20
BH3•THF
+3.54, 5.40,-3.60
NaBH4•I2
(±)-leucine
Ph
MeO
19
F(CF3)
99±1 @ 688Hz
99±1 @ 688Hz
99±1 @ 688Hz
99±1 @ 688Hz
99±1 @ 688Hz
49:51
(682)(690Hz)
Poindexter
Tet. Lett. 1977, 3527
Chelation Control in Enamine Alkylations
H
N
R
MeO
R
LiNPr2
–H+
H
R
N
Li
OMe
"cis"
R
H
–X
R
O
(90-99% ee)
+
N Li
R X
OMe
H3O
"trans"
JACS 1976, 3032
Cram's Cyclic (Chelate) Model
2 MeLi
OEt2
Li
Me
O Li
Me
O
Ether
R
Et2O
Me
OH
R
O
Chelate
Cram (1959, 1963
Collins (1960)
Me
OH
OH
Other Chelation Controlled Asymmetric Additions
R
Eliel (1978)
Mukaiyama (1979)
Posner (1978)
Chiral 1,3-oxathianes
Chiral 1,3-aminals
Chiral vinyl sulfoxides
Me
Auxiliary Based Asymmetric Synthesis
Chelate Controlled Stereo-Alkylation
O
R
H
H
N
Li Base
H
R
N
O
E
Rigid Chelate
Li
E
RCOCl
chiral product
H
CO2H
R
+
HN
hydrolysis
R
H
E
N
O
E
Chiral Auxiliary containing ligand (O,N,P)
Chelate-Driven Chiral Enolate Auxiliaries
O
H2N N
HN
H
H
H
N
MeO
N
MeO
MeO
Evans (1980)
Sonnet (1980)
Enders (1976)
Me
MeN
H
Ph
OH
N
O
anti
Myers (1994)
R
Evans (1982)
H
NH
t-Bu
OBu
syn Cuvigny (1978)
OMe
Schollkopf (1981)
R
O
HN
Koga (1979)
SO2
Oppolzer (1989)
Chiral Oxazolines as Modern Catalyst Ligands
(1989 - Present)
R"
R"
O
R'
O
N
O
R'
N
N
R
R
Carsten Bolm
PPh2
Henri Brunner
R
E.J. Corey
David Evans
O
R'
O
N
R'
N
Günter Helmchen
N
N
R
R
O
Jean-Marie Lehn
R
Satoru Masamune
Hisao Nishiyama
O
O
N
R
O
N
N
R
N
N
O
Andreas Pfaltz
R
R
Tamio Hayashi
Oxazolines as Vehicles in Aromatic Substitution
HO
CO2H
O
O
RLi
H2N
N
N
E+
R
R
R
E
J Org. Chem (1975)
HO
CO2H
O
H2N
N
R
OMe
(F)
R
J.Am.Chem.Soc(1975)
OMe
(F)
O
RLi
or
N
RMgX
R
R
Asymmetric Coupling - Effect of o-Substituent
O
O
R
N
MgBr
+
NR
OMe
THF, 65 °C
OMe
MeO OMe
OMe
R
% yield
S:R
90
20 : 80
CH3
79
90 : 10
CH2OTBDMS
73
93 : 7
75
40 : 60
O
O
CH2OCH3
Tetrahedron Symposium in Print 60, 4459 (2004)
Chelation-Controlled Coupling - Stereochemical Outcome
Br
R
O
O
N
MeO MeO Mg
R
R
OMe
N
MeO MeO Mg
N
MeO MeO Mg
Br
Br
OMe
-entry
-entry
OMe
O
obs
R
MeO
Ox*
O
MeO
(S)
R
N
MeO MeO Mg
MeO
Br
H. Moorlag
(R)
O
N
OTBDMS
AcN
H
O
O
OAc
1) TFA
2) Ac2O, 84%
MeO OMe
MeO OMe
LiAlH4
88%
OHC
HO
CHO
OH
CrO3
100%
MeO OMe
MeO OMe
t1/2 30 h / 90 °C
H2, Pd/C
TFA, 100%
Me Me
Me Me
BBr3
HO OH
[a]D -89.9° (EtOH)
t1/2 25 h / 140 °C
95%
MeO OMe
H. Moorlag
Diastereoselective Amide Additions
But
O
But
Bu
N
O
N
Li
NR2
LiNR2
RI
O
R
N
NR2
HMPA
THF, -78 °C
RI
LiNR2
MeI
N
% yield
92
% de
>99:1
Li
R
N
93
>99:1
LiN
92
>99:1
92
>99:1
MeI
CO2H
NR2
Li
MeI
Br
LiN
cis amino acids
AIM, Shimano
MeI
Li N
-0-
JOC 7445 (1995)
Transformation of Chiral Adducts to Enantiomerically Pure
Dihydronaphthalenes
(Acidic Conditions)
C*
C*
O
E
O
N
R
N Me
R
E
a) MeOTf
b) NaBH4
H+
E
CHO
R(H)
[E = Alkyl]
(+)-quat carbon
chiral or achiral
(E = H)
R
E
Alkyl
Aryl
Vinyl
Alkenyl
TMS (H)
Me, H
Me, H
Me, H
Me, H
Me
C*
O
N—Me
CHO
R
(Trans - 1,2)
J. Am. Chem. Soc. 1988, 110, 4611
Tetrahedron 1989, 45, 6949
H+
R(H)
85 - 90% overall
Aphanorphine Methyl Ether( from Blue-Green Algae)
Morphine analog
23 steps
CH3O
NCH3
<0.1%
[]D = -7.93° ±0.5
S. Takano, J. Chem. Soc. Chem. Commun., 1990, 290
O
Me
MeO
O
N
Me
Si(Me)2Ph
TBAF
O
N
MeO
Me
N
MeO
toluene
Rh(PPh3)3Cl
2:3 = 80:20
25%
2:3 < 2:98
67% over
2 steps
73%
Me
Me
MeO
NMe
[] +7.92°
Lit [] +7.93° ±0.5
I2
Me
NHMe
MeO
MeO
MeNH2
BH3CN–
LiAlH4
72%
[] -1.5°
70%
Me
MeO
A. Hulme
JOC 1265 (1995)
MeOTf
NaBH4
H+
Takano Intermediate
[] +27.4°
MP 47-48 °C
OH
CHO
C2 Symmetric Biaryls via Ullmann Coupling
R* R*
M0 / solvent
R*
R*
X
R R
+
X
R
R
R* = chiral controller
X = I, Br, etc.
M0 = Cu, Ni, ...
F. Ullmann Ann. 1904, 332, 38
T. Nelson
Oxazoline Mediated Asymmetric Ullmann Coupling
N
N
MeO
OMe
O
Br
OMe
Cuo / DMF
Reflux
OMe
O
MeO
OMe
O
MeO
OMe
OMe
N
96% S
4% R
Nelson, T.D. and Meyers, A.I., Tetrahedron Lett., 1994, 35, 3259
Asymmetric Ullmann Coupling- Naphthalenes
Cu, DMF
COOR*
COOR*
COOR*
Br
R*
% ee
I-menthol
13.0
(-)-cholesterol
5.3
(-)-1-phenylethanol
7.5
(-)-2-octanol
1.8
S. Miyano et al. Chem. Letters 1980, 1027
LAH
OH
OH
Oxazoline Mediated Ullmann Coupling
Br
O
R'
N
Cu–pyr
Ox*
Ox*
~100 °C
Diastereomeric
Ratio
R'
S
:
R
Ph
2
:
1
i-Pr
4
:
1
t-Bu
49 :
1
T. Nelson, J. Org. Chem. 2655 (1994)
RR
R
O
O
O
N
N
N
Br
Cu
Cu
Br
N
R
O
Complex B
Complex A
Ox* Ox*
S
Major
Ox* Ox*
49 : 1
R
Minor
T. Nelson
(S)-Gossypol
OHC
HO
H3C
OH
HO
OH
OH
HO
CHO
CH3
Isolation
J. Longmore
J. Soc. Chem. Ind., 1886, 200
Biological Properties
Structure Elucidation
R. Adams and Coworkers
J. Am. Chem. Soc., 1938, 2158
Activity against HIV infection
Racemic Synthesis
J. Edwards and J. Cashaw
J. Am. Chem. Soc., 1957, 2283
Selective toxicity toward cancer cells
In vivo antispermatogenic activity
Retrosynthetic Scheme (After Many Modifications)
OHC
HO
H3C
OH
HO
OH
OH
HO
Ullmann
Coupling
CHO
N
OMe
O
Br
CH3
OMe
OMe
OMe
(S)-Gossypol
Stobbe
Condensation
N
O
OMe
OMe
Tetrahedron 1998 54, 10493
Methoxymethyl
Introduction and
Oxazoline Removal
O
H
OMe
OMe
OMe
Asymmetric Additions to Pyridines: NADH–NAD+ Mimics
HO
CN
N
H2N
(S)
O
R
HCl, EtOH
N
R
MeLi, -78°
O
N
MeOC—Cl
N
Me H
O
R
N
CO2Me
(S,S) via X-ray
MeX
BH4, H3O +
1) OH –
Me H
OH
T. Oppenlander
N
Bn
PhCH2Br
2) LiAlH4
Me H
CHO
N
CO2Me
(S)
JACS 1986, 108, 1989 and ref. cited
NAD+, No Enzyme
Self-Immolation: NADH
O
Ph
Me
CO2Me, Mg(ClO4)2
+
6-10 days
Me
(3 Comp T.S.)
OH
N+
HO
H
Ph
CO2Me
(S) 94, (R) 6
Bn
H
OH
N
H
Ph
OH
Bn
(S,R 94:6)
MeMgCl
THF
Ph
Me
O
O
COCl
<1 min.
N
+
N
Bn
Bn
J. Brown
O
H OMgCl
Me
(S,R 94:6)
(S,R 94:6) (2 Comp T.S.)
JACS, 1987, 109, 3155 and ref. cited
SUMMARY and THOUGHTS
The early efforts of reaching enantiomerically pure compounds by chemical synthesis has
been followed by introduction of the Chiral Oxazoline as an auxiliary and vehicle for reaching
many sec, tert, and quaternary stereogenic carbon carbon bonds.
We must never forget that all of today's wonderful chemical successes in this area are possible only
because we stood on the shoulders of many brilliant chemists over the past 100 years who paved the way
Were it not for new chemical reagents, solvents, analytical techniques, and new understandings of
structure, intermediates, and chemical dynamics these advances we enjoy today would not be possible.
Therefore, we must not be deceived into thinking that the we have made many truly new discoveries
but rather we have improved and developed many of the earlier efforts .This ,of course,is also progress
and the route science has always taken.
ACKNOWLEDGEMENTS
$ = Bristol Myers Squibb, DOD-Army Research Office, GlaxoSmithKline, Merck,
National Institutes of Health, National Science Foundation, PRF
Graduate Students - Ph.D. (1970 - 2001)
** = M.S. Degree
Avila, Walter
Bailey, Ann**
Basil, Laura
Bell, Richard**
Brinkmeyer, Raymond
Degnan, Andrew
Downing, Susan
Flanagan, Michael
Gabel, Richard
Gant, Thomas
Henry, Steven**
Hanagan, Mary
Hoyer, Denton
Hutchings, Richard
Lawson, Jon
Lutowski, Katherine
Munavu, Raphael**
McKennon, Marc
Mihelich, Edward
Malone, Ray
Nguyen, Thanh
Novachek, Katherine
Pansegrau, Paul
Reuman, Michael
Roth, Greg
Slade, Joel
Smith, Roy K.
Snyder, Evan**
Tavares, Francis
Wettlaufer, David
Willemsen, Jeffrey
Williams, Donald
Postdoctoral Fellows (1970 - 2001)
Aguilar, Enrique
Aitken, R. Alan
Amos, Richard
Andrews, Robert
Barner, Bruce
Brich, Zdenek
Brown, Jack
Campbell, Arthur
Collington, Eric
Druelinger, Melvin
Durandetta, Jim
Dvorak, Curt
Dwyer, Michael
Erickson, Gary
Flisak, Joseph
Ford, Michael
Frutos, Rogelio
Haidukewych, Dan
Highashiyama, Kimio
Hillier, Michael
Himmelsbach, Richard
Hulme, Alison
James, Brian
Kamata, Kazuyuki
Kane, Michael
Kendall, Peter
Knaus, Gerald
Kolotuchin, Sergie
Kopach, Michael
Laucher, Dominique
Leonard, William
Licini, Guilia
Linderman, Russel
Mazzu, Arthur
Meier, Anton
moorlag, Hendrik
Nakano, Hiroto
Natale, Nicholas
Nelson, Todd
Ng, Raymond
Nolen, Robert
Oppenlaender, Thomas
Park, Doo Han
Poindexter, Graham
Price, Alan
Price, David
Pryde, David
Rawson, David
Reider, Paul
Reiker, William
Robichaud, Albert
Romine, Jeffrey
Santiago, Braulio
Schmidt, Wolfgang
Schmitz, William
Shimano, Masanao
Shipman, Michael
Stojanova, Diana
Teague, Simon
Temple, Davis
Walker, Donald
Warshawsky, Alan
Whitten, Charles
Williams, Bruce
Yamamoto, Yukio
OMe
O
MeO
Me
HO
OR
O
o o
MeO
MeO
NMe
OBZ
O
MeO
ZBO
OMe
Elligatanin( 1994)
1R,4R(+)-Aphanorphine(1995)
Pr
Me
HO
Me
OH
HO
CHO
OH
H X
HO
CHO OH
OH
Me
Pr
(S)-+ Gossypol (1998)
Me
(S) curcumene (1997), X=H
(S) ar-turmerone(1979), X=O
CO2Me
CO2Me
MeO
OH
MeO
Me
MeO
O
Me
H
MeO
OMe
OMe
(+)-Chlorothricolide(1989)
(-)-Schizandrin, (1990)
O
H
H
(+)-Scopadulcic acid, (1991)
Me
MeO
OH
O
Me
(+)-Lacinilene (1993)
O
O
O
O
CO2Me
Et
OH
O
MeO
O
OH O
MeO
OH
OMe
Aklavinone, 1987
(-)-Steganone, 1987
OH
MeO
OMe
OMe
MeO
O
O
O
O
OMe
OMe
(+)-Phylotetralin, 1988
MeO
OMe
OMe
(-)-Podophylotoxin, 1988
O
N
H
O
H
S
H
HO
OH HO
OH
N
N
H
O
HN
NH
Me Me
N
H
O
O
(-)-Mastgophorene A (1999)
Bistratamide D(1999)
O
O
O
N
OH
O
Me
O
N
H H Me
OH Me
N
H
N
H
O
N
`
(-)-Madumycin II (1996)
Me
O
S
N
H
O
OH
O
H
O
OH
`
(-)-Griseoviridin (2000)
Diterpenoid Quinones with Interleukin-1 Inhibitory Activity
CO2H
O
O
O
OH
H
CH3
H
O
O
(+) - Triptoquinone B
(+) - Triptoquinone A
OH
O
OH
H
O
(+) - Triptoquinone C
Isolation: Takaishi et al., Tetrahedron Lett. 1992, 33, 7177
Synthesis (A): Shishido et al., J. Org. Chem. 1994, 59, 406
OR
O
N
N
1)
Li
O
20% catalyst B

90%
2) Br
OMe
OMe
OR
single diastereomer
87%
N
OR
O
3 steps
OMe
OMe
Ar
(F3C)2MeCO
N
Mo
(F3C)2MeCO
B
Schrock (1990)
Ph
ee - 99%
Me
Me
Synthesis-( Seebach Ded'n Issue) 2064 (2002)
OR
Chelation Effects in Aldol-type Coupling
OLi
O
CHO
LDA
OMe
-780
OMe
H+
CO2Me
OH
threo/erythro 1.2 :1.0
Li
O
O
LDA
O
( )
n
( )
n
O
0
-78
i-Pr
MeO
n= 1
n= 2
+ others
OMe
O
CO2
H+
OH
H
threo/erythro 10:1
Reider JACS 1979
MeO
Total Synthesis of Ellagitanins
s
N
MeO
MeO
MeO
OMe
O
H3O+
S
N
COOH
OMe
O
MeO
MeO
MeO
OMe
S
COOH
MeO
s
MeO
(SSS)
glucose ester
OMe
(S)
MeO
MeO
O
MeO
O
O
O
MeO
O
MeO
)
Nelson, Meyers JOC 59,2577(1994)
O OMe
O
O
O
OMe
OMe
MeO
OMe
MeO
OMe
OMe
"ASYMMETRIC C-C BOND FORMATION FROM CHIRAL OXAZOLINES "
A.I. MEYERS , ACCOUNTS CHEM RESEARCH 1978, 11, 375-381
We wrote:
'' This is not the endit is not even the beginning of the end--but, perhaps it is the end of the beginning"
Winston Churchill (1942)
----------and indeed it was
Berson proposal -----
Conservation of Chirality
R
?
H
CH3CO
Me
4
N
H
CO2Et
CH3CO
oxd 'n
Me
Central chiral element @C-4
(JACS 77, 450 (1955)
Me
4
R
CO2Et
N
Me
Axial chiral element @C-4
Experiment repeated with
Ph
O
N
OMe
N
H
MgBr
R
Ph
O
N
-80Þ, toluene
OMe
N
H
88:12, R:S
free rotation
G=11.1Kcal
DDQ, -780
H
R
CHO
90%
CHO
N
H
N
88:12 R:S
R
JACS 106, 1135,1984
88:12, R:S
ASYMMETRIC SYNTHESIS------THE BOTTOM LINE
kR
C
*
+
A
*
C ----------A
R
PR
RS
*
kS
C ---------- A S
PS
if kR = kS then products (P) are racemic
if kR > kS then products (P) are enantiomer enriched, R>S
If:
G > 2.5 kCal (298 K )
G
PR will be > 98% enant.pure
C + A RS
PS
PR
Reaction
Nucleophilic Addition to Naphthyl Oxazolines
O
HO
CO2H
N
H2N
achiral
80 - 95%
Ph
80 - 95%
HO
BuLi, MeI
(S,S)
H2N
-78 °C
OMe
Ph
O
OMe
O
N
Me
BuLi, MeI
N
Bu
H
-78 °C
chiral
achiral, 98 - 99%, pure trans addition
J. Am. Chem. Soc. 1988, 110, 4611
chiral, 98 - 99%, pure trans addition
and 90 - 95% de