Download General Methods for Enantioselective Cyclopropanations

General Methods of Enantioselective Cyclopropanations
MacMillan Group Meeting
May 19, 2003
Roxanne Kunz
General Methods of Cyclopropanation
R
R
1.
X-ZnCH2X
Simmons-Smith carbenoids
O
EWG
2.
H2C
EWG
S Me
Me
Michael initiated ring closures
O
R
H
RO
M
R
CO2R
N2
3.
Me
Me
metal carbenoids
(M = Rh, Pd, Cu....)
O
O
H
O
M
O
N2
R
4.
HCCl3
base
R
Cl
dihalocarbene
Cl
Charette, A.B. Chem. Rev. 2003, 103, 977.
1
Importance of Cyclopropanes in Nature and Drugs
Me OH
MeO
O
Me
OH
H
O
Me
H
N
Me
O
O
N
O
Me
H
MeO
O
HO
O
FR-900848
O
HO
OH
NH
O
antifungal
Me
callipeltoside C
Cl
anti-cancer
Me
Me
Me
Me
Me
H
N
Me
Me
CO2H
trans-chrysanthemic acid
O
anti-insecticide
U-106305
cholesterol esterase inhibitor
HO2C
NH2
Me
H
H
O
Me
H
O
Et
H
OH
CO2H
aminocarboxylic acids
Me
OH
Me
ambruticin
antifungal antibiotic
Synthetic Utility of Cyclopropanations
! cyclopropanes are reactive toward ring-opening and rearrangments due to special bonding properties
bond angle
60 °
109 °
115 °
28
vinyl cyclopropane rearrangements
26
strain energy
(kcal/mol)
1.4
metal catalyzed cyclizations
CO2Me
heat
MeO2C
CO2Me
MeO2C
Pd
heat
RO
RO
O
N2
H
Buchner reaction
O
AgOBz
Me
Me
H
heat
2
Enantioselective Simmons-Smith Cyclopropanations
general background
! First report by Simmons and Smith in 1958
R1
R3
R2
CH2I2, Zn(Cu)
R1
Et2O
R2
R4
R3
reaction is stereospecific
cis ! cis
and
trans ! trans
R4
! Plethora of contemporary methods for generating active reagent
reactants
Et2Zn, CH2I2
active reagent
EtZnCH2I or Zn(CH2I)2
EtZnI, CH2I2
IZnCH2I
TFA, Et2Zn,CH2I2
CF3COOZnCH2I
Sm(Hg), CH2I2
ISmCH2I
R3Al, CH2I2
R2AlCH2I
ZnX2, CH2N2
Zn(CH2I)2
! In general, the most commonly used is Et2Zn + CH2I2
J. Am. Chem. Soc. 1958, 80, 5323.
Enantioselective Simmons-Smith Cyclopropanations
chiral auxiliary methods: allylic ethers
! Charette's 2-hydroxyglucopyranoside auxiliary
OBn
O
BnO
BnO
Et2Zn (4 equiv)
CH2I2 (5 equiv)
R1
O
R2
CH2Cl2, -30 °C
OH
R3
R1
SugO
R2
R3
d.r.> 99 : 1
93 % yield
R1
H
H
H
H
H
H
-(CH2)4-
R2
Me
Pr
Ph
Me
H
H
-(CH2)4-
R3
H
H
H
Me
Pr
CH2OSiR3
H
OBn
O
BnO
BnO
EtZn
Et
! coordination by second zinc activates CH2I(ZnR) and
enhances chelate structural rigidity
R1
O
O
R2
Zn
R3
! auxiliary is cleaved in two steps (Tf2O, pyr; DMF, pyr)
I
major
! Charette's simplified chiral diol auxiliary
R1
! similar substrate scope and d.r.'s
O
R2
! available by enzymatic resolution
OH
R3
J. Am. Chem. Soc. 1991, 113, 8166.
Tet. Lett. 1993, 34, 7157.
3
Enantioselective Simmons-Smith Cyclopropanations
chiral auxiliary methods: synthesis of coronamic acids
! Switch of olefin geometry provides access to four isomers of coronamic acid
OBn
BnO
BnO
OTIPS
Et2Zn (4 equiv)
CH2I2 (5 equiv)
TIPSO
O
O
CH2Cl2, -30 °C
OH
d.r.> 99 : 1
93 % yield
SugO
Et
Et
OBn
O
BnO
BnO
O
OTIPS
Et2Zn (4 equiv)
CH2I2 (4 equiv)
TIPSO
Et
SugO
d.r.> 66 : 1
98 % yield
Et
CH2Cl2, -60 °C
OH
CO2H
5 steps
82 %
OTIPS
OTIPS
(-)-allo-coronamic acid
BocHN
Et
NHBoc
RuCl3, NaIO4
HO
HO2C
83 %
5 steps
Et
Et
2 steps,
75 %
Et
NHBoc
5 steps
OTIPS
HO
(-)-coronamic acid
HO2C
42 %
OTIPS
RuCl3, NaIO4
Et
91 %
HO2C
HO2C
64 %
Et
Et
(+)-coronamic acid
CO2H
5 steps
BocHN
41 %
2 steps,
80 %
Et
(+)-allo-coronamic acid
J. Am. Chem. Soc. 1995, 117, 12721.
Enantioselective Simmons-Smith Cyclopropanations
chiral controller ligands
! Kobayashi demonstrated the first catalytic asymmetric cyclopropanation
Et2Zn (2 equiv), CH2I2 (3 equiv)
CH2Cl2, -20 °C
R2
R1
OH
R2
R1
OH
13 - 82 % ee
36 - 92 % yield
NHSO2Ar
NHSO2Ar
(12 mol%)
R1, R2 = aryl, Bu3Sn,
SiR3, CH2OR
! low enantioselectivity attributed to background reaction catalyzed by ZnI2
! works well for alkyl olefins, but less well for tri-and tetra-substituted olefins
! later studies by Denmark improved on the ee's by optimizing order of addition of reagents
J. Am. Chem. Soc. 1998, 120, 11943.
ACIE. 1997, 36, 1090.
4
Enantioselective Simmons-Smith Cyclopropanations
chiral controller ligands
! Charette's chiral dioxaborolane ligand
R1
Me2NOC
R2
OH
CONMe2
O
R3
O
Et2Zn (1.1 equiv)
CH2Cl2;
CH2I2 (2.2 equiv)
B
R2
OH
R3
82 - 94 % ee
71 - 98 % yield
Bu
1.1 equiv
R1
R2
R3
H
Bu3Sn
I
Et
CH2OR
Me
H
Bu3Sn
I
Pr
CH2OR
Aryl
vinyl
H
Me
CH2OR
R1
! on > 1 mmol scale, Zn(CH2I)2 prep is explosive!
! therefore, Zn(CH2I)2 DME is used on > 1 mmol scale
! ligand prep is two steps from commercial starting materials
! 1,2,3-trisubstituted cyclopropanes
Me2NOC
Ph
OH
CONMe2
O
O
B
Bu
Me
Zn(MeCHI)2
CH2Cl2, 23 °C
Ph
OH
98 % ee
16 : 1 d.r.
J. Am. Chem. Soc. 1998, 120, 11943.
ACIEE. 1997, 36, 1090.
5
Enantioselective Simmons-Smith Cyclopropanations
Et
chiral lewis acid
! Charette's Ti TADDOLate catalyzed cyclopropanations
R1
R2
OH
R1
R2
R3
H
Ph
Alk
H
Alk
aryl
heteroaryl
vinyl
H
Me
Ph
R1
R2
25 mol% catalyst
O
O
O
Ph
Zn(CH2I)2 (1 equiv)
4 Å MS, DCM, 0 °C
R3
Et
O
48 - 92 % ee
60 - 90 % yield
OH
Ph
i
Pr O
Ti
Ph
i
O Pr
catalyst
R3
! lower ee's were achieved for alkyl olefins
! best for aryl-substitued allylic alcohols
Zn(CH2I)2
OH
OZnCH2I + CH3I
(1 equiv)
L.A.
OZnI
LA
LA
O
O
ZnCH2I
ZnCH2I
! bis(oxazoline), diethyl tartrate, binaphthol type catalysts all gave lower ee's
J. Am. Chem. Soc. 1995, 117, 11367.
J. Am. Chem. Soc. 2001, 123, 12168.
Enantioselective Simmons-Smith Cyclopropanations
synopsis of Barrett's synthesis of FR - 900848
Me2NOC
CONMe2
O
O
B
OH
HO
Bu
, DCM
OH
HO
Charette
CH2OH
90 % yield
>99 % ee
OH
HO
HOH2C
2 steps
Zn(CH2I)2
HOH2C
OTBS
4 steps
93 % yield
single diastereomer
Charette
HOH2C
OTBS
OH
Me
3 steps
H
N
Me
O
4 steps
O
FR-900848
(20 steps)
HO
O
N
OH
NH
O
Chem. Comm. 1997, 1693
6
Enantioselective Michael Initiated Ring Closures
general background
! Michael initiated ring closures (MIRC) are not stereospecific, but may be highly stereoselective
R2
R1
R2
Nuc
R2
or
R1
R1
LG
LG
H
R
CH2LG
H
R
R
A
EWG
B
EWG
H
H
C
! usually, B >> C
EWG
C
R
R
EWG
EWG
! two categories of MIRC substrates
LG
Nuc
EWG
Nuc
EWG2
LG-CH-EWG2
1
EWG
EWG
EWG1
Class I
Class II
Enantioselective Michael Initiated Ring Closures
general background
! Corey pioneered sulfoxonium ylides in 1960's
COPh
Ph
Me2S(O)CH2
Ph
95 %
reagent
COPh
reactivity
ketones/ ! oxiranes
aldehydes
Me2S-CH2
esters & amides
Me2S(O)-CH2
ketones
aldehydes ! oxiranes
Ph2S-CMe2
ketones, esters
amides
aldehydes ! oxiranes
Me2S-CHCO2R
ketones, esters
nitriles, aldehydes
! phosphorus, tellerium, and arsonium ylides are known, but less commonly used
Ph3P=CH2
Ph3P=CMe2
Ph3As=CHCOPh
Bu2Te
SiMe3
Br
J. Am. Chem. Soc. 1962, 84, 866.
7
Enantioselective Michael Initiated Ring Closures
chiral auxiliaries
! Evans' oxazolidinone strikes again, but with limited substrate scope
O
M
O
O
N
R
>1 equiv Zn(OTf)2
N
O
Ph
R
Me
Me
Ph
O
R = Me
95 % ee
R = Ph
36 % ee
Ph
N
N
Xc
R
Ph
O
O
O
O
Ph2S-CMe2
Ph
Ph
! non-selective reaction catalyzed by LiBF4 is competitive
! a chiral sulfide auxiliary finds more success
Me
Me
EtN=P(NMe2)2 -N=P(NMe2)3
("Et-P2")
EtO2C
Me
O
S
1 equiv ?
S
Et-P2H
Me
Me
Me
O
H
Ar
CO2Et
Ar
6 - 19 : 1 d.r.
84 - 99 % ee
O
TfO
OEt
Ar
! ylide generated in situ, but not catalytically
ACIEE 1998, 37, 1689.
Tet. Lett. 2000, 41, 9009.
! the oxirane is formed with !,"-unsaturated aldehyes
Enantioselective Michael Initiated Ring Closures
Aggarwal's methodology
! Aggarwal combined the sulfonium ylide concept with diazo carbenes
R2S
O
R1
Ph
Rh2(OAc)4
PhCHN2
R2
R1
Ph
(syringe pump)
O
R2
R2S
N2
Rh=CHPh
Ph
O
Rh2(OAc)4 (1 mol%)
(Ph)Me
Ph
O
S
Me
PhCHN2, toluene, 23 °C
20 mol%
Ph
O
97 - 98 % ee
4 : 2 d.r.
14 - 38 % yield
Me(Ph)
! yields increased when stoichiometric amount of sulfide was used
! enantioselectivity reduction over the reaction course wasn't seen in the catalytic examples
! sulfide available in two steps from camphorsulfonyl chloride
Chem. Comm. 1997, 1, 1785.
8
Enantioselective Michael Initiated Ring Closures
Aggarwal's improved methodology--a truly catalytic reaction
! generation of carbene in situ from tosyl hydrazones
R2S
O
R1
Rh2(OAc)4
Ph
PTC
PhCHN2
- NaTs
R2
Ph
N
N
Ts Na+
PTC = BnEt3NCl
R1
N2
COR2
R2S
Rh=Ph
Ph
% yield
d.r.
% ee
COPh
73
4:1
91
COPh
50
4:1
90
COMe
12
--
--
10
7:1
--
alkene
COR2
R1
Ph
Rh2(OAc)4 (1 mol%)
N
N
R1
Ph
BnEt3NCl (20 mol%)
COR2
1,4-dioxane, 40 °C
sulfide (20 mol%)
Ts Na+
1.5 equiv
Me
Ph
Ph
CO2Me
EWG
EWG
Ph
S
H
S
H
O
Ph
O
ACIEE 2001, 40, 1433.
major
minor
Enantioselective Michael Initiated Ring Closures
ammonium ylide mediated cyclopropanations
! Gaunt and Ley's intermolecular ammonium ylide methodology
O
NaOH or Na2CO3
(1.5 equiv)
N
Cl
Ph
EWG
Ph
N
EWG
EWG , MeCN, 80 °C
DABCO
(1 equiv)
4 - 19 : 1d.r.
40 - 96 % yield
CO2tBu
C(O)Me
C(O)NMe2
SO2Ph
CN
CHO (40 %)
O
R3N
O
R1
COPh
Ph
Cl
R3N
R2
R1
COR2
Ph
NaOH
Cl R3N
COPh
! one enantioselective example was reported using cinchona alkaloid
Me
MeO
N
N
! catalytic asymmetric examples
were not reported
! base + heat will erode ee over time
1 equiv
94 % ee
58 % yield
ACIEE. 2003,42, 828.
9
Enantioselective Michael Initiated Ring Closures
ammonium ylide mediated cyclopropanations
! extension of Gaunt and Ley's methodology to intramolecular systems
N
Cl
N
EWG
O
NaOH or Na2CO3
(1.3 equiv)
O
CO2tBu
C(O)R
C(O)Ph
EWG
DCE or MeCN, 80 °C
DABCO
(20 mol%)
EWG
H
H
SO2Ph
enone
CHO
42 - 95 % yield
! products isolated as single diastereomers
! one asymmetric example using cinchona alkaloids
O
OMe
Cl
N
O
(CH2)2Ph
H
MeCN, 80 °C
OMe
N
O
NaI
Na2CO3
(1.3 equiv) (40 mol%)
O
(CH2)2Ph
H
95 % ee
64 % yield
20 mol%
! sodium iodide facilitates formation of the ammonium salt
ACIEE. 2004, 43, 2681.
Enantioselective Metal-Carbenoid Cyclopropanations
! examples of the most commonly used !-substituted carbenoid precursors
O
O
P
OR
N2
Ph
NO2
SO2R
N2
N2
N2
N2
O
CN
(OR)2
N2
O
RO
OR
N2
R
R
EWG
LnM
LnM=CH-EWG
EWG
N2
N2
! diazoalkanes (i.e. diazomethane) and aryl, alkenyl, and alkynyldiazo compounds are potentially explosive
! variety of metal salts catalyze diazo reagent decomposition (Rh, Ru, Cu, Pd, Pt..)
! electron-rich olefins are optimal substrates for cyclopropanation
10
Intermolecular Enantioselective Metal Carbenoid Cyclopropanations
some "general" trends
O
R1
H
R2O
N2
R1
R1
CO2R2
CO2R2
Rh, Ru, Cu, Co
R1
R1
CO2R2
cis
CO2R2
trans
! in general, copper catalysts are more selective for trans-cyclopropanes and have widest scope
! rhuthenium catalysts are very effective, but have limited substrate scope
! rhodium catalysts produce lower ee's and d.r.'s
! cobalt catalysts are more selective for cis-cyclopropanes but ligands are hard to prepare
! most methodologies apply only to mono and 1,1-disubstituted olefins
11
Intermolecular Enantioselective Metal Carbenoid Cyclopropanations
Davies' rhodium catalyzed methodology
! enantioselective synthesis of vinylcyclopropanes using dirhodium(II) carboxylates
OMe
R
R2
N2
O
MeO2C
Rh2(TBSP)4 or
Rh2(DOSP)4
O
Ph
pentane, -78 or 23 °C
Ph
Rh
N
SO2
O
Rh
4
R1
% yield
% ee
Ph
68
98
AcO
26
95
EtO
65
93
Bu
63
>90
Et
65
>95
i-Pr
58
95
R
Rh2(DOSP)4 Rh2(TBSP)4
R = C12H26
R = t-Bu
! extension to other substrate types
Me
MeO2C
Me
Ph
MeO2C
MeO2C
Me
95 % ee
52 % yield
O
Me
Ph
Ph
80 % yield
86 % ee
84 % yield
J. Am. Chem. Soc. 1996, 118, 6897.
12
Intramolecular Enantioselective Metal Carbenoid Cyclopropanations
some notable examples
! cyclopropanation of a silylenol ether with Evans' derived catalyst
O
Me
N2
Me
O
O
O
H
CuOTf, DCM, 0 " 23 °C
N
Me
TESO
Me
Me
OTMS
Me
Me
OTES
OTMS
Me
phorbol CD ring
15 mol%
Me
92 % ee
70 % yield
Me
N
! Corey pushes the envelope with !-diazocarbonyl carbenoid
Me
H
DCM, 0 °C
Me
CO2Me
N2
O
Me
Me
t-Bu
N
t-Bu
Cu
90 % ee
77 % yield
Me
H
Me
CO2Me
sirenin precursor
N
O
Tet. Lett. 1996, 37, 2449.
Tet. Lett. 1995, 36, 8745.
General Methods of Enantioselective Cyclopropanations
conclusions
! Charette's Simmons-Smith methodology has widest substrate scope, but ee's and d.r.'s are very
dependent upon reaction conditions
! Metal carbenoid cyclopropanations are powerful, but deleterious side reactions often result due
to indiscriminate reactivity of metal carbenes
! Metal carbenoid cyclopropanations often require exhaustive catalyst screening to achieve good selectivities
! Substrate scope of metal carbenoid reactions is limited, mostly 1,1,-disubstituted and mono-substituted olefins
! Both Simmons-Smith and metal carbenoid reactions are air and water sensitive
! No general catalytic enantioselective MIRC methodology has been reported (YET)
13