Download Reductive Couplings

I.S. Young
Baran Group Meeting
3/11/2009
Reductive Coupling
Searching reductive coupling on Scifinder will lead to two major classes of reactions:
1) Alkyne to carbonyl compounds (aldehydes, imines and ketones): carbonyls lead to allylic
alcohols.
1) Coupling of two carbonyl-type species to form pinacol type products
- why is this good? no need for multistep functionalization to form an organometallic species, also
more ammenable to asymmetric transformations.
Example: McMurry coupling in Nicolau's synthesis of taxol
O
O
Classes of Reductive Coupling
HO
OH
OBn
OBn
R1
TiCl3 (DME)1-5,
O
H
O
O
H
O
O
O
O
Ti
R1 H
TMS
alkyne used in many cases
H
LnNi
H
quench with
electrophile
yields 47-90%
rr 86:24 to >96:4
use H2O
for reductive
OH
R3
R4 +
R2
R1
R3
R4
R2
OH
Sato Tetrahedron Lett. 1995, 36, 3203
R3
R1
1) Ti(O-i-Pr)4 / i-PrMgCl
R2
R1 H
2)
N
R2
R3
R5
R2
R5
R4
R3
R4
R1
+
NH
NH
R3
R4
R2
yields 48-94%
rr >20:1 in most cases
then H2O
reductive
elimination
R5
R1
R4ZnO
- many factors influence the
pathway taken such as;
ligand, reductant, solvent
R1
R4
R4
R1
key catalytic cycle
intermediate
OH
R3
- addition of two molecules of aldehyde to titanocyclopropane not observed
hydrogen introduction
onto metal either from
β-hydride elimination from
ligand/reducing agent or
introduced H2 gas
R2
direct
reductive
elimination
R2
R3
2) Transition metal catalyzed C-C bond forming event where a hydrogen (reductive coupling) is
transferred instead of an alkyl group (alkylative coupling) in the reductive elimination step
R4ZnO
R1
behaves as a vincinal
dianion equivalent
Other C=X (X = heteroatom, ex. nitrones, oximes) etc can be used. SmI2 is frequently employed
in the literature to induce this transformation
R3
O
O
O
LnNi
O-i-Pr
O
Nicolaou Nature 1994, 367, 630
R4
O-i-Pr
then
R2
R2
Zn-Cu, DME
70 oC, 23%
(O-i-Pr)2
Ti
O
R1
Ti(O-i-Pr)4
i-PrMgCl
Sato Tetrahedron Lett. 1995, 36, 5913
Use of Ni to induce RC. ZnEt2 is the reducing agent so run risk of alkylative coupling (Et transfer)
R4
OH
R3
R2
alkylative coupling product
R1
H
H
H
R2
reductive elimination product
R1
O
R3
H
X
ZnEt2
R1
HO
yields 62-74%
Ni(COD)2 : PBu3
1:4
X
Montgomery J. Am. Chem. Soc. 1997, 119, 9065
I.S. Young
Mechanism
R2
LnNi(0)
O
O
L = PBu3
R1 H
H
O
OH
aigialomycin D
L
ZnR42
R2
CH3
MOMO
OTBS
OH
Et3SiH (5.0 equiv)
Ni(COD)2, IMes HCl
t-BuOK (25 mol% each)
use of NHC carbene ligand
R3
R4ZnO
R2
R1 H
LnNi
O
O
HO
small substituent
(or tether chain)
R3
MOM O
CH3
O
R1
R2
H
O
large substituent
R4
LnNi
R4ZnO
R3
Ni
H
H
OH
L
L
R3
R1
Baran Group Meeting
3/11/2009
Reductive Coupling
L
Me
Ni
R3
O
R1
H
Me
N
Cl
N
Me
Me
R2
MOM O
O
CH3
Me
O
Me
IMes HCl
MOMO
L = THF
OH
R1
H
H
OH
R3
R1
H
R2
R4
R2
(intramolecular variant only)
Reductive coupling would only
occur on intramolecular
R3 substrates
with phosphine ligands
- inter always led to alkylative with
these coditions
CH3
1) Et3SiH, Ni(COD)2
PBu3, THF 95%
2) HF pyridine 92%
N
H
3) Lio, NH3, THF 88%
O
H
H3C OBn
R1
Et3SiH also eliminates
alkylative coupling
Me
OTBS
First Catalytic in Nickel, also first intermolecular example using Ni
O
diethyl zinc adds to carbonyls
in comples substrates
61%
1:1 dr
Montgomery Org. Lett. 2008, 10, 811
Applications to Natural Product Synthesis
Me
OTES
- terminal alkynes known to give poor dr as observed,
but reaction of internal alkynes did not yield desired product
R2
R3
H
Me
Ni(COD)2 (10 mol%)
Bu3P (20 mol%)
Et3B (200 mol%)
R1
R3
R2
toluene or THF
Jamison Org. Lett. 2000, 2, 4221
N
OH
yield = 45-89%
rr = 92:8 to 98:2
Asymmetric Variants By Jamison
H
Me OH
OH
allopumiliotoxin 267A
- cyclization step assembles six-membered ring, controls the relative stereochemistry adjacent
to a quaternary center and assembles the alkylidene unit (each event occuring in a highly
selective manner
Montgomery J. Am. Chem. Soc. 1999, 121, 6098
..
P
Me
Ph
Me
Fe
up to 67% ee
J. Org. Chem. 2003, 68, 156
Me
Me
PPh2
(+)-NMDPP, up to 96% ee
J. Am. Chem. Soc. 2003, 125, 3442
I.S. Young
Applications to natural product synthesis
H
Me
O
Me
Ph
H
+
OTBS
OH
terpestacin
Me
alkyne/aldehyde
coupling
H
..
O
Me
Me
could envision forming the macrocycle
by this method but wrong regioisomer was
the only formed product (14 membered ring)
Me
2
Ph
Rh(COD)2OTf (5 mol%)
R
(R)-Cl-MeO-BIPHEP (5 mol%) 1
R2
DCE (0.1 M), 25 oC
H2 (1 atm)
Ph
O
Ph
Ph
D
Ph
Ph
D
Me Me
HO
O
Bryostatin 1
R2
C7H15
Me
O
O
D2
O
RhIII(D)2Ln
O
OTBS
Me
O
O
O
Me
Rh(COD)2OTF (5 mol%)
(R)-Tol-BINAP (5 mol%)
Ph3CO2H (1.5 mol%)
H2 (1 atm), ClCH2CH2Cl)
65 oC
OH
CO2Me
OH
1,3-diynes and glyoxals: J. Am. Chem. Soc. 2003, 125, 11488
1,3-enynes and glyoxals: J. Am. Chem. Soc. 2004, 126, 4664
conjugated alkynes and ethyl (N-sulfinyl)iminoacetates: J. Am. Chem. Soc. 2005, 127, 11269
conjugated alkynes and α-ketoesters: J. Am. Chem. Soc. 2006, 128, 718
silyl substituted diynes to control regioselectivity: Org. Lett. 2006, 8, 3873
intramolecular acetylenic aldehydes cyclizations: J. Am. Chem. Soc. 2006, 128, 10674
heteroaldehydes and chiral Bronstead acid additived: J. Am. Chem. Soc. 2006, 128, 16448
in situ generation of enynes and coupling to carbonyls: J. Am. Chem. Soc. 2006, 128, 16061
in situ generation of enynes and coupling to imines: J. Am. Chem. Soc. 2007, 129, 7242
conjugated alkynes and α-ketoesters: Org. Lett. 2007, 9, 3745
application to the synthesis of hexoses: Org. Lett. 2008, 10, 4133
RhILn
BnO
OH
O
c
Me
O
OAc
OH
Me
O
Ph
MeO2C
O
O
OH
regioselectivity = 2.6:1
diastereoselectivity = 2:1
41% yield desired compound
These rhodium procedures requires the alkyne to be conjugated for increased reactivity
(Krishce Work, uses hydrogen as the reductant)
O
Ph
OTBS
Me
O
Ph
D
81%
H
ligand
O
Ph
OH
Me
Ph
Fe
OSiMe3
Ph
LnRhID
Ni(cod)2 (20 mol%)
ligand (40 mol%)
Et3B (150 mol%)
ethyl acetate
Jamison J. Am. Chem. Soc. 2003, 125, 11514
P
Ph
D
Ph
Me
H
Me
O
RhILn
O
R1
O
Ph
Ph
Me
Me
Me
catalytic cycle
OSiMe3
O
HO
HO
Baran Group Meeting
3/11/2009
Reductive Coupling
BnO
Me
bryostatin C-Ring
BnO
OMe
O
Me
c
4-steps
Me
O
C7H15
O
Me
HO
O
CO2Me
Krische Org. Lett. 2006, 8, 891
OTBS
I.S. Young
Reaction of alkynes with epoxides - first example of coupling to sp3 center
(yields homoallylic alcohols)
R1
Baran Group Meeting
3/11/2009
Reductive Coupling
R2
+
cat. Ni(cod)2
Bu3P
R3
O
R3
R1
R2
Et3B
enatiomerically
pure
TBSO
Me
+
Me
O
Ph
Ni(cod)2 (10 mol%)
Bu3P (20 mol%)
Et3B
>99% ee
yield up to 85%
>99% ee
OH
Me
TBSO
Ph
O
X
cat. Ni(cod)2
Bu3P
OH
Ph
yields up to 88%
> 20:1 endo closure
Et3B
n
n
Me
Ph
benzylidene group is ozonized to produce the carbonyl
group found in the natural product
X
OH
81% yield
99% dr
Jamison J. Am. Chem. Soc. 2003, 125, 8076
Mechanism - endo opening suggests a different reaction mechanism than alkyne/aldehyde
R
R
H
PBu3
PBu3
Ni O
O
LnNi
Ni
R
PBu3
OX
R
alkyne/
epoxide
coupling
OX
R
Me
H
Me
O
(5 steps)
Me
Ni(COD)2 (20 mol%)
PMe2Ph (40 mol%)
Et3B (150 mol%)
toluene, 65 oC
82% yield
n-Bu
Me OH
Ni(cod)2 (20 mol%)
Bu3P (40 mol%)
Et3B
Me
Me
Ph
Me
CH2
HO
O
Jamison
alkyne/
O
aldehyde
macrolactonization
Me
O
Me
pumiliotoxin 251D
Jamison J. Org. Chem. 2007, 72, 7451
Me
HO
N
H
Ph
Me
Et3B
Applications to Natural Product Synthesis
n-Bu
O
PBu3
β−hydride Et
Ni
elimination
OX
O
Me
X= BEt2
N
Me
O
Me
Ph
reductive
elimination H Ni PBu3
R
O
O
H
anti-Bredt olefin
accomadated by longer
Ni-O and Ni-C bonds
H
steps
Amphidinolide T1
O
Me
O
Ph
Me
Jamison J. Am. Chem. Soc. 2004, 126, 998
O
O
44% yield
>10:1 dr
I.S. Young
Example to Show Fine Balance Between Alkylative and Reductive Coupling
Development of NHC Ligands (allow for efficient intermoleuclar RC with triethylsilanes)
- desired reaction is three-component alkylative coupling (RC was a competing problem)
- imines less electrophilic - need hydroxylic solvent and organoboron reagent
- methanol occupies coordination site, hindering β-hydride elimination
R1
R2
H
H
Ni(COD)2 (10 mol%)
(c-C5H9)3P (20 mol%)
R5BX2
R4
HN
R1
R4
R3
MeOAc/MeOH
0 oC, 20 h
N
R5 HN
+
R1
O
alkylative coupling
Ni
PR3
Me
H
Me
reductive coupling
N
+
L
Ar
BEt3
Ar
Me
N BEt2
H
Me
Me
O
Ph
H
Mes N
..
yield = 56-84%
rr = >98:2
R3
N Mes
R2
+ Et3SiD
Ni(COD)2
+ Pr3SiH
ligand
X
R3Si O
Ph
X
From NHC
From PBu3
Et
Et
Pr
Pr
H
D
H
D
<2
55
41
<2
25
34
23
18
using alkene as a regioselective director
R3
R
R2
Ar
PR3
Me
R1
H
PR3 Me
Ni
N BEt2
Me
H
PR3 Me
Ni
N BEt2
Me
aldehyde (n=0)
or
epoxide (n=1)
Et3B
R3
n
R2
R1
Ni(cod)2/Cyp3P (cat)
reference alkynes
(not alkene-directed)
alkene-directed
Me
Ar
Me
Ar
R
R4
OH
effect of
alkenyl group
reverses
regioselectivity
N BEt2
Me
Ar
Ar
reductive
elimination
Me
Ni
Me
MeOH
R1
R
Me
Me
R3P OH Me
Et Ni
N BEt2
Me
Et3SiH
H
Montgomery J. Am. Chem. Soc. 2004, 126, 3698
Me
reductive
elimination
Et3Si O
+
R2
R2
Mechanism demonstrating competing pathways
Me
Ni(COD)2
(10 mol%)
Cross Over Experiment to Show that Ligand Identity Affects Mechanism
reductive coupling
alkylative coupling
(undesired)
(major product with MeOH)
yields 30-98%
rr = > 10:1
Jamison Angew. Chem. Int. Ed. 2003, 42, 1364
alk:red = > 10:1
Me
N BEt2
R1
R4
R3
R2
R3
+
H
R3
Et
Baran Group Meeting
3/11/2009
Reductive Coupling
1 >20
>20 1
t-Bu
t-Bu
(does not couple)
increases reactivity
and controls
regioselectivity
1 >20
Me
circumvents
poor
regioselectivity
β-H elimination
2 1
1 >20
>20 1
Jamison J. Am. Chem. Soc. 2004, 126, 4130
I.S. Young
Baran Group Meeting
3/11/2009
Reductive Coupling
directing effect of remote alkene and impact of phosphine
application of synthetic approach:
reaction doesn't work with 1,2,4 carbon spacer
R1
OMs
+
R2
Et2BO
Ni(COD)2
R1 O
L
with
Cyp3P
Ni
R1
R
Me
O
Me
H
Me
R2
R
or
H
OBEt2
without
Cyp3P
R1
R1
Pd(PPh3)4
Et2Zn
C
Me
R1 O
OH
Me
TiCl4
diaseteroselective
propargylation
(yields 60-82%)
(d.r. 5:1 - >20:1)
Me
Me
i) n-BuLi
ii) ClTi(Oi-Pr)3,
C5H9MgCl
iii)BF3 OEt2, then
Cyp3P
Et3B
R2
BEt2
Ni
Ni
H
Me
Et3B
R2 CHO
- two steps
- two C-C bonds formed
- three new stereocenters (*)
- stereodefined trisubstituted double bond (*)
- no protecting group manipulations
O
R2
R1
R1
O
R2
Me
Me
Me
Me
R1
Me
"
"
Me
OH
R2
*
*
*
Me
Me
Me
Me
OH
Me
R2
H
Me
15
Me
O
O
Me
Me
MeO
substrate for polyols (hydration/dihydroxylation), epoxides (olefin epoxidation
and 1,5-diols (hydrogenation)
Micalizio J. Am. Chem. Soc. 2005, 127, 3694.
Me
Me
Me
Me
Me
O
HO
NMe2
OR
OMe
O
O
H
1
Me
MeO
OH
O
ene-1,5-diol
very
valuable
9
Me
O
H
Me
Me
Me
HO
two step general strategy: alkynation followed by alkyne/aldehyde reductive coupling
R1
OH
*
O
Me
Jamison J. Am. Chem. Soc. 2004, 126, 4130
OH
R1 O
applications to total synthesis
- degree of regioselectivity influenced by remote alkene
- sense of regioselectivity controled by additive
- with directing alkene and ligand combined, completely different mechanism
OH
regioselective
reductive
coupling
yields 42-71%
r.s. 3:1 - 19:1
d.s. 1.5:1 to 4:1
O
H
R2-CHO
*
*
SiMe3
Me
O
Me
NH
MeO
O
R = CONH2
Me
O
macbecin 1
erythromycin A
synthesis of the C-1 to C-15 fragment
Micalizio Org. Lett. 2006, 8, 1181
Total Synthesis
Micalizio Angew. Chem. Int. Ed. 2008, 47, 4005
I.S. Young
Catalytic Version Mechanism
Iridium Chemistry - non-conjugated alkynes can now be coupled
R1
R2
O
R3
OR4
O
Ir(COD)2BARF (2 mol%)
DPPF (2 mol%)
Ph3CCO2H (2 mol%)
H2 (1 atm)
PhCH3, 60 oC
O
R2
R1
OR4
R3 OH
yields: 73-99%
rr usually > 20:1
Et
Et
Ph
OBn
O
O
Et
O
Et
D2
Et
OEt
OH
94%, 95% D
Et
Me
Mori J. Am. Chem. Soc. 1994, 116, 9771
OEt
OH
O2CR
D
H
O
DO2CR
H
Coupling of Other π-Components to Carbonyls
OH
N
100 mol% Ni(acac)2
200 mol% PPh3
Me
N
R1
n
Ni complex
OBn 1.5 eq Et3SiH
toluene
(also works catalytic)
yield 52-86%
20 mol% Ni(cod)2
40 mo% PPh3
Et3SiH (5 equiv)
THF
CHO
O
elaeokanin C
DIBAL-H (2 eq to Ni)
O
OBn
Applications to total synthesis
LnIrIII
OH
OSiEt3
Ni(0)
Et3SiH
O
Et
OEt
LnIrIII
Et
O
reductive
elimination
oxidative
elimination
O
HO2CR
Et
OBn
OEt
LnIrIII
IrIIILn
Me
Et3Si Ni H
Et
LnIrI
O
Ni SiEt3
OBn
O
Et
Et
Et
D
H
insertion
OEt
IrIln
Ni
H
O
O
Mechanism
H
Et3Si
Alkynes and ketones: Krische J. Am. Chem. Soc. 2007, 129, 280.
Alkynes and imines: Krische J. Am. Chem. Soc. 2007, 129, 8432.
Et
Baran Group Meeting
3/11/2009
Reductive Coupling
R1
H
Me
OH
R3
R3 =
or
n
>2:1 ratio of double
bond position isomers
(internal usually favoured)
H
+
O
OSiEt3
N
N
Mori Tet. Lett. 1997, 38, 3931
OBn
OSiEt3
37%
O
Mitsunobu Reaction
81% (4 steps)
36%
I.S. Young
CO2Me
silylethylene-titanium alkoxide complex - reagent originally developed by Kulinkovich. Addition
to an ester makes cyclopropanols. Utility expanded by Sato.
HO
O
Baran Group Meeting
3/11/2009
Reductive Coupling
H
CO2Me
100 mol% Ni-complex
1,3-CHD (150 mol%)
THF, rt
O
O
Me
Me
O
53%
(15% rcvd sm)
O
O
Me
Me
R
H
1,3-CHD is important to obtain double bond
in the desired position. If it is not included it
it migrates one position closer to the newly
formed C-C bond.
CO2H
HO
OH
Me3Si
OH
1) 10% Cp2Ti(PMe3)2
silyl hydride
X
Me
NHR1
SiMe2
OEt
CH3
X
2) workup
CH3
X
R2
Me3Si
OEt
Sato J. Org. Chem. 2000, 65, 6217
Me
+
H+
coupling of allenes / alkynes with chiral imines
- reverse order, Ti reagent is complexed
to imine instead of alkyne/allene
OMe
R
HN
major
(from more stable metallocycle)
Mechanism
Cp2Ti(PMe3)2
Ph2(H)SiO
H
CH3
H3C
+2PMe3
X
N
Ph 2 i-PrMgCl
H
CH3
X
H
R
H
yield = 28-84%
d.r. >98:2
Ph
Ti(O-i-Pr)2
OMe
Ph
R2
X
H
Ph2(H)SiO
TiCp2
Ti(O-i-Pr)4
N
Ar
O
H
MeO
Ph
CH3
Cp2Ti
CH3
H3C
X
-2PMe3
H+
HO
OMe
O
Me
X
H
Ar
Buchwald J. Am. Chem. Soc. 1995, 117, 6785
Crowe J. Am. Chem. Soc. 1995, 117, 6787
48%
SiMe2 75%
OH
Me
R
Me3Si
H+
Ti(O-i-Pr)2
ketones and alkenes - stated as the first catalytic for alkene/alkyne with heteroatom
containing DB. Mori did it with dienes and aldehydes in 1994...?
O
34-87%
R1
R2
Total Synthesis by Mori, Synlett 1997, 734
PGF2α
Me3Si
OH
N
HO
H+
R1
X
- chiral group can be removed to produce chiral primary amines
Sato Org. Lett. 2003, 5, 2145
HN
Ar
Ph
C
H
R2
R1
yields = 45-74%
d.r. >98:2
I.S. Young
Baran Group Meeting
3/11/2009
Reductive Coupling
Allenes and Transfer hydrogenation:
homo-allylic alcohols and imines
- more complex RC as you generate two new stereocenters.
OH
R1
R3
+
Ti(O-i-Pr)4
c-C5H9MgCl
N
HN
yields 61-83%
r.r. > 20:1
d.r. = 4:1 to >20:1
R2
H
OH
(i-PrO)n
R1
R1
R3 PPh3 / CCl4
R1
reflux
C
R2 cyclization
R2
N
76-85%
R3
R3
O Ti N
H
R2
Micalizio J. Am. Chem. Soc. 2007, 129, 7514
C
R
Me
aryl or activate
alkyl aldehyde
- in many cases 4 to 8 equivalents of allyl source is required (no mention of this!)
R1
OH
C
OH
R2
R3
R
Li2CO3 (35 mol%)
DCE-EtOAc (1:1), 60 oC
H2 (1 atm)
Me Me
O
yields: 60-95%
Me
Standard Conditions
D2 (1 atm)
R1 R2
yields: 23-92%
- can also use rhodium based catalysts [RuHCl(CO)(PPh3)] to affect similar transformations
but an acid cocatalyst (m-NO2BzOH or CF3CO2H) is required when the alcohol is used as
the substrate.
OH
Other sources of allyl derivative metal reagents for transfer hydrogenation
O
NO2
R3
Cs2CO3 (5-7.5 mol%)
DCE-EtOAc (1:1), 75 oC
No H2
Krische J. Am. Chem. Soc. 2007, 129, 15134.
D
C
OH
[Ir(BIPHEP)(cod)]BARF (5-7.5 mol%)
- alcohol serves as hydrogen source and electrophilic substrate
- eliminates the need for oxidation prior to allyl nucleophile addition
Mechanism - prenyl group is necessary to prevent over reduction of double bond
O
yields: 50-90%
- basic additive Cs2CO3 also helps to inhibit over-reduction
Krische J. Am. Chem. Soc. 2007, 129, 12678
Me
R1 R2
- no stoichiometric by products produced
R1
[Ir(BIPHEP)(cod)]BARF (5 mol%)
O
R3
Cs2CO3 (5-7.5 mol%)
DCE-EtOAc (1:1), 75 oC
i-PrOH (200 - 400 mol%)
- transfer hydrogenation must be used since H2 over reduces all products besides reverse prenyl
- reverse prenylation with allenyl metal reagents
Me
R3
R2
OH
[Ir(BIPHEP)(cod)]BARF (5-7.5 mol%)
O
Me
NO2
Me
R1
R2
LnIr-D
LnIr-D
D2
D
D
D
LnIr
Me
Me
LnIr
O
OH
Me
R
Me
O
Me
Me
NO2
OAc
OAc
1,3-cyclohexadiene
Org. Lett. 2008, 10, 1033
allyl acetate
JACS 2008, 130, 6340
asymmetric
JACS 2008, 130, 14891
acyclic dienes
JACS 2008, 130, 6338
Me
asymmetric crotylation
JACS 2009, 131, 2415
I.S. Young
Baran Group Meeting
3/11/2009
Reductive Coupling
Vinyl pyridines and imines
ArSO2
R1
Allene Alkyne Coupling
[Rh(cod)2]BARF (5 mol%)
(2-Fur)3P (12 mol%)
N
N
R1
R2
R2
N
Na2SO4 (200 mol%), 65 oC
DCM, 25 oC
H2 (1 atm)
R2
H NSO2Ar
R1
C
Me
R2
1)
Ti(O-i-Pr)2
+
R3
56-97% yield
3:1 -13:1 dr
R1
Sato Chem. Commun. 1998, 271.
Effect of alkoxide on stereochemistry
π-π coulpings where the π-bonds are all carbon
C6H13 1) i-PrMgCl
Paper was about alkylative cyclization but they found that use of phosphine led to RC
alkylative vs reductive cyclizaiton
if X = H
H+
Bu2Zn / BuZnCl
2)
H
Ni(COD)2, 5 mol%
Ph
PPh3, 25 mol%
BuZnO
X = TBS 62:38
H
82:18
reduction
or alkylation
1) i-PrMgCl
if X = H
H+
without phosphine
Bu (51%)
R2 = H (11%)
with phosphine R2 = H (92%)
R2
R1
+
Me XO
XO
2)
R2 =
63%
69%
SiMe3
SiMe3
XO
NiLn
Me
Me
Ti(O-i-Pr)2
X = TBS
H
SiMe3
H
H
+ XO
XO
R2
O
C6H13
C6H13
XO
O
H
R3
2) H+
- need substitution at 6-position of pyridine, otherwise catalyst binds to
nitrogen and no reaction
Krische, J. Am. Chem. Soc. 2008,130, 12592
Ph
yields 45-94%
E:Z ration 64:36 to >20:1
Me
Ti(O-i-Pr)2
X = TBS
H
X = TBS 51:49
H
90:10
73%
70%
- result explained by the fact that the alkoxide is better at locking the transition state in a chair than
the -OTBS even though it is "smaller"
phosphine may force alkyl and alkenyl into a trans orientation, thus preventing reductive elimination
Sato Tetrahedron Lett. 1998, 39, 7329
Montgomery J. Am. Chem. Soc. 1996, 118, 2099
Montgomery J. Am. Chem. Soc. 1997, 119, 4911
alkyne-alkyne coupling to prepare 1,3-dienes
Allenyne Cyclizations
R3
Ti(O-i-Pr)2
R1
R2
n
C
R1
R3
R4
R1
R2
R1
R1
+
yield = 42-98%
rr 4:1 to >20:1
n
R3
Ti(O-i-Pr)2
R2
R2
R1
Ti(O-i-Pr)2
R2
R3
yields 47-93%
rr = 60:40 to >20:1
R4
Sato J. Am. Chem. Soc. 1997, 119, 11295
R2
Sato J. Am. Chem. Soc. 1999, 121, 7342
R3
I.S. Young
Baran Group Meeting
3/11/2009
Reductive Coupling
Cobalt Becomes Involved - alkyne / activated alkene coupling
Proposed mechanism shown for diyne:
Ph
R1
R2
+
R3
R3 = acceptor
[CoI2(PPh3)2], PPh3, Zn
R3
R1
CH3CN, H2O, 80 oC
R2
MeO2C
Ph
MeO2C
Ph
MeO2C
RhIIILnD
MeO2C
Ph
mechanism
Ph
CoII
Zn
Me
Co
CO2-nBu
CoI
LnRhIOTf
D2
CO2-nBu
LnRhID
H2O
Ph
CoIII
CoIII
MeO2C
D
MeO2C
D
CO2-nBu
RhILn
MeO2C
D
Ph
MeO2C
RhIII(D)2Ln
MeO2C
D
D2
Ph
Ph
Me
MeO2C
Ph
Ph
Zn
Ph
CO2-nBu
Ph
Me
Cheng J. Am. Chem. Soc. 2002, 124, 9696
Alkyne-Alkyne Coupling by Micalizio (Similar to Sato)
previous Krische examples showed metal adding across C-O π bond, why not C-C π bond?
R1
X
R1
Rh(COD)2OTf (3 mol%)
rac-BINAP or BIPHEP (3 mol%)
R2
DCE (0.1 M), 25 oC
H2 (1 atm)
- Micalizio different for two reasons: functionalization of the internal alkyne component has only
been achieved with TMS-substituted alkynes and conjugated 2-alkynoates (this introduces limits
for polyketide synthesis)
yields 51-90%
X
- coupling can lead to four possible regioisomers
R2
R
X
DCE (0.1 M), 25 oC
H2 (1 atm)
R1O
R
Rh(COD)2OTf (3 mol%)
rac-BINAP or BIPHEP (3 mol%)
OR2
Me ClTi(Oi-Pr)3, c-C5H9MgCl
-78 to -30
yields 65-91%
X
Me
CH3
Me
R1O
-78 oC then terminal alkyne
yields = 46-87%
r.r. = 5:1 to 8:1
Micalizio Org. Lett. 2005, 7, 5111.
diyne and enyne cyclizations: Krische J. Am. Chem. Soc. 2004, 126, 7875
asymmetric enyne cyclizations: Krische J. Am. Chem. Soc. 2005, 127, 6174
OR2
oC
R3
Me
Me
Me
I.S. Young
R1O
OH
Me
Baran Group Meeting
3/11/2009
Reductive Coupling
alkoxide directed (intramolecular) coupling of alkynes
Me
explanation for regioselectivty
minimization of steric interactions in approach of second alkyne
Me
i-Pr O Oi-Pr
Ti
R1 +
Li
O
Ti catalyst
then
R2
n
O Oi-Pr
Ti
n
R2
R1
R2
R2
intramolecular
carbometalation
n
R2
O Oi-Pr
Ti
R2
R1
R2
+ LiOiPr
R1
R2
i-Pr O
O
OH
R2
R2
Ti
RL
Me
Me
Oi-Pr
Me
Me
R2
HO
regioisomer
not formed
major product
R2
R1
R1
Oi-Pr
R1O
yields 51-58%
n
n
R2
R2
H+
R2
OH
Micalizio J. Am. Chem. Soc. 2006, 128, 2764
also works with allenes to make skipped 1,4-dienes
OH
Ti
RL
Me
Me
Oi-Pr
Me
R3
OH
Me
Ti(Oi-Pr)4 (2.1 equiv)
c-C5H9MgCl (4.2 equiv)
C
R1
R2
R1O
i-Pr O
OH
RL
Me
Me
Me
Me
Application to total synthesis
Oi-Pr
palladium-mediated
coupling
Me
Oi-Pr
R2
R3
Micalizio Chem. Commun. 2007, 4531
R2
Ti
R2
single regioisomer formed in most cases
R4
R2
R5
R1
R5
then
R4
OH
R1O
HO
R2
OH
Ti
Me
O
H
O
O
Me
RL
Me
Oi-Pr
Me
Me
Me
Me
Me
Me
Me
alkyne-alkyne
reductive coupling
callystatin A
Micalizio Angew. Chem. Int. Ed. 2008, 47, 7837.
I.S. Young
TBS O
OTMS
Me
+
Me
Me
Me
Me
H
O
Enones and alkynes (enals cyclize)
ClTi(OiPr)3
c-C5H9MgCl
toluene
Me
OiPr
O
Me
Me
OTMS
H
O
R2
Me
MLn
M
R3
H
R2
R1
H
R3
1) carbometallation
R1
2) H+
R4
BEt2OMe
R1
Et2BOMe
+
R2
R3
R4
R1
R4
R4
+
Me
R4 rr usually >20:1
Mechanism
O
Me
yield = 50-90%
R1
Et3B (3.0 equiv)
MeOH, THF (8:1)
R3
R2
O
- can couple enoates with ynoates without any homocoupling, which is surprising
OiPr
Me
Me
Ni(COD)2 (10 mol%)
PBu3 (20 mol%)
+
R2
Micalizio Angew. Chem. Int. Ed. 2008, 47, 7837.
TBS O
R4
R1
75% yield
r.r. 5:1
Me
R1
Baran Group Meeting
3/11/2009
Reductive Coupling
O
NiLn
Ni(0)Ln
OBEt2OMe
Ni Ln
or
R4
R4
R3
R2
R1
R2
R2
R3
R3
R3
3 other possible
regioisomers
MeOH
Micalizio Angew. Chem. Int. Ed. 2007, 46, 1440
(MeO)Et2 B
O
use remote alkoxide to direct regioselectivity
Li
O
RE
iPr O OiPr
Ti
+
n
RZ
R2
R2
RE
intramolecular
carbometalation
R2
OH
R2
n
RZ
RE
(major product)
H+
O OiPr
H
Ti
R2 or
n
RZ
O OiPr
Ti
RE
2
R
R2
R4
- without alkoxide there
was no reaction
RZ
n
OBEt2
Ln
Ni
R2
bridged conformation less favoured
O
R2
R2
O
Ti
OiPr
RE
n
RZ
R2
H+ H O
R2
R3
O
R4
R2
H
NiLn
product
R1
R4
R3
RE
n
RZ
R3
R2
= aryl or alkyl
NiLn
R3
R4
enal leads to cyclization
Et
R1
R2
R2
R2
R1
OH
R4
=H
R3
R1
- only works with allylic and
homo allylic alcohols
R1
Montgomery J. Am. Chem. Soc. 2007, 129, 8712
I.S. Young
Cobalt mediated alkyne-alkene
HO
[CoI2(dppe)], ZnI2, Zn
X
n
application to total synthesis
R1
R1
CH3CN, H2O, 80
R2
+
R3
[CoBr2(dppe)]
Zn, ZnI2, CH2Cl2
Me
Me
alkyne/allylic alcohol
reductive coupling
OAc
R2
OH
phorbasin C
no additional coupling even though
product is again an allylic alcohol
key step in total synthesis
Me
Me
Co
R2
Me
n
Cobalt mediated alkyne-unactivated alkene coupling
R2
Me
O
X
oC
Cheng J. Am. Chem. Soc. 2007, 129, 12032
R1
Baran Group Meeting
3/11/2009
Reductive Coupling
R3
β-hydrogen
elimination
R1
R2
Me
R3
O
Me
Me
O
Ti(Oi-Pr)4
c-C5H9MgCl, Et2O
+
R1
-78 oC to rt
HO
Treutwein Angew. Chem. Int. Ed. 2007, 46, 8500
O
TMS
47% dr > 20:1
HO
TMS
Me
O
OH
alkynes and allyl alcohols with transfer of oxygen to catalyst (net allyl transposition)
R4
ii)
R5
R2
i) ClTi(Oi-Pr)3, c-C5H9MgCl
Complimentary Claisen-based methods: a stereodivergent product is produced
R4
R1
Micalizio J. Am. Chem. Soc. 2009, 131, 1392
R5
OH
O
Li
R1
R3
R3
R1
yields 42-79%
rr from 1:1 to >20:1
R2
i) Claisen
rearrangement
R3
R1
OH
R2
ii) reduction
R2
typically
> 20:1
alkene substitution pattern has a large
impact on degree of selectivity
then H+
R3
intermediate
This work:
R1
(Oi-Pr)n
Ti
R1
Me
H
O
R2
H+
Me
Me
workup
R1
R2
major product by control of
A-1,3-strain
R1
Me
Si
Cl
i) ClTi(Oi-Pr)3
c-C5H9MgCl
ii) O
R3
R1
R1
R3
Tamao
R3
then 1N HCl
t-BuOOH,
CsOH, TBAF
DMF
[Si] Oxidation
Li
R2
Micalizio J. Am. Chem. Soc. 2007, 129, 15112
similar results reported by Cha J. Am. Chem. Soc. 2008, 130, 15997
R1
R2
typically
> 20:1
OH
R2
Micalizio J. Am. Chem. Soc. 2008, 130, 16870
Cha (J. Am. Chem. Soc. 2008, 130, 15997) reported this result first, but allylic alcohols were
limited to cyclohexyl derived, except for one case
I.S. Young
Reductive Aldols - no prefunctionalization with stoichiometric reagents
O
R2
R3
+
R1
Me3SiH
RhCl3 3H2O
O
R4
O
R4
R3
If
= OMe, no
evidence of silyl
ketene formation
and then aldol
R5
R3
R3
R1
O
R4
R2
R5
H
Rh4(CO)12 (cat.)
R1
R5
R5
R2
Matsuda Tetrahedron Lett. 1990, 31, 5331
R1
R4
R3
H
+
yields - 22-99%
dr 55:45 to 84:16
1) 2.5 mol% [(COD)RhCl]2
5.5 mol% Me-DuPhos
Cl2MeSiH
O
OR2
OH
O
R1
R1
H
H
1) 2.5 mol% [(COD)RhCl]2
6.5 mol% R-BINAP
Et2MeSiH
2) H3O+
1) 2.5 mol% [(COD)IrCl]2
7.5 mol% ligand
Et2MeSiH
2) H3
O
OMe
H
OH
R
R2
yield 44-92%
syn:anti 1.7 to 2.5:1
R
1
2
H2 (1 atm), KOAc (30 mol%)
DCE, 25 oC
For Ketone Additions to Aldehydes Acceptors:J. Am. Chem. Soc. 2002, 124, 15156
For For Ketone Additions to Ketone Acceptors: Org. Lett. 2003, 5, 1143
For Aldehyde Addition to Glyoxals Acceptors: J. Org. Chem. 2004, 69, 1380
For Aldehyde Additions to Ketones Acceptors: Org. Lett. 2004, 6, 691
Increase in syn selectivity using tri-2-furylphosphine: Org. Lett. 2006, 8, 519
Unsymmetrical divinyl ketone addition to aldehydes: Org. Lett. 2006, 8, 5657
Ketone addition to α-amino aldehydes (syn stereotriads): J. Am. Chem. Soc. 2006, 128, 17051
Asymmetric ketone additions to aldehydes: J. Am. Chem. Soc. 2008, 130, 2746.
O
O
Ph
- treatment of substrate with only phosphine
does not lead to Baylis-Hillman
OH
O
R1
O+
O
Me
OH
R
A
H2
yields 48-72%
syn:anti 1.8:1 to 5.1:1
2
OR
ee (syn) = 45-88%
O
Ph
Morken J. Am. Chem. Soc. 2000, 122, 4528
R
R1
O
Rh(COD)2OTf (10 mol%)
(p-CF3Ph)3P (24 mol%)
O
LnRhIII(H)2
OR2
O
O
- The KOAc helps prevent conjugate reduction by
deprotonating complex A or B
Enantioselective Variants
+
n
Mechanism
Me
Morken, J. Am. Chem. Soc. 1999, 121, 12202
O
yield 64-90%
syn:anti 5 to 20:1
OR2
2) H3O+
did experiements in 192 well plates to determine ideal conditions
O
OH
R
H2 (1 atm), KOAc (30 mol%)
DCE, 25 oC
n
OSiMeEt2
O
R2
O
O
R
O
Rh(COD)2OTf (10 mol%)
(p-CF3Ph)3P (24 mol%)
yields = 24-95%
O
+ Et2MeSiH3 +
Hydrogen as the reductant - All work by Krische
OSiMe3
R3
Revis Tetrahedron Lett. 1987, 28, 4809
O
Baran Group Meeting
3/11/2009
Reductive Coupling
LnRhI
avoid this
Ln
Me
yields 47-68%
syn:anti 1.7:1 to 9.1:1
ee (syn) = 82-96%
Morken Org. Lett. 2001, 3, 1829
O
O
N
N
O
N
ligand
Ph
III
O
O LnRh
conjugate
reduction
O
OMe
H
O
OH
Ph
H
Ph
B
H
RhIII
O
enolate
addition
I.S. Young
Baran Group Meeting
3/11/2009
Reductive Coupling
Role of aryl halides in Ni-Catalyzed Reductive Aldols
Three-Component Coupling via Internal Redox (leads to esters and malonates!)
O
O
+
O-t-Bu
H
OH
Et3B
Ni(COD)2
R
O
R
PhI
O-t-Bu
Three-Component enal, alkyne, alcohol additions (no reducting agent is necessary,
it forces reaction to the cycloaddition pathway).
No Reaction
Without PhI
CH3
O
- PhI isn't just serving as a mechanism to generate Ni(II) from Ni(COD)2
R1
H
- proposed to form a boron enolate which then reacts with aldehyde (metal no longer
complexed for this step).
R4
+
MeOH, THF (8:1)
Montgomery Org. Lett. 2007, 9, 537
N
O
+
R1
R3
R4
R2
HO
Ni(COD)2 (10 mol%)
PBu3 (20 mol%)
R2 R3
LNi(OMe)2
(doesn't re-enter
cycle)
H
OMe
R2
R2
Ph
H
O
OMe
R2
O
H
LnNi
R1
MeO
NiLn
R2
R1
NiL
R1
Three-Component Enone, Alkyne, Aldehyde Additions
R1
Ni
O
R2
O
R1
H
H
R1
O
O
ONiL
H
Ln
Ni
O
MeOH
R1
OMe
L = Me2N
NMe2
(1 equiv)
Ph
+
LnNi(0)
NiLn
R4
Ph
OH
O
R2
MeOH
need to add
co-reductant
H
R1
Ni(COD)2 (1 equiv)
Ph
N
yield 58-85%
good dr
Original Stoichiometric Protocol (only worked for intramolecular)
H
O
H
Montgomery J. Am. Chem. Soc. 2006, 128, 14030
O
R3
Cl
Mechanism
R5
R1
Et3B (4.0 equiv)
MeOH, THF (8:1)
R4
R1
Random Reactions
R5
H
O
R3
R2
Intermolecular Enal-Alkyne [3+2] Reductive Cycloadditions
(first example of catalytic and intermolecular)
-synthesis of carbocyclic 5-membered rings via cycloaddtions difficult (traditional 3+2's need a
heteroatom in dipole)
- formal solutions is to use strained rings precursors, vinyl carbenoids or dianion equivalents
- the assembly of an odd-membered ring from two even numbered pi systems would require a net
two electron oxidation or reduction or a hydride shift
- early stoichiometric work in the field by Sato J. Am. Chem. Soc. 1996, 118, 8729 and
J. Am. Chem. Soc. 1997, 119, 10014
OMe R2
Ni(COD)2, KO-t-Bu
O
R2 +
R3
R5
+
H
R4
Ni(COD)2, Ligand
H
R2
R5
O
toluene
Ph
Montgomery J. Am. Chem. Soc. 2008, 130, 469
O
R3
R4
I.S. Young
Reductive Coupling
Mechanism
O
R2
R1
R5
+
R2 Ln
Ni
O
LnNi(0)
R1
RS
R4
R1
H
O
O
O
NiLn
H
O
Ln Ni
R2
R5
R4
R3
H
R5
R1
NiLn
R2
R4
O
O
R1
R3
R5
R3 R2
R3
RL
R4
H
R2
R5
O
O
R1
R4
Reviews on Reductive Coupling
Sato: Bicyclization of dienes, enynes, and diynes with Ti(II) reagetn. New developments towards
asymmetric synthesis. Pure Appl. Chem. 1999, 71, 1511.
Sato: Synthesis of organotitanium complexes from alkenes and alkynes and their synthetic
applications. Chem. Rev. 2000, 100, 2835.
Montgomery: Nickel-catalyzed cyclizations, couplings, and cycloadditions involving three
reactive components. Acc. Chem. Res. 2000, 33, 467.
Montgomery: Nickel-catalyzed reductive cyclizations and couplings. Angew. Chem. Int. Ed. 2004,
43, 3890.
Cheng: Cobalt- and nickel-catalyzed regio- and stereoselective reductive couplings of alkynes,
allenes, and alkenes with alkenes. Chem. Eur. J. 2008, 14, 10876.
Krische: Catalytic carbonyl addition through transfer hydrogenation: A departure from preformed
organometallic reagents. Angew. Chem. Int. Ed. 2009, 48, 34.
Jamison: Nickel-catalyzed coupling reactions of alkenes. Pure Appl. Chem. 2008, 80, 929.
Baran Group Meeting
3/11/2009