Rune Risgaard
Larry E. Overman
- Born in 1943 in Chicago, Illinois
- Raised in Hammond, Indiana
- B.A., Earlham College 1965
- Ph.D., University of Wisconsin 1969
with Professor Howard W. Whitlock
- NIH postdoctoral fellowship with Professor
Ronald Breslow at Columbia University
- He joined University of California, Irvine in 1971
where he is Distinguished Professor of Chemistry
362 publications:
- 128 JACS
- 74 JOC
- 12 Angew. Chem.
- 117 papers with the term "total synthesis"
Research Interests: Organic, Inorganic, Organometallic and Chemical Biology
- Professor Overman's research interests center on the invention of new reactions
and strategies in organic synthesis and the total synthesis of natural products and
their congeners.
11-2-2013
Awards/Honours include:
ACS Arthur. C. Cope Award (2003)
ACS Creative work in Synthetic Organic Chemistry (1995)
2011 - UCI Medal, University of California, Irvine, American Chemical
Society,
2010 - Herbert C. Brown Award for Creative Research in Synthetic
Methods,
2008 - Tetrahedron Prize for Creativity in Organic Chemistry,
2007 - The Nagoya Medal of Organic Chemistry,
2005 - International Society of Heterocyclic Chemistry Senior Award,
2004 - Ta-shue Chou Lectureship Award,
2003 - American Chemical Society Arthur C. Cope Award,
2002-2003 U.C. Irvine Distinguished Faculty Lectureship Award for
Research,
2002 - Yamada Prize
1999 - Japan Society for the Promotion of Science Fellowship,
- S. T. Li Prize for Achievements in Science and Technology,
- Earlham College Distinguished Faculty Award,
1997 - Centenary Medal, Chemical Society, U.K.
1995 - American Chemical Society Award for Creative Work in
Synthetic Organic Chemistry,
1993 - 1994 - Guggenheim Fellowship,
1993 - C.S. Hamilton Award, University of Nebraska
1985 - 1992 - Javits Neuroscience Investigator Award
1989 - American Chemical Society Arthur C. Cope Scholar Award
- Visiting Miller Research Fellow, U.C. Berkeley
1985 - 1987 - Alexander von Humboldt U.S. Senior Scientist Award,
1976-1981 Camille and Henry Dreyfus Teacher-Scholar Award
1981 - U.C. Irvine School of Physical Sciences Distinguished Teaching
Award,
1979 - U.C. Irvine Alumni Association Distinguished Research Award
1975-1977 - Alfred P. Sloan Foundation Fellow
11-2-2013
Larry E. Overman
Rune Risgaard
Charge in rearrangement reactions
Synthesis of cis-fused octahydroindoles and cycloheptapyrrolidines
- One carbon ring expansion
- Present in alkaloids of the Amaryllidaceae, Aspidosperma, and Strychnos familes
Cope
Ar
Oxy-Cope
O
N
Aza-Cope
Ar
R3
OH
N
R3
OH
H
rate acceleration up to1010
relative to Cope
NH
R1
EtOH, reflux,
(66-78 %)
H
R3
Charged atom can distort the reaction pathway of concerted toward nonconcerted
Rate acceleration due to delocalization in transition state
The aza-Cope rearrangement
- Mild conditions (100-200 oC below the corresponding Cope rearrangement)
- Usually occurs near rt.
- Reversible (Driven by aryl conjugation of the product iminium ion)
- Charged intermefiate lowers free energy of activation
N
Mannich
R2
R2
R3
H
R2
N
R1
OH
The aza-Cope-Mannich rearrangement
- Cycloheptapyrrolidine moiety present in Gelsemine
- Directing the rearrangement by intramolecular trapping
- Double bond incorporated in a suprafacial sense
OH X
R2
R1
H
CSA
R2
N
R3
H
R1 =
Benzene, 80 oC, 24h
(54-97 %)
N
[3,3]
R3
R3
HO
HO
R1
Mannich
N
H, CHPh2
Ph
NH
Benzene, reflux,
(66-78 %)
R1
H
N
R1
Tetrahedron Lett. 1982, 2737
R2
Cyanomethyl as a source for the iminium equivalent
- Also functions as protection group
R1
O
Ph
OH
Ph
AgNO3
R1 = alkyl, phenyl, thiophene, pyridine; R2 = alkyl, benzyl; R3 = H, Me
JACS, 1979, 101, 1310
JACS, 1983, 105, 6622
O
CH2O
O
NH2
N
R1
Ph
OH
Synthesis of 3-Acyl-pyrrolidines
R3
R2
R1 = H, Me; R2 = H, Me, n-C6H13; R3 = Ph
JACS 1981, 103, 5579
Tetrahedron Lett. 1982, 2733
R1 CHO
H
H
Tetrahedron Lett. 1982, 2741
N
CN
EtOH, 1h rt.
60 %
R3
R2
H
R1
Acc. Chem. Res., 1992, 25, 352-359
R2
N
R1
OH
O
[3,3]
R2CHO
O
rate acceleration up to1017
relative to Cope
R3
OH
H
N
N
R1
11-2-2013
Larry E. Overman
Rune Risgaard
OBut
Synthesis of (±)pancracine
- Amaryllidaceae alkaloid
OH
OH
O
AgNO3
O
NH
Bn
O
N
Bn
O
O
1) HCl, Pd/C, H2,
MeOH
O
2) Formalin, Et3N,
aq. 6N HCl
H
H
BF3
O
EtOH, rt
(87%)
CN
H
N
.OEt
1) NaH, Benzene, 100oC
2) KOH, EtOH:H2O, 60oC
2
H
N
(CH2O)n, Na2SO4
MeCN, 80 oC
(98%)
(62%)
DCM, -20oC
(97%)
HO
N
Bn
N
O
O
N
N
(±)pancracine
7% overall yield
(17 steps)
Bn
JOC. 1993, 58, 4662
H
OH
NH
OH
H
N
CH2(CO2H)2, Ac2O,
NaOAc, HOAc, 110oC
Me3Sn
OBut
1
O
N
1
2.5% Pd2dba3
22% Ph3As, LiCl
N
I
CO (50 psi)
NMP 70 oC
(80%)
O
OBut
R2N
O
R2N
O
Selected targets acheived with the Aza-Cope-Mannich reaction
1) TBAF, THF, -15oC
2) MsCl, Hünigs base,
DCM, -23oC
3) NH2COCF3, NaH
DMF, rt.
OBut
(83%)
R2N
H
N
O
1) t-BuO2H, Triton-B, THF
2) Ph3P=CH2, THF
(84% 2 steps)
NHCOCF3
N
H
HN
HN
N
HO2C
O
OTIPS
O
H
(-)-Strychnine
20 steps, (3% yield)
OTIPS
N
OH
CO2Me
H
JACS, 1993, 115, 9293-9294
(39%)
(1R, 4S)
N
N
H
OTIPS
AcO
1) LDA, NCCO2Me, THF
-78oC
2) HCl in MeOH, reflux
(70 %, 2 steps)
O
N H
7 steps
OBut
N
O
H
OH
Enantioselective total synthesis of (-)-Strychnine
OH
O
1) Zn, H2SO4, MeOH, reflux
2) NaOMe, MeOH, rt.
3) DIBAL, DCM, -78 oC
N
7 steps
N
N
O
N
O
O
(65%, 2 steps)
N
N
Ar
1) HCHO, KCN
2) Swern
3) t-BuLi,
vinylbromide
O
OH
( ±)-Gelsimine
26 steps, (1.4%)
Angew. Chem., 1999, 38, 2934
(-)-Actinophyllic acid
9 steps, (8%)
JACS, 2010, 132, 4894-4906
O
MeO
O
N
N
H
CO2Me
dl-16-Methoxytabersonine
11 steps
JOC, 1983, 48, 2685
N
H
OH
OBut
O
H
O
N
(-)-Crinine
10 steps, (6%)
Helv. Chim. Acta., 1985, 68, 745
N
H
CO2Me
(±)-Akuammicine
10 steps, (8%)
JACS, 1993, 115, 3966
H
N
H
O
( ±)-Meloscine
24 steps, (3%)
JACS, 1991, 113, 2598
Conversion of allylic alcohols into a cis-vicinal diol
- Conventional oxymercuration-demercuration gives trans-1,3-diol
H
CCl3
OH
O
O
R
H
CCl3
O
Initial asymmetric Pd(II) catalyst developed
- Only useful for N-arylbenzimidates
- Coordination of the basic trichloroacetimidate nitrogen to the palladium center
- Competing elimination reactions
O
N
t-Bu
O
NaBH4
HgX2
CCl3CHO
R
R = H, But;
11-2-2013
Larry E. Overman
Rune Risgaard
X
R
HgX
Na, Et2O, rt
Ar1
CCl3CN
NaH
OH
R2
R3
R1
O
R2
Et2O
R3
R1CCl H
R = H. alkyl
O
R2
R3
R1
six-membered transition state for thermal rearrangement
R2
HN
O
CCl3
JACS, 1976, 98, 2901-2910
JACS, 1974, 96, 597
R
HX
R
N
O
CCl3
HN
5 % catalyst
N
O
R
Dilute NaOH
(60-83% overall)
5 mol % COP
38 C, 18 h.
O
(93%, 93% ee)
R
CCl3
HN
NH2
O
R
R
R = H, alkyl, aryl
F3C
R3
Cl
CF3
O
Pd
Pd
O
N
MX
MX2
HN
NH2
Hg(II) and Pd(II) salts catalyze rearrangement
Mechanism proceeds through a iminomercuration-deoxymercuration
Catalytic effect greater then 1012
R
O
DCM, rt
CCl3
R3
NH
CCl3
3
R2
HN
R1
O
Xylene
NH
N
Ar
Ar1
Catalytic asymmetric rearrangement of allylic trichloroacetimidates
- Catalyzed by monomeric cobalt oxazoline palladacycles (COP)
- >90% ee
- COP-Cl superior in DCM but low solubility
- COP-hfacac soluble in a wide variety of solvents. Higher solubility
[3,3]
25-140 oC
CCl3
2
JOC, 1997, 62, 1449-1456
(25-68% yield, up to 60% ee)
R
Synthesis of amines by rearrangement of allylic trichloroacetimidates
(Overman rearrangement)
Allylic imidate rearrangement discovered in 1937
Works for 1o, 2o and 3o allylic alcohols
Large enthalpic driving force (imidate to amide functionality 15 kcal/mol)
Useful for synthesis of hindered amines
Mild cleavage of the trichloroacetyl group
Trichloroacetimidates often used directly without purification
Preparation typically invole DBU in aprotic solvents or alkali metal hydrides
EWG (CCl3 or CF3) results in more facile rearrangment compared to imidates
High stereoselection (preference for E isomer)
N
Pd
Cl
Ar
Zn, AcOH, reflux
(79 and 88%)
R
R1
N
Fe
2
OH
J.C.S. Chem. Comm., 1972, 1196
Pd
JACS, 1999, 121, 2933-2934
(35-97% yield, 57-93% ee)
OH
X = OCOCF3
O
CCl3
MX2
2+
SiMe3
N
Ph Co Ph O
Ph Co Ph O
Ph
Ph
Ph
COP-Cl (1)
JACS, 2003, 125, 12412-12413
JOC, 2004, 69, 8101
Ph
COP-hfacac (2)
(BF4)2-
11-2-2013
Larry E. Overman
Rune Risgaard
Prins pinacol rearrangement
- Allylic acetals into highly substituted tetrahydrofurans
- Catalyzed by lewis (EtAlCl2, BF3.OEt2, SnCl4) (SnCl4 is generally superior)
- Reaction occurs via chair topography with (E)-oxonium ion
- Incoporation of doublebond in suprafacial sense
- Both diastereoisomers gives the same product
Catalytic asymmetric synthesis of chiral allylic esters and aryl ethers
O
R
NH
O
1mol% COP-OAc
R1COOH
DCM, rt
(60-100%, 87-99%ee)
CCl3
R1
O
R
JACS, 2005, 127, 2866-2867
R
NH
O
1mol% COP-OAc
ArOH
O
DCM, 38oC
(45-88%, 80-98%ee)
CCl3
Org Lett., 2007, 9, 911-913
R1
NH
Cl3C
-OAc
NH
O
R
R
O
RH2C
R = H, alkyl,benzyl; R1 = H, alkyl, phenyl, TMS.
JACS, 1981, 103, 2809
H3C
R1
R2
H3C
H3C
O
O
OH
R1
OH
O
R2
R3
R2
R
R
CH2
tautomerice
H
O
H3C
O
N
CCl3
H
Pinacol
CH3
O
R2
O
CH3
R1
R2
H3C
O
H3C
CH3
Cannot undergo C-C
bond formation (5-endo-trig)
R3
NH2
HN
H
CH3
CH3
R1
O
R1
O
xylene, reflux
(38-92%)
R1
CH3
O
R1
R3
R
CCl3
Prins
R1
O
O
Cl3C
R2
O
H3C
NH Pd C
Thermal rearrangement of propagylic trichloroacetimidates
- Synthesis of trichloroacetamido-1,3.dienes
- High stereoselectivity observed, (1Z,3E) isomer formed
H
H3C
HO
N
HOAc
OCOR1
RH2C
R2
H3C
DCM, -78 - 0oC
(73 and 90 %)
R1
OH
H
AcO Pd C
[3,3]
R1
Mechanism:
R
N
NH
SnCl4
CH3
JACS, 1987, 109, 4748
NH Pd C
Cl3C
Cl3C
O
O
1a or b
R
R
O
CH3
R1
H3C
N
O
O
O
a) R1 = H, R2 = CH3; b) R1 = CH3, R2 = H
AcO Pd C
O
Ar
R
N
Cl3C
CH3
CH3
O
R2
R1
CCl3
OH
MgBr
THF, rt
(41-95%)
CH3
OH
H3C
OH
O
CSA
R1CHO
PhH, 80oC
(64-70%) H3C
R = H, Me, Ph
R1 = Me, Et, i-Pr, CH2CH2Ph, CH=CH2, Ph, (E)-CH=CHPh
[1,5]
R
O
HN
R1
H3C
R
CCl3
JACS, 1991, 113, 5354-5365
Acc. Chem. Res., 1992, 25, 352-359
Can undergo C-C
bond formation (6-endo-trig)
CH3
O
O CH3
R1
O
SnCl4
H3C
DCM, -78 to -23oC
(60-77%)
H3C
H
R
O H1
11-2-2013
Larry E. Overman
Rune Risgaard
- Synthesis of trisubstituted tetrahydropyrans
- Stereochemistry of sidechains evolves from single stereocenter
- Found in polyether antibiotics, marine toxins and pheromones
- DCM not suitable (trapping of carbocation with halide competitive)
Synthesis of oxacyclic ring systems
- High enantiomeric purity obtained from nonracemic diols
Me
O
R
Me
(S)
OH
O
X
3) Ph
Br
RCHO (2 eq.)
SnCl4 or TfOH
O
OH
O
Me
COMe
1) t-BuLi
2) CuCN
X
Me
SnCl4
MeNO2, -23 - 0oC
81-92%, >95% ee
O
R
Ph
85%
OH
MeNO2, -25oC
(50-81%)
H
OH
- Ring-enlarging reactions (cis-fused octahydrobenzofurans and cycloheptatetrahydrofurans)
- In most cases both cis and trans fused diols gives cis-fused rings
R1
(CH2)n
OH
RCHO
OH
O
6-18:1
R = CH2CH2Ph, Me, Bn, i-Pr, t-Bu, Ph, (E)-CH=CHPh
X = NCO2Et, O, CH2; R = Me, Ph
JOC, 2003, 68, 7143-7157
OH
Ph
SnCl4
R1
OH
(CH2)n
DCM, 1h
50-94%
R
n(H2C)
O
R/R1 = H, alkyl, aryl, vinyl
n = 0, 1, 2
H
R
R1
R
HO
O
Ph
R
OH
O
iPr-CHO (2 eq.)
SnCl4
MeNO2, -25oC
68%
Ph
R1
O
(2R,4S,6R)
>99% ee
JACS, 1999, 121, 1092-1093
trans diols
R1
cis diols
O
O
R1
COMe
O
Synthesis of carbocyclic ring systems
- Oxocarbenium external to the ring formed upon Prins
- Synthesis of attached rings with ring contraction
R
n
n
MeO
OH
MeO
MeO
JOC, 1987, 52, 3711
JACS, 1991, 113, 5365
OTIPS
Hexahydroisobenzofuran synthesis
- Alkene contained in ring
- Synthesis of ladiellin, briarellin and asbestinin diterpenes
SnCl4
H
CHO
DCM, 0 oC
50-84%
m
m
m = 1, 2, 3; n = 1,2
MeO
MeO
OH
OHC
OH
BF3Et2O
Ph
DCM, -55oC
(97%)
Ac
OTIPS
H
O
Ph
MeO
H
CHO
MeO
MeNO2, 0 oC
50-84%
(1.4 : 1.0)
(87% ee)
JACS, 2001, 123, 9033
SnCl4
JOC, 2006, 71, 1581
(70% ee)
H
CHO
R
11-2-2013
Larry E. Overman
Rune Risgaard
Synthesis of hydrinans, hydroazulenes scaffolds containg functionalty in both rings
O
OTMS
R
SnCl4
n
CH(OMe)2
O
- Keteniminium ion initiated cyclization-pinacol rearrangements
R
R
RuO4
OMe
DCM
-78 to -23 oC
(75-82%)
n
H
55-72%
overall
TESO
O
O
R
Tf2O, DTBMP
n
H
nH
n = 0, 1, 2; R = H, Me
TMSO
O
n
1) SnCl4, DCM, -78 to -23 oC
OMe
OMe
H
H
R = H, Me; n = 0, 1
Tetrahedron, 2002, 58, 6473
HO
RCHO
BF3.OEt2
MgSO4
Me
Me
- Allyl cation-initiated cyclization rearrangement to install 2-alkenyl substituent.
- Protodesilylation occurs under reaction conditions with TMS
TESO
O
O
Me
Me
DCM, -20oC
(51-71%)
SH
R
Ph
- Synthesis of tetrahydrothiophenes
- BF2.OEt2 performs best
O
2) RuO4, MeCN-H2O
(65-72 %)
nH
N
DTBMP
JOC, 2002, 67, 6421
n
O
KHCO3 (aq)
Et2O
N
O
R = H, Me; n = 1, 2, 3
JACS, 1989, 111, 1514
R
N
DCE, -20
(56-80%)
n
O
OTf
R
S
S
R
OH
S
Me
HO
Me
R = CH2CH2Ph, Ar, (E)-CH=CHPh
JACS, 2000, 122, 8672
Me
Me
Major byproduct
R
Tf2O
DCM, -78oC
(54-80%)
n
- In cases where oxonium fails sulfonium can work as alternative
n
H
>20:1
HO
OTES
n = 1, 2, 3; R = H, Me
n
H
OTES
OH
R
OTES
R1
= H, Me, TMS; ds = 1.5:1, 10:1, 20:1
JOC, 2002, 67, 6421
n
H
R1
H
O
R1
CH(OMe)2
R
R1
n
JACS, 2001, 123,4851
H
Minor
SPh
(80%)
TMSO
SnCl4
R
SPh
CH(SPh)2 DCM, -45oC
OTMS
Major
n
R
R
R1
n
H
DMTSF
O
SiMe3
O
OTMS
OTMS
DCM
H
S
S
BF4
DMTSF
- 2,2-disubstituted 4-acyltetrahydrofurans containing different C2 substituents from
unsymmetric ketone can be formed with high stereoselection
- 4-acyl-3-(dimethylphenylsilyl)-tetrahydrofurans can serve as precusors of 4-acyl-3hydroxytetrahydrofurans
Synthesis of (-)-citreoviral
i) TaCl5, Zn, PhH-DME
O
SiMe2Ph
SiMe2Ph
Me
, THF
OTBDPS
SiMe2Ph
Me
Me
ii) Me
1) TBAF, THF, rt
2) TMSCl, imidazole,
Me
DCM, 0oC
OH
Me
iii) aq. NaOH
Me
Me
OTBDPS
SiMe2Ph
Me
OTBDPS
Me
(41%), >95% ee
1) aq. HF, ACN
2) p-TsOH, MeOH
HC(OMe)3
PhMe2Si
Me
O
Me
OMe
Me
i) Li, NH3, THF-EtOH
ii) TBAF, THF
iii) H2O2, KHCO3, MeOH
O
(62%)
OBz
Me
O
HO Me
O
Me
Me
OBz
Me
DIBALH
hexane-DCM,-78oC
Me
(69%)
Me
O
OMe
Me
TPAP, NMO
O
O Me
O Me
O
DCM, rt
(81%)
1) Bz2O, DMAP, pyridine
2) (CF3CO)2, urea-H2O2
DCM, 0oC
then aq. NaHCO3
(72% +
20% Acetate)
Me
HO
Me
Me
Me
HO
CO2Et
O
Me
Me
OH
DIBALH
hexane-THF
0oC to rt.
(93%)
OH
Me
OH
Me
HO
OH
O
BaMnO4
Me
O
Me
Me
PhH, 80oC
(50%)
H
OH
OAc
Me
O
Me
Me
(-)-citreoviral
(15 steps)
O
Briarellin F
28 steps (0.7%)
JACS., 2003, 125, 6650
O
H
O
H
H
H
H
C7H15CO2
(+)-Shahamin K
20 steps (2.9%)
JACS., 2001, 20, 4851
O
H Br
( ±)-kumausallene
13 steps (5.4%)
JACS., 1991, 113, 5378
OBz
O
H
H
O
CO2Et
(51%, dr = 4:1) Ph3P
PhH, reflux
OBz
H
OH
O
Magellanine
25 steps (1.4%)
JACS., 1993, 115, 2992
Me
Me
HO
H
OH
Me
HO
H
H
OTBDPS
(47%)
O
AcO
N
O
SnCl4, DCM, -78oC, (89%)
O
Me
Me
TMSOTf
DCM, -30oC
Me
O
Selected targets acheived by Prins-Pinacol
OTBDPS
Me
O
Me
O
OTMS
MeO OMe
Me
SiMe2Ph
Me
Org. Lett., 2000, 2, 223
OTMS
(81%, 3 steps)
Me
O Me
11-2-2013
Larry E. Overman
Rune Risgaard
O
N
(+)-Sieboldine A
20 steps
JACS., 2010, 132, 7876
OH
Reaction of arylhalides through neutral pathway often gives lower %ee
Silver and Thallium salts (Ag2CO3, Ag2O, Ag3PO4, Tl2CO3, TlOAc) used to promote the cationic pathway.
(JACS, 1998, 120, 6488)
Common bases used (K2CO3, CaCO3, Et3N, i-Pr2NEt, PMP)
Polar aprotic solvents are typically used (THF, ACN, DMF, DMA, NMP)
Less basic silver salts (AgOAc, AgNO3) results in lower reaction rate and little asymmetric induction (JOC,
1992, 57, 4571)
BINAP is by far the most widely used ligand.
Depending on how HX is scavenged either enantiomer of the product can be formed using a single
enantiomer of a chiral diphosphine.
The order of reactivity X = I>OTf>Br>>Cl
Catalyst loading 5-10%. Most common used precatalysts Pd(OAc)2, Pd2(dba)3
Intramolecular asymmetric Heck reaction
- Initial findings
Pd(OAc)2 (3 mol%)
(R)-BINAP (9 mol%)
Cyclohexene (6 mol%)
CO2Me
11-2-2013
Larry E. Overman
Rune Risgaard
CO2Me
Ag2CO3 (2 eq.)
NMP, 60oC
I
H
74% (46% ee)
- Synthesis of spirocycles with quatenary centers
OTf
Pd(OAc)2
(R,R)-DIOP
PR2 MeO
PPh2
Et3N, Benzene, rt
PR2 MeO
PPh2
O
PPh2
O
O
O
(R)-(+)-BINAP R=Ph
(R)-(+)-Tol-BINAP R=p-tolyl
General features
- Two pathways proposed (Cationic and neutral)
Cationic pathway
P
Y
Pd
O
P
P
Pd
P
P
P
Pd
Ar
P
Ar
Pd
P
AgOTf
Sol Ar
I
ArX
JACS, 1998, 120, 6488
P
Pd
Ar
P
X
P
Pd
Ar
X
Y
X
O
O
(55-75%, 41-96% ee)
(JACS, 1998, 120, 6477)
Intramolecular Heck reactions of (Z)-a,b-unsaturated 2-iodoanilides
- Synthesis of oxindoles
P
P
P
Pd2(dba)3
(R)-BINAP
PMP or Ag3PO3
DMA or NMP, 100 oC
O
Pd
Ar
R2
O
X
Neutral pathway
Pd
X
X = N, O; Y = C=O, CH2
AgX
P
P
(R, R)-CHIRAPHOS
(R, R)-DIOP
(R)-MeO-BIPHEP
Pd
OTf
OTf
X
X = I, Br
P
PPh2
Synthesis of oxindoles, indolines, dihydrobenzofurans
- Depending on how HI is scavenged each enantiomer can be obtained (cationic vs neutral pathway)
- Which HI acceptor is optimal for achieving highest %ee is substrate dependent
P
ArOTf
ArX
PPh2
90% (45% ee)
J. Org. Chem., 1989, 54, 5846
P
PPh2
P
Pd
X
Ar
P
P
X
Pd
N
Ar
R1
I
Pd2(dba)3
(R)-BINAP
PMP or Ag3PO3
DMA, 100 oC
R1 = Me, Ph, t-Bu, CH2CH(OMe)2
R2 = H, OTIPS, OTBDMS, OMe
(JACS, 1998, 120, 6488)
R2
R1
O
N
(53-93%, 69-90% ee)
Synthesis of (+)-Minfiensine
- Strychnos alkaloid
Synthesis of 3-alkyl-3-aryl oxindoles
- A broad range of indole alkaloids contain a diarylsubstituted quatenary center
O
O
1) Methyl propagylic ether
n-BuLi, -78 to -25 oC
2) PhNTf2, -25 oC to rt
OTf
O
(59 %)
N
N
H
Bn
Pd(OAc)2
(R)-BINAP
PMP
OMe
Ar
O
THF, 80 oC
N
H
Bu3SnH
Pd(PPh3)4
OTf
O
0 oC, (84 %)
N
H
OMe
N
H
JACS, 2003, 125, 6261
X
DMF, 100 oC
N
DMF, rt, 85 %
CO2Me
N
Boc
O
N
Ph2P
OTBDMS
1
NHBoc
O
N
N
Oxindole(
yield(
%ee(
OTf$
%$
72$
43$
OTf$
nBu4NI"
62$
90$
OTf$
nBu4NBr"
59$
93$
OTf$
nBu4NCl"
52$
93$
OTf$
nBu4NOTf"
70$
42$
OTf$
PMPHI$
40$
91$
N
OTf$
PMPHBr$
62$
92$
OTf$
PMPHCl$
60$
88$
MeO2C
I$
%$
76$
91$
I$
PMPHI$
62$
91$
I$
PMPHBr$
45$
95$
I$
PMPHCl$
75$
94$
I$
AgOTf$
%$
43$
N
MeO2C
CO2Me
O
63 %, 2 steps
N
Boc
O
1) TFA, DCM, rt
2) K2CO3, ACN, Br
I
N
N
65 %, 2 steps
MeO2C
I
O
10 % PdCl2(dppf),
K2CO3
MeOH, 70 oC, 74 %
t-Bu
1) 9-BBN, THF, 100 oC,
H2O2, NaOH
2) TPAP, NMO, DCM
TFA, DCM
75 %, 2 steps
71 %
CO2Me
TIPSO
10 %, Pd(OAc)2, ligand 1
PMP, toluene, microwave 170 oC
(75-87%, 99% ee)
Triflates can be diverted to neutral pathway
- Higher enantioselection without presence of silver salt
- Identical low ee in presence of AgOTf
- Addition of halide salts to the triflate enhanhced ee
CO2Me
NHBoc
i) 9-BBN, , 0oC - rt.
ii) NaOH, rt
iii) PdCl2(dppf), THF, rt.
CsF,CsCO3,
Comins' reagent
Addi+ve(
Angew. Chem. 1997, 36, 518
N
TIPSO
BocHN
N
N
Bn
TfO
69 %, 3 steps
BocHN
X = OTf or I
Compound(
N
OTIPS
SnBu3
Pd2dba3
P(2-furyl)3, CuI
ArI, NMP, rt
(51-93 %)
1) p-TsOH, PhH, 50oC
2) LHMDS, NCCO2Me,
THF, -78oC
3) NaHMDS, Comins' reagent
O
NH2
TfO
Pd(OAc)2
(R)-BINAP
halide salt
N
O
OMe
Ar
Ar = Ph, 4-MeO-C6H4, 3-pyridyl, 4-AcNH-C6H4, 1-naphthyl, 2-NO2-C6H4,
O
OMe
OTf
O
(48-91%; 71-98% ee)
TBDMSO
11-2-2013
Larry E. Overman
Rune Risgaard
N
MeO2C
N
NaHMDS
Comins' reagent
THF, -78oC, (86 %)
N
Boc
O
OTf
N
OMe
Pd(OAc)2, PPh3, Et3N
N
CO, MeOH, DMF (89%)
N
MeO2C
11-2-2013
Larry E. Overman
Rune Risgaard
N
MeO2C
R
1) LiAlH4, THF, -78 oC
2) NaOH, MeOH,
H2O, 100 oC
OH
N
H
N
(+)-Minfiensine
Vinylsilane terminated cyclization reactions
- Hyperconjugation stabilizes beta carbonium ion
- Carbon-silicon bond is strongly polarized (Electronegativity 2.35 vs. 1.64)
- Electrophile directed to silicon bearing carbon
- Complete regiocontrol of the double bond
- Two mechanisms can be considered: Direct cyclization through beta silyl cation
or via [3,3] aza-cope rearrangement.
R1
R
R2 = TMS
N
exocyclic
85 %, 2 steps
R
R1
R2
N
H
R
N
R2
Vinylsilane-terminated cyclizations occur with preference for carbocation in
sequence: tertitary trialkyl > secondary beta-silyl >tertiary alfa-silyl >
secondary dialkyl > primary beta-silyl cations
O
HN
O
H H
N
N
H
N
H H
N
H H
N
N
O
H
HN
Ph
NH
(+)-Asperazine
22 steps
Tetrahedron, 2007, 63, 8499
H
N
N
H H
O
O
O
O
(±)-Gelsemine
26 steps (1,1% yield)
JACS, 2005, 127, 18054
TMS
HN
R = nC3H7, Ph, PMB
CSA
ACN, reflux
(68-92 %)
R1 = H, nC6H13
R1
N
R
n
N
N
H H
OH
HN
R1CHO
R
H
N
O
Chemical Reviews, 1986, 86, 857
Synthesis of unsaturated azacycles (1,2,5,6-tetrahydropyridine)
- Found in several alkaloids
- A cyanomethyl amine can be used as formaldehyde equivalent.
H
H
N
R2
TMS
N
JACS, 2008, 130, 5368
Ph
N
endocyclic
R1
TMS
R
R1 = TMS
OH
O
Quadrigemine C
19 steps (2% yield)
JACS, 2002, 124, 9008
n
O
O
N
(-)-Morphine
(17 steps)
JACS, 1993, 115, 11028
N
N
H
O
R
N
R = H, Br
n = 1,2
(90-92%)
JACS, 1983, 105, 6994
N
R
N
1) NaBH4, MeOH
2) TFA
TMS
Preparation of enantioenriched tetrahydropyridines from silylpentenylamine
TMS
H
O
O
(-)-Spirotryprostatin B
(10 steps, 9% yield)
Angew. Chem., 2000, 39, 4596
CH2O, p-TsOH
or AgBF4
5 steps
L-alanine
ACN
Ph
R = H, CH2CN
Tetrahedron Lett., 1993, 34, 5243
N
R
Me
N
Me
Bn
(33-69 %, 92-99 %ee)
11-2-2013
Larry E. Overman
Rune Risgaard
O
Synthesis of indoloquinolizidine ring system found in a variety of indole alkaloids
Both (E) and (Z)-trisubstituted vinylsilanes can be cyclized with >98% retention
N
SiMe3 Me
H
O
H
NH
NH
SiMe3
O
H
CSA,
(CH2O)n
ACN, 80 oC
(83 %)
H
(79 %)
CH2OBn
Me
Me
H
OTBDPS
H
Me
O
OTBDPS
N
Me
( ±)-Deplancheine
Me OH
Me
Enantioselective totalsynthesis of Pumiliotoxin B and 251D
- Pulimiotoxin B isolated from Panamanian poison frog Dendrobates pumilio in 1967 and pumiliotoxin 251 D
from skin extracts of the Ecuadorian poison frog
- Dendrabatid alkaloids
- Poison used in blowdarts
- Cardiotonic agent
R
CH3
R=
H
N
CH3
COOMe
R = n-Pr
CH2OBn
TMS
Me
Me OH
Pumiliotoxin 251 D
Pumiliotoxin B
1) 2 eq. MeMgI
2) SOCl2, pyridine, THF
3) m-CPBA, DCM
Me
H
CH2OBn
N
(53 %, 2 steps)
Me OH
Me OH
Me
HO
OH
H
54 % 3 steps
1) i-Bu2AlH, hexane
2) MeLi, Et2O/hexane
3)
N COOBn
H
O
OH
H
H
(2:1)
H
O
N
OH
O
O
N
JACS, 1981, 103, 1851
JACS, 1984, 106, 4192
N COOBn
N COOBn
O
Me H
CHO, CSA, ACN
(60 %, 3 steps)
CH3 OH
N COOBn
H
H
CHO
CH2OBn
N
Pumiliotoxin B
OH
L-proline
LiAlH4, THF,
-20 oC - rt.
(74 %)
OH
H
H3C
SiMe3 Me
H
H
H
JOC, 1982, 47, 5297
DCM, reflux
(71 %)
N
N
O
1) Li/NH3
2) Swern ox.
N
PPh3
N
H
Me
SiMe3
Me
1) KOH, EtOH, H2O, 90 oC
2) Formalin, MeOH
N
HO
O
SiMe3
CH2OBn
(+)-Streptazolin
10 steps (4.2% yield)
JACS, 1987, 109, 6115-6118
H
N
d,l-Epielwesine
6 steps (30% yield)
Tett Lett., 1984, 25, 5739-5742
N
H
H
H3CO2C
(+)-Geissoschizine
11 steps, (7.5% yield)
JACS, 1989, 111, 300-308
H
CH3
OH