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Permutation and Combination in Organic Synthesis
-- Recent Development of Tandem Reactions in Construction of Polycyclic Systems
Zhihua ShangMichigan State University
Oct. 13, 2004
“ We wish to define tandem reactions as combinations of two or more reactions whose occurrence is in a specific order, and if they involve sequential addition of reagents the secondary reagents must be integrated into the products.”
What are Tandem Reactions?
Ho, T. L. Tandem reactions in Organic Synthesis; Wiely: New York, 1992
A Simple Example of Tandem Reaction
Yamamoto, Y.;Yamamoto, H. J. Am. Chem. Soc. 2004, 125, 4128Yamamoto, Y.; Momiyama, H.;Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962
N
NO
+O
N
N
CuPF6(MeCN)4-(S)-SEGPHOS
CH2Cl2
Nitroso Diels-Alder Reaction
Tandem O-nitroso Aldol / Michael Reaction
NO
R+
ON
H+O
N
ONH
R1 R2
NO
RR
R1
R2
A Simple Example of Tandem Reaction
NO
R+
OTMS
ON
RTMSO H+
NO
O R
NO
Ph+
NH
HN NNN
cat.O
R1R2
O
R1R2
ONH
Ph*
Yamamoto, Y.; Momiyama, H.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962Brown, S.; Brochu, M.; Sinz, C.; MacMillan, D. J. Am. Chem. Soc. 2003, 125, 10808
A Simple Example of Tandem Reaction
NO
Ph+
O NON
HHN N
NN
cat.
Ph
O
NHN N
NN
NO
Ph
N
NHNN
NO N
Amine catalysis
64% yield, 99% ee
Yamamoto, Y.; Momiyama, H.;Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962
Advantages of Tandem Reactions in Constructing Polycyclic Systems
• multistep, one-pot procedures; high yields
• dramatic increase in molecular complexity
• building multiple, contiguous stereocenters
• simulating biomimetic pathways towards
synthesis of natural products
High efficiency
Some Polycyclic Natural Products Synthesized using Tandem Reactions
N
O
Tropinone (R. Robinson, 1917)
O
H
O
HH
Progesterone (W. S. Johnson, 1971)
OO
O N
OO
OMe
OH
H
O
O
OMe
OH
HO
H
OME
Rapamycin (K. C. Nicolaou, 1993)
O
O
OH
OOHOOC
OHHOOC
COOH
OAc
(+)-Zaragozic acid A (K. C. Nicolaou, 1994)
Questions about Reactions in a Tandem Process
• Why those Reactions?• Why in such an order?
• What reactions to choose?
• How to put them in an order?
• The prior reaction as a deblocking step for revealing a functional group.characteristic functional groups in the substrates: >C=C<, >C=O, epoxide
• No significant change in reaction conditions from one step to the nextsecondary reactions often intramolecular and spontaneous
• Driving force of the overall transformationthermodynamic stability of the final product
Key Factors of Tandem Reactions
A B Cconditions
(1) (2)
Tandem Wolff/Cope Rearrangement--Background
R
ON2 N2 + R CH:
O
C C OH
R
H2ORCH2COOH
cat.or hν
Wolff Rearrangement
Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 25
Cope Rearrangement
R heat R
Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441
Tandem Wolff/Cope Rearrangement
Wolff Rearrangement
Cope RearrangementN2
O
H
H3CO
OH
H3CO H
AgOBz (0.1eq.)Et3N (1.0 eq.),
THF, 45oCsonification 30min
H3CO O
95%
OO
AcO OH
Guanacastepene A
Sarpong, R.; Su, J.; Stoltz, B. J. Am.Chem. Soc. 2003, 125, 13624
• What reactions to choose?Depending on the structure of the synthetic target.Typical reactions used in constructing polycyclic systems: cycloadditions (Diels-Alder); sigmatropic rearrangement (Cope, oxy-Cope, Claisen, ene), etc.
• How to put them in an order?
Depending on the link between two reactions.Strategies.
Answers to the Questions
A B Cconditions
(1) (2)
How to Make Two Reactions a Tandem Process
• Reactive centers are activated in the prior reaction by:(1) bringing reactive centers closer(2) activating unreactive centers
• Reactive centers are created in the prior reaction by:(1) functional group transformation(2) functional group migration
Activation of Reactive Center
(1) (2)
Bringing reactive centers closer
Bringing Reactive Centers Closer
Nicolaou, K. C.; Xu, J.; Kim, S.; Ohshima, T.; Hosokawa S.; Pfefferkorn J.J. Am. Chem. Soc., 1998, 120, 8661
O
OH
H
H
OH
OO
OTBS
OTBS
Ac
H
H
OO
OTBS
OTBS
Ac
OH
HO
O
O
O
O
O
OTBS
OTBS
H
H OH
OH
Ac
O
O
O
O
OH
OH
H
H OMe
O
Ac
O
N
N
steps
H2, Lindlar
toluene
(78%)
Eleutherobin
Bringing Reactive Centers Closer--Intramolecular Stille/Diels-Alder
Bruckner, S.; Abraham, E.; Klotz, P.; Suffert, J. Org. Lett. 2002, 4, 3391
R'
SnBu3
O O
TfOPd(CH3CN)2Cl2
5% moleLiCl / DMF
R'
O O
R'
H
H
OO
+R'
OO
R'=H, Me, Et, 5-Me, 5,6-OMe
r.t.
(48-70% overall)
Diels-Alder/Carbonyl-Ene Reaction--Background: carbonyl-ene reaction
HO
RHO
R
OH
OHRR
or Lewis Acid
or Lewis Acid
O
HBr
H
OBr
HO
Br+
HOBr
0oC to r.t., 82%
BF3.Et2O H
H
H
Bringing Reactive Centers Closer-- Diels-Alder/carbonyl-ene reactions
Kraus, G.; Kim, J. Org. Lett. 2004, 6, 3115
Activation of the Reactive Center
(1) (2)
Reactive center Potential reactive center
Activating unreactive centers
Activating Unreactive Centers--Total synthesis of (-)-Stemonine
Williams, D.; Shamim, K.; Reddy, J., Amato, G.; Shaw, S. Org. Lett. 2003, 5, 3361
NHO
H3CO
TBSO
H
HTBSON CO2CH3
TBSO
TBSO
H
H H I
HI2, CH2Cl2 / Et2O
NTBSO
TBSO
H
H
H
O
OCH3H
I-
NTBSO
TBSO
H
H H
H
O O
42%
NH
H H
H
O OO
O
H(-)-Stemonine
steps
Activating Unreactive Centers--Aromatic oxidation/Diels-Alder reaction
Drutu, A.; Njardarson, J.; Wood, L. Org. Lett. 2002, 4, 496
O
O
OH OO
O
O
BTIB, CH3CN
O
O
OO
84%
OH
O
OH BTIB, CH3CN
55% OO
H
BTIB bis(trifluoroacetoxy)-iodobenzene
O
H
Creation of Reactive Center
(1) (2)
Functional group transformation
O
O
O
NCbz
NMOM
ON
N OMe
OMeO2C
O
O
Ar
NMOM
ON
N
MeO2C
I2Sm
I2Sm OMe
SmI2HMPA
[pinacol cyclization]
O
O
Ar
NMOM
ON
N
MeO2C
I2Sm
I2Sm OMe
Functional Group Transformation--Radical as trigger
O NH
ON
OHOH
ClON
HN
O
HN
H2N
O
Cl
Originally proposed structure of diazoamide A
Nicolaou, K. C.; Snyder, S.; Giuseppone, N.; Huang, X., Bella, M.; Reddy, M.; Rao, P.; Koumbis, A.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004,126, 10174
O
O
Ar
NMOM
ON
N
MeO2C
I2Sm
I2Sm OMe
O
O
Ar
NMOM
ON
N
MeO2C
I2Sm
I2Sm SmI2
O
HO
NMOM
ON
NH
MeO2C
FmocHN
O
O
NCbz
O
N NH
ON ClO
NHN
O
HN
HO
O
Cl
aq. NH4Cl;FmocValOH,EDC, HOBt
(42%)[peptide coupling]
[N-O cleavage]
diazoamide A
O
Functional Group Transformation--Radical as trigger
Nicolaou, K. C.; Snyder, S.; Giuseppone, N.; Huang, X., Bella, M.; Reddy, M.; Rao, P.;Koumbis, A.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004,126, 10174
Functional Group Transformation--[3+2]-Cycloaddition/carbene insertion
Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001, 123, 5814
O
R
+R1
OCH2R2
10-20 mol%W(CO)5.THF
THF, r.t. 50-94%
O
OR1
R
H
HR2
H
R=H, Me, n-Pr, i-Pr; R1=H, OC2H5, R2=CH3,n-Pr
Functional Group Transformation--[3+2]-Cycloaddition/carbene insertion
Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001, 123, 5814
O
R
(OC)5W
H2O R
O
O5-π−exo
O
i-Pr
THFO
i-Pr
(OC)5W
6-π-endo O
i-Pr
W(CO)5
OEt
OEt
O
i-Pr
W(CO)5
OEt
OEt O
i-Pr
W(CO)5
OEtOCH2CH3
C-H insertion
O
OOEt
i-Pr
H
H
H
W(CO)5.THF
W(CO)5.THF
Functional Group Transformation--Epoxidation/intramolecular [4+3] cycloaddition
O
N
O
R
O
N
O
R O
N
O
HO
R O
X
[4+3]X=O or CH2 X
H
NO
O
RO
DMDOCH2Cl2
R=Ph, i-Pr
Rameshkumar, C.; Hsung, R. Angew. Chem. Int. Ed. 2004, 43, 615
Functional Group Transformation--Epoxidation/intramolecular [4+3] cycloaddition
Rameshkumar, C.; Hsung, R. Angew. Chem. Int. Ed. 2004, 43, 615
O
N
O
Ph
N
O
O PhO
ON
OO
PhO
I
O
2 eq. n-BuLiTHF, HMPA, -78oC
CH2Cl2, -78oC
1 d.r. 95:5
α tethered
DMDO
O
N OO
O
Ph45%
Functional Group Transformation--Epoxidation/intramolecular [4+3] cycloaddition
O
N
O
Ph
R
steps O
N
O
PhH
H
O
TESO
OTESHO
O
N
O O
Ph
2 d.r. 9:1
γ tethered, P:M=1:1
CH2Cl2, -78oC,
DMDO
NO
O
Ph
O
H1OTES
OH2
61%
Rameshkumar, C.; Hsung, R. Angew. Chem. Int. Ed. 2004, 43, 615
Creation of Reactive Center
(1) (2)
Functional group migration
Functional Group Migration--1,7 Hydrogen shift/8π-electrocyclization
Kerr, D.; Wills, A.; Flynn, B. Org. Lett. 2004, 6, 457
MeO Br
OH
+MeMgBr, THF
5 mol% Pd(PPh3)2Cl2
MeO
OMgBr
O
Br
+DMSO, 100oC
O
O
HMeO
O
MeO
O
O
MeO
O
1,7-H shift8π-
electrocycization
61%
Double Bond Migration
O
R
O
R
Claisen Rearrangement
OHR
OH
R R
O
Oxy-Cope Rearrangement
Carbonyl-ene Reaction
HO
RHO
R
OH
OH
Double Bond Migration-- Retro-combinational analysis of oxy-Cope/ene
Carbonyl-ene
HO
RHO
R
HO
R
HO
ROxy-Cope
HO
OHToluene, 220oC
H
OH
72%
Warrington, J.; Yap, G.; Barriault, L. Org. Lett. 2000, 2, 663
Tandem Oxy-Cope/Transannular Ene Reaction
R1R2
R1R2
OH OH H
R1R2
O HH
R2
O HHH
R1
R2
H
H
HO R1
R2
OH
HH
R1R2
OH HH
H
i ii iii
R1
R2OH
H
R1
Warrington, J.; Yap, G.; Barriault, L. Org. Lett. 2000, 2, 663
Total Synthesis of (+)-Arteanniun M Using Oxy-Cope/Ene Reaction
ODPSOH
HDBU
toluene, 220oC
O
SPDO
H
HO
H
H
ODPS
Deon, D.; Barriault, L. Org. Lett. 2001, 3, 1925
ODPSOH
steps
O
O
HOOH
(+)-Arteanniun M
ODPSO
Total Synthesis of Jatrophatrione--Anionic oxy-Cope/methylation/ene reaction
Yang, J.; Long, Y.; Paquette, A. J. Am. Chem. Soc. 2003, 125, 1567
O O
O
H
Jatrophatrione 1
O
O
H
O
OO
HRORO
RO
OHO OCH3
RO
+ Li
OCH3
2 3 4
Total Synthesis of Jatrophatrione--Anionic oxy-Cope/methylation/ene reaction
RO
OHO OCH3
RO
+ Li
O
RO OCH3
OCH3
HH
O
RO OCH3
2 3 4
5 6
Yang, J.; Long, Y.; Paquette, A. J. Am. Chem. Soc. 2003, 125, 1567
Total Synthesis of Jatrophatrione--Anionic oxy-Cope/methylation/ene reaction
BnO
OH
OCH3
O OCH3
RO
+ Br t-BuLi; CeCl3
RO
HO
80%
O
RO OCH3
HH
KO t-Bu, 18-cr-6
CH3I, 70%
O O
O
H
Jatrophatrione 1
RO
Anionic oxy-Cope /methylation
Ene
OCH3
Yang, J.; Long, Y.; Paquette, A. J. Am. Chem. Soc. 2003, 125, 1567
Combination of Three-- Oxy-Cope/Claisen/ene
OOxy-Cope
O
Carbonyl-ene
HOHO
O
ClaisenO
R R
O OHµwaves
toluene, 210oC98% d.r. > 25:1
Sauer, E.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569
Oxy-Cope/Claisen/Ene Reaction
Sauer, E.; Barriault, L. J. Am. Chem. Soc. 2004, 126, 8569
O
Y
X
R
OH
Y
X
R
O
Y
X
R
O
Y
X
R
∆
oxy-Cope
Claisen
ene
Total Synthesis of Wiedemannic Acidusing Oxy-Cope/Claisen/Ene reaction
Sauer, E.; Barriault, L. Org. Lett. 2004, 6, 3329
OH
Y
X
R
OHH
Me
CO2H
Me
O
HH
Me
Wiedemannic acid 1
OHH
Me
O
HR
OHH
Me
OH
HR
O
Me
Me
HR
ORO
Me
R
Total synthesis of Wiedemannic Acid using oxy-Cope/Claisen/ene reaction
Sauer, E.; Barriault, L. Org. Lett. 2004, 6, 3329
µwaves
210oC
O
Me
Me
H OTBSMe
OHH
MeHMe
OTBS
O
Me
Me
HMeOTBS
O
Me
Me
HMeOTBS
Oxy-Cope
Claisen
Ene
91%, d.r.>25:1
Conclusion• Theoretically, a tandem process can be combinations
of any two reactions if happening of one can lead to happening of the other with no big changes in conditions.
• Computations are important, so are experiments.
• New reactions and substrates will lead to more and more tandem processes in the future.
• The basic strategies to organize reactions to make them a tandem process remain the same.
• My Parents
• Dr. Borhan
• Group members
Chrysoula, Courtney, Dan, Jennifer, Jun, Marina,
Montserrat, Stewart, Somnath, Tao
• FriendsBingwei, Chang, Keith, Meng, Xiaoyu, Xin
Acknowledgement
A Simple Example of Tandem Reaction
Total synthesis of (-)-Stemonine
Diels-Alder/carbonyl-ene reaction
H O
BrBr
H O H
H
H
Transition state of Epoxidation/Intramolecular [4+3] Cycloaddition
R2R1N R3
H H
OR2R1N
H
O
R3
H H
R1R2N
O
H
R3 H
R1R2N
O
R3
H
W configuration sickle configuration severe A1,3 strain
O
N OO
O
Ph
endo
compact
NO
O
PhH1
OH2
OH
OPG exo
a
NO
O
Ph
O
H1OPG
endo
n=0,1
n=0, 1
OH2
( )n
( )n
NO
O
Ph
OH2
OH
OPG exoextended
H1
α tethered sickle configuration Bγ tethered
sickle configuration Cγ tethered
W configuration Aγ tethered
b
b
O
O
*N H1 H2OTES
d.r. >95:5
A B C D
Rameshkumar C.; Hsung R. Angew. Chem. Int. Ed. 2004, 43, 615
Stereochemistry change at C9 in Total synthesis of Jatrophatrione
Stereochemistry change at C9 in Total synthesis of Jatrophatrione
(c) NBS, THF, H2O (92%). (d) LiBr, Li2CO3, DMF, (81%). (e) Zn, MeOH(83%). (f) LiAlH4, CuI, HMPA. (g) LiAlH4, ether (88%). (h) MsCl, (i-Pr)2NEt (98%). (i) KOtBu, t-BuOH (87%).
Yang, J.; Long, Y.; Paquette, A. J. Am. Chem. Soc. 2003, 125, 1567
Stereocontrol in Oxy-Cope/Claisen/ Ene Reaction
R4
OR3
R2
ringinversion
R4
OR3
R2
H
R2
R3
OR4
R2
R3
OR4 H R4
OR3
R2
H
R2
R3
OR4 H
Claisen
R2
R3
OHR4 R4
OHR3
R2
R2
R3
OHR4R4
OHR3
R2
A B
C D E F
G H I J
Sauer E.; Barriault L. J. Am. Chem. Soc. 2004, 126, 8569
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