Tandem Reaction Sequences

18 Pages·2005·0.93 MB·English

Tandem Reaction Sequences
Chris Borths
MacMillan Group Meeting
November 21, 2000
I. Cationic Transformations
II. Anionic Transformations
III. Pericyclic Transformations
IV. Metal-catalyzed Transformations
Reviews: Ho, T.L. Tandem Organic Reactions; Wiley: New York, 1992.
Tietze, L.F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131.
Tietze, L.F. CHem. Rev. 1996, 96, 115.
Why Tandem Reactions?
Practical Considerations
! Reduction of waste
! Avoids isolation of intermediates
! Reduces labor, time to effect given transformation
Academic Considerations
! Builds a large degree of complexity in one transformation
! Novel avenues of research, new reaction development
A Definition:
! A tandem reaction is a reaction in which several bonds are formed in sequence without
isolating intermediates, changing reaction conditions, or adding reagents.
Polyene Cationic Cyclization
O
Me
O + O
O O Me O Me
Me
H O
Me Me H O 2 Me H
HO CF3CO2H 65% yield
CH3CHF2 H H H H
-30 ºC
H H
Me O ! Acetals and allylic alcohols are good initiators
Me O
Me
+ O ! Only one out of 32 possible diastereomers formed
H2O
! Double bond geometry controls stereochemistry of
product
! Vinyl fluorides can increase yield by stabilizing
O
+ intermediate carbcations
Me
Me O O
Johnson, W.S. Angew. Chem. Int. Ed. Engl. 1976, 15, 9.
Fish, P.V.; Johnson, W.S. J. Org. Chem. 1994, 59, 2324.
Mannich-Cation Olefin Cyclization
CH O H
NH 2 N 6 steps N
N 40 ºC N N
H H
SO2Ar 63% yield
H H
O
TMS
(±)-Yohimbone
! Allylsilanes are common
terminators of cationic olefin
+ + cyclizations
N N
N N
! This is the first example of an
SO2Ar SO2Ar iminium ion as the initiator
TMS TMS
Grieco, P.A.; Fobare, W.F. J. Chem. Soc. Chem. Commun. 1987, 185.
Cascade Polyether Cyclization
Me
OBz O Me Me O O
O Me
Me O
HCl R
O
Me O
O O Me 30% yield O
OMe H Me DEIPS R3Si Me O+ H
BnO OPMB
DEIPS = diethylisopropylsilyl OPMB
OBz O
OBz O Me Me
Me Me PPTS
(MeO) CH Me
3
Me MeOH OMOe H H O O
O O Me
OH H O 51% yield BnO Me
Me
BnO Me O
O Me
Me
HO OPMB
HO OPMB
C - C of Etheromycin
1 22
! Stereochemistry of epoxide determines the stereochemistry of the polyether
Paterson, I.; Tillyer, R.D.; Smaill, J.B. Tet. Lett. 1993, 34, 7137.
Review: Koert, U. Synthesis 1995, 115.
Diastereoselective Ugi Reaction
C
N
O O
OTBS + RCHO ZnCl2, THF, -78 °C, 3 d R H+ R
OPiv N O
PivO H
N NH3Cl
+ HCO2H PivO O NH2 TBSO Sug* CHO NH3Cl
OPiv
31-99% yield
O
Ugi Coupling R
HO
R d.r. yield NH3Cl
Ph 90 : 10 61%
CH CH(CH ) 97 : 3 80%
2 32
! The opposite enantiomer can be accessed by using
(CH2)4CO2CH3 98 : 2 80% a different sugar auxiliary. Diastereoselectivities are
similar (90:10 - 96:4); yields are lower (48 - 76%).
Bn 98 : 2 85%
(CH ) CF=CHC H 98 : 2 65%
22 6 5
Linderman, R.J.; Binet, S.; Petrich, S.R. J. Org. Chem. 1999, 64, 336.
Ugi Reaction Mechanism
C
N
O
ZnCl , THF, -78 °C, 3 d
OTBS + RCHO 2 R
OPiv N
+ HCO2H PivO H
N
O TBSO Sug* CHO
PivO NH2
PivO
O N Sug* ZnCl Cl2Zn N Sug* C N Ar
+ H2N Sug* 2
R H R H R H +H+
Sug* Sug* R H R
HN HCO2- HN Ar Sug* N
H N Ar
R
N O O O N
Ar
O
H R Sug* R O
Sug* N Ar ~H+ N Ar R
N
O N O NH H
H O H O TBSO Sug* N CHO
Linderman, R.J.; Binet, S.; Petrich, S.R. J. Org. Chem. 1999, 64, 336.
Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8.
Tandem Knoevenagel Diels-Alder Reaction
Me
O
Me
O
CHO 100 °C [4+2]
+
Knoevenagel Me Me O C5H11
O C5H11
Me Me
Me Me
C5H11 i) LDA, PhSeBr
O OH
H ii) MCPBA H
O O
Me
Me 65% yield H 46% yield H
Me
MeMe O C5H11 MeMe O C5H11
(+)-Hexahydrocannabol
! The Diels-Alder reaction is controlled by the chiral center in citronellal.
! The product is a 2:1 (!:") mixture of diastereomers at the alkyl chain.
Tietze, L.F.; Kiedrowski, G.; Berger, B. Angew. Chem. Int. Ed. Engl. 1982, 21, 221.
Tethered Biginelli Condensation
O
H H Ptilomycalin A
H2N NH Me i) O3, Me2S R N CO2R1 OTBS Crambescidin 657
ii) morpholine-HOAc (1:1.1) Neofoliispates 2
R Me
Na2SO4, 70 °C O NH Crambescidin 800
O OTBS
R1O2C
Me
O , Me S
3 2 ! Both cis and trans product can be accessed
based on rxn conditions and guanidine
O
equivalent
H2N NH O cuonmchpaleraxc mteirxitzuerde ! R NH When X=NH2+, trans product is formed
R
When X=O, cis product is formed
H X NH2
Knoevenagel
CO2R1
H H H H
alkyl ~H+ R N CO2R1 -H2O R N CO2R1
O alkyl
O
R NH NH2O O NH alkyl
O NH2
McDonald, A.I.; Overman, L.E. J. Org. Chem. 1999, 64, 1520.
Coffey, D.S.; McDonald, A.I.; Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A. J. Am. Chem. Soc. 2000, 122, 4893.
Tandem Radical Cyclization
O O
O O 1) H O+ Me H
Me H 3
Bu SnH 2) NH NH
3 2 2
Me
Me
Me 66 - 80% yield?
Me Me
Me
(±)-Siliphiperfol-6-ene
Br Me
2.5 : 1 d.r.
65% yield
! The stereochemistry of the
vinyl bromide does not affect
reaction outcome
O O
O O Bu3Sn H HO O ! Direct cyclization of the !,"-
unsaturated ketone is possible,
Me
but favors the !-methyl
Me Me
diastereomer 3:1. The cyclic
Me Me acetal shields the endo face of the
Me
bicyclic system and favors the "-
Me Me Me methyl diastereomer.
Curran, D.P.; Kuo, S.C. J. Am. Chem. Soc. 1986, 108, 1106.
A Biomimetic Cyclization
BnO
OBn
i) Swern
H ii) NH3
HO
iii) HOAc, 70 ºC H
Me
HO 82% yield Me
HN
Me
Me
Isolated intermediates
Me
70 ºC
Swern
Imino-ene reaction
BnO BnO
OBn
O H H HOAc
NH3 r.t Me H
O N Diels-Alder Me
Me N
Me Me
Me Me
Me Me
Heatchcock, C.H. Angew. Chem. Int. Ed. Engl. 1992, 31, 665.
Tandem Michael Reaction
CO2Et Formal
+ O2N Me quanrt..t .yield EtO2C O2N Me Synthesis HO2C Me
HO HO HO2C N
NHBn N H
Bn
(-)-!-Kainic Acid
+H+
-
CO2Et -O EtO2C - +O ! Nitro group used as a
+ O N removable electron-withdrawing
O N Me -H+ Me group
HO Bn
N N
H
Bn
Barco, A.; Benetti, S.; Pollini, G.P.; Spalluto, G.; Zanirato, V. J. Chem. Soc. Chem. Comm. 1991, 390.
Tandem Alkylation, Oxy-Cope, Cyclization
Me
O
O O O O O
2
BrMg Me O OMOM
Me OMOM Me
CO2Me 5 53% yield 5
O
OPMB
PMB
Grignard addition Dieckmann cyclization
MeO O R Me MeO O R Me
5 Oxy-Cope 5
BrMgO BrMgO
OPMB OPMB
! Grignard addition sets up an anion-accelerated oxy-Cope which rearranges through a chair transition state
! The enolate resulting from the oxy-Cope spontaneously cyclizes onto the methyl ester
Chen, C.; Layton, M.E.; Sheehan, S.M.; Shair, M.D. J. Am. Chem. Soc. 2000, 122, 7424.
Tandem Fries rearrangement, Cyclization, Deprotection
Me
Me
O
O
O O 2 O O Fries-like
2
O OMOM TMSOTf O OMOM rearrangement
Me
MeO2C 5 (MeO)3CH MeO2C 5 Me
O OMOM
OMOM
O
O
O
MeO
OMe TMS
MeO
TMS
O O O O O Me O O O O O Me
MeO 2 2
O Me O Me
MeO2C 5 MeO2C 5
O OH
TMS O OMe O
! This intermediate was elaborated iinto (+)-CP-263,114.
Chen, C.; Layton, M.E.; Sheehan, S.M.; Shair, M.D. J. Am. Chem. Soc. 2000, 122, 7424.
Tandem Diels-Alder Retro Diels-Alder
Me Me
O Me
N
MeO Me 136 °C N 136 °C O Me
O Me O
MeO - CH CN
Me 3 OMe
Me O Me O
Me
Me
poor formal
synthesis
! Intramolecular Diels-Alder reaction assures regiocontrol over
Me
product
OH Me
! The rest of the synthesis involves several oxidation-reduction
and deprotonation-reprotonation sequences.
O O
Me O
(±)-Paniculide-A
Jacobi, P.A.; Kaczmarek, C.S.R.; Udodong, U.E. Tet. Lett. 1984, 25, 4859.
Oxy-Cope, Diels-Alder, Retro Diels-Alder
O Me
O H
H O O
O O 160 ºC O O [3,3] O Diels-Alder
Me Me Me O
N
N Me O
OH
Me
Me Me N Me
Me Me Me
H Retro H H
O O Diels-Alder O O hydrolysis O
O O Me - HCN O Me O Me
Me Me O Me O
N
!-Me 45% yield of Gnididione
"-Me 57% yield of Isognididone
! Note: Each olefin geometry (E and Z) was prepared selectively and subjected to the reaction conditions
! Oxy-Cope rearrangement proceeds through a chair transition state, possibly stabilized by intramolecular hydrogen bonding.
Analysis of crude reaction mixtures indicated that less than 2% of material rearranged through the boat conformation.
! Regiocontrol over the Diels-Alder reaction was established by geometrical constraints, and the retro Diels-Alder was
entropically favored.
Jacobi, P.A.; Selnick, H.G. J. Am. Chem. Soc. 1984, 106, 3041.
Tandem Oxy-Cope Claisen
Me
Me
Me
[3,3]
O OTIPS Me
O OTIPS Me
Me 200 ºC O
Me Me
Me OTIPS
Me
Me Me
1) KF-2H O
2
[3,3] Me Me 2) CH2N2 Me Me 7 steps
O O
30% yield Me
OTIPS OMe O H
Me
O
(+)-dihydrocostunolide
! Rearrangement shows no evidence of silyl migration. When TBS is the silyl group, the rearrangement is complicated
by silyl migration.
! Both [3,3] rearrangements occur through chair transition states.
Raucher, S.; Chi, K.W.; Hwang, K.J.; Burks, J.E. J. Org. Chem. 1986, 51, 5503.
Aza-Cope Mannich Reaction
O
Me CSA HO
O CF CH OH Me 3 steps
3 2
Bn NMe C9H19 61 - 68% yield Bn N C9H19 Bn NMe C9H19
Me
80% ee (+)-Preussin
O
HO Me
Bn Me
N Mannich
Me
Bn N C9H19
C-C C9H19 Me
O
rotation
Me
OH
OH
Me [3,3] Me Mannich
Me O H+ MeBn N C9H19 MeBnfavorNed C9H19 Bn NMe C9H19
favored
Bn N C9H19 OH O
Me OH Me [3,3] Me Mannich Me
Me
Me Bn N
H+ Bn N
C9H19 C-C C9H19 Bn NMe C9H19
disfavored
rotation
O
HO Me
Bn Me Mannich
N
Me
favored C9H19 Bn N C9H19
Me
Deng, W.; Overman, L.E. J. Am. Chem. Soc. 1994, 116, 11241.
Tandem Claisen-Ene Reaction
PO CHOMe CO2Me
Me OMe 180 ºC O
HO H
MeMe Me 60 h 14
P = Si + 8 H
MeMe Me MeO
CO2Me 76% yield
after hydrolysis
PO
! Claisen rearrangement proceeds through a chair transition state-- Me CO2Me
evidinced by high 8,14 syn selectivity and the 14S configuration
O
H
! Ene rearrangement proceeds through the bicyclic transition state with
the A,B ring at a pseudo-equatorial position H
PO
Me
O OMe PO CO2Me MeCO2Me
Me PO H
PO O
R H
MeO H H
MeO2C
Mikami, K.; Takahashi, K.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 4035.
Mikami, K.; Takahashi, K.; Nakai, T.; Uchimaru, T. J. Am. Chem. Soc. 1994, 116, 10948.
Cascade Aromatic Annulation
OTIPS
OMe OMe
O OH O
N2 + h! O2, TBAF
MeO 54% yield 67% yield
9 9 nBu O 9 nBu
OTIPS OH
nBu
Maesanin
photochemical Wolff
6 electron ring closure
rearrangement
and tautomerization
OMe
O O
MeO H R
OTIPS
[2+2] 4 electron electrocyclic
ring opening
O R
MeO OTIPS
Danheiser, R.L.; Cha, D.D. Tet. Lett. 1990, 31, 1527.