Carbon-Carbon Bond Formation: Comprehensive Organic Synthesis 1991, Vol. 2, 99
Carbon-Carbon Bond Formation: Comprehensive Organic Synthesis 1991, Vol. 2, 99
Carbon-Carbon Bond Formation: Comprehensive Organic Synthesis 1991, Vol. 2, 99
72
Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99. - -deprotonation of a ketone, aldehyde or ester by treatment with a strong nonnucleophillic base. - carbonyl group stabilizes the resulting negative charge.
O H H H R B: O H H R H H OR
- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3)
O H 3C O H 3C CH3 O CH2 OEt
pKa = 20
pKa = 10
- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3 Enolate Formation: - H+ Catalyzed (thermodynamic)
O H+ OH
:B
O-
B:H
Regioselective Enolate Formation Tetrahedron 1976, 32, 2979. - Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions.
O LDA, THF, -78C O - Li+
C-C BOND FORMATION typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30
N Li
73
Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)
O OR' R LDA, THF, -78C E+ N R O- Li+ OR' R N Li THF, -78C R OR' O
- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form
O - K+ O tBuO- K+, tBuOH O - K+
kinetic
thermodynamic
typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range) - note: the kinetic and thermodynamic enolate in some cases may be the same - for ,-unsaturated ketones
thermodynamic site O kinetic site
Ph O O
CH3Li, THF
CH3Li, THF
Ph O- Li+
Ph O- Li+
- silyl enolethers
Ph O
74
Ph O- M+
Ph O- M+
- tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl enol ether - From Enones
1) Li, NH3 2) TMS-Cl O TMSO 1) MeLi 2) E+ O H
O TMS-Cl, Et3N TMS-OTf Et3N O Li, NH3, tBuOH TMS-Cl OSiMe3
OSiMe3
OSiMe3
Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 1 alkyl halides, allylic and benzylic halides work well 2 alkyl halides can be troublesome 3 alkyl halides don't work
75
DMSO
180
M+ -O
Alkylation of 4-t-butylcyclohexanone:
O R O E R
E H tBu R A
A favored
on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This approach leads directly into a chair-like product. "Equitorial apprach leads to a higher energy twist-boat conformation. Alkylation of ,-unsaturated carbonyls
O- M+ R1 O R1 H H R1 H Thermodynamic R2 O- M+ R2 E R1 H E O R2 Kinetic H R2 E R1 E H O R2
C-C BOND FORMATION Stork-Danheiser Enone Transposition: - overall -alkylation of an ,-unsaturated ketone
O LDA PhCH2OCH2Cl OMe O PhO OMe CH3Li PhO OMe J. Org. Chem. 1995, 60, 7837. HO CH3 H3O
+
76
CH3 PhO O
Chiral enolates- Chiral auxilaries. D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23. Asymmetric Synthesis 1984, 3, 1. - N-Acyl oxazolidinones
O R N Me O R N O H 2N O OH O H 2N O Me Ph Ph norephedrine OH
valinol
O R N Me O N O LDA, THF Et-I R O O Ph LDA, THF Et-I Me Ph major product (96:4) O O N O LiOH, H2O, THF R R O N O O LiOH, H2O, THF R O OH
O R
O R NH2 OMe
(94 - 98 % de)
77
O R N
O N
O O
Ph
Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1
SO2Ph N O O R
H O O SO2N(C6H11)2 Et2CuBF3 LDA, NBS O O SO2N(C6H11)2 O Br O SO2N(C6H11)2
Ar Ar R O N O SO2Ph O
R R N S O2 O
O SO2N(C6H11)2
H HO
NH2 O
J. Am. Chem. Soc. 1998, 120, 591 J. Org. Chem. 1986, 51, 2391
78
tBu
OTMS
Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization
O N O N can not become coplanar
"Kinetic"
O N
"Thermodynamic"
O + N R O E
O O N H H+, (-H2O)
R-I
H2O
enamine
-Chiral enamines
N O E
Imines
Ph N
Hydrazones
C-C BOND FORMATION isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503
O Me2N-NH2 H , (-H2O)
+
79
N N LDA, THF
-N -
E+
N hydrolysis E
O E
- Hydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. - Drawback: can be difficult to hydrolyze. - Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983)
OMe N NH2 SAMP MeO N H 2N RAMP
N N OMe I
LDA OTBS
N N OMe
O3
O H
TBSO
Me O Li R1 E (C,C) R2 H
MeO R1 R2 E H N N
N N Z (C,N)
Aldol Condensation
O H R
- The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers
C-C BOND FORMATION - The aldol reaction is an equilibrium which can be "driven" to completion.
O- M+ R R' + RCHO H R M O O R' work-up H R O OH R'
80
In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+ counterions will stabilize the intermediate -alkoxycarbonyl and push the equillibrium towards products. (JACS 1973, 95, 3310)
O- M+ PhCHO, THF O OH Ph M= Li M= MgBr 16% yield 93% yield
- Dehydration of the intermediate -alkoxy- or -hydroxy ketone can also serve to drive the reaction to the right.
O O O
tBuO- Na +, tBuOH O O H O O H
+
H Z - enolate
E - enolate
OM R2 H
R3CHO
R
O
1
OH R R2
3
erythro (syn)
E -enolate
R
1
OM H R2
R3CHO
R
1
OH R R
2 3
threo (anti)
O
-
MgBr
- +
H O Ph Ph H Mg
Br O
Ph
PHCHCO2 MgBr
OMgBr
"pericyclic" T.S.
81
O R2
M R1
O R1
OH R3 R2
H H O R R3
2
M R1
M O
O R2 R3
M R1
O O R1 R2 OH R3
R2
R3 R1
82
Disfavored Chair
Summary of Aldol Transition State Analysis: 1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates usually give a higher degree of stereoselection than E-enolates. 2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic diastereoselection.
O- M+ Path A R2 H Path B O H R2 Path A R1 R2 R1 R2 O HO R3 R1
O- M+ R1
HO R3
When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent steric influence then path B proceeds. 4. The Zimmerman-Traxler like transition state model can involve either a chair or boat geometry. Noyori "Open" Transition State for non-Chelation Control Aldols Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+ - Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. Z- Enolates:
R1 H H O R1 H R3 O ODisfavored R2 H H H R R2 3 O H R2 O OFavored R2 R3 R3 H O H R2 H O Favored R1 OH R3 R1 R2 R3 R2 R1 OR1 R3 OH R1 R2 O HO R3
Syn Aldol
O HO
R1
O-
Disfavored
Anti Aldol
83
O H
R1 favored R2 H
O H
R1 R3 H R2 H
R1 O H R1 R3 R2 R2 HO
R3 O
-
R3
O favored
-
Syn Aldol
O H
R1 disfavored R2
R1 H
R1 O R3 R1 R3 R2 R2 HO
H O
R3
H H R3 R2 O H O disfavored
Anti Aldol
NMR Stereochemical Assignment. Coupling constants (J) are a weighted average of various conformations.
O R1 R2 HA 60 HA H O O HB R2 R1 R3 R1 O H O HB 60 HA R3 R2 R1 HB R3 O HA OH R2 H O HB R3
non H-bonded H
O R1
OH B R3
R2 HA HA H O O R3 R2 R1 HB R1 O H O R3 HA HB HA OH R2 R1 R3
non H-bonded
Boron Enolates:
Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1; Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3. - Alkali & alkaline earth metal enolates tend to be aggregates- complicates stereoselection models. - Boron enolates are monomeric and homogeneous - B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C bonds (more covalent character)- therefore tighter more organized transition state. Generation of Boron Enolates:
O R2B-X iPrEtN OBR2 X= OTf, I R= Bu, 9-BBN
84
R3N: R1 R2
O
_ + BL2OTf O H R1
OBEt2
R2 E-enolate
OBR2 R
R 3B
OSiMe3
R2B-X
O R N2
R' 3B R
OBEt2 R1 R2
O R3CHO R1 R2 O R3CHO R1
Asymmetric Aldol Condansations with Chiral AuxilariesD.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115. - Li+ enolates give poor selectivity (1:1) - Boron and tin enolates give much improved selectivity
Bu O Me N O O B Bu2BOTf, EtNiPr2 , -78 O - O + N O RCHO R Me Bu OH O N O O
85
H R O
L O
+
L B _ O N O O R
L O B _
L O
+
O N O
RCHO
H R
L O
+
L B _ O N O O R
L O B _
L O
+
N O O
preferred conformation
R2 O L B L O O N H O O H R3 L B L O N O O Disfavored O O N R2 R2 H R3
R3
Favored O O N R2
OH R3
OH R3
Oppolzer Sultam
O N S O2 1) LDA 2) Bu3SnCl R3 Sn O S O N R2 S O2 L 2B N O R2 R3CHO N S O2 R2 O OH R3
O R2
R3CHO N S O2
OH R3 R2
86
1 : 33 (> 99 % ee)
Ph O R SPh ArO2SN B Br
iPrEt2N, PhCHO,-78C
In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors. Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes: proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates.
OSiMe3 OEt RCHO, TiCl4, CH2Cl2, -78C R OH CO2Et CH3 R= iPr (anti : syn) = 100 : 0 C6H11 94 : 6 Ph 75 : 25 RCHO, TiCl4, CH2Cl2, -78C R OEt OH CO2Et CH3 R= iPr (anti : syn) = 52 : 48 C6H11 63 : 37 Ph 67 : 33 + R OH CO2Et CH3 + R OH CO2Et CH3
OSiMe3
87
O OSitBuMe2 SO2N(C6H11)2
O Rc
Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals:
OSiMe3 O TiCl4 or SnCl4 R RCHO or RCH(OR')2 CH2Cl2, -78C
O O O TiCl4, CHCl2, -78 C HO O O
O O
OTMS
+
Cl4Ti O+ O Cl4Ti O
O OSiMe3
OTMS Ph
OEt
88
OTBS R O C6H11
CO2Me
O3 R
1) HIO6 2) CH2N2
89
4
7 6 5 4
OH
OH OH
OH
OH
OH
OH
[O]
CHO
+
CHO O syn aldol OH
CHO
+
CO2H
CHO O
1 HO2C OH 3 OH 5 O 9 OH 11 OH 13
CHO
O O N
O N 1
O N
OH 5
Ph Ph
Ph
O O N
O 3
O 5
O N
O CHO
Ph
O O N
O N 9
O 11
OH 13
O N CH3
OH
OTBS
PMBO TMSO
OTBS
90
X O O OH R L L L O Ti O O H
H CH3
Disfavored
H CH3 CH3 O X
X O
H L CH3 Sn H O O L
Disfavored
OH R
H3C H
X H
H CH3 CH3 O Ti L L
J. Am. Chem. Soc. 1990,112, 866
CH3 CH3
anti-syn
H3C CH3
O L
H3C CH3
O O N
O 3
O 5 CHO 7
PMBO TMSO
OTBS 13
O N
O 3
O 5
OH 7
PMBO O 9 11
OTBS 13
+
8
11
p-MeOC 6H4 OTBS 1) LiOOH 2) TBAF HO 63% 13 O O O O O OH Cl3C6H2COCl iPr2EtN, DMAP (86%
Ph
p-MeOC 6H4 O
10 11 12 13 9 8 7
O
9
11
OH
5 13
O
5 4 3 2
58 % O
O
1 3
OH OH
O
1
O O
O R Ph
91
R
O
1,2-addition
CuI,THF, -78C R
1,4-addition
Organolithium reagents - usually gives 1,2-addition products - alkyllithium are prepared from lithium metal and the corresponding alkyl halide vinyl or aryl- lithium are prepared by metal-halogen exchange from the corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or tbutyllithium.
R-Br X X= Br, I, Bu3Sn nBu-Li Et2 O Li(0) R-Li Li Et2 O
Organocuprates Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1. - selective 1,4-addition to ,-unsaturated carbonyls
2 R-Li
O R2CuLi R
CuI, THF
O
R2CuLi
MeO Cu R
R-Li
Li+
non-transferable ligand
Other non transferable ligands _ _ + Bu3P Cu R Li Me2S Cu R Li+ 2S Cu R CN 2Li
+
_ NC Cu R Li
_
+
F3B Cu R
Li+
Mixed Higher Order Cuprate B. Lipshutz Tetrahedron 1984, 40 , 5005 Synthesis 1987, 325.
Addition to Acetals
O R H3C O R (n-C6H13)2CuLi BF3OEt 2
R H
O O CH3
LA CH3 Nu: R H O O
92
98 % ee
Stereoselective Addition to Aldehydes - Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes may be stereoselective. - Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828. empirical rule
O R
1
M S
OH R1 R
2
M S L
O M L R1 S M
OH S R
2
R2
- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61. based on ab initio calculations of preferred geometry of aldehyde which considers the trajectory of the in coming nucleophile (Dunitz-Burgi trajectory).
O M L R
1
vs. R2
-
O L
R2
better
- Chelation Control Model- "Anti-Cram" selectivity - When L is a group capable of chelating a counterion such as alkoxide groups +
M O OR' R1
*
worse
OH
S M
M S
M+ O OR' HO OR' R2 R1 S
R2
M R
1
Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239. i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic)
O R usually R O +
Benzoin Condensation
KCN PhCHO Ph OH CN
Ph Benzoin
C-C BOND FORMATION 93 Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions
NH2 H NH2
+
N H 3C N N S OPO3PO3 H 3C N N
_ +
N S OPO3PO3
H 3C
H 3C
Thiamin pyrophosphate
CHO H H H H 2C OH OH OH OPO3 H 2C OH O CHO H 2C OH O HO H OH OH OH OPO3
thiamin-PP
H H H 2C
OH OH OPO3
H H 2C
OH OPO3
H H
H H 2C
Trimethylsilycyanohydrins
O R H
TMS-CN
TMSO R
CN H
LDA, THF
TMSO R
CN
Dithianes
B:, THF S R S H S R S R'-I S R S R' R R' Hg(II)
O
Aldehyde Hydrazones
H N N R H tBu
B:
N tBu O E R E
E+
R
LDA, THF
Al(Hg)
R' R'
OH
Sulfoxides
O
_
Ph R S O
OH
LDA, THF
Ph R S O
R'
Raney Ni
Ph S O
R' R' R
OH
94
Nu
OH
O BnO
Me3Al
S O _
OH S S
O S Ph S _
+
(69 %) 1) TBS-Cl 2) MeI, CaCO 3, H+ Ph O OH Ph
OH
R2
SOCl2, Et3N
S O R1 sulfite
O S O R1 O
-
sulfate
H2O
H R2 Nu
HO R1
H R2 Nu
95
O SO2 CO2Me O
1) (CH3)2CuLi 2) TBS-Cl
OBn
1) H2, Rh 2) HF
OMe NCH3
O SO2
OMe H3C
H N
OMe OMe
OH MeO HO NCH3 OBn OMe OBn OBn MeO BnO OMe NCH3
2 3 R
2 3 R
3 R
[3,3]-rearrangement
2 1
H
4 5
96
E,Z (99.7 %)
E,E (0.3 %)
Z,Z (0 %)
H H 3C H 3C H HH
CH3
CH3
H 3C H 3C E
CH3 Z
H 3C
E,Z (0 %)
E,E (90 %)
Z,Z (10 %)
"Chirality Transfer"
Ph R CH3 Ph CH3 H E S CH3 (87 %) Diastereomers Ph Ph H 3C R E H 3C Z CH3 R (13 %) H
Ph
R CH3 Z Ph
E CH3
CH3 R H
Diastereomers Ph Ph H 3C R Z H 3C Z H S CH3
- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43, 93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.
97
OMe
OH
KH OO
Claisen Rearrangements - allyl vinyl ether to an ,-unsaturated carbonyl Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis 1991, 5, 827.
O O
OH O
O CHO
220 C
O H O
Hg(OAc)2
O H O
C-C BOND FORMATION 98 - Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over non-enzymatic reaction
CO2H Chorismate mutase O OH Chorismate CO2H OH Prephenate HO2C O CO2H J. Knowles JACS 1987, 109, 5008, 5013
OH
Opposite stereochemistry
CO2H O CO2H
H H
OH
OH
OH + OH
OH
J. Org. Chem. 1976, 41, 3497, 3512 J. Org. Chem. 1978, 43, 3435
O +
O R H O R H
s CH3 O R H
O R H s CH3
CH3
O H
OH
CH3
OH
CH3 OH CH3 OH
CH3 CO2R
Tocopherol 94 - 99 % ee
99
O O Me OBn LDA, THF TMS-Cl Me Me Me CO2H OBn JOC 1983, 48, 5221
Eschenmoser
R OH EtO BF3 R NMe2 OEt O NMe2 R O NMe2
"Chirality Transfer"
R N O Ph Ph R= Et, Bn, iPr, tBu N O Ph (86 - 96 % de) R N O R aldehyde oxidation state
[2,3]-Sigmatropic Rearrangement
H Z :X Y R R H
-Wittig Rearrangement
O
SnR3
BuLi
_ O
100
TBDPSO nBuLi H
TBDPSO H MeO O O Li
TBDPSO
+
MeO OH O (42%)
H3C H
H3C Ph
CH3 OH (87 %)
CH3 (13 %) OH
Sulfoxide Rearrangement
R S O
-
S O
(MeO) 3P HO O
O CO2Et (MeO) 3P
CO2Et
Ph
O-
HO
Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23, 876; ; Chem. Rev. 1992, 28, 1021.
H H
Ph O
O O H SnCl4 O Ph O
O OH 99.8 % de
Ph O SnCl4
OH + syn isomer
H3C
(94 : 6)
101
- Metallo-ene Reaction
CH3
Cl
MgCl ClMg
intramolecular
BrMg
1)
Li Cl
CH3 MgCl
CHO 2) SOCl2
CH3 OH SOCl2
CH3
Cl
1) Mg(0), Et2 ) 2) 60 C
CH3
MgCl
OH
CH3 CHO H O
H Capnellene
102
BnO 1) O3 2) H2, Lindlar's BnO CHO BnO BnO H O H CH3 OH CHO OMEM 1) MEM-Cl 2) O3 MeAlCl
BnO
O O BnO O
1) 2)
O (CH3 )2S(O)CH 2-
H3O +
3) Swern
O O BnO O
O O
CH O 3
O O HO2C O
O CH3 MeO2C O
O O O O CH3 Ph Phyllanthocin