Chem 206D. A. Evans Carbocations: Stability, Structure, & Rearrangements
Problem 185: Final Exam, 1999. During Corey's synthesis of Aspidophytine
(JACS, 1999, 121, 6771), the pivotal intermediate 3 was assembled by the
union of 1 and 2 under the specified conditions. Provide a mechanism for this
single-pot transformation.
N
OMe
MeO
Me
NH2
OHC
CHO
Me3Si
CO2R
+
1) mix at room
temp, 5 min
2) 2 equiv.
TFAA, 0 °C
N
Rc Rd
Ra Rb 3) excess
NaBH3CN
N
N
MeO
MeO
Me
H
CO2R
1
2
3
Problem 56: Here is a typical carbonium ion question that you should be able
to handle by the end of the course. Write out a mechanism for the following
transformation.
Me
Me
Me
O
A. Srikrishna, Chem Commun 1994, 2259
BF3•OEt2
CH2Cl2
60% yield
H
Me Me
Me
CH2
O
Holton & Co-workers, JACS, 110, 6558 (1988).
Problem 79: In a synthesis of taxusin, the pivotal reaction(s) which generated the bicyclo
[5.3.1.] undecane ring system charactertistic of this family of terpenoids are illustrated
below. Given the illustrated transformation, what specific reagents would you employ to
carry out this process.
HO
Me
OH
HO
Me
R
Me Me
H
Me
Me
OH
O
OH
HO
Me
R
Me
H
?
D. A. Evans
Wednesday
December 13 , 2006
Reading Assignment for this Lecture:
Carey & Sundberg, Advanced Organic Chemistry, 4th Ed.
Part A Chapter 5, "Nucleophilic Substitution", 263-350 .
Saunders, M. and H. A. Jimenez-Vazquez (1991). “Recent studies of
carbocations.” Chem. Rev. 91: 375.
Chemistry 206
Advanced Organic Chemistry
Lecture Number 34
Introduction to Carbonium Ions–2
! Allyl- & Vinylsilanes: The !-Silicon Effect
! Carbonium Ion Rearrangements
Birladeanu (2000). “The Story of the Wagner-Meerwein Rearrangement.”
J. Chem. Ed. 77: 858. (handout)
Lambert, (1999). “The ! effect of silicon and related manifestations of "
conjugation.” Acc. Chem. Res. 32, 183-190. (handout)
http://www.courses.fas.harvard.edu/colgsas/1063
Chem 206Carbocation Rearrangements-1M. Shair, D. Evans
2-electron Huckel transition state
B
A
C
D
B
A
C
D
1,2 Sigmatropic shifts are the most commonly encountered cationic rearrangements.
When either an alkyl substituent or a hydride is involved, the term Wagner-Meerwein
shift is employed to identify this class of rearrangments.
Stereoelectronic requirement for migration....
B
A
C
D
bridging T.S.
retention of stereochemistry
Birladeanu (2000). “The Story of the Wagner-Meerwein Rearrangement.” J.
Chem. Ed. 77: 858. (handout)
Carbocation [1,2] Sigmatropic Rearrangements
OH
MsO
OH
TBSO
H
RO
H
O
OH
H
H
CH2Cl2, -78˚C
S. L. Schreiber et al Tetrahedron Lett. 1989, 30, 3765.
If migration accompanies ionization, the migration terminus will be inverted. Overlap
between the ! C-C (migration origin) and the !* C-X (migration terminus) will be
maximized in an antiperiplanar arrangement.
RO
H
OH
OH
H H
Et2AlCl
OH
OH
O
Pinacol rearrangement (vicinal diol): Driving force is the gen. of C=O
CH2NH2
Deamination
" NO+ "
CH2
OH
Demjanov-rearrangement (Driving force: relief of ring strain)
H+
Me
MeMe
Me
H
Me
Me
H
HMe OH
Me
Me
H
H
Me
Me
Me
HO
H
Wagner-Meerwein Rearrangements: Application in Total Synthesis
!-caryophyllene alcohol
E. J. Corey JACS 1964, 86, 1652 (electronic handout).
OH
H
Me
Me
Me
Meequiv to
A
Preparation of A:
Me
Me
H
H
Me
O
Me
Me
Me
O H
h"
A
MeMgBr
[2+2]
H2SO4
Chem 206Carbocation Rearrangements-2M. Shair, D. Evans
Synthesis of (±)-Isocomene: Pirrung, JACS 1979, 7130; 1981, 82.
Me
Me
Me
Me
(±)-Isocumene
Me
Me
Me
Me
Me
Me
Me
H+
Me
Me
Me
Me
Carbocations: Neighboring Group Participation
R
R
X:
R
R
Y
R
R R
R
X
R
R
X:
R
R
Nuc
Nuc:
Groups with accessable electron density (heteroatoms, arenes) and the correct
stereoelectronic orientation (anti-periplanar) can "assist" in the ionization of a
leaving group.
OTs
O Me
O
OTs
O Me
O
HOAc
HOAc
OAc
O Me
Okrel = 1
krel = 10
+3
O
O
Me
Y-
OTs
H
non-classical
carbonium ion
OTs
HOAc
OTs
krel = 95
krel = 1
R. G. Lawton, JACS 1961, 2399
OTs
MeH
Ph
MeH
The Cram Phenonium Ion Experiments: Cram, JACS 1949, 71, 3865
L-Threo
Me Me
HH
OAc
MeH
Ph
MeH
Ph
MeH
H Me
AcO
L-Threo
D-Threo
98% chemical fidelity
TsO–
OTs
HMe
Ph
MeH
L-Erythro
Me H
MeH
OAc
HMe
Ph
MeH
Ph
HMe
H Me
AcO
98% chemical fidelity
TsO–
L-Erythro
L-Erythro
Chem 206Allyl- & Vinylsilanes: The !-Silicon EffectM. Shair, D. Evans
Allyl– & Vinylsilanes react with electrophiles
References: Lambert Acc. Chem. Res. 1999, 32, 183-190
Lambert, JACS 1990, 112, 8120; 1996, 118, 7867.
Fleming, Organic Reactions 1989, 37, 54.
Fleming, Chem. Rev., 1997, 2063.
R3Si
E E
SiMe3
E
E
"R3Si
+"
"R3Si
+"
(trapped by solution Nu)
Mechanism - the simple picture: !-Silicon stabilizes carbocation
R3Si
E
R3Si E
Nu
E
SiMe3
E
H2C SiMe3
E
Nu
E
Fleming, Organic Reactions 1989, 37, 54.
!-Silicon Effect: the origin of regioselectivity
Si
"Si–C # pz empty
"SiC
pz
E"occ
pz
H3Si
H
H
CH2 versus
H3C
H
H
CH2
Calculation: A more stable than B by 38 kcal/mol.
Jorgensen JACS 1985, 107, 1496.
A B
Magnitude of the !-Silicon Effect
Me3C
H
SiMe3
OCOCF3
H
H
1
Me3C
H
Me
OCOCF3
H
H
2
Solvolysis (CF3CH2OH)
k1
k2
= 2.4 x 10+12
Me3C
H
H
OCOCF3
SiMe3H
3
Me3C
H
H
OCOCF3
Me
H
4
Solvolysis (CF3CH2OH)
k3
k4
= 4 x 10+4
"These figures established the !-effect as one of the kinetically
strongest in organic chemistry": J. Lambert
Data provide no distinction between open and bridged intermediates
In all instances, the solvolysis product is 1-tert-butylcyclohexene
Proof for a stepwise mechanism provided the following protodesilylation
experiment:
Me3Si SiMe2Ph
Me3Si SiMe2Ph
Me3Si SiMe2Ph
Me3Si
SiMe2Ph
both silanes yield the same
product mixture.
Hence, the
reaction proceeds
most likely via a
common
intermediate, a
carbeniumion
H
Chem 206Allyl- & Vinylsilanes: The !-Silicon Effect-2M. Shair, D. Evans
Allylsilanes are more nucleophilic than alkenes
HOMO is higher in energy due to negative hyperconjugation
! (!*) !C–Si
Houk, JACS 1982, 104, 7162.
!Si–C
E
!
!*
!Si–C
!
Electrophile Addition - Stereoelectronics
R3 R2
R1
H
R
Si
R3
R2
H
R
Si
!CSi
E
E
major (trans)
+ Nu - NuSiMe3
anti addition observed
A1,3-strain
minimized
!C–Si
H
R
R3
E
R1
R2
R3 R2
R1
Si
H R
R3
Si
H R
E
R
H
R3
+ Nu - NuSiMe3
E
R1
R2
E
R1
R2
!C–Si
minor (cis)
anti addition
observed
The stereochemical consequences for the major product are:
Examples:
Me
Ph
Me3Si
H CH2Cl2
Ph
t-Bu
H
Me
t-BuCl, TiCl4
JACS 1982, 104, 4962.But
R
Ph
HMe3Si
HF
Protodesilylation
R
Ph
E:Z
88:12!
! trans-alkene:
! anti-addition of E+ with respect to SiR3
Carbonyl Addition of Allylsilanes: Open Transition States
Me3Si
– is not sufficiently Lewis acidic to activate C=O through pre-association;
however (RO)2MeSi
– is Lewis acidic enough to activate C=O through pre-association.
These allylsilanes add to RCHO througl closed transition states
R2R1
O
H R
SiMe3
XnM
R2R1
R
O H
SiMe3
XnM
ORAntiperiplanar TS Synclinal TS
Calculations by Houk et al. show that the relative energy differences between the
antiperiplanar and and synclinal transition states are negligible. Both the antiperiplanar
and synclinal models predict a syn selectivity for the newly formed stereogenic centers.
R
O
Me3Si Me
TiCl4
CH2Cl2
+
R
Me
OH
> 95:5 syn
R
O
Me3Si
TiCl4
CH2Cl2
+
R
Me
OH
Me
R
Me
OH
ca. 65 : 35
syn
Hayashi, TL 1983, 2865.
H
H
Catalytic Enantioselective Addition of Allylic Organometallic Reagents to
Aldehydes and Ketones, Denmark and Jiping Fu, Chem. Rev. 2003, 103, 2763-2793 (handout)
Chem 206Allylsilanes: Reactions with ElectrophilesB. Breit, D. Evans
Allylsilanes add to aldehydes and acetals under Lewis acid promotion
regioselectivity: Allyl inversion
Me3Si Ph
O
Me
TiCl4
OH
n-C3H7
Ph
Me3Si
O
Me
Ph
+
+
TiCl4
OH
n-C3H7
Ph
H
H
Acetals can be used as well
Me3Si Me
Me
Me3Si
Me Me
OCH3
H3CO n-C4H9
+
+
OCH3
H3CO n-C4H9
TiCl4
TiCl4
n-C4H9
OCH3
Me Me
n-C4H9
OCH3
Me
Me
(80%)
(83%)
The Sakurai Reaction (Enone Conjugate Addition)
Me
O
Me3Si
TiCl4
CH2Cl2
Me
OTiCl4
SiMe3
Me
O
Me
O
Me3Si
75%
17%
Fleming, Org. Reactions 1989, 37, 127-133
Me
O
EtAlCl2
CH2Cl2
Me
O
SiMe3
Majetich, Tetrahedron 1987, 43, 5621
78%
Reactions Proceedilng through Silicon-Migration
Me
O
(Pri)3Si
TiCl4
CH2Cl2
Me
OTiCl4
Si(iPr)3
Me
OTiCl4
Si(iPr)3
Me O
(Pri)3Si
A. I. Meyers, J. Org. Chem. 1998, 63, 5517
diastereoselection: 97:3
85% yield
Si migration may be promoted by using hindered Si substituents
MeO2C CO2Me
Ar
ZrCl4
CH2Cl2
(Pri)3Si
Ph(Pri)2Si
CO2Me
Ar
MeO
OZrCl4
–
SiR3
CO2Me
Ar
MeO
OZrCl4
–
SiR3
Ar
MeO2C
MeO2C
SiR3diastereoselection: 96:4
68-70% yield
CO2Me
Me
PhMe2Si
Me
H
O CO2Me
CHO
Me
PhMe2Si
Me
BF3°OEt2
rt 8 h
diastereoselection: >30:1
93% yield
Panek, J. Org. Chem. 1993, 58, 2345
Can you work out the mechanism??
Chem 206Vinylsilanes: Reactions with ElectrophilesB. Breit, D. Evans
Stereochemistry of Electrophile
Addition to Vinylsilanes
R1
R2
H
SiMe3
R1
R2
H
I
RETENTIONN
O
O
I
Vinyl/Allylsilanes in Organic Synthesis - Selected Examples
Fleming, Org. Reactions 1989, 37, 54.
El
R1
R2
Me3Si
H
R1
R2
El
SiMe3
H
R2R1
SiMe3H
El
! R2R1
ElH
+ Nu-
- NuSiMe3
SiMe3
• Rotation in direction a favored
(avoidance of eclipsing interactions,
• Principle of least motion
a
El
a
OH
H
R MeMe
SiMe3
H R
O
Me
Me
TiCl4
Fleming p 289
SiMe3
Et
Et ClCH(OMe)2+
TiCl4
- 78 °C
Et
Et
OMe
(73%)
OMe
N
H
N
Me
N
H
NH
Me
SiMe3
(CH2O)n
TsOH
Fleming p 148
Summary Statements
1. Me3C+ is more stable than Me3Si+ in spite of the fact that Si is less
electronegative than C.
Si C
Me
Me
H
H
H Si C
Me
Me
H
H
H
C C
Me
Me
H
H
H C CMe
Me
H
H
H
C–Si bond length: 1.87 Å
C–C bond length: 1.54 Å
C–Si hyperconjugation is less pronounced than the anaologous C–C hyperconjugation
do to the impact of the longer C–Si bond lengths.
2. Carbonium ions ! to Si are less stabilized than carbonium ions " to Si.
Si C
Me
Me
H
H
Me
Si C
Me
Me
H
H
Me
C
Me3Si
C
H
H
H
H
C
Me3Si
C
H
H
H
H
C(+) ! to silicon
C(+) " to silicon
C–Si hyperconjugation is less pronounced than the anaologous C–C hyperconjugation
do to the impact of the longer C–Si bond lengths.
3. According to Lambert, silicon has a propensity to stabilize !
carbonium ion via hyperconjugation (vertical stabilization) rather than
bridging (nonvertical stabilization.
C
Me3Si
C
H
H
H
H
C
Me3Si
C
H
H
H
HC(+) ! to silicon
hyperconjugation more
important than bridging
C
Me3Si
C
H
H
H
H
4. Silicon has a lower propensity to undergo Wagner–Meerwein like
rearrangements than carbon.
Chem 206M. Shair, D. Evans Stabilized Cations: Iminium-Ions 1
N
R1
R2 R4
R3
R1
R2
O N
R4
R3
H N
R1
R2
R4
R3
N
OR2
R1
N R1
Iminium Ions
Common Methods of Generation:
H+, -H2O
H+, -ROH
or Lewis Acid
or Lewis Acid
X-
N
Me
N
Me
Hg
H
H
X–
X
N
Me
H
Hg(0)
HX
X–
rds
Oxidation of Amines
HgX2
N
N H
H
MeO2C OH
H
N
N H
H
MeO2C OH
H
H
Stereoelectronic Effects on Nu Addition to Iminium Ions
Hg(OAc)2/EDTA
one diastereomer
Stork et al. JACS 1972, 94, 5109.
N
H
H CO2Me OH
H
R
Nu (favored)
C=N Stereoelectronic Effects: Lecture 20
H
H
NaBH4
NMe3Si
Ph
N
Ph
Me3Si
N
H
Ph
H
N H
Ph
SiMe3
H
H
TFA
(E)
(Z)
Overman et al. TL 1984, 25, 5739.
Only in the case of the (Z) vinylsilane is the emerging p orbital coplanar
with C-Si bond. Full stabilization of the empty orbital cannot occur with
the (E) vinylsilane.....hence the rate difference.
rel rates: 7000/1
TFA
(Z) vinylsilane)
N H
Ph
H
H
SiMe3
(E) vinylsilane)
N
O
H
TMS
R
Me
Me
N
H Me
RMe
TMS
N
H
Me
RMe
OH
OH
PPTS, MeOH
80˚C
71 %
one double bond isomer
Overman et al. JOC 1989, 54, 2591.
pumiliotoxin A
"Least Motion Argument"
steps
The Aza-Cope RearrangementD. A. Evans, M. Calter Chem 206
Review:
Heimgartner, H. In "Iminium Salts in Organic Chemistry";
Bohme, H., Viehe, H., Eds.; Wiley: New York, 1979; Part 2,
pp 655-732.
The 3-aza-Cope Rearrangement:
[3,3]
Exothermic as written by ~7-10kcal/mole.
1
2
3 1
2
3
Neutral Variant:
N N
RR
Ammonium Variant:
[3,3] Even more exothermic than the neutral
version, since enamine lacks resonance
and iminium salt has stronger p-Bond
than imine does.
NN
R
R
R
R
2-aza-Cope Rearrangement:
3
2
1
[3,3] 1
2
In the simplest case, degenerate. Steric
effects, conjugation, or selective trapping
of a particular isomer, will drive
equilibrium. As with the 3-aza-Cope, the
cationic version proceeds under much
milder conditions.
N
R
N
R
1-aza-Cope Rearrangement:
3
2
1 3
2
1
[3,3]
The 3-aza-Cope rearrangement can be
driven in reverse by judicious choice of
substrates(i.e., incorporating the imine into
a strained ring or by making R an acyl
group).
N
R
N
R
The 3-aza-Cope Rearrangement
First Neutral Case: Hill TL 1967, 1421.
250oC,
1 hr
"Practically quantitative", no real
yields given.
First Cationic Case: Elkik Compt. Rend. 1968, 267, 623.
80 oC,
2-3 hr
+ +
No yields given.
N
Me
Me
Me
N
Me
Me
Me
Me
N
Me
Me
N
Me
Me
Me
Me
Me
Me
OHC
Me
H2O
Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169.
+ +
OHC R'
R
N
HR''
R'' R
R'
N
R''
R'' X
N
R''
R''
R'
RR
R'
R'''
R'''R'''
O
H
N
R''
R''
R'
R
R'''[3,3]
!
H2O
-H2O
2-aza-Cope
Equilibrium between A and B driven towards B by conjugation of iminium
double bond to the aromatic ring in B.
+
HCHO
HCOOH
100oC, 2hr.
First Reported Case: Horowitz JACS 1950, 72, 1518.
The 2-aza-Cope Rearrangement
Chem 206D. A. Evans, M. Calter The Aza-Cope Rearrangement
NH2Ph Ph N
H
N
H
Ph
H2N
BA
H2O
PhCHO
Yohimbane
15-Methoxy-isoyohimbane
HCHO, MeOH,
Cat. H+, 85%
Yohimbine
Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938.
H
N
N
H
H
NH
O
N
H
N
NH
H
N
N
H
H OMe
H
N
N
H
OH
CO2Me
H
POCl3
NaBH4
N
NH
H
NaBH4
2-aza-Cope, driven by
conjugation
HCHO,
H+, -H2O
Mechanism for Yohimbane Analog Formation:
..
N
NH
H
N
N
H
N
N
H
N
N
H
H OMe
MeOH
N-Acyliminium Ion Rearrangements: Hart JOC 1985, 50, 235.
Hart observed an unusual product while trapping the intermediates of N-acyliminium olefin
cyclizations.
TFA
N
OH
O
C3H7
C3H7
O
N
N
O
C3H7
CF3CO2
C3H7
O
N
Et3SiH
C3H7
O
N
C3H7
O
N
40:60 ratio
2-Aza Cope rearrangements add to
complexity of cyclization process
Chem 206
M. Shair, D. Evans Stabilized Cations: AcylIminium-Ions
N-Acyliminium Ion Rearrangements
Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235.
+
81%
NaBH4,
MeOH,
83%
Me
BnO NH2
O
Me
O O
AcO
NMe
OMe
O
BnO
OAcOAc
BnO
OH
Me O
NMe
N
Me
Me
OBn
O
OAc
HCO2H
OAc
OMe
Me
N
OBn
H
[3,3]
(-)-hastancine
N
OAc
O
Me
Me
HO
Me
Me
O
OH
NN
OH
BnO
BnOHO
N
OAc
O
Me
Me
HCO2
BnO
HCO2H
HCO2H
N
O Me
OH
SiMe3
TFA
N
O Me
SiMe3
N
O
CH2
Me
H
N
O
CH2
Me
H
67%
29%
Gelas-Mailhe, Tet. Lett, 1992, 33, 73
N
O Me
SiMe3
H
[3,3] ???The origin of the modest
diastereoselection has
not been attributed to 2-
aza-Cope process.
Homo-chiral
Mannich
Pinacol
:
cyclization
1.5 hr, 79%
O
N Me
Me
Ph
Ph
N
Ph
Me
Ph
OH
Me Me
OH
Ph
N
Me
Ph
NMe
Me
Ph
Ph
O
Me
OH
Ph
N
Me
Ph
CSA, 60oC,
[3,3]
Competing 2-Aza-Cope and Pinacol
Rearrangements: Which Dominates??
racemic product
2-aza-Cope rearrangements afford a low-barrier to competing processes
Chem 206M. Shair, D. Evans Stabilized Cations: Iminium-Ions 2
N
OR
HO
NR2
N
OR
HO
NR2
2-Aza-Cope-Mannich sequence:
(CH2O)n, Na2SO4
MeCN, 80˚C
[3,3] N
OR
HO
NR2
N
O
NR2
OR
98 %!!
Axial Attack
equivalent to
N
N
OO
H
H
H
strychnine
Overman et al. JACS 1995, 117, 5776.
steps
Mannich
Rxn
N
O
ROH2C
H
NR2
Overman et al. JOC 1991, 56, 5005
Another aza-Cope-Mannich sequence:
HO
O
O
NHBn
Ar
N
O
Bn
OH
N
Bn
Ar
N
Ar
HO
Bn
N
O
Bn
H
H
[3,3]
[3,3]
Mannich
O
O
N
O
H
H
H2/Pd-C
CH2O/HCl
O
H
H
N
O
O
OO
CH2O/HCl
97%
67%
H
N
O
O
HO
HO
Pancracine
steps
Pictet-Spengler
cyclization
BF3
Chem 206D. Evans, E. Shaughnessy The Prins-Pinacol Reaction
References
Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661
Prins & carbonyl ene reactions: Snider, Comprehensive Organic Synthesis, 1991, Vol. 2
O
R1 H
R2
R1
R2
OH
OO
R1
R2
R2
R1
R2
OH
- H+
HX
R1
R2
OH X
The Prins Process:
O
R1 H
H
R2
X–
R1CHO
The Prins-Pinacol Variant:
O
OMe
Ph
Me
Me
Me
O
Me
Me
Ph
Me
Cl4Sn–O
Me
O
Me
Me
Ph
Me
Cl4Sn–O
Me
O
Me
Me
Me
Ph
O
Me
Lewis Acid
SnCl4
>95% ee
Prins
+
–
–
H
H
Pinacol
SnCl4
O
OMe
Ph
Me
Me
Me
O
Me
Me
Ph
Me
O
Me
Evidence for Prins-Pinacol Mechanism
>95% ee
SnCl4, CH2Cl2
O
O
Me
Me
Ph
Me
- Cl4SnO
Me
O
Me
Me
Ph
Me
- Cl4SnO
Me
Ph Me
Me
Me
- Cl4SnO
Me
O
Me
MeMe
PhO
Me
If a [3,3] rearrangement were intervening, the product would be racemic.
Overman, JACS 2000, 122, 8672
Overman, Org Lett 2001, 3, 1225
+
+
enantiopure
racemic
Prins
[3,3]
Aldol (fast)
pinacol
H
>95% ee
Me
MeHO
OH
OMe
O
Me
O
OMe
Me
Me
Me
OMe
Me
Me
O
Me
Ph
7:1 anti:syn
BF3•OEt2
(E)-CH=CHPhCHO
CH2Cl2, -55 °C
97%
SnCl4, CH2Cl2
-70 ! -23 °C
82%
syn
Examples of Stereoselective THF Formation
Chem 206D. Evans, E. Shaughnessy The Prins-Pinacol Reaction
O
O
Me
Me
Ph
Me
- Cl4SnO
Me
O
Me
Me
Ph
Me
- Cl4SnO
Me
Ph Me
Me
Me
– Cl4SnO
Me O
Me
MeMe
PhO
Me
Prins-Pinacol Mechanism
>95% ee
enantiopure
Prins
Aldol
pinacol
H
SnCl4
[3,3]
O
O Me
Me
Ph
Me
Me
CH2Cl2
Homo-chrial
Prins cyclization faster than [3,3] rearrngement
Homo-chiral
Mannich
Pinacol
:
cyclization
1.5 hr, 79%
2-aza-Cope vs. Pinacol:
O
N Me
Me
Ph
Ph
N
Ph
Me
Ph
OH
Me Me
OH
Ph
N
Me
Ph
NMe
Me
Ph
Ph
O
Me
OH
Ph
N
Me
Ph
CSA, 60oC,
[3,3]
racemic product
[3,3] rearrngement faster than Mannich cyclization
Overman: Magellanine Synthesis
JACS, 1993, 115, 2992
TESO
CH(OMe)2
O
OMe
H
N
O
OMe
H
CHPh2
Me
N
O
Me
OH
H
(-)-Magellanine
Me
N
O
Me
OH
H
(-)-Magellanine
57%
Steps
The pivotal transformation
1. OsO4, HIO4
2. Ph2CHNH3Cl
NaBH3CN
SnCl4
TESO
O
Me
TESO
CH(OMe)2
O
OMe
R
H
O
OMe
H
!
!
! mixture of diastereomers
SnCl4
Chem 206D. Evans, E. Shaughnessy The Prins Reaction-3
Overman Synthesis of a Eunicellin Diterpene
Overman & MacMillan JACS, 1995, 117, 10391
O
Me
Me
Me
HH
Me
AcOHO
(-)-7-Deacetoxy-alcyoninacetate
Me Me
Me
TMS
OH
OH
ds = 9:1
OHC OTIPS
Me
OHC
TMSO
OMe
Me
Me
Me Me
Me
I
single stereoisomer
6 steps, 39% yield from (S)-carvone
t-BuLi, THF,
-78 °C
PPTS, MeOH
64%
Me Me
Me
TMS
OH
O
R
BF3•OEt2 (3 equiv.)
CH2Cl2, -55! -20 °C
79%
Me Me
Me
TMS
OH
O
R
Me2HC
Me
TMSO
CHO
[3,3]
Me
OTIPS
Felkin Control (Lecture 20)
Overman: Synthesis of trans-Kumausyne
JACS, 1991, 113, 5378 O
AcO
Et
Br
trans-Kumausyne
OH
OH
O
H
H
O
OBn
BnOCH2CHO
RSO3H, rt
69%
O
OH
OBn
[3,3]
O
OH
OBn
O
H
H
OBn
O
O
m-CPBA
72%
4:1 regioselectivity
1. H2, Pd-C, 88%
2. Swern, 100%
O
H
H
O
O
Et
TMS
BF3•OEt2
-78 °C ! rt
73%
1.
2. TBSCl
O
H
H
O
O
Et
OTBS
O
HO
Et
OTBS
H
O
DIBAL
-78 °C
97%
CHO
Felkin Control (Lecture 20)
Chem 206D. A. Evans The Prins Reaction-4
Mukaiyama Aldol–Prins Cascade
Rychnovsky JACS, 2001, 123, 8420
The Basic Process
OR
El
OR
SiMe3
OR
SiMe3
El
El
El
OR
SiMe3
El
Let El(+) = Lewis acid activated RCHO
Prins
–TMSX
OROR
SiMe3
BF3•OEt2
R
HO
No (