Chem 206D. A. Evans
Matthew D. Shair Monday, December 9 , 2002
http://www.courses.fas.harvard.edu/~chem206/
Reading Assignment for this Lecture:
Iminium Ions and Their Transformations
Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part A Chapter 5, "Nucleophilic Substitution", 263-350 .
Question 13. Final Exam, 1999. During Corey's recent 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
OMeMeO Me
NH2
OHC
CHO
Me3Si
CO2R
+
1) mix at roomtemp, 5 min
2) 2 equiv.TFAA, 0 °C NRc Rd
Ra Rb+ 3) excess NaBH3CN
N
N
MeOMeO Me H
CO2R
1
2
3
Chemistry 206
Advanced Organic Chemistry
Lecture Number 32
Introduction to Carbonium Ions–3
a73 Stabilized Carbocations: Iminium Ions (C=NR2(+))a73 Stabilized Carbocations: Oxo–Carbenium Ions (C=OR(+))
a73 Stabilized Carbocations: Addition & Rearrangements
OHC
CHO
Me3Si
CO2R
+
1) mix at roomtemp, 5 min1
2
N
OR
O
TMS
N
OMeMeO Me
OR
RO
N
OR
O
TMS
N
OMeMeO Me
ORN
OR
O
TMS
NMeOMeO Me
N
N
MeOMeO Me H
CO2R
N
N
MeOMeO Me H
CO2R
H
N
N
MeOMeO Me H
CO2R
NaBH3CN
TFA
reversible?
A
The product-determining step could be step A.
Chem 206M. Shair, D. Evans
NR1R
2 R4
R3
R1
R2 O N R4
R3H NR1
R2 R4
R3
N
OR2
R1 N R1
N
N H
HMeO
2C OH
Iminium Ions
Common Methods of Generation:
H
N
N H
HMeO
2C OH
Stabilized Cations: Iminium-Ions 1
H+, -H2O
H+, -ROH
or Lewis Acid
H
or Lewis Acid
H
Stereoelectronic Effects on Nu Addition to Iminium Ions
Hg(OAc)2/EDTA
one diastereomer
Stork et al. JACS 1972, 94, 5109.
N Me N Me
Hg
H
HX–
X
N Me
H
Hg(0)
HX
X–
rds
Oxidation of Amines
N H
H CO2Me OHH
R
Nu (favored)
NMe3Si
Ph
N
Ph
Me3Si
NH
Ph
H
N H
Ph
SiMe3H
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
HH
SiMe3
(E) vinylsilane)
N O
H
TMS
R
Me
Me N
H Me
RMeTMS
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
C=N Stereoelectronic Effects: Lecture 19
H
H
Related to Polonovski & Pummerer Reactions: Lecture 27
NaBH4
HgX2
X-
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.
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.
123 1 2 3
Neutral Variant:
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.
1-aza-Cope Rearrangement:
321 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).
The 3-aza-Cope Rearrangement
First Neutral Case: Hill TL 1967, 1421.
250oC,
1 hr
"Practically quantitative", no realyields given.
First Cationic Case: Elkik Compt. Rend. 1968, 267, 623.
80 oC,
2-3 hr
+ + No yields given.
Good way to allylate aldehydes: Opitz Angew. Chem. 1960, 72, 169.
+ +
N NRR
NN
R R
R R
N
R
N
R
NR NR
N MeMeMe NMe MeMe
MeN
MeMeNMe
Me
MeMe
Me
OHC R'
Me
R
OHC
Me
N HR''
R'' R
R'NR''
R'' X
NR''R'' R'RRR'
R'''
R'''R'''
O
H
NR''R'' R'R
R'''[3,3]
H2O
?H2O
-H2O
2-aza-Cope, driven byconjugation
HCHO,
H+, -H2O
Mechanism for Yohimbane Analog Formation:
..
2-aza-Cope
Yohimbane
15-Methoxy-isoyohimbane
HCHO, MeOH,Cat. H+, 85%
Equilibrium between A and B driven towards B by conjugation of iminium double bond to the aromatic ring in B.
Yohimbine
Application to Yohimbine Analog Synthesis: Winterfeldt Chem. ber. 1968, 101, 2938.
+
HCHO
HCOOH100oC, 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 NH NHPh
HN
N
H
H
NH
O
H2N
N H N
NH
H
N
N HH OMe
H
N
N H OHCO2MeH
N
NH
H
N
N H
N
N H
N
N HH OMe
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
OC3H7 C3H7 O
N
N
OC3H7
CF3CO2POCl3NaBH4
C3H7 O
N
Et3SiH
C3H7 O
N
C3H7 O
N
40:60 ratio
2-Aza Cope rearrangements add to complexity of cyclization process
MeOH
BA
H2O
PhCHO
Chem 206M. Shair, D. Evans Stabilized Cations: AcylIminium-Ions
N-Acyliminium Ion Rearrangements
Synthesis of (-)-hastanecine: Hart JOC 1985, 50, 235.
+
81%
NaBH4,
MeOH,83%
(-)-hastancine
MeBnO NH
2 O
Me
O O
AcO
NMe
OMe
O
BnO OAcOAcBnO
OH
Me ON
MeN
OAc
Me
Me
OBn
O OAc
OMe
Me N N
OAc
OMe
Me
HOMeMe
O
OH
NN
OH
BnO
BnOHO
OBn
H
[3,3]
N
OAc
OMe
MeHCO
2
BnO
N
O Me
OH SiMe
3TFA
N
O Me
SiMe3
N
O
CH2
Me
H
N
O
CH2
Me
H
67%
29%
Gelas-Mailhe, Tet. Lett, 1992, 33, 73
Homo-chiral Mannich
Pinacol
:
cyclization
1.5 hr, 79%
O
N MeMe
Ph Ph N
Ph
Me
Ph OH
Me Me
OHPh
NMe
Ph
NMe Me
PhPh O
Me OH
Ph
N
Me
Ph
CSA, 60oC,
[3,3]
racemic product
N
O Me
SiMe3H[3,3] ???
Conclusion: 2-aza-Cope rearrangements afford a low-barrier to competing processes
The origin of the modest diastereoselection has not
been attributed to 2-aza-Cope process.
Competing 2-Aza-Cope and Pinacol Rearrangements: Which Dominates??
HCO2H
HCO2H
Chem 206M. Shair, D. Evans Stabilized Cations: Iminium-Ions 2
N
OR
HO NR
2
N
OR
HO NR
2
2-Aza-Cope-Mannich sequence:
(CH2O)n, Na2SO4
MeCN, 80?C [3,3] N
OR
HO
NR2
N
ONR
2 OR
98 %!!
Axial Attack
equivalent to
N
N
OO
H
H
Hstrychnine
Overman et al. JACS 1995, 117, 5776.
steps
MannichRxn
Overman et al. JOC 1991, 56, 5005
Another aza-Cope-Mannich sequence:
HO O
O
NHBn
Ar
N
O
Bn
OH
NBn
Ar
N
ArHO
BnN
O
Bn
H
H
[3,3]
[3,3]
Mannich
O
O
N
O H
H
H2/Pd-CCH
2O/HCl
O H
H N
O
O
OO
CH2O/HCl
97%
67%
H N
O
O
HO
HO Pancracine
steps
Pictet-Spenglercyclization
N
O
ROH2C
H
NR2
BF3
Chem 206D. Evans, E. Shaughnessy The Prins-Pinacol Reaction
References
Prins reaction: Adams, D.R.; Bhaynagar, S. D. Synthesis 1977, 661Prins & 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–
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
MeMe
PhO
Me
Lewis AcidSnCl4 >95% ee
Prins
+– –
H H
PinacolSnCl4
O
OMe
Ph
Me
Me
Me O MeMe
Ph
Me
O
Me
O
O
Me
Me
Ph
Me
- Cl4SnO
Me O
Me
Me
Ph
Me
- Cl4SnO
Me
Ph Me
MeMe- Cl4SnO
Me O
Me
MeMe
PhO
Me
Evidence for Prins-Pinacol Mechanism
If a [3,3] rearrangement were intervening, the product would be racemic.Overman, JACS 2000, 122, 8672
Overman, Org Lett 2001, 3, 1225
+
+
>95% ee
enantiopure
racemic
Prins
[3,3]
Aldol (fast)
pinacol
H
SnCl4, CH2Cl2
MeMeHO
OH
OMe
O
Me
O
OMe
Me
Me
Me OMe Me
Me
OMe
Ph7:1 anti:syn
BF3?OEt2(E)-CH=CHPhCHO
CH2Cl2, -55 °C 97%
SnCl4, CH2Cl2
-70 → -23 °C 82%
syn
Examples of Stereoselective THF Formation
>95% ee
R1CHO
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
MeMe– Cl4SnO
Me O
Me
MeMe
PhO
Me
Prins-Pinacol Mechanism
>95% ee
enantiopure
Prins
Aldol
pinacol
H
SnCl4
[3,3]
Homo-chiral Mannich
Pinacol
:
cyclization
1.5 hr, 79%
2-aza-Cope vs. Pinacol:
O
N MeMe
Ph Ph N
Ph
Me
Ph OH
Me Me
OHPh
N
Me
Ph
NMe
Me
PhPh O
Me OH
Ph
N
Me
Ph
O
O Me
Me PhMe
Me
CH2Cl2
Homo-chrial
CSA, 60oC,
[3,3]
racemic product
Overman: Magellanine Synthesis
JACS, 1993, 115, 2992
TESO
CH(OMe)2
O
OMe
H
N
O
OMe
H
CHPh2
MeN
O
Me OH
H(-)-Magellanine
MeN
O
Me OH
H
(-)-Magellanine
57%
TESO
O Me
Steps
The pivotal transformation
TESO
CH(OMe)2
O
OMe
R
H
O
OMe
H
1. OsO4, HIO42. Ph2CHNH3Cl
NaBH3CN
a54 a54
a54 mixture of diastereomers
Prins cyclization faster than [3,3] rearrngement
[3,3] rearrngement faster than Mannich cyclization
SnCl4
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 MeHHMe
AcOHO(-)-7-Deacetoxy-alcyoninacetate
Me Me
Me
TMS
OH
OH
ds = 9:1
OHC OTIPS
Me
OHC
TMSO OMeMe
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.)CH
2Cl2, -55→ -20 °C 79%
Me Me
Me
TMS
OH
O
R
Me2HC
Me
TMSO
CHO
[3,3]
Me
OTIPS
Overman: Synthesis of trans-Kumausyne
JACS, 1991, 113, 5378 OAcO Et
Brtrans-Kumausyne
OH
OH
O
H
H
O
OBn
O
H
H
OBnO
O
BnOCH2CHORSO
3H, rt
m-CPBA
72%4:1 regioselectivity
1. H2, Pd-C, 88%2. Swern, 100%
O
H
H
OOEt
TMS
BF3?OEt2-78 °C → rt
73%
1.
2. TBSClO
H
H
OO
EtOTBS
O
HO
EtOTBS
H
O
DIBAL-78 °C
97%
CHO
69% O
OH
OBn
[3,3]
O
OH
OBn
Felkin Control (Lecture 20)
Felkin Control (Lecture 20)
Chem 206D. A. Evans The Prins Reaction-4
Mukaiyama Aldol–Prins CascadeRychnovsky JACS, 2001, 123, 8420
The Basic Process
OR ElOR
SiMe3
OR
SiMe3
El
El
El
OR
SiMe3
El
Let El(+) = Lewis acid activated RCHO
OROR
SiMe3
BF3?OEt2 ROH
No (little) control over this (a70) stereocenter
a70
OR
SiMe3 H R
OF3B
R
O BF3
aldol
Prins
Prins
OR R
OX
a70
SiMe3
–TMSX
Application to Leucasandrolide
O OMe O
Me OH
Me
Me
O
O
O OMe O
Me OH
Me
Me
O
HO
The seco acid
OH
The Pivotal Step:
O O
Me
OBn
H
O SiMe3
TBSO
base
base = NMe
3C CMe3
O OH O
Me
OBn OTBS
BF3?OEt2
base, 78%
5.5:1 ratio
Control of hydroxyl center: see Lecture 20
BnO
R
O
H BF3?OEt2
BnO
R
OH
R
O
Evans et al., JACS 1996, 116, 4322
R
OTMS anti selection:~5–8:1
Aldehyde Synthesis
O
NMe
OTBS
BnO
Me
Myers, JACS 1997, 119, 6496
Ph
OH
Me
Chiral enolate alkylation: see Lecture 23
O
NMe
OTBS
BnO
Me
Ph
OH
Me I
LDA
diastereoselection >20:1
H+ O O
Me
OBn
77%
O
OAcMe
OBn
DIBALH
SiMe3
BF3?OEt2O CH2
Me
OBn
H
cyclic oxo-carbenium ion addition: see Lecture 19
H
RCHO
Ac2O