J. Wzorek, D. A. Evans Medium and Large RingsJ. Wzorek, D. A. Evans Introduction Chem 106 A 1 A 2 A...
17
Chem 106 Conformational and Stereochemical Control of Medium to Large Rings Lecture Overview Can a macrocycle be conformationally defined and can their conformations be accurately predicted? Helpful References 1. Classics in Stereoselective Synthesis . Carreira, Erick M.; Kvaerno, Lisbet. Weinheim: Wiley-VCH, 2009. 1-16. 2. Still, Clark W.; Galynker, I. Tetrahedron 1981, 37, 3981-3996. 3. Deslongchamps, P. Pure and Appl. Chem. 1992, 64, 1831-1847. Medium and Large Rings Can a macrocycle be used as a stereocontrol element in stereoselective synthesis? O O Me O O O Me Me Me Me O Me Amphidinolide X O O OH Me Me O Me OH Me Me H Me S N Me O O OH Me Me O Me OH Me Me H Me S N Me O DMDO Epothilone B (anticancer) 12,13-Desoxyepothilone B Selectivity? Conformational Control Elements Macrocyclic Stereocontrol intramolecular reactions intermolecular reactions cyclooctane cyclodecane >10 membered rings O O O OMe O OH Me OH H O Me Me Me Me OH O O HO Me Miyakolide macrocyclic precursor DMDO = Me Me O O J. Wzorek, D. A. Evans
Transcript of J. Wzorek, D. A. Evans Medium and Large RingsJ. Wzorek, D. A. Evans Introduction Chem 106 A 1 A 2 A...
Chem 106
Conformational and Stereochemical Control of Medium to Large Rings
Lecture Overview
§ Can a macrocycle be conformationally defined and can their conformations be accurately predicted?
Helpful References 1. Classics in Stereoselective Synthesis. Carreira, Erick M.; Kvaerno, Lisbet. Weinheim: Wiley-VCH, 2009. 1-16. 2. Still, Clark W.; Galynker, I. Tetrahedron 1981, 37, 3981-3996. 3. Deslongchamps, P. Pure and Appl. Chem. 1992, 64, 1831-1847.
Medium and Large Rings
§ Can a macrocycle be used as a stereocontrol element in stereoselective synthesis?
O
O Me
OO
O
Me
Me
Me
Me
OMe
Amphidinolide X
O OOH
Me
Me
O
Me
OHMe
Me
HMe
S
NMe
O OOH
Me
Me
O
Me
OHMe
Me
HMe
S
NMe
ODMDO
Epothilone B(anticancer)
12,13-Desoxyepothilone B
Selectivity?
ConformationalControlElements
MacrocyclicStereocontrol
intramolecularreactions
intermolecularreactions
cyclooctane cyclodecane
>10 membered ringsO
O
O OMe
O
OHMe
OH
H
OMe
Me
Me
MeOHO
OHO
Me
Miyakolide macrocyclic precursor
DMDO =Me Me
O O
J. Wzorek, D. A. Evans
Chem 106 Introduction
A2 A3A1 A4k21 k34k23
k32
Slow SlowFast
Fast
§ Consider the following kinetic scheme:
§ The above equation describes two quickly interconverting species (conformations of a single molecule for instance) which react at different rates to form product
§ So why can we apply conformational analysis (a ground state phenomenon) to study reactivity?
§ We must make an assumption that the relative position of ground state conformers also translates to the transition state
O
Me
Me2CuLi O
Me
Me
>99% anti
1 2§ The above reaction (which we will return to) involves a selective, exothermic process
O
Me
Me
2
O
Me
Me
2-syn
O
Me1-conf(a)
O
Me1-conf(b)
§ The reaction with the lower absolute barrier, will lead to the major product under this scheme (thus A4 is preferred)
J. Wzorek, D. A. Evans
Chem 106 Introduction
“Erythromycin, with all of our advantages, looks at present quite hopelessly complex, particularly in view of its plethora of asymmetric centers.”"- R. B. Woodward, Perspectives in Org. Chem., 1956
O
O
MeO
Me
OHR
MeEt
MeOH
Me
OHMeOH
R = H, Erythronolide BR = OH, Erythronolide A
O
O
OMe
Et
MeOH
Me
OHMeOH
HOMe
Pikromycin
O
O
MeO
Me
OHHOMeEt
MeOH
O
MeOH
MeO
Me
Me
OHMeO
H
O
Me
NMe2
OH
Erythromycin
§ The discovery of pikromycin, the first macrolide antibiotic, introduced additional complexity to synthetic organic chemists
§ Related natural products erythromycin and aglycons known as the erythronolides became ambitious targets for synthesis
§ How did chemists tackle these challenges for synthesis? § Concavity/convexity was the dominant form of stereocontrol § Often bicyclic systems were used in this capacity, even if they were not present in the final target
H
H
HH
nucnuc
nuc
convex facepreferred
concave face
§ This approach is exemplified by Woodward and coworkers synthesis of erythronolide A
§ Here, a single dithioacetal is used to direct a reduction and oxidation step to secure the desired stereochemistry
Erythronolide A
S SH
OOBn
1) NaBH4
2) MOMI, KH
S SH
OBnOMOM
1) OsO4
2) DMP, TsOH
S SH
OOMOMO
MeMeOBn
steps
J. Wzorek, D. A. Evans
Chem 106 Clark Still: Peripheral Attack Hypothesis
§ Still helped deconvolute the seemingly intractable problems associated with medium and large ring stereocontrol § Consider the following examples:
O
Me
O
Me
Me
LDA, MeI
>95% anti
O O
Me
LDA, MeI
>98% syn
Me Me
§ What sort of principles can we apply to these systems to explain the outcome?
§ 1946 - Born (Augusta, GA) § 1972 - Ph.D. (Emory, Goldsmith) § 1973 - Postdoc (Princeton, Wipke) § 1974 - Postdoc (Columbia, Stork)
§ Career highlights: Flash chromatography (>7400 citations), Macromodel (>2700 citations), Solvation in molecular mechanics (>1500 citations), Monte Carlo searching (>650 citations), Still-Gennari modification of HWE (>650 citations)
§ W. Clark Still
Still, W. C. JACS, 1979, 101, 2493-2495.
“This principle of peripheral attack appears to be general as a strategy for stereochemical control in the synthesis and modification of germacranes and related medium-ring compounds. It does, however, require knowledge of the conformation of the starting olefin.”
§ Peripheral attack: reagents prefer to attack medium-sized rings from the exterior rather than the interior
§ Let us now consider the following rings and their canonical conformations:
cyclooctane cyclodecane
J. Wzorek, D. A. Evans
Chem 106 Cyclooctane
chair boat
or
chair chair
or
boat boatcyclooctane
“Cyclooctane is unquestionably the conformationally most complex cycloalkane owing to the existence of so many forms of comparable energy…”"-Hendrickson, J. B. JACS 1967, 89, 7036-7043.""
Computed energies and conformations: B3LYP/6-31G*
Erel = 3.4 kcal/mol
boat-boat
§ Still argues that torsional effects contribute to the relatively small 0.5 kcal/mol difference between conformers
destabilizing transannularnonbonded interactions!
chair-boat
ΔGrel = 0 kcal/mol
ΔGrel = 0.52 kcal/mol
chair-chair
chair-boat
chair-chair
J. Wzorek, D. A. Evans
Chem 106 Cyclooctane
§ With our newfound understanding of the dominant cyclooctane conformations, let us revisit a reaction that was presented earlier
O
Me
O
Me
Me
LDA, MeI
>95% anti
§ Placing the enolate within the boat relieves transannular nonbonded interactions § For this reason, sp2 hybridized carbon atoms should generally be placed at position 3
Computed energies and conformations: B3LYP/6-31G*
§ Both enolates are very similar in energy, and they both lead to the same anti product § Which conformer is most likely to proceed through the lowest energy transition state?
§ A “thought experiment”: provide a rational for the depicted stereochemical outcome
§ Step 1: consider the conformation of the substrate § Both cis double bonds are placed in a position that relieves transannular strain
Me
Me
Hg(OAc)2, H2O
MeMe Hg
OH
OAc
H
Me Me
Hg
H
OAcOH
H
H
H
H2O
Me
H
Me Me MeHgH
OAc– OAc
Hg(OAc)2
LDA
OLi
Me
OLiMe
H
OLi
MeHor
MeI
11
33
(enantiomer forsimplicity)
ΔGrel = 0.50 kcal/mol
Enolate 1
ΔGrel = 0 kcal/mol
Enolate 2
J. Wzorek, D. A. Evans
Chem 106 Cyclooctenone
§ Cyclooctenone differs in conformation from what one might predict based upon the previous examples § Consider the following reaction:
O
Me
Me2CuLi O
Me
Me
>99% anti
§ Placing unsaturation in the 2-3 positions relieves transannular nonbonded interactions § Is there a problem with this conformation?
insufficient overlapof π-system
§ Placing enone at the 4-5-6 positions affords proper overlap
23
O
Me
H
45
6
45
6
O
HH
Me
H
45
6
O
HH
Me
H
O "Rh", H2 O
Me
Me
91% anti
Me
§ Now consider the hydrogenation of an exocyclic enone
Me
O
CH2O
CH2H
Me
CH2
O
Me
HCH2
O
H
Me
§ Why does the relative stereochemistry of the product predominate?
§ Consider the relevant conformations:
Nuc
(exo-faceattack)
Nuc
(exo-faceattack)
Computed conformations: B3LYP/6-31G*
J. Wzorek, D. A. Evans
Chem 106 Cyclodecane
§ Macrocyles tend to minimize transannular non-bonded interactions and high-energy torsional arrangements
cyclodecane
or
boatchair
boat chairchair
chair
§ While many conformations for cyclodecane exist, two commonly depicted ones are drawn above
§ Consider this dimethylcuprate addition:
Computed energies and conformations: B3LYP/6-31G*
ΔGrel = 0 kcal/mol
boat-chair-boat
ΔGrel = 6.5 kcal/mol
chair-chair-chair
ΔGrel = 1.4 kcal/mol
chair-chair-boat
eclipsed!(4-total)
J. Wzorek, D. A. Evans
OH
Me
ΔGrel = 0.38 kcal/mol
Equatorial Methyl
OMe
Me2CuLi
OMe
Me
94% anti
O
OZ E
Chem 106 Macrocyclic Stereocontrol in Synthesis
O
Me
Me
O
OO
H H
O
OMe
Me
H2C
Periplanone B(cockroach sex pheromone)
§ Originally isolated in 1952
Bn NMe
MeMe OHTriton B:
H
OOTBS
HH
PgOMe
MeH
t-BuOOHTriton B
OOTBS
Me
Me
PgO
O
66%
Still, W. C. JACS, 1979, 101, 2493-2495.
§ To this point, we have discussed the conformational control of 8 and 10-membered rings and the possibility of achieving high selectivity within the context of a given reaction § What about larger rings?
H
OOTBS
HH
PgOMe
MeH
O SMe
Me
75%
OTBS
Me
Me
PgO
O
O
diastereomeric toperiplanone!
§ At this point, the synthesis needed to be reconsidered § How might they obtain the desired stereochemistry?
O
Me
Me
PgOPg = O Me
Et
OOTBS
Me
Me
PgO
Li1)
2) KH, 18-C-6;TMSCl; m-CPBA3) TBSCl
anionicoxy-Cope
J. Wzorek, D. A. Evans
§ General conformational control elements are listed above § Empirically it can be shown that, in large rings especially, acyclic conformational analysis concepts generally hold
H
H MeMe
HHMe
H HMe
HH
gauche anti
H
MeR
H
H
H
MeR Me
H H
O
O RR
O
ROH
HR
R R
O OH
A(1,3)-strainminimization
A(1,2)-strainminimization
dipoleminimization
hydrogenbonding
stereoelectroniceffects
RR
HH
H
HRH
HR
H
Hsyn pentane
Chem 106 Macrocyclic Conformational Control
O O
Me
OO
O
Me
Me
Me
O
MeHH
O OO
O
O
Me
Me
MeMe
O
Me
H HO OO
O
O
Me
Me
Me
O
MeHH
H H
2
3
4
several analogues synthesized
Computed energies and conformations: B3LYP/6-31G*
§ Two lowest energy conformations (result of semi-empirical PM3 Monte Carlo conformational search and further DFT optimization)
§ Indeed, larger rings may be conformationally defined if requisite controlling elements are present
HT29LXFA 629LMAXF 401NLMEXF 462NL
Cell line Type
colorectallungbreastmelanoma
IC50 (µg/mL)1 2 3 4
5.15 >10 3.70 >107.89 >10 8.58 4.297.33 >10
>105.95>106.90
>10>10
§ Analysis of amphidinolide X and analogues also reveals that stereochemical components may stabilize a given conformation
A(1,3)-minimized
A(1,3)-minimized
pseudoequat.
pseudoequat.
pseudoequat.
Fürstner, A. Chem. Eur. J. 2009, 15, 4030-4043.
O O
Me
OO
O
Me
Me
MeMe
O
Me
Amphidinolide X (1)(anticancer)
ΔGrel = 0 kcal/molMajor Conformation
ΔGrel = 4.5 kcal/molMinor Conformation
pseudoaxial
pseudoaxial
J. Wzorek, D. A. Evans
Chem 106 Large Ring Conformational Control Elements Wzorek, Kwan, Evans
Danishefsky, S. J. Tet. Lett. 2001, 6785-6787.
O OOH
Me
Me
O
Me
OHMe
Me
HMe
S
NMe
O OOH
Me
Me
O
Me
OHMe
Me
HMe
S
NMe
ODMDO100%
dr = >25:1
Epothilone B(anticancer)
12,13-Desoxyepothilone B
Reagent
§ How could we go about predicting the stereoselectivity of this reaction? (especially in the synthesis planning stage)
B3LYP/6-31g(d), SMD implicit solv
§ Now identify the next lowest energy conformer that leads to the opposite diastereochemical outcome
Reagent
MeH
MeH
§ How close are the two conformations that lead to opposite stereochemical outcomes in energy?
Relative Energy3.23 kcal/mol
(DFT, solvation)
§ Compute the lowest energy conformation:
preferred
Chem 106 A Protocol to Analyze and “Predict” Stereochemical Outcomes
peripheral attack leads !to major diastereomer!
+3.23kcal/mol
peripheral attack leads !to minor diastereomer!
O OOH
Me
Me
O
Me
OHMe
Me
HMe
S
NMe
O OOH
Me
Me
O
Me
OHMe
Me
HMe
S
NMe
ODMDO100%
dr = >25:1
Epothilone B(anticancer)
12,13-Desoxyepothilone B
0
2
4
6
8
10
12
0 10 20 30 40 50 60 70 80
higher energy structures rejected
0
2
4
6
8
10
mol
ecul
ar m
echa
nics
ene
rgy
(kca
l/mol
)
number of structures
+1 starting structure +2 061 476 candidate structures generated -1 884 397 rejected by ring closure
-57 080 rejected by van der Waals 120 000 candidate structures
+120 000 candidate structures -111 360 duplicates rejected
8 640 unique structures found
global minimumfor molecular mechanics
§ Output from the Monte Carlo conformational search § Done with many software packages (for example, Macromodel)
§ Choose a collection of lowest energy conformers that lead to different diastereochemical outcomes(apply peripheral attack) § After DFT optimization, an Erel of 3.23 kcal/mol was established
Wzorek, Kwan, Evans
Chem 106 How well does the Peripheral Attack Hypothesis Work?
O
Me O
OMe
O
Me
O
Me O
O
Me O
Me
O
Me
OMe
Still et al.cuprate addition
Still et al.cuprate addition
Still et al.cuprate addition
Still et al.hydrogenation
H
Hi-Pr
Me Me
H
H
Me OHcladiell-11-ene-3,6,7-
trioldihydroxylation
O
H
Hi-Pr
Me Me
H
H
Ocladiella-6,11-diene-
3-olketone addition
O
H
Hi-Pr
Me
H
H
sclerophytin Aepoxidation
O
O
OOTBS
i-Pr
periplanone Bnuc. epoxidation
Still et al.cuprate addition
Still et al.cuprate addition
Still et al.cuprate addition
O
Me
Me
O
OBnMe
lonomycin Aepoxidation
fluvirucin B2-5hydrogenation
HN
Et
O
EtO
Et
TBS
fluvirucin B1hydrogenation
HN
Et
O
EtO
Et
OAcO Me
OAc
HN
O
CF3
fluvirucin B2-5hydrogenation
HN
OTBS
EtO
Et
Et
O
O
MeO
OMe
Me
MeO
Me
Me
O
O
MeMe
oleandolidenuc. epoxidation
MeH
O
O
MeOTBS
OH
Me
MeO
MeO
Me
MeMe
Me
oleandolideepoxidation
O
MeO
O
Me
OMe
Me
dihydrocineromycinhydride reduction
O
OH
O
O MeMe
MeMe
Me
OHO
Me
EtMe
erythronolide B hydroboration
BzNO
HBn
Me
TMS
OAc
MeOTBS
epi-cytochalasin Depoxidation
TES
O
OHO MeMe
O
Me OH
Me
Me
H
MeS
N
Me
epothilone Bepoxidation
O
O
Me
Me
Et
OMe
OHOH
Me
3-deoxyrosaranolideepoxidation
O O
O
O
OMe
Me Me
OMe
Porco et al.epoxidation
Me
OMe
TBSO
Me
longithorone ADiels-Alder
O O
O
O
OMe
Me Me
OMe
Porco et al.epoxidation
Me
Me
O
TBSOMe
O
Me
O
MeO NH
O
Me
lankacidin Chydride reduction
NO
O
O
Me
MeO
OMe
OMe
OTBSMeO
MeOTBDPS
monorhizopodinhydride reduction
O OMe
OTBSO
Me
OMe
MeO
Me Me
TBS
dictyostatinhydride reduction
O OMe
O
MeMe
O
Me Me
Still et al.hydroboration
O
O
MeO
Me
Me O
H
H
O
neopeltolidehydrogenation
Me
OMe
9-deoxy-englerin Aepoxidation
O
O
OMe
MeO2C OH
O
O
OMe
MeO2C OH
bielschowskysinhydride reduction
Me
AcO
OH
H
MeHO Me
Blume et al.hydrogenation
TBS
bielschowskysinhydride reduction
§ Over 30 literature examples of intermolecular reactions with chiral macrocycles were studied
Wzorek, Kwan, Evans
Chem 106 Results
§ Accuracy of predicting the major product
§ Accuracy by reaction type
§ Accuracy of predicting the level of selectivity
§ Conclusions § The peripheral attack model is moderately successful § This is not surprising because it relies upon the translation of ground-state conformational preferences to the transition state § Epoxidation reactions are most likely to be accurately predicted, in the absence of a directing group effect
Wzorek, Evans, Kwan
0.3 1.00 Erel (kcal/mol)
0.3 1.0 Erel (kcal/mol)
major product predicted accurately
major productprediction
selectivityprediction
0
selectivity correlates well (Erel > 1 kcal/mol)
§ Major product prediction
§ Selectivity prediction
0.3 1.00 Erel (kcal/mol)
0.3 1.0 Erel (kcal/mol)
major product predicted accurately
major productprediction
selectivityprediction
0
selectivity correlates well (Erel > 1 kcal/mol)
§ The take away message: perform the conformational analysis, and be wary of a modest Erel (or better yet, compute the TS!)
Chem 106 Intramolecular Reactions: Diels-Alder
§ To this point, we have discussed intermolecular reactions involving medium and large rings § Now, let us transition to the study of intramolecular reactions
“[Macrocycles have] a high degree of conformational restriction and as a result, proximity effects become operative and very often, these effects will increase the rate of one reaction and slow down others which are normally competing.”"-Pierre Deslongchamps, Pure and Appl. Chem. 1992, 64, 1831-1847.
J. Wzorek, D. A. Evans
§ An example from Deslongchamps toward hydroxyaphidicolins"
R
Me
O
MeTIPSO
PhMe, 230°C
NEt3
H
Me
H
R = CHO
O
MeTIPSO
**
* *
HO
* *
81%
1 2
Deslongchamps, P. JOC, 2000, 65, 7070-7074
§ How should we approach this problem?"
§ Second, orient the diene such that A(1,3)-strain is minimized"
R
RTIPSO
Me
place substituentsin pseudo equat.positions
RTIPSO
Me
H A(1,3)-minimized
§ Draw the dienophile such that the a pseudo chair conformation still exists (also in this case an endo Diels-Alder TS is probably preferred)"
Me CHO
TIPSO
Me
O
[4+2]
TIPSO
Me
Me
H
CHO
H
O
TIPSO
Me
Me
H H
OO
H
H
H
O
MeTIPSO
HO
H
Me
**
**
Chem 106 Access to Linear 6-6-6 Systems J. Wzorek, D. A. Evans § A transannular cascade inspired by the tetracyclines § Tetracycline:
§ The proposed transformations
§ The transannular Michael addition
§ In practice:
OBn
SEMO MeO
Y
NO
OBnONO
Xenolization
OBn
SEMO MeO
Y
NO
OBnONO
X
M
Me
OH O OH O
OH
NH2
O
NMe2
OH
HHOH
D C B A
linear 6-6-6 system
C14-macrocycle
[4+2]?
12a
Michael addition
OBn
SEMO MeOH
Y
NO
OBnONO
XH
OH
C12a-[O]
OBn
SEMO MeO
Y
NO
OBnONO
XH
HOBn
SEMO MeO
Y
NO
OBnONO
X
OBn
SEMO MeOH
Y
NO
OBnONO
XH
H
5a11a
4a12a
alkylation
§ The Michael addition
§ What does the following conformer distribution and product ratio suggest about this reaction?
OBn
SEMO MeO
OTBS
NO
OBnONO
4
OBn
SEMO MeO
OTBS
NO
OBnONO
H
H
TBSO
O NON
OBn
OCuO
H
Me
OBnO
Ln OAcSEM
O NOBn
OSEMMe
O
HOTBS
ON
OBnOCuLnOAc
favored conformer(predicted)
OBn
SEMO MeO
OTBS
NO
OBnONO
H
38%(55% brsm)
HOBn
SEMO MeO
OTBS
NO
OBnONO
4 Cu(OAc)2 4
incorrect diastereomer(exclusively)
proceeds to product
+1.4 kcal
O NOMe
MOMOMe
O
HOTBS
ON
OMeOCu
XLn
TBSO
O NON
OMe
OCu
X LnO
H
Me
OMOM
MeO
Curtin-Hammett kinetics!
Chem 106 Access to Linear 6-6-6 Systems J. Wzorek, D. A. Evans
OHMe
OOH OH
H
OH
NMe2
O
OHH
O
NH2
tetracyclineOBn O
NO
OTBS
OBn
SEMOOMe
NO
H
H
product from Michael reaction
?
+4.0 kcal
O NOMe
MOMOMe
O
OTBSH
ON
OMeOCu
XLn
H
O NON
OMe
OCu
X LnO
OTBS
Me
OMOM
MeO
proceeds to product
+1.4 kcal
O NOMe
MOMOMe
O
HOTBS
ON
OMeOCu
XLn
TBSO
O NON
OMe
OCu
X LnO
H
Me
OMOM
MeO
§ The opposite diastereomer is a “matched” case
§ In practice:
OBn
SEMO MeO
OTBS
NO
OBnONO OBn
SEMO MeO
OTBS
NO
OBnONO
H
H
4
83%
Cu(OAc)2 44a
§ Remaining obstacles en route to tetracycline § Can TA bond-forming reactions be merged?
4a
OBn
SEMO MeO
OTBS
NO
OBnONO
5 mol % Cu(OAc)2
Ce(OAc)3, O2, MeOH
BnO
SEMO MeOH
OTBS
NO
OBnONOOMe
H
H
OH60%
single diastereomer
12a11a5a
§ A Ce(III)-mediated TA bond-forming reaction
C4-pseudoaxial[O]O
N
OTBS
HH
M
11a5aCeCl3, O2;
Me2S12a
BnO O
NO
OTBS
OBn
SEMOOH
Me
NO
H
OHOBn O
NO
OTBS
OBn
SEMOO
Me
NO
H
H 60%single diastereomer
isoxazole substitution
oxidation;reduction
O NBnO
OSEM
O
OTBSH
ON
OBnHO
HHMe
CeCl3
ceriumcoordination
HOMe
BnO O
NO
OTBS
OBn
SEMOOH
Me
NO
H
HHOMe
§ A model for the oxidation:
