j. wzorek, d. a. evans medium and large ringsj. wzorek, d. a. evans introduction chem 106 a 1 a 2 a...
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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!)
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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
**
**
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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!
![Page 17: J. Wzorek, D. A. Evans Medium and Large RingsJ. Wzorek, D. A. Evans Introduction Chem 106 A 1 A 2 A 3 A 4 k 21 k 23 k 34 k 32 Slow Fast Slow Fast! Consider the following kinetic scheme:](https://reader033.vdocuments.us/reader033/viewer/2022053112/6088a031990fca61300f4dfb/html5/thumbnails/17.jpg)
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: