Conformational Analysis of Medium Rings
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Conformational Analysis of Medium Rings And Applications to Total Synthesis A MacMillan Group Meeting Presented by Brian Kwan 6 June 2003 I. Introduction II. Eight–membered rings A. Conformational preferences B. Applications to total synthesis III. Ten–membered rings IV. Conclusion A. Conformational preferences B. Applications to total synthesis Lead references: Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 1981 Vedejs, E.; Dent III, W. H.; Gapinski, D. M.; McClure, C. K. J. Am. Chem. Soc. 1987, 109, 5437 Introduction ! Medium rings are defined as rings of eight to (usually) fourteen atoms. ! Seven membered rings are not included. The upper limit on the size of these rings is still a matter of debate. ! Medium rings obey different sets of rules regarding conformational analysis, than cyclohexanes, usually emphasizing avoidance of transannular nonbonded interactions. ! Simple computations (i.e. MM2) can usually predict the conformations of these rings with reasonable accuracy. ! Clark Still was the first to recognize this and make use of computation to predict the reactivity of medium ring compounds. He used starting materials, products, or intermediates to approximate transition states (according to the Hammond Postulate). ! The reactivity of eight– and ten– membered rings can be predicted qualitatively with the most reliability. Nine–membered rings or larger often require computational analysis.
Transcript of Conformational Analysis of Medium Rings
Conformational Analysis of Medium Rings
And Applications to Total Synthesis
A MacMillan Group Meeting
Presented by Brian Kwan
6 June 2003
I. Introduction
II. Eight–membered rings
A. Conformational preferences
B. Applications to total synthesis
III. Ten–membered rings
IV. Conclusion
A. Conformational preferences
B. Applications to total synthesis
Lead references:
Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 1981
Vedejs, E.; Dent III, W. H.; Gapinski, D. M.; McClure, C. K. J. Am. Chem. Soc. 1987, 109, 5437
Introduction
! Medium rings are defined as rings of eight to (usually) fourteen atoms.
! Seven membered rings are not included. The upper limit on the size of these ringsis still a matter of debate.
! Medium rings obey different sets of rules regarding conformational analysis, than cyclohexanes, usually emphasizing avoidance of transannular nonbonded interactions.
! Simple computations (i.e. MM2) can usually predict the conformations of these rings withreasonable accuracy.
! Clark Still was the first to recognize this and make use of computation to predictthe reactivity of medium ring compounds. He used starting materials, products, or intermediatesto approximate transition states (according to the Hammond Postulate).
! The reactivity of eight– and ten– membered rings can be predicted qualitatively with themost reliability. Nine–membered rings or larger often require computational analysis.
Conformational Preferences of Eight–Membered Rings
Diaxial interactions not necessarily paramount
! Lowest energy conformers of cyclooctane
HH
HH
HH
"Chair–Chair" (CC) Conformation
H H HH
"Boat–Boat" (BB) Conformation
HH
"Boat–Chair" (BC) Conformationenergetically preferred
! Effect of (methyl) substitution
Position Pseudo A value
kcal mol-1
1 1.8
2 2.8
3 > 4.5
4 – 0.3
5 6.1
Take home lesson: avoidance of unfavorable transannular interactions dictates conformational preferences
H
H H
Why is the corner position favored for substitution?
! Pseudoequatorial substitution
Me
H
AB
sight downA–B bond
H
Me H
H
gauche butane interaction
! Pseudoaxial substitution
H
Me
A
Bsight downA–B bond
H
HMe
H
H
H
gauche butane interaction
! Also, sp2 carbons will primarily go to the 3 or 7 positions
HH
OH
H H
transannular interactionrelieved
Enolate Alkylation of Methyloctanone Derivatives
Boat–chair model proves useful in prediction of stereoselectivity
! Alkylation of 2–Methylcyclooctanone
O
Me
O
Me
Mei) LiNi-Pr2ii) MeI
THF–60 ºC
dr > 95 : 5
! Analysis of enolate intermediates (MM2 minimization)
O
H
MeO
H
Me
Me
H
17.8 17.9
O
Me
HO
Me
H
Me
H
21.2 22.2
24.9
Me H HMe
O OMeH
22.7 19.2
H Me MeH
O OMeH
17.3
Conformers in C avoid transannular interaction in alkylation transition state
A C
B D
Me
Enolate Alkylation of Methyloctanone Derivatives
Different regioisomers lead to different diastereoselectivity
O OMei) LiNi-Pr2ii) MeI
THF–60 ºC
dr > 98 : 2
! Analysis of enolate intermediates (MM2 minimization)
O O
Me
H
18.2 18.6
19.2
O OMeH
17.2
Conformers in C avoid transannular interaction in alkylation transition state
A
B
Me Me
(+ 33% 2,3–Me2regioisomer)
Me
H H
Me
H
Me
H
O O
Me
H
16.7 16.9
C
H
Me Me
H
H
19.8
O OMeH
16.9
DMe
H
Me
! Alkylation of 3–methyloctanone
Conjugate Addition to Methylclooctenone
Planarity of !–system enforces different conformation
O O
Et2O
0 ºCdr > 99 : 1
! Two low energy conformers accessible
Me MeMeMe2CuLi
72%
O
HH
Me
H
O
HH
Me
H
19.5 kcal
21.0 kcal
O
MeMe
Conformers with pseudoaxial methyl groups are destabilized by > 4 kcal
Hydrogenation of !-Methylenemethylcyclooctanone
O
! Stereoelectronic effect explains unusual regioselectivity
MeMe
Assume:
1) LDA, THF, –78 ºC
2) PhSeSePh, Br2
O
MeMe
SePh
O
MeO3
Preparation of substrate yields unexpected regioisomer
1) Only protons perpendicular to the carbonyl "–system can be removed
2) Enolates with trans–cyclooctene resonance forms strongly disfavored
OH
Me
H
HA
HB
Me
remove HBremove HA
16.4 kcal
OH
Me HB
Me
not observed
OH
Me
H
HAMe
Alternate conformer:
O
Me
HA
HB
H
19.9 kcal
H MeH
remove HB
O
Me
HA
H MeH
Typical kinetic bias for formation of less substituted enolate: 1.5–3 kcal mol-1
H
Hydrogenation of !-Methylenemethylcyclooctanone
! Selectivity predicted by analysis of reactant conformers
O
Me Rh / Al2O3
Good selectivity for trans diastereomer observed
O
H2
> 99 %
O
MeMe
dr 10 : 1
H
Me
OMe
HO O
H
Me
Me
H
A B C DStrain
Energy / kcal
17.3 18.7 17.9 17.7
Boltzmann distribution predicts 70 : 30 dr
O
H
Me
C
Rh / Al2O3
H2 O
H
Me
MeH HO
Me
H
D
Rh / Al2O3
H2 O
Me
H
MeH
Peripheral appproach of H2 to olefin of C and D leads to severe nonbonded transannular interactions
O
Schreiber: X–Ray Analysis of Cyclooctadiene DerivativesTangible proof of conformational preferences
1) B2H6
2) H2O2, NaOH
OH
HO
1) (COCl)2, DMSO
2) Et3N
O
OO
89% overall
Et3N, TMSOTf
THF
> 99%TMSO
OTMS
1) CH2I2, Et2Zn
Et2O, O2
2) n-Bu4NF, THF77% overall HO
HO
HOHO
Amberlyst–15
C6H6
79% OO
Me
HMe
H
Schreiber, S. L.; Smith, D. B.; Schulte, G. J. Org. Chem. 1989, 54, 5994.
Kocienski: Intramolecular Mukaiyama AldolsConformational analysis applied to transition states
Cockerill, G. S.; Kocienski, P.; Treadgold, R. J. Chem. Soc. Perkin Trans. 1 1985, 2101.
OTMSMeMe
OR
OR
CH2Cl2–78!–25 ºC
OMeMe
OR1
R, R1 = Me 67%
R = –CH2CH2–, R1 = CH2CH2OH, 48%
! Explanation for dimunition in yield:
TMSO
O
R Me
Me
methyl groups occupycorner position
OTMS
CH2Cl2
–78 ºCO
OTiCl4
O
O
OH
Me Me MeMe
17%
TMSO
O
R
Me
MeH
H H
eclipsing, nonbondedinteractions disfavor
chair–boat TS
BF3•Et2O
Me
Application to Total Synthesis of (±)–PentaleneneEnolate alkylation exploited to set relative stereochemistry
Mehta, G.; Rao, K. W. J. Am. Chem. Soc. 1986, 108, 8015.
! Stereochemical rationale:
O
H
MeO
H
Me H
O
Me
O
Me
i) LHMDSii) Allyl bromide
THF
–78 ºC
dr > 95 : 5
Me Me
75%
Me
Me
Me
Me H
H
(±)–Pentalenene
Allyl bromideLHMDS
O
Me
Me
Me
O
Me
Me
!
Application to Formal Total Synthesis of (+)–Anatoxin AAsymmetric deprotonation used to desymmetrize intermediate
Aggarwal, V. K.; Humphries, P. S.; Fenwick A. Angew. Chem. Int. Ed. 1999, 38, 1985.
O
THF
–100 ºC
89%
N
CBzBn
OP(O)Ph2
N
CBzBn
89% ee
Ph NLi
Ph
Me Me
1)
2) (PhO)2POCl
BocN
Me
O
(±)–Anatoxin A
OHA
N
HB
H
HBn
CBz
O
N
CBzBn
remove HB
OHA
NH
Bn
CBz
! Rationale for selectivity in deprotonation:
Conformational Preferences of Ten–Membered Rings
Preferred conformers minimize eclipsing interactions
! Lowest energy conformers of cyclooctane
! Effect of (methyl) substitution
Position Pseudo A value
kcal mol-1
1 6.6
2 0.0
3 9.2
HH
HH H
H
HH
"Chair–Chair–Chair" (CCC) Conformation "Boat–Chair–Boat" (BCB) Conformationenergetically preferred
Conjugate Addition to Methylcyclodecenones
BCB ground state successfully predicts products
! Peripheral attack of methyl nucleophile gives observed selectivity
Me
OEt2O
0 ºC
Me2CuLi
76%Me
O
Me
dr 94 : 6
OEt2O
0 ºC
Me2CuLi
76%Me
O
Me
dr 94 : 6
Me
O
HH
H
Me
Me2CuLiO
H
H
Me
MeHMe
O
Me
OH
Me2CuLi
HMe
O
Me
HH
Me Me
H
O
HMe
only BCB enolate conformers contribute to lowest energy reaction pathway
Enolate Alkylation of Methylcyclodecanones
Regioisomers drastically affect diastereoselectivity
O
LiNi-Pr2
O
Me
O
HO
Me
H
O
O
Me
Me
MeI
placement of methyl in corner position leads to poor selectivity
! 7–Methyl derivative
dr 1 : 1
O
LiNi-Pr2
O
O
HO
O
O
Me
MeI
! 8–Methyl derivative
dr 86: 14
O
LiNi-Pr2
O
O
HO
O
O
Me
MeI
! 9–Methyl derivative
dr > 99 : 1
Me
Me
HMe
Me
Me
H
Proximity of methyl group to enolate directly proportional to diastereoselectivity
Me
Conjugate Addition to Methylcyclodecenoates
Planarity of !-system requires consideration of alternate conformers
! Energetically accessible conformers:
These conformations inhibit planarity of enone; loss in ester resonance costs ~ 10 kcal
BCB (25.6 kcal) BCC (24.9 kcal)
Conjugate Addition to Methylcyclodecenoates
Planarity of !-system requires consideration of alternate conformers
! Alternate conformers allowing planarity:
distorted BCB (25.9 kcal) 27.0 kcal
Conjugate Addition to Methylcyclodecenoates (cont'd)
distorted BCB (25.9 kcal)
O
OMe
O
O
Me
H
Me2CuLiO
O
Me
H
MeH
O
OMe
Me
dr 99 : 1
8–Me: dr 4 : 1
7–Me: dr 1 : 6! Same conformational bias predicts result of hydrogenation
O
OMe
O
O
Me
H
Rh / Al2O3O
O
Me
H
HMe
O
OMe
Me
dr 10 : 1
8–Me: dr 5 : 1
7–Me: dr 1 : 5
Me
Me
H2
Still: Total Synthesis of (±)–Periplanone B
Peripheral attack of reagents on BCB conformer provides stereocontrol
OOTBS
Me
Me
H
Me
Me
H
O
OTBS
KH, TBHP
THF, –20 ºC
74%
H
Me
Me
H
O
OTBSO
H2C SMe2
dr 4 : 1
DMSO–THF69%
H
Me
Me
H
OTBSO
O
1) TBAF, THF
2) CrO3•2 PyCH2Cl2
81% (2 steps)
OTBS
Me
Me
O
O
O
Me
Me
O
O
(±)–Periplanone B single diastereomer
Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493.
! Periplanone B: sex pheromone of American female cockroach
! Attempts to isolate from cockroaches: 75,000 virgin female cockroaches ! 200 µg periplanone B
Still: Total Synthesis of Eucannabinolide
Still, W. C. J. Am. Chem. Soc. 1983, 105, 625.
Me
BOMO
Me
OO
O
MeMe
O
BOMO
O
O
HH
NaBH4
MeOH
0 ºC
55%
MeMe
HO
BOMO
O
O
HH
H
MeO
OHO
H
OBOM
HMe
HHK2CO3
MeOH
61%Me
AcO
Me
O
O
OH
OHO
O
H
Keq = 9
O
Schreiber: Total Synthesis of Germacrene–D
Schreiber, S. L.; Hawley, R. C. Tetrahedron Lett. 1985, 26, 5971.
Conformational preference dictates regio– and stereo– selectivity of enolization
O
Me
Me
O H
Me
MeH
LHMDS
HMPA
O H
Me
MeH
AB C
! BCC conformation predicted by MM2 minimization
! Newman projection of A–B bond:
HH
antiperiplanar alignment set up for enolization
! Newman projection of C–B bond:
OH
H
H H
formation of enolate requires reorientationand additional strain due to gauche relationship
Total Synthesis of (+)–Dihydrocostunolide
Raucher, S.; Chi, K.–W.; Hwang, K.–J.; Burks, Jr., J. E. J. Org. Chem. 1986, 51, 5503.
Me
CO2Me
HMeMe
MeMe
MeMeO2C
mCPBA
MeMe
MeMeO2C
O
OsO4
MeMe Me
MeO2C
O
HOHO
H
MeMe Me
O
OHO
H
O
Me
Me
O
O
H
Me
Total Synthesis of Bicyclohumulenone
Takahashi, T.; Yamashita, Y.; Doi, T.; Tsuji, J. J. Org. Chem. 1989, 54, 4273.
Cyclopropanation directed by preferred enolate conformation
OMe
Me
Me
Me
Me
OMe
H2C S(O)Me2
DMSO, 0 ºC
Me
OMe
H
Me2(O)S
trans disposition of methyland H avoids eclipsing interactions
Me
OMe
HO
Me
Me
Me
Me
one diastereomer
Conclusion
! The conformational analysis of medium rings relies on mainly on avoidance of transannularstrain, and is usually more complicated than with cyclohexanes.
! Eight– and ten–membered rings often have predictable ground state conformations ("boat–chair" and "boat–chair–boat", respectively).
! When these ground state conformations do not accurately predict or explain reactivity,molecular modeling (on a simple level) can often predict reactivity in a semiquantitative fashion.
