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.
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Conformational Preferences of EightÐMembered Rings · Cyclopropanation directed by preferred enolate conformation O Me Me Me Me Me O Me H2CS(O)Me2 DMSO, 0 ¼C Me O Me H Me2(O)S trans
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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 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
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.