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Synthetic studies of rigid tetracyclic oxanorbornanes. Regioselective reductive Heck arylation of a tetracyclic scaffold

Wållberg, Andreas LU (2000)
Abstract
Rigid or conformationally restricted compounds are intresting from a pharmacological point of view since they do not have to pay the entropy penalty paid by more flexible molecules in binding to e.g. a protein. In this thesis, synthetic transformations of a rigid tetracyclic oxanorbornene scaffold are described, yielding novel compounds with low molecular weight, rigid framework and high oxygen content, which confers reasonable water solubility.



Reductive Heck arylation performed on the tetracyclic oxanorbornene scaffold yielded the exo-arylsubstituted oxanorbornane as one single regioisomer. Because of the expected exo face selectivity the reaction is both regioselective and stereoselective. The regioselectivity... (More)
Rigid or conformationally restricted compounds are intresting from a pharmacological point of view since they do not have to pay the entropy penalty paid by more flexible molecules in binding to e.g. a protein. In this thesis, synthetic transformations of a rigid tetracyclic oxanorbornene scaffold are described, yielding novel compounds with low molecular weight, rigid framework and high oxygen content, which confers reasonable water solubility.



Reductive Heck arylation performed on the tetracyclic oxanorbornene scaffold yielded the exo-arylsubstituted oxanorbornane as one single regioisomer. Because of the expected exo face selectivity the reaction is both regioselective and stereoselective. The regioselectivity appeared to be independent of the aryliodide used; only one regioisomer was detected when the reaction was performed with 2-, 3-, and 4-iodophenols, 2-iodothiophene, 2-chloro-5-iodopyridine and methyl 4-iodobenzoic ester. However, when the oxanorbornene is substituted with an electron withdrawing group the regioselectivity is not complete and also to some extent dependent of the aryliodide used. Hence, a tetracycle substituted with an -OAc group at C-1 gave an 84:16 ratio of regioisomers when the reaction was performed with 4-iodophenol, 97:3 when the Heck arylation was performed with iodobenzene and as one single isomer when the reaction was performed with methyl 4-iodobenzoic acid. It appears that electron rich aryl iodides result in lower regioselectivity and electron poor higher. Though the regioselectivities to some extent are dependent of electronic factors, the major cause are probably steric. Steric repulsion in the transition state between the aryl group and one of the protons alfa to the sulfur atom (H-10) might account for the regiochemical outcome.



The high density of oxygen atoms in the tetracyclic scaffold was further increased by dihydroxylation of the double bond. This structure was used as the polar "head" in synthesis of alipid analog, which would have physical properties similar to glycolipids. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Classon, Björn, Huddinge
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Organic chemistry, oxanorbornane, rigid, Heck-reaction, regioselective, Organisk kemi
pages
58 pages
publisher
Organic Chemistry, Lund University
defense location
Kemicentrum sal C
defense date
2000-10-27 10:15
external identifiers
  • other:LUTKDH/(TKOK-1048)/1-58/(2000)
ISBN
91-7874-079-7
language
English
LU publication?
yes
id
05f68c36-3d9a-4eed-baf3-1a27ec6149de (old id 40862)
date added to LUP
2007-08-01 16:45:25
date last changed
2016-09-19 08:45:11
@phdthesis{05f68c36-3d9a-4eed-baf3-1a27ec6149de,
  abstract     = {Rigid or conformationally restricted compounds are intresting from a pharmacological point of view since they do not have to pay the entropy penalty paid by more flexible molecules in binding to e.g. a protein. In this thesis, synthetic transformations of a rigid tetracyclic oxanorbornene scaffold are described, yielding novel compounds with low molecular weight, rigid framework and high oxygen content, which confers reasonable water solubility.<br/><br>
<br/><br>
Reductive Heck arylation performed on the tetracyclic oxanorbornene scaffold yielded the exo-arylsubstituted oxanorbornane as one single regioisomer. Because of the expected exo face selectivity the reaction is both regioselective and stereoselective. The regioselectivity appeared to be independent of the aryliodide used; only one regioisomer was detected when the reaction was performed with 2-, 3-, and 4-iodophenols, 2-iodothiophene, 2-chloro-5-iodopyridine and methyl 4-iodobenzoic ester. However, when the oxanorbornene is substituted with an electron withdrawing group the regioselectivity is not complete and also to some extent dependent of the aryliodide used. Hence, a tetracycle substituted with an -OAc group at C-1 gave an 84:16 ratio of regioisomers when the reaction was performed with 4-iodophenol, 97:3 when the Heck arylation was performed with iodobenzene and as one single isomer when the reaction was performed with methyl 4-iodobenzoic acid. It appears that electron rich aryl iodides result in lower regioselectivity and electron poor higher. Though the regioselectivities to some extent are dependent of electronic factors, the major cause are probably steric. Steric repulsion in the transition state between the aryl group and one of the protons alfa to the sulfur atom (H-10) might account for the regiochemical outcome.<br/><br>
<br/><br>
The high density of oxygen atoms in the tetracyclic scaffold was further increased by dihydroxylation of the double bond. This structure was used as the polar "head" in synthesis of alipid analog, which would have physical properties similar to glycolipids.},
  author       = {Wållberg, Andreas},
  isbn         = {91-7874-079-7},
  keyword      = {Organic chemistry,oxanorbornane,rigid,Heck-reaction,regioselective,Organisk kemi},
  language     = {eng},
  pages        = {58},
  publisher    = {Organic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Synthetic studies of rigid tetracyclic oxanorbornanes. Regioselective reductive Heck arylation of a tetracyclic scaffold},
  year         = {2000},
}