The chemistry of L-Ascorbic acid derivatives in the asymmetric

245 Pages·2005·7.27 MB·English

by  Ayodele O. Olabisi

The Chemistry of L-Ascorbic Acid Derivatives in the Asymmetric Synthesis of C2- and
C3- Substituted Aldono-γ-lactones

A Dissertation by

Ayodele O. Olabisi

M. S., Wichita State University, 2004
B. S., Wichita State University, 1999

Submitted to the College of Liberal Arts and Sciences
and the Faculty of the Graduate School of
Wichita State University in partial fulfillment of
the requirements for the Degree of
Doctor of Philosophy

August 2005
The Chemistry of L-Ascorbic Acid Derivatives in the Asymmetric Synthesis of C2- and
C3- Substituted Aldono-γ-lactones

I have examined the final copy of this dissertation for form and content and recommend
that it be accepted in partial fulfillment of the requirements for the degree of Doctor of
Philosophy, with a major in Chemistry.

______________________________________
Professor Kandatege Wimalasena, Committee Chair

We have read this dissertation
and recommend its acceptance:

__________________________________________
Professor William C. Groutas, Committee Member

__________________________________________
Professor Ram P. Singhal, Committee Member

__________________________________________
Professor Francis D’Souza, Committee Member

__________________________________________
Professor George R. Bousfield, Committee Member

Accepted for the College of Liberal Arts and Sciences

__________________________________________
Dr. William Bischoff, Dean

Accepted for the Graduate School

__________________________________________
Dr. Susan K. Kovar, Dean
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DEDICATION

To My Parents
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ACKNOWLEDMENTS

I wish to express my deepest and sincerest appreciation to my advisor, Dr
Kandatege Wimalasena for his positive guidance, enlightened mentoring and
encouragement. His passion for the subject matter has greatly improved my knowledge
and interest. My sincere appreciation extends to Dr. Shyamali Wimalasena and Dr.
Mathew Mahindaratne, who helped me with my initial research training and their
assistance in the preparation of my manuscripts. I would also like to give my appreciation
to my other committee members; Dr. William C. Groutas, Dr. Ram Singhal, Dr. Francis
D’Souza and Dr. George Bousfield for their significant recommendations.
I wish to express my heartfelt gratitude to my colleagues, Dr. Srimevan
Wanduragala, Dr. Mehul Bhakta, Dr. Rohan Perera and Samantha Ranaweera, for their
invaluable friendship. It was a joy to work with them.
Finally, I acknowledge some of the many people without whom I could not have
completed my education; my wife, Monica, and children, Angela, Dominique and Folade
for their love, support and encouragement even at times of difficulty. My special
gratitude deeply extends to my parents and sisters for their incomparable love, support
and prayers.
This work was supported by a grant from the National Institutes of Health (NS 39423).

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ABSTRACT

The antioxidant and redox properties of L-ascorbic acid are closely associated
with the electron rich 2, 3-enediol moiety of the molecule and therefore selective
functionalization of the 2- and 3-OH groups is essential for the detailed structure-activity
studies. Reactions of 5- and 6-OH protected ascorbic acid with electrophilic reagents
exclusively produce the corresponding 3-O-alkylated products under mild basic
conditions due to the high nucleophilicity of the C-3-OH. Based on the density functional
theory (B3LYP) electron density calculations, a novel and general method was devised
for the direct alkylation of the 2-OH group of ascorbic acid with complete regio- and
chemo-selectivity. A complete spectroscopic analysis of two complementary series of 2-
O-acetyl-3-O-alkyl and 2-O-alkyl-3-O-acetyl ascorbic acid derivatives was carried out to
define their spectroscopic characteristics and to resolve common inconsistencies in the
literature.
The asymmetric approach to the synthesis of natural products or other
biologically active compounds is impeded by low abundance of natural sources as well as
a limited number of efficient synthetic methods. Nevertheless, carbohydrate-based
systems such as the aldono-1,4-lactones (also known as aldono-γ-lactones) which
generate a host of chiral compounds have been particularly rewarding in this respect. This
study shows a practical approach using 5,6-O-isopropylidene-L-ascorbic acid (ketal of L-
ascorbic acid) as a single common starting material for facile asymmetric synthesis of
protected, optically pure and functionalized aldono-1,4-lactones derivatives, valuable in
the synthesis of derivatives of various pharmacologically active agents for structure-
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activity studies. The practicality of this new approach is demonstrated by the convenient
synthesis of a series of thermal Claisen-rearranged products of 5,6-O-isopropylidene-3-
O-allyl-L-ascorbic acid and 5,6-O-isopropylidene-2-O-allyl-L-ascorbic acid as the
corresponding 5,6-O-isopropylidene-2-allyl-3-keto-L-galactono-γ-lactone and 5,6-O-
isopropylidene-3-allyl-2-keto-L-galactono-γ-lactone respectively. The synthetic routes
are economical, efficient, diastereospecific, and proceed in high yields.

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TABLE OF CONTENTS

CHAPTER 1.......................................................................................................................1
INTRODUCTION..........................................................................................................1
CHAPTER 2.......................................................................................................................4
BACKGROUND AND SIGNIFICANCE......................................................................4
2.1 Discovery and History of L-Ascorbic Acid..........................................................4
2.2 Sources of L-Ascorbic Acid................................................................................10
2.3 Tissue Distribution of L-Ascorbic acid...............................................................12
2.4 Biosynthesis of L-Ascorbic Acid in Animals.....................................................14
2.5 Biosynthesis of L-Ascorbic Acid in Plants.........................................................18
2.6 Commercial Scale Synthesis of L-Ascorbic acid................................................22
2.7 Biological Functions of L-Ascorbic Acid...........................................................26
2.7.1 L-Ascorbic Acid as an Enzyme Cofactor....................................................26
2.7.2 L-Ascorbic Acid in Electron Transport.......................................................31
2.7.3 L-Ascorbic Acid as an Antioxidant in Biological Systems.........................33
2.8 L-Ascorbic Acid Metabolic Enzymes.................................................................36
2.9 Degradation and Oxidation of L-Ascorbic Acid.................................................37
2.10 Cellular Transport and Intestinal Absorption of L-Ascorbic Acid...................40
2.11 Molecular Structure of L-Ascorbic Acid..........................................................41
2.12 Chemical and Physical Properties of L-Ascorbic Acid....................................45
2.13 Synthetic Derivatives and Analogues of L-Ascorbic Acid...............................46
CHAPTER 3.....................................................................................................................53
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RESEARCH OBJECTIVE...........................................................................................53
CHAPTER 4.....................................................................................................................55
RESULTS AND DISCUSSION...................................................................................55
4.1 Chemo- and Regio-Selective Alkylation of L-Ascorbic Acid............................55
4.1.1 3-O-Alkylation of 5,6-O-Isopropylidene-L-Ascorbic Acid.........................56
4.1.2 2-O-Alkylation of 5, 6-O-Isopropylidene-L-Ascorbic Acid........................59
4.1.3 2,3-O-Disubstitution of 5,6-O-Isopropylidene-L-Ascorbic Acid................62
4.2 Acylation of 5, 6-O-Isopropylidene-L-Ascorbic Acid........................................65
4.2.1 C3-O- to C2-O Rearrangements of 3-O-Acyl-L-Ascorbic Acid Derivatives
.....................................................................................................................67
4.3 NMR Spectroscopic Analyses of L-Ascorbic Acid and its Derivatives.............70
4.3.1 NMR Spectroscopic Properties of 2-O- and 3-O-Substituted 5,6-O-
Isopropylidene-L-Ascorbic Acid................................................................71
4.4 The Sigmatropic Claisen Rearrangement of L-Ascorbic Acid Derivatives........75
4.4.1 The C3-O to C2 Sigmatropic Claisen Rearrangement of 5,6-O-
Isopropylidene-3-O-Allylic Derivatives of L-Ascorbic Acid.....................76
4.4.1.1 NMR Spectroscopic Analyses of Products from C3-O to C2
Sigmatropic Claisen Rearrangement of 5,6-O-Isopropylidene-3-O-
Allyl-L-Ascorbic Acid Derivatives......................................................77
4.4.2 The C3-O to C2 Sigmatropic Claisen Rearrangement of 5,6-O-
Isopropylidene-3-O-Cinnamyl-L-Ascorbic Acid Derivatives....................85
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4.4.2.1 NMR Spectroscopic Analyses of Products from C3-O to C2
Sigmatropic Claisen Rearrangement of 5,6-O-Isopropylidene-2-O-
Acetyl-3-O-Cinnamyl-L-Ascorbic Acid Derivative (10A)..................87
4.4.3 The C2-O to C3 Sigmatropic Claisen Rearrangement of 5,6-O-
Isopropylidene-2-O-Allyl-L-Ascorbic Acid Derivatives............................90
4.4.3.1 NMR Spectroscopic Analyses of Products from C2-O to C3
Sigmatropic Claisen Rearrangement of 5,6-O-Isopropylidene-2-O-
Allyl-L-Ascorbic Acid Derivatives......................................................91
4.5 Comparative Analysis and Identificaton of Products of C3-O to C2 and C2-O to
C3 Claisen Rearrangement of L-Ascorbic Acid Derivatives..........................102
4.6 Stereochemistry of Products of C3-O to C2 and C2-O to C3 Claisen
Rearrangement of L-Ascorbic Acid Derivatives.............................................105
4.7 Chemo- and Diastereo-Selective Reduction of Claisen Rearranged Products (E
& F Series) of L-Ascorbic Acid Derivatives...................................................110
CHAPTER 5...................................................................................................................116
EXPERIMENTAL SECTION....................................................................................116
LIST OF REFERENCES............................................................................................144
APPENDIX.................................................................................................................164

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LIST OF TABLES

Table 1 Approximate Levels of L-Ascorbic Acid in Tissues...........................................13
Table 2 List of Enzymes Requiring L-Ascorbic Acid as a Cofactor or as a Modulator of
Activity (adapted from Ref. 118).........................................................................28
Table 3 Physical Properties of L-Ascorbic Acid (adapted from Ref. 211 & 212)............47
Table 4 Products from 3-O-Alkylation of 5, 6-O-Isopropylidene-L-Ascorbic Acid........58
Table 5 Products of 2-O-Alkylation of 5, 6-O-Isopropylidene-L-Ascorbic Acid (1).......61
Table 6 Products of 2-O-Acetylation of 5,6-O-Isopropylidene-3-O-Alkylated-L-Ascorbic
Acid......................................................................................................................63
Table 7 Products of 3-O-Acetylation of 5,6-O-Isopropylidene-2-O-Alkylated-L-Ascorbic
Acid......................................................................................................................64
Table 8 Products of 2,3-O-Disubstitution of 5,6-O-Isopropylidene-L-Ascorbic Acid.....65
Table 9 1H NMR (C-4-H) and 13C NMR (C-2 & C-3) Chemical Shifts (δ) of 2-O-Alkyl
and 3-O-Alkyl Derivatives of 5,6-O-Isopropylidene-L-Ascorbic Acid (1).........72
Table 10 1H NMR (C4-H) and 13C NMR (C2 & C3) Chemical Shifts (δ) of 2,3-O-
Disubstituted Derivatives of 5,6-O-Isopropylidene-L-Ascorbic Acid (1)........74
Table 11 1H-NMR Chemical Shifts (δ) of Claisen Rearranged 5,6-O-Isopropylidene-2-
(1-prop-2-enyl)-3-Keto-L-Galactono-γ-Lactone...............................................79
Table 12 13C-NMR Chemical Shifts (δ) of Claisen Rearranged 5,6-O-Isopropylidene-2-
(1-prop-2-enyl)-3-Keto-L-Galactono-γ-Lactone...............................................80
Table 13 1H-NMR Chemical Shifts (δ) of Claisen Rearranged 5,6-O-Isopropylidene-2-(1-
prop-2-enyl)-3-Keto-L-Galactono-γ-Lactone...................................................81
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