Stereoselective Nucleophilic Additions to α-Amino Aldehydes

60 Pages·2006·0.55 MB·English

Stereoselective Nucleophilic Additions

to α-Amino Aldehydes: Application to

Natural Product Synthesis

Per Restorp

Doctoral Thesis

Stockholm 2006

Akademisk avhandling som med tillstånd av Kungl Tekniska Högskolan i Stockholm
framlägges till offentlig granskning för avläggande av filosofie doktorsexamen i kemi
med inriktning mot organisk kemi måndagen den 18 december kl 10.00 i sal F3, KTH,
Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är
Professor Timothy J. Donohoe, University of Oxford, U.K.
ISBN 91-7178-494-2
ISRN KTH/IOK/FR--06/105--SE
ISSN 1100-7974
TRITA-IOK
Forskningsrapport 2006:105

© Per Restorp
Universitetsservice US AB, Stockholm
Abstract
This thesis deals with the development and application of new synthetic
methodology for stereo- or regioselective construction of carbon-carbon bonds in
organic synthesis.

The first part of this thesis describes the development of a divergent protocol for
stereoselective synthesis of chiral aminodiols by employing Mukaiyama aldol
additions to syn- and anti-α-amino-β-silyloxy aldehydes. The stereoselectivity of
the nucleophilic attack is governed by either chelation to the α-amino moiety or
by nucleophilic attack in the Felkin-Anh sense. This study is also directed
towards the elucidation of the factors that dictate aldehyde π-facial selectivity in
substrate-controlled nucleophilic additions to these and similar systems.

In the second part, a highly stereoselective [3 + 2]-annulation reaction of N-Ts-α-
amino aldehydes and 1,3-bis(silyl)propenes for stereoselective construction of
densely functionalized pyrrolidines is presented. In addition, this methodology is
also implemented as a keystep in a synthetic approach towards the
polyhydroxylated pyrrolidine and pyrrolizidine alkaloids DGDP and (+)-alexine
from a common late pyrrolidine intermediate.

Finally, a divergent protocol for regioselective opening of vinyl epoxides using
alkyne nucleophiles is described, in which the regioselectivity of the nucleophilic
attack is controlled by the choice of reaction conditions. The regioselectivities of
the S 2 and S 2’ processes are, however, significantly influenced by the nature
N N
of the alkyne substituents and the best results are obtained using
ethoxyacetylene. The S 2 opening of vinyl epoxides with ethoxyacetylene as
N
nucleophile is also shown to provide a straightforward entry to functionalized
γ-butyrolactones.

Per Restorp, Stereoselective Nucleophilic Additions to α-Amino Aldehydes:
Application to Natural Product Synthesis. Organic Chemistry, KTH Chemical
Science and Engineering, SE-100 44 Stockholm, Sweden.

Keywords: Stereoselective synthesis, Substrate-control, α-Amino aldehydes,
Mukaiyama aldol, Allylsilanes, [3 + 2]-Annulation, (+)-Alexine, DGDP, Vinyl
epoxides, Regioselectivity, Alkyne nucleophiles.
Abbreviations
DGDP (2S,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol
DMDP (2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol
DMP Dess-Martin periodinane
equiv equivalent
ee enantiomeric excess
dr diastereomeric ratio
Im imidazol
KHMDS potassium hexamethyldisilazane
LA Lewis acid
PCC pyridinium chlorochromate
THP tetrahydropyran
TS transition state
List of Publications
This thesis is based on the following papers, referred to in the text by their
Roman numerals I-V.

I. Diastereoselective Aldol Additions to α-Amino-β-Silyloxy Aldehydes.
Divergent Synthesis of Aminodiols
Per Restorp and Peter Somfai
Org. Lett. 2005, 7, 893-895.

II. Stereoselective Synthesis of Functionalized Pyrrolidines via a [3 + 2]-
Annulation of N-Ts-α-Amino Aldehydes and 1,3-Bis(silyl)propenes
Per Restorp, Andreas Fischer and Peter Somfai
J. Am. Chem. Soc. 2006, 128, 12646-12647.

III. Synthetic Studies Toward the Polyhydroxylated Alkaloids DGDP and
(+)-Alexine utilizing a [3 + 2]-Annulation Reaction of N-Ts-α-Amino
Aldehydes and 1,3-Bis(silyl)propenes
Per Restorp and Peter Somfai
Preliminary manuscript.

IV. Regioselective and Divergent Opening of Vinyl Epoxides with
Ethoxyacetylene
Per Restorp and Peter Somfai
Chem. Commun. 2004, 2086-2087.

V. Regioselective and Divergent Opening of Vinyl Epoxides with Alkyne
Nucleophiles
Per Restorp and Peter Somfai
Eur. J. Org. Chem. 2005, 3946-3951.
The Author’s Contribution to Papers I-V
I. I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
II. I contributed to the formulation of the research problems, performed the
experimental work excluding the X-ray crystallographic analysis and wrote the
manuscript.
III. I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
IV. I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
V. I contributed to the formulation of the research problems, performed the
experimental work and wrote the manuscript.
Table of Contents
1. Introduction.....................................................................................................1
2. Stereodivergent Synthesis of AminodiolsI.....................................................5
2.1 Introduction.................................................................................................5
2.2 Asymmetric induction models....................................................................5
2.2.1 Asymmetric 1,2- and 1,3-induction models under
non-chelating conditions..............................................................................6
2.2.2 Merged model for 1,2- and 1,3-asymmetric induction.........................7
2.2.3 Asymmetric 1,2- and 1,3-induction models under
chelating conditions.....................................................................................8
2.3 Diastereoselective synthesis of aminodiols.................................................9
2.3.1 Synthesis of α-amino-β-silyloxy aldehydes.........................................10
2.3.2 Mukaiyama aldol additions to α-amino-β-silyloxy aldehydes............11
2.3.3 Determination of the relative stereochemistry...................................13
2.4 Discussion of the observed diastereoselectivity........................................14
2.5 Conclusions and outlook...........................................................................16
3. Stereoselective Synthesis of Functionalized PyrrolidinesII-III....................19
3.1 Introduction...............................................................................................19
3.1.1 Allylsilanes as 1,3-dipole equivalents in annulation reactions..........20
3.1.2 Allylsilanes as 1,2-dipole equivalents in annulation reactions..........20
3.2 Stereoselective synthesis of functionalized pyrrolidines...........................21
3.2.1 [3 + 2]-Annulation reactions of N-Ts-α-amino aldehydes and
1,3-bis(silyl)propenes .................................................................................21
3.2.2 Stereochemistry determination and rationalization of the
selectivity.....................................................................................................25
3.3 Conclusions and outlook...........................................................................27
4. Synthetic Approaches Toward DGDP and (+)-AlexineIII..........................29
4.1 Introduction...............................................................................................29
4.2 Synthetic approaches toward DGDP and (+)-alexine...............................30
4.2.1 Retrosynthetic analysis.......................................................................30
4.2.2 Synthesis of DGDP.............................................................................31
4.2.3 Towards the synthesis of (+)-alexine.................................................32
4.3 Conclusions and outlook...........................................................................36
5. Regioselective and Divergent Opening of Vinyl EpoxidesIV-V...................37
5.1 Introduction...............................................................................................37
5.2 Regioselective opening of vinyl epoxides with alkynes............................38
5.2.1 Attack according to the S 2 manifold.................................................38
N
5.2.2 Attack according to the S 2' manifold................................................41
N
5.2.3 γ-Butyrolactones in natural product synthesis...................................45
5.3 Conclusions and outlook...........................................................................46
6. Concluding remarks.....................................................................................47
7. Acknowledgements........................................................................................49
8. Appendix .......................................................................................................51

1
Introduction

Organic chemistry is the study of carbon containing compounds and their
properties. As a science, it bridges biology and medicine as well as material
science and physics and provides a crucial platform for drug discovery and
developments in agriculture, polymer and petroleum industry. Organic chemistry
is also of fundamental importance for gaining a better understanding of the basic
mechanisms of natural systems, including life itself.

Synthetic organic chemistry is the art and science concerned with the
construction of structurally complex organic molecules from readily available
starting materials by a series of rationally designed synthetic transformations.
The ability of carbon to form up to four chemical bonds with other atoms allows
for the construction of a seemingly infinite array of molecules for a wide variety
of applications which is reflected in the enormous structural and functional
diversity of organic compounds.

O
O O O OH
S
HO N O NH O H
O O OHOO O HO
O OH O OH
O CHO
Epothilone B (1) Taxol (2) O H O O
H
HO H H NH3+ H H H O HOH O H
S O O H
N
O CO2- O O H H O H HOH H O
Thienamycin (3) Brevetoxin B (4)
Figure 1. Natural products prepared through organic synthesis.

During the last decades, organic synthesis has grown exponentially (if not
explosively) and new methods allow for the synthesis of complex organic
structures, which previously seemed unattainable. The synthetic efforts toward
many natural products have largely been driven by their intriguing chemical
structures and interesting biological properties.1 For instance, epothilone B (1)
and Taxol® (2) are powerful anti-cancer agents, thienamycin (3) has potent
antibiotic properties and brevetoxin B (4) is a marine neurotoxin (Figure 1).

1 Nicolau, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH Verlagsgesellschaft: Weinheim, 1996.
1
However, organic chemists are by no means limited to naturally occurring
compounds for their synthetic endeavours. At the heart of organic synthesis lies
its truly explorative and creative nature, allowing organic chemists to design and
construct fundamentally new compounds with functions and properties that
merely their imagination and the available synthetic methods set the boundaries
for.2

The world around us is chiral3 and the same holds true for many organic
compounds. In order to synthesize a chiral compound with a defined relative and
absolute stereochemistry, its connectivity and three-dimensional structure must
be considered. The spatial distribution of the substituents in a chiral compound
can have a significant impact on the interactions toward other chiral molecules
(for instance biological receptors) and there are numerous examples where two
enantiomers of a given molecule show fundamentally different behaviour in
living systems.4 Different strategies can be employed to access optically active
products including resolution of a racemic mixture, utilization of the chiral pool,
or by employing asymmetric synthesis. Asymmetric synthesis can further be
divided into three subgroups:

Reagent-control:
The formation of a new stereogenic center is governed by a chiral reagent or
catalyst not covalently bound to the substrate.

Auxiliary-control:
The formation of a new stereogenic center is controlled by a stoichiometric
amount of a chiral auxiliary covalently bound to the substrate but not part of the
final structure.

Substrate-control:
The formation of a new stereogenic center is controlled by chirality already
present in the substrate.

Today, an immense number of organic transformations are available to the
organic chemist for the purpose of complex molecules synthesis but the further
need for efficient and highly selective transformations remains undisputed. The
aim of this doctoral work is to develop new synthetic methodology for stereo- or
regioselective construction of carbon-carbon bonds in organic synthesis and
apply this methodology to tackle synthetic problems encountered in natural
product synthesis. Specifically, the synthetic methodologies presented in
chapters 2-4 have been developed to address the synthesis of polyhydroxylated

2 For an example of moving fullerene-wheeled nanocars and nanotrucks, see Shirai, Y.; Osgood, A. J.; Zhao,
Y. M.; Yao, Y. X.; Saudan, L.; Yang, H. B.; Chiu, Y. H.; Alemany, L. B.; Sasaki, T.; Morin, J. F.; Guerrero, J.
M.; Kelly, K. F.; Tour, J. M. J. Am. Chem. Soc. 2006, 128, 4854-4864.
3 Chiral, greek; handed. Body with non-superimposable mirror images.
4 For several examples, see Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles and Applications of Asymmetric
Synthesis; Wiley-Interscience: New York, 2001, p. 6.
2