Stereoselective Synthesis of Amino Alcohols

80 Pages·2007·2.65 MB·English

Stereoselective Synthesis of Amino Alcohols:
Applications to Natural Product Synthesis

Staffan Torssell

Doctoral Thesis

Stockholm 2007
Akademisk avhandling som med tillstånd av Kungl Tekniska Högskolan i Stockholm
framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i kemi
med inriktning mot organisk kemi fredagen den 14 september kl 10.00 i sal F3, KTH,
Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är
Professor Pher G. Andersson, Uppsala universitet.
ISBN 978-91-7178-734-7
ISSN 1654-1081
TRITA-CHE-Report 2007:52

© Staffan Torssell, 2007
Universitetsservice US AB, Stockholm
Staffan Torssell, 2007: ”Stereoselective Synthesis of Amino Alcohols:
Applications to Natural Product Synthesis” Organic Chemistry, KTH
Chemical Science and Engineering, Royal Institute of Technology, SE-100 44
Stockholm, Sweden.
Abstract
This thesis is divided into four separate parts with amino alcohols as the
common feature.

The first part of the thesis describes the development of an efficient three-
component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a
highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of
carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are
formed in high yields and excellent diastereoselectivities. An asymmetric
version was also developed by employing chiral α-methylbenzyl imines as
dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-amino esters.
This methodology was also applied on a short asymmetric synthesis of the
paclitaxel side-chain as well as in an asymmetric synthetic approach towards
the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II)
carboxylates furnishes the syn-α-hydroxy-β-amino esters in moderate
enantioselectivity (er up to 82:18), which indicates that the reaction proceeds
via a metal-associated carbonyl ylide.

The second part describes the development of a 1,3-dipolar cycloaddition
reaction of azomethine ylides to aldehydes for the synthesis of α-amino-β-
hydroxy esters. Different methods for the generation of the ylides, including
Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have
been evaluated. The best results were obtained with the Ag(I)/phosphine
approach, which yielded the desired α-amino-β-hydroxy ester in 68% yield
and 3.4:1 syn:anti-selectivity.

The last two parts deals with the total synthesis of the amino alcohol-
containing natural products D-erythro-sphingosine and (−)-stemoamide. The
key transformation in the sphingosine synthesis is a cross-metathesis reaction
for the assembly of the polar head group and the aliphatic chain. In the
stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-
sequence for the construction of the β,γ-unsaturated azepine core of
stemoamide followed by a stereoselective bromolactonization/1,4-reduction
strategy for the installation of the requisite C8-C9 trans-stereochemistry.

Keywords: Amino alcohol, asymmetric 1,3-dipolar cycloaddition, azomethine
ylide, carbenoid, carbonyl ylide, cross-metathesis, omuralide, oxazolidine,
rhodium, sphingosine, stemoamide, stereoselective synthesis, total synthesis.
Abbreviations
1,3-DC 1,3-dipolar cycloaddition
9-BBN 9-borabicyclo[3.3.1]nonane
B-I-9-BBN 9-iodo-9-borabicyclo[3.3.1]nonane
BINOL 1,1-bi-2-naphthol
BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphinic chloride
BOX bis(oxazoline)
CM cross-metathesis
Cy cyclohexyl
DBB 4,4’-di-tert-butylbiphenyl
DCE 1,2-dichloroethane
(DHQ)PHAL hydroquinine 1,4-phtalazinediyl diether
2
(–)-DIPT (–)-diisopropyl tartrate
DMAD dimethyl acetylenedicarboxylate
DMI 1,2-dimethylimidazole
DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DOS diversity-oriented synthesis
EDA ethyl diazoacetate
FMO frontier molecular orbital
KHMDS potassium hexamethyldisilazane
LiHMDS lithium hexamethyldisilazane
NaHMDS sodium hexamethyldisilazane
N.A. not available
n.d. not determined
n.r. no reaction
p-TSA p-toluene sulfonic acid
PyBOX pyridine bis(oxazoline)
quant. quantitative yield
QUINAP 1-(2-diphenylphosphino-1-naphthyl)isoquinoline
RCM ring-closing metathesis
Rh(pfb) rhodium perfluorobutyrate
2 4
Rh(S-biTISP) dirhodium bis[bridged-di(S-(N-2,4,6-triisopropyl phenylsulfonyl)prolinate)
2 2
Rh(S-DOSP) dirhodium tetrakis(S-(N-dodecyl benzenesulfonyl)prolinate)
2 4
SAE Sharpless asymmetric epoxidation
X chiral auxiliary
C

Δ heating (typically to reflux)
List of Publications
This thesis is based on the following papers, referred to in the text by their
Roman numerals I-V:

I. 1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines:
A Three Component Approach to syn-α-Hydroxy-β-amino Esters
Staffan Torssell, Marcel Kienle and Peter Somfai
Angew. Chem. Int. Ed. 2005, 44, 3096-3099
Angew. Chem. 2005, 117, 3156-3159

II. 1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines:
Scope, Limitations and Asymmetric Cycloadditions
Staffan Torssell and Peter Somfai
Adv. Synth. Catal. 2006, 348, 2421-2430

III. 1,3-Dipolar Cycloadditions of Azomethine Ylides to Aldehydes:
Synthesis of α-Amino-β-hydroxy Esters
Staffan Torssell and Peter Somfai
Preliminary Manuscript

IV. A Practical Synthesis of D-erythro-Sphingosine Using a Cross-
Metathesis Approach
Staffan Torssell and Peter Somfai
Org. Biomol. Chem. 2004, 2, 1643-1646

V. Total Synthesis of (−)-Stemoamide
Staffan Torssell, Emil Wanngren and Peter Somfai
J. Org. Chem. 2007, 72, 4246-4249
Table of Contents
Abstract
Abbreviations
List of publications

1. Introduction.............................................................................................1
1.1. Stereoselective Synthesis..........................................................................3
1.2. β-Amino Alcohols........................................................................................4
1.3. Synthesis of β-Amino Alcohols...................................................................5

1.3.1. Amino Alcohols from a Pre-Existing Carbon Skeleton.....................................5

1.3.2. Amino Alcohols from C-C Bond Forming Reactions.........................................7
1.4. 1,3-Dipolar Cycloaddition Reactions..........................................................9

1.4.1. 1,3-Dipoles.......................................................................................................10

1.4.2. Dipolarophiles...................................................................................................10

1.4.3. Regio- and Stereoselectivity in 1,3-Dipolar Cycloadditions............................11
1.5. Aim of This Thesis....................................................................................13
2. 1,3-Dipolar Cycloadditions of Carbonyl Ylides to Aldimines:
Synthesis of syn-α-Hydroxy-β-amino Esters......................................15
2.1. Introduction................................................................................................15

2.1.1. 1,3-Dipolar Cycloadditions of Carbonyl Ylides................................................15

2.1.2. Aim of the Study and Synthetic Strategy.........................................................17
2.2. 1,3-Dipolar Cycloadditions.......................................................................18
2.3. Mechanistic Aspects of the 1,3-Dipolar Cycloaddition............................23
2.4. Asymmetric 1,3-Dipolar Cycloadditions...................................................25

2.4.1. Chiral Rh(II) Catalysts......................................................................................25

2.4.2. Chiral Diazo Esters..........................................................................................26

2.4.3. Chiral Imines....................................................................................................27

2.4.4. Chiral Lewis Acids............................................................................................29
2.5. Synthetic Applications: Paclitaxel Side-Chain and Towards the Total
Synthesis of Omuralide............................................................................31

2.5.1. Paclitaxel Side-Chain.......................................................................................31

2.5.2. Omuralide: Introduction....................................................................................32

2.5.3. Retrosynthetic Analysis of Omuralide.............................................................34

2.5.4. Synthetic Efforts Towards Omuralide..............................................................35
2.6. Conclusions...............................................................................................38
3. 1,3-Dipolar Cycloadditions of Azomethine Ylides to Aldehydes:
Synthesis of syn-α-Amino-β-hydroxy Esters......................................39
3.1. Introduction................................................................................................39

3.1.1. Generation of Azomethine Ylides....................................................................39

3.1.2. Aim of the Study and Synthetic Strategy.........................................................41
3.2. 1,3-Dipolar Cycloadditions.......................................................................42

3.2.1. 1,3-Dipolar Cycloadditions of Oxazoline-Derived Azomethine Ylides...........42

3.2.2. 1,3-Dipolar Cycloadditions of Metallo-Azomethine Ylides..............................44

3.2.3. Mechanistic Aspects........................................................................................45
3.3. Conclusions and Outlook.........................................................................47
4. Total Synthesis of D-erythro-Sphingosine.........................................49
4.1. Introduction................................................................................................49
4.2. Retrosynthetic Analysis of D-erythro-Sphingosine..................................50
4.3. Synthesis of D-erythro-Sphingosine.........................................................51

4.3.1. Oxazolidinone Synthesis.................................................................................51

4.3.2. Cross-Metathesis and Completion..................................................................52
4.4. Conclusions...............................................................................................54
5. Total Synthesis of (−)-Stemoamide...................................................55
5.1. Introduction................................................................................................55
5.2. Retrosynthetic Analysis of (−)-Stemoamide............................................56
5.3. Synthesis of (−)-Stemoamide...................................................................57

5.3.1. Construction of the Pyrrolo[1,2-a]azepine Core..............................................57

5.3.2. Lactonization and Completion.........................................................................58
5.4. Conclusions...............................................................................................61
6. Concluding Remarks............................................................................63

Acknowledgements
Appendices

1.
Introduction

During the last decades, organic chemists have achieved spectacular progress
in the synthesis of complex molecules. The synthesis of brevetoxin A and B by
K. C. Nicolaou and co-workers, a project that took 16 years to finish, still
stands as a milestone in total synthesis (Figure 1).1

HO
Me
CHO
H O O
H H
MeH Me H H MeOMe HO O H
O O H
O O
O O O H H H Me
H H H Me
Figure 1. Brevetoxin B

Although synthetic organic chemists have clearly shown, by their amazing
work, that they are capable of synthesizing almost any compound imaginable,
there is a constant, growing demand for new discoveries in the field of organic
chemistry since the synthetic methods existing today are still far from
satisfactory. The challenge in organic chemistry today, lies not so much in the
synthesis of monstrous natural products, which can evidently be achieved with
enough manpower, time and money, as in the development of new,
straightforward methodologies for the construction of complicated targets and
sub-structures. For example, accurate control of the individual functional
groups within a complex molecule (chemoselectivity) still remains an
unanswered question. Traditionally, this challenge has been solved by the use
of protecting group to allow the functional groups to react on an individual
basis. Ideally, this strategy overcomes many of the chemoselectivity problems
encountered in the synthesis of complex molecules but it often adds an
additional layer of synthetic complexity. This not only adds to the amount of
chemical operations within a synthesis, but also lowers the overall efficiency
of the synthesis. Two interesting solutions to the chemoselectivity issue in the
field of natural product synthesis are the four-step enzymatic synthesis of the
anti-cancer agent epothilone C by Khosla and co-workers2 and the protecting

1 (a) Nicolaou, K. C.; Tiebes, J.; Theodorakis, E. A.; Rutjes, F. P. J. T.; Koide, K.; Sato, M.;
Untersteller, E. J. Am. Chem. Soc. 1994, 116, 9371-9372. (b) Nicolaou, K. C.; Yang, Z.; Shi,
G.-S.; Gunzner, J. L.; Agrios, K. A.; Gärtner, P. Nature 1998, 392, 264-269. (c) Nicolaou, K. C.
Tetrahedron 2003, 59, 6683-6738.
2 Boddy, C. N.; Hotta, K.; Tse, M. L.; Watts, R. E.; Khosla, C. J. Am. Chem. Soc. 2004, 126,
7436-7437.
1
group-free synthesis of the marine alkaloids ambiguine H, hapalindole U,
welwitindolinone A and fischerindole I by the Baran group.3 Another new
area, which has grown exponentially during the last decade, is organocatalysis,
pioneered by the MacMillan, List and Barbas groups.4 In organocatalysis,
small organic molecules act as the catalytic species with the advantage of
being metal-free, usually non-toxic, readily available and often very robust.
Due to the absence of transition metals, organocatalysis appear to be an
attractive complement to more traditional methods in areas where metal
contaminations are not tolerated, e.g. the pharmaceutical industry. These are
just a few examples where the chemists are recognizing what could be looked
upon as simple, but still brilliant solutions to many of the problems existing in
modern organic chemistry, such as long, linear synthetic sequences, hazardous
byproducts, the need for expensive and sensitive metal-catalysts. Other areas
like diversity-oriented synthesis5 and chemical genetics6,7 described by
Schreiber and co-workers, have opened new opportunities for chemists to use
small molecules to perturb and gain new understanding of functions required
in living organisms. The use of small molecules to dissect biological pathways
in the same manner as in genetics, where random mutations are used for
screening of specific cellular functions, has led to considerable efforts in
constructing planning algorithms for the synthesis of complex and diverse
collections of compounds.8 From a drug discovery point of view this approach
would lead to a simultaneous identification of target proteins and small
molecules that can act as protein modulators. These are just a few of the new
revolutionizing areas within the organic chemistry community that will set the
standard for future developments.

3 Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404-408. It should be noted that
this is not the first example of a protecting group-free total synthesis, for example see
Robinson’s tropinone synthesis: Robinson, R. J. Chem. Soc. 1917, 111, 762-768. However, due
to the complexity of the molecular framework in the current example it must be considered to
be a landmark within natural product synthesis.
4 For excellent reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726-
3748. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-5175. (c) Berkessel,
A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in
Asymmetric Synthesis; Wiley-VCH Verlag GmbH: Weinheim, 2005. (d) Seayad, J.; List, B.
Org. Biomol. Chem. 2005, 3, 719-724; (e) Lelais, G.; MacMillan, D. W. C. Aldrich. Acta 2006,
39, 79-87.
5 Schreiber, S. L. Science 2000, 287, 1964-1969.
6 Chemical genetics, def: Biological investigation by modulating protein functions with small
molecules.
7 Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127-1152.
8 For a review on “A planning strategy for diversity-oriented synthesis”, see: Burke, M. D.;
Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43, 46-58.
2