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Stereoselective Nucleophilic Additions to α-Amino Aldehydes: Application to Natural Product Synthesis
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

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 SN2 and SN2’ processes are, however, significantly influenced by the nature of the alkyne substituents and the best results are obtained using ethoxyacetylene. The SN2 opening of vinyl epoxides with ethoxyacetylene as nucleophile is also shown to provide a straightforward entry to functionalized γ-butyrolactones.

Place, publisher, year, edition, pages
Stockholm: KTH , 2006. , 52 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2006:105
Keyword [en]
Stereoselective synthesis, Substrate-control, α-Amino aldehydes, Mukaiyama aldol, Allylsilanes, [3 + 2]-Annulation, (+)-Alexine, DGDP, Vinyl epoxides, Regioselectivity, Alkyne nucleophiles
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4233ISBN: 91-7178-494-2 (print)OAI: oai:DiVA.org:kth-4233DiVA: diva2:11383
Public defence
2006-12-18, F3, Lindstedtsvägen 26, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100917Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-17Bibliographically approved
List of papers
1. Diastereoselective Aldol Additions to α-Amino-β-Silyloxy Aldehydes. Divergent Synthesis of Aminodiols
Open this publication in new window or tab >>Diastereoselective Aldol Additions to α-Amino-β-Silyloxy Aldehydes. Divergent Synthesis of Aminodiols
2005 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 7, no 5, 893-895 p.Article in journal (Refereed) Published
Abstract [en]

A divergent protocol for substrate-controlled diastereoselective synthesis of aminodiols has been developed using nucleophilic Mukaiyama aldol additions to alpha-amino-beta-silyloxy aldehydes. The merged stereochemical impact on the diastereoselectivity of the polar alpha- and beta-substituents is highlighted.

Keyword
MERGED STEREOCHEMICAL IMPACT, 1, 3-ASYMMETRIC INDUCTION, ALKOXY ALDEHYDES, LEWIS-ACIDS, ALLYLTRIMETHYLSILANE
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6620 (URN)10.1021/ol0500719 (DOI)000227313400037 ()2-s2.0-15044358964 (Scopus ID)
Note
QC 20100908Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-17Bibliographically approved
2. Stereoselective Synthesis of Functionalized Pyrrolidines via a [3 + 2]- Annulation of N-Ts-α-Amino Aldehydes and 1,3-Bis(silyl)propenes
Open this publication in new window or tab >>Stereoselective Synthesis of Functionalized Pyrrolidines via a [3 + 2]- Annulation of N-Ts-α-Amino Aldehydes and 1,3-Bis(silyl)propenes
2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Journal of the American Chemical Society, Vol. 128, 12646-12647 p.Article in journal (Refereed) Published
Keyword
tetrahydrofuran synthesis, asymmetric-synthesis, 3+2 annulation, allylsilanes, alkaloids, additions, ligands, organocatalysis, derivatives, catalysts
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6621 (URN)10.1021/ja0647102 (DOI)000240795000029 ()2-s2.0-33749516827 (Scopus ID)
Note
QC 20100916Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-16Bibliographically approved
3. 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
Open this publication in new window or tab >>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
(English)Manuscript (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6622 (URN)
Note
QC 20100917Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-17Bibliographically approved
4. Regioselective and Divergent Opening of Vinyl Epoxides with Ethoxyacetylene
Open this publication in new window or tab >>Regioselective and Divergent Opening of Vinyl Epoxides with Ethoxyacetylene
2004 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, no 18, 2086-2087 p.Article in journal (Refereed) Published
Abstract [en]

A divergent protocol for nucleophilic opening of vinyl epoxides with ethoxyacetylide has been developed and demonstrated to give complete regioselectivity depending on reaction conditions.

Keyword
additions, reagents, s(n)2
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6623 (URN)10.1039/b408610d (DOI)000223873000036 ()2-s2.0-6344238803 (Scopus ID)
Note
QC 20100916Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-17Bibliographically approved
5. Regioselective and Divergent Opening of Vinyl Epoxides with Alkyne Nucleophiles
Open this publication in new window or tab >>Regioselective and Divergent Opening of Vinyl Epoxides with Alkyne Nucleophiles
2005 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 18, 3946-3951 p.Article in journal (Refereed) Published
Abstract [en]

A divergent procedure for nucleophilic ring-opening of vinyl epoxides with alkynes has been developed, The combination of lithium acetylides and BF(3)center dot OEt2 afforded the S(N)2 products, whereas alkynylalanes gave S(N)2' addition. The regioselectivity of these processes is affected by the alkyne substituent. Ethoxyacetylene added with complete regiocontrol under both SN2 and SN2' conditions, and the SN2 isomeric adducts could he rearranged into gamma-butyrolactones. The synthetic utility of the process is demonstrated by a short synthesis of gamma-butyrolactone 24, a key intermediate in the synthesis of prostaglandin PGF(20).

Keyword
vinyl epoxides, epoxide opening, alkyne nucleophiles, regioselectivity
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-6624 (URN)10.1002/ejoc.200500321 (DOI)000232068100010 ()2-s2.0-24944439877 (Scopus ID)
Note
QC 20100917Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-17Bibliographically approved

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