Galantamine total synthesis

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galanthamine, a drug used for the treatment of mild to moderate Alzheimer's disease.[1]

The natural source of galantamine are certain species of

US dollar per kilogram, the yield from daffodil is 0.1–0.2% dry weight) alternative synthetic sources are under development by means of total synthesis
.

Outline

Galanthamine numbering scheme and stereocenters
Galanthamine numbering scheme and stereocenters

In 1962

Chemical yield: 1.4%. In addition they isolated (−)-narwardine by chiral resolution
from a mixture of racemic narwedine and 0.5 equivalents of (+)-galanthamine. In this way they were able to obtain (−)galanthamine again by reduction In 1976 Kametani obtained both galanthamine enantiomers by using a derivative of
L-tyrosine[2][3] and in 1988 Carrol optimized the oxidative coupling route to 11% yield based on isovanillin
.

In 1989 Vlahov exploited asymmetric reduction by

Michael reaction-like reaction brought about by triethylamine
.

Resolution of Narwedine
Resolution of Narwedine
Resolution of Narwedine

In 1999 Jordis performed (−)-galanthamine synthesis on a multikilogram scale based on Carrol chemistry and Shieh/Carlson chiral resolution. This would become the basis for current industrial production by Sanochemia (AT). In 2000 Fels proposed an

asymmetric allylic alkylation
and an intramolecular Heck reaction. Improved methods were published in 2002 and 2005 (see below) In 2004 Node obtained (−)-galanthamine via a remote
D-phenylalanine.[5] Brown prepared (−)-galanthamine in 2007 starting from isovanillin.[6] Isovanillin was also used by Magnus (2009) [7] D-glucose was used by Chida (2010).[8]

Syntheses of racemic galanthamine have been reported by Wang in 2006 [9] and by Saito in 2008.[10]

Sanochemia industrial production

The method outlined by Jordis in 1999 forms the basis for industrial galanthamine production.[11]

Narwedine synthesis A Narwedine synthesis A
Narwedine synthesis part A Narwedine synthesis part B

This method is based on

lithiumaluminiumhydride of both the bromine group and the formyl group. In the second phase the ketal group is removed (hydrochloric acid
) forming racemic (S,S/R,R) narwedine 9.

Enantiopure (−)-narwedine is obtained via the dynamic chiral resolution method pioneered by Shieh/Carlson and in the final step the ketone is reduced to the alcohol with L-selectride.

reduction of (−)-narwedine to (−)-galanthamine as the bromide
reduction of (−)-narwedine to (−)-galanthamine as the bromide
reduction of (−)-narwedine to (−)-galanthamine as the bromide

This final step is

Si face as the Re face is shielded by the DB ring system. Formation of the S,S,S epimer
is also avoided by keeping the reaction temperature below −15 °C.

Trost Galanthamine synthesis

The

epi isomer 18.[13]

Trost 2005 Galanthamine total synthesis
Trost 2005 Galanthamine total synthesis
Trost 2005 Galanthamine total synthesis

Eli Lilly / U. of Southampton Galanthamine synthesis

A total synthesis reported by

chiral induction. The allyl alcohol group in 8 is introduced by selenoxide oxidation with an excess of the desired diastereomer. In the final step to galanthamine 9 the hydroxyl group is activated as the triflate and the amine group as the mesylate for intramolecular azepine ring closure via nucleophilic substitution (with 6% epimer
formation).

Galanthamine synthesis 2007 A Galanthamine synthesis 2007 B
Galanthamine synthesis 2007 A Galanthamine synthesis 2007 part B

References and notes

  1. doi:10.1021/cr040415t
  2. doi:10.3987/R-1977-09-1752 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link
    )
  3. doi:10.3987/S(S)-1977-01-0277 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link
    )
  4. doi:10.1021/jo00097a060
  5. PMID 18629982
    .
  6. ^
    PMID 17429978
    .
  7. PMID 19835379
    .
  8. doi:10.3987/COM-10-S(E)27 (inactive 2024-02-17). Archived from the original on 2011-07-22.{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link
    )
  9. PMID 16623560
    .
  10. PMID 18781800
    .
  11. doi:10.1021/op990019q
  12. doi:10.1021/ja054449+
  13. DIBAL-H, m aqueous NaH2PO4 n NaCNBH3
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