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2. 2
“Expedient Method for Intramolecular Enamide Formation
& Total Synthesis of Sanctolide A, Homologated Sanctolide
A, Palmyrolide A and Desmethyl Palmyrolide A”
Suresh Borra
(AcSIR Enrollment No. 10CC11J18075)
Ph.D. Supervisor: Dr. J. S. Yadav (FNA, FTWAS)
(Former Director-IICT, CSIR-Bhatnagar Fellow)
CSIR-Indian Institute of Chemical Technology
Uppal Road, Tarnaka, Hyderabad - 500 007
September 2015
by
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THESIS OUTLINE
Approach for the synthesis of
enamides with examples
Stereoselective total synthesis of the
marine macrolide sanctolide A
An improved method for the
intramolecular enamide formation
between vinyl iodide and primary
amide with examples
Application of methodology in total
synthesis of palmyrolide A, des-
methyl palmyrolide A and
homologated sanctolide A
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2
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CHAPTER 1
 Enamides have a neighboring double bond at the amide nitrogen atom and constitute
important structural motifs. Enamide motif containing molecules exhibit diverse and
wide range of interesting biological activities comprising anti-tumour, anti-microbial,
anti-viral, insecticidal, anti-inflammatory, CNS immuno suppressive and plays an
important role in drug development.
 The molecule with enamide portion and other unusual structural features along with
potent biological activities have attracted attention of synthetic chemists.
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Importance of the enamide moiety for biological activity
Bayer A.; Maier M. E. Tetrahedron 2004, 60, 6665
Enamides in natural and pharmaceutical products
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6. The Cu-catalyzed cross-coupling reaction between an amide and alkenyl halide
has emerged as a powerful tool for the efficient and stereoselective synthesis of
enamides
Methods for synthesis of enamides
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Synthesis of enamide by Cu-mediated cross-coupling
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8. Intramolecular enamide formation reactions
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Stereoselective Total Synthesis of the Marine Macrolide Sanctolide A
Sanctolide A, a 14-membered polyketide-nonribosomal peptide (PK-NRP) hybrid
macrolide and secondary metabolite from the cell extract of cultured
cyanobacterium Oscillatoria sancta (SAG 74.79) contains a rare N-methyl enamide
and 2-hydroxyisovaleric acid functionality embedded into the macrocycle. The
synthesis relied on Yamaguchi esterification and an intramolecular dehydrative
cyclization reaction to construct the core skeleton of the macrolide.
1. Orjala et al. Tetrahedron Lett. 2012, 53, 3563
2. Brimble et al. J. Org. Chem. 2014, 79, 11179
CHAPTER 2
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Retrosynthetic analysis
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Synthesis of sanctolide A
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12. Synthesis of sanctolide A
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Synthesis of sanctolide A
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1H NMR spectra of sanctolide A
Isolated compound
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Conclusion
 A route for the total synthesis of Sanctolide A has been described
 The first total synthesis of Sanctolide A has been accomplished
 Dehydrative macrocyclization afforded the trans N-methyl enamide containing
macrocycle, which completed the total synthesis of the target compound
 Yamaguchi esterification, Maruoka allylation and Noyori’s asymmetric reduction of a
ketone are the other key reactions utilized in this total synthesis
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 This chapter demonstrates an improved method to synthesise enamide
containing macrolides involving Cu-mediated intra molecular enamide formation
between an amide and vinyl iodide.
 Cu- mediated coupling has emerged as a powerful tool for the efficient and
stereoselective synthesis of enamides and one of the mildest methods for the
introduction of enamide moiety in complex natural products employing weak
base, non-polar solvents.
CHAPTER 3
Org. Lett., 2010, 12, 4490; Tetrahedron Lett. 2012, 53, 3563; Tetrahedron Lett. 1996, 37, 7519
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17. Initially, the active copper(I) species reacts with amide by the action of the base
to form copper amidate. Then, oxidative insertion of copper amidate into a vinyl
iodide and subsequent reductive elimination affords enamide via regeneration
of catalyst.
Plausible mechanism for Copper-mediated macroenamidation
Mechanism
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Retrosynthetic analysis
 Our retrosynthetic approach involves the coupling of vinyl iodide and
primary amide in intramolecular fashion followed by N-methylation to yield
cyclic N-methyl enamides.
Synthesis of 15-membered cyclic enamide
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19. S. No Base Ligand Solvent[a] Yield (%)
1 Cs2CO3 N,N’-dimethylethylene diamine DMF No reaction
2 Cs2CO3 (±) -1,2-diaminocyclohexane DMF No reaction
3 Cs2CO3 N,N’-dimethylethylene diamine DMSO No reaction
4 Cs2CO3 N,N’-dimethylethylene diamine 1,4-Dioxane No reaction
5 CsF (±) -1,2-diaminocyclohexane DMF No reaction
6 CsF (±) -1,2-diaminocyclohexane 1,4-Dioxane No reaction
7 Cs2CO3 N,N’-dimethylethylene diamine THF 30%
8 CsF N,N’-dimethylethylene diamine THF 20%
9 CsF (±) -1,2-diaminocyclohexane Toluene 70%
[a] All the reactions were performed in sealed tube at 90 oC for 24 h
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Optimization of intramolecular coupling of vinyl iodide with amide
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20. 1H NMR Spectra of 15-mem. Primary enamide A
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21. 1H & 13C NMR spectra of 15-mem. enamide
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Synthesis of 16-membered cyclic enamide
14 and 12-membered cyclic enamides
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23. Synthesis of aromatic cyclic enamide
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Conclusion:
 This method can be utilized in synthesis of wide range of enamide
containing macrolides 12, 14, 15, 16 and aromatic ring containing cyclic
enamides in intramolecular fashion
 This method results in high yields 75-80%
 This method does not result in isomerisation of trans enamide
Enamide macrocycles
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25. This Chapter describes the application of methodology in total synthesis of 1.
palmyrolide A, 2. desmethyl palmyrolide and 3. homologated sanctolide A
Introduction: 15-membered macrocycle palmyrolide A with a rare N-methyl
enamide and an intriguing t-butyl branch is a potent neuroactive compound from
two genera Leptolyngbya cf and Oscillatoria species. This compound was found
to display sodium channel blocking activity in neuro-2a cell (IC50 = 5.2µM), and
recently found to act as VGSC antagonists to block veratridine-induced sodium
influx.
1.Stereoselective Total Synthesis of the Marine Macrolide palmyrolide A
CHAPTER 4
Isolation: Org. Lett., 2010, 12, 4490
Marine cyanobacterial
assemblage
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Retrosynthetic analysis
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Angew. Chem. Int. Ed.
1998, 37, 1986
Synthesis of palmyrolide A
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Synthesis of palmyrolide A
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29. 1H NMR Spectra of palmyrolide A
Synthetic palmyrolide A (500 MHz, CDCl3)
Isolated palmyrolide A (600 MHz, CDCl3)
Gerwick et al., Org. Lett. 2010, 12, 4490
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2.Total synthesis of desmethyl-palmyrolide A
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31. 1H-NMR Spectra of desmethyl palmyrolide A
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32. Total synthesis of homologated-sanctolide A
Retrosynthetic analysis
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33. Studies towards synthesis of sanctolide A
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Studies towards synthesis of sanctolide A

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Synthesis of homologated sanctolide A
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1H-NMR Spectra of homologated sanctolide A
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37.  This method was successfully utilized in the total synthesis of palmyrolide A,
desmethyl palmyrolide A and homologated Sanctolide A.
 This method gave Palmyrolide A in high yield than the previous reported methods.
 This method did not result in isomerisation as in other cases.
 This method can also be utilized in the total synthesis of other enamide containing
natural products such as Laingolide, laingolide A and laingolide B etc.,
Conclusion
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38.  Stereoselective approach for intramolecular coupling of secondary amides and
vinyl iodides and its application in the total synthesis of palmyrolide A’
 “Synthetic studies on Bafilomycin A1, stereo selective synthesis of C(13) – C(25)
segment”
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39.  Total synthesis of dolabriferol
“Colgate Palmolive Project “Synthesis of Magnolol, Isopropylmagnolol and Honokiol”
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40. (ii) “A Scalable procedure for synthesis of Isopropyl Magnolol”
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41. (iii) “A Scalable procedure for synthesis of honokiol”
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