The document summarizes the total synthesis of (±)-spiroindimicins B and C, which are alkaloids isolated from a deep-sea marine actinomycete. Key steps in the synthesis include installing a spirocenter using an intramolecular Heck reaction, forming a pentacyclic spirobisindole through Fischer indolization, and constructing a trisubstituted pyrrole ring via a late-stage Schöllkopf–Magnus–Barton–Zard reaction. The synthesis confirms the unique heteroaromatic structure of these natural products and demonstrates the use of mild reactions to install functional groups like the spirocenter and pyrrole ring.

1. Total syntheses of (±)-spiroindimicins B and C
enabled by a late-stage Schöllkopf–Magnus–
Barton–Zard (SMBZ) reaction
Presenter: 鄭裕豐
Student ID: 401260018
Date: 5/26/2016
Lachlan M. Blair and Jonathan Sperry*
Chem. Commun., 2016, 52, 800
DOI: 10.1039/c5cc09060a

2. Contents
• Author
• Abstract
• Introduction
• Retrosynthesis
• Synthesis
• Conclusion
• References
2

3. Author
Jonathan Sperry
Biography:
• Feb 2014- 2019. RSNZ Rutherford Discovery Fellow
• Feb 2012- present. Senior Lecturer in Organic and Medicinal Chemistry, University of
Auckland, New Zealand
• Nov 2009- Feb 2012. Lecturer in Organic and Medicinal Chemistry, University of
Auckland, New Zealand
• Nov 2007- Nov 2009. Postdoctoral Research Fellow, University of Auckland, New Zealand,
(RSNZ Marsden Fund, Prof. M. A. Brimble)
• Mar 2006- Nov 2007. Honorary Postdoctoral Research Fellow, University of Auckland,
New Zealand, (Prof. M. A. Brimble)
• Oct 2002- Feb 2006. Ph.D Synthetic Organic Chemistry, University of Exeter, UK.
Biomimetic Oxidations in Natural Product Synthesis (Prof. C. J. Moody)
• 1999-2002. BSc (Hons) Biological and Medicinal Chemistry, 1st class. University of Exeter,
UK. Final year project: A Diels Alder approach to Vitamin B6 analogues
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4. Research Interest
• Organic Synthesis
• Medicinal chemistry
• Sustainable Synthesis / Green Chemistry
Lachlan M. Blair
• Postgraduate student of Jonathan Sperry
4

5. Abstract
• The spiroindimicins are a family of structurally unprecedented
alkaloids isolated from the deep-sea-derived marine actinomycete
Streptomyces sp. SCSIO 03032.
• The total syntheses of (±)-spiroindimicins B and C are disclosed, the
first of any member of this family.
• Central to the successful strategy was installing the spirocentre using
a mild intramolecular Heck reaction, the assembly of a pentacyclic
spirobisindole by Fischer indolization and a late-stage Schöllkopf–
Magnus–Barton–Zard (SMBZ) reaction to construct the trisubstituted
pyrrole.
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6. Introduction
• Deep-sea organisms have evolved to survive under their extreme
environment by adapting a wide range of their biochemical processes
and metabolic pathways
• The spiroindimicins are a family of structurally unprecedented
alkaloids isolated from the deep-sea-derived marine actinomycete
Streptomyces sp. SCSIO 03032.
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7. • Streptomyces sp. SCSIO 03032 produces a range of structurally
unprecedented natural products including spiroindimicins A–D (1–4)
• Biological evaluation revealed 2–4 are moderately cytotoxic to various
cancer cell lines
Introduction
7

8. Introduction
Schöllkopf–Magnus–Barton–Zard (SMBZ) reaction
• The Barton-Zard reaction is a route to pyrrole derivatives via the
reaction of a nitroalkene with an α-isocyanoacetate under basic
conditions. It is named after Derek Barton and Samir Zard who first
reported it in 1985.
• Considering Magnus reported this reaction the year prior to Barton
and Zard, the synthesis should be termed the Schöllkopf–Magnus–
Barton–Zard (SMBZ) reaction (names in chronological order according
to publication date)
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9. Retrosynthesis
9

10. Synthesis
10

11. Synthesis (10 → 9)
• SN2 reaction
• SN2’ reaction
• Occurs as double bond presents
• SN2 reaction and SN2’ reaction will compete to each other and
produce different product respectively
11

12. Synthesis (10 → 9)
• Mechanism
• Synthesis (10 → 9) proceeds via SN2 reaction
12

13. Synthesis (9 → 8 and 9 → 12)
• Heck reaction
13

14. Synthesis (9 → 8 and 9 → 12)
• Intramolecular Heck reaction
• Neutral Pathway
14

15. Synthesis (9 → 8 and 9 → 12)
• Mechanism of reaction expected by author (9→8)
15

16. Synthesis (9 → 8 and 9 → 12)
• Mechanism of reaction in fact (9→12)
16

17. Synthesis (9 → 8 and 9 → 12)
• Mechanism of reaction(9→12)
• Reinsertion of hydridopalladium species: PdH can also be scavenged by
starting alkene, which is always more reactive than the Heck product due to
its smaller size. This process is well-known as it leads to the isomerization of
alkenes, which results in the formation of isomeric Heck products
• Interestingly, silver nitrate could be added to the reductive conditions to
increase the yield of (±)-12 (63% vs. 93%).
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18. Synthesis (9 → 8 and 9 → 12)
• Nuclear Overhauser effect (NOE)
• The transfer of nuclear spin polarization from one spin bath to another spin
bath via cross-relaxation. It is a common phenomenon observed by NMR
spectroscopy
• NOE occurs through space, not through chemical bonds. Thus, atoms that are
in close proximity to each other can give a NOE
• The inter-atomic distances derived from the observed NOE can often help to
confirm a precise molecular conformation
• Some examples of two-dimensional NMR experimental techniques exploiting
the NOE include nuclear Overhauser effect spectroscopy (NOESY),
heteronuclear Overhauser effect spectroscopy (HOESY) and many more.
18

19. Synthesis (12→ 8)
19

20. Synthesis
20

21. Synthesis (8→7)
• Fischer indolization reaction
• A chemical reaction that produces the aromatic heterocycle indole from a
(substituted)phenylhydrazine and an aldehyde or ketone under acidic conditions
• The reaction was discovered in 1883 by Hermann Emil Fischer.
21

22. Synthesis (8→7)
• Mechanism
22

23. Synthesis (8→7)
• Mechanism (Cont’d)
23

24. Synthesis (8→7)
• Mechanism (Cont’d)
24

25. Synthesis (7→6)
• Yonemitsu oxidation
25

26. Synthesis (7→15)
• Compound 15 (compound 6 with Boc attach to N atom on indole) will
be formed by 3-step reaction via formation of compound 13 and 14.
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27. Synthesis (7→15)
27

28. Synthesis (14→15)
28

29. Synthesis
29

30. Synthesis (15→17)
• reaction according to study by T. Mukaiyama and K. Saigo (Chem.
Lett., 1973, 479.)by adding 1 eq. TiCl4 + 2 eq. Et3N + 1.1 eq. thiol.
• In the end the compound 15 remains unreacted
30

31. Synthesis (15→17)
• reaction according to study with excess of reagents
31

32. Synthesis (17→16+18)
• this reaction will produce 2 compounds, compound 16 and compound 18
（ratio= 1.3:1)
32

33. Synthesis (17→16+18)
• To form compound 16 as much as possible from 18, add 1.1eq. TiCl4, 1.5 eq.
K2CO3 and CH2Cl2 as solvent and react for 2 hours in room temperature.33

34. Synthesis (16→19)
Mechanism of Schöllkopf–Magnus–Barton–Zard (SMBZ) reaction
• compound 18 itself is viable substrate for SMBZ reaction ( but lower yield (31%) than
conversion from compound 16 (62%))
(structure confirmed by X-ray analysis)
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35. Synthesis (19→3)
35

36. Synthesis (19→3) (cont’d)
36

37. Synthesis (3→2)
37

38. Conclusion
• In summary, the first total syntheses of spiroindimicins B and C have
been achieved, which serve to confirm the unique heteroaromatic
structure of these deep-sea-derived natural products.
• Some observations with implications beyond this synthetic study
include:
• (1) construction of all-carbon spirocentre using an intramolecular Heck
reaction under mild, reductive conditions promoted by silver(I);
• (2) successful application of the Fischer indolization to construct a pentacyclic
spirobisindole;
• (3) a late-stage SMBZ reaction using both a vinyl sulfoxide and a vinyl sulfone
to form a trisubstituted pyrrole.
38

39. References
• E. M. Boyd and J. Sperry, Org. Lett., 2015, 17, 1344
• D. H. R. Barton and S. Z. Zard, J. Chem. Soc.,Chem. Commun., 1985, 1098
• T. Mukaiyama and K. Saigo, Chem. Lett., 1973, 479.
• Y. Oikawa, T. Yoshioka, K. Mohri and O. Yonemitsu, Heterocycles, 1979, 12,
1457
• A. Nakhi, B. Prasad, U. Reddy, R. M. Rao, S. Sandra, R. Kapavarapu, D.
Rambabu, G. R. Krishna, C. M. Reddy, K. Ravada, P. Misra, J. Iqbal and M.
Pal, Med. Chem. Commun., 2011, 2, 1006
• N. H. Cromwell and H.-K. Leung, J. Org. Chem., 1976, 41, 3241
• M. M. Abelman and L. E. Overman, J. Org. Chem., 1987, 52, 4130
• R. Peng and M. S. VanNieuwenhze, Org. Lett., 2012, 14, 1962
• G. Stork and J. E. Dolfini, J. Am. Chem. Soc., 1963, 85, 2872
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40. Thanks for your participation!
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