248th ACS National Meeting, San Francisco CA, 12.8.2014: The Herman Skolnik Award Symposium: The Publication Chain Revisited: Old Links and New Connections

1. 248th ACS National Meeting, San Francisco CA, Aug. 12, 2014
Of a Landmark Total Synthesis yet Unpublished
in Full Experimental Detail – Vitamin B12

2. A B12 Landmark in Zürich …
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 2

3. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 3

4. A Prologue
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 4

5. «Vitamin B12 Total Synthesis»:
Two Syntheses of Cobyric Acid
AE, Naturwissenschaften 1974
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 5

6. The Beginnings
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 6

7. The Beginnings
ETH: first Ph.D. student on Project
J. Wild, Sep. 13th, 1960
Harvard: first Post-Docs on Project
W. Lenk B. McMurry, Aug. 16th, 1961
ETH Zurich, Laboratory of Organic Chemistry | |
Engelbert Zass 08/12/2014 7
1972: Completion of the Syntheses

8. ETH Zurich, Laboratory of Organic Chemistry Ms. K.F. Jervey Engelbert Zass | 08/12/2014 | 8

9. 77 Post-docs
no Ph.D. students
Total of 1’393 man-months
Aug. 1961 – Dec. 1975
ETH Zurich, Laboratory of Organic Chemistry | |
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Harvard Group

10. 12 Ph.D. students
14 Post-docs
Total of 730 man-months
Sep. 1960 – Aug. 1974
ETH Zurich, Laboratory of Organic Chemistry | |
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ETH Group

11. ETH: Corrin Model Syntheses 1960-1972
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 11

12. Harvard:
67 post-doc reports (not publicly accessible)
48 individual experimental procedures
ETH:
12 Ph.D. theses (print in libraries,
since 2008 publicly accessible in ETH e-Collection)
1 Diploma thesis
(not publicly accessible, major content integrated into thesis)
6 post-doc reports
(not publicly accessible, major content integrated into theses)
ETH Zurich, Laboratory of Organic Chemistry | |
Engelbert Zass 08/12/2014 12
The Total Syntheses of Vitamin B12
Research Records

13. ETH: B12 Theses
Jost Wild
Urs Locher
Alexander Wick
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14. since 2008
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 14

15. Primary Literature
Published lectures (4 + 4)
Ph.D. Theses (12)
Secondary Literature
Tertiary Literature
Web (Wikipedia)
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The Total Syntheses of Vitamin B12
Publication Record

16. Searching for the total synthesis of vitamin B12
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 16

17. Harvard-ETH
A®B
(1973)
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18. ETH
A®D
(1977)
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19. SciFinder
Secondary Literature
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20. SciFinder Topic Search:
Results
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 20

21. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 21

22. Scopus
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23. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 23

24. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 24

25. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 25

26. red: article not covered at all
Query «total synthesis of vitamin B12 / … cobyric acid»:
yellow: article not found
green: article found
ETH Zurich, Laboratory of Organic Chemistry | |
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The Total Syntheses of Vitamin B12
References in Literature Databases

27. DOI: 10.3929/ethz-a-010165162
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 27

28. Tertiary Literature: 38
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 28

29. 20 of 38
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30. Resonance (2003), 8(6), 8-16
8 of 38
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31. until 7/7/2014
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 31

32. Primary Publication Record
Harvard: no exper. details at all
ETH: full exper. details in theses only
Secondary Publication Record
(too many) publications missed altogether
covered publications (too) hard to retrieve
Tertiary Publication Record
Web (Wikipedia)
often incomplete
change of paradigm not recognizable
ETH Zurich, Laboratory of Organic Chemistry | |
Engelbert Zass 08/12/2014 32
The Total Syntheses of Vitamin B12
in the Literature

33. † July 8th, 1979
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 33

34. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 34

35. Only complete list of both Harvard and ETH
coworkers ever made public so far
Only Harvard-ETH A®B discussed,
alternative ETH A®D synthesis
not even mentioned !
Tapes Slides
no longer available
50 Harvard post-docs not mentioned
in other, published RBW lectures !
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 35

36. Miss H. Gächter
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 36

37. The ETH B12 Publication Project
A. Eschenmoser H. Zass-Gächter
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 37

38. The ETH B12 Publication Project (1979 - ?):
A Project without Precendent
Special circumstances
Size of the project:
2’123 man-months
3’732 pages of post-doc reports procedures
1’889 pages of Ph.D. theses
Form must match quality and quantity of content
Designed to render hommage
Quality control (AE)
Standardization of presentation
Project documentation (Meta data)
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39. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 39 453 Sets + 108 Lab journals

40. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 40

41. 77 Post-docs
59 reports in 1st delivery from Harvard (Jan 7th, 1980)
5 reports, 48 procedures, and spectra in 2nd delivery (Apr 22nd, 1980)
Ms. K. Jervey
10 Letters with supplementary information (procedures)
Dr. K. Burri colleagues
75 of 77 Post-docs covered
ETH Zurich, Laboratory of Organic Chemistry | |
Engelbert Zass 08/12/2014 41
Harvard Reports

42. Read and excerpt reports
Sketch synthetic pathways
Draft outline
Define selection criteria
Full experimental details (text, data, schemes)
Reaction Schemes only
Define Layout, Standards and Processes
ETH Zurich, Laboratory of Organic Chemistry | |
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Starting the Project: Harvard First

43. Not an ordinary publication –
both a historic documentation and a tribute
Full experimental details for
successfull synthesis pathways
experimental details also for major failed approaches
reaction schemes for other failed approaches
ETH Zurich, Laboratory of Organic Chemistry | |
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44. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 44

45. Jan 9th – Aug 27th,1980: total of 2’831 pages
Extract the relevant information and getting order into it
Report summaries listings
Identify the synthetic pathways: Flow sheets
Mainstream from published lectures
Additional paths from reports
Compound summaries: Edge-notched Cards
Nomenclature
Available spectra data
ETH Zurich, Laboratory of Organic Chemistry | |
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While reading …

46. Reports: Summaries
71 pages 7 pages
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 46

47. Report Listings
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48. Render Hommage:
Who did what (and when first)
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 48

49. Collecting general information (strategies)
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 49

50. Edge-notched Cards:
Compounds Data
238 compounds
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 50

51. Compounds: «speaking» numbers
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52. Nomenclature
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 52

53. My Office Whiteboard on Dec 11th, 1980
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 53

54. Defining Pathways: Harvard A-D
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 54

55. Flow Sheets:
Synthesis Pathways
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 55

56. Flow Sheets:
Reaction Details
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 56

57. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 57

58. A Tribute: not «best practice only», but something
between an anthology and a synopsis
All the chemists involved at any stage
All the variants described
Best practice described in detail,
augmented with comments (footnotes) for variants
ETH Zurich, Laboratory of Organic Chemistry | |
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Why all this effort ?

59. Attributions: Chapter Headings
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 59

60. Attributions: Individual steps
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 60

61. Attributions: Comments
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 61

62. Schemes:
alternative paths
5XX: alternative
corrnorsterone routes
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 62

63. Compound-centered:
Schemes ⇒ pathways ⇒ compounds
«speaking» compound numbers: NNNN
Modular, stand-alone experimental description
Names and roles of all chemists involved
All information associated with compounds
Footnotes assigned to compounds: NNNNA) …..
References to compounds: [NNNN/1] … (⇒ master list)
Standardized: sequence of data, abbreviations, spellings, …
Reagent solvent quality (⇒ master list)
ETH Zurich, Laboratory of Organic Chemistry | |
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Writing the Manuscripts

64. References
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 64

65. Standards
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 65

66. Reagents
Solvents
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67. Manuscript
(ETH part)
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 67

68. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 68

69. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 69

70. Handwritten ⇒ Remington Typewriter
later re-typed into Macintosh Word
599 pages (ca. 73 %)
Handwritten ⇒ Olivetti ETV 300
later converted into Macintosh Word
210 pages (ca. 25 %)
ETH Zurich, Laboratory of Organic Chemistry | |
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Manuscript Production:
Technology Changes 1979-86

71. The ETH B12 Publication Project (1979 - 1986)
Some Milestones
1979, Nov 12th: Final Decision
1980, Jan 9th: Start Reading
1980, Sep 10th: Start Writing (Harvard A-D: Ring D)
1980, Nov 20th: Ring D manuscript completed
1981, Jan 28th: Ring D finished
1983, Feb 3rd: Harvard A-D finished
1986, Feb 19th: ETH B-C finished
1986, Jul 8th: ETH Ring D finished
Total steps described (9/1980-9/1986): 220
ETH Zurich, Laboratory of Organic Chemistry | |
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72. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 72

73. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 73

74. There were other things to do, though …
Most of non-routine online searches
for the entire ETH Department of Chemistry in
Lockheed DIALOG
SDC ORBIT
CIS (NIH/EPA)
DataStar
Starting in 1981, about 90 % of all (sub)structure
searches
DARC
CAS Online (STN)
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75. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 75

76. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 76

77. 1990, Dec 5th
Conversion of Olivetti Material complete
1991, Jun 6th
Corrigenda A/D Seco-corrin completed
1991, Sep 3rd
Re-typing Remington Material complete
1992, Feb 13th
2006 (Jan): Theses into ETH e-collection (2008)
2009 (Feb): Conversion Word 5.1 (Mac) ⇒ 97-2003 (Win)
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Project resumed:
Jan 18th, 1990

78. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 78

79. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 79

80. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 80

81. ETH Zurich, Laboratory of Organic Chemistry Word Docs: 756 pages, 127’991 words Engelbert Zass | 08/12/2014 | 81

82. Still Missing:
Final steps jointly carried out at Harvard ETH
Harvard: A®B material
ETH: A®D material
ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 82

83. Ms. Kathleen F. Jervey (Harvard Univ.)
Prof. Claude Wintner (Haverford College PA)
Prof. Yoshito Kishi (Harvard Univ.)
Dr. Kaspar Burri (Hoffmann-La Roche)
Dr. Fritz Kreppelt (ETH)
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Engelbert Zass 08/12/2014 83
Acknowledgements

84. The Total Syntheses of Vitamin B12
An Epilogue
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85. 1953 1978
1’393 730
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86. Nature (1989), 342(6247), 227
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87. ETH Zurich, Laboratory of Organic Chemistry Engelbert Zass | 08/12/2014 | 87