Of a Landmark Total Synthesis yet Unpublished in Full Experimental Detail – Vitamin B12

248th ACS National Meeting, San Francisco CA, Aug. 12, 2014

Of a Landmark Total Synthesis yet Unpublished in Full Experimental Detail – Vitamin B12

||ETH Zurich, Laboratory of Organic Chemistry 08/12/2014Engelbert Zass 2

A B12 Landmark in Zürich …



A Prologue


«Vitamin B12 Total Synthesis»:Two Syntheses of Cobyric Acid

AE, Naturwissenschaften 1974


The Beginnings

||ETH Zurich, Laboratory of Organic Chemistry

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

08/12/2014Engelbert Zass 7

1972: Completion of the Syntheses

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


� 77 Post-docs

� no Ph.D. students

� Total of 1’393 man-monthsAug. 1961 – Dec. 1975


Harvard Group


� 12 Ph.D. students

� 14 Post-docs

� Total of 730 man-monthsSep. 1960 – Aug. 1974


ETH Group


ETH: Corrin Model Syntheses 1960-1972


� 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)


The Total Syntheses of Vitamin B12

Research Records


ETH: B12 ThesesJost Wild

Urs Locher

Alexander Wick


since 2008


� Primary Literature

� Published lectures (4 + 4)

� Ph.D. Theses (12)

� Secondary Literature

� Tertiary Literature

� Web (Wikipedia)



Publication Record


Searching for the total synthesis of vitamin B12


Harvard-ETH

A→B(1973)


ETH

A→D(1977)


SciFinderSecondary Literature


SciFinder Topic Search:Results



Scopus





red: article not covered at all

Query «total synthesis of vitamin B12 / … cobyric acid»:

yellow: article not found

green: article found



References in Literature Databases


DOI: 10.3929/ethz-a-010165162


Tertiary Literature: 38


20 of 38


Resonance (2003), 8(6), 8-16

8 of 38


until 7/7/2014


� 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



in the Literature


† July 8th, 1979



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 & Slidesno longer available

50 Harvard post-docs not mentioned

in other, published RBW lectures !


Miss H. Gächter


A. Eschenmoser H. Zass-Gächter

The ETH B12 Publication Project


� 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)


The ETH B12 Publication Project (1979 - ?):A Project without Precendent

||ETH Zurich, Laboratory of Organic Chemistry 08/12/2014Engelbert Zass 39453 Sets + 108 Lab journals



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


Harvard Reports


� 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


Starting the Project: Harvard First


� Full experimental details for

successfull synthesis pathways

� experimental details also for major failed approaches

� reaction schemes for other failed approaches


Not an ordinary publication –both a historic documentation and a tribute



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


While reading …


Reports: Summaries

71 pages 7 pages


Report Listings


Render Hommage:Who did what (and when first)


Collecting general information (strategies)


Edge-notched Cards:Compounds & Data

238 compounds


Compounds: «speaking» numbers


Nomenclature


My Office Whiteboard on Dec 11th, 1980


Defining Pathways: Harvard A-D


Flow Sheets: Synthesis Pathways


Flow Sheets: Reaction Details



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


Why all this effort ?


Attributions: Chapter Headings


Attributions: Individual steps


Attributions: Comments


Schemes:alternative paths

5XX: alternative

corrnorsterone routes


� 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)


Writing the Manuscripts


References


Standards


ReagentsSolvents


Manuscript(ETH part)




� Handwritten ⇒ Remington Typewriterlater re-typed into Macintosh Word

599 pages (ca. 73 %)

� Handwritten ⇒ Olivetti ETV 300later converted into Macintosh Word

210 pages (ca. 25 %)


Manuscript Production:Technology Changes 1979-86


� 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


The ETH B12 Publication Project (1979 - 1986)

Some Milestones




� Most of non-routine online searchesfor 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)


There were other things to do, though …




� 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)


Project resumed:Jan 18th, 1990




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


Still Missing: Final steps jointly carried out at Harvard & ETH

Harvard: A→B material

ETH: A→D material


� 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)


Acknowledgements



An Epilogue


1’393 730

1953 1978


Nature (1989), 342(6247), 227


Science

Of a Landmark Total Synthesis yet Unpublished in Full Experimental Detail – Vitamin B12