Imperial College London

Henry Rzepa

Streptomycin is an antibiotic active against tuberculosis, and its
discovery has become something of a cause célèbre. It was first isolated
on October 19, 1943 by a graduate student [Albert
Schatz](http://www.albertschatzphd.com/?cat=articles&subcat=streptomycin&itemnum=001){target="_blank"}
in the laboratory of Selman Waksman at Rutgers University. I want to
concentrate in this post on its molecular structure. Its initial
isolation was followed by an extraordinarily concentrated period of
about three years devoted to identifying that structure, culminating in
a review of this chemistry in 1948 by Lemieux and
Wolfram.\[cite\]10.1016/S0096-5332(08)60034-X\[/cite\] This review
presents the structure as shown below (left). The modern rendering on
the right is based on a crystal structure done in
1978.\[cite\]10.1098/rspa.1978.0047\[/cite\]^‡^

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| [![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/streptomycin.jpg "streptomycin"){.aligncenter .size-full .wp-image-6861 loading="lazy" decoding="async" width="236" height="546"}](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/streptomycin.jpg) | ![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/05/streptomycin.svg "streptomycin"){.aligncenter .wp-image-6862 loading="lazy" decoding="async" onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('white');jmolApplet([450,450],'load wp-content/uploads/2012/05/STOSEH10.cif;frame 19; zoom 100;');" width="285" height="250"} |

My interest in this was kindled by wondering how elucidating such a
structure would be accomplished during the 1940s. None of the modern
structural techniques were available then (NMR, MS, X-Ray); only IR and
polarimetry (optical rotation). So how was it done? Well, the same way
it had been done for the previous 100 years or so; degradation. In this
case, into three smaller fragments, labelled **A-C** in the rhs diagram,
and named *streptidine*, *streptose* and *glucosamine* in the original
analysis.

1.  This reduction to smaller fragments is set out on page 338 of the
    Lemieux and
    Wolfram article.\[cite\]10.1016/S0096-5332(08)60034-X\[/cite\]
2.  The procedure to isolate streptomycin is described from p343 and the
    purification on p345, which concludes with the molecular formula
    C~21~H~37-39~N~7~O~12~
3.  On p346, after evaluating other methods for determining the
    molecular weight, C~21~H~39~N~7~O~12~ is the final candidate for its
    formula.
4.  Next, "strongly basic" degradation yields streptidine (Ring C), with
    the formula C~8~H~18~N~6~O~4~. Likewise, formulae were established
    for the other components.
5.  On p347, the odyssey to assemble a structure from this information
    begins. I will not dwell on the details. But by p359, a partial
    structure of Streptidine-streptose-N-methyl-L-glucosamine is
    suggested.
6.  By p366, they have boiled it down to two possibilities (they call
    XXXIX and XL), and they abandon the hydrolytic procedures used up to
    that point and adopt oxidative reactions, which narrow it down
    to XXXIX.
7.  The next property to be used to determine the structure is optical
    rotation. They knew it incorporates an L-sugar (whose absolute
    configuration was not known in 1948), and of course there are 15
    stereogenic centres in the entire system (32768 possibilities). P368
    -375 continues discussion of the stereochemistry, and in particular
    the need to demonstrate that none of the degradative/oxidative
    procedures have interfered with it, so to speak.
8.  By p375, it has all boiled down to the stereochemistry of the
    glycosidic bonds (marked with a red ring above). This was assigned
    on the basis of optical rotations and the use of additive rules
    (Table 1 of their article). This discussion ends with the
    stereochemistry shown above. Although initially assigned *trans*, it
    was subsequently revised to *cis*, and then back to *trans* again.
9.  On p382, the wrap up has started. Table III there shows the
    properties of the 18 products obtained merely from the preparation
    of ring A (for comparison with the product obtained by degradation).
    Some 127 articles have been cited for supporting information and
    around 50 pages of tight logical argument presented as evidence,
    similar in length indeed to the longer mathematical proofs!
10. There was one residual uncertainty (green ring above) that had to
    wait for the crystal structure in 1978 to resolve. It took so long
    because of the challenge of finding a crystalline derivative.

I cannot help but note that the skills required to assemble a structure
by degradation, and no use of NMR, MS or X-ray, were formidable, and
very probably there are few chemists alive nowadays who could do a
similar job (the motivation to do so would also be lacking). Assuming
good crystals were available, solving such a structure nowadays using
crystallography would only take 24 hours or so. And structures with 100+
stereogenic centres can now be done. When
Woodward [muse](http://www.youtube.com/watch?v=ph19KFpllDU)d about the
progress in chemistry, he might have had streptomycin in mind. I think
it is worth remembering that the structural chemistry of 60 years ago
was quite an intellectual achievement.

------------------------------------------------------------------------

^‡^In fact the structure was first reported in
1968\[cite\]10.1016/S0040-4039(00)75942-9\[/cite\] but the coordinates
in the CSD (Cambridge structure database) derive from the 1978 report.

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[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
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Streptomycin is an antibiotic active against tuberculosis, and its discovery has become something of a cause célèbre. It was first isolated on October 19, 1943 by a graduate student Albert Schatz in the laboratory of Selman Waksman at Rutgers University. I want to concentrate in this post on its molecular structure.

Postagens de Rogue Scholar

Streptomycin: a case study in the progress of science.