Steganone is an unusual natural product, known for about 40 years now. The assignment of its absolute configurations makes for an interesting, on occasion rather confusing, and perhaps not entirely atypical story. I will start with the modern accepted stereochemical structure of this molecule, which comes in the form of two separately isolable atropisomers.

Imperial College London

Henry Rzepa

***Steganone*** is an unusual natural product, known for about 40 years
now. The assignment of its absolute configurations makes for an
interesting, on occasion rather confusing, and perhaps not entirely
atypical story. I will start with the modern accepted stereochemical
structure of this molecule, which comes in the form of two separately
isolable atropisomers.  
[![steganone](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/steganone3.svg){.aligncenter
.size-full .wp-image-13360 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/steganone3.svg)  
The first reported synthesis of this system in 1977 was racemic, and no
stereochemistry is shown in the article (structure
2).\[cite\]10.1039/P19770001674\[/cite\] Three years later an
"Asymmetric total synthesis of (-)steganone and revision of its absolute
configuration" shows how the then accepted configuration (structure
**1** in this article) needs to be revised to the enantiomer shown
as structure **12** in the
article\[cite\]10.1016/S0040-4039(00)78586-8\[/cite\] and matching the
above representation. The system has continued to attract interest ever
since\[cite\]10.1039/P19820000521\[/cite\],\[cite\]10.1039/A900743A\[/cite\],\[cite\]10.1039/C39950001943\[/cite\],\[cite\]10.1002/ejoc.201402761\[/cite\],
not least because of the presence of axial chirality in the form of
atropisomerism. Thus early on it was shown that the alternative
atropisomer, the (*aS,R,R*) configuration initially emerges out of
several syntheses, and has to be converted to the (*aR,R,R*)
configuration by heating\[cite\]10.1039/P19820000521\[/cite\]. One could
easily be fooled by such isomerism!

Absolute configurations can be established in several ways.

1.  From precursors of known absolute configuration. This was the most
    common method until relatively recently, but it is very expensive
    since asymmetric syntheses are often much more complex and longer
    than racemic ones. There is always a small residual doubt that
    any transformation in the synthesis might have altered the
    configuration in an unexpected manner.
2.  From an X-ray of the final configuration
    ([Bijvoet](http://www.ch.imperial.ac.uk/rzepa/blog/?p=6438 "Confirming the Fischer convention as a structurally correct representation of absolute configuration."){target="_blank"}).
    Very often the structure is determined on a derivative of the target
    compound (the original may not form suitable crystals). There is
    also the doubt that the selected crystals may in fact be a minor
    form and do not represent the bulk of the system in solution. This
    is especially true where atropisomerism is concerned, since the
    solid state structure may not represent the same atropisomer present
    in solution.
3.  In the last decade or so, it has become more common to make use of
    the computation of measured chiroptical spectroscopies to see if
    they match. It turns out that this method appears never to have been
    applied to Steganone, and here I attempt to rectify this.

First, let us compute the optical rotation. The (*aR,R,R*) stereoisomer
is also known as (-)-Steganone, because the measured specific rotation
is \[α\]~589~ -170° ± 30.\[cite\]10.1039/P19820000521\[/cite\] It is
computed (MN12L/6-311++G(d,p)/SCRF=chloroform) as -240°, \[α\]365
-2251\[cite\]10.14469/ch/189647\[/cite\]. The other atropisomer
(*aS,R,R*) is computed to be 4.5 kcal/mol higher in free
energy with \[α\]~589~ +408°\[cite\]10.14469/ch/189646\[/cite\], and
measured as +150.\[cite\]10.1039/P19820000521\[/cite\] There is some
uncertainty in the computed values, since the rotations can be dependent
on the conformation not only of the rings, but the substituents. You
might imagine that the conformation of eg a -OMe group is unimportant,
but this is not so. In this case, I have used a crystal structure of a
related species to serve as the start point for optimising the
MeO conformations. The greater mismatch between computation and
experiment for the (*aS,R,R*) stereoisomer probably needs an exploration
of more conformations of the -OMe groups. At least in both cases the
signs match between computation and measurement.

Next, the electronic circular dichroism (ECD), which has also been
measured\[cite\]10.1039/P19820000521\[/cite\] for the (*aR,R,R*) isomer
as Δε 201nm (-ve Cotton effect), 218 (+ve), 244 (-ve), 276 (+ve) 304
(-ve) and 337 (-ve). Bearing in mind that the baselines in ECD spectra
are notoriously difficult to define (moving it up or down can easily
invert a Cotton effect), the agreement with the calculated spectrum
MN12L/6-311++G(d,p)/SCRF=chloroform,
nstates=200)\[cite\]10.14469/ch/189649\[/cite\] might seem reasonable,
although the calculated version has more peaks in the region 225-265
than are reported (e.g. 235, +ve, 265, -ve).  
[![(R,R)-steganone-9](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/RR-steganone-9.svg){.aligncenter
.size-full .wp-image-13362 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/RR-steganone-9.svg)  
The (*aS,R,R*) isomer seems a less good fit. The +ve peak at 218 is
missing, the +ve 276 peak matches better than the other isomer, but the
337nm peak is again the wrong sign.  
[![(aS,R,R)-steganone](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/aSRR-steganone.svg){.aligncenter
.size-full .wp-image-13365 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/aSRR-steganone.svg)

Of course, in such a game it may be the DFT functional used for the
simulation that itself might be misleading, MN12L in this case. Just to
check, I also include the results using
M062X\[cite\]10.14469/ch/189657\[/cite\] to see how variable these
simulations might be. The measured peaks at 201, 218, 244 and 337nm
match, but the ones at 276 and 304nm do not.

[![s-m062x](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/s-m062x1.svg){.aligncenter
.size-full .wp-image-13381 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/s-m062x1.svg)

Although matching computed with measured ECD spectra is commonly used to
assign absolute configurations of molecules, you can see from these
results that the technique is not a cast iron one! Even scanning through
myriad DFT procedures to find the one that *fits best* is probably not a
complete solution either. Can anything be done to further increase
confidence?

How about Vibrational Circular Dichroism (VCD)
predictions?\[cite\]\[/cite\],\[cite\]10.14469/ch/189651\[/cite\]. Like
ECD, VCD is also sensitive to conformation, which is why some modern
instruments have low temperature probes operating at close to 0K which
strive to capture only a single lowest energy conformation (although of
course in any simulation, you have to identify that conformation
reliably!). At some stage in the future, the VCD spectra of steganone
might indeed be measured, and hence compared with the below. It might
serve to increase confidence in the chiroptical methods as a means of
assigning configuration.

[![(aR,R,R)-steganone](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/aRRR-steganone.svg){.aligncenter
.size-full .wp-image-13370 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/aRRR-steganone.svg)
[![(aS,R,R)-steganone](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/aSRR-steganone1.svg){.aligncenter
.size-full .wp-image-13371 decoding="async"
width="440"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2015/02/aSRR-steganone1.svg)

We might conclude from this short exploration of chiroptical
spectroscopy that no one single measured or computed value can be
absolutely definitive; rather it is the accumulation from various
sources that builds up the case for a particular configuration. But at
least the above simulations do serve to add some useful additional data
for the record.

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


<em>
 <strong>
  Steganone
 </strong>
</em>
is an unusual natural product, known for about 40 years now. The assignment of its absolute configurations makes for an interesting, on occasion rather confusing, and perhaps not entirely atypical story. I will start with the modern accepted stereochemical structure of this molecule, which comes in the form of two separately isolable atropisomers.

Chiroptical spectroscopy of the natural product Steganone.

The assembly of a molecule for a purpose has developed into an art form,
one arguably (chemists always argue) that is approaching its 100th
birthday (DOI:
[10.1002/cber.191104403216](http://dx.doi.org/10.1002/cber.191104403216){target="references"})
celebrating Willstätter's report of the synthesis of cyclo-octatetraene.
Most would agree it reached its most famous achievement with Woodward's
synthesis of quinine (DOI:
[10.1021/ja01221a051](http://dx.doi.org/10.1021/ja01221a051){target="references"})
in 1944. To start with, the art was in knowing how and in which order to
join up all the bonds of a target. The first synthesis in which
(relative) stereocontrol of those bonds was the primary objective was
reported in 1951
([10.1021/ja01098a039](http://dx.doi.org/10.1021/ja01098a039){target="references"}).
The art can be taken one step further. It involves control of the
absolute stereochemistry, involving making one enantiomer specifically
(rather than the mirror image, which of course has the same relative
stereochemistry). Nowadays, a synthesis is considered flawed if the
enantiomeric excess (of the desired vs the undesired isomer) of such a
synthesis does not achieve at least \~98%. It is routine. But ask the
people who design such syntheses if they know exactly the reasons why
their reaction has succeeded, you may get a less precise answer (or just
a lot of handwaving; chemists also like to wave their hands as well as
argue).

Here I set out one such asymmetrically stereospecific scheme, which is
the first part of a reaction used to make both natural and un-natural
configurations of aminoacids; the Strecker synthesis.

::: {#attachment_1988 .wp-caption .aligncenter style="width: 410px"}
![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/05/strecker0.jpg "strecker0"){.size-full
.wp-image-1988 loading="lazy" decoding="async"
aria-describedby="caption-attachment-1988"
onclick="jmolInitialize('../Jmol/');jmolSetAppletColor('yellow');jmolApplet([600,600],'load wp-content/uploads/2010/05/SS.mol;zoom 150;select atomno=96,atomno=81;halo on;select atomno=98;halo on;label %A ρ(r)=0.017;');"
width="400" height="156"}

The asymmetric synthesis of an S(S) sulfoxide. Click for 3D model
:::

It makes use of a natural product based on the camphor ring system which
nature provides as a single enantiomer. It is converted to an
oxaziridine, and this reagent is now used to transfer one oxygen atom to
an imino-thioether (DOI:
[10.1021/ja00030a045](http://dx.doi.org/10.1021/ja00030a045){target="_blank"}).
The result is the formation of a single S(S) enantiomer (the
enantiomeric excess is \> 98%) of a sulfoxide. In the second stage,
cyanide is then delivered asymmetrically (*i.e.* to one face rather than
the other) of the C=N group, the precursor to forming a pure enantiomer
of an amino acid. Here we will probe why the first reaction, the
asymmetric oxygen atom delivery, is so specific. It would be fair to say
that this reaction was probably originally designed with no fundamental
understanding of how it might achieve its magic asymmetric delivery. For
example, those two chlorine atoms on the camphor ring look as if they
were selected by *trial-and-error.* What indeed IS their role? Steric?
Electronic? Other?

If you click on the diagram above, a rotatable 3D model should appear (a
static version is shown below). This is an AIM (atoms-in-molecules)
analysis of the curvature of the electron density in this transition
state (see DOI:
[10042/to-4929](http://hdl.handle.net/10042/to-4929){target="new"}). To
help you navigate, arrow 1 is pointing to the small purple sphere
representing the BCP (bond critical point) for the forming S...O bond.
Three more purple spheres are highlighted with a halo. One of these is
pointed to by arrow 2 below (to see the other two, you really will need
the 3D model). This represents a BCP which appears between the hydrogen
of the N=CH group and one of the oxygen atoms of the sulphone group. The
label indicates the electron density at that point (0.017 au). This is
characteristic of a hydrogen bond, albeit an unusual C-H...O type (a
type that is too rarely invoked when explanations of stereospecificity
are sought), and the density indicates its a reasonably strong one!

::: {#attachment_2005 .wp-caption .aligncenter style="width: 309px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/05/strecker.jpg "strecker"){.size-full
.wp-image-2005 loading="lazy" decoding="async"
aria-describedby="caption-attachment-2005" width="299"
height="292"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/05/strecker.jpg)

AIM analysis of Transition state for oxygen transfer
:::

In fact, two more BCPs can be located between this H and other groups,
and they too are marked with halos. The first leads to the oxygen atom
being transferred, and the second to specifically one of the two
chlorine atoms (there are other interactions to the chlorines as well).
Now, it turns out that these interactions are largely absent for the
alternative transition state (which would form the enantiomeric R(S)
sulfoxide). Since a C-H...O hydrogen bond can easily be worth \~2
kcal/mol, it is no surprise to find that the energy of the favoured
transition state is overall 2.4 kcal/mol lower in free energy compared
to the isomer not formed. This represents (@300K) a ratio of 60:1 in the
predicted ratio of the two species, or indeed an ee \~98%.

Armed with this insight, one could design further experiments to test
the hypothesis. For example, it appears only one of the two chlorines
plays an active role. Replacing the passive chlorine with *e.g.*
hydrogen might make little difference. Suppressing the hydrogen bonds by
changing the N=CH to e.g. N=CF should have a big effect. The two oxygens
of the sulfone also do not play equal roles. Perhaps this can be tested
with a sulfoxide in place of the sulfone? All these hypotheses can of
course first be tested with calculations. Of course, coming up with
synthetic strategies for these new molecules might be tricky. But these
experiments may give confidence (or demolish it) in the AIM technique
used here to analyse the stereospecificity of this reaction.

So the next time you hear a synthetic chemist proudly announce a new
enantioselective synthesis, ask them what their deeper understanding of
why their reaction works is. And be prepared to run away fast if they
growl at you!

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


The assembly of a molecule for a purpose has developed into an art form, one arguably (chemists always argue) that is approaching its 100th birthday (DOI: 10.1002/cber.191104403216) celebrating Willstätter’s report of the synthesis of cyclo-octatetraene. Most would agree it reached its most famous achievement with Woodward’s synthesis of quinine (DOI: 10.1021/ja01221a051) in 1944.

Messaggi di Rogue Scholar

Chiroptical spectroscopy of the natural product Steganone.

Anatomy of an asymmetric reaction. The Strecker synthesis, part 1.