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Primary: Chemistry, Biology and Geosciences
Prof. Mauro F. A. Adamo, Professor (Chair) of Organic and Medicinal Chemistry
Department of Pharmaceutical and Medicinal Chemistry, 123 St Stephen’s Green, Dublin 2,
Dublin
https://research1.rcsi.ie/pi/madamo/
Professor Mauro F. A. Adamo is the Chair of Organic and Medicinal Chemistry at RCSI. He
obtained an M.Sc. in Pharmaceutical Chemistry and Technology (maximum cum Laude,
1997, Florence) and Ph.D. in enantioselective catalysis under the supervision of Prof. V.K.
Aggarwal (2001, Sheffield). He has spent two years as Post-Doc in Oxford working under
the supervision of Prof. J.E. Baldwin before joining RCSI at the end of 2002. The Adamo’s
group research is focussed on the development of new synthetic technologies for the
production of bioactive natural products and pharmaceutical active ingredients. The group
built a strong reputation in the areas of: (a) organocatalysis, (b) enantioselective phase
transfer catalysis, (c) multi component reactions, (d) synthesis of modified nucleosides and
oligonucloetides and lately in (e) peptide-nucleic acids and their application as miRNAbased antitumor. Prof. Adamo is co-founder of Kelada Pharmachem ltd
(www.keladapharmachem.com), a spin-out company which primary mission is the
development of green and cost efficient processes for the manufacture of active
ingredients.
n/a
n/a
Development of metal free green process for enantioselective C-H functionalisation
1. Aims: This projects aims at identifying a set of suitable conditions to convert
enantiopure sulfonyl azides 1 to cyclic sulfonamides 3 (Scheme 1) using photolysis. This
method would constitute a greener methodology to achieve functionalisation of aliphatic
C-H, via generation of nitrene intermediate 2. The photolysis of azides has been reported
to form nitrenes.1 Azide-based nitrene-transfer reactions would not only generate
chemically stable and environmentally nitrogen gas as the only by-product, but could also
proceed under neutral and non oxidative conditions. Despite these potential advantages,
catalytic C-H amination with azides is largely underdeveloped, as the metal-mediated
decomposition of azides is generally considered to be ineffective.2
O
SO2N3
R2
R1
O2 H H
S N
hv
R1
O
1
H
2
R2
O2
S
R1
O
NH
R2
3
Scheme 1
The target sulfonyl azides can be accessed from enantiopure sulfonic acids 4 which we
have prepared via organocatalytic addition of bisulfite to
-unsaturated alkenes.3
Therefore, the method proposed, coupled with enantioselective sulfonylation will provide
a new synthetically useful disconnection to prepare cyclic sulfonamides in enantio and
diastereo controlled fashion (Scheme 2). The synthesis is modular, uses cheap materials 6
and 7 available in great diversity and furnishes enantiopure sulfonamides that are of
interest for drug discovery and synthetic chemistry.
O2
S
R1
NH
O
C-H
insertion
R2
3
O
SO2N3
O
R2
R1
Enantioselective
Sulfonylation
O
SO3Na
R1
O2
S
ORGANO
CATALYSIS
NH
R2
3
PHOTO
CHEMISTRY
6
7
R2
O
O
O
R1
5
4
R1
O
R2
R1
1
R2
O
R2
R1
N3Na
NaHSO3
PCl5
6
7
Scheme 2
2. Background: the amination of aliphatic C-H bonds is a general and selective method for
the efficient preparation of
O2
O2
amines (Scheme 3).4 Among
S
S
HN
NBoc
H2N
NBoc
1 mol% [Rh2(esp)2]
different approaches, metal
PhI(OAc)2, MgO
R
R2 mediated
R
R2
nitrene insertion
i-PrOAc
R1
R1
reactions are one of the most
8
9
general and direct methods for
Scheme 3
installing amino groups.5 This
approach has been exemplified by Du Bois and co-workers; who elegantly demonstrated
that N-Boc protected sulfamides 8 could be selectively converted into cyclic sulfamides by
[Rh2(esp)2] 9 in combination with PhI(OAc)2 and MgO (Scheme 3).6 More recently, it has
been shown that cobalt(II)
O2
O2
complexes of porphyrins
Me
S
Me
S
N
N3
N
NH
[CO"(por)] (2 mol%)
[CO(por)2] act as efficient
PhCF
,
4
A
MS,
40
'C,
20
hours
3
Me
Me catalysts
for
C-H
11
10
amination(Scheme 4).7 This
Scheme 4
system has advantages over
Du Bois and co-worker’s rhodium system in that it accommodates various azide substrates
without the need for terminal oxidants and other additives. Lu et al. reported a class of
cobalt catalysts which efficiently generated 6-membered rings from sulfonyl azides via a
selective 1,6-C-H nitrene insertion process (Scheme 4).8 Interestingly, this system tolerated
a variety of functional groups (esters or amides) without erosion of yields. Under these
catalytic conditions, secondary, tertiary and strong primary C-H bonds were shown to
efficiently undergo amination. Mechanistically, it was proposed that this reaction went
through a ‘radical nitrene’ intermediate. Interestingly, only one paper has reported the
photolysis of sulfonyl azides and insertion of the resulting nitrene into a C-H bond.
However, it is widely accepted that sulfonyl azides decompose to give nitrenes when
photolysed. Based on this information we decided to start a program of research aimed at
identify whether a sulfonyl nitrene such as 1 (Scheme 1) could be employed as chiral
substrate to perform amination of an sp3 hybridised C-H. We have recently discovered a
highly enantioselective process for the sulfonylation of electron withdrawn alkenes 12.3
This process gave sulfonic acids such as 13 in high yields and excellent enantioselectivity
(Scheme 5). The optimal conditions involved using 0.05 equiv of amines 14-15. We have
also shown that compounds 13 could be re-crystallised to obtain enantiopurities superior
to 99%. The use of pseudoenantiomeric catalyst 15 produced the enantiomer of opposite
configuration in similar yields and enantioselectivity.
aq. NaHSO3 (1.1 equiv)
amine 15 or 39 (0.1 equiv)
O
R1
R
12
Toluene : CH3OH,
0oC, 16 h.
CH3O
CH3O
O
R1
SO3Na
R
N
N
85-98% yield
92-99%ee
N
NH
NH
14
13
Scheme 5
N
S
CF3
F3C
NH
NH
15
S
CF3
F3C
We have shown that R and R1 (Scheme 5) could be any substituted aryl, heteroaromatic or
alkyl group (linear or branched). Therefore, the range of enantiopure acids 13 is wide
enough to allow an extensive investigation. We have already shown this process to be
scalable and compounds 13 were obtained in similar yields and ee when the reaction was
conducted either on 100mg or 10g scale.
3. Project layout: We will start this investigation from sulfonyl azide 18 (Scheme 6) which
will be opportunely prepared from commercially available acetophenone 16 and hexanal.
The first step involves an aldol-condensation affording 17 which will then undergo
sulfonylation under the conditions developed in our group.3 Subsequent chlorination of
sulfonate followed by reaction with sodium azide will provide required starting material 19.
1) LDA,
Hexanal
2) TsOH
O
16
O
17
cat. (0.1 equiv.),
NaHSO3 (1.2 equiv.),
MeOH/toluene (3:1),
O
SO3 Na
Ph
1) PCl5
2) NaN3 Ph
O
SO3 N3
19
18
Scheme 6
The photolysis of compound 19 will be therefore studied in various solvents and by
irradiation under stirring in two different set up: (a) Rayonet chamber fitted with 300nm
emitting bulbs; (b) Immersion lamp
O2
set up using a Hg medium pressure
O
SO3N3
Ph
S
hv
NH
lamp. Solvent will be selected from
Ph
O
Solvent
trifluoromethyltoluene,
toluene,
19
20
acetonitrile, tetrahydrofuran and
Scheme 7
acetonitrile. The azide functionality
has a max UV absorption at 300-310 nm while aromatic ketones absorption is set at about
220 nm. Therefore is possibile to selectively activating the azide in presence of the ketone.
We will carry out this test and if this
O
SO3N3
will prove experimentally wrong will
27
21
O
Ph
proceed by reduction of ketone
O
SO3N3
functionality in acid 19 prior to
28
22
Ph
O
formation of azide (vide infra).
Reaction condition will be optimised
O
SO3N3
29
to obtain desired compound 22 in
23
Ph
O
yields superior to 75% and with total
O
SO3N3
diastereocontrol. This will be
O
O
24
O
30
Ph
achieved by systematic variation of
parameters such as concentration,
O
SO3N3
reaction
time,
solvent
and
N
31
25
N
Ph
O
temperature. In this regards we
O
O
O
SO3N3
have planned using the immersion
26
32
O
lamp set up in order to achieve a
Ph
finest
control
of
reaction
Figure 2
temperature which could be made
as lower as -70°C by circulating cryostat temperature controlled liquid. Once obtained a set
of optimal conditions we will study the scope of reaction. This will be done by carrying
aldehydes 21-26 (Figure 2) through the synthesis highlighted in Scheme 6 to prepare
corresponding azides 27-32. In particular, reaction of azide 27 will establish the reactivity
primary C-H in this procedure; reaction of azide 28 the reactivity of tertiary C-H; reaction of
azide 29 the reactivity of benzylic C-H; reaction of azides 30-31 the reactivity of
heteroatom linked C-H; reaction of azide 32 the reactivity of other long chain C-H. We will
also study the reactivity of azides 43 and 51-56 under the CoII catalysed process described
by Lu,8 as these substrates are related but significantly different from those used by these
authors (compare Schemes 4 and 7). As discussed above, we are prepared for eventual
problems arising from the presence of ketone in the photochemical step. Should this
happen, we will reduce the ketone in 19 to deoxygenated 33 (Scheme 8) and then will
proceed to preparation of azide 34.
The rational behind choice of reactants is to use mild, non basic conditions in order to
preserve the chirality in 57 from epimerization. For this reason, we have decided not to
O
SO3Na
Ph
method a: TsNHNH2/NaBH4
method b: NaBH4/ MsCl-NaBH4
method c: FeCl36H2O/PMHS
SO3Na
Ph
19
33
1) PCl5
2) NaN3
SO3N3
Ph
34
Scheme 8
employ the obvious Wolff-Kishner reduction, at least at the onset, because it employs
strongly basic conditions (NH2NH2 excess, KOH) and high temperatures, although the pka
of sulfonic acid -C-H is in the range 24-289 and it is likely that presence of anions (SO3-,
enolate) will push this number higher. The reduction of carbonyls could be carried out
using catalytic hydrogenation, for example PtO2 and H2 or Pd/C and H2. However we aim at
minimising the use of expensive reagents, for which reason we will first attempt the
reduction of compound 42 using the Caglioti reaction10 (Scheme 14, method a) which
involves the formation of a tosylhydrazone and its reduction with NaBH4. Suitable
alternative methods are the reduction with NaBH4 to alcohol, mesylation and subsequent
reduction using NaBH4 (Scheme 14, method b) or the conditions described by Dal Zotto,11
PHMS / Fe3+ (Scheme 14, method c), in which a Lewis acid is activating the C-O bonds
towards the attack of a mild silyl hydride. In is important to notice that sulfonic acids are
remarkably inert to reduction12 and therefore they could be kept unprotected. We will
define a set of optimised conditions required for the reduction of compound 19 by
variation of standard parameters such as solvent, temperature, ratio of reactants, reaction
time. The enantiomeric purity of desired compound 33 will be checked by methylation of
sulfonic acid using TMS diazomethane and chiral HPLC analysis. Compound 34 will then be
used in place of compound 19 in the optimisation process as highlighted above. Similarly,
the scope of reaction will then involve synthesis of derivatives of compound 34 using
aldehydes 21-26.
1. Hoyle, C. E., Lenox, R. S., Christie, P. A., Shoemaker, R. A. J. Org. Chem. 1983, 48, 2056.
2. a) R. P. Reddy, H. M. L. Davies, Org. Lett. 2006, 8, 5013. b) H. Lebel, O. Leogane, K.
Huard, S. Lectard, Pure Appl.Chem. 2006, 78, 363.
3. (a) M. Moccia M., F. Fini, M. Scagnetti, M. F. A. Adamo, Angew. Chem. Int. Ed. 2011, 50,
6893; (b) F. Fini, M. Nagabelli, M. F. A. Adamo, Adv. Synth. Catalysis, 2010, 3163.
4. For a good review on azides in organic chemistry see; Bráse, S., Gil, C., Knepper, K.,
Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44, 5188.
5. a) Collet, F., Dodd, R. H., Dauban, P. Chem Commun. 2009, 5061; b) Davies, H. M. L.,
Manning, J. R. Nature 2008, 451; c) Davies, H. M. L. Angew. Chem. 2006, 118, 6574; Angew.
Chem. Int. Ed. 2006, 45, 6422; d) Davies, H. M. L., Long, M. S. Angew. Chem. 2005, 117,
3584; Angew. Chem. Int. Ed. 2005, 44, 3518.
6. a) Espino, G. C., Du Bois, J., Angew. Chem. 2001, 113, 618; Angew. Chem. Int. Ed. 2001,
40, 598; b) Kurokawa, T., Kim, M., Du Bois, J. Angew. Chem. 2009, 121, 2815; Angew.
Chem. Int. Ed. 2009, 48, 2777.
7. a) Ruppel, J. V., Kamble, R. M., Zhang, X. P. Org. Lett. 2007, 9, 4889; b) Lu, H., Tao, J.,
Jones, J. E., Wojtas, L., Zhang, X. P. Org. Lett. 2010, 12, 1248; c) Lu, H.,Subbarayan, V., Tao,
J., Zhang, X. P. Organometallics 2010, 29, 389.
8. Lu, H., Jiang, H., Wojitas, L., Zhang, X. P. Angew. Chem. Int. Ed. 2010, 49, 10192.
9. Bordwell pKa tables: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
10. L. D. Miranda, S. Z. Zard, Chem. Comm. 2001, 1068; L. Caglioti, P. Grasselli, Chem. Ind.
London 1964:153.
11. C. Dal Zotto, D. Virieux, J-M. Campagne, Synlett, 2009, 276.
12. Comprehensive organic synthesis: Reduction, Volume 8, p408. Ian Fleming editor.
Skills &
techniques that
the student will
learn from the
project
Overview
This project has been carefully designed to deliver innovative and valuable synthetic and
analytical skills. The training components of the project include focus on a variety of
specific scientific disciplines, methodologies used in the synthesis and purification of
organic compounds, include, controlled atmosphere and temperature reactions,
chromatography, 1H-NMR, 13C-NMR, Mass spectroscopy, IR, UV, GC, and HPLC.
Transferrable skills training and acquisition.
In addition to acquiring a complementary and synergistic set of skills in different scientific
disciplines, the trainee will also be considerably enhanced through acquisition of “softer”
transferrable skills which are applicable in whichever career path student ultimately
undertake. Skills such as problem-solving, communication, adaptability, team-working will
naturally be developed as a result of their day-to-day work on their individual projects in
the context of a larger team in their host research group. It is also intended to gradually
increase the responsibilities given to each of the student and thereby build their
management, administrative and communication skills – e.g. tutorials, final-year
undergraduate project supervision, presentations at conferences and symposia,
interaction with patent agents, technology transfer officers etc. These skills will help to
cement the trainee experience and ensure thus boosting their employability credentials independent of geography or sector.
Key distinguishing
points about this
RCSI project
The proposed project offers the opportunity to develop a new area of organocatalysis in
which phase transfer catalysts work as bifucntional molecular machines.
Which
undergraduate
disciplines are
relevant for this
project
Organic synthesis, analytical chemistry.