Tandem Radical Fragmentation/Cyclization of Guanidinylated Monosaccharides Grants Access to Medium-Sized Polyhydroxylated Heterocycles

Article abstract of DOI:10.1021/acs.orglett.0c03091

The fragmentation of anomeric alkoxyl radicals (ARF) and the subsequent cyclization promoted by hypervalent iodine provide an excellent method for the synthesis of guanidino-sugars. The methodology described herein is one of the few existing general metho

Full text of DOI:10.1021/acs.orglett.0c03091

pubs.acs.org/OrgLett
Letter
Tandem Radical Fragmentation/Cyclization of Guanidinylated
Monosaccharides Grants Access to Medium-Sized Polyhydroxylated
Heterocycles
́
́
́
Andres G. Santana* and Concepcion C. Gonzalez*
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ABSTRACT: The fragmentation of anomeric alkoxyl radicals
(ARF) and the subsequent cyclization promoted by hypervalent
iodine provide an excellent method for the synthesis of guanidino-
sugars. The methodology described herein is one of the few
existing general methodologies for the formation of medium-sized
exo- and endoguanidine-containing heterocycles presenting a high
degree of oxygenation in their structure.
he guanidine functional group is a structural motif
frequently found in marine natural products that provides
less frequent; however, it is worth mentioning that a 9-
membered cyclic guanidine (V)11 has been reported as an
intermediate in the synthesis of saxitoxine, and that a few
serendipitous 7-membered guanidines (VI)12 have also been
described as inhibitors of HIV1 proteases (Figure 1).
T
them with potent biological activities.1 In fact, the interest in this
type of compounds has increased dramatically in recent years, as
it has been shown that the incorporation of this moiety into a
given molecule can lead to a wide diversity of applications,2
among which the development of new drugs,3 organocatalysts,4
and even new molecular materials5 can be highlighted. The most
remarkable natural compounds within this group are those
presenting a cyclic guanidinium, such as saxitoxin (I),6
tetrodotoxin (II),7 or crambescin A (III)8 (Figure 1). Due to
In our research group, we have been interested in the search
for new potentially biologically active compounds employing as
a key reaction the β-fragmentation of alkoxyl radicals (β-ARF)
derived from carbohydrates.13 As part of the general efforts
aimed at the preparation of novel nitrogenous compounds as
potential glycosidase inhibitors,14 we have focused our attention
on the study of different nitrogen-containing nucleophiles
leading to novel polyhydroxylated heterocycles of interest not
only because of their structure but also for their putative
activities.15 In this regard, we have been able to synthesize a
battery of imino-sugars15a and iminoketoses15b using protected
amines, as well as tetrazolo-sugars15c and benzimidazolo-
sugars,15d for which the corresponding heterocycles were used
as the nucleophilic counterpart, for the first time, in such
cyclization reactions. Considering the current relevance and
usefulness of the guanidine functional group, and having
recently developed a straightforward method for obtaining
guanidines from azides in a one-pot fashion,16 we decided to
carry out the synthesis of cyclic guanidines derived from
carbohydrates employing an analogous methodology to that
previously reported. Nevertheless, this time the internal
nucleophile, a conveniently positioned Boc-protected guanidine
group, would be responsible for the intramolecular cyclization,
Figure 1. Illustrative examples of natural and synthetic cyclic
guanidinium-containing compounds.
the complexity of their structures, these natural products have
posed a synthetic challenge for organic chemists, which in turn
has led to the development of numerous synthetic method-
ologies, especially in the synthesis of 5- and 6-membered cyclic
guanidines.9 Natural products containing higher-order cyclic
guanidines are, to the best of our knowledge, much scarcer, and
in fact only monanchorin (IV),10 which contains a bridged 7-
membered ring, is reported in the literature. For that reason,
synthetic processes aimed at obtaining these structures are much
Received: September 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03091
© XXXX American Chemical Society
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rather than an amido or an N-heterocyclic group. Another
difference with earlier works arises from the bidentate character
of the guanidine group as a nucleophile, which opens the
possibility of differentiating between the two nonequivalent
nitrogen atoms, thus making the proposed methodology more
versatile, as products of different sizes (endocyclic vs exocyclic
guanidine)17 could be generated (Scheme 1).
Table 1. Synthesis of Hemiacetals 12−17
Scheme 1. Proposed Retrosynthetic Analysis
This unprecedented procedure, which could help elucidate
the mechanistic preference governing the intramolecular
cyclization, would concomitantly allow the preparation of cyclic
polyhydroxylated guanidines of higher order.18 With this idea in
mind, we decided to prepare a series of carbohydrate models
where the guanidine group was located in different positions,
thus allowing us to study the scope in reactivity of both primary
and secondary guanidines. The synthetic sequence carried out is
described in Table 1. As starting substrates, we resorted to
different azido derivatives prepared from carbohydrates in a few
steps, in either the furanose or the pyranose form (1−6).16 The
hydrogenation of the azido group in the presence of a tertiary
amine, and the subsequent in situ protection of the resulting
amine with Goodman’s guanidinylating reagent (N,N′-diBoc-
N′′-triflyl-guanidine, GN-Tf),19 generated the corresponding
guanidinylated compound in good to excellent yields. Next, the
selective deprotection of the anomeric alcohol, employing either
́
Zemplen transesterification conditions or a hydrogenolysis
promoted by Pearlman’s catalyst, furnished the desired
precursor hemiacetals for the β-fragmentation/cyclization
reaction (12−17).
a
Reagents and conditions: (a) azido-derivative (1.0 mmol), 10% Pd/
C (20% w/w), GN-Tf (1.0 mmol), DIPEA (1.5 mmol), EtOAc (15
mL/mmol), under H2 atmosphere (balloon), overnight; (b) MeONa,
MeOH, rt; (c) Pd(OH)2/C (30%), H2 (1 atm), EtOAc, rt; (d)
Isolated yields.
In order to test our hypothesis, and to maximize the
production of cyclic compounds, the radical fragmentation
reaction was carried out using the iodosylbenzene/iodine
(PhIO/I2) system in dry dichloromethane, so that the
disfavored medium-sized cyclizations would not have to
compete with the acetate ions the more common diacetoxy-
iodobenzene reagent would liberate in the reaction medium. To
our delight, the photolysis of the D-lyxo derivative 12 under
visible light showed a total consumption of the starting material
in 3.5 h, to produce a quasi-equimolecular mixture of three
different products, in an overall yield of 83% (Table 2, entry 1).
Given the bidentate nature of the internal nucleophile
mentioned earlier, we were anticipating the formation of two
compounds: one exocyclic 5-membered and one endocyclic 7-
membered guanidine, since both exo-trig cyclizations would be
favored according to Baldwin’s rules. The key to the formation of
the third product lay in the possibility of 7-membered rings to
fuse in a cis or trans fashion to the dioxolane ring. The
assignment of the different structures was not straightforward,
due to the similarities between these regioisomers, and a
combination of different 1D- and 2D-NMR experiments,
dependence with temperature was also studied (see Supporting
Information details). Encouraged by these promising results, the
same protocol was applied to the remaining hemiacetals 13−17
(Table 2).
Similarly, when compound 13 derived from D-ribose and
structurally related to compound 12 was irradiated, again three
products were isolated under the same conditions, albeit with a
lower yield of the exocyclic guanidine 21 (5%) in favor of the
larger sized rings. The fact that the major azepanic compounds
22 and 23 slowly rearranged into the pyrrolidine derivative 21
upon standing in CDCl3 solution indicates both that the 5-
membered exocyclic guanidine is indeed more stable, and
therefore that the β-ARF/cyclization reaction takes place under
kinetic control, thus favoring the formation of the more unstable,
larger sized heterocycles. For the characterization of the
corresponding structures, a similar set of NMR experiments to
those employed in the previous case was used for this model.
The photolysis of hemiacetal 14 was particularly remarkable, as
it produced in only 30 min an exclusive spirocyclic compound in
1
including NOE and H/15N-HMBC, were necessary to fully
characterize all these structures. Additionally, these products
showed a conformational equilibrium in solution, probably
triggered by a slow rotation of the carbamates, whose
B
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Interestingly, the photolysis of the secondary guanidine 16 led
quickly and with good overall performance to an almost
equimolecular mixture of 27 and 28, both 5-membered epimeric
rings at the closing position, which however were easily
separated by rotary chromatography. The fact that only the
endocyclic guanidines were obtained this time underscores the
preferential formation of bigger sized rings. However, the almost
null stereodiscrimination exhibited by the nucleophilic attack
does suggest that, contrary to the photolysis of model 14, in this
case a transient sp2-hybridized oxocarbenium-like intermediate
must have formed upon oxidation, thus rendering compounds
27 and 28 almost in equal rates.
Table 2. Synthesis of Cyclic Guanidines 18−29
Finally, the photolysis of model system 17 also proceeded
smoothly and with good yield to afford pyrimidine derivative 29.
In this case, only one endocyclic guanidine was isolated, as the
rigidity imposed by 6-membered rings seems incompatible with
a trans fusion. Moreover, given that 4-exo-trig-cyclizations are
not as favored as the corresponding 6-exo-trig alternatives also
rules out the formation of the exocyclic azetidine. This particular
reaction was carried out in multigram scale with no apparent loss
of yield, but with a slight increase in reaction time.
A plausible mechanism, by which the tandem β-ARF/
cyclization reaction proceeds, illustrated by the transformation
of D-lyxo-derivative 12, is depicted in Scheme 2. Initially, an
Scheme 2. Plausible Reaction Mechanism for the Synthesis of
Cyclic Guanidines 18, 19, and 20
a
Conditions and reagents per mmol of hemiacetal: PhIO (2.2 mmol),
I2 (1.2 mmol), DCM (25 mL/mmol), hν, rt.
anomeric alkoxyl hipoiodite is generated by the action of the
PhIO/I2 system on the anomeric alcohol. This labile group
rapidly experiences a visible light promoted homolytic scission
to generate the corresponding alkoxyl radical, which in turn
undergoes a β-framentation of the C1−C2 bond, thus
generating a formate group from the former acetalic center
and a new C-centered radical at position C-2. Under the mild
conditions inherent to this reaction, and because of the electron-
donating nature of the substituent at this position, this radical
can now be oxidized to give rise to an oxocarbenium ion-like
intermediate, which is eventually trapped by the internal
nucleophile to render the desired cyclic guanidines. According
to our results, this last nucleophilic step occurs under kinetic
control, thus favoring the formation of larger sized rings over
that of smaller, more stable compounds. This could be due to a
higher nucleophilic character of the NHBoc nitrogen atoms over
the internal NH-nitrogen, attributable to either electronic or
steric factors.
71% yield (Table 2, entry 3). Interestingly, NMR analysis of this
new structure revealed the cyclization had occurred with a net
retention of the configuration at former position C-2, implying
that no rehybridation of the electrophilic carbon took place after
the oxidation of the corresponding C-radical, which is also in line
with a kinetic control of the second step, or that the nucleophilic
attack on such an oxocarbenium-like intermediate occurs
preferentially on one side of the sp2-hybridized carbon.
To further dissect the scope of this reaction, the pyranose
model 15 was prepared, as it could collapse in a 6-membered
(exo) or an 8-membered ring (endo). When treated with PhIO/
I2, two products, identified as the piperidine 25 and the 1,3-
diazocine 26, were obtained in a 1:2.5 ratio and with an overall
yield of 69%. Surprisingly, this time no products corresponding
to the trans-closure was purified, although other minor
byproducts were detected but could not be isolated. As in
previous cases, the predominant product is the kinetic 8-
membered cyclic product, which is an outstanding finding given
the difficulty inherent to these particular cycles.
Notwithstanding, the successful preparation of these medium-
sized guanidines demonstrates the robust versatility and novelty
of the β-ARF/cyclization protocol, enabling the synthesis of
polyhydroxylated nitrogen-containing cyclic structures other-
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(22), 19124−19134. (c) Kudo, M.; Tanatani, A. New J. Chem. 2015, 39,
3190−3196.
wise difficult to access by any reported method to date. It should
also be noted that the methodology described herein is one of
the few general existing methods for the formation of exo- and
endoguanidine sugars presenting oxidation at the pseudoano-
meric position, which gives these compounds a greater degree of
sugar character and could potentially permit subsequent
derivatization through this hemiaminal-like center.20
(6) Tsuchiya, S.; Cho, Y.; Yoshioka, R.; Konoki, K.; Nagasawa, K.;
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Hudlicky, T. Angew. Chem., Int. Ed. 2018, 57, 10994−10998 and
references cited therein.
In our opinion, the proposed methodology can be readily
implemented in the synthesis of numerous guanidine-containing
products, given the mild oxidative conditions inherent to this
protocol and the high degree of tolerance for different functional
and protecting groups, as evidenced by the heavily function-
alized nature of our model saccharidic scaffolds.
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ASSOCIATED CONTENT
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* Supporting Information
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B.; Soural, M. Eur. J. Org. Chem. 2015, 2015, 1869−1886.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03091.
Synthetic procedures, NMR characterization, and mass
spectrometry (PDF)
AUTHOR INFORMATION
Corresponding Authors
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(11) (a) Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem.
Soc. 2007, 129, 9964−9975. (b) Fleming, J. J.; Du Bois, J. J. Am. Chem.
Soc. 2006, 128, 3926−3927.
́
Andres G. Santana − Instituto de Productos Naturales y
(12) Jadhav, P. K.; Woerner, F. J.; Lam, P. Y. S.; Hodge, C. N.;
Eyermann, C. J.; Man, H.-W.; Daneker, W. F.; Bacheler, L. T.; Rayner,
M. M.; Meek, J. L.; Erickson-Viitanen, S.; Jackson, D. A.; Calabrese, J.
C.; Schadt, M.; Chang, C.-H. J. Med. Chem. 1998, 41, 1446−1455.
́
Agrobiologia del C.S.I.C., 38206 La Laguna, Tenerife, Spain;
orcid.org/0000-0003-3568-7714;
Email: andres.g.santana@csic.es
́
́
Concepcion C. Gonzalez − Instituto de Productos Naturales y
́
(13) For review, see: Suarez, E.; Rodríguez, M. S. β-Fragmentation of
́
Agrobiologia del C.S.I.C., 38206 La Laguna, Tenerife, Spain;
Alkoxyl Radicals: Synthetic Applications. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 2, pp 440−454. For selected papers on β-fragmentation of the
orcid.org/0000-0003-4913-0132; Email: ccgm@
ipna.csic.es
́
́
group, see: (a) Hernandez-Guerra, D.; Rodríguez, M. S.; Suarez, E. Eur.
Complete contact information is available at:
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́
J. Org. Chem. 2014, 2014, 5033−5055. (b) Francisco, C. G.; Gonzalez,
́
C. C.; Kennedy, A. R.; Paz, N. R.; Suarez, E. Chem. - Eur. J. 2008, 14,
́
6704−6712. (c) Francisco, C. G.; Gonzalez, C. C.; Kennedy, A. R.; Paz,
Notes
́
́
N. R.; Suarez, E. Tetrahedron Lett. 2006, 47, 35−38. (d) Gonzalez, C.
́
́
C.; Kennedy, A. R.; Leon, E. I.; Riesco-Fagundo, C.; Suarez, E. Chem. -
The authors declare no competing financial interest.
́
Eur. J. 2003, 9, 5800−5809. (e) Francisco, C. G.; Gonzalez, C. C.;
́
Kennedy, A. R.; Paz, N. R.; Suarez, E. Org. Lett. 2003, 5, 4171−4173.
ACKNOWLEDGMENTS
This research study was supported by Mineco/Feder (SAF-
2013-48399-R). A.G.S. thanks the I3P-CSIC Program for a
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(14) Compain, P. Chem. Rec. 2020, 20, 10−22.
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(15) (a) Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Suarez, E.
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N. R.; Francisco, C. G.; Suarez, E.; Gonzalez, C. C. J. Org. Chem. 2013,
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fellowship and MINECO for a JdC-incorporacion contract.
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78, 7527−7543. (c) Paz, N. R.; Santana, A. G.; Francisco, C. G.; Suarez,
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E.; Gonzalez, C. C. Org. Lett. 2012, 14, 3388−3391. (d) Andre-Joyaux,
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