Use of the Nosyl Group as a Functional Protecting Group in Applications of a Michael/Smiles Tandem Process

Article abstract of DOI:10.1021/acs.orglett.6b02105

Concise preparations of elaborated polycyclic and heterocyclic systems present in natural products were obtained using the nosyl group as a functional protecting group not only to mask the reactivity of a sensitive moiety but also to provide a structure desired in the final target. The group is transferred to the substrate during deprotection through a novel extension of the Truce-Smiles rearrangement in tandem with a 1,4-addition. This strategy provides access to a ring system laden with valuable functionalities for subsequent manipulations and can serve as a versatile building block for the construction of more complex molecular architectures such as indoles in a manner compatible with the concepts of green chemistry and atom economy.

Full text of DOI:10.1021/acs.orglett.6b02105

Letter
pubs.acs.org/OrgLett
Use of the Nosyl Group as a Functional Protecting Group in
Applications of a Michael/Smiles Tandem Process
Siomenan Coulibali, Timothe Godou, and Sylvain Canesi*
́
Laboratoire de Met
́
hodologie et Synthes
̀ ́ ́ ̀ ́
e de Produits Naturels, Universite du Quebec a Montreal, C.P. 8888, Succ. Centre-Ville,
Montreal, H3C 3P8, Queb
́
́
ec, Canada
S
* Supporting Information
ABSTRACT: Concise preparations of elaborated polycyclic and heterocyclic systems present in natural products were obtained
using the nosyl group as a functional protecting group not only to mask the reactivity of a sensitive moiety but also to provide a
structure desired in the final target. The group is transferred to the substrate during deprotection through a novel extension of
the Truce−Smiles rearrangement in tandem with a 1,4-addition. This strategy provides access to a ring system laden with
valuable functionalities for subsequent manipulations and can serve as a versatile building block for the construction of more
complex molecular architectures such as indoles in a manner compatible with the concepts of green chemistry and atom
economy.
here is a general understanding that sustainable, environ-
Tmentally benign routes to synthetic targets should be
atom economical1 and protecting group-free,2 yet it is often
difficult to achieve these ideal conditions when preparing
challenging polyfunctional molecules. As a complement of
these important strategies, a new approach would envisage the
development of “functional protecting groups” that not only
mask the reactivity of sensitive ensembles but also carry a
moiety desired in the final target and which will be transferred
to the substrate at the time of deprotection via an extension of
the Truce−Smiles rearrangement,3 Figure 1. This strategy
would provide the benefits of protecting groups while
minimizing the need for additional steps and atom waste.
the aryl moiety has to be electron poor. In this objective, a
Fukuyama-type sulfonamide4 appears to be an ideal function-
ality where the SO2 segment would be used as a leaving tether
group first and as a single byproduct at the end. Futhermore,
the nitro-aryl may be converted into indoles and indolines by a
subsequent reduction. It should be noted that many alkaloids
such as (+)-kopsihainanine A5,6 from the kopsia hainanesis
family or (+)-tabersonine from the aspidosperma family7
contain an aryl group connected to an inherently nucleophilic
carbon atom, Figure 2.
In this paper, we describe the rapid formation of poly- and
heterocyclic systems using the nosyl functionality as a
protecting group and to provide a portion of the target
molecule. This reaction proceeds under slightly basic (cesium
Figure 1. Truce−Smiles transformation.
If the Truce−Smiles transformation opens up several
opportunities in synthesis, this powerful tool would offer a
plethora of novel synthetic strategies if it were judiciously
combined in a tandem manner with another important
transformation such as a 1,4-addition that would be triggered
by the functional protecting group. Since the Smiles rearrange-
ment majoritarily involves an intramolecular Sn-Aryl process,
Figure 2. Functional protecting group approach and alkaloids.
Received: July 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02105
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carbonate) conditions at moderate (65 °C) temperatures.
Acetonitrile was selected as the solvent due to its identification
as an environmentally benign organic solvent by the CHEM21
consortium, with an environmental impact score similar to
ethanol.8 Prochiral dienone starting materials 8 were first
employed to delineate the scope, limits, and stereoselectivity of
the technique. The dienones were obtained in good yields
through a hypervalent iodine activation of phenols9 in the
presence of alcohols10 (Scheme 1).
Table 1. Formation of Pyrrolidine or Piperidine Moieties
entry
n
X
NO2
ortho
R1
R2
yield (%)
a
b
c
d
e
f
1
1
1
2
1
1
2
1
1
1
1
CH2
OMe
OEt
H
H
H
H
90
86
82
94
62
63
73
64
76
75
73
CH2
ortho
para
Scheme 1. Rapid Elaboration of Polycyclic Systems
CH2
OMe
OMe
OMe
OEt
CH2
ortho
ortho
ortho
para
CH2
CO2Me
CH2
CO2Me
g
h
i
CH2
OMe
OMe
NHAc
Et
H
CH2
ortho-para
ortho
ortho
ortho
H
CH2
H
j
O−CH2
O−CH2
H
k
Et
Me
lective pathway were also tested. We were pleased to observe
that formation of the 6-membered ring 12k occurred with good
selectivity.12 However; the process was not effective for the
formation of seven membered rings.
Surprisingly, activation of 8 in the presence of cesium
carbonate yields enone 12 rather than 10 (or 5 described in
Figure 2). This may be the result of a retro-aza-Michael11
reaction on intermediate 10 promoted by its conjugated
enolate form under basic conditions. The process would
terminate with a 1,4-addition on the second double bond
leading to 12 which also appears to be a valuable synthetic
scaffold. In this instance, adduct 5 (Figure 2, or compound 10)
would be present only as an intermediate but would explain the
stereoselectivity12 obtained through an envelope- (n = 1) or
chair- (n = 2) like transition state during the process. A
potential mechanism is depicted in Scheme 2.
This approach is not limited to intramolecular reaction of
sulfonamides and may be extended to carbon-based nucleophile
14 or 16 in an intermolecular pathway. No retro-Michael
process is observed in the presence of carbon-based
nucleophiles, probably due their higher pKa. The same reaction
may be performed in the presence of the ortho- or para-nitro
adducts to produce α-β-disubstituted cyclohexanones 15 and
17 in similar yields. A diastereoselective route13 to 25 was
investigated using 18 as an Evans derivative of 14. This
transformation yielded 20 in 42% yield with excellent
diastereoselectivity (>1:19 dr),12 demonstrating the feasibility
of an asymmetric version of the Michael−Smiles tandem
process (Scheme 3). Compound 19 represents a potential
transition state of this stereoselective transformation.
Scheme 2. Proposed Mechanism of the Michael−Smiles
Process
The transformation has also been extended to dienimines
2114 in the presence of the carbon-based nucleophile 22. As
described in Scheme 3, no retro-Michael process occurred and
the direct formation of the α-β-disubstituted adducts 23 was
Scheme 3. Intermolecular Application of Carbon-Based
Nucleophiles
Compound 12 represents an interesting scaffold containing a
pyrrolidine or a piperidine moiety as well as a cyclohexanone
functionality connected to an electron-withdrawing nitroaryl
group. This core may be obtained in good yield from phenol 7
in only two steps (Scheme 1). The transformation was
extended to several other substrates to investigate the scope
of the new process (Table 1). Interestingly, good diaster-
eoselectivity observed by NMR (1:19 dr) and controlled by the
methyl ester was obtained when a tyrosine derivative was used
(R = CO2Me, 12e and 12f) to yield the 5-membered ring.
Examples including alkyl chains connected through an ether
linkage and an asymmetric center to develop a diastereose-
B
DOI: 10.1021/acs.orglett.6b02105
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
observed. It should be noted that the products were isolated in
their enamine form, probably as the result of conjugation
induced by the nitro-aryl segment, Table 2.
Scheme 4. Michael Acceptor Moiety as the Trigger Process
Table 2. Carbon-Based Michael−Smiles Process on
Dienimines
entry
R
R1
R2
R3
yield (%)
a
Et
n-Pr
OMe
OMe
OMe
OMe
H
H
H
H
H
H
57
52
49
79
Scheme 5. Indole Formation
b
c
CH2CO2Me
OMe
d
CHCH−
CHCH
e
O−CH2−CH2−O
CHCH−
CHCH
62
The approach may also be used to yield ortho-meta-
disubstituted anilines through a 1,4-addition−Smiles-aromatiza-
tion process. Indeed, slightly acidic conditions promoted
elimination of methanol, leading to anilines 25. This method
is tolerant of spectator functionalities such as alcohols and
esters, Table 3.
Table 3. Formation of Polysubstituted Anilines
entry
R1
R2
yield (%)
requires mild conditions to enable the rapid formation of
functionalized cores and provide a new means of accessing
indoles, and releases only sulfur dioxide by gas evolution. This
approach is not restricted to nitrogen-based nucleophiles, but
may also be extended to carbon-based nucleophiles. Direct
applications of this novel approach in total synthesis of natural
products are currently under investigation in our laboratory.
a
Et
H
83
85
b
c
n-Pr
Me
H
a
Me
H
60
a
d
e
CH2OH
66
CH2CO2Me
H
88
a
Directly obtained from their 21 derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
In addition, the migrating aryl segment may be introduced
S
on the Michael acceptor moiety to afford a mixture of
diastereomers 30 through a similar Michael−Smiles process.
Indeed, a 1,4-addition on enimine 26 generated an aza-enolate
28 which triggered the Smiles rearrangement leading to the
α,β-disubstituted cyclohexanone 30 in 63% yield, Scheme 4.
It should be noted that the nosylamide protecting group
transferred during the “Smiles deprotecting step” produces an
aryl-nitro segment that can act as a precursor for a variety of
structures. As an example of the potential of this approach, the
nitro-aryls may be converted into indoles, which are important
bioactive functionalities present in numerous bioactive
products, by reduction with hydrogen on palladium.15 This
method was also employed to transform the mixture of
diastereomers 30 into a single indole 33 in good yield, Scheme
5.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02105.
Experimental procedures and spectral data for key
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: canesi.sylvain@uqam.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
In summary, a novel tandem Michael−Smiles process has
been developed based on the use of a functional protecting
group that not only masks the reactivity of sensitive groups but
also carries a moiety desired in the final product. This strategy
We are very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Founda-
tion for Innovation (CFI), and the provincial government of
Quebec (FQRNT and CCVC) for their precious financial
C
DOI: 10.1021/acs.orglett.6b02105
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Aparici, I.; Guerola, M.; Dialer, C.; Simon
́ ́
-Fuentes, A.; Sanchez-
support in this research. S. Coulibali thanks the “Programme
Canadien de Bourses de la Francophonie” for a scholarship.
Rosello, M.; Del Pozo, C.; Fustero, S. Org. Lett. 2015, 17, 5412.
́
(12) Only one diastereomer was observed by NMR, and the
stereoselectivity has been verified by nuclear Overhauser effect
(NOE). For similar observations on the literature, see: (a) Wipf, P.;
Kim, Y. Tetrahedron Lett. 1992, 33, 5477. (b) Wipf, P.; Kim, Y.;
Goldstein, D. J. Am. Chem. Soc. 1995, 117, 11106. (c) Wipf, P.; Li, W.
J. Org. Chem. 1999, 64, 4576. (d) Wipf, P.; Mareska, D. A. Tetrahedron
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(13) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) For a previous similar approach to produce optically
active bicyclic structures, see: Holub, N.; Jiang, H.; Paixao, M. W.;
Tiberi, C.; Jørgensen, K. A. Chem. - Eur. J. 2010, 16, 4337.
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Org. Lett. XXXX, XXX, XXX−XXX