Asymmetric allylation/pauson-khand reaction: A simple entry to polycyclic amines. Application to the synthesis of aminosteroid analogues

Article abstract of DOI:10.1021/ol500142c

Asymmetric allylation of o-iodoarylsulfinylimines has been achieved in high diastereoselectivities. The thus-obtained o-iodoarylhomoallylic sulfinamides participate in a subsequent Sonogashira coupling followed by a diastereoselective intramolecular Pauson-Khand reaction. In this way, tricyclic amines showing a unique benzo-fused indenyl backbone were obtained. The methodology has been applied to the synthesis of amino steroid analogues.

Full text of DOI:10.1021/ol500142c

Letter
pubs.acs.org/OrgLett
Asymmetric Allylation/Pauson−Khand Reaction: A Simple Entry to
Polycyclic Amines. Application to the Synthesis of Aminosteroid
Analogues
Santos Fustero,*,†,‡ Ruben Lazaro,† Nuria Aiguabella,§ Antoni Riera,§,∥ Antonio Simon-Fuentes,†
́
́
́
and Pablo Barrio*,†
†Departamento de Química Organ
‡Laboratorio de Molec
ulas Organ
§Institute for Research in Biomedicine (IRB Barcelona), c/Baldiri Reixac, 10, 08028 Barcelona, Spain
∥Departament de Química Organ
ica, Universitat de Barcelona, c/Martí i Franques, 1, 08028 Barcelona, Spain
́
ica, Universidad de Valencia, E-46100 Burjassot, Spain
́
́ ́
icas, Centro de Investigacion Príncipe Felipe, E-46012 Valencia, Spain
̀
S
* Supporting Information
ABSTRACT: Asymmetric allylation of o-iodoarylsulfinylimines
has been achieved in high diastereoselectivities. The thus-obtained
o-iodoarylhomoallylic sulfinamides participate in a subsequent
Sonogashira coupling followed by a diastereoselective intra-
molecular Pauson−Khand reaction. In this way, tricyclic amines
showing a unique benzo-fused indenyl backbone were obtained.
The methodology has been applied to the synthesis of amino
steroid analogues.
Scheme 1. Synthetic Versatility of 2-substituted Aromatic
hiral homoallylic amines are versatile building blocks in
Ellman’s Sulfinimines
C
organic synthesis. The presence of a pendant double bond
enables further synthetic transformations for the assembly of
more complex backbones.1 Undoubtedly, the asymmetric
allylation of imines2,3 is the most widely used methodology
for their synthesis, and among the existing methods, the
addition of allylmetal reagents to Ellman’s tert-butylsulfini-
mines4 shows some salient features: high degree of stereo-
control and chemical yields, reliability, and functional group
compatibility, among others. On the other hand, the Pauson−
Khand reaction (PKR) is arguably the method of choice for the
construction of the cyclopentenone ring from acyclic
precursors.5,6 Astonishingly, despite the impressive develop-
ment undergone by these two powerful transformations they
have never been combined for the construction of complex
polyclyclic amines.7 To the best of our knowledge, there is only
one example of PKR of a homoallylic amine bearing a pendant
triple bond in its carbon backbone reported in the literature in a
racemic form.8
disclose here our results in the allylation/PKR sequence giving
rise to polycyclic amines in very high diastereoselectivities
(Scheme 1). Building on the principles of diversity-oriented
synthesis, we selected o-iodobenzylidene tert-butanesulfina-
mides, previously described by our research group, as starting
materials for our study.
First, we tested the allylzinc addition to a model substrate in
order to rule out any possible interaction between the
organometallic reagent and the labile C−I bond12 and check
the diastereoselectivity, which is known to be sensitive to steric
hindrance.13 Based on our recent findings,10b the allylation
reaction was performed on the crude imine giving rise to
On the other hand, our group has been interested in the use
of 2-halobenzaldehyde-derived Ellman’s sulfinimines for the
asymmetric synthesis of a variety of benzo-fused carbo-9 and
heterocycles10 in the context of diversity-oriented synthesis
(DOS).11 Hence, we have found that the introduction of a
suitable functional group at the ortho-position of substrates of
this kind enables a series of reaction sequences initiated by a
nucleophilic addition (AN) of a suitable nucleophile to the
imine, namely: AN/intramolecular aza-Michael reaction,10a,b
AN/RCM,9b and AN/intramolecular hydroamination (Scheme
1).10c Continuing with our interest in expanding the structural
diversity from these readily available starting materials, we
Received: January 15, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
product 2a in good yield and excellent diastereoselectivity. In
view of these results, we decided to prepare a small library of
analogues for the subsequent Sonogashira coupling (Scheme
2). Electron-donating (2b,c), electron-withdrawing (2d), and
conditions, the formation of the intramolecular Heck reaction
byproduct was almost completely suppressed and the desired
product 4a was obtained in good chemical yield.
With these optimized conditions in hand, the o-iodophe-
nylhomoallylic amines 2a−f (Scheme 3) were coupled with a
variety of terminal alkynes affording o-alkynylhomoallylic
amines suitable the intramolecular PKR (Scheme 4). First,
Scheme 2. Asymmetric Allylation of 2-Iodosulfinilimines 1
Scheme 4. Scope of the Sonogashira Cross-Coupling of
a
Substrates 2a−f with Terminal Alkynes
halogen atoms (2e) are suitable substituents on the aromatic
ring giving rise to the desired products in moderate to good
yields and excellent diastereoselectivities in all cases. In
addition, we evaluated the crotylation reaction aimed to the
creation of an additional stereocenter in the final product. To
our delight, compound 2f was obtained in excellent yield and,
more importantly, complete diastereoselectivity.
Next, the Sonogashira cross-coupling of substrate 2a and
phenylacetylene 3a was investigated (Scheme 3). The main
a
A small amount of the intramolecular Heck product (5−10%) was
b
obtained in most cases. Obtained from the corresponding TMS
Scheme 3. Optimization of the Reaction Conditions for the
a
derivative 4k′ in the indicated yield (see the Supporting Information
Sonogashira Cross-Coupling
c
for details). Obtained from 4k in the indicated yield.
substrates 2a−f bearing both electron-donating and electron-
withdrawing groups were coupled with phenyl acetylene
affording products 4a−f, and second, substrate 2a was coupled
with alkynes 3b−f (see the Supporting Information for their
structures) giving rise to products 4g−l.
Once an assorted library substrates had been obtained, we
evaluated the intramolecular PKR (Scheme 5). Again, good to
excellent yields and diastereoselectivitites were obtained
regardless the substitution pattern in the aromatic tether
(6a−e) and the nature of the substituent at the triple bond:
activated (6g) and deactivated (6h,i) aromatic rings, alkyl
chains (6j), terminal (6k), and noteworthy, CF3 (6l) for the
first time in an intramolecular PKR.14 The last two examples
were not obtained by direct Sonogashira coupling. Instead, the
terminal alkyne was prepared from the corresponding TMS
derivative15 by base-mediated desilylation, while the CF3
derivative was obtained from the latter by copper catalyzed
electrophilic trifluorination using Togni’s reagent (see the
Supporting Information for details).
a
Conditions A: 3 equiv of alkyne, 0.1 M. Conditions B: 5 equiv of
alkyne, 0.5 M.
difference with the o-iodohomoallylic amines we recently
described10c is the presence of a pendant double bond, which
may interfere with the cross-coupling processes. Indeed, when
substrate 2a was subjected to cross-coupling with phenyl
acetylene 3a the desired product was obtained in moderate
yield along with an appreciable amount of 5a arising from an
intramolecular Heck reaction (Scheme 3, conditions A). In
order to avoid the formation of this undesired byproduct, the
reaction was carried out with a larger excess of the alkyne (5
equiv) and under more concentrated reaction conditions (0.5
M) to facilitate the intermolecular process over the intra-
molecular one (Scheme 3, conditions B). Under these reaction
The relative configuration of the new stereocenter created
upon the PKR was determined by 2D-NMR experiments
(NOE on 6b, see the Supporting Information) and confirmed
by X-ray diffraction analysis on derivative 6f, exhibiting three
consecutive stereocenters (Figure 1, up).
B
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Letter
Scheme 5. Scope of the Intramolecular PKR
Scheme 6. Removal of the Chiral Auxiliary
Finally, as a further application of our methodology, we
envisioned the synthesis of the steroidal skeleton (Scheme 7).
Scheme 7. Application to the Synthesis of Amino Steroid
Derivatives
Aminosteroids are an important subclass of steroids, and some
of them display interesting biological properties mostly used in
the field of anesthesia.16,17 To this end, substrates 8a,b were
synthesized according to literature procedures18 and subjected
to the methodology reported herein (Scheme 7). Products 9a,b
were obtained in good overall yields (four steps) and
diastereoselectivities and represent, to the best of our
knowledge, the first de novo syntheses of the sterane backbone
of aminosteroids.
Interestingly, the reaction sequence needed to be adapted to
the new skeleton. In this case, the Sonogashira coupling on the
homoallylic amine did not afford the desired product. To
overcome this difficulty, the alkyne was introduced prior to
condensation with the chiral auxiliary. A second difference was
the complete diastereoselectivity obtained even in the presence
of the trimethylsilylethynyl moiety (for the benzaldehyde
derivative 4k′ a 10:1 diastereoselectivity was observed).13
These results show that the order in which the reactions are
carried out to obtain the best chemical yield/diastereoselectivity
balance must be fine-tuned for each individual substrate.
Finally, as opposed to the corresponding benzaldehyde
derivative, the PKR proceeded uneventfully on the TMS-
protected derivative (see ref 15) accomplishing the formation
of the tetracyclic framework. The stereochemistry of 9a was
confirmed by X-ray diffraction analysis (Figure 1, down).
In conclusion, the 2-iodobenzaldehyde-derived Ellman’s
imine allylation/PKR reaction sequence has been established
as a useful tool for the asymmetric synthesis of polycyclic
amines containing the fusion of two ubiquituos domains both
in natural products and drugs, namely the tetrahydronaph-
thalene and the cyclopentenone rings. The new methodology
has successfully been applied to the first de novo synthesis of
aminosteroid derivatives.
Figure 1. ORTEP diagrams for 6f (up) and 9a (down).
Removal of the chiral auxiliary under standard conditions
(HCl in dioxane 10 equiv, MeOH, rt) resulted in partial
racemization of the benzylic stereocenter (for details, see the
Supporting Information). However, by lowering the amount of
acid to 1 equivalent and the reaction temperature to 0 °C, the
chiral auxiliary was successfully removed from two representa-
tive substrates rendering the free amines as the corresponding
hydrochlorides (Scheme 6).
C
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Letter
(10) (a) Fustero, S.; Moscardo,
́
J.; San
́
chez-Rosello,
́
M.; Rodríguez,
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and NMR spectra for all new
compounds as well as crystallographic data (CIF) for
compounds 6f and 9a. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
E.; Barrio, P. Org. Lett. 2010, 12, 5494. (b) Fustero, S.; Herrera, L.;
Lazaro, R.; Rodríguez, E.; Maestro, M. A.; Mateu, N.; Barrio, P.
Chem.Eur. J. 2013, 19, 11776. (c) Fustero, S.; Ibanez, I.; Barrio, P.;
S
́
̃
́
Maestro, M. A.; Catalan, S. Org. Lett. 2013, 15, 832.
(11) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004,
43, 46. (b) Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867.
(c) Schreiber, S. L. Science 2000, 287, 1964.
(12) To the best of our knowledge, only one example of an allylation
reaction (racemic) of an o-iodobenzylidenimine has been described;
see: Hart, D. J.; Kanai, K.-I.; Thomas, D. G.; Yang, T. K. J. Org. Chem.
1983, 48, 289.
(13) In addition, this strategy allows us to obtain homogeneous dr in
the final products regardless of the alkyne used. We have observed that
the reversed reaction sequence results in variable dr’s (2:1 to 10:1)
depending on the substitution at the alkyne.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: santos.fustero@uv.es.
*E-mail: pablo.barrio@uv.es.
Notes
The authors declare no competing financial interest.
(14) For recent reports on the use of CF3-alkynes in the
intermolecular PKR, see: (a) Aiguabella, N.; del Pozo, C.;
Verdaguer, X.; Fustero, S.; Riera, A. Angew. Chem., Int. Ed. 2013,
125, 5463. (b) Kizirian, J.-C.; Aiguabella, N.; Pesquer, A.; Fustero, S.;
Bello, P.; Verdaguer, X.; Riera, A. Org. Lett. 2010, 12, 5620.
(15) The TMS precursor failed to cyclized under a number of
reaction conditions.
ACKNOWLEDGMENTS
We thank the Spanish Ministerio de Ciencia e Innovacion
■
́
(CTQ2010-19774-C02-01, CTQ2011-23620) and the General-
itat Valenciana (PROMETEO/2010/061) and Generalitat
Catalana (2009SGR-00901) for their financial support. P.B.,
R.L., and N.A. thank the Spanish government for a Juan de la
Cierva contract and predoctoral fellowships, respectively.
Technical and human support provided by SGIker (UPV/
EHU, MINECO, GV/EJ, ERDF, and ESF) is gratefully
acknowledged.
(16) For some recent reports on aminosteroids, see: (a) Slavíkova,
́
B.; Bujons, J.; Matyas, L.; Vidal, M.; Babot, Z.; Kristofíkova, Z.; Sunol,
́
́
̃
C.; Kasal, A. J. Med. Chem. 2013, 56, 2323. (b) Fousteris, M. A.;
Schubert, U.; Roell, D.; Roediger, J.; Bailis, N.; Nikolaropoulos, S. S.;
Baniahmad, A.; Giannis, A. Bioorg. Med. Chem. 2010, 18, 6960.
(c) Keyzers, R. A.; Daoust, J.; Davies-Coleman, M. T.; Van Soest, R.;
Balgi, A.; Donohue, E.; Roberge, M.; Andersen, R. J. Org. Lett. 2008,
10, 2959. (d) Khan, S. N.; Kim, B. J.; Kim, H.-S. Bioorg. Med. Chem.
Lett. 2007, 17, 5139.
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