Straightforward synthesis of bridged azaoxa skeletons: Gold-catalyzed aminoketalization of Garner's aldehyde-derived alkynes

Article abstract of DOI:10.1002/chem.201100139

Building bridges with gold: Bridged azaoxa skeletons have been efficiently prepared from easily accessible alkynyloxazolidine substrates under mild reaction conditions (see scheme; Boc=tert-butoxycarbonyl). The reactions were found to proceed with complet

Full text of DOI:10.1002/chem.201100139

DOI: 10.1002/chem.201100139
Straightforward Synthesis of Bridged Azaoxa Skeletons: Gold-Catalyzed
Aminoketalization of Garnerꢀs Aldehyde-Derived Alkynes
Benito Alcaide,*[a] Pedro Almendros,*[b] and Rocꢁo Carrascosa[a]
In memory of Rafael Suau
Although possibly considered metabolically unstable,
N,O-aminal moieties are present in a variety of products ex-
hibiting relevant biological properties.[1] Interesting exam-
ples include the alkaloids of the zoanthamine family, which
contain a bridged N,O-aminal subunit and may be used as
analgesic and antiosteoporotic drugs, in addition to their
potent antileukemia and antiplatelet activities.[2] The last
decade has witnessed dramatic growth in the number of re-
actions catalyzed by gold com-
aminals from oxazolidine-derived alkynes emerged as an at-
tractive transformation to develop.[7]
Taking the above aspects into consideration, we decided
to study the challenging gold-catalyzed direct bis-heterocyc-
lization of Garnerꢀs aldehyde-derived alkynes (latent and
stable alkynic aminoalcohols). The structures of the alkynyl-
AHCTUNGTREGoNNNU xazolidines derivatives 1 that we synthesized and used for
the bis-heterocyclization reaction are shown in Figure 1.[8]
plexes because of their power-
ful soft Lewis acidic nature.[3] In
particular, gold-catalyzed intra-
molecular addition of oxygen
and
nitrogen
nucleophiles
across a carbon–carbon triple
bond is intriguing from the
point of view of regioselectivity
(endo versus exo cyclization)
and because it is one of the
most rapid and convenient
methods for the preparation of
Figure 1. Structures of alkynyloxazolidines 1a–l. Bn=benzyl, Boc=tert-butoxycarbonyl, PMP=4-MeOC6H4.
heterocycles.
However,
it
should be remarked that despite the fact that bicyclic acetals
were successfully obtained with AuI, AuIII, and PtIV-based
catalysts by using two intramolecular hydroxyl groups as nu-
cleophiles,[4] the related direct intramolecular conversion of
alkynes into cyclic N,O-aminals has not been described.[5] In
continuing with our interest in metal-catalyzed processes
employing alkynes and allenes,[6] the direct synthesis of N,O-
To explore the reactivity of functionalized compounds 1 to-
wards intramolecular aminoacetalization we selected alkyne
1a as a model substrate. Attempts of the cyclization reaction
of 1a using PdCl2, AgOTf, and PtCl2 catalysts failed. Nicely,
it was found that [AuClPPh3]/AgOTf is an excellent catalytic
system for this purpose. Adding a stoichiometric amount of
water into the reaction system along with a catalytic amount
of Brønsted acid (PTSA) did improve the yield of 2a. Grati-
fyingly, after considerable experimentation, it was found
that alkynic oxazolidine 1a on exposure to the system
[AuClPPh3] (2.5 mol%), AgOTf (2.5 mol%), PTSA
(10 mol%), and H2O (100 mol%) in dichloromethane at
808C on a sealed tube, directly afforded bridged bicyclic
aminal 2a through a regio- and diastereoselective 7-exo/5-
exo bis-heterocyclization (Scheme 1). AgOTf cannot be con-
sidered as a co-catalyst because its action is generally as-
sumed to be restricted to the formation of cationic gold spe-
cies by anion exchange.[9] Changing the nature of the coun-
terion has little effect in the reaction, because replacing
AgOTf by other silver salts such as AgSbF6 or AgBF4 did
not show any appreciable difference. The comparative stud-
ies of aminal formation with addition of PTSA demonstrat-
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. R. Carrascosa
Grupo de Lactamas y Heterociclos Bioactivos
Departamento de Quꢁmica Orgꢂnica I, Facultad de Quꢁmica
Unidad Asociada al CSIC, Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax : (+34)91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
Instituto de Quꢁmica Orgꢂnica General
Consejo Superior de Investigaciones Cientꢁficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100139.
4968
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4968 – 4971

COMMUNICATION
of terminal alkynyloxazolidines 1 f,g, which lead to the 6-
oxa-3,8-diazabicyclo[3.2.1]octane derivatives 2 f,g through a 7-
exo/5-exo bis-heterocyclization of the oxazolidine group to-
wards the internal alkyne carbon (proximal adducts), the re-
action of alkynyloxazolidines 1h,i substituted at the terminal
end under identical conditions gave the 1,5-oxazocine deriv-
atives 3h,i (distal adducts) as the sole products (Scheme 2),
through an exclusive 8-endo oxycyclization by attack of the
oxygen atom to the external alkyne carbon. To our delight,
when the alkyne substituent was moved from position N1 to
C3, as in 3,4-tethered alkynyloxazolidines 1j–l, it furnished
the corresponding bridged adducts 2j–l in fair yields and as
only one isomer in its reaction with the gold catalytic system
(Scheme 2). The precious metal-catalyzed 8-exo/5-exo bis-
heterocyclization of alkynyloxazolidines 1j–l gave tricyclic
bridged N,O-aminals 2j–l containing a seven-membered ring
(Scheme 2). Remarkably, Scheme 2 shows how the mild con-
ditions of gold catalysis allow the chemoselective formation
of anellated b-lactams without harming the sensitive four-
membered ring. Although complete conversion was ob-
Scheme 1. Controlled N,O-cyclo-aminalization reaction of alkynyloxazoli-
dines 1a–e under gold-catalyzed conditions. PTSA=p-Toluenesulfonic
acid, Tf=triflate.
ed that the presence of the Brønsted acid gives higher
yields, and that the acid additive acts as a collaborator but
not as a catalyst.[10] Thus, the catalytic system may consist of
1
served by TLC and H NMR analysis of the crude reaction
[Au
(OTf)PPh3] generated in situ from [AuClPPh3] and
mixtures, upon purification of sensitive bridged azaoxacycles
2 by flash chromatography, some decomposition was ob-
served, which may be responsible for the moderate isolated
yields.
A possible pathway for the gold-catalyzed alkynyloxazoli-
dine cyclization may initially involve the formation of a p-
complex 4 through coordination of the gold salt to the triple
bond of alkynyloxazolidines 1.[11] Next, 7-exo oxymetalation
forms zwitterionic enol vinylmetal species 5. Intermediates 5
did evolve through demetalation and oxazolidine hydrolysis
forming methylenic oxacycles 6 and releasing the metal cat-
AgOTf. Under the optimized reaction conditions, we inves-
tigated the generality of the catalytic protocol under gold
catalysis for oxazolidine-tethered alkynes 1b–e. By examin-
ing the influence of the R substituents on the alkyne side
chain, we found that substrates 1a–e, which contain hydro-
gen, aryl, heteroaryl, or alkyl groups were smoothly trans-
formed into products 2 in reasonable yields (Scheme 1).
To assess the scope of this reaction, the even more chal-
lenging enantiopure alkynyloxazolidine-tethered 2-azetidi-
nones 1 f–l were tested as cyclization precursors. Using the
terminal alkynes 1 f,g, the
system [AuACHTUNGTRENNUNG(OTf)PPh3] gave the
desired tricyclic bridged N,O-
aminals 2 f,g as the sole
isomers in reasonable yields
(Scheme 2). Next, we investi-
gated the reactivity of nonter-
minal alkynes 1h,i. Notably,
substituted and unsubstituted 2-
azetidinone-tethered alkynes at
the terminal position followed
different reactivity patterns. Al-
kynyloxazolidines 1h,i exclu-
sively afforded the bicyclic ad-
ducts 3h,i, but the bis-cycliza-
tion products could not be ob-
tained (Scheme 2). These re-
sults show that the oxygen
atom participates in the first
cyclization reaction to form a
fused eight-membered ring,
which is not followed by the
second cyclization of the NBoc
group. Significantly, in contrast
to the gold-catalyzed reaction Scheme 2. Direct gold-catalyzed heterocyclization of alkynyloxazolidines 1 f–l. PMP=4-MeOC6H4.
Chem. Eur. J. 2011, 17, 4968 – 4971
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4969

B. Alcaide, P. Almendros, R. Carrascosa
alyst into the first catalytic cycle. Methylenic oxacycles 6
enter the second catalytic cycle generating species 7 by coor-
dination of the alkene group with the metal and thus en-
hancing the electrophilicity of the resulting enol ether. Sub-
sequent intramolecular nucleophilic attack of the nitrogen
to the more substituted alkene position would form the ate
complex 8. Demetalation linked to proton transfer liberates
adduct 2 with concomitant regeneration of the gold catalyst,
thus closing the second catalytic cycle (Scheme 3).
be isolated in moderate yield. It should be noted the pro-
longed reaction time for hydrolysis in comparison with the
short time (2 h) for completion of the reaction of bis-hetero-
cyclization in related alkynyl oxazolidines. Besides, the fact
that the reaction of oxazolidine 1a catalyzed by the p-philic
gold complexes [Au(counteranion)PPh3] alone in the ab-
sence of acid additive proceeded to afford the corresponding
bridged N,O-acetal 2a, may also support this order of steps:
the N,O-acetal in species 1 attacks the alkyne and the result-
ing oxonium is then hydrolyzed.
However, taking all the experi-
ments into account, a mechanis-
tic scenario that involves the in-
itial formation of the 1,2-amino
alcohol followed by bis-hetero-
cyclization cannot be complete-
ly ruled out.
Gold is a possible source of
protons owing to the equilibri-
um between gold(I) and H2O.
Taking into account that alkyl-
gold compounds are difficult to
protonate,[12] it is also likely
that the catalytic cycle on the
left side of Scheme 3 may be
proton-catalyzed.
Scheme 3. Mechanistic explanation for the gold-catalyzed bis-heterocyclization of alkynyloxazolidines 1. L=
ligand.
Although the isolation of bi-
cycles 3h,i from the reactions
In the conversion of alkynyloxazolidines 1 into azaoxacy-
cles 2, a possible first step is water addition onto the triple
bond that results in the corresponding ketone intermediate,
which might suffer a further transacetalization. However,
this mechanistic scenario seems less likely because the addi-
tion of a stoichiometric amount of water into the reaction
system did slightly improve the yield of bridged N,O-acetals
2, but it is not essential. Thus, the reaction of alkynyloxazoli-
dine 1a could be carried out with the exclusion of water to
afford bridged azaoxacycle 2a in a reasonable 52% yield.
It may be contemplated that under these reaction condi-
tions the oxazolidine might be hydrolyzed first. Thus, we
prepared the Boc-protected amino alcohol derived from 1 f
using BiCl3 (for details see the Supporting Information) to
compare the catalytic efficiency with the parent alkynyloxa-
zolidine 1 f. Under the standard bis-cyclization conditions
([AuClPPh3] (2.5 mol%), AgOTf (2.5 mol%), PTSA
(10 mol%), and H2O (100 mol%), dichloromethane, 808C,
sealed tube), comparable yields of adduct 2 f were obtained
starting from both alkynyloxazolidine 1 or its free amino al-
cohol.
of 1h,i outlined in Scheme 2 was fortuitous, the result
argues in favor of the mechanism shown in Scheme 3, be-
cause an observable intermediate of type 6 was formed. This
argument was further corroborated by the observation that
when alkynyloxazolidine 1c was treated under heterocycli-
zation conditions employing D2O (200 mol%) instead of
H2O, adduct 2c with incorporation of two deuterium atoms
at the methylenic group was achieved (Scheme 4).
Scheme 4. Gold-catalyzed bis-heterocyclization of alkynyloxazolidine 1c
in presence of D2O.
Alternatively, we carried out an experiment to check
whether oxazolidines derivatives that do not have the teth-
ered alkyne hydrolyze under gold-catalyzed conditions.
Thus, after treating (R)-tert-butyl-4-[(2R,3S)-3-acetoxy-1-(4-
methoxyphenyl)-4-oxo-azetidin-2-yl]-2,2-dimethyloxazoli-
dine-3-carboxylate under the standard bis-cyclization condi-
tions for 16 hours, the above oxazolidine lacking alkyne
groups gave the corresponding amino alcohol, which could
In conclusion, an efficient gold-catalyzed synthetic route
to bridged azaoxa skeletons from easily accessible alkynyl-
AHCTUNGTREGoNNNU xazolidine substrates under mild conditions has been re-
ported. The reactions were found to proceed with complete
control of product regio- and stereoselectivity in the pres-
ence of the combined gold/silver and acid catalyst system.
Further exploration of the mechanism, scope, and synthetic
applications of the present reaction are currently under way.
4970
www.chemeurj.org
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4968 – 4971

Synthesis of Bridged Azaoxa Skeletons
COMMUNICATION
Almendros, A. Luna, M. R. Torres, Adv. Synth. Catal. 2010, 352,
621; c) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Eur. J. 2009,
15, 9987; d) B. Alcaide, P. Almendros, T. Martꢁnez del Campo, M. T.
Quirꢆs, Chem. Eur. J. 2009, 15, 3344; e) B. Alcaide, P. Almendros,
R. Carrascosa, M. C. Redondo, Chem. Eur. J. 2008, 14, 637; f) B. Al-
caide, P. Almendros, T. Martꢁnez del Campo, Angew. Chem. 2007,
119, 6804; Angew. Chem. Int. Ed. 2007, 46, 6684; g) B. Alcaide, P.
Almendros, T. Martꢁnez del Campo, Angew. Chem. 2006, 118, 4613;
Angew. Chem. Int. Ed. 2006, 45, 4501.
Acknowledgements
Support for this work by the DGI-MICINN (Project CTQ2009-09318),
CAM (Project S2009/PPQ-1752), and UCM-BSCH (Grant GR58/08) are
gratefully acknowledged. R. C. thanks the MEC for a predoctoral grant.
Keywords: alkynes · gold · heterocycles · selectivity
·
synthetic methods
[7] In the current work, popular protected N,O-building blocks are
used. Thus, starting from one N,O-acetal unit and getting another bi-
cyclic N,O-acetal and releasing the protecting group is a new and
very useful reaction; maybe one could find a term for that, for ex-
ample “N,O-transacetalization” (cleavage of one N,O-acetal and for-
mation of another one) as related to transamination.
[1] a) S.-J. Tan, Y.-M. Choo, N. F. Thomas, W. T. Robinson, K. Komiya-
ma, T.-S. Kam, Tetrahedron 2010, 66, 7799; b) J. C. Jewett, V. H.
Rawal, Angew. Chem. 2007, 119, 6622; Angew. Chem. Int. Ed. 2007,
46, 6502; c) X. Jiang, G. J. Fortanet, J. K. De Brabander, J. Am.
Chem. Soc. 2005, 127, 11254; d) J.-H. Sohn, N. Waizumi, M. Z.
Zhong, V. H. Rawal, J. Am. Chem. Soc. 2005, 127, 7290; e) A. B.
Smith III, I. G. Safanov, R. M. Corbett, J. Am. Chem. Soc. 2001, 123,
12426; f) A. Tulinsky, J. Am. Chem. Soc. 1964, 86, 5368.
[2] a) Y. Takahashi, F. Yoshimura, K. Tanino, M. Miyashita, Angew.
Chem. 2009, 121, 9067; Angew. Chem. Int. Ed. 2009, 48, 8905; b) F.
Yoshimura, M. Sasaki, I. Hattori, K. Komatsu, M. Sakai, K. Tanino,
M. Miyashita, Chem. Eur. J. 2009, 15, 6626.
[3] For selected reviews, see: a) A. S. K. Hashmi, Angew. Chem. 2010,
122, 5360; Angew. Chem. Int. Ed. 2010, 49, 5232; b) special issue—
“Coinage Metals in Organic Synthesis”: Chem. Rev. 2008, 108,
Issue 8; c) special issue—“Hybrid Materials”: Chem. Soc. Rev. 2008,
37, Issue 9; d) N. Bongers, N. Krause, Angew. Chem. 2008, 120,
2208; Angew. Chem. Int. Ed. 2008, 47, 2178; e) A. S. K. Hashmi,
G. J. Hutchings, Angew. Chem. 2006, 118, 8064; Angew. Chem. Int.
Ed. 2006, 45, 7896; f) J. Muzart, Tetrahedron 2008, 64, 5815;
g) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180.
[4] For the synthesis of acetals by gold-catalyzed attack of diols onto al-
kynes, see: a) S. Antoniotti, E. Genin, V. Michelet, J.-P. GenÞt, J.
Am. Chem. Soc. 2005, 127, 9976; b) A. Diꢄguez-Vꢂzquez, C. C.
Tzschucke, J. Crecente-Campo, S. McGrath, S. V. Ley, Eur. J. Org.
Chem. 2009, 1698; c) L.-P. Liu, G. B. Hammond, Org. Lett. 2009, 11,
5090. For the platinum-catalyzed synthesis of bicyclic acetals, see:
d) A. Diꢄguez-Vꢂzquez, C. C. Tzschucke, W. Y. Lam, S. V. Ley,
Angew. Chem. 2008, 120, 216; Angew. Chem. Int. Ed. 2008, 47, 209.
[5] The intermolecular formation of N,O-aminals using external N nu-
cleophiles like anilines have been used earlier this year, see: A. S. K.
Hashmi, M. Bꢅhrle, M. Wçlfle, M. Rudolph, M. Wieteck, F. Ro-
minger, W. Frey, Chem. Eur. J. 2010, 16, 9846.
[8] The terminal alkynyloxazolidines 1a and 1e required for our study
were prepared from Garnerꢀs aldehyde, through a metal-mediated
carbonyl-allylation followed by O-propargylation or through a re-
ductive amination followed by a N-carboxylation, respectively (for
details see the Supporting Information). The terminal alkynyloxazo-
lidines 1 f,g and 1j,k were prepared from imines of Garnerꢀs alde-
hyde through a Staudinger reaction (for details see the Supporting
Information). The methyl-substituted alkynyloxazolidine 1b was
prepared through base-promoted O-propargylation (for details see
the Supporting Information). The aryl-substituted alkynyloxazoli-
dines 1c,d,h,i, and l were prepared from 1a,f, and j through a Sono-
gashira coupling (for details see the Supporting Information).
[9] a) A. Duschek, S. F. Kirsch, Angew. Chem. 2008, 120, 5787; Angew.
Chem. Int. Ed. 2008, 47, 5703; b) S. Gaillard, J. Bosson, R. S.
Ramꢆn, P. Nun, A. M. Z. Slawin, S. P. Nolan, Chem. Eur. J. 2010, 16,
13729.
[10] The reaction of alkynyloxazolidine 1a under gold catalysis in the ab-
sence of acid additive (PTSA) proceeded to afford the correspond-
ing N,O-aminal 2a in just a slightly lower yield. For a seminal
review on gold and protons, see: A. S. K. Hashmi, Catal. Today
2007, 122, 211.
À
[11] For references on intramolecular alkoxyauration followed by C O
scission, see: a) G. Zhang, L. Zhang, J. Am. Chem. Soc. 2008, 130,
12598; b) C. Kim, H. J. Bae, J. H. Lee, W. Jeong, H. Kim, V. Sam-
path, Y. H. Rhee, J. Am. Chem. Soc. 2009, 131, 14660.
[12] a) K. E. Roth, S. A. Blum, Organometallics 2010, 29, 1712; b) R. L.
LaLonde, J. W. E. Brenzovich, Jr., D. Benitez, E. Tkatchouk, K.
Kelley, W. A. Goddard III, F. D. Toste, Chem. Sci. 2010, 1, 226.
Received: January 14, 2011
Revised: February 15, 2011
Published online: March 24, 2011
[6] See, for instance: a) B. Alcaide, P. Almendros, R. Carrascosa, T.
Martꢁnez del Campo, Chem. Eur. J. 2010, 16, 13243; b) B. Alcaide, P.
Chem. Eur. J. 2011, 17, 4968 – 4971
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4971