Ag-carbenoid-initiated catalytic hydration cascades: Rapid construction of functionalized bicyclo[3.3.1]nonanes

Article abstract of DOI:10.1021/ol4006954

Remarkable Ag-carbenoid-initiated enone cyclopropanation-hydrolytic fragmentation-competitive 1,2-vs-1,4 addition reaction cascades were uncovered on a range of propargylic esters tethered to cyclohexadienones, leading to the highly efficient and stereosp

Full text of DOI:10.1021/ol4006954

ORGANIC
LETTERS
2013
Vol. 15, No. 10
2362–2365
Ag-Carbenoid-Initiated Catalytic
Hydration Cascades: Rapid Construction
of Functionalized Bicyclo[3.3.1]nonanes
Lu Wang,† Shunyou Cai,† Xiangyou Xing, Ying Gao, Tao Wang,* and
David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Shenzhen Graduate School of Peking University, Shenzhen, China 518055
dzw@pkusz.edu.cn; taowang@pkusz.edu.cn
Received March 16, 2013
ABSTRACT
Remarkable Ag-carbenoid-initiated enone cyclopropanationÀhydrolytic fragmentationÀcompetitive 1,2-vs-1,4 addition reaction cascades were
uncovered on a range of propargylic esters tethered to cyclohexadienones, leading to the highly efficient and stereospecific construction of
densely functionalized bicyclo[3.3.1]nonanes under mild conditions.
Bicyclo[3.3.1]nonane represents a common structural
motif present in many biologically meaningful natural
products1 as well as synthetic substances2 and inter-
mediates.3 The significant utilities of this class of
compounds thus have stimulated considerable synthetic
efforts aimed at exploring efficient and stereoselective
methodologies toward their preparations,4 particularly in
the context of the rapid and controllable construction of
architectural and stereochemical complexities centering
around such frameworks bearing desirable functionalities.
For this purpose it is exciting to witness that some recently
accomplished total syntheses of bioactive natural products
featuring bicyclo[3.3.1]nonane core structures, including
such notable targets as members of Lycopodium alkaloids
and Vibsane-type diterpenes,5 served as platforms for ex-
aminations of the state-of-the-art of those technologies.
Motivated by an ongoing research program focusing on
the design and discovery of metallo-carbenoid species-
enabled tandem catalysis processes6 for rapid construction
of polycyclic complexities in a step- and atom-economical
manner from much simpler “linear” substrates,7 we took a
† These authors contributed equally.
(1) (a) Lin, H. Y.; Snider, B. B. Org. Lett. 2011, 13, 1234. (b) Nakahara,
K.; Hirano, K.; Maehata, R.; Kita, Y.; Fujioka, H. Org. Lett. 2011, 13,
2015. (c) Moosophon, P.; Kanokmedhakul, S.; Kanokmedhakul, K.;
Soytong, K. J. Nat. Prod. 2009, 72, 1442. (d) Amagata, T.; Minoura, K.;
Numata, A. J. Nat. Prod. 2006, 69, 1384. (e) Fukuyama, Y.; Kubo, M.;
Minami, H.; Yuasa, H.; Matsuo, A.; Fujii, T.; Morisaki, M.; Harada, K.
Chem. Pharm. Bull. 2005, 53, 72.
(2) Babine, R. E.; Bleckman, T. M.; Kissinger, C. R.; Showalter, R.;
Pelletier, L. A.; Lewis, C.; Tucker, K.; Moonmaw, E.; Parge, H. E.;
Villafranca, J. E. Bioorg. Med. Chem. Lett. 1995, 5, 1719.
(3) (a) Ronco, C.; Sorin, G.; Nachon, F.; Foucault, R.; Jean, L.;
Romieu, A.; Renard, P. Y. Bioorg. Med. Chem. 2009, 17, 4523. (b) Chu,
W. H.; Xu, J. B.; Zhou, D.; Zhang, F.; Jones, L. A.; Wheeler, K. T.;
Mach, R. H. Bioorg. Med. Chem. 2009, 17, 1222. (c) Mach, R. H.; Yang,
B.; Wu, L.; Kuhner, R. J.; Whirrett, B. R.; West, T. Med. Chem. Res.
2001, 10, 339. (d) Aleu, J.; Hernandez-Galan, R.; Hanson, J. R.; Hitchcock,
P. B.; Collado, I. G. J. Chem. Soc., Perkin Trans. 1 1999, 727.
(5) (a) Lin, H. Y.; Causey, R.; Garcia, G. E.; Snider, B. B. J. Org.
Chem. 2012, 77, 7143 and references cited therein. (b) Schwartz, B. D.;
Tilly, D. P.; Heim, R.; Wiedemann, S.; Williams, C. M.; Bernhardt, P. V.
Eur. J. Org. Chem. 2006, 3181 and references therein.
(4) (a) Wang, D.; Crowe, W. E. Org. Lett. 2010, 12, 1232. (b) Zhao, Y. L.;
Chen, L.; Yang, S. C.; Tian, C.; Liu, Q. J. Org. Chem. 2009, 74, 5622. (c)
Kuninobu, Y.; Morita, J.; Nishi, M.; Kawata, A.; Takai, K. Org. Lett. 2009,
11, 2535. (d) Bertelsen, S.; Johansen, R. L.; Jørgensen, K. A. Chem. Commun.
2008, 3016. (e) Ramesh, N. G.; Hassner, A. Eur. J. Org. Chem. 2005, 1892. (f)
Tilly, D. P.; Williams, C. M.; Bernhardt, P. V. Org. Lett. 2005, 7, 5155. (g)
Geirsson, J. K. F.; Arnadottir, L.; Jonsson, S. Tetrahedron 2004, 60, 9149. (h)
Geirsson, J. K. F.; Jonsson, S.; Valgeirsson, J. Biorg. Med. Chem. 2004, 12,
5563. (i) Butkus, E. Synlett 2001, 12, 1827.
(6) Selected reviews: (a) Marco-Contelles, J.; Soriano, E. Chem.;Eur.
€
J. 2007, 13, 1350. (b) Muller, T. J. J., Ed. Metal-Catalyzed Cascade
Reactions; Topics in Organometallic Chemistry; Springer, Berlin, Germany,
2006; Vol. 19. (c) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Chem. Rev. 2005, 105, 1001.
r
10.1021/ol4006954
Published on Web 05/02/2013
2013 American Chemical Society

special interest in taking advantage of such reliable reac-
tivities as electrophilic activations of carbonÀcarbon triple
bonds by soft metals8 (Ag, Au, Pt, etc.) for the purpose of
robust generation of desirable metallo-carbenoid inter-
mediates. We report herein that, through synergistic inter-
actions between orchestrated efforts and serendipity, an
Ag-catalyzed cascade was uncovered on a range of pro-
pargylic esters tethered to cyclohexadienones, leading to
the atom-economic formation of highly functionalized
bicyclo[3.3.1]nonanes under very mild conditions and with
complete stereochemical controls. The cascade appears to
proceed mechanistically through an unusual sequence that
involves Ag-carbenoid-initiated enone cyclopropanation,
vinyl ester hydrolytic fragmentation, and competitive carbo-
nyl addition-versus-conjugative addition as strategic events.9
The initial catalyst screenings conducted on a readily
accessible model substrate 1 suggested cationic Ag to be a
promising starting point, and the corresponding results
were compiledin Table 1. When1 was treated with5% mol
of AgSbF6 in 1,2-dichloroethane (DCE) for two days, two
products 1a and 1b, both featuring a highly functionalized
bicyclo[3.3.1]nonane skeleton, were isolated (in 25% yield
and 11/14 ratio) and structurally characterized by NMR
spectroscopy and X-ray crystallography (entry 1). The
transformation was essentially a hydration process10 in
whicha water moleculewasincorporatedinto1 toformthe
products. In this process, moist air acted as a viable and
convenient source of water. Evidently, the above-uncov-
ered reactivity and selectivity at this point were both low,
but the rapid evolution of molecular complexity during
this process through a potentially intriguing mechanistic
course (vide infra) and the observed diastereospecificities
demanded our immediate attention. Furthermore, although
Table 1. Ag-Catalysis Reactivity Screenings
(7) Selected reports: (a) Trost, B. M. Science 1991, 254, 1471. (b) Wender,
P. A.; Miller, B. L. Nature 2009, 460, 197. (c) Bennacer, B.; Fujiwara, B.; Lee,
S.-Y.; Ojima, I. J. Am. Chem. Soc. 2005, 127, 17756. (d) Lin, M.; Li, F.; Jiao,
L.; Yu, Z.-X. J. Am. Chem. Soc. 2011, 133, 1690. (e) Cai, S. Y.; Liu, Z.;
Zhang, W. B.; Zhao, X. Y.; Wang, D. Z. Angew. Chem., Int. Ed. 2011, 50,
11133. (f) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am.
Chem. Soc. 2012, 134, 20276.
a Conditions: 1 (0.30 mmol, 1.0 equiv) was mixed with AgSbF6 catalyst
and additive (0.03 mmol, 0.1 equiv) at rt and stirred for indicated
time. b Yields refer to isolated materials. c Byproducts of known structures
(ref 7e) were formed in 71% and 6% yield, respectively. d 80.0 mg of activated
4 A MS were added. e 1.1 equiv of H2O was added. f 2.2 equiv of H2O were
added. g The effects of other Ag catalysts and acids were also tested, see
Supporting Information for details.
(8) Selected reviews on Ag catalysis: (a) Naodovic, M.; Yamamoto,
H. Chem. Rev. 2008, 108, 3132. (b) Weibel, J.-M.; Blanc, A.; Pale, P.
Chem. Rev. 2008, 108, 3149. Au catalysis: (c) Hashmi, A. S. K. Chem.
Rev. 2007, 107, 3180. (d) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
(e) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. Pt catalysis: (f)
€
Furstner, A.; Davis, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(9) Studies on reactivities of Ag-carbenoid species generated from
relevant diazoacetate precursors: (a) Hansen, J. H.; Davies, H. M. L.
Chem. Sci. 2011, 2, 457. (b) Thompson, J. L.; Davies, H. M. L. J. Am.
Chem. Soc. 2007, 129, 6090.
(10) Selected Ag-catalyzed heterogeneous hydration processes: (a)
Rao, K. T. V.; Prasad, P. S. S.; Lingaiah, N. Green Chem. 2012, 14, 1507.
Synergistic Ag/Au catalytic hydrations: (b) Wang, D.; Cai, R.; Sharma,
S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.; Zhang, H.; Liu,
X. B.; Petersen, J. L.; Shi, X. D. J. Am. Chem. Soc. 2012, 134, 9012.
(11) (a) Hardin, A. R.; Sarpong, R. Org. Lett. 2007, 9, 4547. (b) Li,
G. T.; Zhang, G. Z.; Zhang, L. M. J. Am. Chem. Soc. 2008, 130, 3740. (c)
Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436.
(d) Zou, Y.; Garayalde, D.; Wang, Q.; Nevado, C.; Goeke, A. Angew.
literature documentations collectively showed that migra-
tion of an acyloxy group toward a soft metal-activated triple
bond in an electronically relatively unbiased propargylic
ester system generally follows a 6-endo-dig trajectory,11 the
formation of 1a and 1b pointed to the predominance of an
unusual 5-exo-dig reaction mode.12
When the loading of AgSbF6 was gradually increased to
20%, 30%, and 50% (entries 2À4), the reactivities and
product yields were improved to 49%, 65%, and 80%
respectively, but the product ratios remained about 1/1.
Remarkably, when a phosphoric acid13 A (10 mol %,
racemic) was used as the additive (entry 5), a comparable
ꢀ
Chem., Int. Ed. 2008, 47, 10110. (e) Marion, N.; Dıez-Gonzalez, de
ꢀ
Fremont, P.; Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45,
ꢀ
ꢀ
3647. (f) Marion, N.; de Fremont, P.; Lemiere, G.; Stevens, E. D.;
Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem. Commun. 2006, 2048.
ꢀ
ꢀ
(g) Barluenga, J.; Riesgo, L.; Vicene, R.; Lopez, L. A.; Tomas, M. J. Am.
Chem. Soc. 2007, 129, 7772. (h) Cariou, K.; Mainetti, E.; Fensterbank,
L.; Malacria, M. Tetrahedron 2004, 60, 9745. (i) Miki, K.; Ohe, K.;
Uemura, S. Tetrahedron Lett. 2003, 44, 2019. (j) Miki, K.; Ohe, K.;
Uemura, S. J. Org. Chem. 2003, 68, 8503.
(12) (a) Prasad, B. A. B.; Yoshimoto, F. K.; Sarpong, R. J. Am.
Chem. Soc. 2005, 127, 12468. (b) Motamed, M.; Bunnelle, E. M.;
Singaram, S. W.; Sarpong, R. Org. Lett. 2007, 9, 2167.
Org. Lett., Vol. 15, No. 10, 2013
2363

efficient. Finally, the effect of water was studied quantita-
tively. Careful scavenging of water using the activated 4 A
molecular sieves uneventfully led to complete inhibition of
the reactivity (entry 12). Purposeful introduction of 1.1
equiv of water into the system gave the best result (93%
yield, entry 13), and an excessive amount of water (2.2 equiv)
was found to be detrimental (entry 14). These observations
appeared to suggest intricate kinetic interplays between water
incorporation and other steps within the catalytic cycle to be
crucial for the success. These screening results therefore
established the combination of AgSbF6/B/H2O (1.1 equiv)
to be the optimal catalyst system.14
Scheme 1. Survey of Reaction Scope
A series of propargylic esters tethered to symmetrical
(i.e., prochiral) cyclohexadienones structured as 2À8 were
next surveyed to determine the reaction scope. As sum-
marized in Scheme 1, all substrates were transformed into
their expected furan-fused bicyclo[3.3.1]nonane derivatives in
good to excellent yields and in diastereomerically pure forms.
While the ratios of products generally remained around 2/1,
their combined yields responded somewhat sensitively to the
stereoelectronic nature of R1/R2 substituents. With 1taken as
the reference, the substrate with its R2 aryl ring bearing the
electron-releasing OMe group (2a/b, 95% yield) was found
to be more efficient than that substituted by the electron-
withdrawing F atom (3a/b, 81%); sterically bulkier aryl esters
(4À5) and a heteroaromatic ester (6) led to products of lower
yields ranging from 73% to 89%; and notable losses in reac-
tivities as well as selectivities were recorded with aliphatic
ester 7 (56%, 7a/7b = 1.4/1) as well as substrate 8 which has
a larger ethyl group at the prochiral carbon center (81%,
8a/8b = 1.5/1).
Interestingly, when propargylic esters tethered to asymme-
trically substituted cyclohexadienones 9À17 (Y=OorCH2)
were subjected to similar conditions, bicyclo[3.3.1]nonenes
with bridgehead hydroxy groups (i.e., 1,2-addition products,
vide infra) were exclusively formed and again with complete
diastereochemical control (Scheme 2). The general trend was
thus the preservation of a more substituted (thus presumably
less reactive) double bond in the product. Various linear
(9À13) and cyclic (14À16) substitutions and a methylene
linkage (17) in the substrate structures were tolerated, and the
corresponding products15 were produced smoothly with a
respectable average yield of 78%. It merits attention due to,
in the case of 16, the structure of its product 16a being clearly
indicative of a reaction “pattern switch” (when compared to
the 15-to-15a transformation) as the R3/R4 cyclopen-
tane ring originally fused with the cyclohexadienone unit
of 16 formally flips to the bridgehead junction in 16a.
Such a contrast appears to suggest the intriguing activa-
tion effect of the more substituted cyclohexadienone
double bond by the five- but not six-membered ring, as
the smaller ring is notably less accommodative for
geometrical strains incurred by a planar alkene and an
adjacent tetrahedral carbon.
yield was obtained with a significantly reduced reaction
time (76% over 9 h), and the 1a/1b product distribution
was doubled. With an analogous phosphoric acid additive
B bearing four CF3 groups, the yield reached91% after just
8 h, and the product ratio was maintained (entry 6), suggest-
ing the operation of sensitive stereoelectronic effects that
such structurally highly comparable additives might have
imposed on the reaction system. Two additional phosphoric
acids C and D were also examined, and once again subtle
structural variations of such additives were found to affect
the reactivities considerably (entries 7À8). Not surprisingly,
when 10% mol of AuCl(PPh3) was added, the substrate
conversion was nearly quantitative, but the predominant
pathways were evidently those of Au-catalysis (following the
expected 6-endo-dig mode) rather than Ag-cascades (only
19% yield of 1a and 1b obtained), since the major products
isolated were the dihydrofuran-fused cyclohexenone (71%)
and its ring-opening structure (6%).7e The solvent effects
were briefly examined with DCM or toluene being employed
in place of DCE, and both rendered the reactions less
(14) Hamilton, G. L.; Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008,
130, 14984.
(15) With 9 as the exemplifying substrate, an HRMS study confirmed
(13) Akiyama, T. Chem. Rev. 2007, 107, 5744.
18O isotope incorporation when 1.1 equiv of H218O was employed.
2364
Org. Lett., Vol. 15, No. 10, 2013

Scheme 2. Reactivities on Substituted Cyclohexadienones
Scheme 3. Mechanistic Proposal
Mechanistically, we believe that these uncovered reac-
tivities could be collectively rationalized with the cascade
sequence outlined below (Scheme 3). The electrophilic
activation of 1 by means of Ag cation complexation with
its triple bond would trigger an acyloxy migration in the
shown 5-exo-dig trajectory to generate the putative species
F, which then rearranges to the key vinyl Ag-carbenoid
intermediate G. Cyclopropanation on the (less-substituted)
enone double bond then leads to the formation of tricyclic
vinyl ester H. The incorporation of water into H would
proceed through a skeletal rearrangement event involving
the plausible intermediacies of I and J, thereby producing a
labile vinyl orthoformate structure K. The superior promot-
ing effects that phosphoric acid additives demonstrated over
other monofunctional protic acids examined likely originate
from their abilities in bringing about desirable “dual” activat-
ions on K via a pair of spatially complementary H-bonds.
Subsequent vinyl orthoformate collapse would occur com-
petitively through 1,2-carbonyl addition (path a) or 1,4-
conjugative addition (path b) to the enone moiety, leading
to the final products 1a and 1b, respectively.
bicyclo[3.3.1]nonanes under very mild conditions, with
complete stereochemical control, and in single-step manip-
ulations. These reaction cascades appeared to mechanisti-
cally proceed through a unique sequence involving Ag-
carbenoid species in situ generation via the 5-exo-dig mode,
subsequent initiation of enone cyclopropanation, cyclo-
propyl vinyl ester hydrolytic fragmentation, and competitive
carbonyl addition-versus-conjugative addition events. We
believe that this discovery could help shed new light on the
expanding potentials of Ag catalysis by means of some
highly robust yet elusive metallo-carbenoid intermediates.
The results thus suggest promise for exploring new and
rapid complexity-building multiannulations strategies.
Acknowledgment. We thank the NSFC (Grants 20972008
and 21290183 to D.Z.W.), and “973 Project” (Grants
2013CB911500 to T.W. and 2012CB722602 to D.Z.W.)
financial support.
Supporting Information Available. Experimental proce-
1
dures, X-ray crystallographic analysis, and H and 13C
In summary, we have disclosed herein that a simple
combination of AgSbF6/phosphoric acid formulated a
remarkably efficient catalytic system that was capable of
atom-economically converting a range of propargylic esters
tethered to cyclohexadienones into highly functionalized
NMR spectra for new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 10, 2013
2365