there remain limitations. In particular, most catalyst sys-
tems appear to be highly sensitive to the substrate sub-
stitution pattern; alkene and/or alkyne substituents
specifically can have dramatic effects on the enantioselec-
tivity. Ethereal substrates have also been decidedly more
difficult compared to their N-tethered counterparts, being
prone to oligomerization and decomposition promoted by
the Lewis acidic metal. We hypothesized that an alterna-
tive approach, based on chirality transfer, could produce
enantioenriched bicycles in this cycloisomerization. We
anticipated that ether 3, featuring a stereocenter in the
propargylic position, would produce enantioenriched enol
ether 4 under select cycloisomerization conditions. Herein,
we disclose the realization of this goal, demonstrating that
ethereal 1,6-enyne substrates can be isomerized to highly
substituted bicyclo[4.1.0]heptene derivatives with excellent
levels of enantiospecificity.
processes in alkyne π-activation with propargylic esters10,11
offered promise for our proposal.
Scheme 2. Mechanistic Potential for Enantiospecific
Cycloisomerization
We expected this approach would be highly attractive
owing to the general ease of synthesizing chiral propargylic
alcohols.12,13 To initiate our studies, we employed the
transfer hydrogenation chemistry of Noyori13a to generate
the target substrates. Ynone 8 was reduced to form pro-
pargylic alcohol 9 in excellent yield and ee (Scheme 3).
Alkylation with cinnamyl bromide proceeded uneventfully
to afford enyne 10.
Scheme 1. Approaches to Developing Stereochemistry in Ether
Cycloisomerization
Scheme 3. Chiral Propargylic Ether Synthesis
Our reaction design is depicted in Scheme 2. Although
other catalytic reaction pathways have been proposed,4a,5a,6
it is generally believed, in part based on previous calcula-
tions,5f,7 that cyclopropanation occurs prior to the [1,2]-
hydride shift. We hypothesized from this mechanism that the
cyclopropane bond formation could be influenced by a
stereocenter at the propargylic site. There have been reports
of diastereoselective cyclopropane bond formation based
on the allylic carbon; this stereocenter is maintained in the
cycloisomerization product.8 In contrast, the propargylic
stereocenter is not conserved in our proposed transforma-
tion (7 f 8); this process would therefore represent a
traceless generation of stereochemistry. If enantiospecific-
ity were observed, it would constitute both an experi-
mental validation of the proposed mechanistic pathway9
and a differential approach to access these enantioenriched
products. Notably, reports of different enantiospecifc
With the target enantioenriched enyne in hand, we
evaluated several reaction conditions (Table 1). Of the
catalysts investigated, PtCl2 in toluene provided the most
promising lead with respect to both yield and enantio-
specificity (es),14 with enol ether 11 produced in 78%
yield and 89% es (entry 4). Changing the solvent to THF
(10) (a) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2006, 45, 2901–
€
2904. (b) Furstner, A.; Hannen, P. Chem.;Eur. J. 2006, 12, 3006–3019.
(c) Fehr, C.; Winter, B.; Magpantay, I. Chem.;Eur. J. 2009,15, 9773–9784.
€
(d) Furstner, A.; Schlecker, A. Chem.;Eur. J. 2008, 14, 9181–9191. (e)
Soriano, E.; Marco-Contelles, J. J. Org. Chem. 2007, 72, 2651–2654.
(11) Gandon, Fensterbank, Malacria and coworkers have described
an example of chirality transfer with propargylic ester substrates that
ꢁ
first converts to a chiral allene intermediate. See: Gandon, V.; Lemiere,
G.; Hours, A.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed.
(6) He, R.-X.; Li, M.; Li, X.-Y. THEOCHEM 2005, 717, 21–32.
(7) Soriano, E.; Ballesteros, P.; Marco-Contelles, J. J. Org. Chem.
2004, 69, 8018–8023.
(8) (a) Nevado, C.; Ferrer, C.; Echavarren, A. M. Org. Lett. 2004, 6,
3191–3194. (b) Ferrer, C.; Raducan, M.; Nevado, C.; Claverie, C. K.;
Echavarren, A. M. Tetrahedron 2007, 63, 6306–6316. (c) Chen, Z.;
Zhang, Y.-X.; Wang, Y.-H.; Zhu, L.-L.; Liu, H.; Li, X.-X.; Guo, L.
Org. Lett. 2010, 12, 3468–3471. (d) Xia, J.-B.; Liu, W.-B.; Wang, T.-M.;
You, S.-L. Chem.;Eur. J. 2010, 22, 6442–6446.
2008, 47, 7534–7538.
(12) (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824. (b) Trost,
B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963–983.
(13) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738–8739. (b) Noyori, R.; Hashiguchi,
S. Acc. Chem. Res. 1997, 30, 97–102.
(14) Enantiospecificity (es = eeproduct/eereactant  100%) is a straight-
forward method for determining the conservation of stereochemistry in
the transformation. See: (a) Denmark, S. E.; Burk, M. T.; Hoover, A. J.
J. Am. Chem. Soc. 2010, 132, 1232–1233. (b) Greene, M. A.; Yonova,
I. M.; Williams, F. J.; Jarvo, E. R. Org. Lett. 2012, 14, 4293–4296.
(9) Most alternative mechanistic pathways would involve destruction
of the stereocenter prior to cyclopropyl bond formation.
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