Highly enantiospecific platinum-catalyzed cycloisomerizations: Synthesis of enantioenriched oxabicycloheptene derivatives

Article abstract of DOI:10.1021/ol400625f

Enantiospecific cycloisomerizations of 1,6-enynes to form oxabicyclo[4.1.0]heptene derivatives are described. Enantiospecificity is consistently high regardless of alkene or alkyne substitution, providing a general approach to greatly enantioenriched cycl

Full text of DOI:10.1021/ol400625f

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1772–1775
Highly Enantiospecific
Platinum-Catalyzed Cycloisomerizations:
Synthesis of Enantioenriched
Oxabicycloheptene Derivatives
Eric T. Newcomb and Eric M. Ferreira*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States
emferr@mail.colostate.edu
Received March 8, 2013
ABSTRACT
Enantiospecific cycloisomerizations of 1,6-enynes to form oxabicyclo[4.1.0]heptene derivatives are described. Enantiospecificity is consistently
high regardless of alkene or alkyne substitution, providing a general approach to greatly enantioenriched cyclopropanes. Additionally, a model for
stereochemical transfer is proposed.
Enyne cycloisomerizations based on alkyne π-activation
represent a powerful class of transformations in their ability
to provide an array of structurally diverse molecules.1
Enantioselective variants based on asymmetric catalysis
remain challenging, in part owing to the difficulty of estab-
lishing an appropriate chiral environment via single-point
alkyne binding for general and uniform stereoinduction.2
Because chiral induction in alkyne π-activation can be so
demanding, alternative approaches toward enantioenrich-
ment in cycloisomerization may prove equally if not more
appealing. Enantiospecific cycloisomerizations from pre-
generated chirality would represent one such opportunity
if the following criteria were met: (1) the origin of chirality
was easily obtained, and (2) the approach allowed for
reaction versatility unseen in asymmetric catalysis.
Spurred by our interest in the area of alkyne π-
activation,3 a specific transformation that drew our atten-
tion was the cycloisomerization of heteroatom-tethered
1,6-enynes to form bicyclo[4.1.0]heptene derivatives.4
There have been several notable achievements in enantio-
selectivity based on chiral catalysts (Scheme 1, 1 f 2),5 yet
(4) For select examples, see: (a) Blum, J.; Beer-Kraft, H.; Badrieh, Y.
€
J. Org. Chem. 1995, 60, 5567–5569. (b) Furstner, A.; Stelzer, F.; Szillat,
ꢀ
~
H. J. Am. Chem. Soc. 2001, 123, 11863–11869. (c) Mendez, M.; Munoz,
ꢀ
M. P.; Nevado, C.; Cardenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2001, 123, 10511–10520. (d) Ota, K.; Lee, S. I.; Tang, J.-M.;
Takachi, M.; Nakai, H.; Morimoto, T.; Sakurai, H.; Kataoka, K.;
Chatani, N. J. Am. Chem. Soc. 2009, 131, 15203–15211.
(1) For select reviews on catalytic cycloisomerization initiated by
€
Ed. 2007, 46, 3410–3449. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180–3211. (c) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006,
348, 2271–2296.
(2) For select recent reviews featuring asymmetric catalysis based on
alkyne activation, see: (a) Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012,
3, 2899–2919. (b) Marinetti, A.; Jullien, H.; Voituriez, A. Chem. Soc.
Rev. 2012, 41, 4884–4908. (c) Pradal, A.; Toullec, P. Y.; Michelet, V.
Synthesis 2011, 1501–1514.
(3) (a) Rooke, D. A.; Ferreira, E. M. J. Am. Chem. Soc. 2010, 132,
11926–11928. (b) Allegretti, P. A.; Ferreira, E. M. Org. Lett. 2011, 13,
5924–5927. (c) Allegretti, P. A.; Ferreira, E. M. Chem. Sci. 2013, 4, 1053–
1058.
(5) For key representative examples of chiral catalysis approaches,
see: (a) Shibata, T.; Kobayashi, Y.; Maekawa, S.; Toshida, N.; Takagi,
K. Tetrahedron 2005, 61, 9018–9024. (b) Chao, C.-M.; Beltrami, D.;
Toullec, P. Y.; Michelet, V. Chem. Commun. 2009, 6988–6990. (c) Brissy,
D.; Skander, M.; Jullien, H.; Retailleau, P.; Marinetti, A. Org. Lett.
2009, 11, 2137–2139. (d) Nishimura, T.; Kawamoto, T.; Nagaosa, M.;
Kumamoto, H.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 1638–
1641. (e) Nishimura, T.; Maeda, Y.; Hayashi, T. Org. Lett. 2011, 13,
3674–3677. (f) Teller, H.; Corbet, M.; Mantilli, L.; Gopakumar, G.;
alkyne activation, see: (a) Furstner, A.; Davies, P. W. Angew. Chem., Int.
€
Goddard, R.; Thiel, W.; Furstner, A. J. Am. Chem. Soc. 2012, 134,
ꢀ
15331–15342. (g) Barbazanges, M.; Auge, M.; Moussa, J.; Amouri, H.;
Aubert, C.; Desmarets, C.; Fensterbank, L.; Gandon, V.; Malacria, M.;
Ollivier, C. Chem.;Eur. J. 2011, 17, 13789–13794. (h) See the Support-
ing Information (SI) for related works.
r
10.1021/ol400625f
Published on Web 03/25/2013
2013 American Chemical Society

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.
Org. Lett., Vol. 15, No. 7, 2013
1773

provided a noticeable boost in yield, while modestly increas-
ing es. Adding CO resulted in minimal effect.15 While other
Pt(II) catalytic conditions were comparable, ultimately
7mol%PtCl2 in THF at 70 °C gave the optimal reactivity,16
with 11 formed in 90% yield and 90% ee (93% es).
Table 2. Effect of Propargylic Substituent on Chirality Transfer
ee 12
yielda
(%)
Table 1. Catalyst Evaluation for Stereospecific
Cycloisomerization
entry
R
(%) product
ee (%) es (%)
1
2
3
4
5
6
Me (12a)
97
97
96
99
98
96
13a
13b
13c
13d
13e
13f
90
84
93
84
80
<10
80
78
90
96
97
ndb
82
80
94
97
99
ndb
i-Bu (12b)
CH2CH2Ph (12c)
Cy (12d)
i-Pr (12e)
t-Bu (12f)
solvent, temp
ee
es
entry
catalyst (mol %)
(Ph3P)AuNTf2 (5)
(°C)
t (h) yield (%) (%)a
a Isolated yield. b nd: Not determined.
1
2
3
A
5
6
7
8
9
CH2Cl2, 23
0.5
3
52
68
27
78
87
86
84
64
90
84 87
84 87
90 93
86 89
88 91
86 89
86 89
87 90
87 90
[lr(dbcot)Cl]2 (2.5)b,c PhCH3, 100
substrate gave the desired product (15f) in diminished yield.
Tricyclic enol ethers were formed efficiently (e.g., 15g).
Various alkyne substituents were also well tolerated, with
alkyl, ethereal, and heteroaryl substitution all giving the
cyclopropane products in good yields and high stereospeci-
ficity. Importantly, this level of generality with O-tethered
enynes has not been observed with approaches based on
asymmetric catalysis.18
PtCl4 (5)
PtCl2 (5)
PtCl2 (5)
PtCl2 (5)b
PhCH3, 23
PhCH3, 60
THF, 60
1
22
18
14
28
48
18
THF, 60
[(C2H4)PtCl2]2 (2.5) THF, 23
Pt(PhCN)2Cl2 (7)
PtCl2 (7)
THF, 60
THF, 70
a Enantiospecificity (es) = [(eeproduct)/(eesubstrate)] Â 100%. b Under
1 atm of CO. c dbcot: dibenzo[a,e]cyclooctatetraene.
We anticipated that the steric properties of the pro-
pargylic substituent would have a significant effect on the
net chirality transfer. As shown in Table 2, there is indeed a
trend correlating substituent size to the degree of chirality
transfer. Methyl and isobutyl groups were the least effec-
tive substituents in inducing stereospecificity. The ether
with a hydrocinnamyl group in the propargylic position
provided a markedimprovement. Optimally, largergroups
such as cyclohexyl and isopropyl were incredibly effective,
providing near-perfect chiral transfer (97% es and 99% es,
respectively). A larger aliphatic substituent (tert-butyl)
required higher temperatures for reactivity and conse-
quently yielded a complex mixture.
With an effective method and conditions for chirality
transfer, this enantiospecific transformation is efficient
across a broad range of enyne substrates (Figure 1).17 Both
(E)- and (Z)-1,2-disubstituted alkenes afforded the corre-
sponding bicycles (13e, 15aÀc), with the olefin geometry
directly transferred to the cyclopropane stereochemistry.
1,1-Disubstituted alkenes were also efficient reactants in
producing enol ethers (e.g., 15d). Enynes based on trisub-
stituted alkenes were successful, although the prenyl-derived
€
(15) Furstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005,
127, 8244–8245.
(16) The increase to 7 mol % catalyst was to ensure reaction
completion, which we observed did not occur uniformly at 5 mol %
across all substrates. We also opted to use PtCl2, as we had observed a
lack of uniform reactivity across all substrates when using Zeise’s dimer
([(C2H4)PtCl2]2).
Figure 1. Enantiospecific cycloisomerization to form bicyclo-
[4.1.0]heptene derivatives. aReaction performed at 75 °C.
(17) Because of the excellent efficiency of the isopropyl group in
chirality transfer, enynes based on this aliphatic moiety were evaluated.
The trends observed in Table 2 indicate that other groups would provide
synthetically useful levels of enantioenriched products as well.
The absolute stereochemistry of the product cyclopro-
panes was readily confirmed from the cycloisomerization
of enyne 14k (Scheme 4). Like the previous examples,
1774
Org. Lett., Vol. 15, No. 7, 2013

cycloisomerization of 14k proceeded efficiently to form
cyclopropane 15k in 92% yield. An X-ray crystal structure
was obtained, establishing the absolute stereochemistry as
illustrated.19
Scheme 4. Cycloisomerization of Ether 14k
Figure 2. Stereochemical rationalization.
Based on this stereochemical outcome, we have devel-
oped a working model for rationalizing the transfer of
chirality (Figure 2). The enyne substrate is oriented in a
boat-like conformation; the basis for this orientation is
derived from related calculations by Soriano et al.7 After the
propargylic substituent is placed in a favorable pseudoequa-
torial position, the metal catalyst coordinates the alkyne as
drawn in structure 16. An anti nucleophilic attack by the
alkene, in an orientation perpendicular to the alkyne, estab-
lishes the stereochemistry of the cyclopropanation. The
subsequent mechanistic steps ultimately produce ether 15k.
Potentially reactive conformations that would produce the
opposite enantiomer are unlikely. Conformation 14k-B is
sterically destabilized by the pseudoaxial isopropyl group,
while conformation 14k-C is stereoelectronically disfavored,
with insufficient overlap of the nucleophilic π-bond with the
electrophilic alkyne carbon. Albeit a preliminary model,20
this picture is consistent with the impact of the size of the
propargylic substituent on the overall stereospecificity.
An attractive aspect of this enantiospecific transformation
is the synthetic utility of the oxabicycloheptene derivatives.
Enol ether 15a, when subjected to oxidative cleavage condi-
tions,21 was cleanly converted to cyclopropane 18 (Scheme5).
Cyclopropanes are useful intermediates in organic syn-
thesis,22 and new methods for generating stereodefined,
highly substituted cyclopropanes are therefore valuable.23
The generation of the aldehyde and ester functional groups in
this process offers versatile synthetic handles for further
manipulation.
Scheme 5. Synthetic Utility: Oxidative Cleavage
In summary, we have observed chirality transfer in the
cycloisomerization of oxygen-tethered 1,6-enynes with cata-
lytic PtCl2. The process is highly enantiospecific and tolerates
diverse substitutions on both alkene and alkyne. Importantly,
we can generate the breadth of stereogenicity in these cyclo-
isomerization products through this enantiospecific process
from chiral propargylic alcohols, which are trivial to access.
Additionally, these results experimentally reinforce the valid-
ity of the proposed mechanism for this type of cycloisomer-
ization. A model of stereochemical relay was developed on
the basis of the product absolute configuration. We are
currently pursuing the use of this method in natural product
synthesis, in addition to exploring this overall strategy toward
chirality transfer in novel alkyne π-activation processes.
(18) (a) The toluenesulfonamide-tethered enyne substrates, more com-
monly used in asymmetric catalytic systems, also showed measurable
enantiospecificity via this approach. With a substrate bearing a methyl
group in the propargylic position, 82% enantiospecificity was observed. See
the SI for details. (b) Enynes featuring tetrasubstituted alkenes remain
challenging for this process. Preliminary experiments have shown marginal
reactivity with these systems (approximately 10% bicyclic product), but
other reaction products have been observed in these cases.
Acknowledgment. Colorado State University is acknowl-
edged for the support of our program. We thank the Rovis
group for generously sharing their HPLC equipment. Blaine
Pedersen (CSU) is acknowledged for experimental support.
Dr. Brian Newell (CSU) and Kevin Oberg (CSU) are ac-
knowledged for X-ray crystallographic expertise.
(19) The absolute configurations of all other oxabicyclo[4.1.0]heptene
products were assigned by analogy.
(20) It has been observed that stereoselective processes in catalytic alkyne
π-activation can be influenced by remarkably subtle effects. See: (a) Nieto
Faza, O.; de Lera, A. R. Top. Curr. Chem. 2011, 302, 81–130. (b) Reference
10e. (c) Computational efforts to validate our proposed model are ongoing.
(21) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217–3219.
(22) (a) Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthe-
sis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp
899À970. (b) Davies, H. M. L. Tetrahedron 1993, 49, 5203–5223.
(c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.;
Hudlicky, T. Chem. Rev. 1989, 89, 165–198.
(23) (a) Pellissier, H. Tetrahedron 2008, 64, 7041–7095. (b) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977–1050. (c) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911–936.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, spectra, and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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