Rhodium-Catalyzed Asymmetric Cycloisomerization and Parallel Kinetic Resolution of Racemic Oxabicycles

Article abstract of DOI:10.1002/anie.201604937

While desymmetrizations by intermolecular asymmetric ring-opening reactions of oxabicyclic alkenes with various nucleophiles have been reported over the past two decades, the demonstration of an intramolecular variant is unknown. Reported herein is the first rhodium-catalyzed asymmetric cycloisomerization of meso-oxabicyclic alkenes tethered to bridgehead nucleophiles, thus providing access to tricyclic scaffolds through a myriad of enantioselective C?O, C?N, and C?C bond formations. Moreover, we also demonstrate a unique parallel kinetic resolution, whereby racemic oxabicycles bearing two different bridgehead nucleophiles can be resolved enantioselectively.

Full text of DOI:10.1002/anie.201604937

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604937
German Edition: DOI: 10.1002/ange.201604937
Isomerization
Rhodium-Catalyzed Asymmetric Cycloisomerization and Parallel
Kinetic Resolution of Racemic Oxabicycles
+
+
Charles C. J. Loh, Matthias Schmid , Robert Webster , Andy Yen, Shabnam K. Yazdi,
Patrick T. Franke, and Mark Lautens*
Abstract: While desymmetrizations by intermolecular asym-
metric ring-opening reactions of oxabicyclic alkenes with
various nucleophiles have been reported over the past two
decades, the demonstration of an intramolecular variant is
unknown. Reported herein is the first rhodium-catalyzed
asymmetric cycloisomerization of meso-oxabicyclic alkenes
tethered to bridgehead nucleophiles, thus providing access to
tricyclic scaffolds through a myriad of enantioselective CÀO,
CÀN, and CÀC bond formations. Moreover, we also demon-
strate a unique parallel kinetic resolution, whereby racemic
oxabicycles bearing two different bridgehead nucleophiles can
be resolved enantioselectively.
H
erein, we report an unprecedented desymmetrization of
meso-oxabicyclic alkenes 1, bearing various bridgehead
nucleophiles, by an intramolecular enantioselective rho-
dium-catalyzed cycloisomerization (Scheme 1). We also intro-
duce a new class of nucleophile which forms CÀC bonds, and
describe a unique asymmetric parallel kinetic resolution
(
PKR) of racemic oxabicycles 3 arising from differential
attack by two internal nucleophiles.
The rhodium-catalyzed intermolecular asymmetric ring-
opening (ARO) reaction of oxabicycles has been an inten-
sively investigated field in our research group over the past
two decades, and the power of this protocol in generating
enantioenriched hydronapthalene frameworks has been well
Scheme 1. Comparison of known ARO reactions with the newly devel-
oped cycloisomerization and parallel kinetic resolution. cod=1,5-cyclo-
octadiene, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran.
documented with
a
diverse range of nucleophiles
[
1,2]
(
Scheme 1).
Moreover, many other research groups have
made contributions to this field by demonstrating the utility of
various metals such as iridium, ruthenium, platinum, copper,
cobalt, nickel, and palladium to effect intermolecular oxabi-
cycle ARO transformations.
In contrast, the intramolecular cycloisomerization of
meso-oxabicycles such as 1 is unknown, and would offer
new opportunities to access scaffolds which are otherwise
[
4]
challenging (Scheme 1).
Therefore, we initiated our
research in the cycloisomerization of the meso-substrates 1,
whereby a successful execution would directly generate
tricyclic scaffolds such as 2. Moreover, these tricyclic hydro-
napthalene core structures contain motifs which are present
in a wide range of bioactive molecules with known activities
as opioid receptor agonists, analgesic, and narcotic antago-
nists. Some are also known to possess dopaminergic activities
[3]
[
+]
[
*] Dr. C. C. J. Loh, M. Schmid, A. Yen, S. K. Yazdi, Prof. Dr. M. Lautens
Department of Chemistry, Davenport Chemical Laboratories
University of Toronto
[
5]
(
Scheme 1), thus making this protocol an especially attrac-
80 St. George Street, Toronto, Ontario M5S 3H6 (Canada)
tive one.
E-mail: mlautens@chem.utoronto.ca
It is important to emphasize that desymmetrization
[
+]
Dr. R. Webster
[6]
utilizing internal nucleophiles is still rare in catalysis, and
Bayer Pharma Aktiengesellschaft
Aprather Weg 18a, 42113 Wuppertal (Germany)
to date mostly occur with oxygen nucleophiles. Recent
achievements include bromocyclization on alkenes using
internal oxygen nucleophiles by the groups of Hennecke,
Kamashima, and Kan, as well as Yeung, using chiral
Dr. P. T. Franke
Carbogen Amcis AG
Hauptstraße 171, 4416 Bubendorf (Switzerland)
[
7a–d]
+
phosphate salts and Brønsted base catalysis.
A chiral
[
] These authors contributed equally to this work.
phosphoric acid catalyzed desymmetrization of meso-diols by
acetalization was recently reported by Sun and co-workers.
Transition metal catalyzed examples are scarce. In 1995, Trost
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
[7e]
1002/anie.201604937.
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and co-workers reported a desymmetrization of meso bis-
[
7f]
urethanes by employing asymmetric palladium catalysis.
One very recent case of diol desymmetrization by intra-
molecular hydroalkoxylation of allenes using gold(I) catalysis
[
7g]
is reported by Toste and co-workers. Therefore, we envision
that a successful execution of a rhodium-catalyzed asymmet-
ric cycloisomerization of diverse bis-nucleophile-tethered
oxabicycles would result in a significant advance in this area.
We initiated our investigation by utilizing our model
bridgehead diol containing a meso-oxabicyclic alkene 1a as
the test substrate (Table 1). The first-generation [{Rh-
[
a]
Table 1: Optimization of the rhodium-catalyzed cycloisomerization.
[
b]
Entry
[Rh] (Cat./L)
T
t
[h]
Yield
[%]
ee
[%]
[
c]
[d]
[8C]
[
[
e]
e]
1
2
[{Rh(cod)Cl} ] (4:8)
[{Rh(cod)Cl}2]
80
80
15
15
22
25
n.d.
n.d.
2
AgOTf, TBAI (4:8)
[
e]
3
4
5
6
[{Rh(cod)OH} ] (4:8)
80
80
80
50
15
15
2
5
n.d.
97
98
2
Rh(cod) OTf (5:6)
96
>99
>99
2
Rh(cod) OTf (5:6)
2
Rh(cod) OTf (5:6)
0.5
>99
2
[a] All reactions were conducted on 1a (0.2 mmol) in 4 mL solvent
(
0.05m with respect to 1a). [b] Cat./L in units of mol%/mol%. [c] Yield
of product isolated after flash column chromatography. [d] Determined
by HPLC analysis using chiral stationary phases. [e] Yield determined by
NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal
standard. TBAI=tetra-n-butylammonium iodide.
Scheme 2. Scope of the rhodium-catalyzed cycloisomerization: [a] All
reactions were conducted on 1a–j (0.2 mmol) in 4 mL THF (0.05m
with respect to 1a–j). For X-ray structure thermal ellipsoids shown at
(
(
cod)Cl} ] catalyst resulted in a low yield of the target product
Table 1, entry 1) and the second-generation rhodium iodide
2
50% probability. [b] Yield of the isolated 2a–j after flash column
catalyst did not improve the yields (Table 1, entry 2). The
fourth-generation [{Rh(cod)OH} ] was also not effective in
this reaction (Table 1, entry 3), and only trace amounts of
product were detected. Fortunately, the third-generation
chromatography. [c] Determined by HPLC analysis using chiral sta-
tionary phases. [d] This reaction requires 2 h. PMP=p-methoxyphenyl.
2
cationic Rh(cod) OTf furnished the target product smoothly
(Scheme 2). We realized that this protocol has an extremely
broad substrate scope, thus providing access to a wide variety
of tricyclic structures 2a–j with good to excellent yields and
excellent ee values. Oxabicyclic substrates bearing oxygen
nucleophiles are very well tolerated in this desymmetrization
methodology, thus furnishing six-membered ring pyrano and
five-membered ring furano fused hydronapthalene scaffolds
2a–d by a hydroalkoxylation-type CÀO bond-forming reac-
2
at 808C with excellent yield and enantioselectivity (Table 1,
entry 4). Further screening of solvents revealed that toluene
and 1,4-dioxane both gave quantitative yields and excellent
ee values (see the Supporting Information).
Utilizing DCE slightly diminished the yield of the isolated
product to 76% while retaining the excellent ee value (see the
Supporting Information). Interestingly, using acetonitrile
completely shuts down the reaction, and we attribute it
a poisoning of the active rhodium complex, since acetonitrile
can function as a competing ligand (see the Supporting
Information). Finally, we arrived at the optimized reaction
conditions after lowering the temperature to 508C, and thus
showed that this reaction is extremely facile, with almost
quantitative yields and excellent ee values obtained after only
tion. The oxabicycle 1e containing dimethoxy substituents
also yielded the target product 2e with excellent yield and
ee value. In addition, the meso-oxabicycles 1 f–h, bearing an
amine tethered to the bridgehead, were also suitable sub-
strates in this protocol and generated the tricyclic piperidine
fused hydronapthalenes 2 f–h by a hydroamination-type CÀN
bond-forming reaction. The enantioselective CÀN bond
3
0 minutes (Table 1, entry 6).
formation also proceeded with good to excellent yields and
With the optimized reaction conditions in hand, we
excellent ee values.
proceeded to expand the substrate scope of this methodology
2
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The versatility of this protocol is further augmented by
expanding the scope to include new enantioselective CÀC
bond-forming reactions. Access to 2i and 2j with very good to
excellent yields and excellent ee values was achieved
(
Scheme 2). The formation of 2i arises from an ene-type
cycloisomerization, which showcases a new mode of nucleo-
philic carbon reactivity previously unseen in the intermolec-
ular ARO reaction. An additional stereogenic center is
generated diastereoselectively in this instance, to form 2i as
a single diastereomer. Furthermore, the Friedel–Crafts-type
cycloisomerization reaction is also successfully demonstrated
utilizing pyrrole as a carbon nucleophile on the bridgehead
tether, thus furnishing 2j through a rare 7-exo-trig cyclization.
The absolute configurations of our products are assigned by
[
8]
analogy to the X-ray crystal structure of 2b.
In an effort to deepen our understanding of the catalyst
control in the cycloisomerization, racemic oxabicycles bear-
ing two differentiated bridgehead nucleophiles were synthe-
[
9]
sized. We designed a unique PKR reaction where two
different products arose from selective nucleophilic attack,
with excellent ee values when starting from racemic 3. This
process is possible because of the highly selective oxidative
Scheme 4. Scope of the PKR: [a] All reactions were conducted on (rac)-
k–n (0.2 mmol) in 4 mL THF (0.05m with respect to 3k–n). [b] Yield
of 4 and 5 isolated after flash column chromatography. [c] Enantiose-
I
addition of the cationic Rh /(S,R)-PPF-PtBu complex into
2
3
the distal CÀO bond in both enantiomers of (rac)-3 to
generate the intermediates Int-3a and Int-3b (Scheme 3),
thus enabling exclusive attack from the two proximal tethered
lectivities determined by HPLC analysis using chiral stationary phases.
nucleophiles in an S 2’ fashion.
N
cycloisomerization versus the conventional ARO reaction.
Two initial test experiments gave exclusively 2a when 1a was
reacted in the presence of 5 equivalents of MeOH or using
MeOH as the solvent (Scheme 5), thus showing the much
greater propensity for internal nucleophilic attack to occur.
Scheme 3. Mechanistic basis of the parallel kinetic resolution (PKR).
The selectivity of the PKR is demonstrated by the
capability of this protocol to resolve two constitutional
isomers with different ring sizes (4k,l and 5k,l), between
oxygen and carbon nucleophiles (4m and 5m), as well as
between oxygen and nitrogen nucleophiles (4n and 5n), all
Scheme 5. Control experiments with 1a in the presence of MeOH.
[10]
with excellent enantioselectivities (Scheme 4). The abso-
lute configurations of the PKR products are also confirmed by
When 1i was reacted with increasing amounts of MeOH
in the cycloisomerization, an unexpected product was iden-
tified (Table 2). We detected a competition between the ARO
reaction (8a,b) and a new pathway yielding 7a (Table 2,
entries 2–4). Further investigation revealed that as the
quantity of MeOH increases towards 50 equivalents, the
yield of 7a increases to a maximum of 59% (Table 2, entry 4).
However, 100 equivalents of MeOH switches the primary
mechanism towards formation of more 8a and less 7a
[
8]
analogy to the X-ray crystal structures of 4k and 5m.
We were interested in probing the mechanistic details of
the cycloisomerization by perturbing the reaction with
methanol as an external nucleophile. The objective was to
create a competition between the internal and external
[11]
nucleophiles in the crucial proton-transfer step.
The
resulting product distribution allowed us to better understand
the intricate relationship between the favorability of the
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Table 2: Perturbation experiments with ROH as an external nucleophile.
Scheme 6. Diastereoselective hydrogenation.
nucleophile tethered oxabicyclic alkenes, which furnishes
tricyclic motifs that possess privileged scaffolds prevalent in
biologically relevant molecules. A parallel kinetic resolution
was also demonstrated, where racemic oxabicyclic alkenes
bearing two different bridgehead nucleophiles can be
resolved into two constitutional isomers enantioselectively
by selective internal nucleophilic attack. Proton perturbation
experiments with an external nucleophile led to a deeper
understanding of the intricacies of alternating pathways due
to competitive proton transfer between internal and external
nucleophiles. A cationic cyclization pathway was also uncov-
ered in the proton perturbation experiments. Further inves-
tigations are currently underway.
[
b]
[c]
Entry
ROH
equiv)
Yield [%] (ee [%])
(
2
i
7a–c
8a–b
1
2
3
4
5
No ROH
97 (>99)
45 (>99)
29 (>99)
15 (>99)
9 (>99)
–
–
–
MeOH (5)
MeOH (20)
MeOH (50)
MeOH (100)
Neat MeOH
iPrOH (50)
tBuOH (50)
40 (>99)
54 (>99)
59 (>99)
54 (>99)
39 (>99)
47 (>99)
19 (>99)
Traces
14 (97)
24 (99)
33 (97)
50 (97)
8 (>99)
–
[
d]
6
7
8
40 (>99)
80 (>99)
Acknowledgements
[
a] All reactions were conducted on 1i (0.2 mmol) in 4 mL THF. [b] Yield
The authors thank Solvias AG, Umicore and Johnson
Matthey for the generous donation of ligands and rhodium
catalysts. The National Sciences and Engineering Research
Council (NSERC) is gratefully acknowledged for financial
support. C.C.J.L. thanks the Deutsche Forschungsgemein-
schaft (DFG) for a postdoctoral fellowship (LO 2065/1-1). Dr.
Paul Leong is acknowledged for preliminary studies. Brendan
Peters is acknowledged for synthesizing a substrate. Dr. Alan
Lough (University of Toronto) is gratefully acknowledged for
single-crystal X-ray analysis.
of product isolated after flash column chromatography. [c] Enantiose-
lectivity given within parentheses determined by HPLC analysis using
chiral stationary phases. [d] Reaction was conducted in neat anhydrous
MeOH (4 mL) instead of THF.
(
Table 2, entry 5). Performing the reaction in neat MeOH
gave 8a as major product (50% yield) and 7a as minor
product (39%). The formation of 7 is proposed to go through
a cationic trapping pathway reminiscent of biomimetic
[
11–13]
cationic cyclizations.
Further investigation with 50 equiv-
alents of iPrOH (Table 2, entry 7) and tBuOH (Table 2,
entry 8) also revealed the dependence of the cationic
cyclization pathway upon the steric hindrance of the proton
source, with increasing yields of 2i and diminishing yields of 7
as the steric hindrance of the alcohol increases. It is note-
worthy to point out that 2i, 7, and 8 were generated with
excellent ee values in all cases, independent of the quantity of
alcohol added. Hence, the proton perturbation experiments
revealed alternating mechanisms towards three distinct
products and depend upon the quantity of the added external
proton source.
Keywords: alkenes · heterocycles · isomerization ·
kinetic resolution · rhodium
[
1] For selected reviews, see: a) M. Lautens, K. Fagnou, S. Hiebert,
Acc. Chem. Res. 2003, 36, 48 – 58; b) K. Fagnou, M. Lautens,
Chem. Rev. 2003, 103, 169 – 196; c) T. Hayashi, K. Yamasaki,
Chem. Rev. 2003, 103, 2829 – 2844; d) P. A. Evans in Modern
Rhodium-Catalyzed Organic Reactions, Wiley-VCH, Weinheim,
2005.
We also demonstrated that our protocol is amenable to
scaling up through a gram-scale reaction of 1a, using
a reduced catalyst loading (see the Supporting Information),
generating 2a with very good yield and excellent ee value
[
2] For selected examples of the rhodium-catalyzed ARO, see:
a) M. Lautens, K. Fagnou, T. Rovis, J. Am. Chem. Soc. 2000, 122,
5650 – 5651; b) M. Lautens, K. Fagnou, J. Am. Chem. Soc. 2001,
123, 7170 – 7171; c) M. Lautens, K. Fagnou, D. Yang, J. Am.
(
88%, > 99% ee). Moreover, we further exploited enan-
Chem. Soc. 2003, 125, 14884 – 14892; d) L. Zhang, C. M. Le, M.
Lautens, Angew. Chem. Int. Ed. 2014, 53, 5951 – 5954; Angew.
Chem. 2014, 126, 6061 – 6064; e) C. C. J. Loh, X. Fang, B. Peters,
M. Lautens, Chem. Eur. J. 2015, 21, 13883 – 13887; f) C. C. J. Loh,
M. Schmid, B. Peters, X. Fang, M. Lautens, Angew. Chem. Int.
Ed. 2016, 55, 4600 – 4604; Angew. Chem. 2016, 128, 4676 – 4680.
3] For selected ARO reaction catalyzed by other metals, see: a) M.
Lautens, J.-L. Renaud, S. Hiebert, J. Am. Chem. Soc. 2000, 122,
1804 – 1805; b) D. K. Rayabarapu, C.-F. Chiou, C.-H. Cheng,
tioenriched 2a as a chiral framework in a diastereoselective
hydrogenation of the trisubstituted alkene, a reaction which
installs an additional stereogenic center to give 9 as the sole
diastereomer, presumably by selective hydrogenation on the
sterically more accessible convex face (Scheme 6).
[
In conclusion, we demonstrate for the first time an
asymmetric rhodium-catalyzed cycloisomerization of bis-
4
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Org. Lett. 2002, 4, 1679 – 1682; c) F. Bertozzi, M. Pineschi, F.
Macchia, L. A. Arnold, A. J. Minnaard, B. L. Feringa, Org. Lett.
002, 4, 2703 – 2705; d) K. Villeneuve, W. Tam, J. Am. Chem.
Soc. 2006, 128, 3514 – 3515; e) K. Villeneuve, W. Tam, Eur. J.
Org. Chem. 2006, 5449 – 5453; f) A. Tenaglia, S. Marc, J. Org.
Chem. 2006, 71, 3569 – 3575; g) A. Tenaglia, S. Marc, L.
Giordano, I. De Riggi, Angew. Chem. Int. Ed. 2011, 50, 9062 –
13838 – 13841; f) B. M. Trost, B. Breit, S. Peukert, J. Zambrano,
J. W. Ziller, Angew. Chem. Int. Ed. Engl. 1995, 34, 2386 – 2388;
Angew. Chem. 1995, 107, 2577 – 2579; g) W. Zi, F. D. Toste,
Angew. Chem. Int. Ed. 2015, 54, 14447 – 14451; Angew. Chem.
2015, 127, 14655 – 14659.
2
[8] CCDC 1480984 (2b), CCDC 1480985 (4k) and CCDC 1480991
(5m) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre. (See supporting
information).
9065; Angew. Chem. 2011, 123, 9228 – 9231; h) H. Cheng, D.
Yang, J. Org. Chem. 2012, 77, 9756 – 9765; i) P. H. Bos, A.
Rudolph, M. Pꢀrez, M. FaÇanꢁs-Mastral, S. R. Harutyunyan,
B. L. Feringa, Chem. Commun. 2012, 48, 1748 – 1750; j) L. Meng,
W. Yang, X. Pan, M. Tao, G. Cheng, S. Wang, H. Zeng, Y. Long,
D. Yang, J. Org. Chem. 2015, 80, 2503 – 2512; k) Y. Huang, C.
Ma, Y. X. Lee, R.-Z. Huang, Y. Zhao, Angew. Chem. Int. Ed.
[9] Our previous studies of regiodivergent resolution on ARO of
racemic oxabicycles showed that substrate control diminishes
the ee value of one of the regioisomers, whereas the parallel
kinetic resolution described here is strictly catalyst controlled,
thus yielding both constitutional isomers with excellent ee val-
ues: a) R. Webster, C. Bçing, M. Lautens, J. Am. Chem. Soc.
2009, 131, 444 – 445; Based on a reviewerꢆs comment, we
detected a transcriptional error in Scheme 5 and Table 1 of our
previous manuscript, Ref. [9a]. The ligand used should be (S,R)-
PPF-PtBu instead of (R,S)-PPF-PtBu to give the enantiomers
2015, 54, 13696 – 13700; Angew. Chem. 2015, 127, 13900 – 13904.
[
4] For two examples of intramolecular racemic ring-opening
reactions of nonsymmetric oxabicycles are known, using
a Lewis acid catalyst, see: a) W-D. Z. Li, K. Wei, Org. Lett.
2004, 6, 1333 – 1335; for a stoichoimetric Lewis acid mediated
example, see: b) C. S. Schindler, S. Diethelm, E. M. Carreira,
2
2
Angew. Chem. Int. Ed. 2009, 48, 6296 – 6299; Angew. Chem.
drawn in Ref. [9a]. For selected reviews: b) J. R. Dehli, V. Gotor,
Chem. Soc. Rev. 2002, 31, 365 – 370; c) E. Vedejs, M. Jure,
Angew. Chem. Int. Ed. 2005, 44, 3974 – 4001; Angew. Chem. 2005,
117, 4040 – 4069; d) R. R. Kumar, H. B. Kagan, Adv. Synth.
Catal. 2010, 352, 231 – 242; e) L. C. Miller, R. Sarpong, Chem.
2
009, 121, 6414 – 6417.
5] a) Y. Lambert, J.-P. Daris, I. Monkovi c´ , J. Med. Chem. 1978, 21,
23 – 427; b) N. Tagmatarchis, K. Thermos, H. E. Katerinopou-
[
4
los, J. Med. Chem. 1998, 41, 4165 – 4170; c) G. Stemp, S. A.
Smith, C. N. Johnson, S. Waldon, Datchworth, International
Patent WO 097/47602, 1997; d) R. L. Dow, K. K-C. Liu, A. G.
Swick, International Patent WO 00/66522, 2000; e) Purdue
Pharma, L. P., International Patent WO 2015/097545, 2015.
6] Reviews in desymmetrization: a) M. C. Willis, J. Chem. Soc.
Perkin Trans. 1 1999, 1765 – 1784; b) ꢂ. Enrꢃquez-Garcia, E. P.
Kꢄndig, Chem. Soc. Rev. 2012, 41, 7803 – 7831; c) M. D. Dꢃaz-de-
Villegas, J. A. Gꢁlvez, R. Badorrey, M. P. Lꢅpez-Ram-de-Vꢃu,
Chem. Eur. J. 2012, 18, 13920 – 13935; d) P.-A. Wang, Beilstein J.
Org. Chem. 2013, 9, 1677 – 1695.
Soc. Rev. 2011, 40, 4550 – 4562.
1
[10] The J
coupling constant is a characteristic indicator of the
C-H
cyclic nature of cycloisomerization and PKR products; see the
Supporting Information.
[
[
[11] For selected reviews of polyene and cationic cyclizations, see:
a) W. S. Johnson, Angew. Chem. Int. Ed. Engl. 1976, 15, 9 – 17;
Angew. Chem. 1976, 88, 33 – 41; b) C. N. Ungarean, E. M.
Southgate, D. Sarlah, Org. Biomol. Chem. 2016, 14, 5454 – 5467.
[12] See the Supporting Information for postulated mechanism of
cycloisomerization, PKR, and cationic cyclization pathway
towards 7.
[13] Re-subjecting 2i to the rhodium-catalyzed cycloisomerization
conditions using MeOH as the reaction solvent did not yield 7a,
thus precluding the formation of 7a from 2i by rhodium
catalysis.
7] For desymmetrization of meso-substrates with internal nucleo-
philes: a) U. Hennecke, C. H. Mꢄller, R. Frçhlich, Org. Lett.
2
011, 13, 860 – 863; b) K. Ikeuchi, S. Ido, S. Yoshimura, T.
Asakawa, M. Inai, Y. Hamashima, T. Kan, Org. Lett. 2012, 14,
016 – 6019; c) D. W. Tay, G. Y. C. Leung, Y.-Y. Yeung, Angew.
Chem. Int. Ed. 2014, 53, 5161 – 5164; Angew. Chem. 2014, 126,
261 – 5264; d) Z. Ke, C. K. Tan, F. Chen, Y.-Y. Yeung, J. Am.
6
5
Chem. Soc. 2014, 136, 5627 – 5630; e) Z. Chen, J. Sun, Angew.
Chem. Int. Ed. 2013, 52, 13593 – 13596; Angew. Chem. 2013, 125,
Received: May 19, 2016
Published online: && &&, &&&&
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Communications
Isomerization
The oxabicycle dance! An unprecedented
rhodium-catalyzed cycloisomerization of
meso-oxabicyclic alkenes bearing bis-
tethered nucleophiles is presented. A
parallel kinetic resolution was also dem-
onstrated, where racemic oxabicycles
bearing two different tethered nucleo-
philes can be resolved enantioselectively
to give two constitutional isomers by
differential nucleophilic attack.
C. C. J. Loh, M. Schmid, R. Webster,
A. Yen, S. K. Yazdi, P. T. Franke,
M. Lautens*
&&&& — &&&&
Rhodium-Catalyzed Asymmetric
Cycloisomerization and Parallel Kinetic
Resolution of Racemic Oxabicycles
6
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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