Rhodium(I)-catalyzed domino asymmetric ring opening/enantioselective isomerization of oxabicyclic alkenes with water

Article abstract of DOI:10.1002/anie.201200390

Water-induced asymmetric ring opening: Enantio-enriched 2-hydroxy-1-tetralones are formed from oxabicyclic alkenes through a novel Rh^I-catalyzed domino reaction. The proposed mechanism involves water-induced asymmetric ring opening to generate chiral trans-1,2-diol intermediates and subsequent enantioselective isomerization (see scheme). Copyright

Full text of DOI:10.1002/anie.201200390

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DOI: 10.1002/anie.201200390
Domino Reactions
Rhodium(I)-Catalyzed Domino Asymmetric Ring Opening/
Enantioselective Isomerization of Oxabicyclic Alkenes with Water**
Gavin C. Tsui and Mark Lautens*
Rhodium(I)-catalyzed asymmetric ring-opening (ARO) reac-
tion of strained bicyclic alkenes has been demonstrated as
a highly efficient and enantioselective process for generating
a functionalized dihydronaphthalene core.[1] Our group has
previously reported that chiral RhI complexes catalyze ring
opening of oxa- and azabicyclic alkenes with soft nucleophiles
such as alcohols, phenols, thiols, amines, anilines, malonates
and carboxylates in high yield and enantioselectivity.[2] The
products are generated by an SN2’ nucleophilic displacement
of the bridgehead leaving group with inversion to give the 1,2-
trans product as a single regio- and diastereomer. This method
has been recently demonstrated as a viable strategy for
Scheme 1. Formation of 2-hydroxy-1-tetralone 3a by RhI-catalyzed ARO
synthesizing bioactive aminotetralins rotigotine and (S)-8-
of oxabenzonorbornadiene 1a with water.
OH-DPAT.[3]
Although various heteroatom nucleophiles have been
employed in ARO, the use of water—the simplest nucleo-
Table 1: Combined effects of ligand, catalyst loading, concentration, and
reaction temperature.
phile—has not been demonstrated. Based on previous
studies,[2] water-induced ARO of oxabenzonorbornadiene
1a should yield chiral trans-1,2-diol 2a. Instead, we isolated
the unexpected 2-hydroxy-1-tetralone product 3a exclusively
in the presence of catalytic [Rh(cod)Cl]2/(R,S)-PPF-PtBu2
(cod = cyclooctadiene) in aqueous THF[4] (Scheme 1). Reac-
tion at 258C afforded enantio-enriched 3a (enantiomeric
ratio, e.r. = 33:67), a higher reaction temperature (50 or 808C)
caused a significant decrease in enantioselectivity. To the best
of our knowledge, the formation of tetralone products such as
3a is unprecedented in ARO reactions. We subsequently
investigated the effects of ligand, catalyst loading, concen-
tration, and reaction temperature (Table 1).
No reaction took place without added ligand (entry 1).
Reaction at 258C (0.2m concentration) with 5 mol% [Rh-
(cod)Cl]2 and 10 mol% (R,S)-PPF-PtBu2 gave tetralone
product 3a in 79% yield (entry 2, cf. Scheme 1). As the
catalyst loading was decreased to 2 mol%, we obtained
a mixture of diol 2a (major product) and tetralone 3a
Entry Ligand
Catalyst
T
t [h]
2a
[%]
3a
[%] [%]
4a
loading[c] [8C]
1
–
5/–
25
25
25
25
25
25
50
25
25
25
75
25
25
80
15–17 <5
15–17 <5
15–17 53[a]
15–17 74[a]
15–17 <5
<5 <5
79[a] <5
29[a] <5
10[a] <5
70[a] <5
81[b] <5
80[b] <5
2
3
(R,S)-PPF-PtBu2 5/10
(R,S)-PPF-PtBu2 2/4.4
(R,S)-PPF-PtBu2 2/4.4
(R,S)-PPF-PtBu2 2/4.4
(R,S)-PPF-PtBu2 2/4.4
(R,S)-PPF-PtBu2 2/4.4
(R,S)-PPF-PtBu2 1/2.2
(R,S)-PPF-PtBu2 0.5/1.2
4[d]
5[e]
6
40
2.5
7[b]
<5
7
8
9
15–17 89[a,f] <5 <5
72
35[a,g] <5 <5
10
11
12
13
14[k]
(S,S)-DIOP
DPPF
(S)-BINAP
BIPHEP
TPPDS
5/10
5/10
5/10
5/10
5/15
15–17 59[a,h] <5 <5
17
26[a,i] <5 <5
15–17 <5
15–17 <5
13
<5 91[a,j]
<5 70[b]
<5 <5
[*] G. C. Tsui, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
<5
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy of
the crude material. [c] Mol% [Rh(cod)Cl]2/mol% ligand. [d] Concentra-
tion=0.1m. [e] Concentration=0.4m. [f] e.r. >99:1. [g] Recovered 39%
of starting material. [h] e.r.=87:13. [i] No product formation at 258C
after 17 h. [j] e.r.>99:1. [k] Reaction was run in neat water with and
without sodium dodecyl sulfate.
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML/
[**] This research was supported by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the Merck Frosst
Centre for Therapeutic Research, and the University of Toronto. We
gratefully thank Dr. Alan Lough (Chemistry Department, University
of Toronto) for single-crystal X-ray structure analysis, Dr. Bernard
Leroy for the initial studies using azabicycles, and Solvias AG for the
generous gift of chiral ligands.
(entry 3). Reaction concentration also had a significant effect
on product distribution. Lower concentration (0.1m) favored
diol formation whereas higher concetration (0.4m) favored
tetralone formation (entries 4 and 5). It was found that
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200390.
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elevated reaction temperature and prolonged reaction time
caused preferential formation of tetralone 3a over diol 2a
(entries 6 and 7). At 1 mol% catalyst loading, diol 2a was
formed cleanly in good yield (89%) and excellent enantio-
selectivity (e.r. > 99:1) (entry 8).[5] Further decreases in cata-
lyst loading led to incomplete conversion (entry 9). Other
ligands that gave diol 2a included (S,S)-DIOP (entry 10) and
DPPF (entry 11), albeit in lower yields, the latter required
heating at 758C. A lower e.r. of 87:13 was observed by using
(S,S)-DIOP as the chiral ligand. When (S)-BINAP (entry 12)
and BIPHEP (entry 13) were used, the dimeric product 4a
was obtained in good yields through a RhI-catalyzed cyclo-
dimerization process that has been previously described.[6]
However, our conditions employed a neutral RhI catalyst in
the presence of water whereas the literature reports used
cationic RhI sources under strictly anhydrous conditions. Both
protocols gave the product in excellent enantioselectivity
(e.r. > 99:1). Finally, reactions carried out in neat water using
a water-soluble ligand TPPDS did not yield any product
(entry 14).[7] We also screened other RhI sources such as
[Rh(cod)OH]2, [Rh(CO)2Cl]2, and Rh(cod)2OTf, all of which
showed no reactivity.[8]
which suggested the formation of a common achiral inter-
mediate during isomerization. Furthermore, the process was
catalyst-controlled since the (S,R)-ligand gave the opposite
enantiomer of 3a. These results supported the notion that
a RhI-catalyzed domino reaction[10] took place to generate 3a
from 1a (cf. Scheme 1): diol 2a was first formed from
oxabicycle 1a by RhI-catalyzed ARO with water as the
nucleophile, at a higher catalyst loading 2a was subsequently
converted to tetralone 3a by RhI-catalyzed enantioselective
isomerization. The presence of the allylic alcohol is crucial for
the isomerization since the analogous allylic methyl ether
(obtained from MeOH-induced ARO) did not isomerize after
17 h at 508C.
To investigate the generality of RhI-catalyzed ARO with
water, we next studied the scope of oxabicyclic alkenes
(Table 2). The effects of the remote substituents on the
Table 2: Scope of oxabicyclic alkenes in RhI-catalyzed ARO with water:
diol formation.[a]
We speculated that 2a is an intermediate en route to 3a
through an isomerization process. To test this hypothesis, we
subjected 2a (various enantiomeric compositions) to the
catalytic conditions (Scheme 2). In all cases, 2a isomerized to
3a in good yields.
Entry Substrate
Product
Catalyst
Yield[c]
loading[b] (e.r.)
83
(>99:1)
1[d]
2/4.4
82
(>99:1)
2
1/2.2
64
(>99:1)
3
0.5/1.1
Scheme 2. RhI-catalyzed enantioselective isomerization of diol 2a to
tetralone 3a.
68
(>99:1)
4[e]
5/10
5/10
An interesting feature of this isomerization is that a much
higher e.r. was observed than in the one-pot process using
oxabicycle 1a (cf. Scheme 1). At 258C, the enantio-enriched
(R)-3a was obtained in 15:85 e.r. whereas the one-pot process
only gave 33:67 e.r.[9] When repeating this reaction with
different concentrations, we found a significant impact on
conversion. At 0.1m concentration, only 12% product was
isolated (e.r. = 24:76) with 88% unreacted starting material.
At 0.4m concentration, the product was obtained in a high
yield of 89% (e.r. = 22:78). However, changing the concen-
tration did not lead to any improvement in enantioselectivity.
Preliminary studies showed that the conversion increased
linearly with catalyst loading and suggested that the reaction
is first order in the Rh catalyst (see Supporting Information).
The enantioselectivities (no significant differences) were not
dependent on the enantiopurity of the starting material,
79
(>99:1)
5[e]
[a] Reaction conditions: substrate 1b–f (0.2–1.2 mmol scale),
[Rh(cod)Cl]2 (0.5–5 mol%), (R,S)-PPF-PtBu2 (1.1–10 mol%), H2O
(56 equiv), THF (0.2m). [b] Mol% [Rh(cod)Cl]2/mol% (R,S)-PPF-PtBu2.
[c] Yield [%] of isolated product. [d] Reaction was run for 48 h. [e] No
formation of tetralone product at 258C or 508C.
oxabicyclic alkenes were studied by using difluoro-substituted
1b, dimethoxy-substituted 1c, and methylenedioxy-substi-
tuted 1d. Chiral trans-1,2-diol products 2b–d were obtained
with excellent enantioselectivities (e.r. > 99:1) (entries 1–3).
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The trans stereochemistry was unambiguously confirmed for
2d by X-ray crystallography.[5] Substrate 1b required 2 mol%
catalyst and longer reaction time (entry 1), whereas 1d
required only 0.5 mol% catalyst to furnish the product
(entry 3). We have also previously observed a similar activat-
ing effect by the electron-donating group on the aromatic ring
of oxabicyclic alkenes in MeOH-induced ring opening.[1a]
More sterically hindered dimethyldibromo substrate 1e and
the bridgehead dimethyl-substituted substrate 1 f required
higher catalyst loadings (entries 4 and 5). Both diol products
2e and 2 f were obtained with excellent e.r. (> 99:1).
ARO with water to give the amino alcohol product 6
[Eq. (2)]. The e.r. was significantly lower than that from the
Under the same reaction conditions but higher catalyst
loadings, tetralone products 3b–d were formed by the domino
process from oxabicycles 1b–d (Table 3). No tetralone
oxabicyclic alkenes and the reaction required a higher
temperature. No isomerization was observed with 6 and the
Boc-protected azabicycle was unreactive.
The mechanism of water-induced ARO to form chiral trans-
1,2-diol products 2a–f is presumably analogous to the
previously proposed mechanistic working model using alco-
hols as the nucleophile.[1a] But the pathway for the formation
of 2-hydroxy-1-tetralone products 3a–d is of particular
interest since it is unprecedented in ARO reactions. Reaction
conducted in D2O showed deuterium-incorporation at the a-
and b-positions of the tetralone product 7 [Eq. (3)]. The
deuterium-labeled oxabicyclic alkene 8 afforded the tetralone
product 9 with retention of one deuterium at the benzylic
position [Eq. (4)].
Table 3: RhI-catalyzed domino ARO/isomerization of oxabicyclic alkenes
with water.[a]
Entry
Substrate
Product
Catalyst
Yield[c]
(e.r.)
loading[b]
65
(37:63)
1
2
3
5/10
2/4.4
2/4.4
64
(42:58)
83
(47:53)
[a] Reaction conditions: substrate 1b–d (0.2–1.2 mmol scale), [Rh-
(cod)Cl]2 (2–5 mol%), (R,S)-PPF-PtBu2 (4.4–10 mol%), H2O (56 equiv),
THF (0.2m). [b] Mol% [Rh(cod)Cl]2/mol% (R,S)-PPF-PtBu2. [c] Yield [%]
of isolated product.
Based on the these results and the isomerization studies,
we proposed the following mechanism for RhI-catalyzed
domino ARO/enantioselective isomerization of oxabicyclic
alkene 1a with water to generate diol 2a and tetralone 3a
(Scheme 3).
formation was observed with substrate 1e and 1 f even at
higher reaction temperature (508C) (cf. Table 2, entries 4 and
5). Although products 3b–d were formed in moderate to good
yields, only low enantioselectivities were obtained (Table 3).
However, it is noteworthy that the e.r. obtained in the
isomerization of 2b to 3b gave a significant improvement
compared to the domino process (21:79 vs. 37:63) [Eq. (1)].
Nos-protected azabicyclic alkene 5 underwent RhI-catalyzed
Dimeric Rh complex 10 is cleaved by solvolysis or other
processes to give monomeric complex 11 (a). The oxidative
À
insertion with retention into a bridgehead C O bond is the
enantio-discriminating step which gives the enyl Rh alkoxide
complex 12 (b). Protonation by water generates cationic Rh
complex 13 and a hydroxide (c). Previous kinetic studies in
alcohol-induced ARO reactions supported the formation of
the cationic Rh species 13 and anionic nucleophile.[1a]
Nucleophilic attack with inversion occurs in an SN2’ fashion
to afford the trans-1,2-diol product 2a as well as regenerates
the catalyst 11 (d). Since an allylic alcohol is present in 2a, at
a higher catalyst loading, it undergoes a RhI-catalyzed
isomerization process which leads to enol 16 (e)–(g).[11] We
also recently reported a RhI-catalyzed domino process where
ARO is followed by allylic alcohol isomerization then
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reaction takes place at higher cata-
lyst loadings to form 2-hydroxy-1-
tetralone products by a RhI-cata-
lyzed ARO/isomerization process
where the RhI catalyst plays distinc-
tive roles in each step. 3) The isomer-
ization of diol intermediates is enan-
tioselective at room temperature to
give enantio-enriched tetralone
products, presumably through an
oxy-p-allyl mechanism or an enan-
tioselective protonation step. An
additional benefit of our method is
the use of water to generate valuable
products.[17] Chiral trans-1,2-diol
frameworks such as 2a–f are usually
synthesized by multi-step organic
transformations or enzymatic reso-
lution and are useful building blocks
for chiral 1,2-diphosphane and 1,2-
diamine ligands in asymmetric catal-
ysis.[18] Synthetic applications of the
chiral diol products as well as further
studies to improve the enantioselec-
tivity for the formation of tetralone
products and to understand the
Scheme 3. Proposed catalytic cycle of RhI-catalyzed domino ARO/enantioselective isomerization of
oxabicyclic alkene 1a with water.
oxidation to form bicyclo[2.2.2]lactones enantioselectively.[12]
Tautomerization of enol 16 leads to 1-hydroxy-2-tetralone 17
(h), which explains deuteration at the b-position [cf. Eq. (3)].
Intermediate 17 undergoes further tautomerization via the
ene-diol 18 to furnish the more thermodynamically favored 2-
hydroxy-1-tetralone product 3a (i)–(j), where protonation/
deuteration takes place at the a-position [cf. Eq. (3)].
Tautomerization of this type is known in the literature,
especially at elevated temperature and prolonged reaction
times.[13] One of the deuterium atoms is lost in 9 [cf. Eq. (4)]
during the tautomerization step (i), in the presence of much
larger excess of H2O, protonation rather than deuteration
takes place (i)–(j). Control experiments showed that water is
needed for the isomerization process and step (j) is irrever-
sible.[14] If 3a is formed via an achiral intermediate 18, then
the origin of the enantioselectivity is of particular interest.
Bosnich and co-worker proposed an oxy-p-allyl mechanism
for Rh-catalyzed isomerization of enols to carbonyl com-
pounds.[15] In the same report, they obtained a chiral aldehyde
with low enantioselectivity from a prochiral enol substrate by
using a chiral Rh catalyst. It is therefore possible that 18 was
converted to 3a via an oxy-p-allyl Rh intermediate 19.
However, the possibility of an enantioselective protonation
pathway of 18 through coordination of the chiral Rh catalyst
to the two OH groups to generate 3a cannot be completely
ruled out.[16]
mechanism of the enantioselective isomerization step are
on-going in our laboratory and will be reported in due course.
Received: January 15, 2012
Revised: March 6, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · domino reactions ·
isomerization · rhodium · water chemistry
.
[1] a) M. Lautens, K. Fagnou, Proc. Natl. Acad. Sci. USA 2004, 101,
5455; b) M. Lautens, K. Fagnou, S. Hiebert, Acc. Chem. Res.
2003, 36, 48; c) K. Fagnou, M. Lautens, Chem. Rev. 2003, 103,
169; d) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829;
e) P. A. Evans, Modern Rhodium-Catalyzed Organic Reactions,
Wiley-VCH, Weinheim, 2005.
[2] a) M. Lautens, K. Fagnou, V. Zunic, Org. Lett. 2002, 4, 3465;
b) M. Lautens, K. Fagnou, J. Am. Chem. Soc. 2001, 123, 7170;
c) M. Lautens, K. Fagnou, M. Taylor, Org. Lett. 2000, 2, 1677;
d) M. Lautens, K. Fagnou, T. Rovis, J. Am. Chem. Soc. 2000, 122,
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[3] R. Webster, A. Boyer, M. J. Fleming, M. Lautens, Org. Lett.
2010, 12, 5418.
[4] Preliminary studies showed that 56 equivalents of water in THF
was the optimal solvent mixture (see Supporting Information).
[5] The absolute configuration assignment (1R,2R) of 2a was based
on comparison of the sign of the specific rotation of the
hydrogenated 2a with that reported in the literature: R. Miura,
S. Honmaru, M. Nakazaki, Tetrahedron Lett. 1968, 9, 5271.
Hydrogenated 2a: (1R,2R) [a]D25 =+ 100 (c 0.32, CHCl3). Lit.:
enantiomer of hydrogenated 2a (1S,2S) [a]D25 = À111 (c 1.05,
CHCl3). CCDC 861063 (2d) contains the supplementary crys-
In conclusion, we have made the following new discov-
eries from the studies of RhI-catalyzed ARO of oxabicyclic
alkenes with water. 1) Water is an effective nucleophile in the
asymmetric ring-opening reactions of oxabicyclic alkenes.
Chiral trans-1,2-diol products can be synthesized in one step
with good yields and excellent enantioselectivities under mild
conditions and with low catalyst loadings. 2) A domino
4
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tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Gree, Chem. Rev. 2003, 103, 27; d) R. C. van der Drift, E.
Bouwman, E. Drent, J. Organomet. Chem. 2002, 650, 1.
[12] A. Boyer, M. Lautens, Angew. Chem. 2011, 123, 7484; Angew.
Chem. Int. Ed. 2011, 50, 7346.
[13] For examples of tautomerization of acyloins, see: a) K. Smithies,
M. E. B. Smith, U. Kaulmann, J. L. Galman, J. M. Ward, H. C.
Hailes, Tetrahedron: Asymmetry 2009, 20, 570; b) S. J. Miller,
S. M. Mennen, J. Org. Chem. 2007, 72, 5260; c) S. A. Fleming,
S. M. Carroll, J. Hirschi, R. Liu, J. L. Pace, J. T. Redd, Tetrahe-
dron Lett. 2004, 45, 3341.
[14] The isomerization reaction from 2a to 3a gave very poor
conversion without water. When (R)-3a (15:85 e.r.) was
subjected to the catalytic conditions using (S,R)-PPF-PtBu2, we
only recovered the starting material with the same e.r. (17:83).
[15] S. H. Bergens, B. Bosnich, J. Am. Chem. Soc. 1991, 113, 958.
[16] For reviews on enantioselective protonation, see: a) J. T. Mohr,
A. Y. Hong, B. M. Stoltz, Nat. Chem. 2009, 1, 359; b) C. Fehr,
Angew. Chem. 1996, 108, 2726; Angew. Chem. Int. Ed. Engl.
1996, 35, 2566.
[17] For recent reviews on organic synthesis in aqueous media, see:
a) R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302; b) A.
Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725; c) C. I.
Herrerꢁas, X. Yao, Z. Li, C.-J. Li, Chem. Rev. 2007, 107, 2546.
[18] a) S. Demay, F. Volant, P. Knochel, Angew. Chem. 2001, 113,
1272; Angew. Chem. Int. Ed. 2001, 40, 1235; b) S. Demay, A.
Kotschy, P. Knochel, Synthesis 2001, 863.
[6] a) T. Nishimura, T. Kawamoto, K. Sasaki, E. Tsurumaki, T.
Hayashi, J. Am. Chem. Soc. 2007, 129, 1492; b) A. Allen, P.
Le Marquand, R. Burton, K. Villeneuve, W. Tam, J. Org. Chem.
2007, 72, 7849.
[7] We have previously reported the use of TPPDS in RhI-catalyzed
coupling reactions in water: M. Lautens, A. Roy, K. Fukuoka, K.
Fagnou, B. Martin-Matute, J. Am. Chem. Soc. 2001, 123, 5358.
[8] See Supporting Information for a full list of catalyst and ligand
screen.
[9] The (R)-configuration assignment of 3a was based on compar-
ison of the sign of the specific rotation with that reported in the
literature: I. Lunardi, T. Cazetta, G. J. A. Conceiżo, P. J. S.
Moran, J. A. R. Rodrigues, Adv. Synth. Catal. 2007, 349, 925.
25
(R)-3a: [a]D25 =+ 25.9 (c 0.98, CHCl3) for 58% ee. Lit.: [a]D
+ 44.5 (c 1.54, CHCl3) for 99% ee.
=
[10] For classifications of domino reactions, see: L. F. Tietze, G.
Brasche, K. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, 2006.
[11] For recent reviews on Rh-catalyzed isomerization of allylic
alcohols, see: a) L. Mantilli, C. Mazet, Chem. Lett. 2011, 40, 341;
b) K. Tanaka in Comprehensive Organometallic Chemistry III,
Vol. 10 (Eds.: R. H. Crabtree, D. M. P. Mingos, I. Ojima),
Elsevier, Oxford, 2007, pp. 71 – 100; c) R. Uma, C. Crꢀvisy, R.
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Communications
Domino Reactions
Water-induced asymmetric ring opening:
Enantio-enriched 2-hydroxy-1-tetralones
are formed from oxabicyclic alkenes
through a novel RhI-catalyzed domino
reaction. The proposed mechanism
involves water-induced asymmetric ring
opening to generate chiral trans-1,2-diol
intermediates and subsequent enantio-
selective isomerization (see scheme).
G. C. Tsui, M. Lautens*
&&&& — &&&&
Rhodium(I)-Catalyzed Domino
Asymmetric Ring Opening/
Enantioselective Isomerization of
Oxabicyclic Alkenes with Water
6
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