Catalytic asymmetric synthesis of 8-oxabicyclooctanes by intermolecular [5+2] pyrylium cycloadditions

Article abstract of DOI:10.1002/anie.201402834

Highly enantioselective intermolecular [5+2] cycloadditions of pyrylium ion intermediates with electron-rich alkenes are promoted by a dual catalyst system composed of an achiral thiourea and a chiral primary aminothiourea. The observed enantioselectivity is highly dependent on the substitution pattern of the 5π component, and the basis for this effect is analyzed using experimental and computational evidence. The resultant 8-oxabicyclo[3.2.1]octane derivatives possess a scaffold common in natural products and medicinally active compounds and are also versatile chiral building blocks for further manipulations. Several stereoselective complexity-generating transformations of the 8-oxabicyclooctane products are presented. A dual thiourea catalyst system enables the title reaction to be carried out to form useful chiral building blocks that can participate in a series of complexity-generating transformations to achieve varied molecular architectures.

Full text of DOI:10.1002/anie.201402834

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DOI: 10.1002/anie.201402834
Synthetic Methods
Catalytic Asymmetric Synthesis of 8-Oxabicyclooctanes by
Intermolecular [5+2] Pyrylium Cycloadditions**
Michael R. Witten and Eric N. Jacobsen*
Abstract: Highly enantioselective intermolecular [5+2] cyclo-
additions of pyrylium ion intermediates with electron-rich
alkenes are promoted by a dual catalyst system composed of an
achiral thiourea and a chiral primary aminothiourea. The
observed enantioselectivity is highly dependent on the sub-
stitution pattern of the 5p component, and the basis for this
effect is analyzed using experimental and computational
evidence. The resultant 8-oxabicyclo[3.2.1]octane derivatives
possess a scaffold common in natural products and medici-
nally active compounds and are also versatile chiral building
blocks for further manipulations. Several stereoselective com-
plexity-generating transformations of the 8-oxabicyclooctane
products are presented.
C
hiral 8-oxabicyclo[3.2.1]octane architectures reside at the
core of numerous natural products and biologically significant
compounds (Scheme 1).[1,2] Heterocycles of this class have
also proven to be valuable intermediates in the stereoselec-
tive synthesis of oxygenated seven-membered carbocycles[3]
Scheme 2. Enantioselective [5+2] cycloadditions. Bz=benzoyl.
work, while also embedding a reactive a,b-unsaturated
ketone in the bicyclic core.[9,10] The products can thus be
subjected to stereoselective elaboration to afford a diverse
array of chiral structures in just one or two steps (see below).
We reported recently that a dual catalyst system consisting of
the chiral primary amine 2 and the achiral thiourea 3 catalyzes
enantioselective intramolecular [5+2] cycloadditions of alke-
nylpyranones of structure 1 through the proposed intermedi-
acy of thiourea-complexed aminopyrylium salts (4,
Scheme 2).[11–13] While this method enables the preparation
of a range of complex tricyclic products, the corresponding
intermolecular reaction would provide more general access to
8-oxabicyclo[3.2.1]octane derivatives from simpler and more
accessible starting materials.[14] However, initial efforts to
effect intermolecular variants of these reactions proved
unsuccessful (< 40% ee).[11] Here, we disclose that closer
examination of this reaction manifold has revealed striking
substrate structure-enantioselectivity effects and has led to
the successful development of highly enantioselective inter-
molecular [5+2] cycloadditions.
Scheme 1. The 8-oxabicyclo[3.2.1]octane core in selected natural prod-
ucts.
and tetrahydrofuran derivatives.[4] Successful stereoselective
approaches to the 8-oxabicyclo[3.2.1]octane framework have
relied on transition-metal-catalyzed [3+2] cycloadditions,[5]
[4+3] cycloadditions,[6] diastereoselective [5+2] cycloaddi-
tions,[7] and diastereoselective cascade cyclizations.[8]
The [5+2] cycloaddition of a pyrylium ylide precursor
with a C2 dipolarophile (e.g. 6 to 7, Scheme 2) provides
a concise approach to the 8-oxabicyclo[3.2.1]octane frame-
[*] M. R. Witten, Prof. Dr. E. N. Jacobsen
Department of Chemistry and Chemical Biology, Harvard University
12 Oxford St., Cambridge, MA 02138 (USA)
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-43214) and an NDSEG
Predoctoral Fellowship to M.R.W. (32CFR168a). We thank Dr. Shao-
Liang Zheng for crystal-structure determination and Dr. Noah Z.
Burns and Andreas R. Rçtheli for helpful discussions.
The racemic pyranone 8a (Scheme 3), which is super-
ficially analogous to pyranone substrates 1 identified as
optimal for the intramolecular reaction,[11] was examined
initially as a model substrate for the study of the intermo-
lecular cycloaddition. Treatment of 8a with a series of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402834.
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Further improvement in both the enantioselectivity and
the yield of the cycloaddition reaction was achieved through
electronic tuning of the leaving group on the pyranone. While
the p-thiomethylbenzoate leaving group had been identified
as optimal in the intramolecular reaction, electron-deficient
analogues 9b–d were found to be advantageous in the
intermolecular manifold (entries 3–5).[16] In particular, 3,4,5-
trifluorobenzoate derivative 9d provided the best balance of
reactivity and enantioselectivity, and further improvement in
the ee values could be achieved by carrying out the reaction at
ambient temperature and decreasing the amount of ethyl
vinyl ether from 10 to 5 equivalents relative to pyranone
(entry 6).
Having thus established viable parameters for effecting
highly enantioselective intermolecular [5+2] cycloadditions
of a pyrylium ion precursor, an investigation of the reaction
substrate scope was carried out (Table 2).[17] Pyranones
bearing longer alkyl chains at the 6-position also undergo
cycloaddition with ethyl vinyl ether with high enantioselec-
tivity (entry 2); however b-branching in the side chain has
a deleterious effect on reactivity (entries 3 and 4). Cyclo-
adducts bearing siloxymethylene groups could be accessed in
Scheme 3. Screen of 2p components.
terminal alkenes under the dual catalyst conditions developed
in the original study revealed that the electronic properties of
the 2p component had a strong effect on reactivity.[15]
Electron-deficient olefins such as acrylonitrile and methyl
acrylate were completely inert; styrene displayed measurable
but low reactivity to afford racemic product; electron-rich
olefins such as benzyl vinyl ether and ethyl vinyl ether
underwent cycloaddition with higher conversions and encour-
aging enantioselectivity. The observation that a nucleophilic
2p reactant is required in the catalytic reaction is consistent
with a mechanism involving a cationic, electron-poor amino-
pyrylium intermediate analogous to 4 (Scheme 2) rather than
an ambiphilic, zwitterionic oxidopyrylium intermediate.[9f,g]
It proved possible to affect the enantioselectivity of the
intermolecular cycloaddition reaction to a remarkable degree
through relatively subtle modifications to the structure of the
pyrylium precursor. All substrates shown to undergo intra-
molecular [5+2] cycloadditions with high enantioselectivity in
the original study possessed a linkage to the 2p component
through the 6-position of the pyranone (1, Scheme 2).[11] The
possibility that the presence of a 6-substituent might affect the
enantioselectivity in the intermolecular reaction was eval-
uated by comparing the reaction of 8a with that of methylated
pyranone 9a (Table 1, entries 1 and 2).[15] The dramatic
improvement in the enantioselectivity observed with methy-
lated derivative 9a suggests a critical role of that substituent
in controlling the transition-structure geometry in the cata-
lytic reaction (see below).
Table 1: Reaction optimization.[a]
Entry
Substrate
t [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
8a
9a
9b
9c
9d
9d
48
48
48
48
48
72
53
55
63
65
73
75
47
90
94
93
92
96
Figure 1. a) Formation of intermediate aminopyrylium. b,c) Lowest
energy calculated structures (B3LYP/6-31G(d)) of the aminopyrilium
ions 2·8 and 2·9. In both cases, the major conformer has the face of
the aminopyrilium ion that leads to the major observed enantiomer of
cycloadduct exposed, while the other face is shielded. The difference in
energy between the major and minor conformers is substantially
higher for 2·9, however, and that is a potential explanation for the
higher enantioselectivities obtained in cycloadditions of 9. (b) and (c)
were generated using CYLview.[25]
5
6[d]
[a] Reactions were performed on a 0.07 mmol scale. [b] Determined by
1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.
[c] Determined by HPLC using commercial columns with chiral sta-
tionary phases. [d] 5 equiv ethyl vinyl ether, room temperature.
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Table 2: Substrate scope.[a]
with very low (< 15%) ee values. Enamines and
polysubstituted vinyl ethers also proved to be poor
substrates, the former undergoing hydrolysis under
the reaction conditions and the latter exhibiting very
low reactivity.[15]
We sought to elucidate the basis for the signifi-
cant difference in enantioselectivity between the
reactions of pyranones 8 and 9 (e.g. Table 1, entries 1
and 2) as a possible path toward gleaning insight into
the mechanism of stereoinduction in these reactions.
The formation of the adduct 2·9 (Figure 1a) was
confirmed by mass spectrometric analysis of a reac-
tion mixture sampled prior to addition of the vinyl
ether component.[15] The lowest energy structures of
the two aminopyrylium ions 2·8 and 2·9 were located
Entry Substrate
R3
Et
Product
Yield [%] ee[b] [%]
1[c,f]
69
59
22
26
64
96
90
88
67
86
2
Et
Et
Et
Et
computationally (Figure 1b,c left).[18] Rotation about
2
À
the C(sp ) N bond in each structure and reoptim-
3[c]
ization then yielded ground-state structures in which
the opposite face of the aminopyrilium ion is
exposed (Figure 1b,c right).[19] In the minor confor-
mer of 2·9, a steric interaction between the methyl
substituent and the catalystꢀs cyclohexyl backbone
causes a significant distortion and energetic penalty
(> 6 kcalmolÀ1 relative to the major conformer).
That steric interaction is absent if the methyl group is
omitted (Figure 1c), resulting in a much smaller
energy difference between the conformations of 2·8.
We propose that the methyl substituent in 9 thus
enforces a dominant reactive conformation of the
aminopyrilium ion adduct, which results in a more
highly enantioselective cycladdition pathway.
4
5
6[c,d]
Et
Et
95
75
64
89
The 8-oxabicyclooctane cycloadducts possess
several functional group handles for potential elab-
oration (Scheme 4). The synthesis of 10 was carried
out successfully on 0.70 g batches of starting material
under the conditions described in Table 2 to give
cycloadduct in 69% yield and 96% ee. Products
resulting from conjugate addition (26), epoxidation
(27),[20] Diels–Alder reaction (28),[21] or Luche
reduction (29) and subsequent acylation (30) were
all generated as single diastereomers within detec-
tion limits. The cycloadduct 10 can also be subjected
to hydrogenation to another key intermediate,
saturated ketone 31.[22] This heterocycle undergoes
Grignard addition stereoselectively to afford tertiary
alcohol 32. Tosylhydrazone 33, which is primed to
undergo Shapiro or Bamford–Stevens reactions, can
also be readily synthesized from intermediate 31.
Finally, s-bond insertion of cyclohexyne yields an
unusual 9,6-fused ring system (34) in a single step.[23]
The oxygen bridge of the 8-oxabicyclo-
7
8[c]
Bn
88
54
89
91
9[e]
MOM
[a] Reactions were performed on a 0.2 mmol scale. Yields of isolated products after
chromatography on silica gel. For details on substrate synthesis, see the Supporting
Information. [b] Determined by HPLC using commercial columns with chiral
stationary phases. [c] 15 mol% 2 + 15 mol% 3. [d] 96 h at 08C. [e] 10 equiv vinyl
ether. [f] The absolute configuration of a derivative of 10 was determined by X-ray
crystallography (see the Supporting Information), and that of all other products was
assigned by analogy. MOM=methoxymethyl, TBS=tert-butyldimethylsilyl,
Bn=benzyl.
moderate-to-good enantioselectivity under the catalytic con-
ditions (entries 5–7). Products of this type have found
extensive synthetic applications.[3a,d,7a,e,f] Benzyl vinyl ether
(entry 8) and (methoxymethoxy)ethene (entry 9) were also
used successfully as 2p components in the cycloaddition
reaction, thereby affording products with readily cleavable
ethers. However, styrene derivatives remain poorly reactive
in reactions with 9d, with the resultant cycloadducts formed
[3.2.1]octane framework can also be cleaved reductively. In
the case of iodide 36, this results in formation of an interesting
seven-membered product possessing an exocyclic enone
(Scheme 5).[24] As in all of the previous examples, the product
was generated as a single diastereomer and without compro-
mise of the optical purity of the initial cycloadduct.
In summary, the catalytic, asymmetric, intermolecular
[5+2] pyrylium cycloadditions developed in this study provide
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Setiawan, N. Kotoku, M. Kobayashi, J. Am. Chem. Soc. 2006,
128, 3148 – 3149; Hedyosumin C: f) Z.-S. Su, S. Yin, Z.-W. Zhou,
Y. Wu, J. Ding, J.-M. Yue, J. Nat. Prod. 2008, 71, 1410 – 1413.
[2] Compounds containing the chiral 8-oxabicyclo[3.2.1]octane core
have been identified recently as psychoactive analogues of the
tropane alkaloids with promising pharmaceutical potential:
a) P. C. Meltzer, A. Y. Liang, P. Blundell, M. D. Gonzalez, Z.
Chen, C. George, B. K. Madras, J. Med. Chem. 1997, 40, 2661 –
2673; b) P. C. Meltzer, S. Liu, H. S. Blanchette, P. Blundell, B. K.
Madras, Bioorg. Med. Chem. 2002, 10, 3583 – 3591; c) P. C.
Meltzer, O. Kryatova, D.-P. Pham-Huu, P. Donovan, A. Janow-
sky, Bioorg. Med. Chem. 2008, 16, 1832 – 1841.
[3] a) P. A. Wender, H. Y. Lee, R. S. Wilhelm, P. D. Williams, J. Am.
Chem. Soc. 1989, 111, 8954 – 8957; b) P. A. Wender, H. Kogen,
H. Y. Lee, J. D. Munger, R. S. Wilhelm, P. D. Williams, J. Am.
Chem. Soc. 1989, 111, 8957 – 8958; c) S. M. Bromidge, P. G.
Sammes, L. J. Street, J. Chem. Soc. Perkin Trans. 1 1985, 1725 –
1730; d) P. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamura,
A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc. 1997, 119, 12976 –
12977; e) P. A. Roethle, P. T. Hernandez, D. Trauner, Org. Lett.
2006, 8, 5901 – 5904; f) Y. Li, C. C. Nawrat, G. Pattenden, J. M.
Winne, Org. Biomol. Chem. 2009, 7, 639 – 640; g) K. C. Nicolaou,
Q. Kang, S. Y. Ng, D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132,
8219 – 8222.
[4] a) C. W. G. Fishwick, G. Mitchell, P. F. W. Pang, Synlett 2005,
285 – 286; b) U. Murali Krishna, Tetrahedron Lett. 2010, 51,
2148 – 2150; c) A. A. Yadav, P. S. Sarang, G. K. Trivedi, M. M.
Salunkhe, Synlett 2007, 989 – 991; d) M. A. Ali, N. Bhogal,
J. B. C. Findlay, C. W. G. Fishwick, J. Med. Chem. 2005, 48,
5655 – 5658.
Scheme 4. Derivatization reactions. Reaction conditions: a) 2
(15 mol%), 3 (15 mol%), AcOH (15 mol%), ethyl vinyl ether, toluene;
b) Me2CuLi, Et2O; c) tBuOOH, NaHCO3, H2O, MeOH; d) cyclopenta-
diene, ZnCl2, C6H6; e) CeCl3·7H2O, NaBH4, MeOH; f) p-BrBzOH,
DMAP, pyr., CH2Cl2; g) SiH2Ph2, ZnCl2 (10 mol%), [Pd(PPh3)4]
(2 mol%), CHCl3; h) MeMgI, Et2O; i) H2NNHTs, THF, H2O; j) cyclo-
hexenylphenyl iodonium tetrafluoroborate, KOCEt3, THF. All products
are isolated in d.r.>20:1. DMAP=4-dimethylaminopyridine, pyr.=pyr-
idine, Ts=toluene-4-sulfonyl.
[5] a) S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno, C. Umeda, N.
Watanabe, S. Hashimoto, J. Am. Chem. Soc. 1999, 121, 1417 –
1418; b) D. M. Hodgson, A. H. Labande, F. Y. T. M. Pierard,
M. ꢂ. Expꢃsito Castro, J. Org. Chem. 2003, 68, 6153 – 6159;
c) D. M. Hodgson, T. Brꢄckl, R. Glen, A. H. Labande, D. A.
Selden, A. G. Dossetter, A. J. Redgrave, Proc. Natl. Acad. Sci.
USA 2004, 101, 5450 – 5454; d) N. Shimada, M. Anada, S.
Nakamura, H. Nimbu, H. Tsutsui, S. Hashimoto, Org. Lett.
2008, 10, 3603 – 3606; e) K. Ishida, H. Kusama, N. Iwasawa, J.
Am. Chem. Soc. 2010, 132, 8842 – 8843.
Scheme 5. Stereocontrolled preparation of cycloheptanone 37. Reac-
tion conditions: a) SiH2Ph2, ZnCl2 (10 mol%), [Pd(PPh3)4] (2 mol%),
CHCl3; b) AcOH, HCl, THF, H2O; c) I2, PPh3, imidazole, C6H6; d) Zn,
MeOH.
[6] a) M. Harmata, S. K. Ghosh, X. Hong, S. Wacharasindhu, P.
Kirchhoefer, J. Am. Chem. Soc. 2003, 125, 2058 – 2059; b) J.
Huang, R. P. Hsung, J. Am. Chem. Soc. 2005, 127, 50 – 51.
[7] a) P. A. Wender, K. D. Rice, M. E. Schnute, J. Am. Chem. Soc.
1997, 119, 7897 – 7898; b) F. Lꢃpez, L. Castedo, J. L. MascareÇas,
Org. Lett. 2000, 2, 1005 – 1007; c) F. Lꢃpez, L. Castedo, J. L.
MascareÇas, Org. Lett. 2002, 4, 3683 – 3685; d) U. Murali K-
rishna, K. D. Deodhar, G. K. Trivedi, Tetrahedron 2004, 60,
4829 – 4836; e) P. A. Wender, F. C. Bi, N. Buschmann, F.
Gosselin, C. Kan, J.-M. Kee, H. Ohmura, Org. Lett. 2006, 8,
5373 – 5376; f) P. A. Wender, N. Buschmann, N. B. Cardin, L. R.
Jones, C. Kan, J.-M. Kee, J. A. Kowalski, K. E. Longcore, Nat.
Chem. 2011, 3, 615 – 619.
multifunctional chiral building blocks that are immediate
precursors to a wide range of compound classes. Studies into
the mechanism of catalyst cooperativity, as well as extension
of the principle into other transformations, are the focus of
continuing efforts in this laboratory.
Received: February 26, 2014
Revised: March 26, 2014
Published online: April 29, 2014
[8] B. Li, Y.-J. Zhao, Y.-C. Lai, T.-P. Loh, Angew. Chem. 2012, 124,
8165 – 8169; Angew. Chem. Int. Ed. 2012, 51, 8041 – 8045.
[9] For recent reviews, see a) V. Singh, U. Murali Krishna, Vikrant,
G. K. Trivedi, Tetrahedron 2008, 64, 3405 – 3428; b) H. Pellissier,
Adv. Synth. Catal. 2011, 353, 189 – 218; c) K. E. O. Ylijoki, J. M.
Stryker, Chem. Rev. 2013, 113, 2244 – 2266; for pioneering
reports, see d) J. B. Hendrickson, J. S. Farina, J. Org. Chem.
1980, 45, 3359 – 3361; e) P. G. Sammes, L. J. Street, J. Chem. Soc.
Chem. Commun. 1982, 1056 – 1057; f) P. G. Sammes, L. J. Street,
J. Chem. Soc. Perkin Trans. 1 1983, 1261 – 1265; g) P. G. Sammes,
L. J. Street, J. Chem. Res. Synop. 1984, 196 – 197.
Keywords: asymmetric catalysis · conformational analysis ·
cycloaddition · hydrogen bonds · organocatalysis
.
[1] For example, Englerin A: a) R. Ratnayake, D. Covell, T. T.
Ransom, K. R. Gustafson, J. A. Beutler, Org. Lett. 2009, 11, 57 –
60; Descurainin: b) K. Sun, X. Li, W. Li, J. Wang, J. Liu, Y. Sha,
Chem. Pharm. Bull. 2004, 52, 1483 – 1486; Intricarene: c) J.
Marrero, A. D. Rodrꢁguez, C. L. Barnes, Org. Lett. 2005, 7,
1877 – 1880; Anthecularin: d) A. Karioti, H. Skaltsa, A. Linden,
R. Perozzo, R. Brun, D. Tasdemir, J. Org. Chem. 2007, 72, 8103 –
8106; Cortistatin A: e) S. Aoki, Y. Watanabe, M. Sanagawa, A.
[10] Other than our earlier study (Ref. [11]), there is only a single
report of an enantioselective [5+2] pyrylium cycloaddition
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(product < 20% ee): D. M. Hodgson, P. A. Stupple, C. John-
stone, ARKIVOC 2003, vii, 49 – 58.
[11] N. Z. Burns, M. R. Witten, E. N. Jacobsen, J. Am. Chem. Soc.
2011, 133, 14578 – 14581.
[12] For a review of anion-binding asymmetric catalysis, see K. Brak,
E. N. Jacobsen, Angew. Chem. 2013, 125, 558 – 588; Angew.
Chem. Int. Ed. 2013, 52, 534 – 561.
effect on yield or enantioselectivity. In all other cases, this
reduction in catalyst resulted in significantly diminished yields.
[18] B3LYP/6-31G(d) has been established as an appropriate level of
theory for studying [5+2] pyrylium cycloadditions; see a) F.
Lꢃpez, L. Castedo, J. L. MascareÇas, J. Org. Chem. 2003, 68,
9780 – 9786; b) S. C. Wang, D. J. Tantillo, J. Org. Chem. 2008, 73,
1516 – 1523.
[13] For preparation and use of catalyst 3, see a) P. R. Schreiner, A.
Wittkopp, Org. Lett. 2002, 4, 217 – 220; b) A. Wittkopp, P. R.
Schreiner, Chem. Eur. J. 2003, 9, 407 – 414.
[14] For diastereoselective intermolecular [5+2] cycloadditions, see
a) K. Tchabanenko, C. Sloan, Y.-M. Bunetel, P. Mullen, Org.
Biomol. Chem. 2012, 10, 4215 – 4219; b) E. C. Garnier, L. S.
Liebeskind, J. Am. Chem. Soc. 2008, 130, 7449 – 7458.
[15] See the Supporting Information for details.
[19] These calculations apply to the conformations of the amino-
pyrilium ground states prior to the cycloaddition step, rather
than to the actual transition structures for cycloaddition. They
are further simplified in that they omit the thiourea 3·benzoate
counteranion. Nonetheless, we propose that the pronounced
energy difference calculated for the conformations of 2·9d is
expected to translate to the relevant cycloaddition transition
structures that lead to the two enantiomers 10.
[16] In Ref. [11], we proposed that the low solubility of the p-
thiomethylbenzoic acid by-product was a crucial driving force in
the intramolecular reaction. In contrast, 3,4,5-trifluorobenzoic
acid is fully soluble under the reaction conditions employed in
this study. The improved reactivity imparted by the 3,4,5-
trifluorobenzoate group in 9d relative to less electron-deficient
analogues may be ascribed simply to its superior properties as
a leaving group. However, the 3,4,5-trifluorobenzoate leaving
group is inferior in the intramolecular reaction. See the
Supporting Information for details.
[20] K. A. Marshall, A. K. Mapp, C. H. Heathcock, J. Org. Chem.
1996, 61, 9135 – 9145.
[21] V. Nair, G. Anilkumar, T. S. Sujatha, J. S. Nair, Synth. Commun.
1998, 28, 2549 – 2557.
[22] D. A. Archer, S. M. Bromidge, P. G. Sammes, J. Chem. Soc.
Perkin Trans. 1 1988, 3223 – 3228.
[23] C. M. Gampe, S. Boulos, E. M. Carreira, Angew. Chem. 2010,
122, 4186 – 4189; Angew. Chem. Int. Ed. 2010, 49, 4092 – 4095.
[24] N. Ohmori, J. Chem. Soc. Perkin Trans. 1 2002, 755 – 767.
[25] C. Y. Legault, CYLview, version 1.0b; Universitꢅ de Sherbrooke,
2009; http://www.cylview.org.
[17] For certain indicated substrates, catalyst loading could be
reduced to 15 mol% 2 and 15 mol% 3 without detrimental
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