Copper-Catalyzed Enantio-, Diastereo-, and Regioselective [2,3]-Rearrangements of Iodonium Ylides

Article abstract of DOI:10.1002/anie.201705317

The first highly enantioselective, diastereoselective, and regioselective [2,3]-rearrangement of iodonium ylides has been developed as a general solution to catalytic onium ylide rearrangements. In the presence of a chiral copper catalyst, substituted allylic iodides couple with α-diazoesters to generate metal-coordinated iodonium ylides, which undergo [2,3]-rearrangements with high selectivities (up to >95:5 r.r., up to >95:5 d.r., and up to 97 % ee). The enantioenriched iodoester products can be converted stereospecifically into a variety of onium ylide rearrangement products, as well as compounds that are not accessible by classical onium ylide rearrangements.

Full text of DOI:10.1002/anie.201705317

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Copper-Catalyzed Enantioselective, Diastereoselective, and
Regioselective [2,3]-Rearrangements of Iodonium Ylides
Authors: Bin Xu and Uttam Krishan Tambar
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705317
Angew. Chem. 10.1002/ange.201705317
Link to VoR: http://dx.doi.org/10.1002/anie.201705317
http://dx.doi.org/10.1002/ange.201705317

10.1002/anie.201705317
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Enantioselective, Diastereoselective, and
Regioselective [2,3]-Rearrangements of Iodonium Ylides
Bin Xu and Uttam K. Tambar*
Dedicated to Professor Qi-Lin Zhou on the occasion of his 60th birthday
Abstract: The first highly enantioselective, diastereoselective, and
indication of the regioselectivity or diastereoselectivity.[9] To date,
there are no catalytic rearrangements of these reactive
substrates that can generate one product in high selectivity. In
this Communication, we describe the first highly enantioselective,
diastereoselective, and regioselective [2,3]-rearrangements of
substituted iodonium ylides, and we disclose the synthetic
versatility of the resulting iodoester products (Scheme 1C).
regioselective [2,3]-rearrangement of iodonium ylides has been
developed as
a
general solution to catalytic onium ylide
chiral copper catalyst,
rearrangements. In the presence of
a
substituted allylic iodides couple with α-diazoesters to generate
metal-coordinated iodonium ylides, which undergo [2,3]-
rearrangements with high selectivities (up to >95:5 rr, up to >95:5 dr,
and up to 97% ee). The enantioenriched iodoester products can be
converted stereospecifically to
a
variety of onium ylide
rearrangement products, as well as compounds that are not
accessible via classical onium ylide rearrangements.
Catalytic enantioselective [2,3]-onium ylide rearrangements are
historically important reactions that have been utilized for the
synthesis of structurally complex chiral molecules.[1,2] The power
of these transformations lies in their ability to convert achiral
starting materials into products with vicinal stereocenters in high
enantioselectivity and diastereoselectivity. In this context,
catalytic processes via metal carbenoid intermediates have been
especially useful (Scheme 1A). Traditional approaches have
relied on the use of different conditions for the individual
development of [2,3]-rearrangements of allylic ammonium,[3]
sulfonium,[4] and oxonium[5] ylides.[6] We were interested in
developing
a more unified approach to [2,3]-onium ylide
rearrangements. We envisioned that the discovery of an
enantioselective and diastereoselective [2,3]-iodonium ylide
rearrangement would provide access to chiral iodoesters that
could be converted stereospecifically to products of many onium
ylide rearrangements. Moreover, we could access products that
are not accessible via classical onium ylide rearrangements.
Despite the potential utility of iodonium ylide rearrangements
as a versatile class of reactions, selective [2,3]-rearrangements
of these substrates have been rarely investigated.[7] In particular,
substituted allylic iodonium ylides can generate up to 8 isomeric
products via unselective [2,3]- and [1,2]-rearrangements
(Scheme 1B). We recently reported the regioselective [2,3]- and
[1,2]-rearrangements of iodonium ylides for the generation of
racemic iodoester products.[8] Seminal studies by Doyle and co-
workers reported that
a single iodonium ylide substrate
generated from unsubstituted allylic iodide underwent
enantioselective rearrangement (69% ee), but there was no
[*]
Dr. B. Xu, Prof. Dr. U. K. Tambar
Department of Biochemistry
The University of Texas Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, TX 75390-9038 (USA)
E-mail: Uttam.Tambar@utsouthwestern.edu
Homepage: http://www.utsouthwestern.edu/labs/tambar/
Scheme 1. Unified Approach to Enantioselective Onium Ylide
Rearrangements.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.xxxxxxx.
We commenced our studies with the substituted cinnamyl
iodide (E)-1a and coupled it with benzyl α-diazoester 2a in the
This article is protected by copyright. All rights reserved.

10.1002/anie.201705317
Angewandte Chemie International Edition
COMMUNICATION
presence of 5 mol% [Cu(MeCN)4]PF6 and 6 mol% of various
ligands (entries 1-9). Phosphine ligands BINAP L1,
phosphoramidite L2, and QUINAP L3 favored the formation of
[1,2]-rearrangement product 4 (entries 1-3).[10] Alternatively,
bisoxazoline ligands L4-L9 preferentially yielded [2,3]-
rearrangement product 3 with a range of regioselectivities,
diastereoselectivities, and enantioselectivities (entries 4-9). t-
Butyl-substituted
bisoxazoline
L7
provided
the
best
Table 1. Optimization of Enantioselective [2,3]-Rearrangement of Iodonium
regioselectivity and enantioselectivity for the [2,3]-rearrangement
(entry 7, 87:13 rr, 75% and 81% ee). A screen of alternate
copper sources in the presence of optimal ligand L7 did not
improve the selectivities (entries 10-12). When cinnamyl iodide
(E)-1a was replaced with its olefin isomer (Z)-1a, the
diastereoselectivity (80:20) was drastically improved without
affecting the regioselectivity (entry 13). To our delight, the
bulkier t-butyl α-diazoester 2b reacted with cinnamyl iodide (Z)-
1a with enhanced enantiomeric excess (entry 14, 82% ee). A
screen of temperatures (entries 14-16) revealed –20 °C as the
optimal temperature for this process. Under these conditions,
[2,3]-iodonium ylide rearrangement product 3 was isolated in 82%
yield, >95:5 rr, >95:5 dr, and 96% ee (entry 16).
Ylides[a]
[Cu][b]
3 : 4
dr of 3[c]
T
Yield
(%)
ee of 3 [d]
(%, %)
Entry
Ligand
(oC)
1[e]
2
(R)-L1
(S)-L2
(S)-L3
(S)-L4
(S)-L5
(S)-L6
(S)-L7
(S)-L8
(S)-L9
(S)-L7
(S)-L7
(S)-L7
(S)-L7
(S)-L7
(S)-L7
(S)-L7
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuPF6
CuCl
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
19
21
29
62
71
73
82
64
56
63
57
59
80
85
84
82
11 : 89
18 : 82
<5 : 95
64 : 36
58 : 42
57 : 43
87 : 13
65 : 35
56 : 44
60 : 40
74 : 26
75 : 25
83 : 17
80 : 20
90 : 10
>95 : 5
48 : 52
58 : 42
-- : --
--, --
69, 31
--, --
Table 2. Scope of Aryl-Substituted Allylic Iodides[a]
3
4
34 : 66
32 : 68
40 : 60
45 : 55
36 : 64
37 : 63
42 : 58
45 : 55
45 : 55
80 : 20
91 : 9
26, 20
41, 31
22, 24
75, 81
2, 25
5
6
7
8
9
42, 12
10, 74
56, 71
59, 71
73, 70
82, --
90, --
96, --
10
11
12
13[f]
14[f,g]
15[f,g]
16[f,g]
CuOTf
Cu(OTf)2
CuPF6
CuPF6
CuPF6
CuPF6
94 : 6
-20
>95 : 5
[a] Regioisomeric ratio (rr) is reported as [2,3] : [1,2]. Diastereomeric ratio
(dr) is reported as anti : syn.
[a] Reaction conditions: allylic iodide (0.4 mmol), α-diazoester (0.48 mmol),
copper salt (5 mol%), ligand (6 mol%), CH2Cl2 (0.1M). [b] CuPF6 is an
abbreviation for [Cu(MeCN)4]PF6. CuOTf is an abbreviation for
(CuOTf)•½PhMe. [c] anti : syn ratio. [d] ee of anti diastereomer of 3 , ee of syn
diastereomer of 3. [e] 12 mol% ligand. [f] (Z)-1a was utilized. [g] t-
Butyldiazoester 2b was utilized.
Using the optimal conditions, we evaluated the reactions of
various aryl-substituted allylic iodides 1a‒m with t-butyl α-
diazoester 2b (Table 2). The enantioselective rearrangement
This article is protected by copyright. All rights reserved.

10.1002/anie.201705317
Angewandte Chemie International Edition
COMMUNICATION
exhibited good tolerance to different aromatic hydrocarbon rings
(5a–5d). Substituents at the para or meta positions of the aryl
ring had a negligible impact on the yield and selectivity of the
reaction. Substrates with either electron-withdrawing groups
(ketone, ester, amide, fluoro and trifluoromethyl) or with
electron-donating groups (methyl and trifluoromethoxyl),
underwent [2,3]-rearrangement smoothly and afforded the
corresponding chiral α-iodoester products (5e–5k) in good yields
(63–87%) with excellent selectivities (up to >95:5 rr, up to >95:5
dr, and 90–97% ee). Aryl-substituted allylic iodides with ortho
substituents (5l–5m) afforded very good diasteroselectivities
(>95:5 dr) and enantioselectivities (95% ee) but relatively low
yields and low regioselectivities. Upon transformation of
iodoester 5i to primary alcohol 6i, rearrangement product 5i was
determined to have the (2R,3S)-configuration by means of X-ray
diffraction analysis of a single crystal.[11]
rearrangements as a general solution to catalytic asymmetric
onium ylide rearrangements (Scheme 2). First, the
enantioselective [2,3]-rearrangement of iodonium ylides could be
easily conducted on gram-scale without significant reduction of
the yield or selectivities (Scheme 2A).
Second, we explored stereospecific transformations of the
C‒I bond to other bonds (Scheme 2B). For example, the iodide
in the rearrangement product 5a was displaced by thiophenol to
form a new C‒S bond without any diminished enantioselectivity
(7a). This product resembles the α-thioesters that are generated
by sulfonium ylide rearrangements. Even for the much bulkier
product 5v, the C‒I bond was transformed to a C‒N bond with
100% es. The synthetically versatile chiral α-azidoester product
(8v) successfully underwent a bioorthogonal click reaction with
phenylacetylene to furnish a chiral α-triazoloester (S11).[12]
Table 3. Scope of Alkyl and Poly-Substituted Allylic Iodides [a]
Scheme 2. Synthetic Applications of Enantioselective [2,3]-Rearrangement
Products. Regioisomeric ratio (rr) is reported as [2,3] : [1,2]. Diastereomeric
ratio (dr) is reported as anti : syn. Conditions: (i) 5a (0.1 mmol, >95:5 rr, >95:5
dr, 97% ee), 1.5 equiv PhSH, 1.5 equiv K2CO3, Acetone, 23 °C, 12 h. (ii) 5v
(0.1 mmol, >95:5 rr, 91% ee), 5 equiv NaN3, DMSO, 90 °C, 24 h. (iii) 5a (0.1
mmol, >95:5 rr, >95:5 dr, 97% ee), 1 equiv NaH, 1.5 equiv CH2(CN)2, THF,
80 °C, 12 h. (iv) 5a (0.1 mmol, >95:5 rr, >95:5 dr, 97% ee), 1.1 equiv
PhCH2CH2MgCl, THF, 0 °C – 23 °C, 2 h; H2O, 23 °C.
[a] Regioisomeric ratio (rr) is reported as [2,3] : [1,2]. Diastereomeric ratio
(dr) is reported as anti : syn.
Furthermore,
we
converted
the
iodonium
ylide
We also investigated the [2,3]-rearrangements of various
alkyl-substituted allylic iodides 1n-r and poly-substituted allylic
iodides 1s-y (Table 3). To obtain satisfactory enantioselectivities,
the rearrangements of alkyl-substituted allylic iodides were
rearrangement products to compounds that are inaccessible via
traditional onium ylide rearrangements. α-Iodoester 5a was
treated with sodium malononitrile, which resulted in the
formation of product 9 with a new C‒C bond in 99% es.
Treatment of rearrangment product 5a with Grignard reagent
and aqueous workup converted the C‒I bond to a C‒H bond via
magnesium-halogen exchange.[13] The resulting chiral ester 10a
was obtained with high optical purity (96% es).
In conclusion, we developed a highly enantioselective,
diastereoselective, and regioselective copper-catalyzed [2,3]-
rearrangement of iodonium ylides with a broad substrate scope
of substituted allylic iodides. The resulting chiral α-iodoester
products can be converted stereospecifically to a variety of
onium ylide rearrangement products, as well as compounds that
are not accessible via classical onium ylide rearrangements. We
carried out at
a lower temperature (–45 °C). The [2,3]-
rearrangement products were provided in good yields,
regioselectivities (>95:5), diastereoselectivities (>93:7) and
enantioselectivities (87–93% ee) in the presence of several
functional groups, including a silyl ether, chloride, and protected
amine. By using poly-substituted allylic iodides bearing 5‒7
membered rings or heterocycles, structurally complex products
(5t–5x) containing a quaternary carbon center adjacent to a
stereocenter were obtained with good yields and selectivities.
Next, we performed several experiments to demonstrate the
potential utility of highly selective [2,3]-iodonium ylide
This article is protected by copyright. All rights reserved.

10.1002/anie.201705317
Angewandte Chemie International Edition
COMMUNICATION
4705−4708; e) J. S. Clark, M. Fretwell, G. A. Whitlock, C. J. Burns, D. N.
A. Fox, Tetrahedron Lett. 1998, 39, 97−100; f) M. A. Calter, P. M.
Sugathapala, Tetrahedron Lett. 1998, 39, 8813−8816; g) D. M.
Hodgson, M. Petroliagi, Tetrahedron: Asymmetry 2001, 12, 877−881; h)
S. Kitagaki, Y. Yanamoto, H. Tsutsui, M. Anada, M. Nakajima, S.
Hashimoto, Tetrahedron Lett. 2001, 42, 6361−6364; i) N. Shimada, S.
Nakamura, M. Anada, M. Shiro, S. Hashimoto, Chem. Lett. 2009, 38,
488−489; j) Z. Li, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132,
396−401; k) Z. Li, B. T. Parr, H. M. L. Davies, J. Am. Chem. Soc. 2012,
134, 10942−10946; l) Z. Li, V. Boyarskikh, J. H. Hansen, J. Autschbach,
D. G. Musaev, H. M. L. Davies, J. Am. Chem. Soc. 2012, 134,
15497−15504.
believe this transformation will benefit stereoselective C‒X bond
constructions in complex molecular settings.
Acknowledgements
Financial support was provided by W. W. Caruth, Jr. Endowed
Scholarship, Welch Foundation (I-1748), National Institutes of
Health (R01GM102604), National Science Foundation
(1150875), and Sloan Research Fellowship. We thank
Dr.Vincent Lynch for X-ray structural analysis.
[6]
For catalytic enantioselective onium ylide rearrangements that do not
involve metal carbenoid intermediates, see: a) K. Mikami, O. Takahashi,
T. Tabei, T. Nakai, Tetrahedron Lett. 1986, 27, 4511−4514; b) T.
Kawasaki, T. Kimachi, Tetrahedron 1999, 55, 6847−6862; c) K.
Tomooka, N. Komine, T. Nakai, Chirality 2000, 12, 505−509; d) A.
McNally, B. Evans, M. J. Gaunt, Angew. Chem. Int. Ed. 2006, 45,
2116−2119; Angew. Chem. 2006, 118, 2170−2173; e) M. Kitamura, Y.
Hirokawa, N. Maezaki, Chem. Eur. J. 2009, 15, 9911−9917; f) J.-C.
Marié, Y. Xiong, G. K. Min, A. R. Yeager, T. Taniguchi, N. Berova, S. E.
Schaus, J. A. Porco, J. Org. Chem. 2010, 75, 4584−4590; g) A. Kondoh,
M. Terada, Org. Lett. 2013, 15, 4568−4571; h) S. E. Denmark, L. R.
Cullen, J. Org. Chem. 2015, 80, 11818−11848; i) Reference 2, and
references therein.
Conflict of interest
The authors declare no conflict of interest.
Keywords: iodonium • ylide • [2,3]-rearrangement • copper •
iodoester
[1]
a) M. P. Doyle, Chem. Rev. 1986, 86, 919−939; b) M. P. Doyle, D. C.
Forbes, Chem. Rev. 1998, 98, 911−936; c) Nitrogen, Oxygen, and
Sulfur Ylide Chemistry: A Practical Approach in Chemistry (Ed.: J. S.
Clark), Oxford University Press, New York, 2002; pp. 1−308; d) A. C.
Jones, J. A. May, R. Sarpong, B. M. Stoltz, Angew. Chem. Int. Ed. 2014,
53, 2556−2591; Angew. Chem. 2014, 126, 2590−2628
[7]
a) P. J. Giddings, D. J. Ivor, E. J. Thomas, Tetrahedron Lett. 1980, 21,
395−398; b) M. P. Doyle, W. H. Tamblyn, V. Bagheri, J. Org. Chem.
1981, 46, 5094−5102; c) P. J. Giddings, D. I. John, E. J. Thomas, D. J.
Williams, J. Chem. Soc., Perkin Trans. 1 1982, 2757−2766; d) P.
Krishnamoorthy, R. G. Browning, S. Singh, R. Sivappa, C. J. Lovely, H.
V. R. Dias, Chem. Commun. 2007, 731−733; e) Q.-H. Deng, J. Chen,
J.-S. Huang, S. S.-Y. Chui, N. Zhu, G.-Y. Li, C.-M. Che, Chem. Eur. J.
2009, 15, 10707−10712.
[2]
T. H. West, S. S. M. Spoehrle, K. Kasten, J. E. Taylor, A. D. Smith,
ACS Catal. 2015, 5, 7446−7479.
[3]
a) T. H. West, D. S. B. Daniels, A. M. Z. Slawin, A. D. Smith, J. Am.
Chem. Soc. 2014, 136, 4476−4479; b) T. H. West, D. M. Walden, J. E.
Taylor, A. C. Brueckner, R. C. Johnston, P. H. Cheong, G. C. Lloyd-
Jones, A. D. Smith, J. Am. Chem. Soc. 2017, 139, 4366−4375.
a) Y. Nishibayashi, K. Ohe, S. Uemura, J. Chem. Soc., Chem. Commun.
1995, 31, 1245−1246; b) T. Fukuda, T. Katsuki, Tetrahedron Lett. 1997,
38, 3435−3438; c) K. Itoh, T. Fukuda, H. Kitajima, T. Katsuki, Yuki
Gosei Kagaku Kyokaishi 1997, 55, 764−773; d) T. Fukuda, R. Irie, T.
Katsuki, Tetrahedron 1999, 55, 649−664; e) D. W. McMillen, N. Varga,
B. A. Reed, C. King, J. Org. Chem. 2000, 65, 2532−2536; f) S. Kitagaki,
Y. Yanamoto, H. Okubo, M. Nakajima, S. Hashimoto, Heterocycles
2001, 54, 623−628; g) X. Zhang, Z. Qu, Z. Ma, W. Shi, X. Jin, J. Wang,
J. Org. Chem. 2002, 67, 5621−5625; h) X. Zhang, M. Ma, J. Wang,
Tetrahedron: Asymmetry 2003, 14, 891−895; i) X.-M. Zhang, M. Ma, J.-
B. Wang, Chin. J. Chem. 2003, 21, 878−882; j) M. Ma, L. Peng, C. Li, X.
Zhang, J. Wang, J. Am. Chem. Soc. 2005, 127, 15016−15017; k) M.
Liao, J. Wang, Green Chem. 2007, 9, 184−188.
[8]
[9]
a) B. Xu, U. K. Tambar, J. Am. Chem. Soc. 2016, 138, 12073−12076;
b) B. Xu, J. A. Gartman, U. K. Tambar, Tetrahedron 2017, DOI:
10.1016/j.tet.2017.01.048.
[4]
a) M. P. Doyle, D. C. Forbes, M. M. Vasbinder, C. S. Peterson, J. Am.
Chem. Soc. 1998, 120, 7653−7654; b) M. P. Doyle, W. Hu, I. M. Phillips,
C. J. Moody, A. G. Pepper, A. G. Z. Slawin, Adv. Synth. Catal. 2001,
343, 112−117.
[10] The enantioselectivities for [1,2]-rearrangement product 4 were low (0%
to 30% ee). For more complete optimization data, see Supporting
Information.
[11] See Supporting Information. CCDC 1550761 (6i) contains the
supplementary crystallographic 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.
[12] See Supporting Information.
[13] P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T.
Korn, I. Sapountzis, V. A. Vu, Angew. Chem. Int. Ed. 2003, 42,
4302−4320; Angew. Chem. 2003, 115, 4438−4456.
[5]
a) N. McCarthy, M. A. McKervey, T. Ye, M. McCann, E. Murphy, M. P.
Doyle, Tetrahedron Lett. 1992, 33, 5983−5986; b) L. Ferris, D. Haigh, C.
J. Moody, Tetrahedron Lett. 1996, 37, 107−110; c) M. P. Doyle, C. S.
Peterson, Tetrahedron Lett. 1997, 38, 5265−5268; d) N. Pierson, C.
Fernández-García, M. A. McKervey, Tetrahedron Lett. 1997, 38,
This article is protected by copyright. All rights reserved.

10.1002/anie.201705317
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
A highly enantio-, diastereo-, and
regioselective [2,3]-rearrangement of
iodonium ylides is reported as a
general solution to catalytic onium
ylide rearrangements. In the presence
of a chiral copper catalyst, substituted
allylic iodides couple with α-
Bin Xu, Uttam K. Tambar*
Page No. – Page No.
Copper-Catalyzed Enantioselective,
Diastereoselective, and
Regioselective [2,3]-Rearrangements
of Iodonium Ylides
diazoesters to generate metal-
coordinated iodonium ylides, which
undergo [2,3]-rearrangements with
high selectivities. The enantioenriched
iodoester products are converted
stereospecifically to a variety of useful
chiral building blocks.
This article is protected by copyright. All rights reserved.