Enantioselective Nickel-Catalyzed Intramolecular Allylic Alkenylations Enabled by Reversible Alkenylnickel E/Z Isomerization

Article abstract of DOI:10.1002/anie.201703380

Enantioselective nickel-catalyzed arylative cyclizations of substrates containing a Z-allylic phosphate tethered to an alkyne are described. These reactions give multisubstituted chiral aza- and carbocycles, and are initiated by the addition of an arylboronic acid to the alkyne, followed by cyclization of the resulting alkenylnickel species onto the allylic phosphate. The reversible E/Z isomerization of the alkenylnickel species is essential for the success of the reactions.

Full text of DOI:10.1002/anie.201703380

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Accepted Article
Title: Enantioselective Nickel-Catalyzed Intramolecular Allylic
Alkenylations Enabled by Reversible Alkenylnickel E/Z
Isomerization
Authors: Connor Yap, Gabriel MJ Lenagh-Snow, Somnath N Karad,
William Lewis, Louis J Diorazio, and Hon Wai Lam
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703380
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10.1002/anie.201703380
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Enantioselective Nickel-Catalyzed Intramolecular Allylic
Alkenylations Enabled by Reversible Alkenylnickel E/Z
Isomerization
Connor Yap, Gabriel M. J. Lenagh-Snow, Somnath Narayan Karad, William Lewis, Louis J. Diorazio,
and Hon Wai Lam*
Abstract: Enantioselective nickel-catalyzed arylative cyclizations of
substrates containing a Z-allylic phosphate tethered to an alkyne are
described. These reactions give multisubstituted chiral aza- and
carbocycles, and are initiated by the addition of an arylboronic acid
to the alkyne, followed by cyclization of the resulting alkenylnickel
species onto the allylic phosphate. The reversible E/Z isomerization
of the alkenylnickel species is essential for the success of the
reactions.
Enantioselective metal-catalyzed allylic substitutions of achiral
or racemic substrates using carbon-centered nucleophiles are a
major class of reactions for preparing enantioenriched chiral
compounds.[ 1 ] Although numerous developments have been
described,[1] there are only a few reports of the enantioselective
allylation of alkenyl nucleophiles.[2] Chiral copper–N-heterocyclic
carbene catalysts are highly effective in the enantioselective
additions of alkenylaluminum,[2a–c] alkenylboron,[2d,f,h] and
allenylboron[2e] reagents to achiral allylic phosphates. Chiral
iridium[2g] and rhodium[2i] catalysts are also effective in
enantioselective additions of alkenylboron reagents to racemic
allylic alcohols[2g] and allylic halides, [2i] respectively.
While the aforementioned examples provide valuable
enantioenriched chiral 1,4-diene building blocks,[2] several
aspects remain underdeveloped. For example, reactions
Scheme 1. Arylative cyclizations of enynes.
involving fully substituted alkenyl nucleophiles are rare.[3] The
integration of these reactions into domino processes that form
tetrasubstituted exocyclic alkene.[3a,b] However, only two
enantioselective reactions were reported, and low selectivity was
more than one new carbon–carbon bond is also not well-
3
]
established.[
Murakami and co-workers have partially
observed in the initial addition to the alkyne, which led to other
products being formed.[3b] Therefore, the availability of other
methods to meet these challenges would significantly enhance
the utility of domino alkyne carbometalation–allylic alkenylations.
Here, we describe highly enantioselective intramolecular
alkenylations of allylic phosphates with fully substituted
alkenylnickel species, which are themselves generated by the
nickel-catalyzed addition of arylboronic acids to internal alkynes
(Scheme 1B). Notably, this process gives chiral 1,4-diene-
containing hetero- and carbocycles that are inaccessible from
these substrates with established conditions using rhodium
catalysis.[3] These include 4,5-diaryl 1,2,3,6-tetrahydropyridines,
which are seen in naturally occurring alkaloids such as (–)-
septicine and (–)-tylophorine (Scheme 1C).[5]
Our studies began with the arylative cyclization of substrate
1a, which contains a Z-allylic phosphate tethered to an alkyne
(Table 1). Guided by our recent work,[ 6 ] we anticipated that
arylnickelation of the alkyne to place nickel distal to the
electrophile, followed by reversible E/Z isomerization of the
alkenylnickel species, would provide a species capable of
cyclizing onto the allylic phosphate to give products of formal
anti-carbometalation (Scheme 1B).[7] However, of the existing
reports of enantioselective nickel-catalyzed allylic substitutions
addressed these issues by developing rhodium-catalyzed
cyclizations of 1,6-enynes, in which the reaction is triggered by
addition of an arylboronic acid to the alkyne (Scheme 1A).[3,4]
These reactions give cyclopentanes containing a
[]
C. Yap, Dr. S. N. Karad, Prof. H. W. Lam
The GSK Carbon Neutral Laboratories for Sustainable Chemistry,
University of Nottingham, Jubilee Campus, Triumph Road,
NG7 2TU, United Kingdom
E-mail: hon.lam@nottingham.ac.uk
Homepage: http://www.nottingham.ac.uk/~pczhl/
C. Yap, Dr. G. M. J. Lenagh-Snow, Dr. S. N. Karad, Dr. W. Lewis,
Prof. H. W. Lam
School of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD, United Kingdom
Dr. L. J. Diorazio
AstraZeneca, Pharmaceutical Technology and Development,
Etherow F53/20, Charter Way, Macclesfield, Cheshire, SK10 2NA,
United Kingdom
Supporting information for this article is available on the WWW
under http://dx.doi.org/
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Table 1. Evaluation of reaction conditions.[a]
Entry
Ligand
2a:3a[b]
Combined yield [%][c]
ee of 2a [%][d]
1
L1
L2
L3
L4
L5
L6
L6
10:1
10:1
10:1
–
46
44
60
<5
80
33
80
−36[e]
80
2
3
98
4
–
5
>19:1
>19:1
>19:1
90
6
>99
96
7[f]
Scheme 2. Scope of 1,6-enynes. Reactions were conducted using 0.30 mmol
of 1. Yields are of isolated products. Values in parentheses refer to the ratio of
2:3 as determined by 1H NMR analysis of the crude reactions. Unless stated
otherwise, the minor isomers 3 were not evident in the isolated products.
[a] Reactions were conducted using 0.05 mmol of 1a. [b] Determined by 1H
NMR analysis of the crude reactions. [c] Determined by 1H NMR analysis
using 1,4-dimethoxybenzene as an internal standard. [d] Determined by HPLC
analysis on a chiral stationary phase. [e] Major product was the enantiomer of
2a. [f] Conducted at 100 °C.
Enantiomeric excesses were determined by HPLC analysis on
a chiral
stationary phase. [a] Product 2i contained trace quantities of inseparable,
unidentified impurities, and the ratio of 2i:3i could not be determined.
with carbon-centered nucleophiles,[8,9] none describe the use of
alkenyl nucleophiles, and success in this ring-closing step was
therefore uncertain.
alkenyl group on the alkyne is also tolerated, though the product
2g was formed in 49% ee. The reaction of a substrate containing
a methyl group on the alkyne gave only a complex mixture of
products. Replacement of the p-toluenesulfonyl group with a 4-
nitrobenzenesulfonyl group is possible (2h). Finally, changing
the linking group between the alkyne and the allylic phosphate to
an all-carbon tether enabled the formation of carbocycle 2i in 51%
yield and 96% ee.
Pleasingly, this process is compatible with a range of other
(hetero)arylboronic acids, which gave products 2j–2r in 47–66%
yield and 96–99% ee from three different 1,6-enynes (Scheme
3). The scope includes para- (2p and 2q), meta- (2j and 2r),
ortho- (2m), and disubstituted phenylboronic acids (2k and 2n),
containing methyl (2k and 2p), halide (2j, 2m, and 2n), alkoxy
(2n), nitrile (2q), or ester groups (2r). In addition, 3-
thienylboronic acid (2l) and 2-naphthylboronic acid (2o) are also
tolerated.
Further studies of the scope of the alkyne-tethered allylic
phosphate are shown in Eq. (1–3). A trimethylsilyl-substituted
alkyne 1j gave low conversions under the standard conditions,
but replacing ligand L6 with L5 gave 2s in 70% yield and 69%
ee [Eq. (1)]. The Z-stereochemistry of the allylic phosphate
appears to be essential, as E-allylic phosphate 4 only underwent
hydroarylation to give 5 in 63% yield, as a 2:1 ratio of geometric
isomers [Eq. (2), stereochemistry of 5 not assigned]. Although
the reasons for this observation are not understood, one
possibility is that the steric demands of this reaction are better
accommodated by Z-allylic phosphates. The standard conditions
were ineffective in the formation of a cyclopentene from 1,5-
enyne 6, but use of (R)-Ph-PHOX (L1) in place of L6 gave 7 in
64% yield and 42% ee [Eq. (3)].
We were pleased to observe that reaction of 1a with
PhB(OH)2 (2.0 equiv) in the presence of Ni(OAc)2·4H2O (10
mol%) and various chiral P,N-ligands (10 mol%) in mixtures of
MeCN with THF or 2-MeTHF did indeed provide the anti-
carbometallative cyclization product 2a. However, these
reactions proceeded in low conversions (<10%) and 2a was
accompanied by comparable amounts of pyrrolidine 3a, resulting
from arylnickelation of the alkyne with the opposite
regioselectivity. No reaction was observed in other solvents such
as DMF, dioxane, and toluene. Fortunately, in 2,2,2-
trifluoroethanol
(TFE),
reactions
conducted
with
phosphinooxazoline (PHOX) ligands L1–L3[ 10 ] gave 2a in
moderate NMR yields and in 36–98% ee, accompanied by only
a small quantity of pyrrolidine 3a (entries 1–3).[11] (S,S)-t-Bu-
FOXAP (L4) gave no reaction (entry 4). Improved selectivities
(>19:1) in favor of 2a were obtained using NeoPHOX ligands[12]
L5 and L6 (entries 5–7).[13] Although the enantioselectivity was
higher using (S)-t-Bu-NeoPHOX (L6) (compare entries 5 and 6),
the conversion was modest (entry 6). However, increasing the
temperature to 100 °C gave a significantly higher yield of 2a with
only a small decrease in enantioselectivity (entry 7). The
conditions of entry 7 were subsequently employed to test the
generality of this process.[14]
The scope of this reaction with respect to the alkyne-
tethered allylic phosphate was then explored in reactions with
PhB(OH)2, which gave products 2a–2i in 45–92% yield and 49–
99% ee (Scheme 2). High selectivities (≥14:1) in favor of the six-
membered ring products were observed. Regarding the
substituent on the alkyne, the reaction is compatible with a
phenyl group (2a), various para- (2b and 2c), meta- (2d), and
ortho-substituted benzenes (2e), and a 2-thienyl group (2f). An
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Scheme 4 illustrates a possible catalytic cycle for these
reactions, using 1a and PhB(OH)2 as representative reactants.
Transmetalation of PhB(OH)2 with the chiral nickel species 9,
which could have hydroxide, acetate, 2,2,2-trifluoroethoxide, or
diethylphosphate ligands resulting from the possible species in
the reaction, gives arylnickel species 10. Syn-phenylnickelation
of 1a gives alkenylnickel species (E)-11, which undergoes
15
]
reversible E/Z isomerization to give (Z)-11.[6,7a,
The
mechanism of E/Z isomerization is not currently known, but may
involve the intermediacy of zwitterionic carbene-type
species.[15a, 16 ] Migratory insertion of the alkene of the allylic
phosphate into the carbon–nickel bond of (Z)-11 gives
alkylnickel species 12, from which β-phosphate elimination
would liberate the product 2a, regenerating the nickel species 9.
This mechanism for allylic substitution[ 17 ] is similar to that
proposed by Murakami and co- workers for arylative cyclizations
[3a,b]
of 1,6-enynes.
Furthermore, it stands in contrast to other
related Ni-catalyzed allylic substitutions, which are thought to
[1j,8j−l, 18 ]
proceed through allylnickel intermediates.
However,
Scheme 3. Scope of boronic acids. Reactions were conducted using 0.30
mmol of 1. Yields are of isolated products. Values in parentheses refer to the
ratio of 2:3 as determined by 1H NMR analysis of the crude reactions. Unless
stated otherwise, the minor isomers 3 were not evident in the isolated products.
although we have proposed that nickel remains in the +2
oxidation state throughout, we do not rule out alternative
mechanisms involving Ni(I) species. [7a]
Enantiomeric excesses were determined by HPLC analysis on
a chiral
stationary phase. [a] Products 2p–2r contained trace quantities of inseparable,
unidentified impurities, and the ratio of 2:3 could not be determined.
Scheme 4. Postulated catalytic cycle.
In conclusion, we have reported enantioselective nickel-
catalyzed allylic alkenylations of allylic phosphates which
provide a range of chiral 1,4-diene-containing hetero- and
carbocycles in high enantiomeric excesses. This reaction further
demonstrates the power of the reversible E/Z isomerization of
alkenylnickel species in providing products that would otherwise
be inaccessible using syn-selective alkyne carbometalation
processes.
Finally, replacing the arylboronic acid with other
pronucleophilic species was examined. Although no reaction
occurred with methylboronic acid, (E)-2-phenylvinylboronic acid
reacted with 1a to give 8 in 98% ee, albeit in 13% yield [Eq. (4)].
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Acknowledgements
5257. l) Y. Kita, R. D. Kavthe, H. Oda, K. Mashima, Angew. Chem., Int.
Ed. 2016, 55, 1098-1101.
We thank the EPSRC and AstraZeneca (Industrial CASE
Studentship to C.Y., grant number EP/N509309/1), the EPSRC
Centre for Doctoral Training in Sustainable Chemistry (grant
number EP/L015633/1), the European Commission (Marie
Skłowdowska-Curie Fellowship to S.N.K., project number
702386), the University of Nottingham, and GlaxoSmithKline for
support of this work.
[9]
For examples of enantiospecific rather than enantioselective Ni-
catalyzed allylic or benzylic substitutions, see: a) B. L. H. Taylor, E. C.
Swift, J. D. Waetzig, E. R. Jarvo, J. Am. Chem. Soc. 2011, 133, 389-
391. b) B. L. H. Taylor, M. R. Harris, E. R. Jarvo, Angew. Chem., Int. Ed.
2012, 51, 7790-7793. c) M. R. Harris, L. E. Hanna, M. A. Greene, C. E.
Moore, E. R. Jarvo, J. Am. Chem. Soc. 2013, 135, 3303-3306. d) Q.
Zhou, H. D. Srinivas, S. Dasgupta, M. P. Watson, J. Am. Chem. Soc.
2013, 135, 3307-3310. e) H. M. Wisniewska, E. C. Swift, E. R. Jarvo, J.
Am. Chem. Soc. 2013, 135, 9083-9090. f) I. M. Yonova, A. G. Johnson,
C. A. Osborne, C. E. Moore, N. S. Morrissette, E. R. Jarvo, Angew.
Chem., Int. Ed. 2014, 53, 2422-2427. g) H. D. Srinivas, Q. Zhou, M. P.
Watson, Org. Lett. 2014, 16, 3596-3599. h) E. J. Tollefson, D. D.
Dawson, C. A. Osborne, E. R. Jarvo, J. Am. Chem. Soc. 2014, 136,
14951-14958. i) E. J. Tollefson, L. E. Hanna, E. R. Jarvo, Acc. Chem.
Res. 2015, 48, 2344-2353.
Keywords: allylic substitution
cyclization • isomerization • nickel
•
asymmetric catalysis
•
[1]
Selected reviews: a) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996,
96, 395-422. b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103,
2921-2944. c) A. Alexakis, J. E. Bäckvall, N. Krause, O. Pàmies, M.
Diéguez, Chem. Rev. 2008, 108, 2796-2823. d) S. R. Harutyunyan, T.
den Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008,
108, 2824-2852. e) J. F. Hartwig, L. M. Stanley, Acc. Chem. Res. 2010,
43, 1461-1475. f) W.-B. Liu, J.-B. Xia, S.-L. You, Top. Organomet.
Chem. 2012, 38, 155-207. g) C. Moberg, Top. Organomet. Chem. 2012,
38, 209-234. h) J.-B. Langlois, A. Alexakis, Top. Organomet. Chem.
2012, 38, 235-268. i) P. Tosatti, A. Nelson, S. P. Marsden, Org. Biomol.
Chem. 2012, 10, 3147-3163. j) A. H. Cherney, N. T. Kadunce, S. E.
Reisman, Chem. Rev. 2015, 115, 9587-9652.
[10] a) P. von Matt, A. Pfaltz, Angew. Chem., Int. Ed. Engl. 1993, 32, 566-
568. b) J. Sprinz, G. Helmchen, Tetrahedron Lett. 1993, 34, 1769-1772.
c) J. V. Allen, S. J. Coote, G. J. Dawson, C. G. Frost, C. J. Martin, J. M.
J. Williams, J. Chem. Soc., Perkin Trans. 1 1994, 2065-2072.
[11] The exact reasons for the beneficial effect of TFE are not known at the
present time, but one possibility is that TFE engages in hydrogen-
bonding with the phosphate, activating it as a leaving group in allylic
substitution. Use of TFE in combination with other solvents such as
THF, dioxane, or MeCN gave much lower yields.
[2]
a) Y. Lee, K. Akiyama, D. G. Gillingham, M. K. Brown, A. H. Hoveyda, J.
Am. Chem. Soc. 2008, 130, 446-447. b) K. Akiyama, F. Gao, A. H.
Hoveyda, Angew. Chem., Int. Ed. 2010, 49, 419-423. c) F. Gao, K. P.
McGrath, Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 14315-
14320. d) R. Shintani, K. Takatsu, M. Takeda, T. Hayashi, Angew.
Chem., Int. Ed. 2011, 50, 8656-8659. e) B. Jung, A. H. Hoveyda, J. Am.
Chem. Soc. 2012, 134, 1490-1493. f) F. Gao, J. L. Carr, A. H. Hoveyda,
Angew. Chem., Int. Ed. 2012, 51, 6613-6617. g) J. Y. Hamilton, D.
Sarlah, E. M. Carreira, J. Am. Chem. Soc. 2013, 135, 994-997. h) F.
Gao, J. L. Carr, A. H. Hoveyda, J. Am. Chem. Soc. 2014, 136, 2149-
2161. i) M. Sidera, S. P. Fletcher, Nature Chem. 2015, 7, 935-939.
a) T. Miura, M. Shimada, M. Murakami, J. Am. Chem. Soc. 2005, 127,
1094-1095. b) T. Miura, M. Shimada, M. Murakami, Chem. Asian. J
2006, 1, 868-877. For a related process, see: c) M. Shimada, T.
Harumashi, T. Miura, M. Murakami, Chem. Asian. J 2008, 3, 1035-1040.
For reviews of domino carbometalation sequences triggered by the
rhodium-catalyzed addition of organoboron reagents, see: (a) T. Miura,
M. Murakami, Chem. Commun. 2007, 217-224. (b) S. W. Youn, Eur. J.
Org. Chem. 2009, 2597-2605.
[12] M. G. Schrems, A. Pfaltz, Chem. Commun. 2009, 6210-6212.
[13] The absolute configuration of 2a obtained using ligand L5 was
determined by X-ray crystallography, and the absolute configurations of
the remaining products were assigned by analogy. CCDC 1539326
contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Centre.
[14] Repeating the experiment of Table 1, entry 7, but in the absence of L6,
gave none of 2a. Instead, 3a was formed in 12% NMR yield, along with
a 10% NMR yield of what appeared to be the product of hydroarylation
of 1a without cyclization.
[3]
[4]
[15] a) J. M. Huggins, R. G. Bergman, J. Am. Chem. Soc. 1981, 103, 3002-
3011. b) A. Yamamoto, M. Suginome, J. Am. Chem. Soc. 2005, 127,
15706-15707. c) M. Daini, A. Yamamoto, M. Suginome, Asian. J. Org.
Chem. 2013, 2, 968-976.
[16] a) M. Murakami, T. Yoshida, S. Kawanami, Y. Ito, J. Am. Chem. Soc.
1995, 117, 6408-6409. b) P.-S. Lin, M. Jeganmohan, C.-H. Cheng,
Chem. Eur. J. 2008, 14, 11296-11299. c) T. Sperger, C. M. Le, M.
Lautens, F. Schoenebeck, Chem. Sci. 2017, 8, 2914-2922.
[5]
[6]
[7]
D. L. Comins, X. Chen, L. A. Morgan, J. Org. Chem. 1997, 62, 7435-
7438.
[17] Sawamura and co-workers have described stereospecific Pd-catalyzed
reactions between allylic esters and arylboronic acids, in which allylic
substitution is proposed to occur by migratory insertion of the alkene
followed by β-oxygen elimination: a) H. Ohmiya, Y. Makida, T. Tanaka,
M. Sawamura, J. Am. Chem. Soc. 2008, 130, 17276-17277. b) H.
Ohmiya, Y. Makida, D. Li, M. Tanabe, M. Sawamura, J. Am. Chem. Soc.
2010, 132, 879-889. c) D. Li, T. Tanaka, H. Ohmiya, M. Sawamura, Org.
Lett. 2010, 12, 3344-3347.
C. Clarke, C. A. Incerti-Pradillos, H. W. Lam, J. Am. Chem. Soc. 2016,
138, 8068-8071.
For related Ni-catalyzed anti-carbometallative cyclizations, see: a) X.
Zhang, X. Xie, Y. Liu, Chem. Sci. 2016, 7, 5815-5820. b) X. Wang, Y.
Liu, R. Martin, J. Am. Chem. Soc. 2015, 137, 6476-6479. c) M.
Börjesson, T. Moragas, R. Martin, J. Am. Chem. Soc. 2016, 138, 7504-
7507.
[18] a) B. M. Trost, M. D. Spagnol, J. Chem. Soc., Perkin Trans 1 1995,
2083-2097. b) Y. Kobayashi, R. Mizojiri, E. Ikeda, J. Org. Chem. 1996,
61, 5391-5399. c) Y. Kobayashi, K. Watatani, Y. Kikori, R. Mizojiri,
Tetrahedron Lett. 1996, 37, 6125-6128.
[8]
Selected examples of enantioselective Ni-catalyzed allylic alkylations or
arylations: a) G. Consiglio, F. Morandini, O. Piccolo, Helv. Chim. Acta
1980, 63, 987-989. b) G. Consiglio, O. Piccolo, L. Roncetti, F.
Morandini, Tetrahedron 1986, 42, 2043-2053. c) T. Hiyama, N. Wakasa,
Tetrahedron Lett. 1985, 26, 3259-3262. d) G. Consiglio, A. Indolese,
Organometallics 1991, 10, 3425-3427. e) A. F. Indolese, G. Consiglio,
Organometallics 1994, 13, 2230-2234. f) U. Nagel, H. G. Nedden, Inorg.
Chim. Acta 1998, 269, 34-42. g) E. Gomez-Bengoa, N. M. Heron, M. T.
Didiuk, C. A. Luchaco, A. H. Hoveyda, J. Am. Chem. Soc. 1998, 120,
7649-7650. h) K.-G. Chung, Y. Miyake, S. Uemura, J. Chem. Soc.,
Perkin Trans 1 2000, 15-18. i) S. Son, G. C. Fu, J. Am. Chem. Soc.
2008, 130, 2756-2757. j) J. D. Shields, D. T. Ahneman, T. J. A. Graham,
A. G. Doyle, Org. Lett. 2014, 16, 142-145. k) Z. Zeng, D. Yang, Y. Long,
X. Pan, G. Huang, X. Zuo, W. Zhou, J. Org. Chem. 2014, 79, 5249-
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COMMUNICATION
C. Yap, G. M. J. Lenagh-Snow, S. N.
Karad, W. Lewis, L. J. Diorazio, H. W.
Lam*
Page No. – Page No.
Enantioselective Nickel-Catalyzed
Intramolecular Allylic Alkenylations
Enabled by Reversible Alkenylnickel E/Z
Isomerization
Enantioselective nickel-catalyzed arylative cyclizations of substrates containing a Z-
allylic phosphate tethered to an alkyne are described. These reactions give
multisubstituted chiral aza- and carbocycles, and are initiated by the addition of an
arylboronic acid to the alkyne, followed by cyclization of the resulting alkenylnickel
species onto the allylic phosphate. The reversible E/Z isomerization of the
alkenylnickel species is essential for the success of the reactions.
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