Copper-catalyzed γ-selective and stereospecific direct allylic alkylation of terminal alkynes: Synthesis of skipped enynes

Article abstract of DOI:10.1002/anie.201300785

Skipping out: The title reaction using internal secondary allylic phosphates proceeded with excellent γ regioselectivity and E stereoselectivity to give skipped enynes. Enantioenriched secondary allylic phosphates proceeded with 1,3-anti stereochemistry t

Full text of DOI:10.1002/anie.201300785

.
Angewandte
Communications
DOI: 10.1002/anie.201300785
Homogeneous Catalysis
Copper-Catalyzed g-Selective and Stereospecific Direct Allylic
Alkylation of Terminal Alkynes: Synthesis of Skipped Enynes**
Yusuke Makida, Yurie Takayama, Hirohisa Ohmiya,* and Masaya Sawamura*
Skipped enynes, that is, 1,4-enynes, are versatile building
blocks which can be further derivatized through various
stereoselective transformations.[1,2] The development of facile
and efficient methods for the synthesis of skipped enynes is
thus important. In particular, stereoselective synthesis of
chiral 1,4-enynes with a stereogenic center at the propargylic/
allylic position is highly desirable.[3] Among the routes to
skipped enynes, allylic alkylation of alkynyl nucleophiles is
particularly efficient and versatile because the substrates and
the reagents are readily available and the reactions are highly
reliable in terms of regio- and stereoselectivities. Kobayashi
and co-workers reported a g-selective allylic alkylation of
stoichiometric alkynylcopper(I) reagents with excellent 1,3-
anti stereoselectivity.[4] More recently, Hoveyda and co-work-
ers developed copper-catalyzed enantioselective allylic alky-
lation with highly reactive alkynylaluminum reagents, which
were prepared by metalation of terminal alkynes with
DIBAL-H, thus giving chiral skipped enynes having a termi-
nal alkene moiety.[5] These methods are useful for the
preparation of chiral skipped enynes, but require prefunc-
tionalization of the alkyne substrate and are problematic
regarding functional-group compatibility. In this regard, the
direct use of terminal alkynes for selective synthesis of
enantioenriched skipped enynes is a desirable strategy.[6]
Herein, we report a copper-catalyzed direct allylic alky-
lation of terminal alkynes with internal secondary allylic
phosphates, and it proceedes with excellent g regioselectivity
and E stereoselectivity.[7] The reaction of enantioenriched
secondary allylic phosphates proceeded with 1,3-anti stereo-
chemistry to afford the corresponding chiral 1,4-enynes with
a controlled stereogenic center at the propargylic/allylic
position. The protocols are versatile and useful for the
synthesis of functionalized skipped enynes because various
terminal alkynes such as silyl, aromatic, or aliphatic alkynes
can be used without prefunctionalization. This method is
particularly useful for the synthesis of skipped enynes with an
internal alkene moiety. The chiral skipped enynes can be used
for various derivatizations such as heterocyclic annulations as
demonstrated by a formal total synthesis of a gonadotropin
releasing hormone (GnRH) antagonist.
Specifically, the reaction of triisopropylsilylacetylene (1a;
0.48 mmol) with the Z-allylic phosphate 2a (0.4 mmol) in the
presence of CuCl (10 mol%), 1,10-phenanthroline (phen;
12 mol%), and LiOtBu (0.4 mmol) in THF (0.8 mL) at 608C
for 10 hours afforded the allylated alkyne product (skipped
enyne) 3aa in 87% yield (90% conv.) with excellent regio- (g/
a > 99:1) and stereoselectivity (E/Z > 99:1) [Eq. (1); TIPS =
triisopropylsilyl]. The reaction of the constitutional isomer 2b
proceeded with slightly decreased but still high g selectivity
(95:5) to afford 3ab along with the corresponding a-
substitution product [Eq. (2)]. The slight difference in the
regioselectivities of the reaction with the isomeric substrates
suggests that relative steric demands of the a and g substitu-
ents perturb the regioselectivity to some extent. These results,
however, indicate that a useful level of g selectivity is
attainable against this unfavorable steric effect.
Several observations concerning the optimum reaction
conditions for the reaction between 1a and 2a [Eq. (1)] are to
be noted. No reaction occurred in the absence of CuCl or
when KOtBu was used instead of LiOtBu. The reaction
proceeded in the absence of 1,10-phenanthroline, but with
lower efficiency (77% yield).[8] The use of 2a with an
E configuration resulted in decreased yield and regioselec-
tivity (54%, 61:39). Allylic substrates with carbonate or
chloride leaving groups were not reactive or afforded
complicated mixtures.
The steric effects of the a and g substituents of allylic
phosphates (2) on the reactivity and regioselectivity were
further evaluated (Table 1, entries 1–6). The allylic phos-
phates possessing bulkier substituents (nBu or iBu), in place
of the g-Me substituent of 2a, also proceed with the excellent
regioselectivity (entries 1 and 2). The allylic phosphate 2e
bearing an even bulkier cHex substituent at the g position was
efficiently coupled with 1a, albeit with decreased g selectivity
(entry 3). The 2-phenylethyl group at the a position of 2a
could be replaced with nBu (2 f), cHex (2g), and iPr (2h)
groups without a change in the regioselectivity (entries 4–6).
[*] Y. Makida, Y. Takayama, Prof. Dr. H. Ohmiya, Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science, Hokkaido University
Sapporo, 060-0810 (Japan)
E-mail: ohmiya@sci.hokudai.ac.jp
sawamura@sci.hokudai.ac.jp
Homepage: http://barato.sci.hokudai.ac.jp/~orgmet/index-
Eng1.html
[**] This work was supported by the Grants-in-Aid for Young Scientists
(A), JSPS to H.O. and by CRESTand ACT-C, JST to M.S. Y.M. thanks
the JSPS for their scholarship support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300785.
5350
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 5350 –5354

Angewandte
Chemie
Table 1: Copper-catalyzed allylic alkylation with 1a.[a]
Table 2: Copper-catalyzed allylic alkylation with various aromatic alky-
nes.[a]
Entry
Phosphate
Product[b]
Yield[c] (g/a[d])
Entry
Alkyne
Phosphate
Product[b]
Yield[c] (g/a[d])
1
2
3
2c (R=nBu)
2d (R=iBu)
2e (R=cHex)
3ac 70% (>99:1)
3ad 88% (>99:1)
3ae 84% (89:11)
1
2
1b
1b
2a
2b
3ba 79% (96:4)
3bb 81% (94:6)
4
2 f
3a 99% (>99:1)
3
4
1b
1b
2j
3bj 72% (99:1)
3bk 99% (–)
5[e]
2g
2h
3ag 74% (>99:1)
3ah 68% (>99:1)
2k
6
5
6
7
1c (R=OMe)
1d (R=CF3)
1e (R=CO2Me)
2a
2a
2a
3ca 88% (>99:1)
3da 82% (>99:1)
3ea 87% (96:4)
7
8
2i
2j
3ai 81% (>99:1)
3aj 76% (>99:1)
8
1 f
1g
1h
2a
2a
2a
3 fa 88% (92:8)
3ga 71% (91:9)
3ha 73% (96:4)
9
10
2k (n=1)
2l (n=2)
3ak 89% (–)
3al 74% (–)
9
[a] The reaction was carried out with 1a (0.48 mmol), 2 (0.4 mmol), CuCl
(10 mol%), phen (12 mol%), and LiOtBu (0.4 mmol) in THF (0.8 mL) at
608C for 10 h. [b] Isomeric ratio E/Z>99:1 (except for entries 9 and 10).
[c] Yield of isolated product. [d] Determined by 1H NMR or GC analysis of
the crude reaction mixture. [e] The reaction was carried out on
a 1.0 mmol scale.
10
[a] The reaction was carried out with 1 (0.24 mmol), 2 (0.2 mmol), CuCl
(10 mol%), phen (12 mol%), and LiOtBu (0.2 mmol) in THF (0.4 mL) at
608C for 15 h. [b] Isomeric ratio E/Z>99:1 (except for entry 4). [c] Yield
of isolated product. [d] Determined by H NMR or GC analysis of the
crude reaction mixture. TBS=tert-butyldimethylsilyl.
The compatibility of various functional groups on the allylic
phosphates 2 was also investigated. Triisopropylsilylacetylene
(1a) reacted with phosphates bearing ester (2i) and silyl ether
(2j) substituents to afford the products in 81% and 76%
yields, respectively (entries 7 and 8). The protocol was also
applicable to six- or seven-membered ring allylic phosphates
(2k,l; entries 9 and 10).
Aromatic alkynes are also suitable substrates for this
copper catalysis (Table 2).[9] Phenylacetylene (1b) reacted
with various allylic phosphates in high yields with high
g selectivities (entries 1–4). The reactions of phenylacetylene
derivatives with electronically and positionally diverse sub-
stituents including p-MeO, p-CF3, p-CO2Me, and o-TBSO
groups (1c, 1d, 1e and 1 f) were compatible with the reaction
1
conditions and afforded the corresponding products in high
yields with high regioselectivities (entries 5–8). A sulfur-
containing heteroaromatic alkyne, 2-ethynyl-5-methylthio-
phene (1g), was also a suitable substrate (entry 9). The 1,3-
enyne derivative 1h underwent the reaction with 2a to afford
the corresponding dienyne (3ha) with 96% g-selectivity
(entry 10).
The applicability toward aliphatic alkynes is shown in
Table 3. In this case, CH3CN was the appropriate solvent
Angew. Chem. Int. Ed. 2013, 52, 5350 –5354
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5351

.
Angewandte
Communications
Table 3: Copper-catalyzed allylic alkylation with various aliphatic alky-
Table 4: Reactions with 1,3-anti stereochemistry.[a]
nes.[a]
Entry Alkyne
Phosphate
Product[b]
Entry Arene
Phosphate Product[b]
Yield[c] (g/a[d])
Yield[c] (ee [%][d]; anti/syn)
1
2
1a (R=iPr)
(S)-(Z)-2a 95% ee (À)-(E)-3aa 92% (90; 97:3)
(S)-(Z)-2a 95% ee (R)-(E)-3na 64% (88; 96:4)
1
2
1i
1i
2a
2b
3ia 81% (>99:1)
3ib 89% (92:8)
1n (R=Me)
3
4
1c
1 f
(S)-(Z)-2h 99% ee (À)-(E)-3ch 44% (93; 97:3)
(S)-(Z)-2a 95% ee (À)-(E)-3 fa 88% (91; 98:2)
3
4
1i
1i
2j
3ij 62% (>99:1)
3ik 77% (–)
2k
5
1o
(S)-(Z)-2a 95% ee (À)-(E)-3oa 75% (91; 98:2)
(S)-(Z)-2a 95% ee (À)-(E)-3ja 78% (79; 92:8)
5
1j
2a
3ja 78% (96:4)
6
7
1j
6
7
1k
1l
2a
2a
3ka 87% (96:4)
3la 72% (96:4)
1p
(S)-(Z)-2a 95% ee (À)-(E)-3pa 52% (94;
99:1)
[a] The reaction was carried out with 1 (0.24 mmol), 2 (0.2 mmol), CuCl
(10 mol%), phen (12 mol%), and LiOtBu (0.2 mmol) in THF (entries 1–
5) or CH3CN (entries 6 and 7) (0.4 mL) at 408C for 15–24 h. [b] Isomeric
ratio (entries 1–6, g/a>99:1, E/Z>99:1; entry 7, g/a 97:3, E/Z>99:1).
Determined by 1H NMR or GC analysis of the crude reaction mixture.
[c] Yield of isolated product. [d] The ee values were determined by HPLC
analysis using a chiral stationary phase.
8
1m
2a
3ma 88% (93:7)
[a] The reaction was carried out with 1 (0.24 mmol), 2 (0.2 mmol), CuCl
(10 mol%), phen (12 mol%), and LiOtBu (0.2 mmol) in CH3CN
(0.4 mL) at 608C for 15 h. [b] Isomeric ratio E/Z>99:1 (except for
entry 4). [c] Yield of isolated product. [d] Determined by 1H NMR or GC
analysis of the crude reaction mixture.
tion of 3-branched 1,4-enyne structures (Table 4). Specifically,
the alkylation of the silylacetylenes 1a and 1n with (S)-(Z)-2a
(95% ee) at 408C (24 h) proceeded with high anti stereose-
lectivities, thus affording (À)-(E)-3aa and (R)-(E)-3na,
respectively (entries 1 and 2). The reaction of arylacetylenes
with p-MeO, o-TBSO, and 3,4,5-trimethyl groups (1c,f,o) also
proceeded with high 1,3-anti stereoselectivities (entries 3–5).
In addition, the aliphatic alkynes 1j and 1p were successfully
utilized for this protocol to furnish (À)-(E)-3ja and (À)-(E)-
3pa, respectively, with useful levels of stereoselectivities (anti/
syn 92:8, entry 6; 99:1, entry 7).
As shown in Equations (3) and (4) (BOM = benzyloxy-
methyl), the reactions of chiral propargylic alcohol deriva-
tives with enantioenriched allylic phosphates produced con-
trolled stereogenic centers at both the propargylic positions.
Specifically, the reaction of (S)-2-triisopropylsilyloxy-3-
butyne ((S)-1q) with (S)-(Z)-2a (95% ee) afforded (À)-(E)-
3qa in an excellent yield (96%) with high stereoselectivity
instead of THF. Specifically, the reactions between 6-chloro-
1-hexyne (1i) and 2a gave the chlorinated product (3ia) in
high yield (81%) with excellent regioselectivity (entry 1). The
alkyne 1i also showed good reactivity toward other allylic
phosphates (2b,j,k,; entries 2–4). Functionalized aliphatic
alkynes with a pivalate ester (1j), phthalimide (1k), or
dibenzylamine (1l) substituent at their chain termini reacted
in high yields with high g selectivities (entries 5–7). Cyclo-
propylacetylene (1m) reacted with 2a albeit with slightly
decreased g selectivity (entry 8).
The direct allylic alkylation of terminal alkynes with
enantioenriched allylic phosphates proceeded with 1,3-anti
stereochemistry, thus allowing the stereocontrolled construc-
5352
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 5350 –5354

Angewandte
Chemie
(anti/syn 95:5, product d.r. 93:7) [Eq. (3)]. Furthermore, the
chiral ethisterone derivative 1r reacted with (S)-(Z)-2m
(95% ee) to afford (À)-(E)-3rm, thus allowing stereocon-
trolled elongation of the steroidal side chain (d.r. 99:1) with
the a,b-unsaturated carbonyl moiety remaining untouched
[Eq. (4)].
TBAF = tetra-n-butylammonium fluoride]. These transfor-
mations demonstrate the usefulness of branched skipped
enynes as precursors to various heteroarenes with a controlled
stereogenic center located a to the aromatic rings.
We then used this skipped enyne strategy for a formal
total synthesis of the GnRH (Gonadotropin Releasing
Hormone) antagonist 9 (Scheme 2).[14] Thus, Larock indole
synthesis between (À)-(E)-3oa (89% ee)[15] and the iodoani-
line derivative 6 afforded 7 (43%) along with the isomer 7’
(35%).[16] The major isomer was treated with OsO4/NaIO4/
2,6-lutidine. Reductive acetylation and subsequent deacety-
lation produced the alcohol 8 with 89% ee. The synthesis of 9
from 8 was reported previously.[14] Thus, a formal total
synthesis of GnRH antagonist was achieved.
In considering a reaction mechanism, it is noted that the
present copper-catalyzed allylic alkylation of terminal alkynes
has some common features with the copper-catalyzed allylic
alkylation of electron-deficient heteroarenes, work we pre-
viously reported. These features include comparable
pKa values of the pronucleophiles, reaction conditions using
a stoichiometric LiOtBu base, and the g-selectivity pattern
which is dependent on steric effects of the substituents.[10]
Accordingly, the active organocopper species is likely in the
form of a monoorganoalkoxycuprate ([alkynyl-Cu-OtBu]À)
rather than a neutral organocopper(I) species. As shown in
Scheme 1, the reaction would proceed through oxidative
In summary, we have developed a copper-catalyzed
protocol for direct allylic alkylation of terminal alkynes with
Scheme 1. Possible mechanism.
addition of a heterocuprate (A) to an allylic phosphate to
form allylcopper(III) intermediates.[11] The g selectivity
should be determined at the oxidative addition step as
a consequence of the asymmetric nature of B and B’.
Facile conversion of the alkyne moieties in the enantio-
enriched enyne derivatives into heterocyclic scaffolds was
achieved by desilylation and subsequent copper-catalyzed
[3+2] cycloaddition or palladium-catalyzed hereroannula-
tion, thus affording the triazole (S)-(E)-4 (86% ee)[12] and
benzofuran (+)-(E)-5 (91% ee),[13] respectively [Eqs. (5) and
(6);
bpy = 2,2’-bipyridine,
dba = dibenzylideneacetone,
Scheme 2. Formal total synthesis of a GnRH antagonist.
Angew. Chem. Int. Ed. 2013, 52, 5350 –5354
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5353

.
Angewandte
Communications
Angew. Chem. 2012, 124, 1079 – 1082; Angew. Chem. Int. Ed.
2012, 51, 1055 – 1058.
[4] a) Y. Kiyotsuka, Y. Kobayashi, J. Org. Chem. 2009, 74, 7489 –
7495; b) Q. Wang, Y. Kobayashi, Tetrahedron Lett. 2010, 51,
5592 – 5595; c) Q. Wang, Y. Kobayashi, Org. Lett. 2011, 13, 6252 –
6255.
[5] J. A. Dabrowski, F. Gao, A. H. Hoveyda, J. Am. Chem. Soc.
2011, 133, 4778 – 4781.
[6] J. F. Normant, Synthesis 1972, 63 – 80.
internal secondary allylic phosphates, which proceeded with
excellent g and E selectivities. The protocol was applicable to
various alkynes including silyl, aromatic, and aliphatic
alkynes. The reaction of enantioenriched allylic phosphates
showed excellent 1,3-anti stereoselectivity to generate a sec-
ondary stereogenic center at the allylic and propargylic
position. As a result, the copper-catalyzed protocol allows
straightforward access to enantioenriched chiral skipped
enynes, which are useful precursors for various derivatiza-
tions.
[7] Reviews of copper-catalyzed allylic substitutions: a) Modern
Organocopper Chemistry (Ed.: N. Krause), Wiley-VCH, Wein-
heim, 2002; b) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem.
2008, 3765 – 3780; c) A. Alexakis, J. E. Bꢁckvall, N. Krause, O.
Pꢂmies, M. Diꢃguez, 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.
[8] 1,10-Phenanthroline (phen) should not ligate to the copper
center because of the anionic nature of the copper species (see
mechanistic discussion). Instead, phen may coordinate to the Li
cation and play a role in preventing unfavorable participation of
the Li cation in the reaction of the alkynylcopper species.
[9] Although the produced phenylacetylene derivatives underwent
concomitant isomerization to conjugated 1,3-enallenes, such
byproducts were formed in less than 5% yield and were easily
separable by silica gel chromatography.
[10] For a copper-catalyzed g-selective and stereospecific allylic
alkylation of electron-deficient heteroarenes with internal
secondary allylic phosphates, see: Y. Makida, H. Ohmiya, M.
Sawamura, Angew. Chem. 2012, 124, 4198 – 4203; Angew. Chem.
Int. Ed. 2012, 51, 4122 – 4127.
[11] a) N. Yoshikai, S.-L. Zhang, E. Nakamura, J. Am. Chem. Soc.
2008, 130, 12862 – 12863; b) M. Yamanaka, S. Kato, E. Naka-
mura, J. Am. Chem. Soc. 2004, 126, 6287 – 6293. For a review, see:
c) N. Yoshikai, E. Nakamura, Chem. Rev. 2012, 112, 2339 – 2372.
[12] Synthesis of triazole derivatives: M. Meldal, C. W. Tornoe,
Chem. Rev. 2008, 108, 2952 – 3015.
[13] Synthesis of benzofuran derivatives: a) A. Arcadi, S. Cacchi,
M. D. Rosario, G. Fabrizi, F. Marine, J. Org. Chem. 1996, 61,
9280 – 9288; b) Y. Hu, K. J. Nawoschik, Y. Liao, J. Ma, R. Fathi,
Z. Yang, J. Org. Chem. 2004, 69, 2235 – 2239.
[14] The total synthesis of GnRH antagonist: T. F. Walsh, R. B.
Toupence, F. Ujjainwalla, J. R. Young, M. T. Goulet, Tetrahedron
2001, 57, 5233 – 5241.
[15] The enyne 3oa with 89% ee was obtained from the reaction
between 1o and (S)-(Z)-2a (97% ee) on a 7.6 mmol scale.
[16] Larock indole synthesis: a) R. C. Larock, E. K. Yum, J. Am.
Chem. Soc. 1991, 113, 6689 – 6690; b) R. C. Larock, E. K. Yum,
M. D. Refvik, J. Org. Chem. 1998, 63, 7652 – 7662.
Received: January 29, 2013
Published online: April 9, 2013
Keywords: alkynes · allylic compounds · copper ·
.
homogeneous catalysis · synthetic methods
[1] Selected examples of transformations of 1,4-enynes: a) T. P.
Heffron, T. F. Jamison, Org. Lett. 2003, 5, 2339 – 2342; b) T. P.
Heffron, J. D. Trenkle, T. F. Jamison, Tetrahedron 2003, 59,
8913 – 8917; c) X. Shi, D. J. Gorin, F. D. Toste, J. Am. Chem. Soc.
2005, 127, 5802 – 5803; d) B. A. Bhanu Prasad, F. K. Yoshimoto,
R. Sarpong, J. Am. Chem. Soc. 2005, 127, 12468 – 12469; e) A.
Buzas, F. Gagosz, J. Am. Chem. Soc. 2006, 128, 12614 – 12615;
f) D. Vasu, A. Das, R.-S. Liu, Chem. Commun. 2010, 46, 4115 –
4117; g) T. Sato, T. Onuma, I. Nakamura, M. Terada, Org. Lett.
2011, 13, 4992 – 4995.
[2] The importance of 1,4-enynes as intermediates in total synthesis:
a) M. Jacobson, R. E. Redferm, W. A. Jones, M. H. Aldridge,
Science 1970, 170, 542 – 544; b) G. Stork, M. Isobe, J. Am. Chem.
Soc. 1975, 97, 4745 – 4746; c) K. Iida, M. Hirama, J. Am. Chem.
Soc. 1994, 116, 10310 – 10311; d) V. Hickmann, M. Alcarazo, A.
Fꢀrstner, J. Am. Chem. Soc. 2010, 132, 11042 – 11044.
[3] Synthesis of chiral 1,4-enynes with a controlled stereogenic
center at the propargylic/allylic position. For nickel- or rhodium-
catalyzed ring-opening alkynylations, see: a) D. K. Rayabarapu,
C.-F. Chiou, C.-H. Cheng, Org. Lett. 2002, 4, 1679 – 1682; b) T.
Nishimura, E. Tsurumaki, T. Kawamoto, X.-X. Guo, T. Hayashi,
Org. Lett. 2008, 10, 4057 – 4060; c) S. Crotti, F. Bertolini, F.
Macchia, M. Pineschi, Chem. Commun. 2008, 3127 – 3129.
Nickel-catalyzed addition of alkynes to 1,3-dienes: d) M. Shir-
akura, M. Suginome, Angew. Chem. 2010, 122, 3915 – 3917;
Angew. Chem. Int. Ed. 2010, 49, 3827 – 3829. Copper-catalyzed
allylic alkylation of chlorinated enynes: e) H. Li, A. Alexakis,
5354
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 5350 –5354