Asymmetric synthesis of β-alkynyl aldehydes by rhodium-catalyzed conjugate alkynylation

Article abstract of DOI:10.1002/anie.200904486

To the point: The rhodium-catalyzed asymmetric conjugate alkynylation of α, β-unsaturated aldehydes with triisopropylsilyl acetylene proceeded efficiently in methanol to give the β-alkynyl aldehydes in high yields with high enantioselectivity (see Scheme)

Full text of DOI:10.1002/anie.200904486

Angewandte
Chemie
DOI: 10.1002/anie.200904486
Synthetic Methods
Asymmetric Synthesis of b-Alkynyl Aldehydes by Rhodium-Catalyzed
Conjugate Alkynylation**
Takahiro Nishimura,* Takahiro Sawano, and Tamio Hayashi*
Catalytic asymmetric conjugate addition of terminal alkynes
to a,b-unsaturated carbonyl compounds provides a powerful
method to construct a chiral carbon center at the propargylic
position, realizing high atom efficiency.[1] In 2006, Carreira
and co-workers reported the first example of copper-cata-
lyzed asymmetric conjugate addition of terminal alkynes to
electron-deficient alkenes derived from Merdrumꢀs acid,
giving chiral b-alkynyl diesters with high enantioselectivity.[2]
In contrast, we recently reported a rhodium-catalyzed reac-
tion which realizes the asymmetric conjugate addition of a
silylacetylene to a,b-unsaturated ketones giving chiral
b-alkynyl ketones.[3–5] We next focused on the synthesis of a
chiral b-alkynyl aldehyde, which is an important chiral
building block in organic synthesis.[6] Diverse transformations
of both the formyl group and the alkynyl group on b-alkynyl
aldehydes offers access to useful compounds. For example,
(+)-8-epi-xanthatin, which has promising biological activities,
has been synthesized by way of (S)-3-methyl-5-(triisopropyl-
silyl)-4-pentynal (3a) derived from enantiopure methyl
3-hydroxy-2-methylpropanoate in six steps.[6] The asymmetric
addition of terminal alkynes to a,b-unsaturated aldehydes is
an ideal process for the synthesis of chiral b-alkynyl alde-
hydes, but it potentially includes several pathways leading to
the 1,2-adduct A, the 1,4-adduct B, and the double-addition
product C (Scheme 1).[7] In the rhodium-catalyzed addition of
arylboronic acids to enals, Ueda and Miyaura reported in
2000 that high regioselectivity for the 1,4-addition product
was accomplished by using a cationic rhodium complex in
aqueous methanol.[8] Asymmetric variants of the 1,4-addition
of arylboronic acids to enals have also been reported by
Miyaura and co-workers,[9] Carreira and co-workers,[10] and
our group.[11] In contrast, catalytic asymmetric conjugate
alkynylation of enals has not been reported, to the best of our
knowledge.[12] Herein we report the rhodium-catalyzed asym-
metric conjugate alkynylation of enals, giving chiral b-alkynyl
aldehydes in high yields with high enantioselectivity.
In the first set of experiments, addition of triisopropylsilyl
acetylene (2) to 2-butenal (1a) was examined under several
reaction conditions (Table 1). Treatment of 1a with 2
Table 1: Rhodium-catalyzed asymmetric conjugate alkynylation of enal
1a.[a]
Entry
Solvent
Yield of 3a [%][b]
Yield of 4 [%][b]
1
2
3
4
1,4-dioxane
21
71
63
10
48
0
17
55
0
MeOH/THF (4:1)
iPrOH/THF (4:1)
tBuOH/THF (4:1)
MeOH
5
79
6[c]
MeOH
93 (96% ee (S))[d]
0
[a] Reaction conditions: enal 1a (0.20 mmol), alkyne 2 (0.40 mmol),
[{Rh(OAc)(C2H4)2}2] (5 mol% of Rh), (R)-DTBM-segphos (6 mol%),
1
solvent (0.4 mL) at 608C for 6 h. [b] Determined by H NMR analysis.
[c] Performed at 408C for 24 h. [d] Determined by HPLC analysis of
3-methyl-5-(triisopropylsilyl)-4-pentynyl benzoate derived from 3a.
(2.0 equiv) in 1,4-dioxane at 608C for six hours in the
presence of in situ generated [Rh(OAc)((R)-DTBM-seg-
phos)][13] (5 mol%), which is a standard set reaction con-
ditions for the rhodium-catalyzed asymmetric alkynylation of
enones,[3] gave a mixture of 1,4-addition product 3a (21%)
Scheme 1. Selectivity on an alkynylation of a,b-unsaturated aldehydes.
[*] Dr. T. Nishimura, T. Sawano, Prof. T. Hayashi
Department of Chemistry, Graduate School of Science
Sakyo, Kyoto 606-8502 (Japan)
and bis(alkynyl) alcohol
4 (48%, d.r. = 1:1; Table 1,
entry 1).[14] The chemoselectivity of the reaction was strongly
dependent on the solvent. Thus, the use of a mixed solvent
system composed of methanol and THF[11] furnished the 1,4-
addition product 3a in 71% yield as the sole addition product
(Table 1, entry 2). The reaction using 2-propanol or tert-butyl
alcohol instead of methanol increased the yield of the
bis(alkynyl) alcohol 4 (Table 1, entries 3 and 4). The reaction
in methanol displayed the perfect selectivity for the 1,4-
addition to give 3a in 79% yield (Table 1, entry 5). The
Fax: (+81)75-753-3988
E-mail: tnishi@kuchem.kyoto-u.ac.jp
thayashi@kuchem.kyoto-u.ac.jp
[**] This work has been supported by a Grant-in-Aid for Scientific
Research (S) from the MEXT (Japan). We thank Takasago Interna-
tional Corporation for the gift of (R)-DTBM-segphos.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904486.
Angew. Chem. Int. Ed. 2009, 48, 8057 –8059
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8057

Communications
Table 2: Rhodium-catalyzed asymmetric conjugate alkynylation of
reaction under milder reaction conditions (408C for 24 h)
enals.[a]
proceeded to give 3a in 93% yield with an enantiomeric
excess (ee) of 96% (Table 1, entry 6).[15] The absolute config-
uration of 3a was determined to be S-(+) by correlation with
terminal alkyne 5 [½aꢀD20 = + 53 (c = 1.05, CHCl3) for 96% ee
(S); lit. ½aꢀ2D6 = ꢁ51.2 (c = 1.14, CHCl3) for (R)-5],[16] which
was derived from 3a in three steps (see Scheme 3). The
absolute configuration of (S)-3a is in good agreement with the
stereochemical pathway shown in Scheme 2, the enal inter-
mediate A being attacked by the alkynylrhodium on its a-re
face in the present reaction.
Entry
R
Yield [%][b]
ee [%][c]
1
CH3 (1a)
CH3 (1a)
CH2Ph (1b)
C5H11 (1c)
CH(CH3)2 (1d)
91 (3a)
84 (3a)
90 (3b)
86 (3c)
88 (3d)
93 (3e)
61 (3 f)
92 (3g)
85 (3h)
79 (3i)
74 (3j)
83 (3k)
83 (3l)
96 (S)
96 (S)
98 (S)
98 (S)
99 (R)
95 (S)
94 (S)
96 (S)
93 (S)
95 (S)
97 (S)
93 (S)
96 (S)
2[d]
3
4
5
6
7
8
9
10
11
12
13
=
(Z)-(CH2)2CH CHC2H5 (1e)
(CH2)2CH2Br (1 f)
(CH2)8CH2OH (1g)
CH2OCH3 (1h)
(CH2)2CH2OC(O)Ph (1i)
(CH2)3C(O)Ph (1j)
(CH2)2CH2NO2 (1k)
(CH2)2CH2SO2Ph (1l)
[a] Reaction conditions: enal 1 (0.20 mmol), alkyne 2 (0.40 mmol),
[{Rh(OAc)(C2H4)2}2] (5 mol% of Rh), MeOH (0.4 mL) at 408C for 24 h.
[b] Yield of the isolated product. [c] Determined by HPLC analysis. The
absolute configurations of 3b–3l were assigned by analogy to product in
entry 1. [d] The reaction of 1a (2.0 mmol) with 2 (4.0 mmol).
Scheme 2. Stereochemical pathway.
The present rhodium-catalyzed asymmetric alkynylation
displayed tolerance to a wide range of functional groups
(Table 2). The reaction of alkyne 2 with b-substituted enals
having alkyl (1a–1d) and alkenyl groups (1e) proceeded well
to give the corresponding b-alkynyl aldehydes 3a–3e in good
yields with the enantioselectivity ranging between 95 and
99% ee (Table 2, entries 1–6). The alkynylation of enals
having bromo (1 f), hydroxy (1g), ether (1h), ester (1i),
keto (1j), nitro (1k), and sulphonyl (1l) groups gave the
corresponding b-alkynyl aldehydes in good yields with high
enantioselectivity (Table 2, entries 7–13).
Scheme 3. a) NaBH4, EtOH, RT, 1 h. b) p-Methoxybenzyl chloride,
NaH, Bu4NI, DMF, RT, 2 h. c) Bu4NF, THF, RT, 2 h (90% in three
steps). DMF=N,N-dimethylformamide.
The b-alkynyl aldehydes obtained here with high enan-
tioselectivity are readily converted into functionalized com-
pounds without loss of enantiomeric purity (Scheme 3 and 4).
For example, the reduction of the formyl group on 3a, then
etheration of the resulting alcohol, and final desilylation by
treatment with tetrabutylammonium fluoride gave terminal
alkyne 5, which is one of the key intermediates for the
syntheses of natural products, ciguatoxin,[16] frondosin B,[17]
and goniodomin A[18,19] (Scheme 3). As another example of a
synthetic application, the Pinnic oxidation[20] of 3b, and then
esterification of the resulting carboxylic acid with Me3SiCHN2
gave b-alkynyl ester 6 in 77% yield (Scheme 4). The Wittig
olefination of 3b gave d-alkynyl-a,b-unsaturated ester in
86% yield (98% ee).
Scheme 4. a) NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, tBuOH/
=
H2O, RT, 1 h. b) Me3SiCHN2, benzene/EtOH, 08C, 15 min. c) Ph3P
CHCO2Et, CH2Cl2, 408C, 13 h.
enantioenriched b-alkynyl aldehydes, which are useful chiral
building blocks. The chemoselectivity of the product was
strongly dependent on the solvent, and the reaction in
methanol displayed perfect selectivity for the formation of
1,4-addition products of enals.
In summary, we have developed a rhodium-catalyzed
conjugate alkynylation of a,b-unsaturated aldehydes giving
8058 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 8057 –8059

Angewandte
Chemie
=
=
[7] For examples of rhodium-catalyzed alkynylation of C C or C O
bonds, see: a) G. I. Nikishin, I. P. Kovalev, Tetrahedron Lett.
1990, 31, 7063; b) M. Yamaguchi, K. Omata, M. Hirama,
Tetrahedron Lett. 1994, 35, 5689; c) R. V. Lerum, J. D. Chisholm,
Tetrahedron Lett. 2004, 45, 6591; d) P. K. Dhondi, J. D. Chisholm,
Org. Lett. 2006, 8, 67; e) P. K. Dhondi, P. Carberry, J. D.
Chisholm, Tetrahedron Lett. 2007, 48, 8743; f) P. K. Dhondi, P.
Carberry, L. B. Choi, J. D. Chisholm, J. Org. Chem. 2007, 72,
9590; g) S. Crotti, F. Bertolini, F. Macchia, M. Pineschi, Chem.
Commun. 2008, 3127.
Experimental Section
A mixture of [{Rh(OAc)(C2H4)2}2] (2.2 mg, 5 mmol, 10 mmol of Rh)
and (R)-DTBM-segphos (14.2 mg, 12 mmol) in methanol (0.4 mL)
was stirred at room temperature for 15 min. Then a,b-unsaturated
aldehyde 1 (0.20 mmol) and (triisopropylsilyl)acetylene (73.0 mg,
0.40 mmol) were added to the solution, which was then stirred at 408C
for 24 h. The mixture was passed through a short column of silica gel
with diethyl ether as the eluent. After evaporation of the solvent, the
residue was subjected to column chromatography on silica gel with
hexane/ethyl acetate to give compound 3.
[8] M. Ueda, N. Miyaura, J. Org. Chem. 2000, 65, 4450.
[9] R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem. 2003, 68, 6000.
[10] J.-F. Paquin, C. Defieber, C. R. J. Stephenson, E. M. Carreira, J.
Am. Chem. Soc. 2005, 127, 10850.
Received: August 11, 2009
Published online: September 18, 2009
[11] T. Hayashi, N. Tokunaga, K. Okamoto, R. Shintani, Chem. Lett.
2005, 34, 1480.
[12] For an example of iodotrimethylsilane-promoted 1,4-addition of
copper acetylides to enals, see: M. Eriksson, T. Iliefski, M.
Nilsson, T. Olsson, J. Org. Chem. 1997, 62, 182.
Keywords: 1,4-addition · aldehydes · alkynylation ·
asymmetric addition · rhodium
.
[1] a) B. M. Trost, A. H. Weiss, Adv. Synth. Catal. 2009, 351, 963;
b) S. Fujimori, T. F. Knꢁpfel, P. Zarotti, T. Ichikawa, D. Boyall,
E. M. Carreira, Bull. Chem. Soc. Jpn. 2007, 80, 1635.
[2] T. F. Knꢁpfel, P. Zarotti, T. Ichikawa, E. M. Carreira, J. Am.
Chem. Soc. 2005, 127, 9682.
[13] T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura, H.
Kumobayashi, Adv. Synth. Catal. 2001, 343, 264. DTBM-
segphos = 5,5’-bis{di(3,5-di-tert-butyl-4-methoxyphenyl)phos-
phino}-4,4’-bi-1,3-benzodioxole.
[14] The formation of 1,2-addition product was not observed.
[15] The reaction of 1a with tert-butyldimethylsilyl acetylene,
triethylsilyl acetylene, phenylacetylene, and 1-octyne under the
same conditions gave the corresponding b-alkynyl aldehydes in
25, 8, 5, and 1% yield, respectively.
[16] Compound 5 is prepared from 1,3-propanediol in eight steps by
using the Sharpless epoxidation as a key transformation. T. Oka,
A. Murai, Tetrahedron 1998, 54, 1.
[17] C. C. Hughes, D. Trauner, Angew. Chem. 2002, 114, 1639;
Angew. Chem. Int. Ed. 2002, 41, 1569.
[3] T. Nishimura, X.-X. Guo, N. Uchiyama, T. Katoh, T. Hayashi, J.
Am. Chem. Soc. 2008, 130, 1576.
[4] For examples of our recent studies of rhodium-catalyzed
alkynylations, see: a) T. Nishimura, X.-X. Guo, K. Ohnishi, T.
Hayashi, Adv. Synth. Catal. 2007, 349, 2669; b) T. Nishimura, T.
Katoh, K. Takatsu, R. Shintani, T. Hayashi, J. Am. Chem. Soc.
2007, 129, 14158; c) R. Shintani, K. Takatsu, T. Katoh, T.
Nishimura, T. Hayashi, Angew. Chem. 2008, 120, 1469; Angew.
Chem. Int. Ed. 2008, 47, 1447; d) T. Nishimura, X.-X. Guo, T.
Hayashi, Chem. Asian J. 2008, 3, 1505; e) T. Nishimura, E.
Tsurumaki, T. Kawamoto, X.-X. Guo, T. Hayashi, Org. Lett.
2008, 10, 4057; f) T. Nishimura, S. Tokuji, T. Sawano, T. Hayashi,
Org. Lett. 2009, 11, 3222.
[5] For examples of catalytic asymmetric conjugate alkynylation of
enones, see: a) Y.-S. Kwak, E. J. Corey, Org. Lett. 2004, 6, 3385;
b) T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2005, 127, 3244. For
selected examples of enantioselective conjugate alkynylations,
see: c) J. M. Chong, L. Shen, N. J. Taylor, J. Am. Chem. Soc.
2000, 122, 1822; d) M. Yamashita, K. Yamada, K. Tomioka, Org.
Lett. 2005, 7, 2369.
[18] T. Katagiri, K. Fujiwara, H. Kawai, T. Suzuki, Tetrahedron Lett.
2008, 49, 3242.
[19] Similar alkynes having different protecting groups are also
important chiral building blocks for the synthesis of natural
products; a) S. Kurosawa, K. Mori, Eur. J. Org. Chem. 2000, 955;
b) N. F. Langille, J. S. Panek, Org. Lett. 2004, 6, 3203; c) A.
Fꢂrstner, L. C. Bouchez, J.-A. Funel, V. Liepins, F.-H. Porꢃe, R.
Gilmour, F. Beaufils, D. Laurich, M. Tamiya, Angew. Chem.
2007, 119, 9425; Angew. Chem. Int. Ed. 2007, 46, 9265; d) L.
Deng, Z. Ma, G. Zhao, Synlett 2008, 728.
[20] B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981,
37, 2091.
[6] D. A. Kummer, J. B. Brenneman, S. F. Martin, Tetrahedron 2006,
62, 11437.
Angew. Chem. Int. Ed. 2009, 48, 8057 –8059
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8059