The stereoselective synthesis of α-amino aldols starting from terminal alkynes

Article abstract of DOI:10.1039/c4cc04786a

A new procedure for the stereoselective synthesis of syn α-amino β-oxy ketones is reported. It consists of two steps; in the first step, α-amino silyl enol ethers having a (Z) geometry are prepared from 1-alkynes via 1-sulfonyl-1,2,3-triazoles. In the sec

Full text of DOI:10.1039/c4cc04786a

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The stereoselective synthesis of a-amino aldols
starting from terminal alkynes†‡
Cite this: Chem. Commun., 2014,
50, 10474
Tomoya Miura,* Takayuki Nakamuro, Kentaro Hiraga and Masahiro Murakami*
Received 24th June 2014,
Accepted 18th July 2014
DOI: 10.1039/c4cc04786a
www.rsc.org/chemcomm
A new procedure for the stereoselective synthesis of syn a-amino b-oxy
ketones is reported. It consists of two steps; in the first step, a-amino silyl
enol ethers having a (Z) geometry are prepared from 1-alkynes via
1-sulfonyl-1,2,3-triazoles. In the second step, the silyl enol ethers
undergo the TiCl4-mediated Mukaiyama aldol reaction with aldehydes
to produce a-amino b-oxy ketones with excellent syn-selectivity.
Fig. 1 Construction of syn a-amino b-siloxy ketones starting from term-
inal alkynes and tosyl azide.
b-Hydroxy carbonyl units are contained in the structures of many
natural as well as synthetic target molecules. The directed cross-aldol
reaction presents a powerful method for the synthesis of such
oxygenated units, and the Mukaiyama aldol reaction using silyl enol
ethers (silyl enolates)1 is one of the most utilized protocols. Silyl
enol ethers are usually prepared from the corresponding carbonyl
compounds by a-deprotonation using a stoichiometric amount of a
base such as lithium diisopropylamide (LDA) and triethylamine.
Whereas this carbonyl-based method is useful and practical, an
alternative method starting from non-carbonyl precursors2 would
significantly expand the scope of the Mukaiyama aldol chemistry.
Furthermore, such methods that would allow the presence of other
functional groups are highly desired. We report herein a new
sequential procedure starting from 1-alkynes ultimately leading to
syn a-amino b-oxy carbonyl compounds,3 which are substructures
often found in various bioactive compounds (Fig. 1).4 The procedure
consists of two steps; in the first step, a-amino silyl enol ethers
having a (Z) geometry are prepared stereoselectively from 1-alkynes
under almost neutral conditions via 1-sulfonyl-1,2,3-triazoles.5 In the
second step, the obtained silyl enol ethers are subjected to the TiCl4-
mediated Mukaiyama aldol reaction with aldehydes to produce syn
a-amino b-oxy carbonyl compounds stereoselectively.
Initially, a mixture of phenylethyne (1a, 1.0 equiv.), tosyl azide (2a,
1.0 equiv.) and copper(I) thiophene-2-carboxylate (10 mol%, CuTC) in
chloroform was stirred at room temperature for 6 h to form 4-phenyl-
1-tosyl-1,2,3-triazole (3a).6 Then, tert-butyldimethylsilanol [4 (Si-OH),
1.5 equiv.],7 Rh2(OCOC7H15)4 (1.0 mol%), and 4 Å molecular sieves
(4 A MS) were added to the same reaction vessel, which was heated at
100 1C under microwave irradiation for 15 min. a-Amino silyl enol
ether 5a was isolated in 76% yield (eqn (1)). Notably, the (Z)-isomer of
5a was exclusively obtained within the detection limit of 1H NMR.
Next, the obtained silyl enol ether 5a was treated with 4-chrolo-
benzaldehyde 6a (1.1 equiv.) in the presence of TiCl4 (1.1 equiv.) in
dichloromethane at ꢀ78 1C for 13 h. An aqueous workup followed by
chromatographic isolation afforded a-amino b-siloxy ketone 7aa in 88%
yield with excellent syn-selectivity (495 : 5).8 Thus, sequential combi-
nation of the two reactions, i.e., the preparation of silyl enol ether and
the ensuing Mukaiyama aldol reaction provides a new synthetic path-
way starting from 1-alkynes leading to syn a-amino b-oxy ketones.
(1)
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Katsura, Kyoto 615-8510, Japan. E-mail: tmiura@sbchem.kyoto-u.ac.jp,
murakami@sbchem.kyoto-u.ac.jp; Fax: +81 75 383 2748
† This paper is dedicated to Professor Teruaki Mukaiyama on the occasion of his
88th birthday (Beiju).
‡ Electronic supplementary information (ESI) available: Experimental procedures,
spectral data for the new compounds and details of the X-ray analysis for
compound 7fc. CCDC 1006110. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc04786a
Scheme 1 presents a mechanistic explanation for this pathway.
Initially, a [3+2] cycloaddition reaction of 1a with tosyl azide (2a)
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Table 1 Stereoselective synthesis of a-amino b-siloxy ketones 7 starting
from 1-alkynes 1
Yielda,b
(%)
Entry 1 R1–
5
6
R3–
7
Yieldb,c (%)
1
2
3
4
5
6
7
1b p-Tol–
5b 76
1c p-MeO–C6H4– 5c 66d
1d p-CF3–C6H4– 5d 74e
6b Ph–
6b Ph–
7bb 80
7cb 71
6a p-Cl–C6H4– 7da 51g
1e 3-Thienyl–
5e 69
5f 70
5a 76
5a 76
6b Ph–
7eb 79
1f Ph–f
6c p-Br–C6H4– 7fc 75
6d p-NO2–C6H4– 7ad 71
6e CH3(CH2)5– 7ae 91
Scheme 1 Plausible mechanism for the formation of syn-7aa.
1a Ph–
1a Ph–
occurs at room temperature under Fokin’s conditions.6 The
resulting triazole 3a undergoes a ring-chain tautomerization to
generate a-diazo imine 3a0, which reacts with rhodium(II)
to afford the a-imino carbene complex A.9,10 Nucleophilic
addition of the silanol 4 to the electrophilic carbenoid carbon
of A furnishes the zwitterionic intermediate B.11,12 The anionic
rhodium then releases an electron pair, which induces the
intramolecular abstraction of the O–H proton by the imine
nitrogen to form the (Z)-5a stereoselectively.5
a
b
A 0.40 mmol scale. Using TsN3 2a (Ar = p-Tol-) unless otherwise noted.
c
d
Isolated yield (average of two runs). A 0.20 mmol scale. A small
e
amount of unidentified impurities included. The second step at 120 1C.
f
g
Using p-Br–C6H4–SO2N3 2b (Ar = p-Br–C6H4–). Syn : anti = 87: 13.
Table 2 Rh(II)-catalyzed addition of silanol 4 to various 1-tosyltriazoles 3
In the second step, the Mukaiyama aldol reaction proceeds
through the open transition state C, in which the carbonyl
oxygen of an aldehyde and the a-amino nitrogen of the silyl enol
ether 5a chelate titanium(IV).13 The transition state C in which
the aryl group of 6a is anti to the a-amino group is favored over
the transition state D in which these two groups are gauche,
probably due to steric reasons. Thus, the (Z) geometry of 5a is
transferred to the syn stereochemistry of the product 7aa.
Other arylethynes 1b–e were subjected to the sequential
reaction using the copper(I) and rhodium(II) catalysts to furnish
the corresponding (Z)-silyl enol ethers 5b–e in isolated yields
ranging from 66% to 76% based on 1 (Table 1, left column). Then,
the (Z)-silyl enol ethers 5b–e were reacted with various aldehydes
(Table 1, right column). The electron-rich silyl enol ether 5c was
Entry
3
R1–
Temp (1C)
5
Yielda,b (%)
1
2
3
4
5
6
7
8
3a
3g
3h
3i
3j
3k
3l
Ph–
100
100
120
120
140
140
140
140
5a
5g
5h
5i
5j
5k
5l
96
98
85
p-Ph–C6H4–
p-EtO2C–C6H4–
p-MeC(O)–C6H4–
o-Tol–
87
75c
nPr–
71c,d
65c,d
67c,d
iBu–
3m
BzO(CH2)4–
5m
a
c
A 0.20 mmol scale. b Isolated yield (average of two runs). Rh2(OCO1-Ad)4
d
(2.5 mol%), 4 (6.0 equiv.), neat. NMR yield using an internal standard
(average of two runs).
more reactive than the electron-deficient one 5d in the Mukaiyama modified conditions using 2.5 mol% of Rh2(OCO1-Ad)4 (ref. 14)
aldol reaction (entries 2 and 3). Of note was that not only aryl and no solvent were suitable for alkyl-substituted substrates
aldehydes 6a–d but also alkyl aldehyde 6e exhibited excellent syn- (3k–m), suppressing 1,2-hydride migration15 potentially occurring
selectivity (495:5) as well as chemical yield (entry 7).
with the rhodium carbene complex (entries 6–8).16,17 Of particular
With the sequential procedure in hand, we focused on the note was that only (Z)-isomers of 5 were formed within the
1
reaction of triazoles with silanols in order to delineate their detailed detection limit of H NMR in all cases.
scope. Thus, various isolated 1-tosyl-1,2,3-triazoles 3 were subjected
As for the sulfonyl substituent, not only aryl groups but alkyl
to the reaction with silanol 4 (Table 2). The 4-aryltriazoles were groups such as methyl, benzyl and 2-(trimethylsilyl)ethyl groups
all competent substrates for the reaction in CHCl3, and the were all competent (Table 3, entries 1–4). Even a 2-(1,3-dioxan-2-yl)-
corresponding a-amino silyl enol ethers (5a, 5g–j) were isolated ethyl substituent, an acid-labile N-protective group, was also
in good to excellent yields (entries 1–5). The carbonyl groups suitable (entry 5).18
remained intact, being suggestive of the relatively low basicity
For comparison, we attempted to prepare a-amino silyl
of the reaction conditions. A sterically hindered ortho-tolyl enol ethers using the conventional preparative method based
group was also eligible as the 4-substituent. On the other hand, on a-deprotonation under basic conditions.19 For example,
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Table 3 Sulfonyl substituent of 4-phenyltriazoles 3
(c) S. Kanemasa, T. Mori, E. Wada and A. Tatsukawa, Tetrahedron
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(e) M. Sawamura, Y. Nakayama, T. Kato and Y. Ito, J. Org. Chem., 1995,
´
´
´
´
60, 1727; ( f ) T. Patonay, E. Juhasz-Toth and A. Benyei, Eur. J. Org.
Chem., 2002, 285; (g) I. B. Seiple, J. A. M. Mercer, R. J. Sussman,
Z. Zhang and A. G. Myers, Angew. Chem., Int. Ed., 2014, 53, 4642.
For a method using oxazole-carbonyl photocycloaddition, see: (h) A. G.
Griesbeck, M. Fiege and J. Lex, Chem. Commun., 2000, 589.
4 (a) Y. Hayashi, M. Shoji, S. Yamaguchi, T. Mukaiyama, J. Yamaguchi,
H. Kakeya and H. Osada, Org. Lett., 2003, 5, 2287; (b) F. Berhal,
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G. Tsujiuchi, M. Ohyama, S. Gomi, K. Shito and T. Murata, Bioorg.
Med. Chem. Lett., 2009, 19, 1457.
Entry
3
R2–
5
Yielda,b (%)
1
2
3
4
3n
3o
3p
3q
p-MeO–C6H4–
Me–
PhCH2–
5n
5o
5p
5q
96
85c
82
Me3SiCH2CH2–
94
5
3r
5r
92
5 For a reaction of triazoles with Ph3SiOH, see: S. Chuprakov,
B. T. Worrell, N. Selander, R. K. Sit and V. V. Fokin, J. Am. Chem.
Soc., 2014, 136, 195, the resulting triphenylsilyl enol ethers, how-
ever, were considerably less reactive than t-butyldimethylsilyl enol
ethers. We attempted the Mukaiyama aldol reaction of triphenylsilyl
enol ethers under the identical conditions using TiCl4 only
to recover the starting materials in addition to the corresponding
a-amino ketone formed by hydrolysis.
a
b
c
A 0.20 mmol scale. Isolated yield (average of two runs). 120 1C.
the a-amino ketone (2-tosylamino-1-phenylethanone) was treated
with LDA (2.7 equiv.) and subsequently with tert-butyldimethyl-
silyl chloride (1.7 equiv.) at ꢀ78 1C.20 However, only an intractably
complex mixture was formed, indicating the poor accessibility
of a-amino silyl enol ethers from a-amino ketones. Thus, the
present reaction provides an alternative useful preparative
method starting from 1-alkynes.
In summary, we have developed a new method for the
stereoselective synthesis of syn a-amino b-siloxy ketones starting
from 1-alkynes based upon the Mukaiyama aldol reaction of
(Z)-a-amino silyl enol ethers, which are difficult to prepare from
the corresponding carbonyl compounds.
We thank Dr Y. Nagata (Kyoto University) for his kind help in
an X-ray analysis. This work was supported by MEXT (Grant-in-
Aid for Scientific Research on Innovative Areas Nos. 22105005
and 24106718, Young Scientists (A) No. 23685019, Scientific
Research (B) No. 23350041) and JST (ACT-C).
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7 Other silanols such as Me3SiOH, Et3SiOH, tBuPh2SiOH, and Me2Ph-
SiOH gave inferior results.
8 The syn stereochemistry of 7fc was determined by a single-crystal
X-ray analysis. Those of other products 7aa and 7ae were determined
by NMR. See the ESI‡ for details.
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16 Alkyl-substituted silyl enol ethers were labile enough to be partially
hydrolyzed during chromatographic isolation. The difficulty in isolation
resulting a-amino silyl enol ether during the subsequent Mukaiyama-
aldol reaction.
in a pure form made it hardly possible to apply them to the aldol reaction. 18 I. Sakamoto, N. Izumi, T. Yamada and T. Tsunoda, Org. Lett., 2006,
17 An attempted one-pot sequential reaction of an alkyl-substituted 8, 71.
triazole gave a simple hydrolyzed a-amino ketone as the major 19 M. E. Garst, J. N. Bonfiglio, D. A. Grudoski and J. Marks, J. Org.
product with the desired aldol product formed in low yield. The Chem., 1980, 45, 2307.
silanol 4 remaining after the first reaction caused hydrolysis of the 20 See the ESI‡ for experimental details.
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