Highly diastereoselective additions of methoxyallene and acetylenes to chiral α-keto amides

Article abstract of DOI:10.1039/b100355k

α-Keto amides bearing (S)-indoline chiral auxiliaries reacted with lithiated methoxyallene or lithium acetylides to produce the corresponding dihydrofuranones 7 through formation of the tertiary α-hydroxy allenes, or tertiary α-hydroxy acetylenes, respect

Full text of DOI:10.1039/b100355k

Highly diastereoselective additions of methoxyallene and acetylenes to
chiral a-keto amides†
So Won Youn, Yong Hae Kim,* Jeong-Wook Hwang and Youngkyu Do*
Center for Molecular Design & Synthesis, School of Molecular Science, Department of Chemistry, Korea
Advanced Institute of Science and Technology, Taejon, 305-701, Korea. E-mail: kimyh@mail.kaist.ac.kr
Received (in Cambridge, UK) 9th January 2001, Accepted 24th April 2001
First published as an Advance Article on the web 15th May 2001
a-Keto amides bearing (S)-indoline chiral auxiliaries reacted
with lithiated methoxyallene or lithium acetylides to pro-
duce the corresponding dihydrofuranones 7 through forma-
tion of the tertiary a-hydroxy allenes, or tertiary a-hydroxy
acetylenes, respectively, at 278 °C with high diastereo-
selectivities (up to > 99% de).
tion gave the crude residue, which was purified by column
chromatography on SiO2 to give dihydrofuran derivatives 6
which were treated with 5% HCl and extracted with diethyl
ether and EtOAc at pH 11. The combined organic layers were
dried over MgSO4 and concentrated to give dihydrofuranones 7.
The results obtained are summarized in Table 2.
Table 1 Diastereoselective additions of lithiated methoxyallene 2 and
lithium acetylides 3 to chiral a-keto amides 1
A number of diastereoselective nucleophilic additions of
organometallic reagents to a-keto amides1 bearing appropriate
chiral auxiliaries have been reported as useful methods for the
synthesis of optically active tertiary a-hydroxy acid derivatives,
which are valuable for the asymmetric syntheses of medicinal
agents and natural products.2 Creating a tertiary alcohol center
in which the stereochemistry can be controlled by a defined
chiral environment in the addition of organometallic reagents to
ketones still represents a significant challenge.3
Lithiated methoxyallene4–6 is a promising nucleophile be-
cause the products produced by its addition to carbonyl
compounds7–8 can be converted into a variety of interesting
compounds such as enones9 or dihydrofuran derivatives.10 In
particular chiral propargylic alcohols11 are useful intermediates
in the synthesis of natural products.2,12 Although a number of
stereoselective additions of acetylides to aldehydes11a–c have
been reported, asymmetric addition of acetylides to ketones to
produce chiral tertiary alcohols is little known.11d,e A highly
enantioselective addition of cyclopropanylacetylide to aryltri-
fluoromethyl ketone as a special substrate has been reported as
the first example.11d,e However, a general method to prepare
chiral tertiary a-hydroxy acetylenes has not yet been re-
ported.
Recently, we reported that chiral a-keto amides derived from
(S)-indoline-2-carboxylic acid resulted in high stereoselectivity
in stereocontrolled additions of organometallics1b and allyla-
tion.1c On the supposition that these chiral a-keto amides might
be good chiral auxiliaries, we examined the diastereoselective
additions of lithiated methoxyallene 2 and lithium acetylides 3
to various chiral a-keto amides 1.
Run Substrate R
RA
RB
Product Yield (%)a drb
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1a
1b
1d
Me
Et
n-Hex Me
Ph
Me
Ph
Me
Et
Ph
Me
Me
—
—
—
—
4a
4b
4c
4d
4e
4f
42
54
45
56
32
33
71
91
53
62
72
88
66
99+1
94+6
98+2
96+4
80+20
83+17
98+2
94+6
95+5
99+1
99+1
99+1
> 99+1
Me
SiMe2Bu-t —
SiMe2Bu-t —
Me
Me
Me
Ph
Ph
Ph
5a
5b
5c
5d
10 1e
11 1a
12 1a
13 1a
Me
Me
Me
Me
SiMe2Bu-t Ph
Me
Me
Me
CH2OMe 5e
n-Bu
SiMe3
5f
5gc
a Isolated yields. b Determined by HPLC (Daicel chiral OD column). c RB =
H+SiMe3 was removed.
Table 2 Transformation of crude products 4 to dihydrofuran derivatives 6
and 3(2H)-dihydrofuranones 7
The lithiated methoxyallene 2 was generated by treatment of
methoxyallene (2.5 eq.) with n-BuLi (2.0 eq.) in THF at 278 °C
for 30 min.7b Lithium acetylide 3 was prepared by addition of n-
BuLi (1.5 eq.) to a solution of acetylene (1.7 eq.) in THF at 0 °C,
followed by cooling to 278 °C after 30 min.11a Lithiated
methoxyallene or lithium acetylide was reacted with a-keto
amides at 278 °C in THF. Since the allene adducts 4 are
generally labile7b,c so giving low yields (Table 1), the crude
product 4 was reacted to obtain 6 without purification. Two
equivalents of 2 were added to 1 at 278 °C in THF. The reaction
mixture was stirred for 10 min at 278 °C and then quenched
with distilled water. Extraction with CH2Cl2, drying over
MgSO4, and concentration gave crude product 4, which was
treated with a solution of t-BuOK (0.5 eq.) in DMSO at 50 °C.
The reaction mixture was stirred for 1 h and then quenched with
H2O. Extraction with Et2O, drying over MgSO4, and concentra-
6
7
Run
R
Yield (%)a,b drc
Yield (%)a
drc
1
2
3
4
Me (1a)
Et (1b)
n-Hex (1c)
Ph (1d)
33 (6a)
41 (6b)
35 (6c)
44 (6d)
> 99+1
80 (7a)
76 (7b)
75 (7c)
78 (7d)
> 99+1
> 99+1
> 99+1
> 99+1
> 99+1
> 99+1
> 99+1
† Electronic supplementary information (ESI) available: synthesis and
spectroscopic data for 4b, 5g, 6b and 7b. See http://www.rsc.org/suppdata/
cc/b1/b100355k/
a Isolated yields. b Overall yields from 1. c Determined by 1H NMR.
996
Chem. Commun., 2001, 996–997
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b100355k

Scheme 2
intermediates, chiral tertiary a-hydroxy acid derivatives with
high diastereoselectivities.
Notes and references
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Kim, I. S. Byun and J. Y. Choi, Tetrahedron: Asymmetry, 1995, 6, 1025;
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2 (a) S. Hanessian, Total Synthesis of Natural Products: The Chiron
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McPherson and F. F. Knapp, J. Org. Chem., 1996, 61, 8335; (c) Y.
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A. V. R. Rao, J. S. Yadav and M. Valluri, Tetrahedron Lett., 1994, 35,
3613; (e) W. L. White, K. L. Ricciardelli and M. K. Chaguturu, US Pat.,
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3 T. Akiyama, K. Ishikawa and S. Ozaki, Synlett, 1994, 275; D. A. Evans,
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5 S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim. Pays-Bas, 1968,
87, 916.
6 For recent reviews of the chemistry of alkoxyallenes, see: R. Zimmer,
Synthesis, 1993, 165; P. v. R. Schleyer, C. Lambert and E. U.
Würthwein, J. Org. Chem., 1993, 58, 6377.
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S. W. Goldstein, L. E. Overman and M. H. Rabinowitz, J. Org. Chem.,
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59, 67; (d) W. Schade and H.-U. Reissig, Synlett, 1999, 632.
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Fig. 1 X-Ray structure of 5g.
The purified products 4, 5 and 6 were identified by H, 13C
NMR,7b–d IR and MS. The ratios of diastereomers were
determined by HPLC using a chiral OD column. The absolute
configuration of 5g was determined by comparison of the
1
25
specific rotation of 8 ([a]D 240.2°, c = 1.7, acetone) with the
literature value13 ([a]D 241.0°, c = 10, acetone) and its
24
structure determined by X-ray analysis (Fig. 1).14 The ratios of
diastereomers were unaltered during the process. Compound 8
has been found in plant growth regulators2e and highly
enantiomeric excess synthesis of 8 has not been reported
previously.
Enol ethers of 2,5-dihydrofuran derivatives 6 were readily
hydrolyzed by HCl solution (H2O+1,4-dioxane = 10+1) to
provide the corresponding 3(2H)-dihydrofuranones 7 in good
yields (75–80%), which are interesting intermediates as ana-
logues of muscarone.15b Their structural element appears in
other biologically active compounds15 and their transformation
to certain deoxy sugar derivatives can be performed. The
indoline a-keto amides have a great advantage in terms of
cleavage of the amide bond to give chiral products and recover
the indoline chiral auxiliary.1b,c,16 The cleavage of the amide
bond of indoline amides is much easier than that of alkyl amides
such as proline amides. For instance, the chiral products 5g or
7b were readily hydrolyzed with 5% HCl in 1,4-dioxane under
reflux for 3 h to give the corresponding 2-hydroxy-2-methylbut-
3-ynoic acid 8 or 2-ethyl-3(2H)-dihydrofuranone-2-carboxylic
acid 9 in 94–98% yields, respectively, as shown in Scheme 1.
The chiral auxiliary was recovered in 95–98% yield without
loss of optical purity. Earlier work11d,e on asymmetric addition
of acetylide to a ketone (not a chiral auxiliary) gave one chiral
tertiary alcohol from a specific ketone leading to one com-
pound. Our method, however, provides a general methodology
to produce chiral tertiary a-hydroxy carboxylic acid acet-
ylenes.
9 S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim. Pays-Bas, 1968,
87, 1179.
10 S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim. Pays-Bas, 1969,
88, 609.
11 (a) T. Mukaiyama and K. Suzuki, Chem. Lett., 1980, 255; (b) G. M. R.
Tombo, E. Didier and B. Loubinoux, Synlett, 1990, 547; (c) E. J. Corey
and K. A. Cimprich, J. Am. Chem. Soc., 1994, 116, 3151; (d) A. S.
Thompson, E. G. Corley, M. F. Huntington and E. J. J. Grabowski,
Tetrahedron Lett., 1995, 36, 8937; (e) L. Tan, C. Chen, R. D. Tillyer, E.
J. J. Grabowski and P. J. Reider, Angew. Chem., Int. Ed., 1999, 38, 711;
(f) D. A. Evans, D. P. Halstead and B. D. Allison, Tetrahedron Lett.,
1999, 40, 4461; (g) Z. Li, V. Upadhyay, A. E. DeCamp, L. Di Michele
and P. J. Reider, Synthesis, 1999, 1453; (h) D. E. Frantz, R. Fässler and
E. M. Carreira, J. Am. Chem. Soc., 2000, 122, 1806.
12 K. C. Nicolaou and S. E. Webber, J. Am. Chem. Soc., 1984, 106, 5734;
E. J. Corey, K. Niimura, Y. Konishi, S. Hashimoto and Y. Hamada,
Tetrahedron Lett., 1986, 27, 2199; W. R. Roush and R. J. Sciotti, J. Am.
Chem. Soc., 1994, 116, 6457; D. Vourloumis, K. D. Kim, J. L. Petersen
and P. A. Magriotis, J. Org. Chem., 1996, 61, 4848.
13 D. Dugat, M. Verny and R. Vessière, Tetrahedron, 1971, 27, 1715.
14 Crystal data for 5g: C15H17NO3: Mr = 259.3, orthorhombic, space
group P212121, a = 10.300(2), b = 10.536(2), c = 25.810(6) Å, V =
2800.9(11) Å3, Z = 8, Dc = 1.230 g cm23, F(000) = 1104, m(Mo-Ka)
= 0.086 mm21, R1 = 0.0333, wR2 = 0.0404 for 2661 reflections (Fo
>
Scheme 1
4s(Fo)). (Note two independent molecules which have the same
configuration are contained in the unit cell of the crystal of 5g.) The
absolute configuration could not be determined (Flack parameter: –0.43
(76)). CCDC 156841. See http://www.rsc.org/suppdata/cc/b1/
b100355k/ for crystallographic data in .cif or other electronic format.
15 (a) J. E. Semple and M. M. Joullié, Heterocycles, 1980, 14, 1825; (b) M.
DeAmici, C. Dallanoce, C. DeMicheli, E. Grana, A. Barbieri, H.
Ladinsky, G. Schiavi and T. Zonta, J. Med. Chem., 1992, 35, 1915.
16 S. M. Kim, I. S. Byun and Y. H. Kim, Angew. Chem., Int. Ed., 2000, 39,
728.
Conversion of the hydroxyalkylated allenes into the a,b-
unsaturated ketones under acidic conditions is also a useful
reaction.9 It is noteworthy that treatment of 4b with 5% HCl
provided enone 10 within 10 min at 25 °C as shown in Scheme
2. The ratio of diastereomers was also unaltered during
hydrolysis. The enone moiety may be an interesting precursor
for Michael-type additions or cycloadditions.17
In summary, it has been demonstrated that the reaction of a-
keto amides derived from (S)-indoline-2-carboxylic acid with
lithiated methoxyallene or lithium acetylide can provide useful
17 For examples: W. Choy, L. A. Reed and S. Masamune, J. Org. Chem.,
1983, 48, 1139.
Chem. Commun., 2001, 996–997
997