Asymmetric Ti-crossed Claisen condensation: Application to concise asymmetric total synthesis of alternaric acid

Article abstract of DOI:10.1039/c3cc43180k

Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-2,5-dione chiral template and its successful application to total synthesis of chiral alternaric acid are described.

Full text of DOI:10.1039/c3cc43180k

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Asymmetric Ti-crossed Claisen condensation:
application to concise asymmetric total synthesis of
alternaric acid†‡
Ryohei Nagase,a Yumiko Oguni,a Satoko Ureshino,a Hiroaki Mura,a
Tomonori Misaki*b and Yoo Tanabe*a
Cite this: Chem. Commun., 2013,
49, 7001
Received 30th April 2013,
Accepted 12th June 2013
DOI: 10.1039/c3cc43180k
www.rsc.org/chemcomm
Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-
2,5-dione chiral template and its successful application to total
synthesis of chiral alternaric acid are described.
The chiral template methodology is a well-recognized strategy for the
synthesis of acyclic and multi-functionalized chiral building blocks.
1
2
´
¨
Seebach–Frater’s (1,3-dioxolan-4-ones), Schoellkopf’s (bis-L-lactim),
Williams’ (morphorin-4-one),3 and Kellogg’s (oxathiolan-4-one)4
chiral template methodologies are representative methods that have
been successfully applied for total synthesis of natural products and
pharmaceuticals.
Scheme 1
The crossed-Claisen ester condensation is a fundamental and
useful C–C bond forming reaction in organic syntheses.5 Ti-crossed
Claisen condensations provide a variety of functionalized b-ketoesters6
and the asymmetric version is a highly anticipated extension. Here we
disclosed the first and efficient asymmetric crossed-Claisen condensa-
tion mediated by the TiCl4–N-methylimidazole (NMI)–amine reagent
to produce less accessible chiral building blocks, a-alkyl-a-hydroxy-b-
Fig. 1 Chiral alternaric acid.
ketoesters 4 (Scheme 1). The present method utilizes chiral templates, (i) Despite the difficulty in Claisen condensation using a,a-disubsti-
3-methyl-3-phenyl-1,4-dioxane-2,5-diones 2, which are readily prepared tuted esters,5 all examples examined afforded successful results. (ii)
by cyclocondensation between commercially available (S)-atrolactic Excellent anti-diastereoselectivity between Ph and R1CO groups was
acid (1) and (ꢀ)-a-haloacid halides in good to excellent yield.7
realized, probably due to a rational template effect, i.e. the Si-face
To demonstrate the utility of the present method, we describe attack of Ti-enolate with an activated acylimidazolium intermediate11
successful concise asymmetric total synthesis of chiral alternaric predominates over Re-face attack, as depicted in Scheme 2. This result
acid (Fig. 1),10 a natural product exhibiting phytotoxic and anti- is consistent with Seebach’s concept for the chiral template.1c
fungal activities.
(iii) Terminal double bond, chloro-, and benzyloxy groups were
Diastereocontrolled Ti-crossed Claisen condensation of 2 with compatible. (iv) Optimization of the conditions revealed that more
R1COCl was successfully performed to obtain various chiral acylated reactive linear acid chlorides used Bu3N as the amine (method A;
precursors 3 in good yield with excellent diastereoselectivity entries 1–10), whereas less reactive a-branched acid chlorides used
(Table 1). The salient features of the present reaction are as follows. sBu2NH (method B; entries 11–14). (v) With regard to the NMI
activator, 2-ethyl-N-methylimidazole was superior when linear acid
chlorides were used, whereas N-methylimidazole matched with
3,3-dimethylbutanoyl chloride and a-branched acid chlorides.
This tendency is consistent with the outcome of the Ti-crossed
Claisen condensation between simple esters and acid chlorides.6c
a Department of Chemistry, School of Science and Technology,
Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
E-mail: tanabe@kwansei.ac.jp; Fax: +81-79-565-9077; Tel: +81-79-565-8394
b Graduate School of Material Science, University of Hyogo, 3-2-1, Kohto, Kamigori,
Hyogo 678-1297, Japan
´
(vi) Ti-Claisen condensation using Seebach–Frater’s template, how-
† This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the
40th anniversary of the Mukaiyama aldol reaction.
ever, failed to proceed due to the acid liability of the dioxolane moiety.
Simple and mild methanolysis of 3 using MeONa–MeOH at
0–5 1C gave the desired product 4 in good yield with maintaining
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc43180k
c
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Table 1 Asymmetric Ti-crossed Claisen condensation of chiral template 2 with
acid chloridesa
Entry R1
Substrate R2
R
Product Yieldb/%
1
2
2a
2b
Me
Bu
Et 3a
Et 3b
74
72
Scheme 3
3
4
2a
2b
Me
Bu
Et 3c
Et 3d
76
73
5
6
2a
2b
Me
Bu
H
H
3e
3f
84
83
7
8
2a
2b
Me
Bu
Et 3g
Et 3h
82
79
9
10
2a
2b
Me
Bu
Et 3i
Et 3j
61
61
11
12
2b
2c
Bu
Allyl
H
H
3k
3l
74
58
13
14
15c
2b
2cd
2d
Bu
Allyl
H
H
H
H
3m
3o
3p
72
54
71
a
Method A for entries 1–10 [R1COCl (1.4 equiv.), TiCl4 (2.5 equiv.),
Bu3N (3.0 equiv.), ꢁ50 to ꢁ45 1C]. Method B for entries 11–14 [R1COCl
(3.0 equiv.), TiCl4 (3.5 equiv.), sBu2NH (4.0 equiv.), 0–5 1C, 1 h, 20–25 1C,
b
1 h]. Isolated de was determined after methanolysis of 3 (see Table 2).
c
R1COCl (1.5 equiv.), TiCl4 (2.0 equiv.), iPr2NEt (2.5 equiv.), ꢁ50
d
to ꢁ45 1C. Antipodal (3R)-isomer was used (see Scheme 3).
Scheme 4
Trost pointed out that concise preparation of (2R,3R,4S)-
synthon 6 is a crucial issue for the total synthesis of chiral
alternaric acid (Scheme 4).10 Gratifyingly, anti-stereoselective
reduction of 5 using NaBH4–ZnCl2 gave the desired (3R)-diol 6
with excellent diastereoselectivity (3R : 3S = >97 : 3). This type of
a,b-dihydroxyl ester comprises a useful chiral building block for
the synthesis of various natural products.12
Scheme 2
Ene-type reaction between 6 and t-butyl 5-trimethylsilyl-4-
pentynoate using an efficient CpRu(CH3CN)3+PF6ꢁ catalyst13 pro-
excellent enantiomeric excess and simultaneous recovery of ceeded smoothly to afford the desired regioselective vinylsilane adduct
methyl atrolactate 10 in >80% yield.
7 in 78% yield. Selective Cl3CCO– protection of the secondary hydroxyl
The present asymmetric Ti-Claisen condensation was applied to group in 7 giving 8 (99%), followed by deprotection of both t-Bu and
the expeditious asymmetric total synthesis of chiral alternaric acid,8 TMS groups using CF3CO2H, afforded the core carboxylic acid
a natural product with a unique structural scaffold possessing three segment 9. Regioselective C-acylation of (R)-6-methyldihydro-2H-
contiguous asymmetric centers. The first total and second formal pyran-2,4(3H)-dione (10)9b,14 with 9 was successfully performed in
syntheses were accomplished by Ichihara’s group9 and Trost’s association with the formation of 1,2-carbonate to obtain the pre-
group,10 respectively.
cursor 11 in 72% overall yield from 8. Finally, LiOH-promoted
Key chiral precursor 5 was readily prepared by the methanolysis hydrolysis of methyl ester concurrent with deprotection of 1,2-carbo-
of 3o in 49% yield from 2c (Scheme 3). A stereocomplementary nate in 11 successfully provided chiral alternaric acid in 55% yield.
method involving Tsuji–Trost allylation of 3p gave 3o0, followed by Compared with the previously reported syntheses, the present
methanolysis to produce 5 in slightly better yield (2 steps; 63%). method improved the efficiency and overall yield.
Note that the allylation also proceeded with excellent anti-selectivity
(>95% de) due to an expected template effect.
In conclusion, we have reported the first successful TiCl4-mediated
asymmetric crossed-Claisen condensation. The present method
c
7002 Chem. Commun., 2013, 49, 7001--7003
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Table 2 Preparation of chiral a-alkyl-a-hydroxy-b-ketoesters 4 by methanolysis
of 3a
Colorless oil; 97% ee [HPLC analysis of its phenylhydrazone
derivative (flow rate: 0.50 ml minꢁ1, solvent: hexane–2-propanol =
95 : 5), tR (racemic) = 13.29 min and 15.69 min, tR (4b) = (13.31 min)];
[a]2D3 + 38.2 (c 1.03, CHCl3); 1H NMR (300 MHz, CDCl3) d 0.89 (t, 3H,
J = 6.9 Hz), 0.90 (t, 3H, J = 6.9 Hz), 1.12–1.40 (m, 8H), 1.59 (quint, 2H,
J = 7.2 Hz), 1.90 (ddd, 1H, J = 5.2, 10.7 Hz, Jgem = 14.1 Hz), 2.09
(ddd, 1H, J = 4.8, 11.4 Hz, Jgem = 14.1 Hz), 2.51 (dt, 1H, J = 7.2 Hz,
Jgem = 17.9 Hz), 2.69 (dt, 1H, J = 7.6 Hz, Jgem = 17.9 Hz), 3.79 (s, 3H),
4.04–4.35 (br, 1H); 13C NMR (75 MHz, CDCl3) d 13.84, 22.35, 22.66,
23.15, 25.24, 31.13, 35.14, 36.65, 53.19, 84.21, 171.61, 207.29; IR
(neat) 3484, 2959, 2934, 1721, 1262, 1221 cmꢁ1; HRMS (ESI) calcd for
C13H24O4 (M + Na+) 267.1572, found 267.1579.
Entry Substrate R1
R2
Product Yieldb/% eec/%
1
2
3a
3b
Me 4a
Bu 4b
81
82
96
97d
3
4
3c
3d
Me 4c
Bu 4d
81
82
92
92d
5
6
3e
3f
Me 4e
Bu 4f
89
78
96
93
Notes and references
7
8
3g
3h
Me 4g
Bu 4h
69
69
98
86
´
1 (a) D. Seebach and R. Naef, Helv. Chim. Acta, 1981, 64, 2704; (b) G. Frater,
U. Mu¨ller and W. Gu¨nther, Tetrahedron Lett., 1981, 22, 4221; (c) Review:
D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int. Ed. Engl.,
1996, 35, 2708; (d) A recent example among many applications:
9
10
3i
3j
Me 4i
Bu 4j
88
85
91
92
´
A. Larivee, J. B. Unger, M. Thomas, C. Wirtz, C. Dubost, S. Handa and
a
b
c
ca. 80% of 10 were recovered. Isolated. Determined by HPLC
A. Fu¨rstner, Angew. Chem., Int. Ed., 2011, 50, 304; (e) Facile and robust
preparations: T. Misaki, S. Ureshino, R. Nagase, Y. Oguni and Y. Tanabe,
Org. Process Res. Dev., 2006, 10, 500; ( f ) R. Nagase, Y. Oguni, T. Misaki
and Y. Tanabe, Synthesis, 2006, 3915.
d
analyses of the benzoyl ester derivative unless otherwise noted. Deter-
mined by HPLC analyses of the phenylhydrazone derivatives.
¨
2 (a) U. Schoellkopf, W. Hartwig and U. Groth, Angew. Chem., Int. Ed.
produces less accessible chiral building blocks, a-alkyl-a-hydroxy-b-
ketoesters, utilizing chiral templates, 3-methyl-3-phenyl-1,4-dioxane-
2,5-diones. The present strategy was successfully applied to achieve
concise asymmetric total synthesis of chiral alternaric acid.
Engl., 1979, 91, 922. Recent examples: (b) Y. Chen, Y. Wu,
P. Henklein, X. Li, K. P. Hofmann, K. Nakanishi and O. P. Ernst,
Chem.ꢁEur. J., 2010, 16, 7389; (c) W. Li, W. Ye and S. W. Schneller,
Tetrahedron, 2012, 68, 65.
3 (a) R. M. Williams and M. N. Im, J. Am. Chem. Soc., 1991, 113, 9276;
(b) Recent examples: C. Song, S. Tapaneeyakorn, A. C. Murphy, C. Butts,
A. Watts and C. L. Willis, J. Org. Chem., 2009, 74, 8980; (c) B. Hill,
V. Ahmed, D. Bates and S. D. Taylor, J. Org. Chem., 2006, 71, 8190.
4 (a) B. Strijtveen and R. M. Kellogg, Tetrahedron, 1987, 43, 5039;
(b) R. P. Hof and R. M. Kellogg, J. Chem. Soc., Perkin Trans. 1, 1995,
1247; (c) Y. Tanabe, H. Yamamoto, M. Murakami, K. Yanagi,
Y. Kubota, H. Okumura, Y. Sanemitsu and G. Suzukamo, J. Chem.
Soc., Perkin Trans. 1, 1995, 935.
The typical procedure of Table 1 (entry 2): hexanoyl chloride (94 mg,
0.70 mmol) was added to a stirred solution of (3S)-6-butyl-3-methyl-3-
phenyl-1,4-dioxane-2,5-dione7 (131 mg, 0.50 mmol) and 2-ethyl-1-methy-
limidazole (77 mg, 0.70 mmol) in CH2Cl2 (1.0 ml) at ꢁ50 to ꢁ45 1C
under an Ar atmosphere, followed by stirring at the same temperature
for 10 min. TiCl4 (138 mL, 1.25 mmol) and Bu3N (278 mg, 1.50 mmol)
were successively added to the mixture, which was stirred at the same
temperature for 0.5 h. The mixture was quenched with water, which
was extracted twice with Et2O. The combined organic phase was
washed with water, brine, dried (Na2SO4) and concentrated. The
obtained crude oil was purified by SiO2-column chromatography
(hexane : AcOEt = 30 : 1) to give (3R,6S)-3-butyl-3-hexanoyl-6-methyl-6-
phenyl-1,4-dioxane-2,5-dione (3b; 129 mg, 72%).
5 (a) M. B. Smith and J. March, Advanced Organic Chemistry, Wiley,
New York, 6th edn, 2007, p. 1335 and 1452; (b) L. Ku¨rti and B. Czako,
´
Strategic Applications of Named Reactions in Organic Synthesis, Else-
vier, Burlington, 2005, p. 86 and 138; (c) G. Zhou, D. Lim, F. Fang
and D. M. Coltart, Synthesis, 2009, 3350; (d) Selected recent progress;
Y. Nishimoto, A. Okita, M. Yasuda and A. Baba, Angew. Chem., Int.
Ed., 2011, 50, 8623.
6 (a) Y. Tanabe, Bull. Chem. Soc. Jpn., 1989, 62, 1917; (b) S. N. Crane
and E. J. Corey, Org. Lett., 2001, 3, 1395; (c) T. Misaki, R. Nagase,
K. Matsumoto and Y. Tanabe, J. Am. Chem. Soc., 2005, 127, 2854;
(d) A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misaki and
Y. Tanabe, Org. Lett., 2006, 8, 5215; (e) Related Mannich reaction;
T. Funatomi, S. Nakazawa, K. Matsumoto, R. Nagase and Y. Tanabe,
Chem. Commun., 2008, 771.
7 R. Nagase, Y. Iida, M. Sugi, T. Misaki and Y. Tanabe, Synthesis, 2008, 3670.
8 P. W. Brian, P. J. Curtis, H. G. Hemming, C. H. Unwin and J. M. Wright,
Nature, 1949, 164, 534.
9 (a) H. Tabuchi and A. Ichihara, J. Chem. Soc., Perkin Trans. 1, 1994,
125; (b) H. Tabuchi, T. Hamamoto, S. Miki, T. Tejima and A. Ichihara,
J. Org. Chem., 1994, 59, 4749.
Colorless oil; [a]2D5 + 22.8 (c 1.04, CHCl3); 1H NMR (300 MHz,
CDCl3) d 0.73 (3H, t, J = 6.5 Hz), 0.90 (3H, t, J = 6.9 Hz), 1.04–1.38
(8H, m), 1.57–1.69 (2H, m), 1.72–1.84 (1H, m), 1.89–2.02 (1H,
m), 1.98 (3H, s), 2.56 (1H, dt, J = 7.2 Hz, Jgem = 18.6 Hz), 2.81
(1H, dt, J = 7.2 Hz, Jgem = 18.6 Hz), 7.35–7.53 (5H, m); 13C NMR
(75 MHz, CDCl3) d 13.4, 13.8, 22.2, 22.3, 22.9, 25.1, 28.5, 31.0,
33.9, 37.6, 84.9, 91.0, 124.3, 129.2, 129.3, 139.0, 163.1, 166.1,
200.0; IR (neat) 2959, 2934, 2872, 1761, 1269 cmꢁ1; HRMS (ESI)
calcd for C21H28O5 (M + Na+) 383.1834, found 383.1830.
The typical procedure of Table 2 (entry 2): NaOMe (1.0 M in
MeOH, 0.27 mL, 0.27 mmol) was added to a stirred solution of 3b
(195 mg, 0.54 mmol) in MeOH (1.0 mL) at 0–5 1C under an Ar
10 B. M. Trost, G. D. Probst and A. Schoop, J. Am. Chem. Soc., 1998,
120, 9228.
11 (a) K. Wakasugi, A. Iida, T. Misaki, Y. Nishii and Y. Tanabe, Adv.
Synth. Catal., 2003, 345, 1209; (b) H. Nakatsuji, J. Morita, T. Misaki
and Y. Tanabe, Adv. Synth. Catal., 2006, 348, 2057.
atmosphere, followed by stirring at the same temp. for 2 h. The 12 Asymmetric organocatalysis for preparing a-alkyl-a-hydroxy-b-keto-
esters; T. Misaki, G. Takimoto and T. Sugimura, J. Am. Chem. Soc.,
2010, 132, 6286. This method affords the diastereomeric diol isomer
of 6. The utility of these compounds is cited therein.
mixture was quenched with water (5 mL), which was extracted twice
with ether. The combined organic phase was washed with water,
brine, dried (Na2SO4) and concentrated. The obtained crude oil was 13 (a) B. M. Trost, M. Machacek and M. J. Schnaderbeck, Org. Lett.,
2000, 2, 1761; (b) B. M. Trost, M. U. Frederiksen and M. T. Rudd,
purified by SiO2-column chromatography (hexane–AcOEt = 15 : 1 -
Angew. Chem., Int. Ed., 2005, 44, 6630.
10 : 1) to give the desired (2R)-methyl 2-butyl-2-hydroxy-3-oxooctanoate
14 R. W. Hoffman and S. Dressely, Angew. Chem., Int. Ed. Engl., 1986,
4b (109 mg, 82%) and (S)-methyl atrolactate (10) (91 mg, 93%).
25, 189.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7001--7003 7003