C O M M U N I C A T I O N S
Table 2. Ti-Crossed-Claisen Condensation between a 1:1 Mixture
of Methyl Hexanoate and Carboxylic Acids
The Ti-crossed-Claisen condensation of ethyl levulinate (6) with
readily available acid chloride 5 proceeded smoothly to give â-keto
ester 7. The high chemoselectivity should be noted: the reaction
site of 6 was not the R-position of the ketone but that of the ester
(see also Table 1, entry 16), and the ketone function did not require
the protection.18 A one-pot hydrolysis-decarboxylation and an aldol
condensation afforded cis-jasmone (8) in 46% overall yield.
The Ti-crossed-Claisen condensation between both commercially
available methyl 10-undecenate and (R)-citroneric acid afforded
â-keto ester 10, which was converted to ketone 11 by hydrolysis-
decarboxylation. Second-generation ring-closing metathesis of 11,17
followed by catalytic hydrogenation, afforded (R)-muscone (12)
in 53% overall yield. These two syntheses are regarded as simplest
compared with hitherto reported methods.
In conclusion, we developed the Ti-crossed-Claisen condensation
between a 1:1 mixture of esters and acid chlorides or carboxylic
acids. The present method is a new avenue for the synthesis of a
variety of â-keto esters, which will be useful achiral and chiral
synthons. As a notable application, we utilized this method for the
efficient short syntheses of cis-jasmone and (R)-muscone.
Supporting Information Available: Experimental details, analyti-
cal data, and characterization for reactions in Tables 1 and 2 (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
1
a Isolated. b Determined by H NMR of the crude product. c Using the
2-benzloxy propanoic acid (97% ee), we obtained the desired â-keto ester
(93% ee; see ESI).
References
Various functionalities in both esters and acid chlorides were
tolerated during the Ti-crossed-Claisen condensation.
(1) Smith, M. B.; March, J. AdVanced Organic Chemistry; Wiley: New York,
2001; p 569.
(2) (a) Tanabe, Y. Bull. Chem. Soc. Jpn. 1988, 62, 1917. (b) Tanabe, Y.;
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56, 7423. (b) Tanabe, Y.; Makita, A.; Funakoshi, S.; Hamasaki, R.;
Kawakusu, T. AdV. Synth. Catal. 2002, 344, 507.
As a notable extension, we investigated the Ti-crossed-Claisen
condensation using carboxylic acids. We designed a novel protocol
utilizing mixed anhydrides 3 generated in situ between sodium
carboxylates and Cl3CC(dO)Cl. (Table 2) (for screening of the acyl
chloride co-reagents, see Supporting Information). Thus, the
plausible reactive intermediate 4 successfully reacted with methyl
hexanoate to give the desired cross-condensed â-keto esters with
good to excellent yield and selectivity.
Finally, to demonstrate the utility of the present Ti-crossed-
Claisen condensation, we performed the efficient short-step syn-
theses of two natural, representative, and useful perfumes, cis-
jasmone (8)16 and (R)-muscone (12)17 (Scheme 2). Synthesis of
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Scheme 2. Application to the Syntheses of Natural Perfumes,
cis-Jasmone and (R)-Musconea
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the more unhindered and reactive imidazole 1 matched the present reaction.
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a Conditions: (a) 1c, TiCl4-iPr2NEt, CH2Cl2 (61%). (b) 5 M aq KOH,
EtOH, then 1 M aq HCl (76%). (c) 1b, TiCl4-Bu3N, CH2Cl2 (76%). (d) 5
M aq NaOH, MeOH, then 6 M aq HCl (95%). (e) Grubbs catalyst second
generation, ClCH2CH2Cl, then Pd-C, H2, AcOEt (74%).
(17) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123,
11312.
(18) The use of Bu3N caused an undesirable condensation between methyl
ketone of 6 with 5 in ∼10-20%. See also Table 1, entry 16. Bu3N
conducts a powerful crossed aldol additions (ref 7).
these compounds is a standard model for novel reactions due to
their utility and interesting structures.
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