A proline-catalyzed asymmetric Robinson annulation reaction

Article abstract of DOI:10.1016/S0040-4039(00)01180-1

A single-step enantioselective synthesis of the Wieland-Miescher ketone (5) is presented. We show that L-proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson annulation reaction. Other chiral amines are identified as catalysts of Michael and aldol addition reactions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01180-1

Tetrahedron Letters 41 (2000) 6951±6954
A proline-catalyzed asymmetric Robinson annulation reaction
Tommy Bui and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, USA
Received 13 June 2000; revised 29 June 2000; accepted 30 June 2000
Abstract
A single-step enantioselective synthesis of the Wieland±Miescher ketone (5) is presented. We show that
l-proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson
annulation reaction. Other chiral amines are identi®ed as catalysts of Michael and aldol addition reactions.
# 2000 Elsevier Science Ltd. All rights reserved.
Enantiopure Wieland±Miescher (W.M.) ketone (5) has proven to be a particularly useful synthon
for the construction a variety of biologically active compounds including steroids, terpenoids, and
more recently taxol.1 We recently disclosed an antibody aldolase-catalyzed Robinson annulation
reaction of 2-methylcyclohexane-1,3-dione with methyl vinyl ketone in aqueous medium.2 This
one-¯ask annulation provided the W.M. ketone in >95% ee. While the antibody eciently
catalyzed the cyclodehydration step of this reaction with a rate enhancement exceeding 106,
catalysis of the alkylation or Michael addition step was very modest, kcat/kun=125. An intriguing
aspect of this study was that both antibody and the traditional catalysts for W.M. ketone
preparation, l-proline, use an enamine-based reaction mechanism. Provided the success of
antibody catalysis of both steps of the annulation reaction and the reported utility of rubidium
salts of l-proline in asymmetric Michael addition reactions,3 we examined the potential of
l-proline to catalyze the entire annulation reaction. We anticipated that the Michael addition step
could be facilitated by formation of the proline-imine of 1, the enamine of 2, or both. To examine
the general potential of chiral amine catalysis of these reactions, we have also screened a library of
chiral amines using this transformation as the read out.
While routes to enantiopure W.M. ketone continue to be developed,4 the most convenient
synthesis involves modest modi®cations of the procedure ®rst developed in the early 1970s.5 In
the optimized procedure,6 2-methyl-2-(3-oxobutyl)-1,3-cyclohexanedione (3) is prepared by
heating 2-methylcyclohexane-1,3-dione (2) with methyl vinyl ketone (1) in aqueous acetic acid at
75ꢀC for 1 h after which 3 is puri®ed. The cyclodehydration of 3 catalyzed by l-proline is then
performed at 25ꢀC by simple stirring under argon for 120 h. Enantioselection in the cyclization
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01180-1

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step of pro-chiral 3 en route to 5 is in the order of 70% ee. Fractional crystallization then
provides the desired (S)-antipode of 5 with high enantiopurity.
To examine the potential of l-proline to achieve the entire Robinson annulation sequence
(1+2!5), a variety of reaction conditions were explored that involved changes in the molar ratios
of 1 and 2, solvent, and temperature. These studies yielded a single-step annulation that provided
5 in 49% yield and 76% ee in 89 h.7 Thus, like the mechanistically similar catalytic antibody,
proline can also catalyze the entire annulation sequence providing the W.M. ketone more rapidly
and with an overall yield and enantiomeric purity similar to that of the two-step reaction
sequence (Scheme 1).
Scheme 1.
We then studied the potential of other commercially available proline-like derivatives for their
ability to catalyze this reaction sequence.8 Compounds 7±10 demonstrated an activity similar to
proline in the transformation (1+2!5). Compounds 7±9 provided 5 with ee's ranging from 60 to
75%, while 10 provided the product with considerably lower optical purity, <10% ee. Several
other amino acids containing primary amines were not catalysts of this transformation.
To further examine the potential for amine catalysis of this reaction sequence, we screened 16
additional commercially available chiral amines.8 Of these compounds only those bearing a cyclic
secondary amine demonstrated reactivity in this screen and these catalysts could be placed into
two classes. The ®rst class of catalysts consists of compounds 11±14. These compounds were
shown to catalyze the Michael addition reaction of (1+2!3). In these reactions products 4 and 5
were not detected.

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The second class of catalysts consists of compounds 15±18. These compounds were shown to
catalyze the transformation (1+2!3+4) but not the dehydration of 4 to 5. In independent assays,
these catalysts were active in the transformation of 3 to 4, where again formation of 5 was not
observed.9 Examination of the structure/activity relationships of the catalysts reported here,
suggests that chiral compounds containing a secondary amine of the pyrrolidine-type and a
carboxylate functionality are the most ecient catalysts of this asymmetric annulation reaction.
The carboxylic acid functionality appears to be key to the dehydration step, at least when the
reactions are performed at ambient temperatures.
In summary, chiral secondary amines, particularly pyrrolidine-like molecules are catalysts of
Michael and aldol reactions.10 We believe the potential of molecules such as these to act as
asymmetric organic catalysts has not been suciently exploited. Our proline-catalyzed direct
asymmetric aldol reaction,11 MacMillan's amine-catalyzed asymmetric Diels±Alder reaction,12
and the Robinson annulation reaction reported here are recent examples of asymmetric amine
catalysis facilitated by imine and enamine type reaction mechanisms. These results underscore an
interplay between mechanistic enzymology and asymmetric organic catalysis that may enable the
creation of diverse and ecient organocatalysts for a wide variety of reactions.13
Acknowledgements
This study was supported by the NIH (CA27489) and The Skaggs Institute for Chemical
Biology.
References
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J. Org. Chem. 2000, 65, 129±135; (d) Smith III, A. B.; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka,
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2081±2084; (g) Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung,
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2. Zhong, G.; Ho€mann, T.; Lerner, R. A.; Danishefsky, S.; Barbas III, C. F. J. Am. Chem. Soc. 1997, 119, 8131±
8132. For additional studies that compare antibody and proline-catalyzed enantiogroup di€erentiating
cyclodehydrations see: List, B.; Lerner, R. A.; Barbas III, C. F. Org. Ltrs. 1999, 1, 59±61.
3. Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520±3530.
4. Fuhshuku, K.-I.; Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi, H.; Ohba, S.; Sugai, T. J. Org. Chem. 2000, 65, 129±
135.
5. (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496497; (b) Hajos, Z. G.; Parrish,
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7. A solution of l-proline (0.32 g, 2.8 mmol) and 2-methyl-1,3-cyclohexadione (1 g, 7.9 mmol) in 50 mL of
anhydrous DMSO was stirred under argon at 35ꢀC until the ketone and proline were completely dissolved. To
this solution freshly distilled methylvinyl ketone was slowly added dropwise (0.99 mL, 11.9 mmol). The reaction
was vigorously stirred at this temperature for 89 h and then quenched with ethyl acetate/saturated ammonium
chloride. The organic layer and aqueous layer were separated with an addition of brine. The aqueous phase was
extracted several times with ethyl acetate, and combined organic extracts were dried over magnesium sulfate,
®ltered, and evaporated in vacuo. Crude product was puri®ed by column chromatography using hexane:ethyl
acetate (3:2, then 1:1) to a€ord the ketone (0.69 g) as a syrup in 49% yield and 76% ee. Optical purity was
determined as previously described.2a Optical yield was maintained in reactions performed up to 35ꢀC and
decreased at higher temperatures.
8. Screening reactions were performed essentially as described above but at ambient temperature using 30 mol%
catalyst. l-a-Methyl-benzylamine and several other amino acids have previously been shown to be catalysts of the
aldol addition and or condensation step, see Refs. 5a and 1a.
9. With catalyst 18, a small amount of 5 was detected.
10. The use of pyrrolidine as a reagent for the conversion of 3 to þ5 was reported many years ago, see:
Ramachandran, S.; Newman, M. S. Org. Synth. 1961, 41, 38.
11. List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395±2396.
12. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243±4244; for addition studies
concerned with organocatalysis see references listed within this report.
13. We have now determined that several of the catalysts reported here can be used to catalyze direct intermolecular
asymmetric aldol and Mannich reactions. The results of these studies will be reported in due course.