Green and Catalytic Synthesis of Dominicalure I, Major Component of the Aggregation Pheromone of Rhyzopertha dominica (Fabricius) (Coleoptera: Bostrichidae)

Abstract A new concise and efficient catalytic synthesis of dominicalure I, the male-produced aggregation pheromone of the grain borer Rhyzopertha dominica, is herein reported. The synthetic route was designed starting from easily available propanal through an organocatalytic key step and completed with biocatalytic procedures. GRAPHICAL ABSTRACT


INTRODUCTION
The lesser grain borer Rhyzopertha dominica (Fabricius) (Coleoptera: Bostrichidae) is a worldwide pest of stored grains. Together with Sitophilus spp., they constitute the major stored-grain pests, and R. dominica must be regarded as a primary pest because of its ability to disperse by flight and high resistance to pesticides. [1] Both larvae and adults cause significant damage in whole grains. The use of insect pheromones for pest monitoring is a valuable tool for the development of integrated pest-management programs, with the aim of reducing the use of pesticides. [2] The male-produced aggregation pheromone of this beetle was isolated and identified as a mixture of (S)-(þ)-1-methylbutyl (E)-2-methyl-2-pentenoate and (S)-(þ)-1-methylbutyl (E)-2,4-dimethyl-2-pentenoate, dominicalure I and II respectively (Fig. 1), [3] attracting both males and females. [1] Both components of the pheromone were synthesized through different synthetic approaches, but to date, all of them involve either long synthetic sequences or expensive reagents, making them inadequate for monitoring or control purposes. The first synthesis of this pheromone was described by Williams et al. using (S)-2pentanol, obtained from D-glutamic acid, as source of chirality. [3] Almost a decade later, Liu and Lin reported the synthesis of dominicalure I and II with 30% overall yield and 90% enantiomeric excess, employing a modification of Sharpless asymmetric epoxidation as the key step to introduce the adequate chirality. [4] A stereoselective synthesis of dominicalure II was also described using 1-silyl-1-stannylethenes as key intermediates. [5] Razkin et al. reported the stereoselective synthesis of both components of the pheromone, through an asymmetric reduction of 3-penten-2-one to the corresponding (S)-3-penten-2-ol with (S)-BINAL-H as chiral auxiliary and further diimide-mediated reduction of the double bond. [6] Das and coworkers later reported an efficient synthetic route exploiting the potential of Baylis-Hillman adducts for furnishing trisubstituted C¼C bonds with (E)-configuration, as key intermediates. [7,8] Enzyme-mediated introduction of the proper chirality in dominicalure I and II was only described by Morgan et al., with the porcine pancreatic lipase (PPL)-mediated kinetic resolution of racemic (E)-3-penten-2-ol using trifluoromethyl laurate as acyl donor. [9] After 45 h, the reaction achieved 39% conversion and an enantiomeric ratio of 45. The unreacted material was then subjected to a second resolution followed by further hydrogenation of the remaining alcohol, yielding (S)-2-pentanol with high enantiomeric purity.
It is worth noting that there are no recent reports regarding the preparation of either components of the aggregation pheromone of R. dominica. This fact gives this contribution an additional impact, because it not only gives a concise, efficient, and environmentally responsible synthetic approach but also is an update in the field of pheromone chemistry.
Although pheromone chemistry has been widely developed during recent decades, stereoselective syntheses are still challenging tasks for classical organic chemistry. [10] As part of our ongoing program devoted to the synthesis of insect pheromones for developing monitoring programs for agricultural pests, [11][12][13] we attempt to introduce catalytic methodologies (both bio-and organocatalytic ones) in our designed synthetic routes, as a strategy to achieve efficient, economical, and environmentally benign procedures. The use of small organic molecules as catalysts for the preparation of chiral synthons was described for the first time by Eder and Hajos. [14,15] Nevertheless, it was not until the decade of 2000, with the outstanding contribution of List, Lerner, and Barbas III, [16] that the high potential of this methodology was rediscovered and originated an intense study of its synthetic possibilities.
Here we report a strategy that combines both bio-and organocatalytic approaches for the synthesis of dominicalure I, component of the aggregation pheromone of R. dominica as a single isomer. A similar procedure is currently being developed for the preparation of dominicalure II.

RESULTS AND DISCUSSION
A retrosynthetic analysis of dominicalure I shows that it can be obtained through an esterification reaction of the corresponding a,b-unsaturated carboxylic acid with (S)-2-pentanol or transesterification of its derivative. The carboxylic moiety can be prepared by performing pyrrolidine-catalyzed self-aldol condensation of propanal and further oxidation, whereas (S)-2-pentanol comes from the enzymecatalyzed kinetic resolution of the corresponding racemic mixture (Scheme 1).
The first step in the synthetic sequence was the pyrrolidine-catalyzed self-aldol condensation of propanal. The reaction was conducted in hexane at room temperature and it was completed after 48 h. After addition of a solution of 10% HCl the organic solvent was distilled under atmospheric pressure, as well as the resulting a,b-unsaturated aldehyde 2 [17] (Scheme 2). The reaction was highly stereoselective, giving trans-2 as a single stereoisomer. It is worth to notice that herein we improved the efficiency of the reaction, also contributing to a greener synthetic approach, compared to previous report by Ishikawa and Saito, [18] because we conducted it at room temperature with less than 10% of the catalyst, obtaining aldehyde 2 with a better yield. The next step is the oxidative esterification of 2. The oxidation of the unsaturated aldehyde is not an easy task, given its instability. Looking for mild conditions, an easy protocol developed by Corey was found, which, besides being adequate for the oxidation of labile a,b-unsaturated aldehydes, leads directly to an ester group. [19] This method is suitable to conjugated aldehydes and effectively suppresses the isomerization of the double bond. [20] The reaction involves the attack of a cyanide ion to the . Secondary alcohols are not adequate nucleophiles for this reaction, [21] so the ester of (S)-2-pentanol could not be obtained directly. The corresponding methyl ester 3 [17] was successfully obtained in 80% isolated yield. A final treatment with (S)-2-pentanol is needed to obtain the pheromone component.
Enantiomerically pure (S)-2-pentanol was obtained through the enzymecatalyzed kinetic resolution of racemic 2-pentanol using lipase B from Candida antarctica (CaL B, Novozym 435) and vinyl butyrate as acylating agent. The reaction was performed in the absence of solvent, with orbital shaking (150 rpm) and at 37°C (Scheme 3). After 15 min, the reaction yielded the unreacted (S)-2-pentanol (49%,>99% ee, ½a 25 D ¼ þ13:5 [c ¼ 0.5 g=100 ml, CHCl 3 ]) and the corresponding (R)-butylester (48%, 98% ee) in agreement with Kaszlauskas's rule, [22] which were successfully separated by column chromatography. The same reaction was also carried out under microwave heating at 50°C using a previously described protocol, [23] and (S)-2-pentanol and the corresponding (R)-butylester were obtained in 5 min with the same yields and enantiomeric purities (Scheme 4). The reactions were monitored by chiral gas chromatography. Both procedures also fit well with green chemistry principles, [24] being more environmentally responsible than when using organic solvents [25] or ionic liquids. [26] The last step in the synthetic route to dominicalure I was the transesterification of 3 with (S)-2-pentanol. Although it is well known that (S)-secondary alcohols are not the preferred substrates for lipases, the reaction was performed anyway, because of the mildness of this procedure. As expected, using CaL B as catalyst, the reaction rate was very slow, but dominicalure I [4] (½a 25 D ¼ þ13:4 (c ¼ 0.180 g=100 ml, ether) was obtained with 90% yield and >99% ee after 96 h (Scheme 5). The same yield was obtained under microwave irradiation and in solvent-free conditions, [23] but considerably less time was needed, obtaining dominicalure I in 4 h.   In summary, the synthesis of dominicalure I was achieved through a concise three-step sequence, with overall yield of 68% and >99% ee starting from inexpensive materials.

Materials and Methods
Solvents were purified and dried by conventional methods. Commercial reagents were purchased from Sigma-Aldrich Inc. Lipase Novozym 435 (lipase B from C. antarctica, CaL B) was obtained from Novozymes. The purity of the reactants, as well as the development of the reactions, were controlled using analytical thin-layer chromatography (TLC) on silica gel (Kieselgel HF 254 from Macherey-Nagel) and visualized with ultraviolet light (254 nm) and=or p-anisaldehyde in acidic ethanolic solution. Flash chromatography was performed using silica gel (Kieselgel 60, EM reagent, 230-400 mesh).

FUNDING
Financial support for this work from ANII (Agencia Nacional de Investigación e Innovación) and PEDECIBA (Programa de Desarrollo de las Ciencias Básicas) is gratefully acknowledged. The authors also thank Novozymes for the generous gift of Novozym 435.

SUPPORTING INFORMATION
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