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The 9-azabicyclo[3.3.1]nonane ring system is present in several insect- and plant-derived alkaloids. ( − )-Adaline ( 1 ) and (+)-eupho-coccinine ( 2 ), found in secretions of Coccinelid beetles, and (+)- N -methyleuphococcinine ( 3 ), isolated from the Colorado blue spruce Picea pungens , are members of this alkaloid family. Their unique bicyclic system with a quaternary stereocenter, and the po-tent biological activity exerted by these homotropane alkaloids, make them attractive synthetic targets. This work aims briefly to review the chemical ecology of Adalia bipunctata and the recent methodologies to obtain adaline ( 1 ), euphococcinine ( 2 ), and N -methyleuphococcinine


Introduction
Coccinellid beetles contain a variety of defensive alkaloids that makes them unpleasant for various predators [1]. Over 50 alkaloids have been characterized from ladybirds until now, including perhydroazaphenalenes, aliphatic and aromatic amines, piperidines, pyrrolidines, azamacrolides, dimeric alkaloids and homotropanes [2]. The majority of these alkaloids have an endogenous origin. In a dangerous situation or predator attack, the beetles can emit droplets of hemolymph. This substance comes from the tibiofemoral joints situated in their legs, a mechanism known as reflex bleeding. This situation brings the alkaloids to the surface as an early warning signal to the attacker.
King and Meinwald earlier reviewed some of these syntheses in an elegant approach to coccinellids chemistry and biology [29].
The current work reports a brief description of the chemical ecology of Adalia bipunctata. Then we present an up to date review of the synthetic strategies to obtain alkaloids 1-3, including racemic and asymmetric syntheses, aiming to achieve a deep and comprehensive understanding of the area. It also provides suggestions for future studies on homotropane alkaloids. The present review is chronologically organized, encompassing all synthetic works published in the last 25 years.

Review
Chemical ecology of Adalia bipunctata Individuals of Adalia bipunctata species (2-spot ladybird) display aposematic coloration reinforced by the production and release of remarkable amounts of reflex-fluid, in response to predator attack [29][30][31][32]. This liquid can be over 20% of the body weight, in some cases. The amount of the toxic alkaloid (−)-adaline varies between 5-6% of the wet weight of reflex fluid in 2-spot ladybirds. However, the concentration of (−)-adaline found in A. bipunctata is about 6-8 times greater than the concentration of coccineline found in C. septempunctata [31]. This difference may occur to compensate (−)-adaline's lower toxicity than coccineline. Biosynthetic studies carried out by Laurent et al. [33,34] showed that adults of A. bipunctata incubated in vitro with [14,14,14-3 H 3 ]myristic acid incorporated this precursor in (−)-adaline, supporting fatty acid origin for this alkaloid.
Reflex bleeding is costly due to energy expended in chemical synthesis and fluid loss. Therefore, it is only deployed when other strategies have failed, and the ladybird is in severe danger [35,36]. A massive discrepancy in (−)-adaline concentration and reflex-fluid amount can be found within beetles. It suggests that internal aspects such as genetic factors may determine how much energy is invested in chemical defense [30]. Paul et al. [37] demonstrated that parental effects could play a crucial role in determining the color and toxin [(−)-adaline] content of A. bipunctata eggs, once the maternal and paternal aposematic phenotype had the most significant effect on egg traits if compared to the maternal responses to offspring predators. Thus, the phenotype can also contribute to the aposematic signal variation in a ladybird's early life, in addition to genetic factors. In this way, it should consequently lead to success in the species' survival.
Recent elegant studies by Steele et al. [38,39] provide an insight into the impact of pathogen infection upon production of the alkaloid 1 in A. bipunctata. When A. bipunctata was infected by the microsporidian pathogen Nosema adaliae, larval develop-Scheme 1: Synthetic strategies before 1995. ment was significantly delayed. At elevated temperatures, developmental delays caused by infection were reduced, spore counts and infection decreased, and there was an increase in the content of 1 [38]. In a second study, the authors evaluated the effects of the N. adaliae infection and food availability on production of 1 [39]. Infected A. bipunctata were shown to produce more 1 than uninfected adults. Furthermore, the daily fed adults produced more of 1 than those adults that were fed irregularly, and uninfected adults that fed irregularly had the lowest content of 1. The infection load of adults was significantly increased in beetles that were fed irregularly. Taken together, these results suggest that 1 may provide A. bipunctata with chemical defence against pathogen challenge.

Syntheses
A concise overview of the strategies towards the synthesis of homotropane alkaloids: before 1995 As previously reported by King and Meinwald [29], synthetic strategies have been designed and employed in the synthesis of adaline (1) and euphococcinine (2), before 1995. In brief, 1 and 2 were synthesized in both racemic and asymmetric forms. Key (homotropane construction) steps included: i) inter and intramolecular Mannich reaction; ii) double Michael addition in the cyclooctadienone derivative; and iii) intramolecular 1,3-dipolar cycloaddition. As shown in Scheme 1, the azabicyclononane ring is an interesting target for strategies based on the Mannich reaction. This methodology is mostly used in some cases, with few steps, and from commercially available reagents.
The synthetic route performed by the authors allowed accessing both racemic homotropane alkaloids in 8 steps, starting from alcohol 5 (or 6) in 15.0-25.3% overall yields. A relevant consideration in Holmes's synthesis is: the nitrone is the same common intermediate as Gössinger's [25], which is cyclized to form the tricyclic adducts. While the Gössinger route started from the cyclic 1-hydroxypiperidine, Holmes performed in situ cyclization to prepare the nitrone.
This methodology, based on the synthesis of optically active β-sulfinyl nitrones, was proved to be efficient in the synthesis of (+)-euphococcinine (2) in 7 steps from piperidine (17), in an
The catalytic hydrogenation of 28 occurred in platinum (H 2 , Pt/C) under a pressure of 60 psi of hydrogen (about 4 atm), resulting in amide 29 in 96% yield. This hydrogenation occurred with high stereoselectivity producing a single diastereoisomer of 29. Then, the amide was treated with methyllithium at −78 °C to provide ketone 30 in 85% yield. Subsequently, the intramolecular Mannich reaction was carried out, leading to the desired alkaloid, via precursor 32. Ketone 30 was then dissolved in acetic acid/ethanol 1:1 and treated with ten equivalents of ammonium acetate, stirred overnight at a temperature of 75 °C. Work-up followed by chromatographic column purification of the reaction mixture furnished (+)-euphococcinine (2) in 91% yield. This single step procedure from 30 not only led to the formation of the bicyclic system but also resulted in the loss of the chiral auxiliary, providing (+)-euphococcinine (2).
Meyer's approach led to (+)-euphococcinine (2) in 5 steps from lactam 26 in an overall yield of 51.2%. The spectral analysis ( 1 H and 13 C NMR, IR, MS) was identical to that of the natural product [28]. The specific rotation [α] D of +5.7 was also compatible with that found in the literature {lit.
[α] D +6 (c 2.0, MeOH), [19]}. Finally, the synthetic sample obtained by the authors when treated with (S)-Mosher's acid chloride was converted entirely to a Mosher amide, confirming to be a sample with a high level of enantiomeric purity. As in Murahashi's synthesis, Meyers also utilized a chiral auxiliary for asymmetric induction. Nonetheless, this method differed from Murahashi's by presenting a diastereoselective intramolecular Mannich cyclization to form the desired homotropane.
Although being racemic, Ikeda's synthesis employed an innovative "6-exo-dig" cyclization to achieve the azabicyclic system.   In this work, the quaternary center was successfully generated before the key cyclization step. It was also the first example of olefin metathesis in (−)-adaline (1) synthesis. Kibayashi's approach consisted of 13 steps in an overall yield of about 28.3% from precursor 43, previously used by the authors in the synthesis of (−)-adalinine [49]. The spectral data ( 1 H NMR, 13
Treatment of 58 with a mixture of butyllithium and potassium tert-butoxide in the presence of TMEDA and pentane, followed by reaction with the corresponding alkyl iodides in THF, and finally, acidic cleavage of the generated acetal provided aldehydes 59a and 59b (Scheme 7). The key step in this synthesis was the allylic transfer, conducted by the dropwise addition of 64 in PhCF 3 at −20 °C to a mixture of 59a and 59b and the chiral catalyst S-BINOL-TiIV [OCH(CF 3 ) 2 ] 2 providing alcohols 60a and 60b, after 12 h at −20 ºC. In addition to the good yields in this step, both intermediates were obtained with excellent enantiomeric excesses (97% for R = n-C 5 H 11 and 90% for R = CH 3 ).
Compounds 60a and 60b were converted to azido ketones 61a and 61b by Mitsunobu reaction, and then these azido ketones underwent cyclization to furnish tetrahydropyridines 62a and 62b after treatment with Ph 3 P at 20 °C in diethyl ether. 62a and 62b were converted to 63a and 63b through an intramolecular allylic transfer reaction. After several attempts to perform this cyclization, the best conditions found were by using 1.1 equivalents of trifluoromethanesulfonic acid in toluene. After 5 minutes, 1.2 equiv of tributyltin fluoride was added to intermediate A, and at the end of the process, 63a and 63b were obtained after chromatographic purification with 81% yield for 63a and 74% yield for 63b. Finally, the alkenes were oxidized in the presence of osmium tetroxide and potassium periodate, to provide (−)-adaline (1)

Liebeskind synthesis -2009
Liebeskind et al. prepared (−)-adaline (1) from the 5-oxopyridinylmolybdenum complex 66 [51]. This complex was developed as an organometallic enantiomeric scaffold for an asymmetric construction of a wide variety of heterocyclic systems.
The asymmetric synthesis achieved by Liebeskind et al. presented a high enantiomeric excess and good yields. Also, the proposed route differed from the previously mentioned in terms of common intermediaries. Therefore, it's a new synthesis of (−)-adaline (1) and might eventually be applied to related homotropanes. In conclusion, (−)-adaline (1) (1) and (+)-euphococcinine (2) [53]. The main features in this approach consisted of a 3,3-sigmatropic rearrangement to give an all-carbon quaternary center, a ring-closing alkene metathesis to give an 8-membered ring, and the use of a single enantiomer of p-menthane-3carboxaldehyde to make two natural alkaloids of opposite configuration.
Through this methodology, (+)-euphococcinine (2) (1) synthesis. Renbaun generated the quaternary center by adding a chiral amine to the cyclooctatetraene system. On the other hand, Spino et al. firstly made the quaternary center, followed by cyclization. Furthermore, Spino's synthesis involved key reactions such as Claisen rearrangement, olefin metathesis, and the Curtius rearrangement that allowed both natural products in good yields.
Although Kurtis' synthesis was racemic, it presented a few steps and led to N-methyleuphococcinine ((±)-3) in good yields. Besides, arylboronic acids proved to be efficient catalysts for