The pinene scaffold: its occurrence, chemistry, synthetic utility, and pharmacological importance

Plant-based secondary metabolites have been a major source of drug discovery and inspiration for new generations of drugs. Plants offer a wide variety of compound classes, including alkaloids, terpenes, flavonoids, and glycosides, with different molecular architectures (fused bridgehead, bi- and polycyclic, spirocyclic, polycyclic, and acyclic). The diversity, abundance, and accessibility of plant metabolites make plants an attractive source of human and animal medicine. Even though the pinene scaffold is abundant in nature and has historical use in traditional medicine, pinene and pinene-derived compounds have not been comprehensively studied for medicinal applications. This review provides insight into the utility of the pinene scaffold as a crucial building block of important natural and synthetic products and as a chiral reagent in the asymmetric synthesis of important compounds.

The relative abundance of each stereoisomer varies within species. It is also common to have racemic mixtures produced by single species. Steuer and co-workers have demonstrated the value of chiral analysis in authenticating essential oils from different pine species and have recently shown that the dominant pinene enantiomer in Pinus sylvestris is (+)-a-pinene whereas (À)-a-pinene predominates in Pinus nigra and Pinus mugo. 1 a-Pinene is a major component of essential oils from conifers, Cannabis sativa, and Piper. a-Pinene is a signicant component of turpentine, and it is responsible for the strong smell of pine trees. Shari-Rad and co-workers have reviewed some of the reported pharmacological actions of a-pinene and b-pinene, including antimicrobial activities (antiprotozoal, antifungal, antibacterial) and antitumor treatment of pancreatitis, gastrointestinal disorders, and hypothermia, as well as anti-convulsant, antioxidants, and anticoagulant activities. 2 In addition, a recent review on a-pinene by Allenspach and Steuer focused on its pharmacological and synthetic utility for accessing a-turpineol, limonene, and borneol. 3 Both isomers of a-pinene have been studied for biological activities, which include anti-inammatory, 4,5 insecticidal, 6 nematocidal, 7 antioxidative, 8 neuroprotective, 9,10 gastroprotective, 11 antimetastatic and apoptotic, 12 antiapoptotic, 13,14 antitumor activities. Other studies on the potential use of pinene include for its antimicrobial activities against bacteria, 15,16 fungi, 17,18 plasmodium, 19,20 and viruses. 21

Pinene: biosynthesis in plants
As the name suggests, pinenes are found in pine trees, but other plant species and microbes can produce pinene and related compounds such as carvone. Pinene biosynthesis in plants begins with the activation of isoprene units (C 5 ). Activated isoprene exists in equilibrium between two isomers: disubstituted exo-olenic dimethylallylpyrophosphate (DMAPP) 7 and trisubstituted endo-olenic isopentenyl pyrophosphate (IPP) (8), as shown in eqn (1) in Scheme 1 below. DMAPP (7) and IPP (8) are produced via mevalonate and deoxyxylulose pathways. 22 The equilibrium favors 8 because of olenic stability in the trisubstituted position. In the presence of geranyl pyrophosphate synthase, activated DMAPP reacts with IPP to form geranyl pyrophosphate (GPP) (9), as shown in eqn (2) below.
GPP isomerizes to linaloyl pyrophosphate, resulting in an allylic cation 10 (Scheme 2 below). The allylic cation 10 can then cyclize depending on the enzyme that acts on it to produce 11-16. Aer cyclization, the carbocation formed can be terminated through elimination and hydration to afford 11a, 11b, 12a-c, and 13a-c (Fig. 3). Compounds 16a and 16b are produced from the oxidation of alcohols formed from hydration. In pinene synthesis, the cyclization of linaloyl pyrophosphate happens through a six-membered ring transition state and a stable exo-3 carbocation (17) to form the isopropyl group. This is followed by a nucleophilic attack of the 3 carbocation to form a bridgehead endo 3 cation (18) in the cyclohexyl ring, as shown in Scheme 3 below.
The a-pinenes (1 and 3) are produced by eliminating methylene protons (H 2 and H 3 ) vicinal to the carbocation. This is the favored product because the olen is trisubstituted. It is important to note that eliminating methine proton (H 1 ) at the bridgehead would result in a highly strained anti-Bredt compound (19). The loss of methyl proton produces b-pinene. Exo-olens are stable but less favored than endo olens because the former is less substituted than the latter (Scheme 4).
To produce terpenes and terpenoids of higher molecular weight, chain elongation increases by the addition of each isoprene unit (IPP); therefore, monoterpene consists of C 10 (20) carbon atoms di-, tri-, tetra-consists of C 20 (22), C 30 (24), and C 40 (25) carbon units. Triterpenes or squalene 24 (C 30 ) are precursors in the biosynthesis of steroids and triterpenoids, as shown in Scheme 5 below.
The addition of IPP to allylic cation and loss of proton in IPP occur concertedly. Moreover, proton loss in IPP is stereospecic; Scheme 1 Synthesis of geranyl pyrophosphate (GPP) in plants.
Scheme 2 Cationic allylic rearrangement of GPP to allylic cation 10.  therefore, stereochemistry from olenation is dictated by which of vicinal protons is removed, as shown in Scheme 6 below.
Furthermore, the complexity of cyclic compounds formed dramatically increases with each addition of isoprene units. This includes steroids of different scaffolds such as lanosterol, cycloartenol, cucurbitane, and triterpenes 23 of various types, including hopane, lupane, oleanane, and ursane. 24

Pinene: roles and effects in plants
Secondary metabolites present in essential oils help plants communicate, whereas compounds such as bitter and toxic alkaloids discourage herbivores and pests and act as antimicrobial agents against parasites such as fungi and bacteria. 25 Isomers of pinene appear to have deleterious effects on plant pests 26,27 and inuence plant communication. 28 Unlike animals, plants lack mobility, which presents a challenge against pests and herbivores that prey upon them. A few investigators have pursued studies on the effect of a-pinene and b-pinene in various plant species. Kohli and co-workers have reported that a-pinene inhibits radicle growth in Cicer arietinum by increasing solute leakage from roots and increasing the levels of malondialdehyde (MDA), proline, and H 2 O 2 , 29 and b-pinene inhibited the shoot and root growth of Phalaris minor, Echinochloa crusgalli, Cassia occidentalis. 30 b-Pinene has also been shown to reduce Cr(VI)-induced accumulation of reactive oxygen species in maize. 31 In addition, a-pinene was found to inhibit seed germination in P. sativum and Zea mays. 32,33

Pinene chemistry: functionalization and reactions
The olen functional is the primary target in pinene functionalization because it is the most reactive part of the molecule. Pinene functionalization in organic synthesis poses some serious challenges despite its relatively high reactivity. The proximity of the strained cyclobutyl bridgehead (at C-1 and C-5) to the olen functional group is a signicant challenge. The 1,5 carbon-carbon (C-C) bond connection of bridgehead carbon to the cyclohexyl ring creates angular strain due to the cyclobutyl ring. The cyclobutyl C-C-C bond angle is 88 instead of 90 is due to the ring's attempt to relieve torsional strain caused by eclipsing hydrogen atoms adjacent to each other. Therefore, the pinene scaffold is prone to isomerization and 1,2-Wagner-Meerwein rearrangement. 34

Pinene epoxidation
Pinene epoxidation is highly stereospecic. Epoxidation happens on the opposite side of the bridgehead to produce a single pinene oxide isomer (27). Epoxide 26 shown in Scheme 7 is not produced because the dimethyl on the cyclobutyl bridgehead impedes oxidizing reagents such as m-CPBA from attacking double bonds from the top face. The dipole moment in C-O and angle strain in epoxide makes pinene oxide even more strained and susceptible to ring-opening through the epoxide. Spontaneous ring-opening has a signicant impact on pinene oxide yield. A higher yield of pinene oxide is desired because it serves as a precursor in synthesizing campholenic aldehyde (30) and trans-carveol (32) 35 found in fragrances and used as food avor. Pinene oxide, like pinene, is vulnerable to cationic rearrangement. Epoxide ring-opening in the presence of Lewis acid leads to pinene 3 cation (28). Despite being a 3 cation (28), the pinene cyclobutyl ring opens via 1,2-alkyl shi or fracture to relieve angle strain. The 1,2-alkyl shi causes a cyclobutyl ring expansion to produce a norborenyl 2 Scheme 5 Precursors for synthesis of cyclic terpenes (pinene, steroids, and triterpenoids).
Scheme 6 Stereospecific dehydrogenation of farsenyl pyrophosphate (FPP) to form E and Z isomers. carbocation (29). Note that in the norborenyl cation, the carbocation and hydroxyl group have an allylic relationship (Scheme 8). Therefore, carbonylation of the hydroxyl group to an aldehyde and olenation of the norborenyl 2 cation are the driving forces for forming a relatively more stable 2-(2,2,3trimethylcyclopent-3-en-1-yl) acetaldehyde (30).
Some interesting metal-catalyzed epoxidation of a-pinene has been observed and reported. For example, Lu and Tang's epoxidation of a-pinene using nanosized CoO x such as Co 3 O 4 in the presence of dry air and at 100 K yielded 87.68% pinene oxide (27) with a 70.75% conversion rate. The side products from the reaction include verbenone (37) and verbenol (38), and there was no monocyclic product observed (Scheme 12). 37 Conversion rate steadily decreases, whereas selectivity increases with the incorporation of SnO x surfactants.
To date, few synthetic methods can be used in pinene transformation without compromising the integrity of the bicyclic ring structure. Metal-catalyzed metathesis by late transition metals such as ruthenium is one of the effective ways to transform the pinene scaffold without unwanted side products. However, the use of ruthenium containing catalysts such as Grubb's 1 st , 2 nd , and 3 rd generation catalyst ( Fig. 4) have one major drawback the bulky cyclic ligands surrounding the ruthenium center, which inuences the catalyst's stereoelectronic properties is also an Achilles heel and cannot be used in transforming trisubstituted olenic a-pinene, the most abundant pinene 38 isomer in higher plants.
The catalyst's bulky ligands and the methyl group at C-1 in pinene impede ruthenium access to the olen during metal insertion. Therefore, as we shall see later in this review, isomerization of a-pinene to d-pinene is required to harness the synthetic utility of pinene and catalytic potential of Grubb's catalyst.
3 Pinene in the synthesis of key intermediates and other small molecules Pinene's structure, chemistry, abundance in nature, and intrinsic antimicrobial activities make it an affordable and versatile renewable and non-petrochemical molecule for human use. As a result, pinene isomers and their derivatives are used as bulk chemicals in pharmaceutical and material science (polymer and cosmetics) industries. This section provides an overview of the synthesis of some small molecules and synthetic intermediates derived from pinene isomers.

Pinene in the synthesis of carvone
Carvone (p-mentha-6,8-dien-2-one) isomers are important constituents of essential oils. Due to its avor, carvone is used in the food industry and for aromatherapy. Carvone has also been well studied for potential effects on animal physiology and health. For example, Alsanea and co-workers have shown that S-(+)-carvone blocked weight gain, fat accumulation in the liver, and insulin resistance in mice fed with a high-fat diet. Furthermore, it improves the expression of macrophage gene markers (F4/80, Cd11b, Cd11c, Cd206, and Tnf-a) in white adipose tissue, at the same time suppresses the expression of genes (Pparg2, Scd1, Cd36) responsible for lipid synthesis and transportation in the liver. 39 (S)-carvone induces the expression of detoxifying enzymes such as glutathione S-transferases (GSTs) 40 and inhibits nitrosamine-induced carcinogenesis. 41,42 The a,b-unsaturated ketone in carvone acts as a Michael acceptor, thus explaining carvone's ability to induce the expression of GSTs. 43 The antioxidant activities of S-carvone have been studied and reported by Eine and co-workers. S-Carvone was shown to have a remarkable ability to scavenge free radicals, and its antioxidant activity exceeded that of butylated hydroxyanisole (BHA), a-tocopherol, and butylated hydroxytoluene (BHT). 44 S-carvone can be prepared by fractional distillation of caraway oil. However, the synthesis of carvone from cheap and abundant natural sources such as pinene has attracted the attention of chemists due to carvone's versatility in synthesizing other important terpene congeners such as carvomethanol, carvomenthone, limonene, as well as more complex natural products.
Carvone can be prepared from pinene through anodic oxidation of pinene enol acetate (43) derived from oxidative  hydroboration of a-pinene with H 2 O 2 and CrO 3 in the presence of enol acetate (Scheme 13) as demonstrated by Shono 45 and his group. In Shono's anodic oxidation of pinene enol acetate (43), carvone (44) was obtained in 64% yield when 8 : 1 DCM-AcOH and tetraethylammonium p-toluenesulfonate (Et 4 NOTs) were used. Macaev and co-workers also reported the synthesis of carvone and cryptomerlone via anodic oxidation of pinene in AcOH-AcONa solution using RuO 2 , Pt, or TiO 2 anode and carbon electrode. 46 Unlike Shono's method, which produced several side products, Macaev's method yielded sobrerol diacetate (45) as a side product and allylic alcohol (47) in 12% yield. Hydrolysis of the allylic acetate (46) resulted in the corresponding allylic alcohol (47) in high yield, and oxidation of 47 with MnO 2 afforded 65% of carvone (Scheme 14).
The key intermediate in cryptomerlone synthesis, 49, was obtained in 3 steps by protecting the allylic alcohol in 47 with Et 3 SiCl followed by bromination and prenylation reactions. Subsequent removal of the Et 3 Si protecting group from 49 (Scheme 15) followed by Pd/C dehydrogenation led to cryptomerlone (50) in 20% yield. 52 was prepared in 8% yield from perillyl acetate using CrO 3 , 47 and the methyl ester derivative was prepared in 8 steps from carvone. 48 McIntosh and co-workers reported signicant improvements in synthetic steps and an overall yield to produce 52. Using photooxygenation and fragmentation reactions, 52 was prepared from (S)-a-pinene in 3 steps (Scheme 16) via an alcoholic ketone 51. The fragmentation-induced oxidation of 51 afforded (R)-7-hydroxycarvone 52.
In the photooxygenation of pinene carried out in the presence of tetraphenylporphine (TPP) sensitizer, the singlet oxygen attacked the olen from the less hindered bottom face (Scheme 17). The reaction proceeds through a [2 + 2] cycloaddition involving a diradical oxygen intermediate and an unstable 1,2dioxetane 5, which undergoes homolytic C-O cleavage to 54 is quenched by hydrogen radical to peroxide 55.
The presence of Ti(OiPr) 4 in the reaction mixture created a Ti-peroxide complex in the transition state, thus facilitating a stereoselective epoxidation of exo-olen by the peroxide to form epoxide 56 in 92% yield (Scheme 18).

Pinene in the synthesis of pinene-containing conjugated acid derivatives
Cross metathesis of b-pinene allows the addition of carbon atoms and introduction of polar functional groups such as ester, nitrile, and acetate. Thus important synthetic compounds such as nopol and amino derivatives can be cheaply and easily produced from pinene. For example, ruthenium-mediated cross-metathesis of b-pinene with maleonitriles and acrylic olens to produce their corresponding E and Z stereoisomers of acetonitrile (58a-b) and esters (61a-b) was reported by Bruneau and co-workers (Scheme 20). 49

Pinene in the synthesis of nopol, myrtanal, and myrtenol
Nopol can be obtained from pinene through the Prins reaction using formaldehyde. Bain 50 pioneered Prins reaction in nopol synthesis using ZnCl 2 as a catalyst at a relatively high temperature (115-120 C) for several hours. Then, Correa and coworkers improved the synthesis using a Tin-graed catalyst (Sn-MCM-41) 51 (Scheme 21). The reaction showed a 61.3% conversion rate and 98.7% selectivity.

Synthesis of terpineol from a-pinene by liquid-liquid model catalysis
Terpineol is a terpene of high economic importance in the pharmaceutical industry and cosmetics. It is used in perfumes, as an insect repellant, as an antimicrobial, and for the production of copolymers. It is produced by the hydration of apinene with aqueous sulfuric acid industrially. However, the relatively low conversion rate of pinene to terpineol and poor selectivity over side products remains a problem in the hydration reaction. Thus, several homogenous acid-base catalysts have been studied to solve the problem. For example, in the synthesis of terpineol (72) shown in Scheme 24 below, 54 Aguilar and co-workers used aqueous chloroacetic acid and oxalic acids to catalyze the hydration of pinene through cation rearrangement of the a-pinene ring. Rearrangement of the pinene ring produced unconjugated diene(1-methyl-4-(propan-2-ylidene) cyclohex-1-ene) (69), which isomerized to g-terpinene (70). In addition, chloroacetic acid precipitated out of the reaction mixture at 5-7 C, allowing for easier purication. Chloroacetic acid provided better selectivity and a higher conversion rate than acetic acid, oxalic acid, and hydrochloric acid.
Terpineol (72) can also be prepared from a-pinene in a single cationic rearrangement step using mixtures of inexpensive and common acids. Prakoso 55 and his group reported the synthesis of terpineol from a-pinene in 53.5% yield using a mixture of phosphoric acid and acetic acid. Binary mixtures of phosphoric acid with formic acid or p-toluene sulfonic acids produced lower yields of 72. Interestingly, the addition of phosphoric acid was found to enhance the acidity of acetic acid, which is contrary to the common ion effect. Acidic ionic liquid has been seen as an attractive alternative to traditional organic acids because of higher performance through their cations and better selectivity through their anions. Furthermore, ionic liquids eliminate the need for reaction solvents 56 and typically offer easier product purication. In addition, the ionic liquids are recyclable and are environmentally friendly. Liu and co-workers reported the use of 1-methyl-3-(3-sulfopropyl)-imidazolium dihydrogen phosphate ([HSO 3 -pmim]H 2 PO 4 ) in the synthesis of a-terpineol (72) and its acetate derivative from a-pinene in moderate to high yield. 57 3.5.1 Synthesis of terpineol from a-pinene by solid-liquid model catalysis. The use of acid impregnated zeolite in terpineol synthesis has been reported by Vital and co-workers in their approach to the synthesis of terpineol from the hydration of a-pinene. 58 Perhaps, one of the robust syntheses of terpineol from a-pinene using zeolite-acid mixture has been demonstrated by Wijayata and co-workers. 59 In their approach, trichloroacetic acid was impregnated in zeolite to form TCA/Yzeolite. This led to a 66% conversion of a-pinene with 55% selectivity to terpineol in 10 min. The conversion rate of pinene increases over time while selectivity for terpineol declines. Kamfene, limonene, and terpinolene were also produced as minor products. The solid-liquid model is superior to the liquid-liquid model, and the latter method is expensive to separate products from reagents. Zeolite is inexpensive and economically viable in industrial-scale synthesis.
3.5.2 Synthesis of terpineol from a-pinene by biological approach. Microorganisms such as fungi and bacteria are excellent sources of enzymes and biologically active compounds. They are relatively inexpensive to culture, and their use of enzymes in the synthesis of biomolecules offers a significant advantage because of the inherent specicity of biosynthetic enzymes. For example, Lee and co-workers reported the biosynthesis of a-terpineol from a-pinene by white-rot fungus Polyporus brumalis. 60

Pinene in the synthesis of pinenebased ligands
Pinene rigidity, chirality, and unique bicyclic bridgehead provide an excellent pool for chiral ligands. In addition, the presence of olen and methyl groups allows the design and construction of an endless moiety of ligands tailored for general and specic functions depending on the need.

a-Pinene-based organoborane chiral reagents
The discovery of the hydroboration reaction in 1956 and subsequent utility in organic transformations has stimulated the design and synthesis of a wide variety of organoborane   (75), and pinene based organoboranes (Ipc 2 BR 76-84)) as depicted in Fig. 5 below. 61 Hydroboration of olens proceeds in a concerted syn 1,2addition fashion. Therefore, there is no cation or anion intermediate involved, and the addition of two groups occurs on the same face of the olenic bond. The unique feature of hydroboration is the retention of conguration at the carbon center by the migratory group from boron during the substitution of the leaving group. The last stage in hydroboration follows the S N 2 pathway. Therefore, no intermediate is observed. Unlike a typical S N 2, which results in inversion of conguration, stereochemistry is faithfully preserved in hydroboration. The use of a-pinene-based organoborane chiral reagents accentuates the retention of desired stereochemistry by blocking alternative paths of the migratory group to reach carbon carrying a leaving group.
4.1.1 a-Pinene-based organoborane in the synthesis of homoallylic amine. Chiral nitrogen-containing natural products such as linear acyclic and cyclic alkaloid peptides can be synthesized with fewer synthetic steps and high efficiency using homoallylic amines. Though homoallylic amines are not commonly found in natural products, they provide a versatile building block for important pharmacologically valuable molecules such as eponemycin 85, 62,63 pelletierine 86, cryptophycin 87, and (+)-desoxoprosopinine 89 (Fig. 6).
In addition, homoallylic amines can be useful in preparing important synthetic intermediates such as b-amino acids (essential for the synthesis of b-lactams antibiotics), g-amino acids, and g-amino alcohols (Fig. 7).
Therefore, efficient synthetic methods for homoallylic amines and similar molecules are needed. One such method is the allylation of N-trimethylsilylbenzaldimine using chiral borane reagents.
Fernandes and Nallasivam 64 prepared key homoallylic amine 95 intermediates from enantioselective allylation of imine 93 with organotin 94. Further transformation of amines yielded (R)-a-propylpiperonylamine important in the synthesis of human leukocyte elastase inhibitor and (R)-pipecolic acid. Enantioselectivity in allylation was slightly enhanced by adding an electron-donating group (EDG) in the imine substrate. Para-   substituted phenyl groups performed better than orthosubstituted phenyl groups. For instance, para-substituted phenyl in R and R 0 produced homoallylic amine in 90-98% ee compared with 90% ee (Scheme 26). Adding an electronwithdrawing group (EWG) to the phenyl ring has no impact on the yield but drastically reduced enantioselectivity.
Fernandes proposed that the presence of a dimethyl moiety on the cyclobutyl ring of pinene prevents top face allylic transfer. Hence, allylation occurs from the bottom face (Fig. 8).
Allylation by substrate activation with polar reagents such as MeOH or H 2 O is not limited to carbonyl-containing groups. Nitriles can be used and are excellent substrates because of the nitrogen atom. For example, reducing nitrile 69 101 to N-aluminoimine 102 can serve as a precursor for proton activation. Spectroscopic evidence from 11 B-NMR spectroscopy supported    the mechanistic role of protic solvents in the reaction. It was found that in the presence of water or alcohol, aldimine 103 is formed through the protonation of the nitrogen atom. Once formed, the aldimine coordinates with the organoborane forming a Zimmermann-Traxler (Z-T) six-membered ring transition state (Scheme 29), and the homoallylic amine 105 is produced from the oxidation of amine-Ipc adduct 104. Enantioselectivity is determined by steric interaction between proton at prochiral aldimine center and a-pinene ring. In the favored (S) conguration (Fig. 10), only one axial proton from prochiral aldimine carbon encounters steric interaction with a-pinene ring protons. In the disfavored (R) conguration, the axial imine and protons on the prochiral carbon encounter pinene protons.
A similar mechanism happens in the allyboration of N-aluminoimine and in the crotylboration and alkoxyallylboration of imines using a-pinene derivatives, as shown in Scheme 30. For example, the a-pinene-containing boronate complex 110 was used in the crotylallylboration and alkoxyallylboration of aldimines 106 (Scheme 30) to produce ether-protected amino alcohol 107 with 65% yield, 9.5% ee, and 98% de.
Pinene-derived iminodiacetic acid (PIDA) 71 ligand 120, shown in Fig. 11 prepared by Burke and co-workers, provides a robust and versatile C(sp 3 ) boronate. Its ability to induce chirality derives from the proximity of the functional group to the pinene, conjugated to the rigid iminodiacetic boronate backbone, during transformation.
The ligand is tolerant to various functional groups in the substrate. Therefore, once the desired stereogenic center has been introduced, the boronate functional group can be removed through a metal-catalyzed coupling reaction.
Compound 121a obtained from the epoxidation of boronate adduct 121 (Scheme 32) was used to synthesize a glucagon receptor antagonist 125b, with potential use in treating type II diabetes.

a-Pinene chiral auxiliary in enantioselective synthesis
Pinene-based amino alcohol chiral auxiliaries were used to synthesize secondary alcohols from aldehydes and diethyl zinc in enantioselective synthesis. Secondary alcohols are key intermediates in the synthesis of natural products such as (+)-(R)gossonorol ( Fig. 12) 72,73 which was studied for its antifungal and antitumor activities.
Marques and co-workers employed four synthetic steps to prepare the chiral amine auxiliaries containing an a-pinene moiety. 74 Ligand 126 showed higher enantioselectivity because of its effectiveness in inducing steric hindrance to the incoming nucleophile (Et 2 Zn). The presence of cyclic amine and bridgehead methyls increases hindrance to alkylation of aldehyde.
The approaching diethyl zinc delivered ethyl group from the bottom where it is less hindered, as shown in Scheme 34 below.

Pinene in the synthesis of polymers
Pinene olenic functional group and its chiral bicyclic bridgehead offer an attractive choice as a monomer in polymer synthesis. Olen functionalization in polymer synthesis can be carried out using a variety of mechanistic pathways such as free radical, cationic polymerization, and metal-mediated metathesis. Furthermore, polymer properties, including thermal and optical activities, can be controlled by manipulating the Scheme 31 Derivatives of GABA uptake inhibitors containing the tetrahydropyridine motif (Eq. 36) and PIDA-promoted enantioselective epoxidation (Eq. 37).  bridgehead of the stereogenic centers (Fig. 13) and the two prochiral olenic carbon centers depending on the mechanism of polymerization.
Pinene isomers provide an excellent substrate for fashioning and tailoring the desired monomer to synthesize specic polymers depending on the intended use. For instance, (+)-pinocarvone (Scheme 35) is the monomer for synthesizing polyketone polymers, as discussed in radical polymerization in the next section.
Polymers derived from pinene scaffold are of economic importance. b-Pinene-derived polymers have been used as resins for many materials, including adhesives and rubber additives. In addition, because of the inert nature of pinene polymers, it is used in food packaging. Improving synthetic methods through better catalysts and activators to increase yield and desirable polymer properties has been an ongoing research endeavor. Lewis acids such as AlCl 3 , SbCl 3 , and transition metal salts have been used in polymer and copolymer synthesis from different monomers.
5.1 Synthesis of polyketone polymer from a-pinene-derived pinocarvone a-Pinene can be transformed into the conjugated exo-olenic a,b-unsaturated ketone, (+)-pinocarvone, through photooxidation using singlet oxygen ( 1 O 2 ) in the presence of tetraphenyl porphyrin as photosensitizer (Scheme 36). Polymerization through pinocarvone offers an advantage over a-pinene because its exo-olenic group is more accessible. Pinocarvone also has an advantage over b-pinene because of its enhanced high reactivity resulting from the conjugation of its exo-olenic group with the ketone functional group. Polyketones 132a and 132b were prepared by photooxidation of (+)-pinocarvone under bulk conditions at 60 C with azobisisobutyronitrile (AIBN) initiator in uorinated solvents. Both polyketones are optically active due to chirality transfer from the cyclohexyl ring of (+)-pinocarvone.
The polymer is composed of an a,b-unsaturated cyclohexanone moiety 131c (>90%) and a pinanone moiety 132d formed during the initial stages of the exo-olen-enabled diradical formation (Scheme 37). This is consistent with the radical mechanism, which favors the most stable 3 radical intermediate formed through b-scission of (+)-pinocarvone.   Interestingly, an attempt to polymerize (+)-pinocarvone via anionic ring-opening failed even in the presence of tert-butyllithium, or the addition of aluminum additives such as triethylaluminium (AlEt 3 ) and bis(2,6-di-t-butylphenoxy) methylaluminum (MeAl(ODBP) 2 ) with tert-butyllithium or with Et 2 Zn (Scheme 38).

Synthesis of 3-lactams derived from b-pinene
Caprolactam is an important industrial chemical with a wide range of uses, including in the production of nylon-6 laments, bers, and plastics. 3-Lactams are prepared from acid-catalyzed Beckmann rearrangement of the oxime (134) derived from the condensation of cyclohexanone (133) and hydroxylamine (Scheme 39). The ring-opening polymerization of 3-lactams 137 produces nylon-6 polymers (138).
The major drawback of using cyclohexanone as the precursor for 3-lactams is the monomer's lack of a chiral center. The absence of a chiral center affects the polymer's photo-and thermostability, durability, and rigidity, which are important for most polymer applications. Therefore, replacing cyclohexanone with b-pinene as the starting material provides a cheap and sustainable alternative. Winnacker and co-workers reported the synthesis of poly (3-lactams) 144a-b from b-pinene (Scheme 40) in ring-opening polymerization of 3-lactams (143a and 143b). 75 Chirality in b-pinene is faithfully preserved in the oxime. Interestingly, Beckmann's ring expansion by 1,2-sigmatropic migration of alkyl at C-2 to nitrogen was not followed by bridgehead C-1 ring expansion to C-2 alkenyl cation 143 (Scheme 41). In Beckmann's rearrangement, the migratory and leaving groups must be anti-periplanar.
Furthermore, migratory aptitude depends on the stability of carbocation. In addition, the 1,2-migration is suprafacial and allowed. In this case, migratory alkyl C-1 in 140 must traverse nitrogen heteroatom to reach alkenyl carbocation 143. Thus, any bridgehead ring expansion would have to follow antrafacial-1,3-s-migration (not allowed in cationic rearrangement) to produce 146.
5.2.1 Cationic polymerization of pinene. As an example of the cationic synthesis of poly(b-pinene), Kamigato and coworkers reported the synthesis of a polymer with a high molecular weight and high glass temperature T g ¼ 130 C (aer hydrogenation) from a mixture of (À)-b-pinene and (À)-a-phellandrene 147. 76 Hydrogenation of the polymer's cyclohexenyl backbone dramatically improved its thermoresistance (T g ¼ 90 C in unsaturated polymer 148 and T g ¼ 130 C in hydrogenated polymer 149). In addition, hydrogenated polymer 145 is durable and resistant to thermal destruction, with only a 10% degradation at a temperature > 400 C (Scheme 42).

Binary
Lewis acids (SbCl 3 /AlCl 3 )-mediated polymerization of a-pinene. Cationic polymerization of a-pinene catalyzed by AlCl 3 occurs via rearrangement isomerization of its cyclohexenyl ring. There are two paths for the rearrangement, starting with carbocation 150 (Scheme 43). First, via the disintegration of cyclobutyl ring to relieve angle strain in 3 carbocation 151, and second, via a 1,2-Meir-Wiegner alkyl shi ring expansion of norbornane-type 2 cation 153 from cyclobutyl to cyclopentyl ring skeleton to relieve angle strain. In both cases, the formation of 152 and 154 proceeds from the nucleophilic attack of another pinene molecule on carbocation 151 or 153.
Deng and co-workers have shown that the polymerization of a-pinene in the presence of AlBr 3 , EtAlCl 2 , or AlCl 3 alone tends to favor the norbornane cation pathway. In contrast, the addition of SbCl 3 to AlCl 3 favored the terpenyl carbocation 151. 77 The SbCl 3 /AlCl 3 (in 0.50 ratio and at À15 C) cationic polymerization of a-pinene produced oligomer 152 (>90% yield) in relatively high molecular weight (M n ¼ 1140 and MW ¼ 2590). 78 Using only AlCl 3 for polymerization produced dimers and low MW oligomers. However, the addition of SbCl 3 rapidly increased the yield and enabled the production of oligomers with higher MW, whereas SbCl 3 alone did not have any catalytic activities. At Sb/ Al ratio > 0.50, the MW, M n, and numbers of dimers formed were not dependent on the catalytic activities of the mixture. 1 H-NMR of polymers formed from Sb/Al mixtures revealed the presence of endo-olenic and single germinal methyl protons at 5-6 ppm and 0.7-1.00 ppm, respectively from 158, and the absence of exo-olenic proton signals. The spectroscopic evidence strongly suggests that the cationic polymerization occurs through the terpeniol cation 157 instead of limonene carbocation 155 (Scheme 44).
In contrast to the polymerization of a-pinene, the polymerization of b-pinene using AlCl 3 as the only catalyst happened very rapidly and produced polymers of relatively high molecular weight (M n approximately 2000), but the addition of SbCl 3 poisoned the catalyst and led to poor catalytic activity. An attempt to produce copolymers of both pinene isomers with SbCl 3 /AlCl 3 catalyst and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as initiator failed and resulted in homopolymerization of individual monomers. 79 In fact, no small MW oligomers were observed in the polymerization of b-pinene, which implies that the two species have remarkable reactivity, but b-pinene is more reactive than a-pinene. The utility of AlCl 3 as a catalyst in cationic polymerization has been well studied for practical  industrial application. For instance, Kennedy and co-workers 80 reported the synthesis of poly(b-pinene) 161 with M n ¼ 40 000 and T g of 65 C, at relatively low temperatures (À23-100 C) using EtAlCl 2 as catalyst and H 2 O as co-initiator. Kostjuk and co-workers also reported the synthesis of thermally stable (T g ¼ 82-87 C) and high molecular weight poly(b-pinene) in AlCl 3 catalyzed reaction (Scheme 45). 81 Kostjuk's synthetic approach is economically feasible for industrial production since it requires low temperature, low concentration of both H 2 O/ AlCl 3 OPh 2 initiator and AlCl 3 (2.5-5.5 mM), and dilute monomer solution. High b-pinene monomer concentration (0.55 M) is tolerable without sacricing polymer molecular weight M n .

Transition metal-mediated polymerization of b-pinene
Transition metal complexes-mediated polymer synthesis provides an efficient synthesis of desirable polymer properties. Transition metal catalysis is less prone to side reactions commonly seen in the cationic rearrangement of the strained ring because ligand around the metal center guides monomer during incorporation to the polymer chain while maintaining the desired conguration in the polymeric chain. Early transition metals such as Nb, Ti, Zr, and Hf have become workhorses in polymer and copolymer synthesis. The metals have higher oxidative states, higher oxygen affinity, lower electronegativity tendencies, and allow the introduction of polar functional groups. Those features make the custom design of polymers to improve desirable features such as polydispersity, rheology, density, and control of molecular architecture (regio-and stereochemistry) in polymeric chains possible. 82 Lu and coworkers reported low temperature (40 C) synthesis of a endfunctionalized polymers and macromonomers from b-pinene using TiCl 3 (OiPr) as the catalyst and a mixture of HCl (aq) and CH 3 CH(OCH 2 CH 2 Cl)Cl as the initiator in the cationic polymerization reaction (Scheme 46). 83 Furthermore, Lu uses the same catalyst and initiator in radical copolymerization reaction to prepare gra copolymers from polar methyl methacrylate (MMA) and gra chain b-pinene (Scheme 47).
5.3.1 Late transition metals in polymerization of b-pinene. Polymerization mediated by late transition metals such as nickel and palladium 84 has an inherent advantage of lower acidity, air and thermostability, functional group, and solvent tolerance because of less affinity to oxygen. For example, the diimine nickel complex in Fig. 14 has been used as a catalyst in polymer synthesis.
Yu and co-workers 85 reported using Schiff-base nickel complex catalyst in synthesizing high molecular weight poly(bpinene) (M n ¼ 10 900) with a high yield of 1.25 Â 10 7 g poly-bpinene/mol of Ni at 40 C. Methylaluminoxane (MAO) was used to activate the nickel complex catalyst at Al/Ni mole ratio ¼ 500. Activated nickel inserts itself in the pinene double bond in 1,2-fashion, which allows a nickel chain transfer from catalyst to the tertiary carbon center (C-2) in the monomer (Scheme 48).  Regeneration of nickel catalyst occurs via proteolysis of Ni-C bond at the polymer head.
Polymerization proceeded through cationic rearrangement of the bicyclic ring. 1 H-NMR showed the presence of a methoxy group at 3.5 ppm from the addition of methanol as chain terminator and incorporation of methoxy group during chain termination. In the absence of methanol, chain termination happened through b-hydride transfer to produce the thermodynamic product, a highly substituted olen with 125.4 ppm and 129.1 ppm. High catalyst productivity was highly dependent on the exibility of the ligand (Scheme 49). Flexible ligands 173 and 174 allow b-pinene monomer ease access to the nickel catalytic center, thus increasing polymer chain elongation.
5.3.1.1 Ring-opening metathesis in the polymerization of dpinene. Despite the ubiquitousness of a-pinene in nature, because of its stability, there are signicant challenges in its utility as a chemical feedstock. The olen in a-pinene is trisubstituted, thus less accessible to steric-sensitive reagents, including metal complex catalysts (Fig. 15). In addition, the cyclobutyl ring's propensity to open to relieve angle strain further complicates its utility in reactions involving cationic or radical species. The use of a-pinene for cationic polymerization suffers from low yields of desired products due to the signicant production of side polymer products from isomerization. Therefore, the transformation of its olenic functionality is needed for its synthetic utility to be fully realized.
Kennemur and co-workers 86 demonstrated that a-pinene to d-pinene isomerization could be carried out in three steps beginning with stereoselective reduction of the olen with organoboron NaBH 4 and BF 3 OEt 2 followed by oxidation with aqueous H 2 O 2 to produce alcohol 182. Protection of the alcohol with tosylate allowed olenation to d-pinene by E 2 mechanism. Therefore, the dehydrotosylation can proceed by deprotonating the proton anti-periplanar to the tosylate (Scheme 50).
Grubb's third-generation catalyst has been studied in ringopening polymerization of d-pinene and apopinene 184 (Scheme 51). 87 Kennemur and co-workers reported > 95% yield in their synthesis of poly(d-pinene) (PdP) 186 (Scheme 52), and the polymer showed a narrow dispersity (<1.2). In addition, the monomer sequences followed regioregularity head to tail arrangement (HT > 95%) micro-structure. The trans-olen accounted for > 98%, and the polymer glass transition temperature T g was approximately 104 C. Specic optical rotation ([a] 24 589 ) in the polymer was +83 AE 1.1 found to be Scheme 48 Nickel-mediated ring opening of b-pinene.
Scheme 49 Chain termination pathways via b-hydride transfer from carbon to nickel complex. opposite and much higher in magnitude to that of the (À)-dpinene ([a] 24 589 ¼ À35 (AE1.2 )) starting material. PdP has high thermostability. Thermogravimetric studies at $337 C showed only about 5% loss. Furthermore, norbornene and d-pinene can be polymerized to form block copolymer 188 with a 1 : 1 monomer composition (Scheme 53).
In addition, Gutierrez and Tlenkopatchev solvent-free synthesis of terpene-terminated oligomers from b-pinene and natural rubber (NR) using Grubb's second-generation catalyst (Grubbs catalyst I 88 ) showed that the molecular weight of oligomers could be manipulated and controlled through b-pinene NR ratio while maintaining excellent yields between 80-90%.

Pinene as intermediate for complex natural products
Like other terpenes, pinene is derived from isoprene units, and it possesses a critical number of carbon atoms in its rings, typical of many carbocyclic natural products. The geminal methyl in its bridgehead (signature evidence of isoprene origin) alongside the methyl in its cyclohexyl group provides a convenient scaffold for synthesizing challenging natural products such as Taxol® or longifolene. In addition, the stereogenic centers in pinene are easily transferable to natural products targeted for synthesis since they share the same isoprene origin during their synthesis. Furthermore, the ubiquitous nature of pinene, its availability, the relatively cheap cost of production, and its stability relative to other strained compounds make it an attractive starting material in synthesizing bioactive natural products or natural products-inspired molecules.

Pinene in taxane synthesis
Taxane diterpenes, originally isolated from the yew plant (Genus Taxus), are essential molecules in medicine. The economic and pharmaceutical importance of the taxane diterpenes led to ongoing research to understand their biosynthesis and pharmacology and to develop efficient organic synthesis routes to produce the challenging scaffold. The anticancer agent Taxol®, the most iconic taxane compound isolated from pacic yew (Taxus brevifolia), prevents cell division by binding to tubulin and microtubule. 89,90 Some of the approved taxanebased antineoplastic drugs (Fig. 16) include paclitaxel, Scheme 52 Grubb's mediated ring opening of d-pinene.
docetaxel, Taxoprexil®, Opaxio®, milataxel, tasetaxel, larotaxel, and ortataxel. 91 Despite their medicinal importance, the synthesis of taxane and derivatives is still challenging due to their structural complexity and multiple chiral centers. Efforts to prepare them efficiently and cheaply in the laboratory remain an active area of research. Pinene is an attractive starting material for taxane synthesis because it contains the scaffold (ring A) found in taxane. In the synthesis of Taxol® by Wender and co-workers, 92

a-Pinene in methyl (+)-trans-chrysanthemate synthesis
(À)-Phaseic acid is a known metabolite of the plant hormone abscisic acid (ABA). 95 It plays a key role in stomata opening and closing, thus allowing the plant to control the amount of water loss through transpiration. (À)-Macmillan and co-workers rst isolated phaseic acid 96 from the immature seeds of Phaseolus multiorous, and Milborrow and Sakan established its relative stereochemistry. 97 Due to its biological signicance and potential use in accessing natural products that bear similar scaffolds, Yamashita and Takahashi 98 carried out a total synthesis to establish its conguration. Furthermore, their de novo synthetic approach provided insight into how to construct chiral bicyclic compounds containing similar skeletons. Because of structural similarities, the key strategic compound for accessing the nal molecule is keto-ester 200 (Scheme 56). Compound 200 was prepared in 3 steps from b-pinene. Its treatment with dry methanolic hydrochloric acid (Scheme 57) led to cationic Scheme 54 Verbenone made from pinene in the synthesis of taxane derivatives.

a-Pinene in the synthesis of garsubellin A
Phloroglucin-like natural products such as hyperforin (Fig. 17), berkeleyone A, berkeleydione, huperzine, upia, mexicanolide, rugulosone, nemorosome, and garsubellin A, C, and D 99 have potential medicinal application in treating inammation, depression, as well as neurologic disorders such as Alzheimer's disease.
The core phloroglucin scaffold is a heavily indented bicyclic ketone containing bicyclo [3.3.1] nonane skeleton. Several approaches in its synthesis have been reported. One synthetic approach was carried out by Mehta and Bera using (À)-a-pinene as starting material and the source of (+)-campholenic aldehyde 208, crucial for further stereospecic transformation and enantioselective functionalization to produce key intermediate 214.
(+)-Campholenic aldehyde 208 was prepared from the epoxidation of pinene and a Lewis acid-mediated isomerization.

(À)-b-Pinene-derived N-heterocyclic carbenes
N-Heterocyclic carbenes (NHCs) are important ancillary ligand and catalysts in asymmetric synthesis. Like phosphine ligands, NHCs are good s-donor and are electronically and sterically tunable. Unlike phosphine ligands, NHCs are relatively inert and bind strongly (through sp 2 carbon) to the metal center, hence reaction can occur with low ligand concentration. NHCs ligands are stable because the lone pairs on the imidazole nitrogen atoms (N1 and N3) are delocalized to the empty porbital of the carbene carbon. Lone pair delocalization in triplet state is more stable than singlet state by >80 kcal mol À1 . The lled sp-orbital donates electron pair to the metal center, as shown in 235 (Fig. 19), and the empty p-orbital is available for pback donation from the metal center. Substituents at nitrogen can signicantly inuence the stereo-electronic behaviors of NHC ligands. A signicant drawback of NHCs is that reductive elimination can happen via methylation of the imidazole to form an imidazolium ion.
The incorporation of b-pinene in triazolium carbene catalyst has been shown to add chirality to the catalytic complex. An inbuilt chirality within the complex is important for asymmetric induction to form the desired product. Ranski and coworkers 104 have reported the successful enantioselective synthesis of 4-chromanone derivatives using b-pinene-based triazolium through intramolecular Stetter reaction (Scheme 65).
Cyclization requires activation of the olen acceptor group by electron-withdrawing group (EWG). For instance, cyclization of compound 242 to 243 proceeded with 92% yield and 95% ee, Scheme 64 Biomimetic synthesis of S-euglobals derivatives from nopol/myrtenol and o-quinone methide. Fig. 19 b-Pinene-based triazolium carbene catalyst. in the presence of ligand 240, because of the presence of methyl acrylate moiety, which acts as Michael acceptor. The nucleophilic attack from aldehyde (Scheme 68) followed a similar path seen in the 1,4-addition reaction.
Attempt to cyclize 244 in the presence of ligand 241 (Scheme 69) failed because its inactive double bond lacks an olenic activator that can enable 1,4-cyclization. In this case, 1,2-addition is the only path for cyclization.
The formation of 247 (Scheme 71) is complex and intriguing. It starts with the activation of aldehyde 245 with NHC 241 to generate carbanion 246a through the loss of proton sharing the same carbon with the alkoxide. Carbanion 246a attacks ketone 246 to afford an alkoxide adduct which undergoes stereospecic [3,3]-oxy-Cope rearrangement to form 246b. The subsequent intramolecular tautomerization-aldo reaction of 246b led to ring closure in 246c to produce cyclopentane alkoxide 246d, which cyclizes to b-lactone 246f and regenerate NHC-catalyst
In a similar study on pinene-derived amides (272-283) and thioureas (284-291, Scheme 74), Song 107 and co-workers prepared a series of thiocyanates and amides like those described in Schemes 72 and 73. They tested the molecules against plant fungi species (Colletotrichum gloeosporioides, Fusarium proliferatum, Alternaria kikucshiana, Phomopsis sp., and Phytophthora capsica) as potential crop protection agents.
6.6 (À)-b-Pinene in the synthesis of (+)-nootkatone The grapefruit sesquiterpenoid Nootkatone inhibits acetylcholinesterase in insects and is a potent insecticidal. 108 Due to its potent insecticidal activity, it has been studied for mosquitoes and agricultural pest control. 109 Short synthetic routes and high yield are important for the commercial viability of most natural products. There have been several approaches to make nootkatone skeleton and various derivatives. For example, Revial and Pfau 110 used an enantioselective Michael addition reaction to prepare (+)-valencenol from protected 2methylcyclohexane-1,4-dione and phenyl crotonate. (À)-b-Pinene can also be used as starting material in synthesizing molecules with decalin skeletons such as nootkatone and valencene. Oxidation of (À)-b-pinene to nopinone 292 provides a good starting material in nootkatone synthesis, as demonstrated by Torri and co-workers. 111 Moreover, Yoshikoshi and colleagues prepared nootkatone from nopinone. The key dione intermediate for the nootkatone core structure was obtained from the transformation of 292 in Yoshikoshi's synthesis (Scheme 75). 112 Allylation of 292 in TiCl 4 catalyzed reaction led to inseparable exo-olenic stereoisomers 295 and 296 in a 4 : 1 ratio. Methylation of tertiary C-4a and functionalization of the olen to ketone afforded dione 297. Cyclization of 297 via HCl acidcatalyzed cyclobutyl ring open in 298 followed by aldol condensation of 291a produced chloro-nootkatone 299, and the dehydrochlorination of 299 led to nootkatone 300 (Scheme 76). The lack of sufficient stereochemical control is the major drawback of Yoshikoshi's synthesis of nootkatone. Introducing a methyl group at the C-4a quaternary center poses a serious challenge because the vicinal methyl impedes the top face methylation. Also, the dimethyl in the bridgehead on the opposite side of the ring blocks bottom face methylation. Furthermore, the chiral center at C-4a poses a steric challenge (syn-pentane) during butane cleavage of the aldol condensation. To overcome the stereochemical challenges at C-4a while employing (À)-b-pinene and acid-mediated aldol cyclization to access nootkatone, Crowe and Sauer (Scheme 78) allylated the ketone functional group (1,2-addition) instead of the olenic functional group (1,4-addition) in a,b-unsaturated ketone 293 (Scheme 77). The alcohol 301a-b obtained was subjected to base-catalyzed stereospecic oxy-Cope rearrangement 113 to produce ketone 302a-b. Oxidation of olenic site to ketone and the addition of acid led to cyclized nootkatone 300. 114,115 6.7 (À)-b-Pinene in the synthesis of (À)-b-pinene-based thiazole Wang and co-workers have reported the synthesis of thiazole derivatives 303 from (À)-b-pinene 116 as potential antineoplastic agents (Scheme 78). The active molecules increased reactive oxygen activities (ROS) in the mitochondrial membrane and caused apoptosis in HeLa cells.

a-Pinene in atmospheric chemistry
Monoterpenes like a/b-pinene constitute a signicant class of volatile organic compounds (VOCs) emitted to the atmosphere by plants. Went and Rasmussen produced seminal reports to link the haze observed over vegetated landmasses with the release of volatile organic materials from plants and speculated about the role of photochemical transformation of the organic materials to particulates in the blue aerosol (haze). 118-120 a-Pinene is now known as the most abundant monoterpene in the troposphere. The monoterpene's major contributor to the atmosphere is the coniferous forest ecosystem of the northern hemisphere. 121,122 Atmospheric photooxidation reactions by terpenes like a/b-pinene with ozone, hydroxide radical, and nitrogen oxides (NO and NO 2 ) are a signicant part of the secondary organic aerosols. 123

Ozonolysis of a-pinene
Because a-pinene constitutes close to 50% of global monoterpene emissions, numerous investigators have studied the ozonolysis of a-pinene to identify and characterize gaseous products and the components of the particle phase secondary organic aerosol (SOA), including highly-oxygenated multifunctional compounds (HOMS), formed through the reaction. [124][125][126][127][128][129][130][131][132][133][134][135] Several components of the SOA have been suggested and are shown in Scheme 80 as summarized by Clain and coworkers. 136 Ozonolysis of a-pinene is known to proceed through the addition of O 3 to the C]C bond, resulting in a primary ozonide 307 that decomposes into excited intermediates (excited Criegee intermediates (ECI 1 and 2) 308 and 309) in the gas phase reactions. In addition, ECI 1 and ECI 2 can be stabilized by N 2 /O 2 to form stabilized Criegee intermediates like 310, which can react with acid and aldehyde to form hydroperoxyl ester 311 and secondary ozonide 312, respectively. Under humid conditions, the SCI reacts with H 2 O to form hydroxy hydroperoxide 313. In addition, ECI 1 can undergo an isomerization reaction into pinonic acid. 137,138 ECI 1 and ECI 2 can also undergo decomposition in parallel to produce organoperoxy radicals (314) through vinyl hydroperoxide (VHP) pathways that lead to the formation of putative compounds containing functional groups such as alcohols (315), hydroperoxide (316), peroxycarboxylic acid (317), etc.
In the particle phase, the hydroperoxides and peroxycarboxylic acids react with ketones and aldehydes to form peroxy and acylperoxy hemiacetals, leading to carboxylic acids and esters (via Baeyer-Villager reactions), alcohols, and aldehydes. In addition, the hydroperoxy esters and hydroxy hydroperoxides from the SCIs are converted to gem-diols and hydroxy esters. Although, as expected, the SOA composition depends on the concentration of oxidizing agents, humidity, and temperature. [139][140][141] Ehn and co-workers had shown that HOM formation decreased about 50 percent when experiments were performed at 0 C compared to 20 C. 142 While the molecular formulae and structures of some of the primary products of the photooxidation reactions have been identied, many mechanistic details, reaction intermediates, and reaction end products have not been denitively characterized, but there has been considerable interest in understanding the SOA in recent years. [143][144][145] The current state of the art and challenges in molecular characterization of SOA components are reviewed by Nozierre, 146 and Mahilang, 147 and their co-workers.

Conclusion and outlook
Pinene isomers are versatile, cheap, and abundant monoterpene with endless scientic applications, especially in organic synthesis. Pinenes, like many terpenes, are very useful starting materials in constructing complex and straightforward bioactive natural products such as nootkatone and Taxol® in a relatively economical approach. Furthermore, pinene rigid and dimethylated chiral centers at bicyclic bridgehead make it useful for designing chiral ligands and catalysts for asymmetric synthesis. In addition, the presence of di or trisubstituted olen allows the transformation of pinene through different pathways. This allows the introduction of desirable chirality at methylated carbon or functionalization of methyl at prochiral double bond with boundless opportunity in diversity-oriented synthesis, new method development, and the discovery and development of new natural products-inspired bioactive molecules. Pinenes are renewable, biodegradable, environmentally friendly, and readily available in high abundance from plants. We hope that pinene and other monoterpenes such as camphor, thujane, and menthol will continue to serve as feedstock for developing new synthetic methods and producing cosmetics, polymeric materials, and pharmaceuticals.

Conflicts of interest
There are no conicts to declare.