Naturally occurring taiwaniaquinoids: biosynthetic relationships and synthetic approaches

The diterpenoids possessing a fused 6,5,6-abeo -abietane skeleton ( 1 , Figure 1) have gained interest from synthetic community owing to their significant biological properties in addition to interesting complex architecture. These are a family of carbotricyclic diterpenoids bearing an unusual 4a-methyltetra-(and hexa-) hydrofluorene skeleton with an all-carbon quaternary stereocenter. A number of abeo -abietanes isolated from different East Asian conifers viz. Taiwanese pine tree Taiwania cryptomerioides and hence they are popularly named as the taiwaniaquinoids. In this review article, we discuss on the biosynthetic proposal as well as recent efforts on the total syntheses of naturally occurring complex taiwaniaquinoids


Introduction
Naturally occurring terpenoids and their derivatives have greatly impacted the human experience.Nearly every human on earth has experienced their effects as flavors, fragrances, poisons, and medicines.In this context, taiwaniaquinoid based natural products are a subset of abeo-abietane, 1 which constitute an important class of diterpenoids (Figure 1).The taiwaniaquinoids share 6,5,6-carbotricyclic core [abeo-abietane diterpenoids 1] and are biosyntically proposed to be arisen from a 6,6,6-abietane skeleton 2 (2, Figure 1) via degradation of one carbon unit from 'B'-ring.Diterpenoids possessing a fused 6,5,6-abeo-abietane skeleton (1, Figure 1) have gained substantial interest owing to their significant biological properties and interesting architecture. 3These are a family of carbotricyclic diterpenoids bearing an unusual 4a-methyltetra-(and hexa-) hydrofluorene structures.Taiwania cryptomerioides Hayata (Taxodiaceae) is an economically important, decay-resistant evergreen tree indigenous to the central mountains of Taiwan.Since 1995, a number of abeo-abietanes isolated from different East Asian conifers viz.Taiwanese pine tree Taiwania cryptomerioides and hence they are named as taiwaniaquinoids. 4,5,6,7 In2010, Majetich and Shimkus reported comprehensive overview of the taiwaniaquinoid family of natural products summarizing the isolation, biosynthesis, and biological activities followed by a discussion of various synthetic strategies to the skeletal framework during 1995-2010. 3Very recently, in 2016, Shi and Guo have reported an excellent review on fluorenone and fluorenone containing natural products highlighting case studies of syntheses representing members of different subgroups. 8

Biological Profiles of Taiwaniaquinoids (abeo-Abietane Diterpenoids)
Total synthesis of natural products is important area of research, as many of the current available drugs are natural products or their derivatives.The advantage of drugs derived from natural products with respect to fully synthesized compounds is their greater structural complexity.Also, the derivatives of natural product tend to be more selective toward a wide range of targets.As per literature report, few members of taiwaniaquinoids are found to exhibit potent cytotoxic activity against KB epidermoid carcinoma cancer cells 9 and one of the members standishinal (1c), could be a promising candidate in breast cancer therapy, due to its aromatase inhibitory potential. 10,11,12 Tese biological activities together with their intriguing carbotricyclic structure make taiwaniaquinoids an attractive synthetic target leading to elegant approaches to this class of diterpenoids.
The promising biological activity and the unusual structure of these terpenoids have stimulated research into the synthesis of this type of compound, 13,14,15 including total and stereoselective syntheses.The synthesis starting with natural terpenoids facilitates the formation of enantiopure taiwaniaquinoids.Recently, Chahboun and Alvarez-Manzaneda and co-workers 16 have synthesized new taiwaniaquinoids starting from natural terpenoids and the evaluation of their in vitro antiproliferative activities, as well as that of other synthesized taiwaniaquinoids, against human breast, colon, and lung tumor cells.This group has shown that, the in vitro antiproliferative activities of some taiwaniaquinoids and related compounds with functionalized A, B, or C rings against human breast (MCF-7), colon (T-84), and lung (A-549) tumor cell lines were assayed (Figure 2). 16It is discovered that the most potent compounds 3a-c were more effective than the naturally occurring taiwaniaquinones A (1d) and F (1e) in all above three cell lines.The structure−activity relationship study of these new taiwaniaquinoids highlighted the correlation between the bromo substituent and the antiproliferative activity, especially in MCF-7 (human breast) cells.These findings indicate that some of the taiwaniaquinoids might be useful as cytostatic agents against breast, colon, and lung cancer cell lines.Therefore, further studies are welcome towards this direction.A plausible biogenetic pathway of taiwaniaquinoids (abeo-abietane diterpenoids) from abietane diterpenoids is shown in Scheme 1. 3 As per Node et.al., 17 biosynthetically, the abeo-abietane diterpenoid skeleton is believed to be arisen from a Prins-type alkylations of dialdehyde 5 (alkylation at ortho-position of phenol), 17 which in turn can be synthesized biogenetically from a more common abietane skeleton ferruginoldiol (4b) via Scheme 1. Biosynthetic relationship of abeo-abietane and abietane diterpenoids.
an oxidative cleavage of vicinal diol (Scheme 1).Hypothetical precursor ferruginoldiol (4b) can be obtained from an oxidation event of dehydroferruginol (4a) or from other congeners of abietane diterpenoids (Scheme 1).A biogenetic proposal for the synthesis of taiwaniaquinoids is reported to go through a key Pinacol rearrangement (Scheme 1) of 5b generated from ferruginoldiol (4b). 18n 2010, Gademann's biogenetic proposal for the synthesis of taiwaniaquinoid skeleton 5f relies on a key benzilic acid rearrangement of 5c through the intermediates 5d and 5e (Scheme 1). 19Later, the same group, in 2013, had reported a biogenetic proposal for the synthesis of taiwaniaquinol A (1o) via Wolf rearrangement of 5g through the intermediacy of ester 5h (Scheme 1). 20In 2010, Alvarez-Manzaneda and coworkers have shown a proposal for the synthesis of taiwaniaquinone A (1d) and taiwaniaquinone F (1E) via a key Aldol condensation aldehyde 5j (which was synthesized from 5i) through the intermediacy of carbotricyclic core 5k (Scheme 1). 21

Representatives of Taiwaniaquinoids (abeo-Abietane Diterpenoids)
Since 1995, a number of abeo-abietane diterpenoids have been isolated from various sources.The representatives of these diterpenoids are shown in Figures 4-6.In 1995, while continuing their investigation of the leaf extracts, Cheng et al. discovered 22,23 a new family of diterpenoids (four diterpenes and one norditerpene) possessing a [6,5,6]-abeo-abietane skeleton 24 previously unknown in nature. 25They named these compounds as taiwaniaquinones A (1d), B (1n), and C (1l) and taiwaniaquinols A (1o) and B (1f) (Figures 3 and 4) according to their botanical origin, C-ring functionality, and order of isolation, respectively.Cheng's continued work expanded this family in 1996, when the leaf extracts yielded taiwaniaquinones D (1s) and E (1q) (Figure 7). 23A similar skeleton was soon discovered in other families of abietane-rich plants.In 1999, Kawazoe et al. reported the isolation of three structurally similar compounds (Figures 1 and 3) from the roots of Salvia dichroantha Stapf (Lamiaceae), a Turkish flowering sage.These new compounds were named dichroanals A (1b) and B (1h) and dichroanone (1a).Tanaka and co-workers have isolated the compound designated standishinal (1c) from the bark of Thuja standishii (Cupressaceae), a Japanese conifer, in the same year. 27Meanwhile, Kuo et al. reinvestigated the bark extracts from T. cryptomerioides, and the structures of taiwaniaquinone F (1k) and taiwaniaquinols C (1r) and D (1m) were reported in 2003. 28Further study of the bark extract resulted in the 2005 report of taiwaniaquinones G (1j) and H (1g) and taiwaniaquinols E (1i) and F (1k). 29 Figure 7 shows a number of abeoabietane diterpenoids having an additional carbon as compared to taiwaniaquinoids shown in figure 6. 30 It is also interestingly to note that there could be oxidized A-ring present in taiwanaquinoids, such as taiwaniaquinol F (1k) (Figure 6).

Synthetic Approaches to the Taiwaniaquinoids (abeo-Abietane Diterpenoids)
The synthetic approaches to this class of diterpenoids are shown in sections 5.1 and 5.2.

Scheme 3. Intramolecular domino Friedel-Crafts acylation/carbonyl -tert-alkylation by Fillon (2005).
Node and co-worker, in 2006, have developed a new efficient method to prepare a 4amethyltetrahydrofluorene system.The key reaction of this approach is an intramolecular Heck cyclization of the novel diene compound with a triflate functionality 8c to furnish carbotricyclic core 8d (Scheme 4). 34The methodology was applied to the synthesis of (±)-dichroanal B (1h) with an improved yield, compared to the previously reported total synthesis.The required arene triflate 8c was synthesized from arylvinylcarbinol 8b in 4 steps, which in turn was synthesized from acetophenone 8a in 5 steps (Scheme 4).This methodology also provides the opportunity for a convenient construction of chiral 4a-methyltetrahydrofluorene.

Scheme 12. Collective Total syntheses by Li and co-workers (2013).
In 2014, Hu and Yan reported protecting group-free total synthesis of (±)-taiwaniaquinone H (1g) via a key thermal ring expansion/4π-electrocyclization of 2-hydroxy-cyclobutenone derivative 18c (Scheme 13). 47In a synthetic sequence, cyclobutenedione 18b was prepared in 90% yield from dimethyl squarate 18a and isopropylmagnesium bromide following Moore's established protocol. 48Ethynylmagnesium bromide was added to commercially available -cyclocitral 10 at −30 °C, which was subsequently treated with t BuLi and cyclobutenedione 18b sequentially to afford 18c in 39% yield in a one-pot fashion. 49Thermal ring expansion/4π-electrocyclization of 18c afforded the desired ring expansion product 18f in 69% yield.However, when the reaction was carried out in the presence of TiCl 4 , the expected thermal ring expansion/4πelectrocyclization process afforded (±)-taiwaniaquinone H (1g) in 41% yield from 18c.

Scheme 15. Optimization of cyclization of arylvinylcarbinol 20a-b.
Later, benzyl alcohol 23d was treated with BF 3 . Et 2 O leading to the formation of 23e and 23f in 2.1:1 ratio (Scheme 16), which on subsequent allylic oxidation using SeO 2 afforded 24a as an exclusive product. 53The later was oxidized under Swern oxidation to furnish ,-unsaturated aldehyde 24b in 94% yield (Scheme 16).Next, compound 24b was treated with BBr 3 followed by oxidation using ceric (IV) ammonium nitrate simply afforded potential p-quinone intermediate 24c.
Further, the same group have reported total syntheses of taiwaniaquinoids, dichroanal A (1b), dichroanal B (1h) and keto form of caryopincaolide H (1p) following a key Nazarov type cyclization. 53Initially, it was thought to access from a Nazarov type cyclization of arylvinyl carbinol 20c (Scheme 18).However, under the optimized conditions A and B, 20c went through a highly regioselective manner to afford only 22d in 97-98% and no traces of 22c was observed.

Scheme 18. Retrosynthetic analysis of (±)-dichroanals A (1b) and B (1h).
Compound 22d was converted into bromoarene 22e, which afforded suitable single crystal for X-ray analysis (Scheme 19).Therefore, regioisomer 22d was unequivocally proved by X-ray crystal analysis of 22e.This reaction clearly indicate that the regioselectivity of Nazarov type reaction is completely governed by electronic nature of aromatic ring, but not the sterics imposed by the bulky i-pr group of arylvinyl carbinol 20c (Scheme 19).Based on the result of Scheme 19, carbotricylic core 26a (prepared from a Nazarov type cyclization of 20d) was envisioned for total synthesis of dichroanal B (1g) (Scheme 20).Towards this, hydrogenation of 26a to afford 26b in 99% yield as sole diastereomer.Next, bromination of 26b in presence of N-bromosuccinamide in dichloromethane afforded 26c in 93% yield (Scheme 20).The later was reacted with sodium methoxide to obtain catechol dimethylether derivative 26d.CrO 3 -Oxidation of 26d afforded tricyclic ketone 25 (Scheme 20).A simple demethylation using PhSH in the presence of K 2 CO 3 led to the synthesis of keto form of caryopincaolide H (1p) in 92% yield.Scheme 20.Synthesis of keto form of (±)-caryopincaolide H (1p) and advanced intermediate (±)-28a.
Later, ketone 27 was reduced to benzyl alcohol 28a in presence of LiAlH 4 (Scheme 20).The excellent diastereoselectivity observed in LiAlH 4 -meidated reaction was attributed to the approach of the hydride from the less hindered convex face of substrate 27.Benzyl alcohol 28a was treated with N-bromosuccinamide, where a one-pot bromination and dehydration led to the formation of 28b in 71% yield.Finally, total synthesis of (±)-dichroanal B (1h) was completed in 2 steps in 87% overall yield viz. treatment with n-BuLi and DMF to form aldehyde 28c followed by demethylation using thiophenol in the presence of K 2 CO 3 (Scheme 21). 53© ARKAT USA, Inc Scheme 21.Total synthesis of (±)-dichroanal B (1h).

Stereocontrolled total syntheses of taiwaniaquinoids
In the year 2006, Stoltz and co-worker, have reported first enantioselective synthesis of (-)-dichroanone (1a) featuring an enantioselective Pd(0)-catalyzed decarboxylative allylation strategy. 54This synthesis takes advantage of a Pd(0)-catalyzed asymmetric allylation methodology to generate all-carbon quaternary centres adjacent to carbonyls.Catalytic enantioselective decarboxylative allylation (DcA) of compound 29b (prepared from 29a by reacting with allylchloroformate) installed the quaternary center in 29c with 91% ee (Scheme 22).Wacker oxidation 55 of 29c followed by condensation provided bicyclic enone 29e in excellent yield. 56Michael addition of the lithium enolate of 29e to methyl vinyl ketone (MVK) formed the keto-enone 29f with high diastereoselectivity.The later was reacted under Robinson annulation strategy followed by reaction with Nphenyltriflimide afforded enoltriflate 29g (Scheme 22).The later was immediately subjected to Kumada coupling with isopropenylmagnesium bromide led to a mixture of isomeric products, which converted irreversibly compound 29h upon exposure to acid.Later, a formylation 29h afforded aldehyde 29i in 79% yield, which was under Baeyer-Villiger sequence installed the first oxygen in 29j (74% yield).Finally, a oxidative reaction sequence was followed to complete the synthesis of (+)-dichroanone (1a) under protecting group-free manner.Scheme 22.Total syntheses of (+)-dichroanone (1a) by Stoltz.

Scheme 23. Thermal 6-electrocyclization by Alvarez-Manzaneda (2009).
In 2010, Node and co-worker have reported asymmetric total syntheses of (-)-dichroanal B (1h), (-)dichroanone (1a), taiwaniaquinone H (1g), by using a catalytic intramolecular asymmetric Heck reaction.59, 60 They have designed substrate 32b bearing a rigid acetonide group in the catechol moiety, which was prepared by modifying a previously reported method.Commercially available 31a was treated with acetone in the presence of BF 3 .Et 2 O to give the acetonide which was under bromination with NBS afforded 31b in excellent yield.After lithiation of the bromide 31b with n-butyllithium, the aryllithium generated was reacted with β-cyclocitral (10) to afford the benzylic alcohol 32a.Dehydration of 32a by treatment with methanolic hydrochloric acid gave the diene as a mixture of E and Z isomers (ca.1:4), which after demethylation and subsequent triflation afforded required diene 32b.
The intramolecular asymmetric Heck reaction of triflate 32b (a mixture of E/Z isomers) in the presence of palladium(II) acetate, (R)-BINAP (34a) afforded 33 in 77% ee (Scheme 24).Following exhaustive optimization, it was found that the Heck reaction of triflate 32b and successive hydrogenation gave 33 in good yield (<86% in 2 steps) with excellent ee (94-98%ee) when (R)-Synphos (34b) was used.Later, the acetonide of 33 was subjected to deprotection with HCl-MeOH followed by a reaction with dichloromethoxymethane in the presence of BCl 3 completed total synthesis of (-)-dichroanal B 1h.Further treatment of 33 with Nbromosuccinimide followed by reaction with sodium methoxide in the presence of CuI followed by removal of the acetonide and oxidation with DDQ afforded total synthesis of (-)-dichroanone A (1a).Finally, the later was reacted with the Meerwein reagent to complete total synthesis of (-)-taiwaniaquinone H (1g) (Scheme 24).
In 2010, Alvarez-Manzaneda and co-worker, 21,61 have reported semisynthesis of taiwaniaquinone A (1d) and F (1e) from abieatic acid (Scheme 25).A new strategy for synthesizing taiwaniaquinoids, based on the cleavage of the C7−C8 double bond of abietane diterpenes is described in this strategy.This procedure is the only one reported for synthesizing C 20 taiwaniaquinoids bearing a carbon function on the cyclopentane B ring, such as taiwaniaquinone A (1d) and F (1e), and it is also applicable to the synthesis of 4amethyltetrahydrofluorene derivatives, such as taiwaniaquinone H (1g) and dichroanone (1a), and 4amethylhexahydrofluorene derivatives, having an A/B trans-fused system, such as taiwaniaquinone G (1j), or an A/B cis-fused union, such as taiwaniaquinol B (1f).In 2010, Gademann reported a biogenetic hypothesis for the transformation of an abietane-type diterpene into the 6-5-6 skeleton of the taiwaniaquinoids by a ring contraction of an oxidized precursor (Scheme 26). 19,20 he overall hypothesis of this strategy is summarized in Scheme 26, which was utilized for the total synthesis of (+)-taiwaniaquinone H (1g) under protecting group-free condition.Scheme 26.Hypothesis of conversion of abietane (37a) to abeo-abietane (37d) by Gademann.
The starting material 38a was obtained from commercially available methyl dehydroabiate in 5 steps. 62,63 e hydroxydiketone functionality of the key intermediate 38b was installed through a Sharpless asymmetric dihydroxylation reaction 64 (Scheme 27).Treatment of the hydroxydione 38b with LHMDS gave the hydrofluorene derivative 38c, as per proposal shown in Scheme 26, which was reduced with NaBH 4 to afford 38d.Later, a one-pot sequence of hydroxy-group-directed ortho lithiation of the benzylic alcohol 38d, 65,66 and subsequent borylation of the aryl lithium compound and oxidation of the corresponding aryl boronate gave the hydroxylated phenol derivative, which was dehydrated under under acidic conditions to furnish dehydrated phenol 38e in 64% yield over 2 steps (Scheme 27).The later was then cleanly oxidized using Fremy's salt to the corresponding p-quinone 38f.Electrophilic bromination of the quinone 38f followed by substitution with a methoxy group completed total synthesis of (+)-taiwaniaquinone H (1g) in 63% yield over 3 steps (Scheme 27).Scheme 27.Total syntheses of (+)-taiwaniaquinone H (1g) by Gademann.

Conclusions
This review is intended to provide an overview of the complex taiwaniaquinoids where biosynthetic relationship of diterpenoids and synthetic approaches to this family of diterpenoids have been discussed elaborately.The literature on the synthesis of taiwaniaquinoids summarized in this review very well suggest that they have been proposed in the literature to be arisen from abietane diterpenoids.It has been over 23 years since the first member of the abeo-abietane family was isolated in 1995 from the roots of Salvia dichroantha Stapf (Lamiaceae), a Turkish flowering sage.Since that time, an additional twenty abeo-abietanes have been isolated from a variety of plant species from variety of species.The fascinating molecular architecture of the members of this natural product family has stimulated the interest of numerous synthetic chemists which has led to a number of creative synthetic approaches and beautiful total syntheses.Although, the biological activities of only a few numbers of taiwaniaquinoids are reported, the exhaustive biological potential of the majotiry of taiwaniaquinoids has yet to be evaluated.The knowledge from biological stidues would be useful in screening these products for therapeutic applications.