Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

This account provides an overview of recent work, including our own contribution dealing with Suzuki–Miyaura cross coupling in combination with metathesis (or vice-versa). Several cyclophanes, polycycles, macrocycles, spirocycles, stilbenes, biaryls, and heterocycles have been synthesized by employing a combination of Suzuki cross-coupling and metathesis. Various popular reactions such as Diels–Alder reaction, Claisen rearrangement, cross-metathesis, and cross-enyne metathesis are used. The synergistic combination of these powerful reactions is found to be useful for the construction of complex targets and fulfill synthetic brevity.


Introduction
Transition-metal catalysts are used in metathesis and cross-coupling reactions. Such advances have opened the door for efficient construction of C-C bonds in organic synthesis. These catalysts tolerate diverse functional groups and the reaction occurs under mild reaction conditions. Among different metathetic processes, ring-closing metathesis (RCM) [1][2][3][4][5][6] is of a greater interest than cross-metathesis (CM). It is a widely used protocol for the synthesis of unsaturated cyclic systems [7]. Palladium-catalyzed Suzuki-Miyaura (SM) cross-coupling reaction is also considered as one of the most versatile methods for C-C bond formation [8][9][10][11][12]. Application of a wide range of organometallic reagents (e.g., organoboron reagents) are possible due to their commercial availability. Owing to the mild reaction conditions and ease of handling of organoboron reagents [13][14][15][16][17] have propelled the growth of the SM cross coupling. A synergistic combination of these two elegant methods (i.e., SM coupling and metathesis) [18] was found to increase the synthetic efficiency of complex targets (e.g., macrocycles [19][20][21][22], oligomers [23,24], polycyclic ethers [25], heterocycles [26], nonbenzenoid aromatics [27], and spirocycles [28,29]) by decreasing the number of steps. Different metathesis catalysts used in this study are shown in Figure 1.

Review Annulation
Grela and co-workers [30] demonstrated a useful protocol to build indene derivatives by employing SM coupling and RCM in sequence. To this end, the SM coupling of triflate 7 was accomplished by using pinacol boronic ester 8 in the presence of a palladium catalyst to give the cross-coupling product 9 (75%). Later on, exposure of the diolefinic precursor 9 to [Ru-2] catalyst 5 gave the ring-closure product 10 in quantitative yield (Scheme 1).
Due to their useful biological activity and intricate structural features of angucyclines such as 16-19 ( Figure 2), several approaches have been reported for their assembly. In this context, de Koning and co-workers [33] demonstrated an efficient route for the construction of the benz[a]anthracene structural unit by employing SM cross coupling followed by RCM sequence. Treatment of the bromonaphthalene derivative 20 with  (2-formyl-4-methoxyphenyl)boronic acid (21) in the presence of a palladium catalyst generated the cross-coupling product 22 (72%). Next, aldehyde 22 was subjected to Wittig olefination to provide the corresponding alkene 23 (69%), which on subsequent treatment with KOt-Bu in THF gave the isomerized product 24 (73%). Later, RCM of isomerized olefin 24 with the help of G-II catalyst offered the ring-closure product 25 (84%). Finally, CAN oxidation gave the desired tetracyclic compound 26 in 84% yield (Scheme 3).

Spirocycles
In another event, an efficient approach to spirocyclopentane derivatives has been described, where the combination of RCM and SM coupling was employed [34]. In this respect, the key building block 29 was derived by employing a sequential O-allylation and CR, then again O-allylation, and CR [35] starting with a commercially available 6-bromo-2-naphthol (27). Subsequently, the diallyl derivative 29 was exposed to G-II catalyst 2 to deliver a ring-closure product 30 (83%). Finally, the spiro compound 30 was subjected to the SM coupling using two different boronic acids to produce the aryl substituted spiro compounds such as 31 (96%) and 32 (79%) (Scheme 4).
Along similar lines, we have also demonstrated the synthesis of bis-spirocycles such as 37 by adopting a double RCM sequence followed by SM coupling [36]. The key precursor 34 was assembled from a commercially available tetralone 33 via  tetraallylation sequence. Then, tetraallyl derivative 34 was subjected to RCM with the aid of the G-I catalyst 1 to furnish the bis-spirocyclic compound 35 (90%). Next, the cyclized product 35 was subjected to SM coupling using phenylboronic acid (36) to afford the cross-coupling product 37 (97%, Scheme 5).
In another instance, a simple synthetic approach to spiro-fluorene derivative 41 was described involving a serial usage of RCM and SM coupling [37]. To this end, bromofluorene 38 was reacted with allyl bromide (28) in the presence of 50% NaOH to deliver the expected 9,9′-diallylfluorene derivative 39 (90%). Next, diallyl compound 39 was subjected to RCM with the aid of the G-I catalyst 1 to furnish a ring-closure product, spirofluorene derivative 40 (93%). Later, the dibromide 40 was subjected to SM coupling in the presence of phenylboronic acid (36) to generate the new spirofluorene 41 (88%, Scheme 6).
Interestingly, highly substituted truxene derivatives 45-49 were also synthesized by applying the RCM and SM coupling protocol (Scheme 7).

Heterocycles
Couture and co-workers [38] demonstrated an elegant approach to highly substituted isoquinolones (e.g., 57a-d, Scheme 8) by employing a SM coupling followed by RCM. To this end, they started with o-vinylbenzoic acid and it was transformed to the benzamide derivatives 50 by employing a four-step synthetic sequence. Later, compound 50 was treated with KHMDS in THF at −78 °C to produce enolate 51. Further, it was reacted with diphenyl chlorophosphate to generate vinyl phosphate 52, which was subjected to SM coupling in the presence of different 2-formylboronic acids 53 with the aid of the Pd(PPh 3 ) 4 catalyst to provide the respective coupling products 54a-d  (72-87%). Next, exposure of the diolefins 54a-d to G-II catalyst 2 delivered ring-closure products, iso-quinolones 55a-d (76-88%). Finally, the cyclized products 55a-d were converted into the corresponding indeno[1,2-c]isoquinolin-5,11-diones 57a-d (73-85%) through cyclization with the aid of HCl followed by pyridinium dichromate (PDC) oxidation (Scheme 8).
In another event, Magnier and co-workers [40] described a simple synthetic route to sulfoximines by adopting SM coupling and RCM as key steps. In this respect, SM coupling of sulfoximine 65 with potassium vinyltrifluoroborate (66) in the presence of a palladium catalyst produced vinyl sulfoximine derivative 67 (73%). Next, N-alkenylation of sulfoximine 67 was accomplished with Z-vinyl bromide (68) to generate diolefinic substrate 69 (86%). Finally, diolefin 69 was exposed to Hoveyda-Grubbs 2nd generation catalyst (HG-II) 3 to deliver the cyclic sulfoximine 70 in 98% yield (Scheme 10).
Naphthoxepine derivatives play an important role as cosmetics and as pharmaceutical ingredients. Therefore, we conceived a simple approach, where the SM coupling and RCM were employed as critical steps [42,43]. Our journey begin with O-ally-

Stilbene derivatives
Hoveyda and co-workers [44] reported the synthesis of Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron derivatives via CM by using Mo complex 6. In this regard, they assembled stilbene derivative 85 as an antitumor agent by a two-step strategy that involve catalytic CM and SM coupling. To this end, the Z-selective CM of a styrene derivative (e.g., 81) with vinyl-B(pin) 82 was realized in the presence of Mo complex 6 to provide a highly substituted vinyl-B(pin) 83 (73%) with Majchrzak and co-workers [45] demonstrated a synergistic approach involving SM cross coupling and CM to synthesize various substituted trans-stilbene derivatives 89-95 stereoselectively. In this context, 4-vinylphenylboronic acid (86) was subjected to SM coupling using diverse bromoarenes 87a-g in the presence of [Pd(η 2 -dba){P(o-tolyl) 3 } 2 ] catalyst to obtain the cross-coupling products 88a-g (81-96%). Finally, exposure of olefins 88a-g to G-II catalyst 2 in CH 2 Cl 2 led to the formation of the respective trans-stilbene derivatives 89-95 in high yields (Scheme 14). It is worth mentioning that the loading of only 0.0001 mol % catalyst can effect a CM in an efficient manner.

Biaryl derivatives
In view of the interesting properties of biaryl derivatives, we have identified a three-step sequence, which involve crossenyne metathesis (CEM), DA reaction followed by SM coupling [46]. To this end, acetylene derivatives 96a,b were subjected to CEM with G-I catalyst 1 under ethylene, which resulted in the formation of the dienes 97a (63%) and 97b (83%, Scheme 15). Further, treatment of dienes 97a,b with dimethyl acetylenedicarboxylate (DMAD, 98) separately delivered the corresponding cycloadducts. Subsequently, aromatization was achieved by using DDQ to give biaryl products 99a,b.
Scheme 16: Synthesis of the dibenzocyclooctadiene core of schisandrene.
Very recently, Suresh Babu and co-workers [47] demonstrated a new route to construct the dibenzocyclooctadiene lignan core of the natural product schisandrene via SM coupling and RCM as key steps. In this context, the SM reaction of boronic acid 102 with bromoaldehyde 103 in the presence of Pd 2 (dba) 3 and the S-Phos ligand provided the cross-coupling product 104 (82%). Later, it was transformed into the allyl substrate 105 by following a three-step sequence. Afterwards, the aldehyde 105 was treated with vinylmagnesium bromide (106) to furnish diallyl derivative 107 (85%). Next, diolefinic substrate 107 was exposed to G-II catalyst 2 to furnish the ring-closure product 108 (89%). Then, MnO 2 oxidation of compound 108 offered the keto derivative in 90% yield. Corey-Bakshi-Shibata (CBS) reduction of the resulting keto derivative produced the hydroxy compound 109 (85%, ee 98%). Eventually, hydroxy olefin 109 was subjected to Sharpless asymmetric epoxidation to generate the corresponding epoxide 110. Unfortunately, generation of epoxide was not realized (Scheme 16).

Macrocycles
To develop new synthetic strategies to various cyclophanes, we conceived a sequential usage of the SM coupling and RCM as key steps [48,49]. In this context, the required dialdehyde 113 (80%) was prepared via a SM coupling of the dibromo compound 112 with 4-formylphenylboronic acid (100). Treatment of dialdehyde 113 with allyl bromide (28) in the presence of indium powder furnished the RCM precursor 114. Under the influence of the G-II catalyst 2 RCM of diolefinic compound 114 was realized. Then, the cyclized product was subjected to the oxidation sequence with pyridinium chlorochromate (PCC) to generate cylophane derivative 115 in 75% yield (Scheme 17).
Similarly, treatment of dialdehyde 113 with a freshly prepared Grignard reagent derived from 4-bromobut-1-ene (116) afforded dialkenyl substrate 117, which was subjected to RCM with the aid of G-II catalyst 2 to produce a mixture of products A variety of macrocycles were synthesized through SM cross coupling followed by RCM as key steps [50]. To this end, dibromo compound 123 was subjected to diallylation by using allylboronate ester 12 to form the diallyl derivative 124 (73%). Treatment of compound 124 with G-I catalyst 1 gave unsaturated dimer 126 (30%) and monomer 125 (15%). Subsequently, hydrogenation of compounds 126 and 125 was accomplished with H 2 under Pd/C catalysis conditions to afford the respective saturated macrocyclic products 127 (80%) and 128 (90%). Since the small ring cyclophane is highly strained, compound 125 was formed as a minor product (Scheme 19).
Recently, Li et al. [51] disclosed an elegant synthesis of MK-6325 (141) through a sequential usage of RCM and SM coupling as key steps. In this respect, the required RCM precursor 130 was derived from 129 by employing a six-step synthesis sequence. Next, the alkene derivative 130 was subjected to RCM under the influence of Zhan-1B catalyst 4 to deliver the cyclized product 131 (91%). Later, TFA-mediated deprotection of cyclized product 131 gave amine 132 (97%). Treatment of chloro derivative 132 with boronate ester 133 provided the SM coupling precursor 134 (77%). Later, an intramolecular SM coupling of Bpin derivative 134 was realized in the presence of a Pd(OAc) 2 catalyst with the aid of the ligand cataCXium A (135) to generate the macrocyclic product 136. Eventually, synthesis of MK-6325 (141) was achieved by adopting saponification followed by amidation (Scheme 20).

Conclusion
In this review, we have summarized various approaches to a wide range of carbocycles and heterocycles that deals with a strategic utilization of SM coupling and metathesis as key steps. Interestingly, application of these two powerful methods in combination for a C-C bond formation process shorten the synthesis sequence for the assembly of the target molecules and thus enhances the ease of preparation of various functional molecules. These processes are considered as "green" because of atom economy and synthetic brevity [52] involved in these reactions [12,53,54]. Additionally, several methods are available to remove palladium and ruthenium impurities in minor amounts from the reaction mixture. This aspect is also important in the pharmaceutical industry [4,55]. Later, in 2001, he was promoted to Professor. He has published 250 publications in peer-reviewed journals and elected fellow of various academies (FNASc, FASc, FRSC and FNA). He was also associated with editorial advisory boards of several journals. His research interests include: organic synthesis, green chemistry, development of new synthetic methods for unusual amino acids, peptide modifications, cross-coupling reactions, and metathesis. Currently, he occupies the Pramod Chaudhari Chair Professor in Green Chemistry.