MSc Chemistry
Track Molecular Sciences
Literature Thesis
Oxidative dearomatization/Diels–Alder strategies in the
total synthesis of natural products
by
Suzanne Reus
11239492
15
thof October 2020
12 EC
Augustus – October 2020
Supervisor/Examiner:
Dr. Eelco Ruijter
Table of contents
Abstract ... 3
1. Introduction ... 3
2. Intramolecular Diels–Alder reactions ... 5
2.1 Total synthesis of diterpenoid alkaloids ... 5
2.2 Total synthesis of diterpenes ... 12
2.3 Total synthesis of other natural compounds ... 17
2.4 Selectivity of the oxidative dearomatization/intramolecular Diels–Alder sequence ... 18
3. Intermolecular Diels–Alder reactions ... 19
Abstract
The oxidative dearomatization of o-alkoxyphenol and o-alkylphenol derivatives results in the formation of dienes which can subsequently undergo an intra- or intermolecular Diels–Alder reaction, forming polycyclic products. This oxidative dearomatization/Diels–Alder sequence can be used in the total synthesis of complex natural products, often belonging to the diterpenoid alkaloid or diterpene class. This review aims to give an overview of the recent applications of this reaction sequence and the strategies that are most commonly employed after its application to access different carbon frameworks.
1. Introduction
Simple strategies towards polycyclic frameworks are desirable for the total syntheses of complex natural products. Cycloadditions are especially suited to quickly introduce a high degree of molecular complexity. For example, the Diels–Alder reaction, first described in 1928 by Otto Diels and Kurt Alder,1
can be considered one of the most important reactions in organic chemistry. This reaction between a diene and dienophile, forming a cyclohexene derivative, can be used to obtain as many as four new stereocenters at the same time. It allows for a good control of stereo- and regiochemistry, since it is a stereospecific reaction and its regioselectivity can be predicted through the use of frontier molecular orbital theory. In the case of intramolecular Diels–Alder reactions, the regiochemistry is often simply set by the geometry of the molecule. Moreover, the endo product is often the only or main diastereomer that is formed. This is known as the endo rule, where the more sterically hindered transition state (TS) leading to the endo product is preferred over the TS leading to the exo product, which is frequently attributed to favorable secondary orbital interactions in the endo TS (Figure 1).
Figure 1. Primary and secondary orbital interactions in the formation of the endo and exo adduct of the Diels–
Alder reaction between cyclopentadiene and maleic anhydride. The secondary orbital interactions are indicated in blue and are only present in the TS leading to the endo adduct.
The most common Diels–Alder reactions involve an electron-rich diene and electron-deficient dienophile, also referred to as normal electron demand Diels–Alder reactions. In this case, the highest occupied molecular orbital (HOMO) of the diene interacts with the lowest unoccupied molecular orbital (LUMO) of the dienophile. Less common are the inverse electron demand Diels–Alder reactions, where the LUMO of an electron-deficient diene interacts with the HOMO of an electron-rich dienophile. To use these reactions in total synthesis, suitable dienes and dienophiles have to be designed. In this aspect, the electron-deficient dienes in cyclohexa-2,4-dienones derivatives are of high interest, since they have been shown to undergo both normal and inverse electron demand Diels– Alder reactions, reacting with both electron-deficient and electron-rich dienophiles.2–7 These dienes
can be readily prepared through the oxidative dearomatization of aromatic compounds, which proceeds more efficiently for electron-rich aromatics, so often o-alkoxyphenol and o-alkylphenol derivatives are used as substrates.
Scheme 1 shows a general procedure for the oxidative dearomatization/Diels–Alder reaction of o-alkoxyphenol and o-alkylphenol derivatives 1. The electron-donating substituents at the ortho position of aromatic compounds 1 allow for facile, regioselective dearomatization towards o-benzoquinone monoketals (2) or o-quinols (3). The Diels–Alder reaction with a dienophile, for example ethylene, then proceeds to give bicyclo[2.2.2]octenone 4.
Scheme 1. Oxidative dearomatization/Diels–Alder reaction of o-alkoxyphenol and o-alkylphenol derivatives.
Several methods for the oxidative dearomatizion/Diels–Alder procedure have been developed. In the 1970s, Yates and co-workers developed a tandem procedure as shown in Scheme 2.8,9 Starting from
2-methylphenol derivatives (5), they synthesized several different bicyclo[2.2.2]octenones (7). Their work used a modified version of the Wessely oxidation,10 using lead tetraacetate in combination with
several different unsaturated acids (6) instead of acetic acid. This resulted in the formation of o-quinol esters which upon heating underwent an intramolecular Diels–Alder reaction. Later, they also applied this method to the synthesis of coronafacic acid (8, Scheme 2).11
Scheme 2. Yates’ synthesis of bicyclo[2.2.2]octenones via a modified Wessely oxidation/Diels–Alder procedure
and the structure of coronafacic acid.
Some of the more recent syntheses still use a procedure similar to the one developed by Yates, however, the use of hypervalent iodine reagents has become much more prevalent given their much milder nature. The use of this type of oxidant in oxidative dearomatization/Diels–Alder sequences was pioneered by Liao and co-workers, who used phenyliodine(III) diacetate (PIDA) and phenyliodine bis(trifluoroacetate) (PIFA) for the conversion of o-methoxyphenols into o-benzoquinone monoketals, which they named masked o-benzoquinones (MOBs).12 In 1994, they reported the synthesis of several
bicyclo[2.2.2]octenones via MOB intermediates using PIDA as an oxidant (Scheme 3).13 The
o-methoxyphenols 9 were oxidized to MOBs 10 or 14 in the presence of methanol or nucleophiles 13 respectively. An intermolecular Diels–Alder reaction with dienophiles 11 or an intramolecular Diels– Alder reaction resulted in the products 12 and 15.
Liao’s group has been especially active in studying the synthesis, stability and reactivity of MOBs. MOBs can act as both dienes and dienophiles in Diels–Alder reactions and their high reactivity often results in undesired dimerization. However, this issue can be circumvented through the use of a retro-Diels– Alder/Diels–Alder cascade reaction after dimerization has taken place. Alternatively, the MOBs can be stabilized through halogenation of their 4 position,14,15 addition of a small electron-donating group at
their 5 position16 or addition of large, electron-donating groups to their 2 or 4 position.5,16,17 These
modifications were found to lower the rate of dimerization and allow for the desired Diels–Alder reaction to take place, after which the abovementioned substituents can either be removed or further modified. A large excess of dienophile with respect to the MOB may also suppress dimerization in the case of intermolecular Diels–Alder reactions. Intramolecular Diels–Alder reactions generally suffer less from dimerization owing to the much closer proximity of the dienophile.
This review aims to give an overview of applications of the oxidative dearomatization/Diels– Alder reaction sequence in the total synthesis of natural products in the last 15 years. The syntheses will be divided based on whether the Diels–Alder reaction that is a part of this strategy is intra- or intermolecular. The regio- and stereoselectivities of these reactions will be discussed and common strategies for the synthesis of different carbon frameworks employing an oxidative dearomatization/ Diels–Alder reaction will be outlined.
2. Intramolecular Diels–Alder reactions
Most of the total syntheses that have an oxidative dearomatization/Diels–Alder sequence as a key step use an intramolecular Diels–Alder reaction, as opposed to an intermolecular one. This type of reaction suffers less from the competing dimerization because the dienophile is already much closer to the cyclohexa-2,4-dienone diene. In addition, the regiochemistry of the cycloaddition is often fully controlled by structural constraints. The dienophile can either be introduced earlier in the synthesis or during the oxidative dearomatization step, like in the synthesis of bicyclo[2.2.2]octenones by Yates and co-workers mentioned above (Scheme 2). The oxidative dearomatization/Diels–Alder sequence has mainly been used as a key step in the synthesis of natural products belonging to the diterpenoid alkaloid or diterpene classes. The following subsection will discuss total syntheses of compounds belonging to the former class, the section after that will focus on the diterpenes. This division by natural compound class allows for the comparison of similar substrates of the oxidative dearomatization/Diels-Alder reactions.
2.1 Total synthesis of diterpenoid alkaloids
Many of the natural products that have been synthesized using an oxidative dearomatization/Diels– Alder sequence as a key step belong to the class of diterpenoid alkaloids. These can be classified into the C18-, C19-, and C20-diterpenoid alkaloids based on the size of their central framework. The skeletons
can be categorized even further into several sub-types based on their connectivity. Six diterpenoid alkaloid skeletons relevant to this review are shown in Figure 2.
Figure 2. One C19- and five C20-diterpenoid alkaloid skeleton categories.
The C18-diterpenoid alkaloid weisaconitine D was successfully synthesized by the Sarpong group in
2015 in a total of 30 steps.18 In the same paper, the authors also report the synthesis of the C 19
-diterpenoid alkaloid liljestrandinine. Both natural products are derived from the common tricyclic precursor 16 (obtained in 11 steps) (Scheme 4). The synthesis of weisaconitine D proceeded with the
conversion of 16 to compound 17 in three steps (Scheme 4, route a). PIDA was used for the formation of MOB 18 in 99% yield, which underwent intramolecular Diels–Alder cycloaddition when heated to 150 ᵒC, resulting in 19 in 77% yield. The bicyclo[2.2.2] framework present in 19 had to be converted to the bicyclo[3.2.1] framework found in weisaconitine D. This was achieved (after several other manipulations) through a Wagner-Meerwein rearrangement. Upon treatment of triflate 20 with DBU in DMSO, an 1,2-alkyl shift converts the bicyclo[2.2.2] framework to the desired bicyclo[3.2.1] framework, forming 21. Weisaconitine D (22) was finally obtained after eight more steps.
Scheme 4. Sarpong’s syntheses of weisaconitine D, liljestrandinine, cochlearenine,
N‑ethyl-1α-hydroxy-17-veratroyldictyzine and paniculamine.
Sarpong’s synthesis of the aconitine-type liljestrandinine (24) was completed in a total of 29 steps, including the same key steps as the weisaconitine D synthesis (Scheme 4, route b). Compound 23, differing from 18 only by the presence of a methoxymethylene group at the C4 position (shown in green in Scheme 4) and obtained in six steps from 16, was in this case the substrate for the oxidative dearomatization/Diels–Alder sequence. A yield of 89% was reported for the oxidative dearomatization of 23 and the Diels–Alder reaction proceeded in 60% yield after the ensuing reduction (not shown). The common intermediate 16 was further used in 2016, when Sarpong and co-workers reported the synthesis of cochlearenine, N‑ethyl-1α-hydroxy-17-veratroyldictyzine and paniculamine in 25, 26, and 26 steps respectively (Scheme 4, route c).19 These denudatine-type C
20-diterpenoid alkaloids have an
additional methyl group at the C4 position, shown in red, and a methylene group connected to the bicyclo[2.2.2] structure, shown in blue, as part of their central carbon core. Compound 25 containing the desired methyl group was obtained from 16 in six steps. The oxidative dearomatization followed, transforming 25 into MOB 26 with a yield of 61% including the two previous steps (not shown).
All syntheses proceed through the common intermediate 16 and include an oxidative dearomatization/Diels–Alder sequence. The only difference between the substrates for this step is the substituent on the C4 carbon: a hydrogen, methyl or methoxymethylene group. The yields for the oxidative dearomatization/Diels–Alder reactions have not all been recorded separately, but those that have are comparable. For the oxidative dearomation of 17 and 23 yields of respectively 99% and 89% were reported, for the Diels–Alder reactions of 18 and 26 yields of respectively 77% and 81% were reported.
Another denudatine-type diterpenoid alkaloid, gymnandine, was synthesized by Qin and co-workers in 2016.20 They developed a unified synthesis for the atisine-, denudatine-, hetidine- and
acajonine-type skeletons, but the focus here will be on their total syntheses of gymnandine and the atisine-type diterpenoid alkaloid, dihydroajaconine (Scheme 5A). Phenol 32, obtained from known compound 31 in seven steps, was subjected to a cascade oxidative dearomatization/Diels–Alder reaction using PIDA in methanol. The resulting pentacycle 33 was obtained in 79% yield and converted in seven steps to 34. Treatment of 34 with NaNO2, CuCl and HCl/Et2O initially forms the diazonium salt
(41) of this compound, which is reduced using Cu(I) to give aryl radical 42 (Scheme 5B). A subsequent 1,5-H shift and oxidation of the resulting C19 and C20 α-amidyl radicals 43a and 43b gives rise to the two regioisomeric N-acyliminium ions 44a and 44b. Attack of the hydroxy group in 34 can take place on C20 in 44a, resulting in 35 (42%). External attack of water at C19 in 44b results in 36 (45%). This amide oxidation method was developed by Weinreb and co-workers.21 The synthesis of gymnandine
was continued with two steps from 35, forming 37, which was subjected to an aza-pinacol coupling using SmI2 and N-acetylation. This creates the final C-C bond that is present in the denudatine-type
skeleton and in six steps from 38 gymnandine (39) was obtained. The synthesis of dihydroajaconine (40) was completed in four steps from 36.
Scheme 5. A) Qin’s syntheses of gymnandine and dihydroajaconine. B) Mechanism for the conversion of 34 to 35 and 36.
The oxidative dearomatization/Diels–Alder sequence can often be used to obtain common intermediates for the synthesis of multiple different diterpenoid alkaloid frameworks, like in the abovementioned syntheses by Sarpong and Qin. Another example is the synthesis of atisine-type azitine and hetidine-type navirine C in 2018 by Ma and Liu (Scheme 6).22 Navirine C was obtained as
the structure proposed after its isolation and characterization,23 but it was found that the spectra of
the synthetic compound did not match with the reported data of the isolated natural product. Further comparison of the isolated natural product and the synthetic compound was not possible because the original sample of the natural product and its spectra were lost, so it is unsure whether the compound that was synthesized is navirine C or not. This proposed structure of navirine C and azitine were obtained in 14 and 12 steps, respectively, from 46, in turn derived from cyclohexenone (45) in five steps. Phenol 46 underwent oxidative dearomatization using PIDA, after which the Diels–Alder reaction took place upon heating to 105 ᵒC in toluene forming tetracycle 47 in 88% yield. From 47, the common intermediate 48 could be obtained in six steps. Reductive cyclization of this intermediate using LiAlH4 afforded amidine 49, which could be further reduced to 50 with Li/NH3(l) in 46% yield over
two steps, after which azitine (51) could be obtained in three steps. Alternatively, 47 could be subjected to a hydrogen atom transfer reaction using Mn(dpm)3, TBHP and PhSiH3. Reduction of
Mn(dpm)3 by PhSiH3 forms HMn(dpm)2, which in turn abstracts a hydrogen atom from 48. Radical
cyclization then forms the desired compound 52 in 68% yield, which can be converted into navirine C (53) in six additional steps.
Scheme 6. Ma’s and Liu’s syntheses of azitine and the proposed structure of navirine C.
In 2019, Sarpong’s group reported the synthesis of the arcutine-type C20-diterpenoid alkaloid
arcutinidine in a total of 24 steps (Scheme 7A).24 The precursor for the oxidative dearomatization
reaction (55) was obtained through selective demethylation of tetracyclic compound 54 using TMSI. This allowed for a modified Wessely oxidation using lead tetraacetate and acrylic acid, forming MOB
56 in a diastereoselective manner in 60% yield. The introduced acrylate moiety acts as the dienophile
in the ensuing Diels–Alder reaction which takes place upon heating to 110 ᵒC in toluene. The arcutine-type framework is nearly complete in the resulting Diels–Alder adduct 57, only requiring one more C-C bond to be formed. This was achieved through a pinacol coupling of 58 (three steps from 57) using SmI2 to give 59. With the arcutine core complete, arcutinidine (60) was finally obtained after nine
Scheme 7. A) Sarpong’s synthesis of arcutinidine. B) Qin’s synthesis of arcutinine and arcutinidine.
Around the same time, Qin and co-workers reported their total synthesis of arcutinine in 20 steps, from which arcutinidine could be obtained by saponification (Scheme 7B).25 In their synthesis, the
alcohol in 61 was subjected to TMS protection to ensure a higher diastereoselectivity in the following aza-Wacker cyclization. This palladium catalyzed cyclization was used for the formation of arcutinine’s pyrrolidine ring and resulted in compound 62 (52%) and its C20-epimer (21%) as a separable mixture of diastereomers. After three additional steps, PIDA in refluxing methanol was used for the oxidative dearomatization/Diels–Alder cascade, selectively forming endo adduct 64 out of 63 in 67% yield. To complete the arcutine-type framework, 64 was subjected to a ketyl-olefin cyclization using SmI2
providing 65 in 85% yield. Initially, 64 was treated with SmI2 for 10 minutes in THF/MeOH to remove
the ketal, which was followed by treatment with SmI2/HMPA in THF/t-BuOH to allow the ketyl-olefin
cyclization to take place. This second step also resulted in reduction of the remaining ketone, which then had to be oxidized in a third step. The authors later found that treatment of 64 with SmI2 in
THF/MeOH for a longer time of 12 hours allowed for formation of 65 without reduction of the other ketone. The total synthesis of arcutinine (66) was completed in five steps and arcutinidine (60) could be obtained in one additional step.
In 2020, Inoue and co-workers reported the total synthesis of talatisamine, a C19-diterpenoid
alkaloid (Scheme 8).26 The substrate for their oxidative dearomatization/Diels–Alder reaction step, 67a, was obtained in 19 steps from cyclohexene. HCl/MeOH was used for in situ protection of the
tertiary amine, after which oxidative dearomatization using PIDA could take place, forming MOB 68a. The Diels–Alder reaction of 68a in refluxing toluene only resulted in 17% yield of the desired 70a and 8% yield of 69a. The authors hypothesized that these low yields were caused by the competing dimerization of 68a, and they speculated that bromide substitution of the MOB would make it less susceptible to dimerization. This approach was successful, and compounds 69b and 70b were obtained in 28% and 61% yield, respectively. The formation of minor products 69 proceeds through a boat-like TS 1), while the formation of major products 70 proceeds through a more stable chair-like TS
(TS-2). After 70b was successfully obtained, the bromine was removed by radical reduction and the
co-workers in their synthesis of liljestrandinine and weisaconitine D (Scheme 4) was used by Inoue to convert the bicyclo[2.2.2] framework to a bicyclo[3.2.1] ring system. The Wagner-Meerwein rearrangement afforded 72 in 83% yield. Talatisamine (73) was synthesized in seven more steps, including a Hg(OAc)2-mediated aza-Prins cyclization to form the final C-C bond.
Scheme 8. Inoue’s synthesis of talatisamine.
The napelline-type C20-diterpenoid alkaloid liangshanone was very recently synthesized by Qin’s group
(Scheme 9).27 Interestingly, the oxidative dearomatizion/Diels–Alder sequence was used to directly
obtain the B-ring of liangshanone (82), while the other discussed syntheses of similar diterpenoid alkaloids employ this method for the formation of their respective C- (and D-) rings. Precursor 74 was treated with PIDA and NaHCO3 in methanol, which initially resulted in the formation of a dimer (not
shown). This dimer was immediately converted to the desired endo-adduct 75a in 48% yield and its C1-epimer 75b in 39% yield upon heating in mesitylene through a retro-Diels–Alder/Diels–Alder sequence. Oxidation and reduction of 75b gave more of the desired 75a, from which 76 was obtained in six steps. Oxidative cleavage of the alkene followed by a Mannich cyclization then resulted in the formation of tetracyclic 77, cleaving the C-C double bond and forming new C-C and C-N bonds. At this point, the bicyclo[3.2.1] system still had to be synthesized. To this end, 77 was converted in four steps into 78, which was subjected to an intramolecular aldol addition using LDA. The resulting 79 was transformed into 80, from which hydrolysis of the methyl enol ether and another intramolecular aldol addition took place, completing the carbon framework of liangshanone as seen in 81. The total synthesis of liangshanone (82) was completed with seven steps.
Scheme 9. Qin’s synthesis of liangshanone.
Two relatively simple atisine-type diterpenoid alkaloids, atisine and isoazitine, were synthesized by Wang and co-workers in 2012 (Scheme 10).28 Compound 83 was the substrate of the oxidative
dearomatization/Diels–Alder reaction, producing pentacycle 84 in 78% yield upon exposure to PIDA in methanol followed by heating in xylene. Intermediate 85 was obtained in three steps from 84 and further converted to atisine (86) using a known procedure developed by Pelletier.29,30 Alternatively,
isoazitine (87) could be formed in three steps from 85.
Scheme 10. Wang’s syntheses of atisine and isoazitine.
Wang’s group also reported the synthesis of several other atisine-type diterpenoid alkaloids and related diterpenes in 2015 (Scheme 11).31 In this case, they used a relatively flexible tether connecting
the dienophile to the diene, resulting in the initial formation of dimer 89 in 95% yield after oxidative dearomatization of 88. Heating this dimer in mesitylene gave the desired tricycle 90 via a retro-Diels– Alder/Diels–Alder cascade in 91% yield. This compound was further converted to 91 in nine steps, after which another ring of the atisine-type framework was installed using a Ru-catalyzed cycloisomerization, resulting in 92. Twenty more steps were needed to obtain 93, from which dihydroajaconine (40) and spiramilactone B (94) could be made in three and two steps, respectively.
94 could be further converted into spiraminol (95) upon DIBAL-H reduction. Finally, the alkaloids
Scheme 11. Wang’s syntheses of dihydroajaconine, spiramilactone B, spiraminol and spiramines C and D.
2.2 Total synthesis of diterpenes
The abovementioned spiraminol and spiramilactone B are already examples of diterpenes made using the oxidative dearomatization/Diels–Alder sequence as a key step in their total synthesis. Another diterpene synthesis that employs this method is the total synthesis of atropurpuran, a natural product related to the arcutine-type diterpenoid alkaloids. It was synthesized by two different groups using an oxidative dearomatization/Diels–Alder strategy as the key step. Interestingly, both groups used this key step in very different stages of their syntheses. In 2016, Qin and co-workers used it in a relatively early stage of their synthesis, forming endo adduct 99 from 98 in 72% yield using PIDA in methanol and then changing the solvent to xylene and heating (Scheme 12A).32 After another six steps, aldehyde 100
underwent an aldol addition followed by a SmI2-mediated ketyl-olefin cyclization to obtain the desired
framework present in 102. Before the cyclization could take place, a bulky TBS group was introduced to force the E-ring to adopt a boat conformation instead of a chair conformation, bringing the ketone and olefin closer together. The subsequent ketyl-olefin cyclization proceeds without removal of the cyclic ketal. While the dimethyl ketal in Qin’s synthesis of arcutinine was removed (Scheme 7), this cyclic ketal is untouched because it is not at the α-position of a ketone. Eleven more steps were needed to complete the synthesis of atropurpuran (103).
In contrast, the synthesis reported by Xu and co-workers in 2019 uses the oxidative dearomatization/Diels–Alder sequence to finalize the atropurpuran framework (Scheme 12B).33 From 101, a ring-closing enyne metathesis reaction is used to make tricycle 105 in 50% yield, which was then
treated with PIDA in methanol. The double oxidative dearomatization introduces two methoxy groups selectively at the ortho position. However, when the reaction was carried out at 0 ᵒC instead of room temperature, para selectivity was obtained, which does not result in the formation of a MOB. A proposed mechanism for the double oxidative dearomatization is given in Scheme 12C. After the initial oxidation, tautomerization takes place to restore the aromaticity and a second oxidative dearomatization takes place. Heating to 160 ᵒC in mesitylene afforded 55% of 106, in which the artropurpuran core structure is complete. After nine more steps, atropurpuran (103) was obtained.
Scheme 12. A) Qin’s synthesis of atropurpuran. B) Xu’s synthesis of atropurpuran. C) Proposed mechanism for
double oxidative dearomatization of 105.
Several different groups achieved the synthesis of the ent-kaurene diterpenoid maoecrystal V, two of which applied an oxidative dearomatization/Diels–Alder strategy. In 2010, Yang and co-workers reported the first total synthesis of maoecrystal V (Scheme 13A).34,35 Diazophoshonate 111 was
converted into tricycle 112 by rhodium-catalyzed O-H bond insertion with 60% yield. Two more steps then furnished the key precursor 113. At this point, a Wessely oxidation resulted in the formation of two diastereomers, 114 and 115, due to acetoxylation taking place on either side of the aromatic ring. Both underwent Diels–Alder reactions in toluene at 145 ᵒC, forming products 116a-c, although only one diastereomer gave the desired endo product via TS-5b (36% yield). The synthesis was continued from this compound 116c, resulting in maoecrystal V (117) after seven steps. In 2015, Yang’s group published an asymmetric total synthesis of (−)-maoecrystal V, which includes the same oxidative dearomatizion/Diels–Alder sequence, transforming enantiopure 113 into 116c.36
A different approach was taken by Zakarian and co-workers in 2013 (Scheme 13B).37 They used
a rhodium-catalyzed C-H bond insertion followed by three more steps to get oxidative dearomatization precursor 120. After oxidation using PIFA, a vinyl silyl tether was introduced, giving 121 in 85% yield. The intramolecular Diels–Alder reaction of 121 took place in toluene at 110 ᵒC, selectively forming the
endo adduct 122 (95%). This is in contrast with the synthesis of Yang’s group, where both endo and exo adducts were formed due to a low facial selectivity. In Zakarian’s synthesis , the tether ensures
that the dienophile reacts with the correct face of the diene. After four steps from 122, the lactone ring of maoecrystal V was installed by radical cyclization of 123 to give 124. The total synthesis was completed with another nine steps. Zakarian’s group also completed an enantioselective total synthesis of (−)-maoecrystal V through the use of a chiral auxiliary in their C-H bond insertion step.38
Scheme 13. A) Yang’s synthesis of maoecrystal V. B) Zakarian’s synthesis of maoecrystal V.
Another diterpenoid, vinigrol, was synthesized by Njarðarson and co-workers in 2013 (Scheme 14).39,40
The substrate of the oxidative dearomatization/Diels–Alder reaction (126) was prepared from 125 by DIBAL reduction, conversion of the resulting hydroxy group to a trifluoroethyl ether and Dakin oxidation of the aldehyde. The more electron-withdrawing trifluoroethyl ether group was introduced to improve the regioselectivity of the oxidative dearomatization. It deactivates the undesired ortho position, since it makes the carbon atom it is attached to more electron-deficient compared to the
Scheme 14. Njarðarson’s synthesis of vinigrol.
In 2006, Danishefksy and co-workers reported the total synthesis of 11-O-debenzoyltashironin (133, Scheme 15A).41 Interestingly, they used an oxidative dearomatization/Diels–Alder sequence to make
all four rings of this molecule in one step. Allene 130 was treated with PIDA in dichloromethane to give MOB 131, which underwent a transannular Diels–Alder reaction upon microwave irradiation (600 watt). This completes the carbon skeleton of 11-O-debenzoyltashironin as seen in 132 in a single step with 65% yield. Eight more steps were needed to complete the synthesis.
A formal total synthesis of 11-O-debenzoyltashironin was also completed by Mehta and Maity in 2011 (Scheme 15B).42 Oxidative dearomatization of 134 in the presence of allylic alcohol 135 gave
Diels–Alder precursor 136 in 65% yield. The cycloaddition took place in refluxing toluene, forming three of the four rings of the final product with a yield of 80%. A ring-closing metathesis was used to form the final ring system, resulting in the formation of 137 in 66% from 138. Nine more steps were needed to obtain the methyl ester (139) of 11-O-debenzoyltashironin, completing the formal total synthesis, as the conversion of 139 to 133 was known from the patent literature.43
Scheme 15. A) Danishefksy’s synthesis of 11-O-debenzoyltashironin. B) Mehta’s and Maity’s formal total
synthesis of 11-O-debenzoyltashironin.
The diterpenoids (−)-scabronine A, G and (−)-episcabronine A, do not contain a bicyclo[2.2.2]octenone or similar framework, but their synthesis by Nakada and Kobayakawa in 2013 still employs the oxidative dearomatization/Diels alder sequence as one of its key steps (Scheme 16A).44 Allene 140 was
converted into 141 in 97% using PIDA in methanol at 0 ᵒC, after which it was allowed to react at room temperature for seven days. The use of higher temperatures for the Diels–Alder reaction resulted in the formation of a number of unknown side products. This forms the five- and six-membered rings present in all three diterpenoids. After five more steps, PIDA-mediated oxidative vicinal diol cleavage and subsequent ring-closing metathesis using the Grubbs II catalyst constructed the desired
seven-membered ring, forming tricycle 143 from 142. While (−)-scabronine G (146) could be obtained in only three steps from 143, the syntheses of (−)-episcabronine A (147) and (−)-scabronine A (145) took another 11 steps, proceeding from the common intermediate 144. In 2014, they further employed this approach for the synthesis of diterpenoid (−)-cyathin B2 (148, Scheme 16B).45 The ring-closing
metathesis product 143 could be converted into this natural product in five steps.
Scheme 16. A) Nakada’s and Kobayakawa’s syntheses of (−)-scabronine A, G and (−)-episcabronine A. B) Nakada’s
and Kobayakawa’s synthesis of (−)-cyathin B2.
In 2019, Ding and co-workers reported the synthesis of diterpenoids rhodomolleins XX and XXII (Scheme 17).46 After desilylation of 149 using TBAF, oxidative dearomatization/Diels–Alder took place
using PIDA in methanol at 65 ᵒC. The Diels–Alder reaction can take place at both faces of the formed MOB, resulting in the formation of two diastereomers, 150a (25%) and 150b (70%). The desired major isomer 150b was then converted in two steps to epoxide 151, which underwent ring opening followed by a Beckwith-Dowd rearrangement, forming the bicyclo[3.2.1] framework in 153 (61%) and side product 152 (15%). Rhodomolleins XX (154) and XXII (155) were obtained after another six or five steps, respectively.
Scheme 17. Ding’s synthesis of rhodomolleins XX and XXII.
2.3 Total synthesis of other natural compounds
The total synthesis of yunnaneic acids C and D and rufescenolide was achieved in 2013 by the group of Snyder (Scheme 18).47 These natural products are oligomers of caffeic acid and could potentially be
made via an oxidative dearomatization followed by a Diels–Alder dimerization. However, the three natural products are all the less favored exo adducts, which poses a selectivity problem for the intermolecular Diels–Alder reaction. Snyder and co-workers solved this problem by using a Wessely oxidation to attach two units to each other, allowing for an intramolecular Diels–Alder reaction that resulted in the desired exo adducts. To this end, precursor 156 was treated with Pb(OAc)4 and the
other reaction partner 157 was added, resulting in a 1:1 inseparable mixture of 158 and its epimer of the chiral carbon next to the ester linkage in 50% yield. Reduction of the ketone in 158 gave alcohols
159 and 160 and their respective diastereomers, which could now be separated. From 159, yunnaneic
acid D (161) could be obtained in three steps, while 160 could be converted into yunnaneic acid C (162) in four steps. Rufescenolide was obtained using the same oxidative dearomatization/Diels–Alder procedure, converting 163 and 164 to 165 in 69% yield, from which rufescenolide (166) could be obtained in three steps.
Scheme 18. A) Snyder’s syntheses of yunnaneic acids C and D. B) Snyder’s synthesis of rufescenolide.
2.4 Selectivity of the oxidative dearomatization/intramolecular Diels–Alder sequence
Generally, the oxidative dearomatization/intramolecular Diels–Alder reactions proceed with moderate to very good yields and excellent selectivities. Selectivity problems were only observed in the syntheses of talatisamine (Scheme 8), maoecrystal V by Yang (Scheme 13) and the rhodomolleins (Scheme 17). In the case of the rhodomolleins this can be attributed to the longer carbon chain connecting the diene and dienophile, since a seven-membered ring is formed next to the bicyclo[2.2.2] unit in this reaction as opposed to a six-membered ring in most of the other syntheses. In Yang’s synthesis of moaecrystal V both endo and exo products are formed, due to the low facial selectivity of the reaction. This is in great contrast with all the other intramolecular Diels–Alder reactions, where the more stable endo products are solely obtained. An exception is the synthesis of yunnaneic acids and rufescenolide, where the exo product is actually desired (Scheme 18). The synthesis of talatisamine also shows a low facial selectivity, but in this case both diastereomers still arise from an endo TS because a boat-like conformation is adopted in one of them. In contrast, Diels–Alder reactions that start from similar precursors (e.g. Scheme 10) all proceed highly diastereoselectively. The only clear difference between these precursors and the one used for the synthesis of talatisamine is the position of the ketone and methyl ketal on the MOB, so perhaps the boat-like conformation leading to the undesired endo adduct
3. Intermolecular Diels–Alder reactions
In the oxidative dearomatization/Diels–Alder reaction sequence, the intramolecular variant of the cycloaddition has been much more applied than the intermolecular one. However, there have still been some total syntheses that apply this strategy. Most commonly, the intermolecular Diels–Alder reaction with ethylene or other simple dienophiles and the dimerization of several phenol derivatives have been successfully applied to the synthesis of natural products. Because the application in of the intermolecular variant of the oxidative dearomatization/Diels–Alder sequence in total synthesis is less than that of the intramolecular one, the syntheses have not been divided based on natural product class, like in section 2.
Fukuyama and co-workers synthesized two different diterpenoid alkaloids, the denudatine-type (−)-lepenine in 2014 and the aconitine-denudatine-type (−)-cardiopetaline in 2016 (Scheme 19).48,49 The
precursor for the oxidative dearomatization/Diels–Alder sequence was obtained after protection of the tertiary amine in 167 as its ammonium salt. Treatment with PIDA in methanol gave MOB 168 in 88% yield, which then underwent an intermolecular Diels–Alder reaction with ethylene (70 bar), selectively affording 169 in 84% yield. The selectivity of this reaction may be attributed to the more shielded β-face in 168, leading to exclusive approach from the α-face. With this reaction, the denudatine-type framework was complete and (−)-lepenine (170) could be obtained in an additional eight steps. Alternatively, 169 could be converted to epoxide 171 in ten steps. To obtain the aconitine-type framework of (−)-cardiopetaline, a Wagner-Meerwein rearrangement was used to obtain the bicyclo[3.2.1] system. Heating of 171 at 150 ᵒC in methanol by microwave radiation resulted in the desired rearrangement, capture of the intermediate cation by methanol and ketone formation through elimination of benzenesulfinic acid. Next, this ketone was reduced using NaBH(OAc)3 and lastly the
MOM and methyl ether were cleaved to give (−)-cardiopetaline (172).
Scheme 19. Fukuyama’s syntheses of (−)-lepenine and (−)-cardiopetaline
In 2015, Liu’s group reported the synthesis of several atisane-type diterpenoids (Scheme 20A).50 Their
initial aim was to use an intermolecular Diels–Alder reaction between a MOB and ethylene, as in Fukuyama’s synthesis of (−)-lepenenine. However, this did not result in formation of the desired product and similar reactions with trimethylsilylacetylene as the dienophile also failed to form the cycloadduct. A successful reaction was finally achieved through the use of unmasked ortho-benzoquinone 174, which was formed from 173 using Ce(SO4)2·4H2O. Addition of MnO2 was needed
during the Diels–Alder reaction of 174 with trimethylsilylacetylene to prevent reduction of the unmasked ortho-benzoquinone to its diol. The resulting product was an inseparable 7:1 mixture of
major diastereomer : [Σminor diastereomers] in 78% combined yield. The preference for the major product (175) can be attributed to lower steric hindrance in the corresponding TS. DFT calculations (M06-2X/6-31G(d,p)) were also performed to gain insight into the facial selectivity of the reaction. It was found that the TSs leading to α-facial selectivity were less geometrically distorted than the ones leading to β-facial selectivity, which accounts for the high α-facial selectivity observed in the formation of 175. The common intermediate 176, obtained in two steps from 175, could be converted to lactone
177 in 5 steps. Treatment of 177 with p-TsOH in benzene resulted in a cascade reaction: ketal
deprotection, opening of the lactone, deprotonation resulting in the formation of the isopropenyl unit and lactonization gave the new lactone 178. Crotobarin (179) was obtained in two steps from this lactone. The common intermediate 176 could also be converted to 180 in two steps, from which crotogoudin (181) could be obtained in an additional six steps, including the cascade reaction that was also used for the synthesis of crotobarin. Alternatively, 180 could be converted into atisane-3β,16α-diol (182) or 16S,17-dihydroxy-atisan-3-one (183) in four and eight steps, respectively.
Sarpong’s group achieved the synthesis of (−)-crotogoudin in 2017 (Scheme 20B).51
Tetramethylguanidine was used to selectively cleave the aryl ester in 184, which was followed by a double oxidative dearomatizion to give MOB 185 in 65% yield. Its MOB isomer and the para-quinol ether were also obtained as side products, both in yields of 11-13%. Similarly to Fukuyama’s synthesis of (−)-lepenenine (Scheme 19), a Diels–Alder reaction with ethylene was used to obtain 186 in 90%. However, the temperature needed to achieve this reaction was much higher, 140 ᵒC compared to 70 ᵒC, and a mixture of diastereomers was obtained (6:1 dr), which was not the case in Fukuyama’s synthesis. This difference in reactivity may be caused by the distortion in Fukuyama’s substrate due to the additional ring systems that are present in 168 compared to 185. (−)-crotogoudin (187) could be obtained in three steps from 186.
Scheme 20. A) Liu’s syntheses of crotobarin, crotogoudin, atisane-3β,16α-diol and
16S,17-dihydroxy-atisan-3-one. B) Sarpong’s synthesis of (−)-crotogoudin.
(−)-Hydroxyzinowol, a dihydro-β-agarofuran sesquiterpene, was synthesized in 2014 by Inoue and co-workers (Scheme 21).52 Oxidative dearomatization of 188 using NaIO
4 resulted in attack of the nearby
hydroxyl group, leading to epoxide 189. Diels–Alder reaction with ethynyl p-tolyl sulfone selectively gave 190 in 70% yield and set the desired stereochemistry at C10. At first sight, approach of the dienophile from the α-face of 189 may seem counterintuitive, but NMR analysis of 189 and 190 proved otherwise. It indicated that both compounds adopt a twist-boat conformation, where approach from the β-face (shown in blue) is shielded, while the α-face is free to approach (shown in green). From 190, Nineteen additional steps were needed to complete the total synthesis of (−)-hydroxyzinowol (191).
Scheme 21. Inoue’s synthesis of (−)-hydroxyzinowol.
The dimerization of o-quinols is not always undesired, since it can also be used to synthesize several natural products. In 2007, Quideau and co-workers synthesized (+)-aquaticol from compound 192 via SIBX (stabilized IBX53) mediated hydroxylative dearomatization, followed by dimerization (Scheme
22A).54 This dearomatization is not as regioselective as PIDA-mediated oxidative dearomatization,
since the other ortho-position is also hydroxylated. Furthermore, it also produces two diastereomers, (S,R) and (S,S), which only dimerize with themselves in an endo-selective Diels–Alder reaction. This results in the formation of diastereomers (+)-aquaticol (193a) and 193b in 49% combined yield, with catechol 194 (22% yield) as a side product. The observed stereoselectivity was investigated using a TS search (B3LYP/6-31G(d)) and natural bond order analysis. The calculations suggested that the stereoselectivity in this Diels–Alder reaction is determined by a Cieplak hyperconjugation effect55,56 in
both reactants of the dimerization. Plausibly, the same explanation can be given for the stereoselectivity observed in the other three reactions of chiral o-quinones in Scheme 22.
Later in 2007, the same group reported the synthesis of grandifloracin using identical reaction conditions (Scheme 22B).57 Compound 195 was converted into grandifloracin (196) using SIBX in 30%
yield. Again, a catechol side product was formed, but in this case it was unstable and not isolable. The same stereoselectivity as in the synthesis of (+)-aquaticol was observed, resulting in the formation of a single diastereomer.
Grandifloracin was synthesized in 2015 by Stoltz’s group as well (Scheme 22C).58 Their focus
was on diversification of the dimerization product, so the benzoyl groups are installed in the final step, instead of already being present. Oxidative dearomatization using NaIO4 in water resulted in the
formation of an epoxide, which dimerized to give adduct 198 as a mixture of diastereomers (>10:1 dr) in 89% yield. While the selectivity of this step is lower than in the synthesis of grandifloracin by Quidea, the yield is much higher, which can be attributed to the regioselectivity of the oxidative dearomatization step. However, two additional steps were needed to complete the synthesis of grandifloracin (196).
SIBX-mediated hydroxylative dearomatization was used for the synthesis of illicidione A and illihendione A by Yu and co-workers in 2015 (Scheme 22D).59 Conversion of 199 to 200 and 203 in five
and four steps, respectively, yielded the desired precursors. The hydroxylative dearomatization of both compounds proceeded with facial selectivity due to the bulky benzyl groups. Homodimerization of 200 resulted in the selective formation of 201 with 53% yield, which could be converted into illihendione A (202). Heterodimerization of 200 and 203 gave a mixture of homodimer 201 in 37% yield and heterodimer 204 in 26% yield. It was found that the MOB derived from precursor 203 only reacts as a dienophile, so the other two possible products were not obtained. Illicidione A (205) was obtained from 204 by benzyl deprotection.
Scheme 22. Syntheses employing a dimerization strategy. A) Quideau’s synthesis of (+)-aquaticol. B) Quideau’s
synthesis of grandifloracin. C) Stoltz’s synthesis of grandifloracin. D) Yu’s syntheses of illihendione A and illicidione A.
In 2009, Snyder and co-workers reported the synthesis of helisorin, helisterculin A and helicterin B (Scheme 23).60 Their synthesis proceeds through a retro-Diels–Alder/Diels–Alder mechanism. The
dimer which is initially formed was thought to be the kinetic product, after which heating to higher temperatures results in the desired thermodynamic product. Dimer 207 is formed from 206 as a 1:1 mixture of diastereomers in 99% yield after treatment with PIDA in methanol/dichloromethane. The Diels–Alder adduct 209 was obtained as a 1:1 separable mixture of diastereomers when dimer 207 was heated at 220 ᵒC in the presence of 208. The stereocenters in 206 and 208 were too distant to influence the facial selectivity of the reaction, which is why two diastereomers were obtained. Furthermore, the explanation given for the stereoselectivity in the reactions of Scheme 22 cannot be applied to this dimerization, since the MOB does not contain a chiral center. Helisorin (210) and helicterin B (213) could be obtained in two and eight steps from 209, respectively. The synthesis of helisterculin A required the reaction of dimer 207 with dienophile 211, which proceeded with 44% yield and 1:1 dr. Helisterculin A (212) was obtained after three additional steps.
Scheme 23. Snyder’s syntheses of helisorin, helisterculin A and helicterin B.
4. Conclusion and outlook
An overview has been given of recent applications of the oxidative dearomatization/Diels alder reaction sequence in the total synthesis of natural compounds. These reactions mostly proceed with excellent stereoselectivity, especially in the case of an intramolecular Diels–Alder reaction. Furthermore, the oxidative dearomatization/Diels alder reaction allows for the facile synthesis of bicyclo[2.2.2]octenones, from which several strategies can be applied to obtain more complex frameworks. In most syntheses, the resulting ketone, dimethyl acetal and/or double bond are removed or converted to a different functional group, but the bicyclo[2.2.2]octenone system remains intact and no new carbon bonds to it are formed. However, several strategies have also been used to obtain more complex frameworks directly from the bicyclo[2.2.2]octenone system. Either a Wagner-Meerwein rearrangement, as in the syntheses of weisaconitine D and liljestrandine by Sarpong (Scheme 4) and the synthesis of talatisamine by Inoue (Scheme 8), or a Beckwith-Dowd rearrangement, as in Ding’s
atropurpuran (Scheme 12A). A ring-closing metathesis was used to complete the framework of 11-O-debenzoyltashironin in Mehta’s and Maity’s formal synthesis (Scheme 15B). A Heck cascade reaction was used by Njarðarson to obtain the vinigrol framework (Scheme 14). Of note, in the syntheses of atropurpuran by Xu (Scheme 12B) and 11-O-debenzoyltashironin by Danishefksy (Scheme 15A), the oxidative dearomatization/Diels–Alder reaction immediately furnishes the complete carbon framework of these compounds. Finally, a C-C bond in bicyclo[2.2.2]octenone framework can also be broken, which was achieved in the synthesis of (epi)scabronines by Nakada and Kobayakawa (Scheme 16) and hydroxyzinowol by Inoue (Scheme 21) using a vicinal diol cleavage and ozonolysis, respectively. A C-C bond breaking reaction was also employed in the synthesis of liangshanone by Qin’s group, where oxidative cleavage of the alkene followed by a Mannich cyclization was used to alter the bicyclo[2.2.2]octenone framework (Scheme 9).
Many of the synthesized natural products are either diterpenoid alkaloids or diterpenes with similar carbon frameworks, belonging to only a few different sub-types. In the future, total synthesis of compounds from these two classes using the oxidative dearomatization/Diels–Alder sequence will most likely continue, but might focus on increasing the amount of framework sub-types that can be accessed. The total synthesis of the liangshanone, belonging to a sub-type from which a natural product had not been synthesized using the oxidative dearomatization/Diels–Alder sequence before, already indicates that it is possible to access other types of frameworks than the most commonly synthesized ones. So, total syntheses of natural products belonging to different and perhaps more complex sub-types could be achieved in future research.
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