Total Synthesis of Bioactive Natural Prod- Tancy

SYNPACTS ▌1

Totalsynpacts Synthesis of (+)-Fusarisetin A: A Biomimetic Approach JunBiomimetic Yin, Synthesis ofShuanhu (+)-Fusarisetin A Gao* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, P. R. of China Fax +86(21)62604784; E-mail: [email protected] Received: 26.08.2013; Accepted after revision: 17.09.2013

Abstract: This article outlines our recent efforts to synthesize (+)-fusarisetin A, a naturally occurring 3-acyltetramic acid, by a route based on a hypothetical biosynthesis. Our research suggests that the biosynthesis of (+)-fusarisetin A might involve the aerobic oxidation of equisetin, possibly mediated by metal oxidants or by photochemically produced reactive oxygen species. Key words: radical reactions, total synthesis, biosynthesis, hetero- cycles, polycycles

Natural products have proven to be an indispensable Jun Yin (left) was born in Shandong Province, China, in 1977. He 1 source of human therapeutic agents. Many significant received his bachelor’s degree in 2000 and his master’s degree in drugs are based on natural products or compounds derived organic chemistry in 2003, studying under Professor Jianwu Wang from natural products, such as penicillin (antibiotic), qui- at Shandong University. From 2003 to 2005, he worked at WuXi nine and artemisinin (antimalarials), lovastatin (lipid-con- AppTec. (Shanghai) as a chemist. From 2006 to 2011, he worked at 2 Roche R&D Center (China) Ltd. as a medicinal chemist. In 2011, he trol agent), and taxol and doxorubicin (anticancer drugs). joined Professor Shuanhu Gao’s group to pursue doctoral studies at Historically, these drugs have revolutionized human life the Department of Chemistry of East China Normal University. His by improving health standards and lengthening life expec- research projects focus on total synthesis of bioactive natural prod- tancy. These natural therapeutics have also served as driv- ucts. ing forces for the exploration of natural product synthesis, Shuanhu Gao (right) was born in Ningxia Province, China, in 1979. the growth of which not only promotes the development He received his B.S. degree from Lanzhou University in 2001. In 2006 he obtained his Ph.D. from Lanzhou University under the direc- of new synthetic methodologies, but also provides a plat- tion of Professor Yongqiang Tu. From 2007 to 2010, he was a post- form for further studies on medicinal chemistry and chem- doctoral fellow in Professor Chuo Chen’s group at the UT Southwestern Medical Center at Dallas. He began his independent ca- reer as a professor in the Department of Chemistry at East China Nor- OH Me Me OH mal University in October 2010. His current research interests focus N N 3 primarily on the synthesis of complex natural products and on medic- HO E O O E OH inal chemistry. O O 4 O D 1 O Me D C Me C 5 Me 16 Me ical biology. Therefore, natural product synthesis is an H B H H H H A A B H important aspect of both academic and pharmaceutical Me Me H H chemistry. originally proposed structure of revised structure of fusarisetin A (+)-fusarisetin A (1) The goal of natural product synthesis has been to provide the target molecule efficiently and in adequate amounts;3 19 Me R1 this requires practicing chemists to pay attention to such O O 2 N OH N OH 4 5a,b 3 issues as chemoselectivity, atom economy, step econ- E 5c–e 5f,g This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 1 18 HO omy, and redox economy. In this SynPact article, we HO 4 22 17 Me O Me O wish to outline our recent efforts to achieve an efficient 16 Me20 Me 14 13 15 6 synthesis of (+)-fusarisetin A, a promising anticancer H B 7 5 H A 10 agent, based on a hypothetical biosynthesis of the mole- 21Me 12 8 R2 11 H 9 H cule. We believe that our scalable synthesis will permit equisetin (2) R1 = H, R2 = Me, trichosetin (3) structure–activity relationship studies and facilitate fur- 1 2 R = Me, R = CH2OH, ophiosetin (4) ther studies on the medicinal chemistry of this molecule. Figure 1 Structures of (+)-fusarisetin A and biogenetically related Tetramic acid based natural products6 typically contain a natural products pyrrolidine-2,4-dione moiety, which normally exists as a SYNLETT 2014, 25, 0001–0007 mixture of keto/enol tautomers (Scheme 1; I and II). Most Advanced online publication: 05.11.20130936-52141437-2096 tetramic acids carry acyl substituents in the C-3 position DOI: 10.1055/s-0033-1340153; Art ID: ST-2013-P0821-SP and can therefore generally form four detectable tauto- © Georg Thieme Verlag Stuttgart · New York 2 J. Yin, S. Gao SYNPACTS

O R2 the corresponding peptide (A and B, respectively); this, in 3 3 O R HO R3 R turn, might be derived from a carboxylic acid and an ami- 4 N COOH fast 3 no acid. Because of their unique structures and potential 5 R1 2 O R N R2 2 O A biological activities, naturally occurring tetramic acids 1 N have attracted a considerable degree of interest from or- R1 1 R ganic chemists since the 1960s.6 I II R2 O (+)-Fusarisetin A (1; Figure 1), a new 3-acyltetramic acid, tetramic acid R3 HN COOH OH was isolated from the soil fungus Fusarium sp. FN080326 pyrrolidine-2,4-dione 1 R 7 carboxylic acid amino acid by Ahn and co-workers in 2011. As a fungal metabolite, (+)-fusarisetin A is a potent inhibitor of acinar morpho- H genesis, cell migration, and cell invasion in MDA-MB- H O O 231 cells. Investigations of cell growth and cell death in O R6 O R6 4 fast 3 this breast-cancer cell line indicated that (+)-fusarisetin A O O R5 7 5 does not exhibit significant cytotoxicity. These findings 5 O 5 O R N 2 R N 1 R6 N COOH suggest that (+)-fusarisetin A might be a valuable antican- R4 R4 R4 cer agent, especially for the inhibition of cancer-cell me- III IV B tathesis. Besides its promising biological activity, (+)- fusarisetin A (1) has some interesting structural features. slow slow It contains a pentacyclic ring system (A–B–C–D–E) that R5 R6 R6 O O includes a trans-decalin moiety (rings A and B), a spiro O O O O fast HN COOH moiety (rings C and E), and a 3-acyltetramic acid moiety R6 OH H H R4 (ring E). It has ten stereocenters, including two all-carbon 5 O carboxylic acid amino acid 5 O R N quaternary centers (C-1 and C-16) and a hetero-quaterna- R N 4 ry center (C-4). Ahn and co-workers confirmed the rela- 4 R R tive configuration of (+)-fusarisetin A by x-ray VI V crystallographic analysis. The absolute stereochemistry of 3-acyltetramic acid 1 was originally assigned by means of the exciton chirali- Scheme 1 Tetramic acids and 3-acyltetramic acids ty circular dichroism method, but was subsequently revised by Li and co-workers as a result of their chemical synthesis.8a The molecule has attracted considerable at- mers, consisting of the two pairs of rapidly interconvert- tention from the synthetic chemistry community since its ing internal tautomers III/IV and V/VI. Biogenetically, discovery. To date, four groups, including ourselves, have the construction of tetramic acids and 3-acyltetramic acids accomplished total syntheses of fusarisetin A. Li and co- might involve the formation of bond between the C-3 and workers achieved the first synthesis by using a palladium- C-4 atoms by an intramolecular Dieckmann cyclization of catalyzed oxygen-to-carbon allylic rearrangement to give

OH O

Me OH O N OH O N E Me 1 biomimetic HO 4 O cyclization coupling Me O Me 6 Me H B H 5 Me A Me H equisetin (2) Me

aerobic polyenoylamino acid (5) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. oxidation

O Me OH NH2 N O S-Enz HO O OH O O HO 1 4 O D (S)-serine (6) Me C 5 Me 6 Me H H Me H Me H (+)-fusarisetin A (1) Me unsaturated fatty acid (7)

Scheme 2 Research plan based on a biosynthetic hypothesis

Synlett 2014, 25, 1–7 © Georg Thieme Verlag Stuttgart · New York SYNPACTS Biomimetic Synthesis of (+)-Fusarisetin A 3 the enantiomer (−)-1; as a result, they revised the absolute for the exploration of its laboratory synthesis and biolog- configuration of the molecule.8a Theodorakis and co- ical functions. During our retrosynthetic analysis, we con- workers proposed a biosynthetic pathway from equisetin ducted a careful literature search that showed that, in (2) and they accomplished a biomimetic synthesis of (−)- addition to (+)-fusarisetin A, several other tetramic acids 1 by a one-pot radical cyclization/aminolysis approach.8b,c can be isolated from fungi. These biogenetically related 3- Recently, Yang and co-workers reported a synthesis of acyltetramic acids include equisetin (2),10 trichosetin (+)-1 in which their intramolecular version of the Pauson– (3),11 and ophiosetin (4)12 (Figure 1). Equisetin (2) was Khand reaction served as a key step.8d isolated from the white mold Fusarium equiseti in 1974, 9 and it shows strong antibiotic activity, HIV inhibitory ac- Our research group is interested in the synthesis of bioac- 10 tive natural products with anticancer potential. We con- tivity, and selective cytotoxicity to mammalian cells. sidered that (+)-fusarisetin A (1) would be a perfect target Surprisingly, we found that both (+)-fusarisetin A (1) and

O OEt

Me CHO Me

2 steps a) 10, CH2Cl2 b) HCl Me O O CHO 91% THF Me Me O Me O (+)-citronellal (8) 9 11, E:Z = 16:1

O OEt O OEt

Me Me Me c) 13, LHMDS, THF d) DIBAL

CHO 63% (2 steps) CH2Cl2 Me Me 94% 12 14, E/Z > 15:1 Me R H Me Me Me f) BF ⋅OEt 3 2 O

CH2Cl2 H Me 15, R= CH OH Me e) DMP 2 16, R= CHO endo-selectivity

EtO O CHO Me O Me then 18 g) 20, toluene H Me Me A B H 47% 68% (3 steps) Me H H H 17 Me H 19 OMe OTBS

O Me N O O Me h) NaOMe, N OH MeOH, 72% O HO This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Me Me i) HF, MeCN Me 95% O Me H H H Me Me H H 21 equisetin (2)

O N2 H O N CO2Et O MeO Me Me P OEt Ph3P Me OEt OEt TBSO 1013 18 20

Scheme 3 First-generation synthesis of equisetin (2)

© Georg Thieme Verlag Stuttgart · New York Synlett 2014, 25, 1–7 4 J. Yin, S. Gao SYNPACTS equisetin (2) have similar natural sources and similar lecular Diels-Alder reaction by using the polyenoylamino structural properties, including the basic skeletal rings A, ester 27. Under chemical conditions, without the help of B, and E, although they differ in their oxidation states. It an enzyme, we obtained a mixture of four diastereomers. is reasonable to assume that (+)-fusarisetin A and equise- We therefore consider 29 to be involved in the biosynthe- tin are biogenetically related and share a common biosyn- sis of equisetin (2). In comparison with our first-genera- thetic pathway from the polyenoylamino acid 5 (Scheme tion synthesis, our second-generation approach gives 2). Acid 5 might be derived by coupling of naturally oc- equisetin (2) more efficiently in eight steps from (+)-cit- curring (S)-serine (6) with the unsaturated fatty acid 7. An ronellal (8), and is capable of being scaled up. intramolecular Diels–Alder reaction,13 followed by a Dieckmann cyclization, should transform acid 5 into equi- O St-Bu O St-Bu setin (2). We surmised that the keto–enol tautomers of the O O 3-acyltetramic acid moiety in equisetin should be readily a) KHMDS c) 13, LHMDS oxidizable to give a radical that might be further trans- THF, 22 b) 1 N HCl THF 9 Me Me formed into (+)-fusarisetin A through aerobic oxidation, 75% THF 65% from 23 C1–C6 bond formation, and oxidation of C-5. O CHO Guided by this biosynthetic analysis, we planned to syn- Me O Me thesize equisetin (2) first and then to use it as a biogenetic 23 (E/Z = 30:1) 24 precursor of (+)-fusarisetin A (1). We developed two syn- OH O theses of equisetin (2). Our first-generation synthesis was based on the pioneering studies of Danishefsky,14a OMe 14b,c 14d O St-Bu O N Ley, and Shishido and their respective co-workers. Me e) BF ⋅OEt d) F3CCO2Ag 3 2 CH Cl , 2 h The chiral methyl group at C-12 of both 1 and 2 could be O Et3N, 26 O 2 2 produced from (+)-citronellal (8).15 As shown in Scheme 63%, dr = 17:1 Me THF, 85% Me 3, this approach is straightforward and efficient. By using Me Me classical chemical transformations, we were able to pre- pare aldehyde 16 from aldehyde 9 in five steps. The Lewis 13 acid-promoted intramolecular Diels–Alder reaction ste- Me Me reospecifically transformed aldehyde 16 into the trans- 25 (E/Z = 15:1) 27 14a OMe OH decalin 17 (the A and B rings) with endo-selectivity. O This intramolecular Diels–Alder reaction and the subse- Me OMe O f) MeONa quent Roskamp reaction could be mediated by the same Me N MeOH N O 2 OH Me Lewis acid (boron trifluoride etherate). We then installed Me 100%, the 3-acyltetramic acid moiety (E ring) of equisetin by us- O O dr = 1:1 ing the aminolysis/Dieckmann cyclization sequence de- O Me Me 14a veloped by Danishefsky. Simple deprotection of the H tert-butyl(dimethyl)silyl group then gave equisetin (2) in H H Me Me 95% yield. This first-generation approach gave equisetin H endo-selectivity 28 (2) in 11 steps from the commercially available (+)-citro- 29 nellal (8). However, the efficiency of this approach did O Me H not satisfy us, so we planned to develop a biomimetic syn- N thesis of 2, based on our biosynthetic hypothesis, starting t-BuS OEt MeO Me P OEt from the polyenoylamino acid 5 and involving a cycliza- O O O HO tion sequence. 22 26 Our second-generation synthesis began with the prepara- Scheme 4 Second-generation synthesis of equisetin (2) tion of polyenoylamino ester 27, the methyl ester of 5, which contains all the required parts of equisetin. Alde- Having developed a scalable synthesis of equisetin (2), we This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. hyde 9 was efficiently converted into the unsaturated thio began to investigate its bioconversion into (+)-fusarisetin ester 25 by a sequence of two Horner–Wadsworth– 14b,c A (1). On the basis of our proposed biogenetic relation- Emmons reactions with phosphonates 22 and 13, re- ship between 1 and 2, we believed that aerobic oxidation spectively (Scheme 4). Ester 27 was then prepared by cou- of 2 should give a key radical intermediate that should un- pling ester 25 with the (S)-serine derivative 26. The dergo an aerobic radical cascade process to form the C1– intramolecular Diels–Alder reaction of 27 smoothly gave C6 bond (C ring) as well as oxidizing C-5 to close the D the desired trans-decalin A and B rings of ester 29. The ring through hemiketalization. We selected manga- stereoselectivity of this reaction was substrate-controlled nese(III) acetate16 as a single-electron oxidant to initiate and involved the chair-like transition state 28. Finally, es- the aerobic radical cascade, because this reagent is suit- ter 29 was converted into equisetin (2) by Dieckmann cy- 16 14b,c able for use with enolizable carbonyl compounds. The 3- clization under basic conditions. We also induced the acyltetramic acid (E ring) moiety theoretically contains a Dieckmann cyclization and then performed the intramo- tricarbonyl group that should be readily oxidized by man-

Synlett 2014, 25, 1–7 © Georg Thieme Verlag Stuttgart · New York SYNPACTS Biomimetic Synthesis of (+)-Fusarisetin A 5 ganese(III) acetate. Because the radical intermediate Undoubtedly, solar energy (visible light) is the basic ener- might also be trapped by oxygen to form endoperoxides or gy source, and its energy is normally transformed, by hydroperoxides under aerobic conditions, we planned to means of a photosensitizer, into chemical energy that can use the manganese(III)/dioxygen conditions17 for the oxi- be stored. Dioxygen acts as a potent oxidant in nature. We dation of equisetin to effect simultaneous closure of the therefore speculated that the desired biooxidation of equi- C ring and selective oxidation of the C-5 atom. setin to form (+)-fusarisetin A might be initiated by visi- We extensively surveyed the reaction conditions and were ble light and a photocatalyst in the presence of air or pleased to find that oxidation of equisetin (2) with a stoi- oxygen. With this idea in mind, we designed two distinct chiometric amount of manganese(III) acetate under air or approaches test this hypothesis. The first approach in- oxygen (1 atm) in acetic acid at room temperature gave volved an organometallic photocatalyst-promoted, aero- peroxyfusarisetin 32 and its C5-epimer 33 in 62% com- bic, radical-cascade process, and the second involved a bined yield (dr = 1.3:1) (Scheme 5). The relative stereo- dye-type photocatalyst-mediated cyclization process in- chemistry of 33 was unambiguously confirmed by X-ray volving singlet oxygen. crystallography. We believe that the reaction of manga- To test the first approach with an organometallic photo- nese(III) acetate with the 3-acyltetramic acid moiety in catalyst (Scheme 6), a solution of equisetin (2) in aceto- equisetin gives the manganese enolate 30, which then di- nitrile containing a catalytic amount of rectly cyclizes in a 5-exo-trig manner to form the C1–C6 tris(bipyridyl)dichlororuthenium (35)19 and triethylamine bond (C ring), giving the radical intermediate 31. This (4.0 equiv) under air or oxygen was irradiated by sunlight radical intermediate is trapped by dioxygen and hemike- or light from a household compact fluorescence lamp. The talizated to form the peroxy derivatives 32 and 33 under desired peroxyfusarisetin 32 and its C5-epi-isomer 33 aerobic conditions. We surmised that the termination of were obtained (dr = 2:1) in 68% combined yield. These re- –• 20 this radical cascade involves a hydrogen abstraction from sults suggest that the superoxide radical anion (O2 ), a equisetin. If this were so, the reaction should be initiated reactive oxygen species,21 plays a key role in this aerobic by a catalytic amount of manganese(III) acetate. Indeed, oxidation. The superoxide radical anion is generated by we found that the reaction of equisetin with 10 mol% of reduction of dioxygen by the ruthenium complex. We be- manganese(III) acetate gave the peroxides 32 and 33 in a lieve that the superoxide radical anion acts as an initiator yield (60%, dr = 1.1:1) that was comparable to that of the for the reaction by abstracting hydrogen from equisetin noncatalytic process. Note that Theodorakis and co-work- (2) to give the key radical intermediate 34, which under- ers have reported that cerium(IV) ammonium nitrate is an goes the same reaction as that which occurs under manga- effective oxidant for initiating this reaction.8c nese(III)/dioxygen conditions, to give 32 and 33. To examine further the biosynthesis of (+)-fusarisetin A Next, we examined the use of a dye-type photocatalyst, (1) from equisetin (2), especially the biooxidation of 2 to and we found that the oxidative cyclization reaction of eq- peroxyfusarisetin, we needed to consider the reaction as a uisetin (2) with methylene blue (37) as the photocatalyst natural process. By analogy to photosynthesis,18 the bio- gave 32 and 33 (dr = 3:1) in 70% yield (Scheme 6). In con- synthetic aerobic oxidation requires three components: an trast to the reaction catalyzed by the ruthenium complex, 1 22 energy source, a means of energy transfer, and an oxidant. singlet oxygen ( O2), another reactive oxygen species, is This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Scheme 5 Aerobic oxidation of equisetin to peroxyfusarisetin promoted by Mn(III)/O2. Reagents and conditions: (a) Mn(OAc)3·2H2O (2.0 equiv), air or O2 (1 atm), 25 °C, 1 h: 62% (dr = 1.3:1 at C-5); (b) Mn(OAc)3·2H2O (0.1 equiv), air or O2 (1 atm), 25 °C, 2 h: 60% (dr = 1.1:1 at C-5).

Me compound. Indeed, we found that this reduction could be O N OH induced by using trimethyl phosphite to give 1 and C5-

HO epi-1 in 75% yield (Scheme 7). Theodorakis and co-work- Me ers have reported that thiourea is also an effective reagent O Me for this reduction.8c H Me H Me OH Me OH equisetin (2) N N O OH O OH a) or b) O O O O • 32 + 33 + reactive oxygen species 1 Me 5 Me 5 a)O2 O b) (ROS) 2 H H Me H H Me H H Me Me OH Me Me O H N OH H N (+)-fusarisetin A (1) C5-epi-1 O 1 O O HO – O O Scheme 7 Synthesis of (+)-fusarisetin A (1) by reduction of peroxy- Me O O Me Me + fusarisetin. Reagents and conditions: (a) Zn (30.0 equiv), AcOH, 6 O 5 50 °C, 2 h: 75% (combined); (b) P(OMe) , (40.0 equiv), MeCN, H 6 5 3 H 80 °C, 3 h: 75% (combined). Me H Me H Me H 34 36 We were intrigued by the possibility of performing the aerobic oxidation and the subsequent single-electron re- 32 + 33 32 + 33 duction as a one-pot operation to provide a more conve- dr = 2:1 (at C-5) dr = 3:1 (at C-5) nient approach for preparing (+)-fusarisetin A (1) and, indeed, we were pleased to find that direct addition of zinc to the dioxygen-trapping oxidative radical sequence gave Me Me 1 in 41% yield from equisetin (Scheme 8). This permits N S N+ N Me Me the efficient preparation of 1 on a large scale in ten steps – Ru 2 Cl Cl– starting from (+)-citronellal (8). N N 6 H2O 37

3 Me OH dye-type [Ru(bpy) ]2+Cl 35 Me 3 2 photocatalyst O N N OH organometallic one-pot reaction O OH photocatalyst O HO Mn(OAc)3, O Me AcOH, O2, Me Scheme 6 Aerobic oxidation of equisetin to peroxyfusarisetin medi- O Me then Zn, H Me ated by photochemically generated reactive oxygen species. Reagents H H and conditions: (a) Ru(bpy) Cl (5 mol%), Et N (4.0 equiv), under air 50 °C, H 3 2 3 Me 2 h, 41% Me or O2, compact fluorescent lamp or sunlight, 23 °C, 4 h: 68% (dr = 2:1 H H equisetin (2) (+)-fusarisetin A (1) at C-5); (b) methylene blue (5 mol%), Et3N (4.0 equiv), under air or O2, compact fluorescent lamp or sunlight, 25 °C, 4 h: 70% (dr = 3:1 at C-5). Scheme 8 Preparation of (+)-fusarisetin A (1) from equisetin (2) by a one-pot reaction generated in this reaction. The photoexcited methylene blue 37* transfers light energy to activate the triplet oxy- In summary, we have described our recent studies on syn- 1 theses of naturally occurring tetramic acids. An efficient gen to form singlet oxygen ( O2), which, in turn, reacts se- lectively with the C5–C6 double bond to form 36; this total synthesis of (+)-fusarisetin A (1), a promising anticancer agent, was achieved by a biomimetic approach, undergoes rearrangement to form 32 and 33. Both the or- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ganometallic and dye-type photocatalyzed reaction condi- starting from equisetin (2). Our research suggests that tions are physiologically relevant, suggesting that a both 1 and 2 are derived from polyenoylamino acid. The reactive oxygen species may be involved in the biosynthe- biosynthesis of (+)-fusarisetin A (1) might involve an aer- sis of (+)-fusarisetin A from equisetin. obic oxidation of equisetin (2), which could be mediated by metal oxidants or by photochemically produced reac- To complete our synthesis of (+)-fusarisetin A (1), we tive oxygen species. We are optimistic that this approach needed to cleave the peroxide bonds reductively to form could provide biogenetically related natural products effi- the tetrahydrofuran ring (D ring). Reduction of the mix- ciently. We have already prepared a variety of derivatives ture of 32 and 33 with zinc and acetic acid gave (+)-fusa- of 1 by using a similar strategy. This will facilitate studies 8a risetin A (1) and 5-epi-1 in 75% combined yield on structure–activity relationships and further studies on (Scheme 7). Biogenetically, the single-electron reduction medicinal chemistry. would be performed by a phosphine- or sulfur-containing

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