13-Step Total Synthesis of Atropurpuran - Journal of the American

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13-Step Total Synthesis of Atropurpuran Shengling Xie, Gui Chen, Hao Yan, Jieping Hou, Yongping He, Tongyun Zhao, and Jing Xu J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00391 • Publication Date (Web): 13 Feb 2019 Downloaded from http://pubs.acs.org on February 13, 2019

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Journal of the American Chemical Society

13-Step Total Synthesis of Atropurpuran Shengling Xie‡, Gui Chen‡, Hao Yan‡, Jieping Hou, Yongping He, Tongyun Zhao and Jing Xu* Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, China.

Supporting Information Placeholder ABSTRACT: Herein, we report a concise total synthesis of atropurpuran, a unique and synthetically challenging pentacyclic diterpene that bears a tetracyclo[5.3.3.04,9.04,12]-tridecane skeleton that is unprecedented among natural terpenes. This 13-step approach features a strategy that include early-stage rapid skeleton formation and the late-stage introduction of reactive functional groups, thus allowed a high overall synthetic efficiency with minimal use of PGs. The key transformations of our work include a rapid construction of the spiro[5.5]undecane moiety through an RCEM reaction and an efficient formation of the tetracyclo[5.3.3.04,9.04,12]-tridecane scaffold via an RDOD/IMDA reaction cascade. This efficient approach should also inspire further advances in the synthesis of related complex diterpenes and diterpenoid alkaloids.

Biogenetically and structurally related diterpenes and diterpenoid alkaloids, with their intriguing bioactivity and complicated architectures, constitute a fascinating natural product family.1 Many members of this family, such as atropurpuran (1, Fig. 1),2 spiramilactone B3 (atisane type), atisine4, isoatisine5 and azitine6 (atisine type), septedine7 (hetidine type), gymnandine8, lepenine9 and paniculamine10 (denudatine type), nominine11, cossonidine12 and spirasine IV and XI13 (hetisine type), share a common carbon skeleton (Fig. 1, highlighted in orange). The intriguing chemical structures of these natural products have attracted intensive synthetic interest that has culminated in many imaginative syntheses.1–14 Arcutane-type diterpene atropurpuran was isolated from genus Aconitum by the Wang group in 2009.15 HO

H

H H

CHO O

H

N

O Spiramilactone B (atisane type)

Atropurpuran, 1 (arcutane type)

OH

OH

H

N

O

Gymnandine (denudatine type)

OH

N

N

Isoatisine (atisine type)

OH H

OH H

H

Lepenine (denudatine type)

H

OH O

Azitine (atisine type)

Septedine (hetidine type)

OH

HO OH

N Et

H H

HO

H

OH

HO

H

N O Paniculamine (denudatine type)

H

H

H

H N Et

O

HO

H H

O

Atisine (atisine type)

H

H

HO

H H

O

O

HO

H

OH H

While its biological properties remain unknown, atropurpuran possesses a highly constrained tetracyclo[5.3.3.04,9.04,12]-tridecane that contains two contiguous bicyclo[2.2.2]octane motifs. To our knowledge, atropurpuran is the only known natural terpene that possesses such a motif. Therefore, the chemical synthesis of atropurpuran poses a highly attractive yet formidable challenge. Despite pioneering synthetic studies of atropurpuran by Kobayashi,16 Hsung,17 Qin18 and Singh19, the only successful synthesis was accomplished by Qin and co-workers in 2016.2 Qin’s inspiring approach features an oxidative dearomatization/IMDA cycloaddition cascade and SmI2-mediated ketyl–olefin cyclizations. Here, we report a 13-step20 synthesis of atropurpuran (1) that not only demonstrates the successful combination of an efficient strategy and chemoselective transformations21, but also exhibits the possibility of divergent syntheses22 of other structurally complex and related diterpenes and diterpenoid alkaloids.1,23 For accessing an efficient synthesis21,24–29 of atropurpuran with minimal use of protecting groups (PGs)30, our retrosynthetic analysis of 1 (Fig. 2) indicated that it could be obtained from diol 2, which shares the same pentacyclic carbon ring skeleton as 1, through the late-stage introduction of reactive functional groups (RFGs). The highly congested tetracyclo[5.3.3.04,9.04,12]-tridecane ring skeleton of 2 could be rapidly accessed from phenol derivative 3 through a regioselective double oxidative dearomatization (RDOD)14g and an intramolecular Diels–Alder (IMDA) reaction cascade2,16. Finally, compound 3 could be achieved from commercially available starting material, 5methoxytetralone (4), through a ring-closing enyne metathesis (RCEM) reaction to

N Nominine (hetisine type)

H R1

H N Cossonidine (hetisine type)

H

R2

N Spirasine IV (R1 = R2 = O) Spirasine XI (R1 = H, R2 = OH) (hetisine type)

Figure 1. Common skeletons shared by atropurpuran (1) and many other related diterpenes and diterpenoid alkaloids.

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Late-stage introduction of reactive enone and allylic alcohol functionality

HO

H

OH

O

H

OMe

OMe H

H O Atropurpuran, 1

OHC

Regioselective double oxidative dearomatization (RDOD)

Rapid spiro[5.5]undecane formation via RCEM

OMe

H

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OH

OH

2

OH

Quick formation of the tetracyclo[5.3.3.04,9.04,12] tridecane via IMDA

Late-stage introduction of reactive aldehyde moiety

OH

O 5-Methoxytetralone, 4

3 Diastereoselective double reduction

Commercially available starting material

Figure 2. Retrosynthetic analysis of atropurpuran (1). rapidly form the spiro[5.5]undecane motif, followed by diastereoselective double reduction of the 1,3-diketone moiety. As shown in Scheme 1, our synthesis commenced with commercially available 5-methoxytetralone (4), which was treated with lithium bis(trimethylsilyl)amide (LHMDS) and 4-pentenoyl chloride to afford the selective C-acylated product. Exposure of this 1,3-diketone to n-tetrabutylammonium fluoride (TBAF) and Waser’s reagent (TMS-EBX)31 at 78 C afforded -alkynyl-1,3diketone 5, which was then subjected to an intramolecular ringclosing enyne metathesis (RCEM) reaction using Grubbs 2nd generation catalyst, which rapidly produced the spiro[5.5]undecane moiety, while the linked terminal olefin motif would later serve as the dienophile in the IMDA reaction. It was not necessary to isolate the RCEM product, so the RCEM reaction mixture was cooled to 78 C and boron tribromide was added to smoothly remove the O-methyl group and afford the corresponding phenol compound. To further improve the overall efficiency of our synthesis, a pre-mixed AlCl3/LiAlH4 solution was then added to the reaction mixture to achieve

diastereoselective double reduction of the 1,3-diketone moiety, which constituted the last transformation in the one-pot RCEM/demethylation/double reduction reaction. This reduction was necessary for the following cycloaddition, otherwise dimerization, along with the production of other unidentified side products, would occur. Although the diastereoselectivity of this double reduction should be inconsequential, it greatly benefited the purification and characterization of products from this step and the IMDA step. The stereoconfiguration of diol 3 was confirmed by single crystal X-ray diffraction of an analogue of 3 (see SI for details). Inspired by the pioneering works of Sarpong14g, Kobayashi16 and Qin2, we next sought to explore a one-pot RDOD/IMDA reaction for rapid formation of the key tetracyclo[5.3.3.04,9.04,12]-tridecane scaffold. Accordingly, the RDOD reaction14g of 3 at room temperature successfully introduced two methoxy groups onto the phenol ortho-position to form the corresponding diene functionality. Interestingly, this RDOD reaction was para-selective when the reaction temperature was kept at

Scheme 1. 13-Step total synthesis of atropurpuran. OMe

O

4) PhI(OAc)2, rt 5 h, MeOH;

3) Grubbs-II Catalyst CH2Cl2, rt, 12 h;

2) TBAF, TMS-EBX THF, 12 h, 92%

78 oC, BBr3, 2 h; AlCl3/LiAlH4, 10 min, 50%

O

O

OH

3 OMe

OMe O 15

H

9) Crabtree's catalyst H2, CH2Cl2, 1 h;

O 8

HO

8) TFAA, DMSO, CH2Cl2, Et3N 55% over two steps

H

O

CHO O

2 h, 42% dr = 3:1

H

16

6) KHMDS, PhNTf2

H

OMe

H 4

O

H

O 6

OHC

OMe 11) SmI2, THF, MeOH H 25 oC, 20 min

O

H

SIMes

O O

Cl

I

Cl

12) TMMN, Ac2O, DMF 95 oC, 6 h OHC 57% over two steps

O

Atropurpuran, 1

+ PCy3 N


H

OHC

Ir

BHT

H

(Ref. 29)

H O

OH

Cy3 P

HO

H

13) NaBH(OMe)3 THF, MeOH, 72% H

11

Ru

Grubbs-II Catalyst

O

H

10

TMS-EBX

OMe

O

H

THF, 10 min, 85%

O

H

9

TMS

13 14

OH

7

OMe 10) tBuOK, tBuOH, MeI, 26 oC H

14

4

H 20

OMe

O

OMe

10

OMe

OMe H

1

OH 2 5) Crabtree's catalyst, H2, CH2Cl2, 8 h; TPAP, NMO, 10 min, 63%

H

OTf

O

H

O

H

7) Pd(PPh3)4, CO, nBu3SnH THF; DIBAL

OMe H

Dess-Martin periodinane, 1 h, 68%

BHT, mesitylene 160 oC, 1 h, 55%

OH

5

5-methoxytetralone, 4 commercially available

OMe

OH

OMe

1) LHMDS 4-pentenoyl chloride THF, 24 h, 80%

Crabtree's catalyst

PF6

N

N

TMMN

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Journal of the American Chemical Society 0 C. Without any isolation or purification, the afforded diene underwent an IMDA reaction2,16 by removal of methanol, adding mesitylene and butylated hydroxytoluene (BHT) to the above reaction mixture and heating to 160 C for 1 h. This one-pot RDOD/IMDA reaction cascade produced desired pentacycle 2, containing the critical tetracyclo[5.3.3.04,9.04,12]-tridecane core, in 55% yield. The success of this cycloaddition possibly benefited from the presence of the spiro[5.5]undecane moiety, which provided highly favorable proximity between the diene and the dienophile. The next task was to selectively hydrogenate the C13/C-14 trisubstituted olefin in presence of the C-1/C-10 trisubstituted olefin. Several heterogenous hydrogenation attempts failed. Aided by the presence of the C-20 hydroxyl group, homogeneous hydrogenation of 2 using Crabtree’s catalyst,32 followed by a Ley oxidation in the same pot produced the desired diketone 6 in 63% yield. Owing to the highly constrained caged structure of 2, the hydrogenation only occurred from the convex face. With rapid access to pentacycle 6 achieved, we next needed to construct the C-4 quaternary center that holds an aldehyde moiety and a methyl group and, subsequently replace the C-16 geminal methoxyl groups with an alkene functionality. Numerous trials, including homologation of the C-4 carbonyl group of diketone 6 and various late-stage modifications based on this compound were unsuccessful (Scheme 2). For example, subjecting diketone 6 to Wittig, Van Leusen6 or Corey-Chaykovsky2 reactions resulted only in decomposition or other ring-opening side products. It was postulated that the 1,3-diketone moiety might undergo ringopening reactions, such as retro-Dieckmann condensation and retro-aldol reactions, when one of the two ketone motifs was attacked by nucleophiles. However, controlled ring-opening of this diketone could lead to efficient syntheses of many other related natural products (Fig. 2). Efforts to use this ring-opening reaction towards these natural products are currently under investigation.

Scheme 2. Other late-stage detours led to only dead ends. OMe

KHMDS, PhNTf2 THF, 10 min, 85%

O

H

OMe

Wittig, Van Leusen, Corey-Chaykovsky...

H Homologation of C-4 ketone

4

O

OMe O

H

H

O

OMe Pd(PPh3)4, CO nBu3SnH, THF 62%

OTf

O 7

3

OMe

O 8

H

1) SmI2, HMPA, MeOH H CHO O 2) H2, Crabtree's catalyst 12 3) KHMDS, HCO2Et, PhMe, 70 oC; aq. HCHO, THF, 50 oC 4) Dess-Martin periodinane 30% over four steps

O 11

H

O

H H

OHC

1,4-reduction of ,-unsaturated aldehyde

4

H

HO

OMe

O

H

OMe

OMe O 15 H

Pd(PPh)3, Bu3SnCH2OH LiCl, THF, 75 oC

H

6 H

H

O

H

H

Methylation

CHO O

H

13

We also investigated two different types of cross coupling reactions to convert 6 into advanced intermediates through enol triflate 7 (Scheme 2). Unfortunately, direct Stille coupling between 7 and (tributylstannyl)methanol6 resulted in only unidentified side products. While the reductive cabonylative coupling successfully converted 7 to ,-unsaturated aldehyde 12, various attempted 1,4-reductions33 of this aldehyde were unsuccessful. In turn, one-pot SmI2-mediated reaction selectively

reduced the aldehyde moiety and concurrently removed two methoxy groups from 12. Selective hydrogenation, methylenation9 and oxidation of the corresponding primary alcohol afforded enone 13 (30% over four steps). Unfortunately, all aldehyde -methylation trials failed to give even a trace amount of the Qin’s key intermediate2 11 resulting only in decomposition. This failure was possibly due to the presence of the highly sensitive enone functionality. Pleasingly, a reductive carbonylative coupling using enol triflate 7 followed by a global reduction in the same pot successfully produced the corresponding triol as a mixture of diastereomers (Scheme 1). The stereoconfiguration of these diastereomers were inconsequential and thus was not assigned, since the so-afforded two secondary hydroxyl groups were immediately oxidized in a selective manner under TFAA/DMSO/Et3N conditions34 to produce allyl alcohol 8. Although one might anticipate that a 1,2-reduction of the ,unsaturated aldehyde motif of 12 could also produce the desired compound 8, this seemingly simple transformation gave unexpected results showing that under various conditions, the least hindered C-15 ketone motif was always reduced first, before the highly hindered aldehyde motif could be reduced. A one-pot regioselective hydrogenation/Dess-Martin oxidation smoothly converted allylic alcohol 8 into aldehyde 9. -Methylation successfully formed the quaternary center of 10 with moderate yield and diastereoselectivity (42%, 3:1). Attempts to optimize this methylation resulted in only lower diastereoselectivities or, poor regioselectivity that mainly affording the C4,C14dimethylated product. Next, a SmI2-mediated demethoxylation of 10, followed by an -methylenation of C-15 ketone using N,N,N',N'-tetramethylmethanediamine (TMMN) and acetic anhydride,35 funished enone 11, which was the final intermediate in Qin’s synthesis2 for which the 1H and 13C NMR spectra completely matched those for Qin’s intermediate. Finally, a diastereoselective reduction of enone 11 using sodium trimethoxyborohydride2 afforded atropurpuran (1). Synthetic 1, produced from our concise route, was found to be identical in all aspects to natural15 and synthetic atropurpuran2 (1H NMR, 13C NMR, and HR-MS). In conclusion, we have accomplished a concise total synthesis of complex diterpenoid atropurpuran in only 13 steps20 with minimal use of PGs. Although the O-methyl group, which was originated from the commercially available starting material, could be considered as a PG, it barely has any impact on the overall synthetic efficiency since it did not have to be introduced or removed in an extra step. Key to the success of our approach were: (i) An efficient strategy that adopted several pot-economic transformations; (ii) rapid early-stage constructions of the spiro[5.5]undecane moiety and tetracyclo[5.3.3.04,9.04,12]tridecane scaffold through an RCEM reaction and an RDOD/IMDA reaction cascade, respectively; (iii) several chemo-, regio-, and diastereoselective reactions that allowed the late-stage introduction of RFGs without resort to protecting group chemistry. Efforts to expand this concise strategy to the synthesis of other structurally related diterpenes and diterpenoid alkaloids are currently ongoing in our laboratory.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and spectral data for all new compounds (PDF).

AUTHOR INFORMATION



Corresponding Author *[email protected]

Author Contributions ‡These authors contributed equally.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We appreciate financial support from NSFC (21772082), SZSTI (JCYJ20170817110515599 and KQJSCX20170728154233200), SZDRC Discipline Construction Program and Shenzhen Nobel Prize Scientists Laboratory Project (C17783101). The authors thank Prof. M. J. Dai (Purdue University) for helpful discussions.

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(10) Kou, K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale, A. G.; Sarpong, R. Syntheses of denudatine diterpenoid alkaloids: Cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine. J. Am. Chem. Soc. 2016, 138, 10830. (11) a) Muratake, H.; Natsume, M. Total synthesis of (±)-nominine, a heptacyclic hetisine-type aconite alkaloid. Angew. Chem. Int. Ed. 2004, 43, 4646; b) Peese, K. M.; Gin, D. Y. Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar and dienamine-Diels−Alder cycloadditions. J. Am. Chem. Soc. 2006, 128, 8734; (f) Peese, K. M.; Gin, D. Y. Asymmetric synthetic access to the hetisine alkaloids: Total synthesis of (+)-nominine. Chem. Eur. J. 2008, 14, 1654. (12) Kou, K. G. M.; Pflueger, J. J.; Kiho, T.; Morrill, L. C.; Fisher, E. L.; Clagg, K.; Lebold, T. P.; Kisunzu, J. K.; Sarpong, R. A benzyne insertion approach to hetisine-type diterpenoid alkaloids: Synthesis of cossonidine (davisine). J. Am. Chem. Soc. 2018, 140, 8105. (13) Zhang, Q.; Zhang, Z.; Huang, Z.; Zhang, C.; Xi, S.; Zhang, M. Stereoselective total synthesis of hetisine-type C20-diterpenoid alkaloids: Spirasine IV and XI. Angew. Chem. Int. Ed. 2018, 57, 937. (14) For other selected examples: a) Wiesner, K.; Tsai, T. Y. R.; Nambiar, K. P. A new stereospecific total synthesis of chasmanine and 13desoxydelphonine. Can. J. Chem. 1978, 56, 1451; b) Wiesner, K. Total synthesis of delphinine-type alkaloids by simple, fourth generation methods. Pure Appl. Chem. 1979, 51, 689; c) Hamlin, A. M.; de Jesus Cortez, F.; Lapointe, D.; Sarpong, R. Ga(III)-catalyzed cycloisomerization approach to the diterpenoid alkaloids: construction of a core structure for the hetidines and hetisines. Angew. Chem. Int. Ed. 2013, 52, 4854; d) Breitler, S.; Carreira, E. M. Total synthesis of (+)-crotogoudin. Angew. Chem. Int. Ed. 2013, 52, 11168; e) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.; Lilien, R.; Sarpong, R. Network-Analysis-Guided synthesis of weisaconitine D and liljestrandinine. Nature 2015, 528, 493; f) Song, L.; Zhu, G.; Liu, Y.; Liu, B.; Qin, S. Total synthesis of atisane-type diterpenoids: Application of Diels–Alder cycloadditions of podocarpane-type unmasked orthobenzoquinones. J. Am. Chem. Soc. 2015, 137, 13706; g) Finkbeiner, P.; Murai, K.; Röpke, M.; Sarpong, R. Total synthesis of terpenoids employing a “benzannulation of carvone” strategy: synthesis of (–)crotogoudin. J. Am. Chem. Soc. 2017, 139, 11349; h) Kou, K. G. M.; Kulyk, S.; Marth, C. J.; Lee, J. C.; Doering, N. A.; Li, B. X.; Gallego, G. M.; Lebold, T. P.; Sarpong, R. A unifying synthesis approach to the C18-, C19-, and C20-diterpenoid alkaloids. J. Am. Chem. Soc. 2017, 139, 13882; i) Zhou, R.-J.; Dai, G.-Y.; Zhou, X.-H.; Zhang, M.-J.; Wu, P.-Z.; Zhang, D.; Song. H.; Liu, X.-Y.; Qin, Y. Progress towards the synthesis of aconitine: construction of the AE fragment and attempts to access the pentacyclic core. Org. Chem. Front. 2019, 6, 377. (15) Tang, P.; Chen, Q.-H.; Wang, F.-P. Atropurpuran, a novel diterpene with an unprecedented pentacyclic cage skeleton, from Aconitum hemsleyanum var. atropurpureum. Tetrahedron Lett. 2009, 50, 460. (16) Suzuki, T.; Sasaki, A.; Egashira, N; Kobayashi, S. A synthetic study of atropurpuran: construction of a pentacyclic framework by an intramolecular reverse-electron-demand Diels–Alder reaction. Angew. Chem. Int. Ed. 2011, 50, 9177. (17) Hayashi, R.; Ma, Z. X.; Hsung, R. P. A tandem 1,3-H-shift– 6pelectrocyclization–cyclic 2-amido-diene intramolecular Diels–Alder cycloaddition approach to BCD-ring of atropurpuran. Org. Lett. 2012, 14, 252. (18) a) Chen, H.; Zhang, D.; Xue, F.; Qin, Y. Synthesis of the atropurpuran A-ring via an organocatalytic asymmetric intramolecular Michael addition. Tetrahedron 2013, 69, 3141; b) Chen, H.; Li, X.-H.; Gong, J.; Song, H.; Liu, X.-Y.; Qin, Y. Synthetic approach to the functionalized tricyclic core of atropurpuran. Tetrahedron 2016, 72, 347. (19) Jarhad, D. B.; Singh, V. π4s + π2s Cycloaddition of spiroepoxycyclohexa-2,4-dienone, radical cyclization, and oxidation−aldol−oxidation cascade: Synthesis of BCDE ring of atropurpuran. J. Org. Chem. 2016, 81, 4304. (20) The step count here is based on literature definition (A reaction step is defined as one in which a substrate is converted to a product in a single reaction flask (irrespective of the number of transformations) without intermediate workup or purification), see: a) Kawamura, S.; Chu, H.; Felding, J.; Baran, P. S. Nineteen-step total synthesis of (+)-phorbol. Nature 2016, 532, 90; b) Chu, H.; Smith, J. M.; Felding, J.; Baran, P. S. Scalable Synthesis of (−)-Thapsigargin. ACS Cent. Sci. 2017, 3, 47. (21) a) Trost, B. M. Selectivity — a key to synthetic efficiency. Science 1983, 219, 245; b) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S.


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13-Step Total Synthesis of Atropurpuran - Journal of the American

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