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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Org Lett. Author manuscript; available in PMC Sep 7, 2013.
Published in final edited form as:
PMCID: PMC3466107
NIHMSID: NIHMS403798
Stereoselective Synthesis of Acortatarins A and B
Jacqueline M. Wurst, Alyssa L. Verano, and Derek S. Tancorresponding author§
Tri-Institutional Training Program in Chemical Biology, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065
Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065
§Molecular Pharmacology & Chemistry Program and Tri-Institutional Research Program, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, Box 422, New York, NY 10065
corresponding authorCorresponding author.
Derek S. Tan: tand/at/mskcc.org
Abstract
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Object name is nihms403798f7.jpg Object name is nihms403798f7.jpg
Acortatarins A and B have been synthesized via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol sidechain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde sidechain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A.
Acortatarins A and B are novel spiroketal pyrrole alkaloids from the roots of Acorus tatarinowii (Figure 1).1 Structurally related pollenopyrrosides A and B were isolated contemporaneously from the pollen of Brassica campestris.2 Notably, acortatarins A and B exhibited significant antioxidant activity in a renal cell model for hyperglycemia-induced production of reactive oxygen species (ROS).1 Thus, these natural products are potential starting points for the development of new therapeutics to treat diabetic complications, cancer, and other conditions in which ROS are implicated.3 However, due to low isolation yields from the natural sources,4 efficient synthetic routes are needed to enable detailed biological evaluation. Herein, we report concise, modular syntheses of acortatarins A and B via stereoselective spirocyclizations of glycals. The thermodynamic preferences of both spiroketal natural products and the crystal structure of acortatarin B are also described.
Figure 1
Figure 1
Original1 and revised5 structures of the acortatarins.
In the original isolation paper, the relative configuration of acortatarin A was established by crystallography and an unnatural absolute l-configuration was assigned based on Mosher analysis.1 An α-ribo relative configuration was assigned to acortatarin B based on ROESY analysis and the l-configuration assumed by analogy. Notably, pollenopyrroside B was separately assigned the enantiomeric d-configuration of acortatarin A based on crystallographic analysis of its pyranose congener pollenopyrroside A (not shown).2
Subsequently, Sudhakar reported the first total syntheses of acortatarins A and B from 2-deoxy-d-ribose and d-arabinose, respectively, leading to structural revisions of both absolute configurations as well as the relative configuration of acortatarin B (Figure 1).5 Thus, acortatarin A and pollenopyrroside B are now recognized to be identical. A second synthesis of acortatarin A from d-mannitol was also reported recently by Brimble.6 These reports provide the first synthetic access to the acortatarins, but their practical utility is limited by low overall yields and reliance upon classical acid-catalyzed spiroketalization reactions that afford low or even undesired diastereoselectivity.7
Our laboratory has a long-standing interest in the stereocontrolled synthesis of spiroketals from glycals,8, 9, 10 and we envisioned that both acortatarins A and B could be synthesized by spirocyclizations of glycals 1 (Figure 2). Direct spirocyclization would provide acortatarin A while epoxidation–spirocyclization would lead to acortatarin B. In the latter case, we recognized that the oxidation state of the pyrrole substituents would be important for enabling chemoselective epoxidation of the glycal. These key intermediates 1 would originate from coupling of appropriate pyrroles 2 with ribal derivative 3, accessed via nucleobase elimination of thymidine.11 At the outset of our studies, the revised structures of the acortatarins had not been reported but, recognizing that both enantiomers of thymidine are commercially available, initial work was carried out with the less expensive, natural d-congener.
Figure 2
Figure 2
Retrosynthetic analysis of acortatarins A and B (original structures) via key pyrrologlycal intermediates 1.
Thus, TIPS-protected12 ribal 611 underwent C1-formylation13 and reduction to provide hydroxymethyl ribal 7, which was then converted to iodide 8 (Figure 3).14 The pyrrole dicarboxaldehyde 915, 16 was then coupled under biphasic conditions17 to afford the key pyrrologlycal 10.
Figure 3
Figure 3
Synthesis of key pyrrologlycal intermediate 10 from d-thymidine and pyrrole dicarboxaldehyde 9.
To access acortatarin A, we initially attempted reductive spirocyclization of dialdehyde 10 (TFA, Et3SiH), envisioning cyclization of an aldehyde carbonyl followed by in situ reduction of the resulting spirocyclic oxocarbenium intermediate, but this led to a furan side product via Ferrier-type elimination (Figure S1).16 Similarly, stepwise reduction to monoalcohol 11 (Figure 4) followed by treatment with dichloroacetic acid led to a 1:1 mixture of a 2,3-dehydro-α-spiroketal (cf. 12) via Ferrier rearrangement and the undesired β-spiroketal 13.16
Figure 4
Figure 4
Synthesis of acortatarin A (14) via mercury-mediated spirocyclization of pyrrole monoalcohol 11. Acid equilibration of spiroketals 12–15 favors the α-spiroketals.
Thus, we next investigated oxidative spirocyclizations of pyrrole monoalcohol 11 that would yield spiroketals having a removable C2-substituent, and were delighted to find that treatment with Hg(II) salts afforded the desired 2-mercurial spiroketals, which were then reduced with NaBH4 to afford the diastereomeric spiroketals 12 and 13.9d Initial reactions with Hg(OAc)2 or Hg(TFA)2 led to modest stereoselectivity favoring the desired α-spiroketal 12 (Table 1, entries 1–5). Notably, Hg(TFA)2 resulted in 30% formation of the same Ferrier rearrangement-derived 2,3-dehydro-α-spiroketal observed above (entry 2).
Table 1
Table 1
Mercury-mediated spirocyclizations of glycal 11.16
The Hg(OAc)2-derived 2-mercurial spiroketals exhibited a 7.8 Hz C2-H/C3-H coupling constant, consistent with a 2,3-trans relationship arising from β-mercuration (Figure S2).16 Since the expected anti-oxymercuration would then lead to the desired α-spiroketal 12,18 we postulate that the undesired β-spiroketal 13 arises from net syn-oxymercuration via an oxocarbenium intermediate. Thus, to accelerate anti-oxymercuration, pyrrole monoalcohol 11 was pretreated with NaHMDS to form a more reactive alkoxide nucleophile, resulting in increased stereoselectivity for the desired α-spiroketal 12 (entry 7). Surprisingly, however, longer reaction times prior to NaBH4 reduction led to further increased stereo-selectivity, indicative of an unanticipated equilibrium effect in this reaction (entries 6–10). Such equilibration was not observed without base,16 and other bases provided comparable or lower stereoselectivity.16 Desilylation of the mixture of 12 and 13 then provided the separable acortatarin A (14) and C1-epi-acortatarin A (15).16, 19
Next, we pursued an epoxidation–spirocyclization approach to acortatarin B.9l In initial epoxidation studies, pyrrole monoalcohol 11 and its diol congener (not shown) were prone to pyrrole oxidation. In contrast, pyrrole dicarboxaldehyde 10 underwent chemoselective β-epoxidation of the glycal with DMDO to form the putative epoxide 16 (Figures 5 and S3).16 Addition of NaBH4 in MeOH afforded the α-spiroketal methanol adduct 22a (Table 2, entry 1). In contrast, NaBH4 in THF provided the desired β-spiroketal 17 as a single diastereomer, along with a tetracyclic side product 21 (entry 2). Attempted ionic reduction with Et3SiH resulted only in tetracycle 21 (entry 3). Conversely, reductive spirocyclization with acidic NaBH3CN yielded the epimeric α-spiroketal 18 and tetracycle 21 (entry 4). NaBH(OAc)3 led to α-spiroketal acetate adduct 22b (entry 5) while LiEt3BH and L-Selectride yielded complex mixtures (entries 6,7). Finally, Bu4NBH4, aided by its solubility in CH2Cl2, provided the desired β-spiroketal 17 in excellent yield and diastereoselectivity (entries 8, 9). Spiroketals 17 and 18 were seperable and desilylation provided acortatarin B (19) and its C1-epimer (20).16, 20
Figure 5
Figure 5
Synthesis of acortatarin B (19) via epoxidation and reductive spirocyclization of pyrrole dicarboxaldehyde 10. Acid equilibration of spiroketals 17–20 favors the α-spiroketals.
Table 2
Table 2
Reductive spirocyclizations of glycal epoxide 16.
We next investigated acid-catalyzed equilibration of the natural products and their unnatural C1-anomers, as well as the TIPS-protected congeners (12–15, 17–20).21 In both series, the α-spiroketal was favored by a 65:35 ratio (Figures 4, ,55).16 Notably, this favors the unnatural anomer of acortatarin B. Accordingly, although it is commonly assumed that spiroketal biosynthesis is a spontaneous, thermodynamically-controlled process, acortatarin B is a contrathermodynamic spiroketal whose biosynthesis may be under enzymatic stereocontrol.22, 23
Finally, we obtained a crystal structure of acortatarin B for comparison to the reported structure of acortatarin A (Figure 6).1 Interestingly, acortatarins A and B adopt distinct furanose envelope conformations (E1 vs. E2) and morpholine half-chair conformations (OH1 vs. 1HO) to allow double anomeric stabilization in both systems.
Figure 6
Figure 6
Crystal structures of acortatarin A1 and acortatarin B reveal distinct ring conformations and double anomeric stabilization. 50% probability ellipsoids shown for heavy atoms.
In conclusion, we have developed efficient, stereocontrolled syntheses of acortatarins A and B from a key pyrrologlycal 10. Acortatarin A was synthesized in 9 steps and 30% overall yield from d-thymidine, with 9:1 diastereoselectivity at the spiroketal-forming step and acortatarin B was accessed in 8 steps and 41% overall yield with complete diastereoselectivity. This compares favorably to previous syntheses7 and provides practical access to the natural products and a variety of analogues. Mechanistic analysis of the opposite stereoselectivities observed in these two spirocyclizations and biological studies are ongoing and will be reported in due course.
Supplementary Material
1_si_001
2_si_002
Acknowledgment
We thank Prof. Yong-Xian Cheng (Kunming Institute) for providing samples of the acortatarins, Dr. George Sukenick, Dr. Hui Liu, Hui Fang, and Dr. Sylvi Rusli (MSKCC) for expert NMR and mass spectral support, Dr. Kristen Kirschbaum (U. Toledo) for X-ray crystallographic analysis, and the NIH (P41 GM076267, T32 CA062948-Gudas) for financial support.
Footnotes
Supporting Information Available. Detailed experimental procedures and analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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4. 50 kg A. tatarinowii root yielded 7.3 mg acortatarin A and 3.4 mg acortatarin B (ref 1); 15 kg B. campestris pollen yielded 6 mg pollenopyrroside A and 5 mg pollenopyrroside B (ref 2).
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7. Ref 5 provides acortatarin A in 3.7% over 10 steps, with the key spirocyclization proceeding in 1.4:1 diastereoselectivity; accounting for epimerization of both anomers in a subsequent step to a 9:1 mixture favoring the desired diastereomer, the overall yield increases to 6.4%. Acortatarin B is accessed in 0.9% yield over 10 steps, with the key spirocyclization proceeding in 1:4.6 unfavorable diastereoselectivity. Ref 6 provides acortatarin A in 1.7% yield over 13 steps, with the key spirocyclization proceeding in 1.5:1 diastereoselectivity.
8. (a) Potuzak JS, Moilanen SB, Tan DS. J. Am. Chem. Soc. 2005;127:13796–13797. [PubMed](b) Moilanen SB, Potuzak JS, Tan DS. J. Am. Chem. Soc. 2006;128:1792–1793. [PubMed](c) Liu G, Wurst JM, Tan DS. Org. Lett. 2009;11:3670–3673. [PubMed](d) Wurst JM, Liu G, Tan DS. J. Am. Chem. Soc. 2011;133:7916–7925. [PubMed]
9. For selected early studies on the synthesis of spiroketals from cyclic enol ethers, see: Knabe J, Schaller K Arch. Pharm. 1968;301:457–464. [PubMed] Clark-Lewis JW, McGarry EJ Aust. J. Chem. 1975;28:1145–1147. Boeckman RK, Jr, Bruza KJ, Heinrich GR J. Am. Chem. Soc. 1978;100:7101–7103. Danishefsky SJ, Pearson WH J. Org. Chem. 1983;48:3865–3866. Amouroux R Heterocycles. 1984;22:1489–1492. Iwata C, Hattori K, Uchida S, Imanishi T Tetrahedron Lett. 1984;25:2995–2998. Cremins PJ, Wallace TW J. Chem. Soc. Chem. Commun. 1986:1602–1603. Bernet B, Bishop PM, Caron M, Kawamata T, Roy BL, Ruest L, Soucy P, Deslongchamps P Can. J. Chem. 1985;63:2814–2818. Yeates C, Street SDA, Kocienski P, Campbell SF J. Chem. Soc. Chem. Commun. 1985:1388–1389. Diez-Martin D, Grice P, Kolb HC, Ley SV, Madin A Tetrahedron Lett. 1990;31:3445–3448. Kurth MJ, Olmstead MM, Rodriguez MJ J. Org. Chem. 1990;55:283–288. Friesen RW, Sturino CF J. Org. Chem. 1990;55:5808–5810. Dubois E, Beau JM Tetrahedron Lett. 1990;31:5165–5168. Jeong JU, Fuchs PL J. Am. Chem. Soc. 1994;116:773–774. Boyce RS, Kennedy RM Tetrahedron Lett. 1994;35:5133–5136. Holson EB, Roush WR Org. Lett. 2002;4:3719–3722. [PubMed]
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16. See Supporting Information for full details.
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19. The optical rotation of synthetic d-acortatarin A (14), equation M1 (c 0.4, MeOH), matched that of an authentic sample, equation M2 (c 0.4, MeOH), confirming the revised absolute stereochemical assignment as 2-deoxy-d-ribo (refs. 5, 6).
20. The optical rotation of synthetic acortatarin B (19), equation M3 (c 0.1, MeOH), matched that of an authentic sample, equation M4 (c 0.1, MeOH). Examination of the NOESY spectrum of acortatarin B, in comparison to the original ROESY spectrum (ref 1) suggests that mis-assignment of the relative C2–C3 stereochemistry was due to assignment of ambiguous C2-H/C5-H2 crosspeaks, and to non-assignment of an ambiguous C8-H/C5-H crosspeak (Figure S4). Notably, in the structural revision paper (ref 5), C2-H/C5-H2 ROESY crosspeaks also appear but were apparently discounted in favor of clear C5-H/C8-H2 crosspeaks. The reported 7.7 Hz C2-H/C3-H coupling constant is also more consistent with a 2,3-trans relationship: Lemieux RU, Stevens JD Can. J. Chem. 1966;44:249–262.
21. In contrast to 6-membered ring spiroketals, the conformational flexibility of 5-membered rings makes such thermodynamic preferences difficult to predict a priori based on anomeric stabilization: Deslongchamps P, Rowan DD, Pothier N, Sauve T, Saunders JK Can. J. Chem. 1981;59:1105–1121. Tlais SF, Dudley GB Org. Lett. 2010;12:4698–4701. [PubMed]
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23. For a review on nonanomeric spiroketals, many of which are contrathermodynamic, see: Aho JE, Pihko PM, Rissa TK Chem. Rev. 2005;105:4406–4440. [PubMed]