Total Synthesis and Stereochemical Revision of the 2-Formylpyrrole

Article pubs.acs.org/jnp

Total Synthesis and Stereochemical Revision of the 2‑Formylpyrrole Alkaloid Hemerocallisamine I James M. Wood,† Daniel P. Furkert,*,†,‡ and Margaret A. Brimble*,†,‡ †

School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

‡

S Supporting Information *

ABSTRACT: The first total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is reported. The convergent synthesis features a key Maillard-type condensation of a complex amine derived from cis-4-hydroxy-L-proline with a dihydropyranone, to directly furnish the 2-formylpyrrole ring system. The absolute configuration of hemerocallisamine I has been revised on the basis of optical rotation data obtained for the synthesized compound.

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exhibiting antioxidant, antitumor, hypolipidemic, and antihyperglycemic effects.4 2-Formylpyrrole products result from the Maillard reaction, a group of nonenzymatic reactions of reducing sugars with amines that typically give rise to complex mixtures of compounds.5 Interest in the synthetic application of the Maillard reaction has recently led to the development of conditions to synthesize 2-formylpyrroles directly from reducing sugars and simple amines or amino acids in moderate yields.6 As part of our ongoing interest in the synthesis of 2formylpyrrole natural products, we have developed mild Maillard-type condensation conditions to cleanly generate the 2-formylpyrrole system from amines utilizing a dihydropyranone as a sugar surrogate.7 The relative configuration of hemerocallisamine I (1) was established by X-ray crystallography and NMR analysis. The absolute configuration of hemerocallisamine I (1) was proposed to be (2R,4R)-1 on the basis of the Flack parameter [absolute structure parameter = −0.0(16)].2 Given that 2formylpyrrole natural products arise from the reaction of sugars and biologically common amines, the assignment of the unnatural D-glutamine (2R,4R) configuration was unexpected. We envisioned that a total synthesis from well-defined chiral pool materials would allow unambiguous elucidation of the absolute configuration of hemerocallisamine I (1) and provide material for biological activity investigations.

he daylily (Liliaceae) is widely cultivated as an ornamental plant in North America and Europe; however it has a long history of use as a food and traditional medicine in Eastern Asia. The edible flowers of the plant are known to be used as a sleeping aid in Japan and also exhibit antidepressant effects.1 In 2014, as part of studies to characterize the chemical constituents of the Hemerocallis f ulva daylily flower and identify sedative amino acid derivatives, Matsuda and co-workers isolated the novel glutamine derivative hemerocallisamine I (1) (Figure 1).2

Figure 1. Proposed structure of hemerocallisamine I, (2R,4R)-1. 2Formylpyrrole is in red.

Hemerocallisamine I (1) possesses a 2-formylpyrrole moiety (Figure 1, red) and a 4-hydroxyglutamine fragment. Glutamine and its derivatives have an important role in the treatment of many neurological conditions including sleep disorders.3 The 2formylpyrrole system, meanwhile, is present in a number of natural products isolated from traditional Chinese medicines © 2017 American Chemical Society and American Society of Pharmacognosy

Received: April 10, 2017 Published: June 7, 2017 1926

DOI: 10.1021/acs.jnatprod.7b00314 J. Nat. Prod. 2017, 80, 1926−1929

Journal of Natural Products

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careful preparation under anhydrous conditions.9b In this event, lactam 4 underwent facile ring opening by exposure to concentrated NH4OH in dioxane to afford terminal amide 6 in quantitative yield. Disappointingly, all attempts to remove the N-Boc protecting group under acidic conditions resulted in cyclization to give lactam 7 as the major product. Lowering the temperature of the reaction failed to improve the ratio of the target deprotected amine to the cyclized amide 7 and instead only slowed the rate of the unwanted reaction. It was anticipated that use of an electron-donating amide to protect the terminal amide group might inhibit unwanted competing cyclization of the α-amino group onto the terminal amide. p-Methoxybenzyl (PMB) protected amide 8 was accordingly prepared by aminolysis of lactam 4 with pmethoxybenzylamine (Scheme 3). Pleasingly, this amide

RESULTS AND DISCUSSION Retrosynthesis Analysis. Following our previous work toward the synthesis of 2-formylpyrrole natural products,7 it was anticipated that the ring system of hemerocallisamine I (1) could be constructed by a Maillard-type condensation of 4hydroxyglutamine derivative 2 with the known dihydropyranone 37a (Scheme 1). The initial synthesis target was the Scheme 1. Retrosynthesis Analysis of Hemerocallisamine I (1) Based on a Maillard-Type Condensation Strategy

Scheme 3. Preparation of Amines 9 and 10 by Aminolysis and Boc Deprotection

enantiomer of the proposed absolute structure of hemerocallisamine I, (2S,4S)-1, which would require the preparation of (2S,4S)-4-hydroxyglutamine derivative 2 rather than the (2R,4R)-4-hydroxyglutamine derivative. We postulated that the natural product in fact possessed the (2S,4S)-configuration, and pursuit of this enantiomer would allow investigation of the proposed synthesis route using readily accessible L-amino acid chiral pool reagents. 4-Hydroxy-L-glutamine derivative 2 could potentially be obtained by aminolysis of known lactam 4, which in turn could be prepared from commercially available cis-4hydroxy-L-proline (5) by known methods.8 This synthesis approach would enable the establishment of both stereocenters of hemerocallisamine I (1) at the outset of the synthesis. Synthesis of the Glutamine Fragment. Lactam 4 was prepared over four steps from cis-4-hydroxy-L-proline (5) using established methods (Scheme 2).8 Preparation of the terminal amide required aminolysis of the lactam in the presence of the methyl ester moiety. Aminolysis of N-Boc-protected lactams in the presence of esters often requires use of catalytic KCN9a or aluminum Lewis acid−ammonia conjugates, which require

a

Reaction mixture was concentrated in vacuo directly. extraction was performed from a NaHCO3 solution.

b

Aqueous

underwent Boc-deprotection of the α-amino group with no observed cyclization onto the protected amide function. Direct concentration of the reaction mixture in vacuo resulted in cleavage of the tert-butyldimethylsilane (TBDMS) protecting group, although this could be prevented by prior neutralization of the reaction mixture with a saturated NaHCO3 solution. Generation of the 2-Formylpyrrole System. With the free amines 9 and 10 in hand, attention turned to the key Maillard-type condensation step. Both amines underwent condensation with dihydropyranone 37a in the presence of pyridinium p-toluenesulfonate in pyridine to give their respective 2-formylpyrroles 11 and 12 (Scheme 4). It was found that amine 9 underwent the condensation reaction more readily than its TBDMS-protected counterpart 10, furnishing the 2-formylpyrrole product 11 in 37% yield. Comparable yields for the TBDMS-protected derivative 12 could be achieved only when two equivalents of the amine 10 were used relative to dihydropyranone 3. Previous applications of this reaction have resulted in imine side products from the condensation of the 2-formypyrrole product with a further equivalent of the amine coupling partner;7b however no imine side products were observed in the 1H NMR spectra of either crude reaction mixture. Although the yield appears moderate, this was readily compensated for by the overall efficiency and functional group tolerance of the Maillard condensation, to directly install the functionalized pyrrole group in a single step. Having constructed the 2-formylpyrrole system, elaboration to the proposed natural product hemerocallisamine I (1) required only deprotection of the PMB and TBDMS groups and selective methylation of the primary hydroxy group. It has

Scheme 2. Aminolysis of Lactam 4 and the Unwanted Lactamization of Amide 6

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Scheme 4. Maillard-Type Condensation of Amines 9 and 10 with Dihydropyranone 3 and Elaboration to Hemerocallisamine I (1)

configuration of hemerocallisamine I from (2R,4R)-1 to (2S,4S)-1. The synthesis has also provided reliable access to the revised natural product, which will enable biological activity investigations.

previously been observed by Okada et al. that conversion of an acid-labile protecting group for the 5-hydroxymethylpyrrole substituent into an alkyl ether can be achieved directly under acidic conditions in the presence of an alcohol.10 Accordingly, treatment of TBDMS ether 11 with catalytic para-toluenesulfonic acid in MeOH and CH2Cl2 cleanly afforded methyl ether 13, with no free alcohol side product being observed (Scheme 4). The final deprotection of the PMB amide was initially attempted using ceric ammonium nitrate, but the 5methoxymethyl substituent of the pyrrole moiety underwent oxidation to afford the diformyl compound 14 as the major product. This transformation was supported by the 1H NMR spectrum of the crude reaction mixture, which showed the disappearance of characteristic doublets resonating at δ 7.01 (J = 3.6 Hz) and 6.33 (J = 3.6 Hz) corresponding to the pyrrole protons of the starting material and the appearance of a new singlet resonating further downfield at δ 7.11. This new pyrrole resonance at δ 7.11 and the formyl proton singlet at δ 9.77 both integrated for two protons relative to the other characteristic methine protons. These signals suggested the presence of a symmetrical bisformylpyrrole system, which was confirmed by HRMS with a sodium adduct molecular ion [M + Na]+ observed at m/z 305.0744, corresponding to a molecular formula of C12H14N2NaO6. Pleasingly, deprotection of PMB−amide 13 proceeded cleanly using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, with the addition of pH 7 phosphate buffer to suppress lactonization of the γ-hydroxy ester. The spectroscopic and physical properties of the synthesized hemerocallisamine I (1) agreed with those reported for isolated hemerocallisamine I (1). Most significantly, the sign of the specific rotation of the synthesized sample (2S,4S)-1 ([α]21D −44.0 (c 0.1, MeOH)) prepared from cis-4-hydroxy-L-proline (5) matched that of the natural product ([α]25D −34.6, in MeOH),2 establishing that the absolute configuration of hemerocallisamine I (1) was (2S,4S) as anticipated, and not (2R,4R) as initially reported. In conclusion, a concise synthesis of hemerocallisamine I [(2S,4S)-1] has been achieved over seven steps from the known lactone 4 and 11 steps from commercially available cis-4hydroxy-L-proline (5). The pyrrole nucleus was installed in a single step by Maillard condensation of complex amine 9 and dihydropyranone 3. The specific rotation of the synthesized material enabled reassignment of the initially proposed absolute

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00314. Experimental procedures and analytical data (1H NMR, 13 C NMR, MS) for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel: +64 9 373 7599, ext. 88259. Fax: +64 9 373 7422. E-mail: [email protected]. *E-mail: [email protected]. ORCID

Daniel P. Furkert: 0000-0001-6286-9105 Margaret A. Brimble: 0000-0002-7086-4096 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank The University of Auckland for the award of an Auckland Doctoral Scholarship to J.M.W. REFERENCES

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Total Synthesis and Stereochemical Revision of the 2-Formylpyrrole

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