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Synlett 2024; 35(20): 2554-2558
DOI: 10.1055/a-2361-3510
letter
Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Stereoselective Synthesis of Polyketide Segments of Nemamide A and Euglenatides D–E

Himangshu Sharma 
,
Sujan Paul 
,
Rajib Kumar Goswami  ∗

H.S and S.P thank the Indian Association for the Cultivation of Science and the University Grand Commission for their fellowship. The financial support from the Science and Engineering Research Board (Project no. CRG/2023/000479), India to carry out this work is gratefully acknowledged.
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Abstract

A convergent strategy for the stereoselective synthesis of polyketide segments of hybrid natural products nemamide A and euglenatides D–E has been developed for the first time. The salient features of this gram-scale synthesis include Trost–Rychnovsky alkyne rearrangement, HWE olefination, regioselective epoxide ring opening, Prins–Ritter cyclization, and subsequent reductive cleavage of the substituted THP ring. The optimized route is modular and could be tunable to access the other polyketide counterparts of these families of metabolites.


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Key words

natural products - nemamide A - euglenatides D–E - Trost–Rychnovsky alkyne rearrangement - Prins–Ritter cyclization
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Figure 1 Structures of the nemamides and euglenatides family of hybrid natural products

Polyketide and nonribosomal peptide classes of natural products have significant impact on modern medicine.[1] Natural products bearing polyketide and peptide hybrid frameworks in together captivated attention where many of them possess interesting structural features as well as potential biological activities.[2] During the analysis of the genome of the nematode C. elegans encoded with multimodule hybrid polyketide synthases (PKSs)/nonribosomal peptide synthetases (NRPSs), Butcher and coworkers, in 2016, have isolated two hybrid natural products nemamides A and B (1 and 2, Figure [1]) in minute amounts (<70 μg).[3] These secondary metabolites were found to assist the recovery and survival during starvation-induced larval arrest. However, detailed evaluation of their biological activities remained unexplored due to a lack of requisite materials. The structures of these natural products were deduced using detailed 1D and 2D NMR, mass, and CD analysis along with Marfey’s method which revealed that both of them have a common cyclic pentapeptide core bearing three asparagine and one β-aminobutyric acid residues. The polyketide framework of nemamide A is embedded with three conjugated E-olefins and three asymmetric centers among which two are hydroxylated and one is aminated whereas nemamide B possess an additional conjugated olefin. In 2022, a series of another hybrid natural products euglenatides A–E (3–7, Figure [1]) were discovered by Ganesan and coworkers from biomass extract of E. gracilis, a freshwater unicellular microalga, bearing a gene cluster of NRPSs and PKSs.[4] The structures of these secondary metabolites were established similarly to nemamides where the polyketide frameworks were found to be resembled closely to nemamide A. The saturated chain of these members is two-carbon homologated compared to nemamide A and there is an additional hydroxylated center in the polyketide counterpart for euglenatides A–C (3–5, Figure [1]). The amino acids in the peptide core varies among the members and have the combinations of asparagine, 4,5-dihydroxynorvaline, and β-aminobutyric acid or β-aminoisobutyric acid residues. Euglenatides showed potential inhibitory effect against pathogenic fungi as well as promising cytotoxicity in breast cancer cells lines (IC50 of 4.3 μM in Aspergillus fumigatus and 0.29 μM in MCF-7 for euglenatide B).[4] Our continual interest[5] in natural product synthesis prompted us to embark on the chemical synthesis of biologically promising nemamides and euglenatides family of secondary metabolites. We initially concentrated into the very similar and architecturally attractive polyketide segments of nemamide A and euglenatides D–E and report herein for the first time a general strategy of their synthesis in a stereoselective manner.

The retrosynthetic analysis of the polyketide framework 8 of nemamide A is described in Scheme [1]. We planned to compare the effectivity of Julia–Kocienski olefination and HWE olefination separately to couple sulfone 10 and phosphonate 11 with the aldehyde of alcohol 9, respectively. Both sulfone 10 and phosphonate 11 could further be prepared from ester 12 via Trost–Rychnovsky alkyne rearrangement, whereas aminol 9 could be synthesized from THP derivative 13 via its functional group manipulations and reductive cleavage. Compound 13 could further be made from homoallylic compounds 14 and 15 using Prins–Ritter cyclization protocol as the key step.

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Scheme 1 Retrosynthetic analysis of polyketide framework 8 of nemamide A

The synthesis of requisite sulfone 10 and phosphonate 11 is delineated in Scheme [2]. Commercially available 1-nonayne 16 was transmuted to the corresponding ethyl ester using ClCO2Et/n-BuLi and subjected to Trost–Rychnovsky alkyne rearrangement[6] in the presence of PhOH/Ph3P to access compound 17 in complete regioselectivity. Next, it was reduced to alcohol 18 by DIBAL-H and treated further with 1-phenyl-5-thiotetrazole (19)/DIAD/PPh3 following the Mitsunobu protocol[7] to obtain the corresponding sulfide which was oxidized to sulfone 10 using (NH4)6Mo7O24·4H2O/H2O2. Dioxane was found the best solvent compared to commonly used ethanol in our case when the reaction was performed on gram scale.[8] On the other hand, alcohol 18 was converted into the required phosphonate 11 with good yield in the presence of P(OEt)3/ZnI2.[9]

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Scheme 2 Synthesis of sulfone 10 and phosphonate 11

The synthesis of aminol 9 is described in Scheme [3] where the commercially available epoxide 20 [10] was opened regioselectively using vinylmagnesium bromide/CuI[11] to access homoallylic alcohol 21. It was then treated with Li/naphthalene to get the corresponding diol which was selectively protected as primary tosyl in the presence of TsCl/(n-Bu)2SnO[12] to obtain compound 14 in very good yield. The methylation of homoallylic alcohol 21 using MeI/NaH provided compound 15, which was further subjected to oxidative cleavage using OsO4/NaIO4 to get the corresponding aldehyde. The stage was set to perform the crucial Prins–Ritter cyclization[13] using homoallylic alcohol 14. A detailed optimization of conditions (Table [1]) was performed for having the best outcome. The use of BF3·OEt2 (entry 1),[14a] CeCl3·7H2O/AcCl (entry 2),[14b] and TfOH (entry 3)[14c] in CH3CN provided the substituted THP 13 in 42%, 49% and 60% yield, respectively. Delightfully, use of FeCl3/AcCl[14d] in CH3CN improved the conversion into 81% yield (entry 4). The proficiency of this methodology was found to vary the amount of CH3CN present in the reaction mixture. The use of 3 and 5 equiv. of CH3CN in toluene provided 52% and 60% yield, respectively, whereas utilization of 10 equiv. of CH3CN without any solvent further improved the yield up to 72%. Notably, 20 equiv. of CH3CN or more yielded the best result (entry 4). The NOESY correlation clearly confirmed the syn-relative stereochemistry of the substituents in the THP ring. Next, compound 13 was treated with NaI/acetone and was subsequently subjected to reductive ring rupture using Zn dust in refluxing ethanol[15] to furnish compound 22 in good yield. Considerable challenges were faced to deprotect the N-acetyl group of 22. Our initial trials were to protect the NH-acetyl with the Boc group and then selectively deprotect the acetyl group using hydrazine. Unfortunately, the required HN-Boc-protected compound was obtained in quite low yield (4%), leaving the N-acetylated starting material mostly unreacted. Next, acetyl deprotection using LiOH and NaOH in different solvent systems and temperature were tried which resulted a partial deprotection of acetyl ranging the yield up to 40%. It was our great relief to find KOH in degassed ethanol under refluxing conditions functioned best (90% yield brs). The resulted aminol was treated with TBSOTf/Et3N to obtain compound 23 (crystallize as trifluorosulfonate amine salt) which was validated further by X-ray crystallographic analysis. The free amine of 23 was then protected as N-Boc, and the resultant compound was subjected to oxidative cleavage using OsO4/NaIO4 followed by Pinnick oxidation[16] to get acid 24. It was reacted with MeI/K2CO3 followed by further hydrogenation to deliver suitably protected aminol 9 in quite good overall yield.

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Scheme 3 Synthesis of suitably protected aminol 9

Table 1 Optimization for Multicomponent Prins–Ritter Reaction between 14 and the Corresponding Aldehyde of 15 a

Entry

Conditions

Yield (%)

1

BF3·OEt2 (0.02 equiv.), 0 °C to rt, 28 h

42

2

CeCl3·7H2O (0.02 equiv.), AcCl (1.8 equiv.), 0 °C to rt, 24 h

49

3

TfOH (0.02 equiv.), 0 °C to rt, 12 h

60

4

FeCl3 (0.02 equiv.), AcCl (1.8 equiv.), 0 °C to rt, 36 h

81

a CH3CN was used as reagent as well as solvent under all the tested conditions. It has been used 12 mL/mmol in respect to 14.

Suitably protected aminol 9 was oxidized to aldehyde 25 using DMP and subjected to Julia–Kocienski olefination utilizing sulfone 10 (Scheme [4]). A number of conditions (Table [2]) were screened. KHMDS in THF (entry 3) was found to result in the desired segment 8 in 79% yield. However, the regioselectivity was quite poor (E/Z = 1:1.3). The trials with phosphonate 11 in the presence of NaHMDS following HWE olefination gave 8 in moderate yield but in much improved selectivity (E/Z = 12:1). The isomers have been separated by silica gel column chromatography.

Table 2 Efforts towards the Optimization of Julia–Kochienski Olefination between Aldehyde 25 and Sulfone 10

Entry

Conditions

Yield (%)

E/Z

1

NaH, THF, 0 °C, 15 min

60

1:1

2

LiHMDS, THF, –78 °C, 2 h

68

1:2

3

KHMDS, THF, –78 °C, 3 h

79

1:1.3

4

KHMDS, DME, –65 °C, 3 h

72

 1:0.8

Having the optimized route of the polyketide segment of nemamide A in hand, we then have concentrated to access the common polyketide framework of euglenatides D–E as shown in Scheme [5]. 1-Undecayne (26) was transmuted to phosphonate 28 via the intermediate 27 which was subjected to HWE olefination using aldehyde 25 in the presence of NaHMDS to afford the desired segment 29 in very good overall yield.

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Scheme 4 Completion of the synthesis of polyketide segment of nemamide A

In summary, we have developed a stereoselective synthetic route of polyketide segments of nemamide A and euglenatides D–E from the known epoxide 20 in 15 longest linear steps with 10.4% overall yield. Two approaches for the regioselective installation of the triene moiety has been investigated where the HWE olefination was found much effective in this case. The Prins–Ritter reaction between a homoallylic alcohol and an aldehyde bearing an additional β-methoxy center has been performed where the effect of the amount of CH3CN in the Fe(III)-catalyzed reaction was found prominent. The synthetic route is quite flexible which could be modified to access the other polyketide segments of these classes of natural products. Notably, the optimized strategy provided the targeted frameworks in gram scale.

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Scheme 5 Completion of the synthesis of the common polyketide segment of euglenatides D–E

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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2361-3510. Included are UV-Visible comparison (Figure-SF1), copies of NMR (1H & 13C), 2D NMR correlation data (COSY, HSQC, NOESY) and HRMS of representative compounds.
  • Supporting Information

Corresponding Author

Rajib Kumar Goswami
School of Chemical Sciences, Indian Association for the Cultivation of Science
Jadavpur, Kolkata-700032
India   

Publication History

Received: 08 June 2024

Accepted after revision: 03 July 2024

Accepted Manuscript online:
07 July 2024

Article published online:
18 July 2024

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Zoom Image
Figure 1 Structures of the nemamides and euglenatides family of hybrid natural products
Zoom Image
Scheme 1 Retrosynthetic analysis of polyketide framework 8 of nemamide A
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Scheme 2 Synthesis of sulfone 10 and phosphonate 11
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Scheme 3 Synthesis of suitably protected aminol 9
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Scheme 4 Completion of the synthesis of polyketide segment of nemamide A
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Scheme 5 Completion of the synthesis of the common polyketide segment of euglenatides D–E