Total Synthesis of Nortopsentin D via a Late-Stage Pinacol-like Rearrangement

Letter

Total Synthesis of Nortopsentin D via a Late-Stage Pinacol-like

Rearrangement

Katarina L. Keel and Jetze J. Tepe*

Cite This: Org. Lett. 2021, 23, 5368 −5372

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sı Supporting Information

ABSTRACT: Nortopsentin D is part of a class of bis(indole) alkaloids

known for their biological activity, including inhibitory activity in tumoral

cells and antifungal activity. Herein we describe the ﬁrst total synthesis of

nortopsentin D, in which amidine and dione undergo a pivotal condensation

and subsequent cyclization via a pinacol-like rearrangement. This synthesis

represents a unique strategy for the formation of 5,5-disubstituted (4H)-

imidazol-4-one containing natural products, many of which have yet to

succumb to total synthesis.

ortopsentin D (Figure 1) was originally isolated in 1996

formation of the 5,5-disubstituted (4H)-imidazol-4-one ring

require substrate speciﬁc, linear paths. It is evident there is a

lack of robust, convergent strategies for the formation of (4H)-

imidazol-4-one’s complex tertiary carbon that can be applied to

the synthesis of these natural products.

Herein, we describe the ﬁrst total synthesis of the natural

product, nortopsentin D. The key step of this synthesis

involves a condensation of novel dione and amidine

intermediates followed by a subsequent rearrangement to

produce the core (4H)-imidazol-4-one. This convergent

method for the formation of the (4H)-imidazol-4-one’s tertiary

center is envisioned as a possible method to attain the total

syntheses of several other 5,5-disubstituted imidazol-4-one

containing natural products.

from the axinellid sponge Dragmacidon sp. in deep

waters south of New Caledonia and later from the sponge

Agelas dendromorpha. This is a fascinating structural variant of

the nortopsentin family, whose methylated derivative was

shown to have high cytotoxicity toward tumoral cells (CC 18

nM) as well as antifungal activity against yeast. Over the years,

the nortopsentin family and its synthetic analogues have

displayed a large range of biological activities in the areas of

cytotoxicity, antiplasmodial, antibacterial, antifungal, and

insecticidal activities. Catalytic hydrogenation of nortopsen-

tins A−C was previously reported to render the synthetic

analogue D (Figure 1), which is unfortunately also sometimes

referred to in the literature as nortopsentin D.

Structurally, nortopsentin D is composed of a complex

central trisubstituted (4H)-imidazol-4-one, with a 6-bromoin-

dole at the C2 position and a 4-methyl-1H-imidazol-2-amine

and 6-bromoindole at C5. Nortopsentin D is one of several

known 5,5-disubstituted (4H)-imidazol-4-one containing nat-

ural products. Of the products highlighted in Figure 1, only

four have been previously synthesized. The indole alkaloid

The proposed retrosynthetic plan is shown in Scheme 1.

Due to the highly substituted imidazol-4-one ring, a late-stage

cyclization via condensation of dione (3) and amidine (4) was

proposed. This cyclization involves a pinacol-like rearrange-

ment and is an eﬀective way of forming 5,5-disubstituted

imidazol-4-ones. The dione (3) contains a protected version

of the 4-methyl-1H-imidazol-2-amine and the 6-bromoindole

found at C5 of nortopsentin D, whereas the amidine (4)

contains nortopsentin D’s C2 6-bromoindole. This proposed

route is an opportunity to test the robustness of the cyclization,

isolated from Dendrodoa grossularia was synthesized by Hupp

and Tepe in 2008, where the tertiary carbon was formed

through an oxazole rearrangement, producing a hydantoin that

was later converted into a 2-amino-imidazole. Contrastingly,

the tertiary carbon of (+)-calcaridine A was formed through a

N-sulfonylaziridine driven oxidative rearrangement of imida-

Received: May 19, 2021

Published: June 25, 2021

zole, as reported by Koswatta et al. in 2008. Lastly, dictazole B

was ﬁrst synthesized in 2014 by Skiredj et al. through a [2 + 2]

cycloaddition of aplysinopsin monomors, and a dictazole B-

type skeleton was later used to form (±)-tubastrindole B via

ring expansion. The aforementioned methods for the

2021 American Chemical Society

368

Org. Lett. 2021, 23, 5368−5372

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Letter

Figure 1. Natural products within the nortopsentin family and other 5,5-disubstituted (4H)-imidazol-4-one containing natural products.

Scheme 1. Retrosynthetic Analysis for Nortopsentin D (1)

highlighting its capacity to be exploited for the synthetic eﬀorts

toward other 5,5-disubstituted (4H)-imidazol-4-one containing

natural products.

of the temperature to room temperature led to better control

over the coupling’s chemoselectivity, signiﬁcantly favoring the

desired C3 position.

The synthesis of dione 3 is shown in Scheme 2. It began by

synthesizing terminal alkyne 5. Starting with 6-bromoindole

7), intermediate 8 was produced via iodination and

subsequent N-tosylation, under the inﬂuence of triethylamine

TEA) and 4-dimethylaminopyridine (DMAP) and upon the

The other half of the dione intermediate began via the

condensation of 1-chloroacetone (9) and 2-aminopyrimidine

(10) upon addition of heat, to produce 3-methylimidazo[1,2-

a]pyrimidine 11 in 58% yield. This bicycle represents a

protected form of the 4-methyl-1H-imidazol-2-amine observed

on C5 of nortopsentin D. Iodination of 11 with N-

iodosuccinimide (NIS) led to the desired aryl iodide 6 in

two steps with an overall yield of 50%.

Once intermediates 5 and 6 were in hand, a Sonogashira

coupling led to the desired internal alkyne 12 in 85% yield.

Compound 12 went through extensive experimentation to

identify the best conditions for the oxidation of the internal

alkyne to a dione, as the alkyne proved to be unstable under

(

addition of 4-toluenesulfonlyl chloride (TsCl). This was

followed by a Sonogashira coupling of trimethylsilylethyne

under standard conditions, with a subsequent protodesilylation

of trimethylsilane using tetrabutylammonium ﬂuoride (TBAF),

which produced terminal alkyne 5 in 76% yield. It should be

noted that when the Sonogashira coupling was run at 60 °C,

yields were considerably lower, due to poor chemoselective

coupling at the C3-iodo versus C6-bromo positions. Reduction

369

Org. Lett. 2021, 23, 5368−5372

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Letter

Scheme 2. Synthesis of Dione 3

of indole with an amide was performed using chlorosulfonyl

isocyanate (CSI), followed by potassium hydroxide in aqueous

acetone to produce 14 (58%). Lawesson’s reagent was used to

convert the amide to a thioamide in 89% yield. The resultant

compound 15 was then converted to a methyl thiol imine

using methyl iodide, giving compound 16 in 89% yield. The

last step in the preparation of key intermediate 4 was the

substitution of methyl thiol with an amine using ammonium

chloride in methanol. Overall, this pathway furnished the

desired amidine 4 in 5 steps with an overall yield of 30%.

Once both key intermediates 3 and 4 were produced

through a reliable and multigram scalable route, the formation

of the core (4H)-imidazol-4-one was performed. Eﬀorts in this

cyclization are summarized in Scheme 4. First, following

Scheme 4. Optimization of the Cyclization of Intermediates

and 4

harsh oxidative conditions and high temperatures. Exposure of

2 to a range of conditions (e.g., KMnO /TBAB, ICl/

12 13

AgNO₃, Pd(OAc) /AlCl /DMSO/70−110 °C, PdCl₂/

DMSO/140 °C, RuCl /PhI(OAc) , 2-chloropyridine-N-

oxide/Ph PAuNTf /75−85 °C ) led to low yields and a

variety of complications, including decomposition of the

starting material, loss of the tosyl protecting group, and, in

some cases, oxidation of the 3-methylimidazo[1,2-a]-

pyrimidine. The limitations of high temperature and harsh

oxidation conditions were successfully overcome by use of

mercuric nitrate monohydrate as an oxidation source. Within 8

h at room temperature under air, a 49% yield of the desired

dione 3 was produced. Additionally, the reaction could go for

up to 16 h without any change in yield or evidence of

overoxidation. Overall, dione 3 was synthesized in 4 linear

steps in 14% yield.

With dione 3 in hand, the amidine intermediate 4 was

prepared following a similar pathway as previously described in

the synthesis of nortopsentin B and synthetic analogue D

(

Scheme 3). The synthesis began with 6-bromoindole (7), a

standard conditions reported for this condensation, inter-

mediates 3 and 4 were reacted under basic conditions, using

excess sodium hydroxide and reﬂuxing in ethanol over the

common building block available in multigram quantities. Di-

tert-butyl dicarbonate was used to protect the indole’s nitrogen,

aﬀording 13 in 96% yield. Functionalization of the C3 position

period of 3 h. The procedure provided a 19% yield of the

desired imidazol-4-one product 17 (Scheme 4A), where both

the N-boc and N-tosyl protecting groups were deprotected

during the reaction. Interestingly, the main side product from

this reaction was detosylated dione, which remained

uncondensed even upon heating over an extended period. It

was theorized that the presence of indole’s N-tosyl, and

correlatively the added electrophilicity, may be necessary for

condensation with amidine 4. This theory was tested by using

a weaker, less nucleophilic base (potassium bicarbonate) and

less nucleophilic solvent (isopropanol) to avoid N-tosyl

deprotection (Scheme 4B). After reﬂuxing for 24 h, a 29%

yield of cyclized product 18 was collected, where the indole’s

N-tosyl remained intact, supporting this theory.

Scheme 3. Synthesis of Amidine 4

Curiously, it was observed that the only cyclized product

formed in Scheme 4A and 4B had lost the amidine’s N-boc

protecting group. This prompted a new theory regarding the

nucleophilic nature of 4: N-boc deprotection of the indole

must occur before the amidine will condense with dione 3.

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Org. Lett. 2021, 23, 5368−5372

Organic Letters

The Supporting Information is available free of charge at

Letter

Scheme 4C describes how this theory was tested. First, N-boc

deprotection of amidine 4 was performed, using triﬂuoroacetic

acid (TFA). After reacting for 16 h, volatiles were removed,

and the reaction was basiﬁed (pH = 8) in isopropanol using an

excess of potassium bicarbonate and minimal amount of

sodium hydroxide. Upon introduction of dione 3, the reaction

was heated until cyclization was complete. To simplify the

isolation of this reaction, N-detosylation was performed in one

pot, upon the addition of excess sodium hydroxide and heat.

Overall, this modiﬁed procedure produced 52% yield of the

desired (4H)-imidazol-4-one product. Through this optimiza-

tion process, we determined the condensation of amidine and

dione is susceptible to changes in electron densities and can be

manipulated to improve the conversion to product. A

crystallographic data conﬁrms the presence of a central (4H)-

imidazol-4-one ring.

proposed mechanism for this cyclization is shown in Scheme

Figure 2. X-ray crystal structure of cyclized imidazol-4-one containing

product 17; thermal ellipsoids shown with 50% probability.

Scheme 5. Proposed Mechanism for Imidazol-4-one

Formation via Pinacol-like Rearrangement

In conclusion, we have accomplished the ﬁrst total synthesis

of nortopsentin D. This highly convergent synthesis only

included 7 linear steps with an overall yield of 1.6%. The

structure described in Mancini et al.’s original isolation report

has been conﬁrmed through both NMR and X-ray

crystallography. This pathway features a unique method for

the formation of the 5,5-disubstituted (4H)-imidazol-4-one

ring, which can be envisioned for use in multiple other total

syntheses.

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.1c01681.

Once the cyclization was optimized, we moved onto the last

step of this total synthesis. Here, the 3-methylimidazo[1,2-

a]pyrimidine of 17 was deprotected using hydrazine

monohydrate, aﬀording the title compound, nortopsentin D,

in 70% yield (Scheme 6).

Experimental procedures, characterization data, X-ray

crystal data and experimental, and NMR spectra (PDF)

Accession Codes

CCDC 2081971 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Scheme 6. Final Step in the Total Synthesis of Nortopsentin

AUTHOR INFORMATION

Corresponding Author

■

Jetze J. Tepe − Michigan State University, Department of

Chemistry, East Lansing, Michigan 48824, United States;

orcid.org/0000-0001-5467-5589; Email: tepe@

chemistry.msu.edu

Spectroscopic data obtained from 1 is in full agreement with

Author

the original isolation paper (for a direct comparison, see Table

Katarina L. Keel − Michigan State University, Department of

Chemistry, East Lansing, Michigan 48824, United States

S1 in the Supporting Information). Interestingly, and as Pietra

and co-workers reported, several carbon peaks associated with

the (4H)-imidazol-4-one ring were very broad and only made

visible through enhanced apodization (exponential = 8 Hz).

To further conﬁrm the presence of the central heterocyclic

ring, X-ray crystallography was used to determine the crystal

structure of cyclized product 17 (Figure 2). The X-ray

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c01681

Notes

The authors declare no competing ﬁnancial interest.

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Org. Lett. 2021, 23, 5368−5372

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Kondracki, M.-L.; Barker, D.; Copp, B. R. Synthesis and Biological

Letter

(

10) (a) Fong, H. K. H.; Brunel, J. M.; Longeon, A.; Bourguet-

ACKNOWLEDGMENTS

■

Evaluation of the Ascidian Blood-Pigment Halocyamine A. Org.

Biomol. Chem. 2017, 15 (29), 6194 −6204. (b) Unsworth, W. P.;

Cuthbertson, J. D.; Taylor, R. J. K. Total Synthesis of Spirobacillene

A. Org. Lett. 2013, 15 (13), 3306−3309.

(11) Zhang, F.; Wu, X.; Wang, L.; Liu, H.; Zhao, Y. General and

Efficient One-Pot Synthesis of Novel Sugar/Heterocyclic(Aryl) 1,2-

Diketones from Sugar Terminal Alkynes by Sonogashira/Tetra-n-

Butylammonium Permanganate Oxidation. Carbohydr. Res. 2015, 417,

We gratefully acknowledge the ﬁnancial support provided by

the National Institutes of Health (R01AG066223-02). Addi-

tional thanks go to Dr. Richard Staples and the MSU Center

for Crystallographic Research for identifying the crystal

structure of compound 17. The Rigaku Synergy S Diﬀrac-

tometer was purchased with support from the MRI program by

the National Science Foundation under Grant No. 1919565.

12) Yang, W.; Chen, Y.; Yao, Y.; Yang, X.; Lin, Q.; Yang, D. ICl/

1−51.

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