Stereocontrolled Synthesis of (&#177;)-Melokhanine e via an Intramolecular Formal [3 + 2] Cycloaddition

Intramolecular Formal [3 + 2] Cycloaddition

Letter

Stereocontrolled Synthesis of (± )-Melokhanine E via an

‡

Anna E. Cholewczynski, Peyton C. Williams, and Joshua G. Pierce*

Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04546

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sı Supporting Information

ABSTRACT: A convergent sequence to access the indole alkaloid

±)-melokhanine E in 12-steps (8-step longest linear sequence)

(

and an 11% overall yield is reported. The approach utilizes two

cyclopropane moieties as reactive precursors to a 1,3-dipole and

imine species to enable stereoselective construction of the core

scaﬀold through a formal [3 + 2] cycloaddition. The natural

product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported

eﬀorts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.

ew natural product skeletons with antimicrobial activity

faecalis). A key structural motif of the melokhanines is a core

piperidine heterocycle bearing C3 quaternary substitution.

This structural element is found in an array of bioactive natural

products and represents a signiﬁcant synthetic challenge (2−5,

are of signiﬁcant interest as there is a pressing need for

−3

the development of novel antimicrobial agents.

Melokha-

nine E (1 , Figure 1 ) and a series of related compounds were

Figure 1). We therefore sought to develop a synthetic route

to access melokhanine E (1) to conﬁrm its antibacterial activity

while developing innovative solutions to access its pentacyclic

core. During the course of our eﬀorts, a 14-step synthesis of 1

was reported as part of studies developing rearrangement

approaches toward this broad class of natural products.

Herein we describe a short synthetic sequence to stereo-

selectively access 1, conﬁrm its chemical structure, and explore

its potential as an antimicrobial lead.

A number of strategies have been developed to install the

quaternary substituted piperidine motif found in many

alkaloids. Pandey and co-workers have utilized a Birch

reduction/alkylation followed by auxiliary removal as well as

an approach utilizing a Johnson-Claisen rearrangement that

provided greater than 99% ee. One of the most successful and

broadly used strategies was developed by the Stoltz group,

which employs racemic 3,3-disubstituted piperidines and chiral

palladium catalysis to obtain enantioenriched 3,3-disubstituted

piperidines with good yields and up to 99% enantiomeric

11−13

excess.

While high-yielding and stereoselective, these

Figure 1. Representative biologically active natural products

containing a piperidine C3 all-carbon quaternary center.

approaches yield products at nonideal oxidation states for their

direct advancement to the target natural products. The

approach to the piperidine scaﬀold presented herein is inspired

by Waser and co-workers’ eﬀorts on push−pull cyclopropane

opening and subsequent cycloadditions, allowing for direct

isolated in 2016 from Melodinus khasianus, a subtropical plant

used in traditional Chinese medicine as a treatment for

14−16

access to piperidines at the desired oxidation states.

rheumatic heart disease and meningitis. These indole alkaloids

possess a 6/5/5/6/6 pentacyclic structure and are reported to

exhibit potent antimicrobial activity against Gram-negative

pathogens P. aeruginosa and E. coli as well as Gram-positive

pathogens such as E. faecalis. Within the family, melokhanine E

is of particular interest due to its superior broad-spectrum

activity (MIC = 2 μM against P. aeruginosa and 5 μM against E.

Received: December 18, 2019

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

cycloaddition (Figure 2 ).

Letter

Inspired by Carreira’s utilization of a regioisomeric version

of our oxindole 1,3-dipole for intermolecular cycloadditions,

we set out to devise a concise retrosynthesis of melokhanine E

featuring a similar oxindole 1,3-dipole-based intramolecular

17−21

Our retrosynthetic approach to

Figure 2. Retrosynthetic access to melokhanine E (1).

therefore began by recognizing that intramolecular formal [3

2] cycloaddition within biscyclopropane 7 would enable all

relative stereochemistry in the molecule to be set in a single

transformation based on the conﬁguration of the quaternary

piperidine moiety. We envisioned that the stereoselectivity of

this transformation would derive from sterically favored exo

approach of the revealed oxindole 1,3-dipole functionality into

the imine as well as kinetically favored attack of the 1,3-dipole

anti- to the ethyl group. We initially proposed that the kinetic

preference for anti- addition into the imine would derive from

the kinetically favored chairlike transition state that would be

formed upon addition onto the antiface of the ring, a process

that is likely supplemented by steric predisposition to the

antiface of attack. Thus, a late stage intramolecular cyclo-

addition of an appropriately functionalized 1,3-dipole tethered

to an imine or iminium derivative, represented by 6 (Figure 2),

enables an extremely rapid approach to the core of 1. Then 6

was envisioned to arise from coupling of spirocyclic cyclo-

propane 8 with cyclopropanated piperidine 9, followed by

subsequent Lewis acid/thermal opening of both cyclopropanes

to generate the requisite reactive functionality in situ. Both

cyclopropane precursors 8 and 9 are available through

literature protocols, with 9 arising from cyclopropanation of

Figure 3. (a) Synthesis of spirocyclic cyclopropane 8; (b) synthesis of

fused bicyclic cyclopropane 9.

under basic conditions and is simultaneously epimerized to the

more stable exoisomer 9 (Figure 3b).

At this stage, we began to explore coupling conditions to

unite 8 and 9 through the amide linkage to set the stage for our

key intramolecular cycloaddition. The coupling of indolinone 8

and piperidine 9 proved to be more challenging than

anticipated. We postulate that the diﬃculty of this amide

bond formation is a result of steric bulk on both coupling

partners as well as deactivation of the nucleophile via

resonance with the 3-keto functionality of the indolinone.

After exploring various conditions, we discovered that an acid

chloride-based coupling approach proved most fruitful, with

triphosgene providing our desired acid chloride species with

minimal substrate decomposition. Our initial attempt with

triphosgene provided 16% yield of the desired coupled product

after 16 h at room temperature (Table 1). We found that

14,22

enecarbamate 10.

The synthesis of coupling partners 8 and 9 was achieved via

Table 1. Optimization of Coupling Conditions for 7

14,22

modiﬁcation of literature procedures (Figure 3).

To target

the spirocyclic cyclopropane 8, anthranilic acid (11) was

reacted with bromo-lactone 12 to provide amino acid 13 in

2% yield. Activation of the carboxylic acid functionality in the

presence of base and heat forges the spirocyclic bicycle 14 in

1% yield. Heating this compound in the presence of NaCl

enables a Krapcho decarboxylation-ring contraction sequence

that reveals the desired alpha-keto cyclopropane 15 in 73%

yield. Finally, methanolysis of 15 aﬀords 8 in four steps and

entry

time (h)

temp (°C)

solvent

yield (%)

3.5

CH Cl₂

2% overall yield (Figure 3a). Synthesis of the desired fused

CH Cl₂

cyclopropane-piperidine coupling partner 9 begins with an

alkylation-protection of delta-valerolactam (16) to generate 17

CH Cl₂

(

⁶¹^%^,^t^w^o^s^t^e^p^s⁾^.^R^e^d^u^c^tⁱ^oⁿ^o^f^t^h^e^l^a^c^t^a^m^wⁱ^t^h^N^a^B^H4

CH Cl

2 2

followed by dehydration of the resulting hemiaminal with

THF

H SO aﬀords Boc-protected enamine 10 (82%, two steps).

Copper(I) triﬂate-mediated cyclopropanation of enecarbamate

0 then aﬀords fused ester 18 in 73% yield, which saponiﬁes

Lutidine was used in place of collidine.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

increased temperature allowed for shorter reaction time and

higher yield; however, increased reaction time at elevated

temperature decreased the overall yield, likely due to slow

decomposition of the substrates or product. At this stage, we

elected to take these conditions and press forward with the

synthesis, having access to 7 in 45% yield. It should be noted

that upon isolation and storage 7 can ring-open to the

hydrated hemiaminal piperidine motif; however, this has no

consequence on the yield of the subsequent cycloaddition

chemistry.

enantiopure natural product will enable us to rule out the

unlikely possibility that the unnatural enantiomer has a

negative impact on the natural products’ antimicrobial activity.

In conclusion, a concise, stereoselective synthesis of

(±)-melokhanine E has been reported in eight steps (longest

linear sequence) and in 11% overall yield. The key step of our

synthesis is a MgI promoted ring opening/cyclization that

successfully provides the natural product core in excellent yield

and as a single detectable diastereomer. The stereochemical

control of this transformation relies on the piperidine C3 all-

carbon quaternary center, presenting an opportunity to expand

this approach to a number of related natural products with

validated biological activities. The current work is focused on

developing an asymmetric synthesis of 9 and extending this

With coupled biscyclopropane 7 in hand, we sought to

explore the generation of our key cycloaddition intermediates

via cyclopropane opening. To this end, 7 was subjected to

cycloaddition conditions utilizing MgI to promote spirocycle

opening, and thermolysis of the Boc-carbamate to reveal the

chemistry to the bisleuconothine family of natural prod-

17−21

5,24,25

reactive imine intermediate.

We envision a sequence of

ucts

(5, Figure 1), and these eﬀorts will be reported in

Boc-deprotection/cyclopropane opening and MgI -promoted

due course.

cyclopropanation opening to generate the reactive 1,3 dipole

0, which undergoes stepwise imine addition/nitrogen

ASSOCIATED CONTENT

sı Supporting Information

■

alkylation to generate the formal [3 + 2] cycloaddition

product (Figure 4 ). In our ﬁrst attempt (0.43 equiv MgI ₂,

https://pubs.acs.org/doi/10.1021/acs.orglett.9b04546.

Experimental details, spectroscopic and analytical data of

all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

■

Joshua G. Pierce − NC State University, Raleigh, North

Carolina; orcid.org/0000-0001-9194-3765 ;

Email: jgpierce@ncsu.edu

Other Authors

Anna E. Cholewczynski − NC State University, Raleigh,

North Carolina

Peyton C. Williams − NC State University, Raleigh,

North Carolina

Figure 4. Formal [3 + 2] cycloaddition to synthesize (±)-melokha-

nine E (1).

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.9b04546

THF, sealed vessel, 125 °C), we obtained 15% of the desired

natural product 1 as a single diastereomer with no other

related melokhanine products observed. To our delight,

performing the reaction in toluene at 200 °C under microwave

heating provided 88% yield of (±)-melokhanine E, again as a

single detectible diastereomer (1, Figure 4). Interestingly, in

Author Contributions

^‡These authors contributed equally.

Notes

The authors declare no competing ﬁnancial interest.

the absence of MgI , the reaction still proceeds, albeit at an

exceptionally slow rate (29% yield after 8.5 h at 200 °C).

With the racemic natural product in hand, we next sought to

conﬁrm the biological activity reported in Luo and co-workers’

isolation report. In the isolation report, Luo and co-workers

reported impressive antibiotic against Gram-negative bacteria

ACKNOWLEDGMENTS

■

We are grateful to the NIH (R01GM117570) for partial

support of this work and to NC State University for support of

our program. Mass spectrometry data, NMR data, and X-ray

data were obtained at the NC State Molecular, Education,

Technology and Research Innovation Center (METRIC).

Kaylib Robinson (NC State) is acknowledged for the training

to conduct the antimicrobial assays, and Dr. Vincent Lindsay

(NC State) is acknowledged for helpful discussion throughout

the project.

(P. aeruginosa MIC 2 μM, 0.62 μg/mL) as well as Gram-

positive bacteria (E. faecalis MIC 5 μM, 1.56 μg/mL). We

explored the activity of 1 against both the pathogens reported

in the isolation report as well as the ATCC numbers reported

and found in all cases the activity of the natural product was

256 μg/mL. Disappointed by these initial results, we have

adjusted the assay conditions to nonstandard protocols (see

Supporting Information for biological protocols and Table S1

for full data) and have explored alternate growth media but

have not yet uncovered conditions that provide the reported

levels of antimicrobial activity. Going forward, access to the

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