A Proposal for the Synthesis Route of Lyaline

Shuang Wu

, Xu Han

and Jiedong Li

Xiwai International School, Shanghai 201600, China

Shenzhen College of International Education, Shenzhen 518043, China

University of California, Santa Barbara, CA 93106, U.S.A.

Keywords: Lyaline, Synthesis Route, Dials-Alder Addition, Fischer-Indole Mechanism.

Abstract: Lyaline is a monoterpene indole alkaloid first isolated in 1974. After attempts of proposing a synthesis route

of this compound, researchers found its structure to be unstable and that the proposed structure to be incorrect.

Later researchers revised the structure and set lyaline as the first naturally occurring nacycline analogue.

While most previous research examine the spectroscopic data of lyaline and came up with a structure, this

work assess the possibility of retrosynthesizing this compound and propose a theoretical synthesis pathway

for the revised structure of lyaline. Through online research and books, we decided to retrosynthesize this

molecule by first separating it into a cyclohexene and an indole. And with 3 starting materials—molecule 1

and 2 presented below, and an indole—it is possible to synthesis lyaline through a series of nucleophilic

substitutions and Dials-Alder cyclic addition. This proposal will finally make the molecule of lyaline, though

not completed. The following researches can be done by experimenting and resolving the stereoselectivity of

the specific Dials-Alder reaction and using a better protection to increase the yield of the amine formation.

1 INTRODUCTION

The molecule lyaline was first isolated from the root

of the plant named Pauridiantha paucinervis. Its

structure was proposed by researchers based on

limited spectroscopic data and was later proven

incorrect through attempts in retrosynthesising this

compound. Significant difference from the original

spectroscopic data and the fragile nature of the

synthesized compound indicates that the initially

proposed structure was incorrect. Through thorough

analysis of the 1H NMR spectrum by analyzing the

peaks produced and through comparison with the

array of MIA structural variants, a new structure of

lyaline was proposed. Though there is possibility that

degradation of the sample analyzed may have

occurred, which may invalidate the tests done,

experiments have been done to proved the stability of

MIA collections. Since most research done on lyaline

was examination of the spectroscopic data of the

sample containing lyaline, this work aims to propose

a synthesis route for the revised the structure of

lyaline so that this molecular structure can be

synthesized and further test can be carried out to

examine its property.

Figure 1: The revised structure of lyaline.

2 GENERAL OUTLINE

As shown in Figure 2, the first step starts with

breaking the N-C21 bond and C14-C15 bond to

divide the huge molecule into an indole-containing

molecule and a cyclohexene containing molecule.

Next, a Dials-Alder mechanism to break the

cyclohexene into smaller molecules. We believe that

the indole containing molecule is purchasable, but in

case it cannot, we can synthesize it using a Fischer-

Indole mechanism.

Figure 2: The3 two parts that the original molecule is broken

into.

134

Wu, S., Han, X. and Li, J.

A Proposal for the Synthesis Route of Lyaline.

DOI: 10.5220/0012003600003625

In Proceedings of the 1st International Conference on Food Science and Biotechnology (FSB 2022), pages 134-137

ISBN: 978-989-758-638-5

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

3 METHODS

3.1 Breaking N-C21 Bond and

C14-C15 Bond

Upon considering the procedure to connect C-21 and

nitrogen in the pentagon, and the connection of C-14

and C-15, the basic logic was to make form the easier

bond and then the other bond. This logic allows us to

avoid the influence of the problem of choosing the

point to connect. This means that with the application

of a sequential procedure rather than a spontaneous

reaction, we can form the desired bond first.

In this case, the bond between C-21 and that

particular nitrogen is considered to be formed through

formation of a trisubstituted amine. The reaction

starts with the central nitrogen in a substituted indole.

We will use a base to deprotonate the nitrogen,

producing a nitrogen anion. In the lower part, there

are initially two carbons connect with halogens, that

are C-21 and C-15. In this case, with the contribution

of the lone pair electron from the nearby nitrogen of

C-21, the amine formation of C-21 is more likely to

perform rather than C-15. The reason is that the lone

pair nitrogen is likely to attack C-21 due to the

inductive effect of bromine’s negativity, which makes

C-21 more electropositive. The negatively charged N

will then perform a SN2 nucleophilic substitution to

connect to C-21, forming the target bond between C-

21 and nitrogen in the indole (ABU-SHANAB, 2010).

Attempt to make the C-14, C-15 bond:

With a treatment of a base, a carbon anion could

form at C-14 on the indole structure of the upper

section. The base deprotonates the methyl group of C-

14 and forms a carbon anion. This anion again

performs an SN2 nucleophilic substitution on the

electropositive C-15 that is bonded to a Cl. Upon

attacking C-15 with the carbon anion and ejecting Cl-,

the desired C15-C14 bond is formed, so is the desired

product (Figure 3).

It is worthy noticing that benefiting from the

amine alkylation of the previous step, the strong base

added to the reaction in this stage only deprotonates

C-14 instead of forming anion on the nitrogen that is

to connect with C-21 (Hunt, 2021).

3.2 Breaking the Cyclohexene

To form the cyclohexene, use 2 smaller molecules:

Figure 4: The starting materials to make the cyclohexene.

With the starting ingredients shown in Figure 4,

the initializing step here uses a double-bonded O

instead of C on molecule 1 because the O can

mesmerically withdraw electrons, which makes the

left most C more electropositive; the reason why not

separate the ester out from part 2 and name it as part

3 is that the ester can also draw electrons toward the

O in the ester through resonance, which also helps

make C bonded to Cl more electropositive; and

connect N to a R-group because it can help stabilize

the electrons on N. All of these helps the Dials-Alder

reaction proceed (Wilson, 2001; Juhl M, 2009).

Figure 3: The mechanism for making C-14, C-15 bond.

A Proposal for the Synthesis Route of Lyaline

135

Figure 5: The mechanism for the Diels-Alder reaction to form the cyclohexene.

Figure 6: The mechanism for synthesizing the indole using Fischer-Indole Mechanism.

To start synthesis the ring, the electron on N will first

attack the carbon connecting to Bromine and start the

reaction as shown in Figure 5. The double bond

connecting bromine will shift one bond to form new

sigma bond with the carbon connecting Chlorine in

part 2. Then the double bond near Chlorine will also

shift the bond to left to form new double bond. And

the double bond originally connecting nitrogen will

shift one bond to help form C-N bond and finish to

form the final product (Jagora et al., 2021).

After forming the product, change the C=O in

molecule 1 back to a C=C using a Wittig mechanism.

Unfortunately, there is not a clear way to change the

N-R to an N-H in molecule 2, which could be an aim

for future research.

So, with molecule 1, molecule 2, and the indole

containing molecule as starting materials and with a

reliable way to change N-R to NH in molecule 2 after

forming the cyclohexene, the above mechanism could

be a possible way of synthesizing the molecule

lyaline.

3.3 Breaking the Pyradine Structure

into Simpler and Easier to

Purchase Ingredients

As shown in figure 6, the indole can possibly be

formed with the Fischer-Indole mechanism using the

two starting materials shown above and heated in

acidic solution. As it is unfavorable to perform an

imine formation on a benzene (because benzene is

electron dense, it therefore repels the lone pair of

electrons on the nucleophile), a N2 is used. As the N2

leaves as a gas, it leaves the C it connected to

positively charged, which makes it easier for the lone

pair on the N of the other starting material to attack.

Then the molecule would perform a [3, 3]

sigmatropic rearrangement. This step is favourable

because of 2 reasons: 1. From an orbital symmetry

perspective, according to the Woodward-Hoffman

rules, the reaction is thermally allowed as its total

number of (4q+2)s and (4r)a components is odd; 2.

From a enthalpy perspective, the original N-N bond

has lower bond enthalpy than the new C-C bond while

the original C=C has the same bond enthalpy as the

new C=N, so the reaction is also enthalpy favoured.

The last step is reforming the aromaticity of the

benzene, which gives an aminal, then expulsing

ammonia.

4 CONCLUSIONS

As shown above, the molecule lyaline can possibly be

FSB 2022 - The International Conference on Food Science and Biotechnology

136

synthesized through a series of nucleophilic

substitutions and Dials-Alder cyclic addition, using

the starting materials molecule 1, molecule 2, and the

indole. However, most research done in this work are

through the internet and books as we were not yet able

to experiment on each step of our proposal, thus we

could not give the accurate yield of each step at the

moment. In future research, we would test this

proposal in experimentation and keep making

improvements on this synthesis route.

ACKNOWLEDGEMENT

We would like to thank Professor Brian Stoltz from

California Institute of Technology, who taught us

knowledge of retrosynthesis and helped giving

insights to our research.

REFERENCES

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(2010). ChemInform Abstract: Methylpyridines and

Other Methylazines as Precursors to Bicycles and

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1002/chin.199731246

Jagora, A., Gallard, J.-F. ̧., Beniddir, M. A., & Pogam, P. L.

(2021, September 15). A Reappraisal of the Structure of

Lyaline as the First Naturally Occurring Nacycline

Monoterpene Indole Alkaloid. ACS Publications.

Retrieved November 19, 2021, from https://pubs.

acs.org/doi/10.1021/acs.jnatprod.1c00572?ref=pdf&

Juhl M, Tanner D. Recent applications of intramolecular

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Chemical Society Reviews, 2009.

Hunt, L. (n.d.). Alkylation of Amines. University of Calgary.

Retrieved November 19, 2021, from https://www.

chem.ucalgary.ca/courses/350/Carey5th/Ch22/ch22-3 -

1.html

Wilson, R. (2001, January 24). Intramolecular Diels-Alder

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