Scribd
Upload
9 views3 pages

Total Synthesis of Mobiustrine A

This document details the total synthesis of the macrocycle polyketide mobiustrine A, derived from isoheptane, highlighting key synthetic steps including cycloadditions and rearrangements. Mobiustrine A, isolated from the fungus Kleptomyces negligencii, features a unique molecular Möbius strip topology and is believed to play a role in the organism's metabolic processes. The synthesis employs various innovative chemical reactions and methodologies to achieve the final product, showcasing the complexities of organic synthesis.

Uploaded by

Алексей Кондратьев
Copyright
© All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
9 views3 pages

Total Synthesis of Mobiustrine A

This document details the total synthesis of the macrocycle polyketide mobiustrine A, derived from isoheptane, highlighting key synthetic steps including cycloadditions and rearrangements. Mobiustrine A, isolated from the fungus Kleptomyces negligencii, features a unique molecular Möbius strip topology and is believed to play a role in the organism's metabolic processes. The synthesis employs various innovative chemical reactions and methodologies to achieve the final product, showcasing the complexities of organic synthesis.

Uploaded by

Алексей Кондратьев
Copyright
© All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd

Orgasmic Letter

P Cite This Orgas. Lett. 2025, 69, 420–422


Letters

You Twist Me Right Round Baby: The Total Synthesis of Mobiustrine A


Postdoc Malone,† ❀ Günther Schlonk§*❀

† Department of Government Inefficiency, NIH Headquarters Crawl Space, Bethesda MD 20982


§ Department of Pyrofrolics and Inorganometallics, University of West Failure, Schlappenplatz, West Failure, 90210

S Supporting Information

Abstract: We report the total synthesis of the supernatural product mobiustrine A, starting from isoheptane. The key
steps in our synthesis were a [2+2]+[2+2] cycloaddition, a Bonnie-Clyde cross-conjugal visitation, an enzymatic
epoxide unzipping, and a Morbin rearrangement.

M obiustrine A is a macrocycle polyketide, which was


isolated from the fungus Kleptomyces negligencii in
2019 (Figure 1).2 Similar “extremophilic” organisms
undertake this task, and we used a piece of paper as a
model system to inform our retrosynthetic analysis
(Scheme 1).
have been a rich font of interesting chemistry, most
notably the enzyme Taq polymerase, which was Scheme 1. Retrosynthetic Analysis of Mobiustrine A
originally obtained from bacteria inhabiting thermal
springs.3 K. negligencii thrives in an environment far
more inimical than a puddle of hot water: it grows in the
fume hoods of Ivy-League universities. This mold
embodies the idiom “life finds a way”. It has adapted to
its environment masterfully, and subsists on a different
kind of organic matter to all other detritivores: organic
solvents. It is believed that the mobiustrines are We began with amino aldehyde 2, which is prepared
enzymatic cofactors in a metabolic process that in two steps from the unnatural amino acid sarahpaline
converts dichloromethane and hexanes to phosgene (Scheme 2). Addition of Hodenkobold’s reagent (3)
and CO2.4 This unique form of cellular respiration makes followed by rearrangement and THP protection
K. negligencii the only known petrol-powered fungus. delivered allene 4. This compound was subjected to a
Butkus oxidation with Dean–Martin’s phosiodinane (5)
Figure 1. Chemical Structure of Mobiustrine A
to obtain nitroso-furan 6. This was followed by a
Me H H Me
O O O O nitroso-Wittig reaction to generate intermediate 8,
which underwent a spontaneous photochemical
NHMe
AcO [2+2]+[2+2] cycloaddition. The product (9) was
O O Me
H H H deprotected with radium triflate, followed by ring
O expansion, global tosylation and a Diels-Alder reaction
O to yield 12.
N
O The penultimate ring system was installed with a
H
Bonnie–Clyde cross-conjugal visitation, followed by a
MeO N O H
H N H H Me Schutlipz cuprate addition, which set up compound 15
Me
O for an autophaliative conjugate addition. Finally, an
Mobiustrine A
intramolecular Hashwig–Buckwig–Hartwald coupling
1 was used to generate the strained alkyne of compound
Quite aside from its fascinating and poorly- 17, which was secured by X-ray crystallomancy.6
understood biochemistry, mobiustrine A also exhibits Turning next to the other half of mobiustrine A, we
an interesting topological feature, in that it is a began by pouring a liter of isoheptane (24) and some
molecular Möbius strip. While not the first of its kind,5 bromine into a sunbed, removing the UV filters and
it is self-evidently the coolest, and alongside its turning the power to full blast. The ensuing mixture was
aforementioned metabolic import, this is a compelling distilled with the aid of a 10 m fractional column packed
motivator for its total synthesis. We decided to with buckyballs, and the fraction collected between 327
and 329 °C was determined to be our desired product
Received: February 1, 2023 (25). This tetrabromoheptane was subjected to
Published: April 1, 2025 elimination conditions, and the resultant diolefin was

ASC Publications ©2025 Austrian Society of Chemists 420 DOI: 10.1021/orgaslett.287-77-4


Orgas. Lett. 2025, 69, 420–422
Orgasmic Letters Letter

Scheme 2: Synthetic routes to two halves of mobiustrine A


O O
Ph Ph
Ph P I P Ph • THP
PMe3
THP THP Cl O
O Cl MgCl Ts N
•
3 Cl O Cl O
Me 7
H 4 equiv • 5 • H
a. THF, -78 ℃ – r.t. H b. CH2Cl2, r.t. H
then DHP, TsOH c. pentane, -100 – -40 ℃ • N O
O 78% yield
H 2N 87% yield then hv (160 nm)
H 2N O O N O 23% yield Ts N
2 4 Butkus Oxidation 6 Nitroso-Wittig Reaction Me
8

S [2+2]+[2+2]
Cycloaddition
S NH2
Br O
O O O THP
Br NH2 Me O
Br Me O Cl Cl Cl
13 O 11
O
f. P4-t-Bu, NaI, MeCN O H Me e. PhMe, 150 ℃ O d. Ra(OTf)2, MeOH 80 ℃ N O
Ts N N Ts N N Ts
90 ℃, 13% yield O 13% yield, 9:5 er then TsCl, NEt3 N
1:1 E/Z Me Ts Me Ts 55% yield
Me
Bonnie-Clyde 12 10 9
Cross-Conjugal Visitation
Diels–Alder Cycloaddition

S OH

S O H O
O H g. 10 equiv Hg(OAc)2 O H N
O N O N O
S Et2O, r.t. – -78 ℃ Cl O Cl
O then O H
h. DBU, THF (0.00001M) Me
O Me O Cu LiCl O Me O H
Ts O H Ts O H reflux, 68% yield Ts N N
N N 13% yield, 1:1 dr N N H O
O O
Me Ts Me Ts Me
Autophaliative Intramolecular
14 Schutlipz Cuprate Addition 15 16
Conjugate Addition

i. AuCl(SMe2), Pd2(dba)18
ChonkPhos, KOtBu
O O EtOH (0.0000000001 M)
N O
Cl 120 ℃, 2% yield
O H
Me
O H Hashwig–Buckmi–Hartwald
HN N
H O Intramolecular Cross-Coupling
X-ray Me
17

Me Br Me Br

AcO Me Br

l. 𝚫
AcO AcO
MeO Zn OMe
AcO
Me 450 ℃, <1 mmHg k. Grubbs Lite© j. [PdI(PtBu3)]2, THF
5 % yield Me CH2Cl2, r.t. Me 5 ℃, 50 % yield
83 % yield I
Me Me
MeO Thermal MeO MeO
22 Rearrangement 21 Olefin Metathesis 20 Kumada Coupling 19 18

m. 5 equiv [RhCl(CO)(PPh3)2],
DMA, 120 ℃,
24 % yield

Me
Ph3P CO Me O
Rh Me H
H O
PPh3
AcO H O Me
AcO Me AcO O
Br Me O
TIPSO TIPSO H O
r. [Ni(COD)2], PMe(tBu)2 s. Ba2XeO6, PhBr H
Me THF, -78 ℃, Me
dioxane, 80 ℃, Me O
O 0.00391% yield
71 % yield TIPSO
Me Me Me
MeO O MeO
O MeO
23 30 Isuzu Coupling 31 Saquan Oxidation 32
+ 255 other isomers
q. 29, BF3·Et2O, DBU, (99.996% combined yield)
CH2Cl2, 0 ℃ Al-Dohl
then TIPSCl Condensation
58 % yield
O Me
O
TMSO O Me Br
Me 27 Me
O
Me Br
p. PPh3, THF, reflux Br o. KOtBu, MeCN Br Br
Me O Br Br n. Br2, hv (150 nm), neat
29 then LDA, -78 ℃, then 27 40 ℃, 12 % yield reflux, 4 % yield
O 50 % yield
28 Wittig Reaction 26 E2 Elimination 25 Radical Bromination 24

coupled with aldehyde 27 via a Wittig reaction. (21) was used to construct the benz(e)azulene core
Subsequently, we used the conditions developed by the (22). Care should be taken with this reaction, as the high
Arabian chemist Muhammad Salman Al-Dohl to temperatures can also cause the reactants to thermally
condense the resultant aldehyde (28) with ester 29.7 rearrange into CO2 and H2O with some force, if oxygen
With this coupling partner in hand, we set about the is not excluded.
preparation of the azulene-containing counterpart (30). We selected the Isuzu reaction to cross-couple the
To this end, we reacted diarylzinc species 18 with polyolefinic (30) and azulene (23) fragments on the
iodide 19 in a Kumada reaction, and used Grubbs Lite© grounds of novelty. This reaction is underutilized,
to perform an intramolecular olefin metathesis. A probably because many chemists balk at using
thermal rearrangement of the resultant phenanthrene superstoichiometric quantities of rhodium as an

DOI: 10.1021/orgaslett.287-77-4
421 Orgas. Lett. 2025, 69, 420–422
Orgasmic Letters Letter

Scheme 3: It’s morbin time


Me Me H H Me
O O O O O
H O H
Me AcO NHMe O
AcO H O Cl O
O O O N
H O O H H H
O
H Me
a. MeNH2, then Davisase, TIPSO
HN O H
Me O2, MTBE, 35 ℃, 48 h Me N O H H Me
Me H H
98% yield O
TIPSO Me
MeO Epoxide Zipping Reaction
MeO
32 33 17

b. ScF3, then
Tandem [4+2] Cyclisation Rose Bengal, TrCl
Azulene Radical Conjunction AgPF6, C6H6, hv (550 nm)
-10 ℃, 29% yield
Me H H Me Me H H Me
O O O O O O O O
NHMe NHMe
AcO AcO
O O Me O O Me
H H H H H H
c. TBAOH, THF, 50 ℃
O then MsCl, DBU
O O O
N O
d. NaBH(OAc)3, THF, 0 ℃ N
H O 29% yield (2 steps) O
H
MeO N O H N O H
N Me MeO
Me H H H H N O H H Me
O Morbin Rearrangement Me H
O
Mobiustrine A
1 34

expendable leaving group. We, however, just got a devised. Untrammeled by lack of purpose or
massive grant, so you can all suffer in your jocks. Also, practicality, these obsessives will leave no stone
stoichiometric rhodium isn’t really an issue when you unturned, in case there’s an algae harboring some novel
only have 7 mg of material. The coupling proceeded compound underneath it. In this paper, we chose to
smoothly, and we obtained a satisfactory yield of make mobiustrine A, not because it was easy, but
compound 31. Finally, we used barium perxenate to because we thought it would easily get into JACS. Damn.
generate bromosobenzene in situ, which epoxidized 31
∎ ASSOCIATED CONTENT
in excellent yield and abysmal stereoselectivity. This
was of little import, however, as the next step was S Supporting Information
enzyme-catalyzed, and everyone knows that enzymes The Supporting Information is available free of charge
can do anything. on the ASC Publications website at DOI:
The enzyme davisase was developed in the [Link].287-77-4
laboratory of Kacey Nicolaou, to aid them in their
Experimental details, procedures, compound
eternal quest for a synthesis of maitotoxin. It functions
characterization data, NMR spectra, and X-ray
as a “molecular zipper”, and was intended to facilitate
crystallographic data (PDF).
the construction of maitotoxin’s core ring systems by
chaining about 30 epoxides together. Unfortunately, it ∎ AUTHOR INFORMATION
gets stuck after four epoxides, when another part of the Corresponding Author
substrate gets caught in the active site and jams it. It was *[Link]/schlonkitup
perfectly sufficient for our purposes, however, and it
elegantly collapsed all 256 isomers from reaction s into ORCHID ❀

a single product (33). Postdoc Malone: 0000-0003-1415-9263


To unite the two halves of mobiustrine A, we Günther Schlonk: 0000-1300-6555-0606
subjected 33 and 17 to a second Diels-Alder-type [4+2] Notes
cyclisation, followed by a Vollpfosten radical The authors declare that if they had any financial
confabulation to deliver the not-Möbius-strip 34. interests, they wouldn’t still be in a sodding chemistry
Finally, morbin time arrived, and we performed a lab.
Morbin rearrangement and imine reduction, which
delivered mobiustrine A (1) in 29% yield. The
∎ REFERENCES
(1) Sparks, J. The Writings of Benjamin Franklin, Vol. X
mechanism of the morbin rearrangement, including all
(1789-1790). 1856, Macmillan. p. 410.
29 transition states, will be made available on request. (2) Davis, A.; Helsinki, V., It’s morbin time: a topologically
∎ CONCLUSION challenged natural product. JAX, 2019, 5837, 2–6.
Seasons change, the stars turn and empires rise and (3) According to Taq polymerase (personal communication)
(4) Ipsum, L. A petrol-powered fungus. CNS, 2019, 1, 4–444.
fall, yet some things endure. Benjamin Franklin wrote
(5) Walba, D. M.; Richards, M. R.; Haltiwanger, C. R; Total
that only two things in this world are certain: death and synthesis of the first molecular Moebius strip, J. Am. Chem.
taxes.1 He should have appended a third inevitability to Soc. 1982, 104 (11), 3219-3221.
his list, for as long as the sun shines, chemists will (6) Rosiland, F.; Crockson, J.; Wick, F.; Schlonk, G. X-ray
attempt to synthesize every obscure alkaloid, twisted Crystallomancy: A Practical Guide. J. Immat. Sci. 2022, 2, 57.
terpene and perverse polyketide that ever nature (7) Al-Dohl, M. S. A novel condensation reaction, Orgas. Lett.
1899, 4, 650–666.

DOI: 10.1021/orgaslett.287-77-4
422 Orgas. Lett. 2025, 69, 420–422

Common questions

Powered by AI

The synthesis of Mobiustrine A underscores challenges in selecting and executing complex, non-traditional synthesis routes that require innovative thinking in synthetic chemistry. Reactions such as the Morbin rearrangement and the use of enzymes like davisase to zip epoxide chains together demonstrate creative solutions to achieve targeted synthetic goals, despite inherent difficulties like stereochemical control and low yields.

The synthesis process of Mobiustrine A mirrors the complexity of natural product synthesis through its multi-step synthetic route involving intricate reactions and rearrangements. Key steps in the synthesis include a [2+2]+[2+2] cycloaddition, a Bonnie–Clyde cross-conjugal visitation, an enzymatic epoxide unzipping, and a Morbin rearrangement . Each reaction step introduces challenges such as selectivity, yield, and molecular control, illustrating the compounding difficulties faced in natural product synthesis.

The concept of molecular topology, such as the Möbius strip in Mobiustrine A, adds a layer of structural and conceptual intrigue to the synthesis of such compounds . The Möbius strip formation is a rare configuration in molecules, transforming synthetic pursuits into challenges that go beyond simple structural assembly, highlighting symmetry and spatial considerations unique to topology-driven chemistry.

The synthesis of Mobiustrine A showcases the integration of both traditional and modern synthetic techniques, demonstrating innovation in complex molecule assembly. Techniques like the Kumada coupling show reliance on well-established methods, while methods such as X-ray crystallomancy reflect advances in applying cutting-edge techniques . The synthesis process necessitates adaptive strategies leveraging established methodologies alongside novel approaches to navigate intricate reactivity landscapes and stereochemical challenges.

The synthesis of natural products like Mobiustrine A, despite a lack of immediate practical application, is pursued due to the intellectual challenge, opportunity for discovery, and potential future applications that might arise from understanding complex molecular structures . Such endeavors advance the field by refining synthetic techniques and contributing to a deeper understanding of molecular architecture, underscoring the fundamental spirit of scientific exploration for knowledge and potential benefit.

Interdisciplinary integration, using biological insights in chemical processes, crucially enhances complex synthesis projects like Mobiustrine A. Utilizing enzymes exemplifies how biological principles streamline complex reaction sequences in chemistry, as with enzymatic zipping of epoxide chains to collapse isomers post-reaction . Such practices bridge chemistry and biology, broadening the toolkit available for intricate syntheses, fostering collaboration between fields to innovate efficient and creative chemical synthesis strategies.

K. negligencii's adaptation to thrive in extreme environments, such as Ivy-League fume hoods, impacts its biochemical capabilities by harnessing unique metabolic processes that utilize organic solvents as energy sources . This adaptation is pivotal in producing Mobiustrine A, reflecting a novel form of cellular respiration converting dichloromethane and hexanes to more reactive compounds like phosgene and CO2, indicating enzymatic resilience in unfavorable conditions.

Synthesizing Mobiustrine A under potentially challenging and hazardous conditions, like employing high temperatures and reactive agents, underscores the risks and rewards in chemical synthesis. High temperatures necessary for thermal rearrangements risk decomposition into CO2 and H2O if precautions, like oxygen exclusion, are not met . Nevertheless, these conditions assist in achieving reactions that are otherwise kinetically unfavorable, emphasizing the delicate balance of safety and reactivity in advanced chemistry.

Kleptomyces negligencii is the natural source of Mobiustrine A, isolated from this fungus due to its unique metabolic processes, such as converting dichloromethane and hexanes to phosgene and CO2 . This adaptation showcases extremophilic properties relevant to its enzymatic characteristics, making it significant in understanding the biochemical context of Mobiustrine A's synthesis.

Advanced enzymatic techniques like the use of davisase are crucial for achieving synthesis success of complex alkaloids such as Mobiustrine A. Davisase significantly aids in resolving complex structural isomerism issues by facilitating the catalytic 'zipping' of epoxide rings into a singular product form . Enzymes provide specificity and efficiency that chemical processes cannot inherently mimic, streamlining reactions and improving yields, offering innovative tools in natural product synthesis.

You might also like