The Journal of Immaterial Science

MISCOMMUNICATION
CHEMISTRY
Received: 17th April 2023
The Structural Determination, Total Synthesis
Revised:
Accepted:
10th April 2023
1st April 2023 and Endochronicity of Thiotimoline
DOIOU: 10.01123581321
Marry CurryA, Herbert WestB and Günther SchlonkC*
Abstract: The natural product thiotimoline was isolated from the bark of Rosaceae Karlsbadensis rufo and its structure was
unambiguously determined by time-resolved X-ray crystallomancy and spectroscopy. A total synthesis of thiotimoline was
conducted following a convergent strategy. The pivotal transformations in this synthesis were a tandem Suzuki-
Miyaura/Schinkenfaust radical cross-spifflication, a Szymankowszczyzna allylic inquisition and a [3+2+3+2] Puccini-Gershwin
echocyclisation in A♭ major. An unnatural isomer of thiotimoline was also synthesised, and a theory of kairality and
chronomers is presented and discussed.

Thiotimoline (1) was discovered in 1930 by researchers (Fig. 1A, 2) to thiotimoline on the basis of IR spectroscopy (Fig.
cataloguing the phytochemicals of the Rosaceae genus.1 The 1B).7 This assignment was disputed both at the time and since,
molecule went largely unremarked for almost two decades until and the authors themselves remarked that “the quality of our
Isaac Asimov and co-workers reported peculiarities in its data leaves much to be desired”.
solubility profile.2 Specifically, it was observed that when Despite the obscurity surrounding the intricacies of
thiotimoline was combined with water, it dissolved up to 1.1 thiotimoline’s structure, Asimov was able to formulate a theory
seconds before the water was added. This remarkable property to rationalise its endochronicity. He proposed that at least one
was termed “endochronicity” by Asimov, who developed an carbon within thiotimoline was subject to such profound steric
instrument (the endochronometer) to quantify this effect. He hinderance that two of its bonds were forced into the temporal
went on to conduct multiple studies on thiotimoline and its plane.4 Such a chronomeric carbon would, he believed, possess
applications in chemistry, psychology and meteorology.3–5 a pair of bonds within the spatial dimensions, one bond pointing
Asimov conducted his exploratory studies in the late 1940’s, into the future, and another pointing into the past. As no
when the spectroscopic sciences had not attained their present convention exists to depict such chronospatial bonds, we have
heights of sophistication. Thus, the minutiae of thiotimoline’s taken the liberty of defining one:
chemical structure were unknown to him. By probing the
physical and reactive properties of thiotimoline, Asimov was bond backwards in space bond forwards in time
able to deduce the presence of “at least 14 hydroxy groups, two C C
bond forwards in space bond backwards in time
amino groups and a sulphonic acid” as well as a potential nitro
group.6 In 1949, the Tinúviel lab tentatively assigned a structure
Research on thiotimoline has languished since 1960, at least in
A
HO3S
part because the relevant material has become difficult to
OH
HO OH obtain. Asimov’s original report stated “Since no method of
OH HO
HO O
HO NH laboratory synthesis of the substance has been devised, it may
O
O C be practically obtained only through tedious isolation from its
OH HN
HO
HO
O
O2N OH
OH
S OH
natural source, the bark of the shrub Rosaceae Karlsbadensis
S
O
tBu
O
iPr OH HO O rufo”.3 This plant (Fig. 2) is native to alpine valleys surrounding
O
N
C O O OH the West Failian town of Karlsbaden, but its populations have
OH O
HS OH
O OH HO
diminished drastically since the 1940’s. This decline has been
HOS3 O
HO OH HO O OH attributed to climatic disturbances, habitat loss and foliar
OH
HN O HO
O
OH
pathogens, and surviving enclaves of K. rufo are rigorously
OH protected. Multiple kilograms of bark are required for the
1 2
Thiotimoline Not Thiotimoline extraction of thiotimoline in useful quantities, the collection of
B which is typically lethal to the plant in question. K. rufo has
resisted cultivation outside of its native environs, further
detracting from its sustainability as a source of thiotimoline.

We have assessed that meaningful progress in the field of

chronochemistry requires both the full structural
characterisation of thiotimoline, and a practical synthesis
thereof. Our research group has a long-standing interest in the
synthesis and isolation of supernatural products, so it is to these
tasks that we have addressed ourselves in this
miscommunication.8a-d

A School of Visual Arts, Totodile University, New Bark Town

Figure 1: A) The structure of thiotimoline as determined in this work
B School of Chemistry, Miskatonic University
(1), and the incorrect structure proposed by Tinúviel in 1949. B) The IR C School of Pyrofrolics and Inorganometallics, University of West Failure
data used by Tinúviel to assign the structure of 2. * Corresponding author contact: goodenough.immaterial.science@gmail.com

J. IMMAT. SCI. | VOLUME 3 | 2023 Socials: Submissions: goodenough.immaterial.science@gmail.com 38

MISCOMMUNICATION The Journal of Immaterial Science

Figure 2: A scientific illustration of Rosaceae Karlsbadensis rufo. Karlsbadensis refers to the West Failian town of Karlsbaden, near which the plant
was first documented. The species name is a tribute to Rufus Bruce Brown, the Australian botanist who discovered it.

J. IMMAT. SCI. | VOLUME 3 | 2023 39

MISCOMMUNICATION
Experiments and Results
Logically, it was deemed essential to determine the structure of
thiotimoline before attempting to synthesise it. The reverse
scenario has rarely been met with success (for example,
consider Henry Perkin’s failed syntheses of quinine). To obtain
an authentic sample of 1, we conducted an isolation of
thiotimoline from 80 kg of K. rufo leaves. Though the compound
is less abundant in the leaves than in the bark, the former may
be collected in bulk without drastic detriment to the plant.
Asimov’s description proved accurate, for the extraction is
indeed a tedious process. The leaves were dried, macerated,
and extracted with ethyl acetate/H2O, a process that produced
fearsome emulsions (Scheme 1). The extract was exhaustively
chromatographed on silica to give crude thiotimoline, which
was further purified by the technique of endochronic filtration,
as described by Asimov.4
solvent chromatography
extraction
K. rufo leaves
pure endochronic
thiotimoline filtration
Scheme 1: Protocol for the extraction of thiotimoline (1) from the leaves
of K. rufo.
We analysed our extracted thiotimoline by endochronometry
and obtained a time-of-solution (Ts) of -1.10 seconds, a
comparable measurement to those disclosed in Asimov’s
original report. It should be noted that all organic trace
impurities must be removed from the water used to conduct
endochronometry. This can be accomplished by refluxing the
water with Caro’s acid, followed by distillation. With the purity
of our sample thus established, we subjected it to a range of
modern analytical techniques.
The endochronicity of thiotimoline is readily apparent under
spectroscopic conditions. We first observed this effect when we
attempted to record NMR spectra of our extract. After some
initially confusing spectra were obtained, we examined the
relevant free induction decay (FID) data and noticed a
peculiarity. Figure 3A displays the 1H FID we obtained after a
single 90˚ excitation of 1. As expected, the 90˚ pulse prompts an
immediate decay curve lasting several milliseconds. The
peculiar element is a second excitation-decay sequence which
occurs 1.12 seconds before the pulse, and a third 1.12 seconds
after it. We suggest that these extra sequences correspond to
the excitations of the portions of thiotimoline present in the
future and past respectively. Regrettably, spectra of 1 exhibited
very significant signal broadening, precluding the inference of
useful structural information. The reason for the broadening is
not currently understood, but it is presumed to be associated
with the molecule’s endochronicity.
Through a presumably similar mechanism, time-of-flight mass-
spectrometry (TOF-MS) also gave unusual results when used to
analyse thiotimoline. As a result of a 1.12 second lag time, an
ion was registered with a molar weight of 3.9 solar masses.
X-ray crystallomancy proved to be far more productive in the
structural elucidation of 1. Crystals of thiotimoline were grown
J. IMMAT. SCI. | VOLUME 3 | 2023
The Journal of Immaterial Science
by vacuum sublimation and subjected to collimated X-rays.9 The
data we obtained was bafflingly disordered, with almost every
atom displaying partial occupancy. We attributed this disorder
to the same endochronicity that had thwarted our NMR and MS
analyses. However, we surmised that by pulsing the X-ray
source and collecting data before, during and after each pulse,
we might obtain resolved data on each of thiotimoline’s three
temporal domains. We tested this theory by exposing crystals
of 1 to 50 µs bursts of X-rays and recording data simultaneously,
and at 1.12 second intervals before and after each pulse. Even
with a synchrotron as the radiation source, 116 days of
continuous data collection were required to obtain results of
publishable quality.
A
1.2 s 1.2 s
FID
90˚
Pulse Program
10 µs
B C
crude
thiotimoline
Trel = -1.12 s Trel = +1.12 s
D
Trel = 0 s
Figure 3: A) FID and pulse-program for a single-scan 1H NMR experiment
on 1. X-axis not to scale. B–D) Time-resolved pulsed-X-ray crystal
structures of thiotimoline, recorded at 1.12-second intervals. Selected
hydrogens, solvent and OPPh3 removed for clarity, ellipsoids at 100%
sphericity.
Gratifyingly, our strategy succeeded, and we obtained three
fully-resolved structures. The data acquired 1.12 seconds
before each X-ray pulse revealed a structure consistent with the
disaccharide (+)-fucnose (Fig. 3B), while X-ray data collected
1.12 seconds after each pulse revealed the presence of
protonated atom of sulphur (Fig. 3C). Data collected
concomitantly with X-ray exposure revealed an entirely
different structure: the core of thiotimoline. The hydrocarbon
framework of thiotimoline represents a hitherto-unknown class
of natural product. 1 constitutes a complex, polyhydroxylated
hydrocarbon scaffold supporting a number of uncommon
functionalities. Prominent among them are a Csp4–type
pentavalent carbon, and a thiothiosulphonic acid. At the time of
Asimov’s original studies, such moieties were unknown, thus it
is unsurprising that the structure of thiotimoline eluded him.
Interested readers should consult Fielding and Barratt’s
40
MISCOMMUNICATION The Journal of Immaterial Science
comprehensive review “The Moiety Boosh” for a history of
unconventional functional groups.10 A

3Cl O CN2 O
The most intriguing element of 1 is a central divalent carbon Cl
N
O N3 N
C
atom with an apparently linear geometry. Flanked by bulky, Cl
Cl
N S
N2
C
S N4 N2 HS
Csp3–hybridised carbons, it is neither alkyne nor allene. It can I
N
II III IV V
only be the chronomeric carbon proposed by Asimov over 70 B OH
HO O2N
years ago. We propose that the fucnosyl and thiol fragments HO OH
OH
O
observed in our time-resolved X-ray experiments are bound to
HO OH O
S
O O
iPr
this carbon through bonds spanning forwards and backwards in N O
tBu
HO O
N3
O
OH
time, respectively. This hypothesis is supported by HOS3 CCl3 HO O
HO S O
OH
thiotimoline’s reactivity: the hydrophilic disaccharide is
B(OH)2
HO O
OH I
projected forwards into time, allowing the molecule to dissolve N3
OH HN
O

in water before the bulk of the sample even makes contact with 3 4 5

it. Conversely, the thiol is projected into the past.

Asimov’s predictions of thiotimoline’s structure have proved
remarkably accurate (Table 1). Such prescient foresight was
ever a hallmark of Asimov’s work. Most impressive among his
predictions was the divination of the endochronic carbon’s
nature, without recourse to modern NMR or X-ray techniques.
Asimov’s Prediction X-ray Confirmed
14 hydroxyls 15 hydroxyls
2 amino groups 1 arylamine, 1 amide
1 sulphonic acid 1 thiothiosulphonic acid
0–1 nitro 1 nitro
partially aromatic hydrocarbon 1 biphenyl, 1 benzofuran
- 1 ketone
- 1 sulfcarbide
- 1 mercaptan
1 chronomeric carbon 1 chronomeric carbon
- 1 pentavalent carbon
Table 1: Asimov’s predications of thiotimoline’s structural elements,
compared to those observed by X-ray crystallomancy.
Synthesis
With the structure of thiotimoline secured, we turned our
attention to its synthesis. Undoubtably, the foremost challenge
in such an endeavour was contriving a method of forcing parts
of a molecule into the temporal plane through steric repulsion.
As Asimov conjectured in 1948, the endochronic carbon is
ensconced in the centre of the molecule, sheltered by the
stalwart bulk tert-butyl and isopropyl groups. Functionalisation
of this carbon after the placement of these groups is
impracticable, as density-dysfunctional calculations have
implied that not even methylcaesium could penetrate such a
steric shield, much less a cumbersome disaccharide (vide
supportus).
To overcome the extravagant energetic barrier inherent to such
a transformation, we deemed it essential to incorporate a
thermodynamic driving force into the crucial time-space
displacement reaction. The expulsion of N2 was the obvious
candidate for this purpose, which led us to select the
Schinkenfaust radical cross-spifflication for the pivotal
disconnection (Fig. 4A).
This reaction was developed by Schinkenfaust and
Krankenwurst for the preparation of epihemithioacetals in the
conventional three spatial dimentions.11 It was our hypothesis
that if sufficient steric bulk were present on the spectating
groups, two of them might be propelled into the temporal
dimension by the 112 kcal/mol of enthalpy generated by the
collapse of intermediate IV. With this strategy in mind, we set
about preparing the required precursors 3, 4 and 5.
Figure 4: A) Simplified mechanism for the Schinkenfaust radical cross-
spifflication. B) Three fragments that through a tandem Suzuki-Miyaura
cross-coupling/radical spifflication might join to form thiotimoline.
We began with the preparation of (+)-O-azidofucnose 4. The de
novo synthesis of saccharides is “a laborious pursuit, brimming
with adversity and tedium yet lacking the glamour and cache of
alkaloid chemistry”. So reads the opening line of Xazavian
Kersplunkit’s authoritative tome on the subject: “The Dance of
the Protecting Groups”.12 As such, any route to 4 beginning
from an intact disaccharide was deemed desirable, regardless
of yield. Previously, our group has pioneered a protocol for the
functionalisation of primary alcohols in the presence of multiple
secondary alcohols.13 We adapted this methodology to affect
the azidation of (+)-fucnose (6) (Scheme 2A). This was
accomplished by reacting 6 with fat arsine 7, followed by
electrochemical oxidation and displacement of the resultant
arsinium cation with potassium azide. The product (4)
decomposes rapidly and with some force at ambient
temperature, thus it was deemed expeditious to generate it in
situ immediately before subjecting it to the Schinkenfaust
reaction.
The Western Chemisphere
We next considered the synthesis of 3, the western
chemisphere of thiotimoline. This fragment contains the
thiothiosulphonic acid, the sulfcarbide and six stereocentres.
Scheme 2B details our selected disconnections, the full
retrosynthetic analysis is left as an exercise for the reader. This
sequence began with the Suzuki-Miyaura cross-coupling of 3-
bromo-4-nitrophenol (8) and 2-thiopheneboronic acid (9). To
deter ortho-functionalisation of the aryl ring, the bulky di-tert-
butylmethylsilyl group was selected from the pantheon of
silanes to protect the cross-coupled product (10). Thus,
subsequent electrophilic thiothiosulphonylation of 10 with
thiothiothiosulphuric acid was directed predominantly to the
meta position. Technically, the predominant product was tar,
but the next most dominant product was the desired one, which
was esterified with methanol to give 11.
An enantioselective Schlepper-Klunk dearomatisation was used
install a protected aldehyde at the 3’ position of the thiophene.
This remarkable reaction proceeds by a 1-electron oxidation of
thiophene 12 at a chiral nickel electrode, followed by migration
of the resultant radical (13), which is annexed by an alkylnickelIII
intermediate. Obstructive elimination proceeds rapidly
therefrom to deliver dioxetane 14, which was obtained in
moderate ee and disheartening yield. X-ray crystallomancy
confirmed the desired stereochemical configuration was
present at the quaternary carbon.

J. IMMAT. SCI. | VOLUME 3 | 2023 41

MISCOMMUNICATION The Journal of Immaterial Science

A B HO S
OH

HO OH HO OH O O O S (HO)2B
HO OH HO OH 9
Ra2CO3, DMSO O O
O O N
HO 60 ℃, 7 days HO 15 tBu
Br As OH Rb
O OH then (+)┃Pb(–), 12.6 V O HOS3
O2N Br CCl3
O KN3, 18-crown-6, DMSO O O
OH 15% yield O N3 B(OH)2
O CCl3
OH Br 19
6 7 4 O
8 OH 13 ½
C
a. Pd(PPh3)4 S S
NO2 NO2 S S
S Na2CO3, PhMe/H2O c. S4OH2, PhMe S NO2 S NO2
reflux, 95% yield S reflux, 26% yield O e. (+)Ni│(–)C 2 V O
Br S S
b. DTBMSiCl, NEt3 d. SOCl2, MeOH
(HO)2B CH2Cl2, r.t., 92% yield r.t., 82% yield
OH DTBMSO
DTBMSO DTBMSO
8 9 10 11 12

O
O O O O O O
MeOS3 NO2 Br
O S MeOS3 NO2
O O
S
15 13 ½ S
O O N
2 f. [Rh(COD)Cl]2, piperidine [NiCl4], TEMPO
(R,R)-(+)-DTBIPDMI-SEGPHOS DTBMSO O NBu4PF6, MeCN, r.t.
MeOS3 O DTBMSO
O C6H6, r.t., 82% yield, 97% ee 30% yield, 76% ee
O
Orhorhoro hydrothiolation X-ray Schlepper–Klunk
dearomatisation
DTBMSO 16 14 13

g. NCS, CH2Cl2 O O O O O
H
r.t., 74% yield
O O
h. DIBALH, CH2Cl2 O i. B2(OH)4, 4,4’-bpy CCl3 O
S S CCl3
-78 ℃, 61% yield Cl S PhMe, r.t. 19
Cl Cl
NO2 O
then 3Å MS, reflux N j. caffeine, H2O, 85 ℃ N k. tBuRb•RbCl
MeOS3 69% yield then 19, LiOtBu, THF, r.t. PMDETA,
O 56% yield Et2O/pentane,
O MeOS3 MeOS3 -95 ℃ 11% yield
O
ODTBMS ODTBMS
DTBMSO
17 18 20

HO O O O
HO Bpin O
O O
tBu m. TBAF, THF, r.t. tBu tBu O
S O S O pinB Bpin S O S CCl3
CCl3 then TsOH, H2O r.t. CCl3 23 CCl3 Cl
N then LiOH, MeB(OH)2 N l. [Ir(bpy)(Bpin)7] N N
B(OH2) acetone, r.t., 79% yield dioxane, r.t., 91% yield
Bpin Rb
HOS3 MeOS3 MeOS3 MeOS3
OH ODTBMS ODTBMS ODTBMS
3 24 Birchtwig borylation 22 21

Scheme 2: A) Selective O-azidation of (+)-fucnose with a fat arsine. B) Retrosynthetic approach to the western chemisphere of thiotimoline. C)
Synthesis of the western chemisphere, with a Crangleburt-Finkledink nucleophilic cascade (20–22) as the pivotal step.

The next two stereocentres were set with an Orhorhoro-type

A
enantioselective olefin deoxohydrothiolation. This reaction N
Tf OH
iPr O Ph
delivered 16 in good yield at a modest 70 mol% catalyst loading. N SH
OH O
O2N OH
N3
Thence, 𝛼-chlorination and DIBALH reduction gave aldehyde 17. Br NH2
N N O
O2N OH

Reduction of the nitro group prompted spontaneous cyclisation O

OH O
iPr O TES
to imine 18, which was selectively deprotected with caffeine O
N3
O
OH Bu H
and subjected to an aldol condensation with trichloroacetone HO S O
Sn
Br OBn OH O
(19). The resultant enone (20) was primed for a Crangleburt- OTHP
OBn
Finkledink nucleophilic cascade. This transformation proved I
OH HN
O
PMSO B(OH)2 ➢ aza-Splooche reduction
extremely challenging when tBuLi was employed as the Br ➢ Orhorhoro thiolation
O
nucleophile. We surmised that competing attack on the imine OPMS
N
H
➢ Szymankowszczyzna
allylic inquisition
was leading to unproductive side-reactions and tested other B
O Cl
nucleophiles to address the issue. Sodium and potassium P
Cl
OBn
analogues gave similar results, while tBuCs ignited the starting OBn a. NBS, CH2Cl2
r.t., 18% yield
Br OBn N
S tBu Br

material. Tert-butylrubidium proved to be an acceptable b. NH2OH, neat, 35 ℃ b. DMF, 0 ℃

2% yield N
compromise. The product (22) was borylated with B3pin3 under O N
OH
73% yield H O

Birchtwig’s conditions and globally deprotected to give 3 in 25 26 Feckmann Rearrangement 27

0.07% yield over 13 steps.
Scheme 3: A) Retrosynthetic fragments of thiotimoline’s eastern
The Eastern Chemisphere
chemisphere. B) Preparation of fragment 27 by a Feckmann reaction.
Finally, we confronted the synthesis of fragment 5. Once again,
we have elected to leave the detailed retrosynthesis to the To preclude any persnickety snark from the reviewers regarding
reader. In brief, we envisioned a [3+2+3+2] Puccini-Gershwin the “total” nature of this synthesis, we elected to begin our
echocyclisation could be used to construct the core carbocyclic preparation of 3 from crude oil. A simple 12-step sequence of
framework from a biaryl precursor (Scheme 3A). To that end, literature reactions delivered ester 29 on kilogram scale. The
we prepared diminuendophile 27 from ketone 25 by venerable Suzuki-Miyaura reaction served to couple 29 with
bromination and condensation with hydroxylamine followed by boronic acid 30 in exaltant yield. Pentamethylsilyl (PMS) groups
a Feckmann rearrangement (Scheme 3B). were employed to prevent hydroquinone 31 from participating
in deleterious side-reactions.

J. IMMAT. SCI. | VOLUME 3 | 2023 42

MISCOMMUNICATION The Journal of Immaterial Science

O O O
b. Pd2(dba)3, I
PMSO B(OH)2
O Trifutylphosphine O c. ICl, DBU O
C PMSO PMSO
a. 12 steps K2CO3, PhMe, reflux CH2Cl2, r.t., 23% yield
Br OBn OPMS 98% yield OBn OBn
2.3% yield
OTHP OTHP
OTHP OPMS OPMS
crude oil (28) kilogram scale 29 30 decagram scale 31 gram scale 32
d. iPrMgCl, then ZnCl2 THF, -60 ℃ iPr O
then Ni(COD)2, (+)-iBu-PyBOX, 33
76% yield, 87% ee Br NH2
33

O NH2 O NH2 O NH2

O O
g. ThCl3, LiAlH4 e. DIBALH
S
iPr OH DME, -50 ℃ iPr N tBu CH2Cl2, -78 ℃, 27% yield iPr O
PMSO 44% yield, 1:1.01 dr PMSO f. (–)-tBuS(O)NH2 PMSO
OBn OBn OBn
3Å MS, PhMe, r.t., 89% yield
OTHP OTHP OTHP
OPMS OPMS OPMS
X-ray 36 aza–Splooche Reduction 35 34
!
h. AIBN, 27 | Echocatalysis |
PhMe, 50 ℃
36% yield

NH2 O O
O ‡
OH OH
OH O
O
PMSO iPr THP
H2NOC
OBn O i. [Ir(COD)Cl]2, BINAP
DCE, r.t. 36% yield HO k. TsOH, MeOH, r.t. 98% yield
THPO OBn HO
PMSO iPr H2NOC
l. Shrubb’s cat. G7
H2NOC
OPMS OBn OBn j. acryloyl chloride, NEt3 PMSO iPr OBn
iPr OBn
CH2Cl2, r.t. 93% yield OBn CH2Cl2, r.t. 80% yield PMSO
OBn
O
O PMSO HN O
HN O
PMSO HN PMSO HN
37 38 Alalayah-Allylation 39 Ring-Closing Metathesis 40
O
O O OH
. O
H 2N iPr
iPr
H 2N o. (COCl)2, pyridine
O CH2Cl2, 0 ℃ 28% yield O O
PMSO O
O OBn p. KN(tBu)2, THF, -78 ℃ H2NOC
PMSO n. TfOH, CH2Cl2 OBn m. DBU,
OBn 20% yield OBn 0 ℃ 39% yield PMSO iPr DMF, 80 ℃
OBn OBn 76% yield
O PMSO
PMSO HN HN O O
PMSO HN
X-ray
43 42 41 40

Scheme 4: Construction of the first halt of thiotimoline’s eastern chemisphere.

Iodination with ICl was followed by an enantioconvergent The generation of pentavalent carbons has been acknowledged
Negishi cross-coupling with racemic 𝜶-bromoamide 33.14 A as a challenging pursuit since their discovery. We harnessed the
selective reduction of ester 34 proved challenging, and high-energy nature of ketene 43 to mitigate the inaccessibility
significant over-reaction and amide reduction diminished the of such carbons by employing it in a Szymankowszczyzna allylic
yield of the desired aldehyde. This aldehyde was condensed inquisition (Scheme 5).16 This reaction was promoted by UV
with one of Ellman’s chiral sulfinamides in the hope of imparting irradiation of 43 in CCl4, in the presence of cycloxystananene 44.
some enantioselectivity on the subsequent aza-Splooche As the ketene undergoes a [2+2] cycloaddition, a tin-derived
reduction. Alas, this attempt met with abject failure, as alcohol carbon radical populates the olefinic π* omnibonding orbital
36 was obtained as a 1:1.01 mixture of diastereomers. (45), forming an allylated Csp4 carbon (46).
In accordance with standard practice for echocatalytic Schmaltzof’s chiral oxaziride was employed to affect the 𝛼-
reactions,15 we performed cyclic echometry on 27 and 36 to hydroxylation of ketone 47,17 and the resultant acyloin (48) was
determine their resonant frequencies. The C=C and C-Br bond protected as an acetal (49). A modified Satsuma–Campari
of 27 were found to resonate in E♭ and B♭ respectivly, while the transpositon was used to rearrange the allylic alcohol and trap
olefins of 36 harmonise in C♮ and E♭. Thus, to affect the it as an oxyacetalide, followed by debenzylation to give 50.
conjunction of 27 and 36, our [3+2+3+2] Puccini-Gershwin Meta-chloroperperoxybenzoic acid (51) served as a mild ozone
echocyclisation was conducted in A♭ major. Wagner’s Ring cycle source to cleave the resultant terminal olefin, and the aldehyde
was found to be an appropriate echocatalytic agent, and the thus formed smoothly cyclised to hemiacetal 52.
product was obtained in middling yield. The final sequence in the preparation of fragment 5 began with
Swift progress was made thenceforth. Alalayah allylation of 38 a gold-catalysed Hashie-Toast annulation of the oxyacetyide
followed by acylation with acryloyl chloride gave diene 39, the with nitroresorcinol 53. Subsequent aryl iodination proceeded
orthogonally-protected alcohol of which was revealed by with abysmal selectivity, while acetal hydrolysis (TsOH) and
tetrahydropyran hydrolysis. Cyclisation by ring-closing PMS deprotection (ethanolic theobromine) were
metathesis with Shrubb’s catalyst G7 yielded pelargolactone 40. straightforward. Finally, a Spanker-Donk azidothionation with
An intramolecular Michael addition proceeded smoothly to Donk’s azide (55 ½) generated the desired azidothione (5). The
form 41, which underwent one-pot hydrolysis/elimination with sheer instability of 5 precluded its comprihensice purification
triflic acid to give 42. The corresponding acid chloride was and characterisation, and it was necessary to use the crude
generated with oxalyl chloride and eliminated with KN(tBu)2 to material immediately in the subsequent Schinkenfaust reaction.
generate ketene 43, alongside copious carbonised The Schinkenfaust Radical Cross-Spifflication
residue/amorphous precipitate (CRAP). This compound was As with any complex transformation, careful tuning of reaction
highly unstable and decomposed rapidly in light and at ambient conditions is essential for a successful radical spifflication. The
temperature. complexity of our reaction was compounded by our
J. IMMAT. SCI. | VOLUME 3 | 2023 43
MISCOMMUNICATION The Journal of Immaterial Science

O Bu H O ‡ O O
. Sn . Bu H Tf
OH
O OH N OH
iPr iPr Sn iPr iPr
H 2N H 2N O H 2N O H 2N
O 44 O O O
O OBn O OBn OBn 47 O OBn
PMSO a. hv (250 nm) PMSO PMSO O PMSO
OBn OBn b. BEMP, MeCN, r.t. OBn
CCl4, 0 ℃ 4% yield OBn
59% yield, 87% ee
O O O
PMSO HN PMSO HN PMSO HN O
PMSO HN
43 Szymankowszczyzna 45 46 48
allylic inquisition c. (CH2OH)2, 3Å MS
CH2Cl2, r.t. 94% yield
O TES
O O O
OH O Cl O OH
O TES O OH O O OH HO
O TES
iPr iPr d. ReMeO3, DIPEA iPr
H 2N H 2N H 2N
O 51 O CH2Cl2, r.t. 45% yield O
OH
O O g. MCPPBA, DCE, -20 to r.t. O OH e. TMSI, NEt3 O OBn
PMSO then SMe2, 50 ℃, 77% yield PMSO CH2Cl2, r.t., 94% yield PMSO
OH OH OBn
f. TBAF, THF, r.t., 97% yield

O O O
PMSO HN PMSO HN PMSO HN
OH 52 50 Satsuma–Campari 49
h. AuF(IMes), NEt3 transposition
MeCN, reflux, 77% yield
Hashie–Toast annulation
O2N OH OH
OH O2N
53 O2N Ph
O O2N O
O O N
N3 SH OH O
H 2N iPr OH OH OH O
O i. I2, K2CO3 N N iPr O
iPr O
O CH2Cl2, r.t., 16% yield N3
PMSO O H 2N 55 ½ O
O O OH
j. TsOH, H2O, r.t., 86% yield OH l. PPh3, DMF O
O OH O 50 ℃, ~6% yield HO S
k. theobromine, EtOH HO O OH
OH r.t., 97% yield OH
PMSO Spanker–Donk I
HN I O
O O azidothionation OH HN
OH HN
54 55 5

Scheme 5: Completion of thiotimoline’s eastern chemisphere, including the formation of the pentavalent carbon by allylic inquisition.

requirement for intermediate 56 to persist in solution long and -46 ˚C, and we sought conditions that would affect a Suzuki-
enough for an intramolecular Suzuki-Miyaura reaction to occur. Miyaura cross-coupling at such temperatures.
Conversely, we required conditions for a Suzuki reaction that An automated, high-throughput sceening approach was
would take a place at a temperature low enough to stabilise adopted to evaluate reaction conditions for the final cross-
intermediate 56. coupling. This necessitated the preparation of 4 and 5 more
We observed that the starting materials (3, 4 and 5) were than twenty times to provide sufficient starting material.
consumed when combined in 13:9 THF/PhMe at temperatures Comprehensive optimisation data is presented in pages 35–598
higher than -85 ˚C, as determined by ESIMS. A new ion was of the positronic supporting information. The culmination of
observed at m/z = 1879, which corresponds to intermediate 56. this work was the set of reaction conditions presented in
When the reaction was warmed above -46 ˚C, this ion was in Scheme 6.
turn consumed, and an ion of m/z = 1799 replaced it as the Pd(COD)4 was selected as the palladium source, as it is
predominant component of the mixture. This ion matches the exceptionally labile, even at low temperature. In combination
product of a radical cross-spifflication without cross-coupling. It with a bulky, electron-rich monodentate ligand and caesium
was thus determined that intermediate 56 persists between -85 hydroxide, this catalysts system formed small amounts of

A
OH
OH
HO OH
HO OH OH
O OH
N HO O
HO O O
N O
OH O
N O O2N OH HO
OH HO O2N OH
3 HO O
HO O O
[CuBr(SMe2)], TBTA OH then [Pd(COD)4], L iPr OH
O O S tBu
S tBu CsOH, THF/PhMe, -47℃ O O
Cl THF/PhMe, -90 to -47℃ O N iPr O C
Entry Ligand Yield (%) O O
Cl N
Cl N O L1
OH 1 2 HS OH
S O L2 O OH
4 HO N4 2 7 HOS3
HOS3 B(OH)2 OH 3 L3 0 HO OH
4 L4 0 OH
N3 OH I O 5 L5 3 HN O
OH HN
6 L6 14
S
56 7 L7 19 (𝜒/𝛏)-1
5 (asyn)–Thiotimoline
B
Np
Cy N
Ad iPr iPr
tBu Cy Cy Cy N O N N
P iPr N tBu
N tBu C
P P Cy iPr
tBu
Ad Cy C N CH2
P iPr
tBu N tBu C tBu
Cy iPr N
Ad Cy Cy O N N
N iPr
iPr
Cy N
Np

L1 L2 L3 L4 L5 L6 L7
P(tBu)3 PBcp3 ChonkPhos CyCyCyPhos IDipp C(IiPr)2 supercarbone
phosphine phosphine phosphine phosphine carbene dicarbocarbene carbodi(dicarbocarbene)

Scheme 6: A) Unity of thiotimoline’s eastern and western chemispheres by tandem Schinkenfaust radical cross-spifflication/Suzuki-Miyaura cross-
coupling. B) A selection of ligands screened in the aforementioned reaction.
J. IMMAT. SCI. | VOLUME 3 | 2023 44
MISCOMMUNICATION
thiotimoline 1 (as detected by MS). Phosphine ligands L1 and L2
were competent, while the bulkier ChonkPhos (L3) and
CyCyCyPhos (L4) were ineffective. NHCs such as IDipp (L5) did
catalyse the desired reaction, albeit in atrocious yield. We
hypothesised that a more electron dense ligand was needed to
facilitate oxidative addition at such a low temperature, and
turned to a dicarbocarbene. Indeed, L6 furnished a
comparatively pleasing 14% yield of 1. Finally, we employed
carbodi(dicarbocarbene) L7 (the most electron-rich ligand we
could think of) and obtained a 19% yield of thiotimoline.
With optimised spifflication/cross-coupling conditions in hand,
we conducted a large (50 mg) scale reaction and attempted to
isolate thiotimoline from the reaction mixture. This proved to
be easier than expected. A reverse-phase TLC of the reaction
mixture was run in 10% MeCN/H2O, and a spot was observed
above the solvent line with an Rf of 1.2 (Fig. 5A). Such an unusual
retention factor could only be the characteristic of an
endochronic molecule, and indeed a sample of pure
thiotimoline isolated from the natural source produced an
identical Rf. Thus informed, we subjected the crude reaction
mixture to flash column chromatography on C18-silica and
obtained 9.5 mg of a white crystalline solid, which eluted before
the solvent did. One milligram of this compound dissolved in
water in -1.12 seconds, and it was spectroscopically identical to
the thiotimoline isolated from K. rufo.
These TLC’s contained a second startling element: a spot with
an apparent Rf. of -0.2. The movement of a compound against
the flow of solvent in a chromatographic context has, to the
best of our knowledge, never been observed before. Naturally,
we wished to isolate this material so that it’s composition might
be determined. This was accomplished by filling the headspace
of the column with eluent, and allowing half to flow through the
silica. The remaining eluent was decanted and concentrated
under reduced pressure, to give a further 9.5 grams of white
solid. When 1 mg of this material was placed in 1 mL water,
there was no observable reaction for 1.12 seconds. Then almost
instantly, the material dissolved, with an alacrity akin to an
iodine clock.
A
Product Reaction
B pondered since its discovery. Isaac Asimov described the use of
𝜒–thiotimoline Rf = 1.2
– final solvent line, Rf = 1 C C
HS *
𝜒 Chronomer
– initial substrate line, Rf = 0 𝜒 Chronomer = heavier group (*) facing
backwards in time
𝜉 –thiotimoline, Rf = -0.2 𝜉 Chronomer
forwards in time
Figure 5: A) A reverse-phase TLC of our impure, synthetic thiotimoline
(right) against a sample extracted from K. rufo. B) The natural (left) and
unnatural (right) chronomers of thiotimoline, produced by our reaction
as an asynchronous mixture.
On the basis of this observation and subsequent spectroscopic
analysis, we contend that this substance is an unnatural isomer
of thiotimoline. Put simply, this compound has the opposite
configuration of substituents at the chronomeric carbon. The
thiol is projected 1.12 seconds into the future, and the fucnose
lags 1.12 seconds into the past. Hence, the negative Rf and
positive time of solution.
We believe these results imply the existence of a type of
isomerism thus far unknown to science. That is, two molecules
J. IMMAT. SCI. | VOLUME 3 | 2023
The Journal of Immaterial Science
whose structures differ only by the distribution of two or more
substituents in the temporal plane (Fig. 5B). We suggest the
term “kairality” be used to describe this type of isomerism, a
word we have derived from the ancient Greek “Kairos” meaning
“time” or “the opportune moment”. Furthermore, we propose
a system to classify such isomers, which we have termed
“chronomers”. The priority of the two chronomeric substituents
should be determined in accordance with the principles of
Cahn, Ingold and Prelog. Thenceforth, the chronomer bearing
the higher-priority substituent projected into the future is
designated the 𝜉-chronomer, and its counterpart the 𝜒-
chronomer. Under these rules, the compound extracted from K.
rufo is 𝜒 -thiotimoline, while that generated by our radical cross-
spifflication is an asynchronous mixture.
Discussion
The results presented above have definitively answered
questions that have puzzled and intrigued chemists for more
than 70 years, by providing a structural basis for understanding
molecular endochronicity. As is so frequently the case in
research, answering these question prompts the posing of
others. Our first question is this: might it be possible to prepare
molecules other than thiotimoline that display endochrinicity?
Our synthesis is far too lengthy and inefficient to provide
practical amounts of thiotimoline for any future applications,
but this drawback would be negated entirely if a smaller and
simpler analogue could be prepared.
Another quandary as yet unanswered is the nature of
thiotimoline’s biosynthesis. As evidenced by our extraction, K.
rufo produces only one of two possible chronomers of
thiotimoline. Ergo, the plant possesses some mechanism of
selectively generating a carbon centre with a defined
chronochemical configuration. We can only speculate as to the
nature of this mechanism, as the molecular biology of K. rufo is
entirely unexplored. Perhaps an enzyme involved in the
biosynthesis of 1 also contains chronomeric carbons in its active
site, which project a hydrophilic pocket or steric bulk into the
future, thus biasing the geometric outcome of a crucial reaction.
The applications of molecular endochronicity have been
thiotimoline in the determination of NaCl concentration, in
O * SH
willometry, and micropsychiatry. He further speculated on its
use in endochronic batteries, meteorological instruments and
O even weapons of mass destruction. All such applications would
become more feasible with the availability of mass-produced
𝜉 Chronomer thiotimoline analogues. Our aspirations, however, lie within the
field of synthetic chemistry. Specifically, we are intrigued by the
concept of a “chronal auxiliary”. That is, the appendage of a
= heavier group (*) facing chronomeric unit or “chronophore” to another molecule in
order to facilitate its separation/purification from a complex
mixture. In a manner similar to a chiral auxiliary, a compound
tagged with a chronophore could be readily purified
chromatographically if it’s resultant Rf was larger than 1 or less
than 0. Investigation into this principle of “flash column
chronotography” are currently underway in our laboratory,
concurrent with attempts to produce novel endochronic
compounds.
Conclusion
The structure of thiotimoline has been unambiguously assigned,
which represents the solution to a mystery over 90 years old.
We have probed the nature of the chronospatial bonds that
make thiotimoline so distinctive by physical and spectroscopic
means. Furthermore, we have conducted the first total
45
MISCOMMUNICATION
synthesis of thiotimoline, and uncovered a novel form of 8b
molecular isomerism: kairality, for which we have devised both
theory and notation. We hope this work will serve to
reinvigorate the field of chronochemisty and pave the way for 8c
future studies on the theory of endochronicity and the synthesis
of novel endochronic molecules. 8d
Experimental details, spectra and optimisation data are
9 “X-ray Crystallomancy: A Practical Guide” Rosiland, F.; Crockson,
contained in the positronic supported information, which is
available in the basement of the planning office, in a locked
filing cabinet in a disused lavatory, next to a sign reading
10
“beware of the leopard”.
Acknowledgements 11
G.S. acknowledges Melon Husk and LeDong James for fruitful
discussions. The authors thank Bob and Dave’s Auto Repairs for
their generous gift of cut-price rhodium sponge, and Mike 12
Donovan and Greg Powell for assistance automating the
optimisation of the radical cross-spifflication. G.S. thanks 13
Howard Shore and Camellia Sinensis for moral support.
Author Contributions
H.W. and G.S. determined the structure of 1. M.C. prepared 14
figure 2. G.S. conducted the experiments and prepared the
manuscript. 15
Conflicts of Interest
The authors declare the conflict between their interest in
whimsical science and the demands of the real world.
16
Declaration of Funding
This work was not funded. 17
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Notes and references

1 “Natural products isolated from the shrubs of the genus Rosacea”
Roundin, A.; Lev, B.; Prutt, Y.J. 1930, Proc. Sci. Plant Chem. 80, 11–
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2 “Concerning the Anomalous Solubility of Thiotimoline” Krum, R.;
Eshkin, L. Asimov, I. 1944, J. Chem. Sol. 27, 109–114.
3 “The Endochronicity of Resublimated Thiotimoline” Asimov, I.
1948, Ast. Sci. Fic. 41(1), 120–125.
DOI: https://tinyurl.com/4rymfsbf
4 “The Micropsychiatric Properties of Thiotimoline” Asimov, I. 1953,
Ast. Sci. Fic. 52(4), 107–116. DOI: https://tinyurl.com/yc6w5dh3
5 “Thiotimoline and the Space Age” Asimov, I. 1960, Ast. Sci. Fic.
66(10), 155–162. DOI: https://tinyurl.com/mt78bw6j
6 “Structure of Thiotimoline, Parts I & II” Krum, P.; Eshkin, L.; Nile,
O.; Asimov, I. 1945, Annals of Synthetic Chemistry, 115, 1122–
1145.
7 “On the infra-red absorption of thiotimoline and inferences of its
structure” Tinúviel, L. 1949, Middle J. Chem. 3, 3001.
8a “Supernatural Products: an Illiterature Review” Schlonk, G. 2023,
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