Short Total Synthesis of Ajoene, (E,Z)-4,5,9-Trithiadodeca-1,6,11-triene 9-oxide, in Batch and (E,Z)-4,5,9-Trithiadodeca-1,7,11-triene in Continuous Flow

Article abstract of DOI:10.1002/chem.202001598

A short total synthesis of ajoene, (E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide, has been achieved over six steps. In addition, a continuous flow synthesis under mild reaction conditions to (E,Z)-4,5,9-trithiadodeca-1,7,11-triene is described starting from simple and easily accessible starting materials. Over four steps including propargylation, radical addition of thioacetate, deprotection, and disulfide formation/ allylation, the target product can be obtained at a rate of 0.26 g h^?1 in an overall yield of 12 %.

Full text of DOI:10.1002/chem.202001598

Accepted Article
Accepted Article
Title: Short Total Synthesis of Ajoene In Batch and an Isomeric
Precursor in Continuous Flow
Authors: Marina Yamamoto Raynbird, Filipa Silva, Harry Smallman,
Shaista S. Khokhar, Daniel Neef, Gareth J. S. Evans, and
Thomas Wirth
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001598
Link to VoR: https://doi.org/10.1002/chem.202001598
01/2020

10.1002/chem.202001598
Chemistry - A European Journal
COMMUNICATION
Short Total Synthesis of Ajoene, (E,Z)-4,5,9-Trithiadodeca-1,6,11-
triene 9-oxide, in Batch and (E,Z)-4,5,9-Trithiadodeca-1,7,11-triene
in Continuous Flow
Marina Yamamoto Raynbird,[a] Filipa Silva,[a] Harry Smallman,[a] Shaista S. Khokhar,[b] Daniel Neef,[b]
Gareth J. S. Evans[b] and Thomas Wirth*[a]
Abstract: A short total synthesis of ajoene, (E,Z)-4,5,9-Trithiadodeca-
1,6,11-triene 9-oxide, has been achieved over 6 steps. In addition, a
continuous flow synthesis under mild reaction conditions to (E,Z)-
4,5,9-trithiadodeca-1,7,11-triene is described starting from simple and
easily accessible starting materials. Over four steps including propar-
gylation, radical addition of thioacetate, deprotection and disulfide for-
mation / allylation, the target product can be obtained at a rate of 0.26
g/h in an overall yield of 12%.
required.[8] The scope of the analogues were extended later when
both terminal allyl moieties of the ajoene have been altered.[9]
In 2018, we reported the first total synthesis of 3 (Scheme 1d).
The chemical total synthesis overcame such obstacles such as
the instability and volatility of 2 by replacing allicin with alternative
starting materials to develop a reliable and robust five step syn-
thesis.[10]
(a)
Alliinase
NH2
CO2H
O
S
NH2
CO2H
O
S
+
-H2O
S
Garlic extracts are frequently reported in the literature for exhibit-
ing a wide range of biological properties. For example, ajoene (3),
a component that is derived from naturally occurring compounds
in garlic, is a potent antithrombotic agent with platelet aggregation
inhibitory properties.[1] Other compounds obtained from garlic ex-
tracts have shown to be beneficial against coronary thrombosis
and atherosclerosis, as well as displaying a range of antibacterial
and antifungal activities.[2,3] (E/Z)-Ajoene 3 was first observed in
1983 by Apitz-Castro,[4] however, it was not until 1984 that 3 was
fully characterised by E. Block.[1] Block and co-workers have ob-
tained (E/Z)-3 through a thermal rearrangement of allicin (2),
which itself is formed from alliin 1 (Schemes 1a, 1b). Although
Block isolated 3 in 37% yield as a mixture of its geometric isomers,
an array of other rearrangement and decomposition products
were also obtained, including mono and polysulfides as well as
vinyl-dithiins.
2 Allicin
1 Alliin
(b)
(c)
(d)
O
O
S
S
S
S
Acetone/water (3:2)
reflux
S
(2)
3 Ajoene
37%, E:Z 4:1
1. TsSallyl
2. mCPBA
O
S
RS
SAc
S
S
R
4
1. KOH / TsSallyl
2. H2O2
O
S
S
PhSe
S
SAc
S
3 Ajoene
23%, E:Z 1:1
Scheme 1. Synthesis of ajoene 3 as described by Block et al. in 1984. (a) for-
mation of allicin 2 from alliin 1 by the action of alliinase. (b) Formation of E/Z-
ajoene 3 from 2 by thermal rearrangement in aqueous acetone. (c) Synthesis of
ajoene analogues 4 by Hunter et al. (d) Synthesis of ajoene 3 by Silva et al.[10]
Since 1984 there have been numerous reports of oxidising diallyl
disulfide using simple oxidants such as meta-chloroperbenzoic
acid,[5] Oxone®[6] and hydrogen peroxide,[7] thus eliminating the
requirement for an enzymatic process.
Analogues of 3 have been reported in the literature in the search
of synthetic analogues 4 with higher bioactivity than 3. Hunter et
al. described a synthetic route for the synthesis of substituted
ajoene analogues 4 where the terminal group of the sulfoxide is
varied (7 examples, Scheme 1c). However, an allyl group at the
sulfoxide, thus yielding 3 as final product, could not be obtained
due to the instability of the vinyl radical precursor that would be
We were able to install the terminal allyl group from the sulfoxide
using a selenoxide elimination as key step. Using two equivalents
of a simple oxidant such as hydrogen peroxide, oxidation of the
sulfur to sulfoxide occurred as well as the selenide to the selenox-
ide. Due to the presence of β-hydrogens, the selenoxide sponta-
neously eliminates furnishing the terminal allyl functionality. De-
spite this novel route overcoming some previous obstacles, the
total synthesis has inherent drawbacks. These are, firstly, the dif-
ficulty of scaling-up due to the use of selenium, and secondly, a
low overall yield.
Herein, we describe a novel synthesis of sulfide 8 where four
steps have been performed in continuous flow with high atom
economy. Originally intended to be a precursor for the synthesis
of ajoene 3, it was found that 8 is an isomeric sulfide leading to a
revised short total synthesis of 3. The new route eliminates the
need for selenium or high molecular weight protecting groups.
[a]
[b]
M. Yamamoto Raynbird, Dr. F. Silva, H. Smallman, Prof. Dr. T. Wirth
School of Chemistry
Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-Mail: wirth@cf.ac.uk
Dr. S. S. Khokhar, Dr. D. Neef, Dr. G. J. S. Evans
Neem Biotech
Roseheyworth Business Park North
Abertillery NP13 1SX (UK)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001598
Chemistry - A European Journal
COMMUNICATION
Conditions: HPLC K120 Knauer Analytical pump with thioacetic acid and pro-
pargyl bromide (0.4 M) in dry solvent, column: K2CO3/sand (20 g total) in Omni-
Sep® column (15 x 150 mm). [a] column: repacked Biotage® SNAP Ultra car-
tridge (30 g total). The column volume and therefore flow rate was varied be-
tween each run due to the percentage of base.
For the generation of the central double bond, a radical addition
of thioacetate to 5 was employed using azobisisobutyronitrile
(AIBN) as initiator. A range of solvents were investigated in batch
where toluene gave the largest isolated yield of 5, 60% (Scheme
3). Since the continuous in-flow system would require each step
to be compatible with the previous step, tetrahydrofuran and di-
chloromethane were also investigated. The presence of dichloro-
methane seemed to be advantageous and increased the yield
from 8% to 51% when in a ratio of (1:3) with tetrahydrofuran.
Scheme 2. Short synthesis of potential isomeric ajoene precursor 8.
In order to install the terminal allyl group, the synthetic route
herein utilises thioacetic acid rather than a free thiol (Scheme 2).
The acetate protecting group provides stability to the resulting vi-
nyl radical intermediate that could form under the conditions of
radical formation with AIBN. An additional advantage to being a
facile group to cleave, is that the acetate will provide acetic acid
as the only by-product.
AcSH (1.1 equiv.), AIBN (10 mol%)
AcS
SAc
AcS
Solvent, 85 °C, 2 h
5
6
The batch propargylation of thioacetic acid with organic bases
such as triethylamine and diisopropyl ethylamine were unsuc-
cessful. It was found that potassium carbonate in a mixed solvent
system of THF:CH2Cl2 (1:1) yielded 5 in up to 95% yield after 4
hours at room temperature while purification was not required.
Solvents such as toluene and CH2Cl2 were also investigated alt-
hough required longer reaction times. Using toluene as solvent
complicated isolation of 5 due to the volatility of the product being
higher than the solvent.
In the development of the corresponding flow process, an Omni-
Sep® column was packed with a mixture of potassium carbonate
and sand. This mixture reduced the build-up of pressure as the
base is consumed over time and allowed the flow rate to stay con-
sistent. When using a mixed solvent system, the eluted mixture
showed that the reaction had not achieved complete conversion
(Table 1, entries 1 – 5) despite an increased loading of base or
an increased residence time. In contrast, where THF was em-
ployed as solvent, the reaction was able to achieve complete con-
version (Table 1, entries 7 – 10) where 5 was obtained in yields
of up to 84% in 18 minutes. Increasing the base percentage to 56
wt.% saw a decrease in yield, likely to be the result of the product
being unable to elute efficiently from the column. Entry 10 con-
firmed the reproducibility of entry 8 where a larger column, and
therefore an increased residence time, was used.
batch (2 h)
flow (5.1 min, 40 psi)
60%
51%
10%
8%
15%
51%
39%
33%
toluene
THF : CH2Cl2 (3:1)
THF : CH2Cl2 (1:1)
THF
Scheme 3. Batch reaction for the radical addition of thioacetic acid to terminal
alkyne 5.
Translating the batch reaction to a flow system required the use
of a Uniqsis® Heated Reactor to heat the PTFE reactor coil to 85
ºC. A back-pressure regular (40 psi) was fitted to ensure that the
system remained homogenous, despite the evolution of nitrogen
gas. A mixed solvent system of THF:CH2Cl2 (3:1) gave the highest
yield of 5 in flow and was isolated in 51% yield (Scheme 3).
Since the solvent system of first two steps were similar, both steps
could be coupled easily, and the resulting flow system was used
for the investigation of the residence time in step 2. In order to
achieve a THF:CH2Cl2 (3:1) solvent mixture in step 2, step 1 was
performed in THF and AIBN and thioacetic acid was added in a
solution of THF:CH2Cl2 (1:1). Column 2 (C2) was trialled with
PTFE tubing of a reduced internal diameter (0.2 mm). However,
this gave inconsistent results because of varying flow rates due to
increased pressure. Therefore, a PTFE tubing with internal diam-
eter of 0.8 mm was used. The increase in residence time from 6
minutes to 38 minutes for C2 resulted in a yield of 6 of 61% over
two steps (Scheme 4). Longer residence times for C2 were not
investigated due to practical considerations as the time would ex-
ceed one hour for the first two steps. Boron-based radical initia-
tors were also considered, although these gave a less clean re-
action with inferior yields of 6 (see supporting information).
Table 1. Propargylation of thioacetic acid to obtain thioester 5 in flow.
K2CO3/sand
AcS
Br
AcSH
0.4 M
+
0.4 M
5
Residence
Base
(wt%)
Entry
Solvent
Yield 5 [%]
time [min]
1
2
THF:CH2Cl2 (1:1)
THF:CH2Cl2 (1:1)
THF:CH2Cl2 (1:1)
THF:CH2Cl2 (1:1)
THF:CH2Cl2 (1:1)
THF
7
7
20
40
60
30
30
20
30
18
14
24
19
42
45
49
46
50
79
84
57
82
3
7
4
14
21
7
5
6
7
THF
21
42
56
42[a]
8
THF
9
THF
10
THF
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10.1002/chem.202001598
Chemistry - A European Journal
COMMUNICATION
Reagents and conditions: Vinyl thioacetate 6 (1.0 equiv.), allyl thiotosylate (1.1
equiv.) in MeOH, KOH (1.05 eq.) in MeOH. C.V.: 1 mL, id: 0.8 mm. [a] Coil sub-
merged in cold bath. [b] Reagents and conditions: KOH (1.4 equiv.). [c] Reagents
and conditions: allyl thiotosylate (3 equiv.), KOH (2 equiv.).
AcSH
+
Br
0.4 M in THF
0.4 mL/min
C1
Bisdisulfide compound 9 is a natural product that has been ex-
tracted from Chinese garlic with acetone.[12] The flow system
therefore provides the first reported chemical synthesis of 9. Entry
5 shows the potential to tune the reaction toward the bisdisulfide
9. Where the equivalents of base are greater than that of the elec-
trophile, the reaction favours the formation of 9. Increasing the
equivalents further would increase yields of 9 to give a selective
reaction.
With the vinylic disulfide moiety installed in 7, the deprotection of
the second acetate was investigated in flow using allyl bromide as
electrophile. The equivalents of allyl bromide and base were con-
trolled through the concentration whilst keeping the flow rate con-
stant. The effect of temperature using caesium carbonate as base
and the equivalents of allyl bromide were varied and saw an im-
provement in yield from 12% to 20% by increasing the base con-
centration. Potassium hydroxide gave an increased yield of 8 to
29% under the same conditions as caesium hydroxide. To opti-
mise the yield of product 8, a DoE study was conducted (see sup-
porting information). The optimum reaction conditions as a result
of the DoE study indicate that the equivalents of allyl bromide and
potassium hydroxide should be increased to 3 to obtain 8 in 43%
yield. Sodium hydroxide, ammonium hydroxide and caesium car-
bonate as bases were also investigated, although these gave in-
ferior yields. The comparable batch reaction using allyl bromide
and caesium carbonate for the deprotection and allylation for-
mation yields 8 in 45% yield.
K2CO3 / sand
C2
AcS
SAc
BPR
AcSH
AIBN (10 mol%)
+
85 ºC
6
THF:CH2Cl2 (1:1)
0.4 mL/min
residence volume yield 6
time (C2)
(C2)
6 min
25 min
38 min
4.8 mL
20 mL
32 mL
44%
47%
61%
Scheme 4. Investigating the effect of residence time on the yield of product 6
over two coupled flow steps.
The subsequent deprotection of the vinylic sulfur atom proceeded
cleanly using potassium hydroxide in methanol with good selec-
tivity for the vinylic thioacetate, however, the other thioacetate
was also cleaved partially and side product 8 was formed (Table
2). The concentration, temperature and residence time, along with
equivalents of the allyl thiotosylate electrophile and potassium hy-
droxide were investigated and results are summarised in Table 2.
Entries 1 and 2 indicate that a more concentrated reaction leads
to a less selective cleavage of the acetate group. The temperature
was reduced from room temperature (entry 3), resulting in an in-
crease in yield of 7 to 46%. Despite varying the residence time,
concentration and temperature further (entries 4-5), no significant
differences in the isolated yields of 7 or 9 were observed. To in-
crease the yield of desired product, a Design of Experiments
(DoE) study was conducted to indicate a reaction ‘sweet-spot’
(see supporting information). In this study, residence time, tem-
perature and the equivalents of electrophile and base were inves-
tigated. The optimum reaction conditions as a result of this DoE
study are given in entry 7, where the equivalents of allyl thiotosyl-
ate and base were increased to obtain 7 in 56% yield. This result
S
AcS
S
7
Br
(3 equiv.)
MeOH
S
S
S
KOH (3 equiv.)
MeOH
1 mL
0.05 mL/min
0 ºC
8 (43%)
was also repeated with
a
mixed solvent system of
Scheme 5. Flow setup for step 4 to yield compound 8.
THF:CH2Cl2:MeOH (3:1:4) giving a similar result. The comparable
batch reaction for the deprotection and disulfide formation yields
7 in 51% and 9 in 10%, similar to recent publications on the syn-
thesis of disulfides from thioacetates and thiosulfonates.[11]
With each step optimised, all four steps were combined, and the
resulting system was tested. Calculating from the yields of the in-
dividual steps (1 and 2: 61%; 3: 56%; 4: 43%), an overall yield of
15% was expected. To our delight, 8 could be obtained in 12% as
the major product with a production rate of 0.26 g/h (Scheme 6).
This is comparable to the batch reactions where 8 can be ob-
tained in 13% yield. Although the flow synthesis does not currently
improve upon the batch yield, it provides the first example of a
continuous flow synthesis for the potential precursor of ajoene 3
without any inline purification. This saves time, energy and re-
sources as only a single silica gel chromatography column is re-
quired in the purification of 8 after the reaction sequence.
Table 2. Flow set-up for the investigation of step 3 to yield compound 7.
AcS
SAc
S
6
AcS
S
S
7
Ts
+
KOH
MeOH
S
S
MeOH
S
S
9
Conentra-
tion 6 [M]
0.1
Tempera-
Residence
Yield
Yield 9
[%]
9
Entry
ture [ºC]
time [min]
7 [%]
1
r.t.
5
5
35
2
0.2
r.t.
22
46
41
34
46
56
10
9
3[a]
4[a]
5[a,b]
6[a]
7[a,c]
0.1
0
5
0.1
0
–40
10
10
15
5
6
0.1
31
11
10
0.05
0.1
–5 to –10
0
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10.1002/chem.202001598
Chemistry - A European Journal
COMMUNICATION
C1
with chronic wounds. The assays conducted were Minimum Bio-
film Inhibition Concentration (MBIC) and Quorum Sensing Inhibi-
tion (QSI) studies. The former determines the minimum concen-
tration of a compound required to limit the biofilm production to
50%, when compared with bacteria in the absence of the com-
pound. The results for S. aureus MBIC assay were comparable
between entries 1-3, however, a larger difference could be ob-
served against P. aeruginosa. In this case, compound 8 showed
to be significantly more active resulting in an IC50 value 37% lower
than ajoene and 58% lower than its mono-disulfide analogue. This
suggests that the disulfide moiety in the compound plays a signif-
icant role its mode of action. Interestingly, compound 8 displayed
no activity in QSI studies against S. aureus.
K2CO3/sand
AcSH, AIBN
Br
0.4 mL/min
0.4 M in
THF:CH2Cl2 (1:1)
20 mol% AIBN
AcSH
32 mL
C2
C3
0.4 mL/min
0.4 M in THF
BPR
KOH
0.4 mL/min
0.44 M in MeOH
allylSTs
0.4 mL/min
0.675 M in MeOH
8.7 mL
KOH
0.4 mL/min
0.437 M in MeOH
allylbromide
0.4 mL/min
0.437 M in MeOH
24 mL
C4
S
Table 3. Biological evaluation of ajoene, compound 8 and compound 9.
S. aureus
MBIC
IC50 (µM)
P. aeru-
ginosa
MBIC IC50
(µM)
P. aeru-
ginosa
QSI (% at
75 µM)
S. aureus
S
Com-
S
Entry
QSI (mM)
pound
8
(12%)
0.26 g/h
1
2
3
ajoene 3
0.69
45
67.5
28
78
94
89
30
35
0
Scheme 6. Flow setup for all consecutive reactions to produce compound 8.
8
9
<2.25
<2.25
However, it was not compound 8 but compound 12 which was
intended to be the product of the flow synthesis. It turned out that,
after deprotection of the acetate in compound 7, the resulting thi-
olate 10 reacts with the disulfide moiety in an intra- or intermolec-
ular fashion as this is a reactivity well known also in biological
systems.[13] The product is the more stable vinyl thiolate 11 which
is being allylated to give 8. While oxidation of 12 would lead to
ajoene 3, oxidation of 8 with mCPBA resulted in the formation of
aldehyde 13.[14] This transformation is suspected to be the result
of epoxidation of the central olefin, followed by migration of the
allyl sulfide with ring opening of the epoxide to form the aldehyde.
Alternatively, treatment of 8 with mCPBA could form the sulfoxide,
which in turn could undergo a thio-Claisen rearrangement.[15]
In light of the above findings, a revised synthesis to ajoene 3 has
been developed to overcome the scrambling of the disulfide and
sulfide positions. The radical addition of 4-methoxybenzyl thiol af-
fords product 14 with both an acid and base sensitive protecting
group on both sulfur atoms. The unambiguous deprotection of the
acetate allows for allylation at the desired sulfur atom yielding 15
in 88% yield. Treatment under acidic conditions deprotects the
para-methoxy benzyl (PMB) group and traps the resulting al-
kenethiol as the thioacetate 16. This occurs in situ as the al-
kenethiol is a strong nucleophile and reacts with the activated
acetic acid. Trapping the thiol as 16 allows to employ the basic
reaction conditions needed for the disulfide formation. Treating a
PMB protected thiol with trifluoroacetic anhydride (TFAA), and
then directly treating with KOH and TsSallyl were trialled in a pre-
vious project but did not result in the desired product. The yield
suffers due to the instability and volatility of the deprotected al-
kene thiol intermediate. Other thiol protecting groups have not
been considered here. With potassium hydroxide and allyl thioto-
sylate formation of the disulfide bond in the vinylic position is
achieved in good yield (70%). Finally, oxidation of sulfide 12 af-
7
KOH
Br
S
S
S
S
S
S
10
12 (not observed)
Br
S
S
S
S
S
S
fords ajoene 3 in 49% yield (Scheme 8).
11
8
1. KOH
mCPBA
PMB-SH
2. allyl-
AIBN (20 mol%)
bromide
AcS
SPMB
AcS
S
toluene, 85 °C
14 (71%)
S
S
5
OHC
AcOH
TFAA
13
S
SPMB
S
SAc
Scheme 7. Proposed mechanism for the formation of compound 8.
15 (88%)
16 (21%)
Compound 8, as the major product of the flow system, and com-
pound 9, a natural product obtained as a side product of the flow
system, were biologically evaluated by Neem Biotech Ltd. and
compared with naturally obtained ajoene. Biological evaluation re-
sults are summarised in Table 3. Compounds were tested against
Staphylococcus aureus (S. aureus) and Pseudomonas aeru-
ginosa (P. aeruginosa), bacteria which are commonly associated
1. KOH
2. TsSallyl
mCPBA
S
S
S
3 (49%)
12 (70%)
Scheme 8. Batch synthesis of ajoene 3 over 6 steps.
In conclusion, a short, novel synthesis of sulfide 8 has been es-
tablished in batch and a subsequent continuous flow system has
This article is protected by copyright. All rights reserved.

10.1002/chem.202001598
Chemistry - A European Journal
COMMUNICATION
been developed. In addition to this, a revised short synthesis of
ajoene 3 has also been established using two different protecting
groups. Biological evaluations of sulfide 8 and the natural product
9 have been conducted in comparison to ajoene 3 which show
promising results for quorum sensing inhibition in P. aeruginosa.
following two column volumes were collected and concentrated in vacuo
at room temperature to yield product 5 as a yellow oil (453 mg, 95%).
Acknowledgements
We thank Neem Biotech Ltd. notability Danielle Williams, and
Lucy Andrews for biological assay support and the KESS 2 pro-
gram (MYR) and the School of Chemistry, Cardiff University, for
financial support. Knowledge Economy Skills Scholarships
(KESS) is a pan-Wales higher level skills initiative led by Bangor
University on behalf of the HE sector in Wales. It is part funded by
the Welsh Government’s European Social Fund (ESF) conver-
gence programme for West Wales and the Valleys.
Experimental Section
Flow procedure for the synthesis of S-(prop-2-yn-1-yl) ethanethioate 5:
Potassium carbonate (8.4 g, 0.06 mol) and sand (11.6 g) were shaken
until a homogenous mixture was achieved. The K2CO3/sand (20 g) was
packed into a glass OmniSep® (150 x 15 mm). The packed column was
weighed, and dry tetrahydrofuran (THF) was flowed through at 0.4
mL/min for 1 hour, after which, the column was reweighed. The mass dif-
ference equated to the calculated column volume (CV, 7.1 mL, residence
time: 18 minutes). To an oven dried glass, thioacetic acid (0.4 M) and
propargyl bromide (0.4 M) were added to dry THF under argon. The re-
action mixture was passed through the column at 0.4 mL/min using a sy-
ringe pump and the first column volume of solution was discarded. The
Keywords: ajoene • disulfides • flow chemistry • garlic • organo-
sulfur compounds
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10.1002/chem.202001598
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
A continuous flow synthesis of a novel sulfide is reported over four
steps and has been biologically evaluated. In addition, a novel synthe-
sis of ajoene has been established.
Marina Yamamoto Raynbird, Filipa
Silva, Harry Smallman, Shaista S.
Khokhar, Daniel Neef, Gareth J. S.
Evans, Thomas Wirth*
Page No. – Page No.
Short Total Synthesis of Ajoene,
(E,Z)-4,5,9-Trithiadodeca-1,6,11-
triene 9-oxide, in Batch and
(E,Z)-4,5,9-Trithiadodeca-1,7,11-
triene in Continuous Flow
This article is protected by copyright. All rights reserved.