Studies towards the Synthesis of the Antibiotic Tetrodecamycin

Article abstract of DOI:10.1055/s-0037-1609303

A study towards the natural product tetrodecamycin is reported. A modified Schlosser-Wittig reaction was utilized to prepare the precursor for the subsequent intramolecular Diels-Alder reaction, which delivered the trans -decalin ring of the natural product. The tetronic acid moiety of the molecule was prepared by a Dieckmann cyclization. The cyclization of the tetronic acid to the trans -decalin double bond to form a seven-membered ring was examined.

Full text of DOI:10.1055/s-0037-1609303

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
J. He et al.
Letter
Synlett
Studies towards the Synthesis of the Antibiotic Tetrodecamycin
Jing He
O
O
Jack E. Baldwin
H
Victor Lee*
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HO
Department of Chemistry, University of Oxford,
Chemistry Research Laboratory, 12 Mansfield Road,
Oxford, OX1 3TA, UK
H
H
O
OH
HO
victor.lee@chem.ox.ac.uk
O
HO
O
OH
H
Tetrodecamycin
O
HO
H
Received: 28.12.2017
Accepted after revision: 19.01.2018
Published online: 16.03.2018
of this natural product. Previously the synthesis of a trans-
decalin fragment of 1 using silyl enol ether chemistry was
reported by He et al.3d Herein, we present the investigation
of an alternative approach towards 1. Retrosynthetically, it
was envisaged that 1 could be obtained from 2 (Scheme 1).
In turn 2 could be available by ring closure of hydroxyfura-
none 3, and compound 3 could be synthesized by Dieck-
mann cyclization of 4. Intermediate 4 could be prepared by
aldol condensation–oxidation from trans-decalin aldehyde
5. Bicyclic compound 5 could be obtained from an intra-
molecular Diels–Alder reaction of precursor 6. Compound 6
could be synthesized by E-selective olefination of aldehyde
7 (Scheme 1).
DOI: 10.1055/s-0037-1609303; Art ID: st-2017-d0925-l
Abstract A study towards the natural product tetrodecamycin is re-
ported. A modified Schlosser–Wittig reaction was utilized to prepare
the precursor for the subsequent intramolecular Diels–Alder reaction,
which delivered the trans-decalin ring of the natural product. The
tetronic acid moiety of the molecule was prepared by a Dieckmann
cyclization. The cyclization of the tetronic acid to the trans-decalin
double bond to form a seven-membered ring was examined.
Key words Schlosser–Wittig reaction, intramolecular Diels–Alder
reaction, aldol reaction, Dieckmann cyclization, tetronic acid
O
Tetrodecamycin (1), an antimicrobial antibiotic that was
isolated from a strain of Streptomyces sp. MJ885-mF8 has
shown to be active against Pasteurella piscicida, the bacteri-
um that causes pseudotuberculosis in cultured fish, methi-
cillin-resistant Staphylococcus aureus and Bacillus an-
thracis.1 The structure of 1 was determined by analysis of
the NMR data of 1 and its reduced acetyl derivative. The ab-
solute configuration of this natural product was established
by the modified Mosher’s method.2 The structure of 1 con-
sists of a 6-6-7-5-membered tetracyclic core. The middle
six-membered ring is fully substituted and contains two
quaternary carbons at C-7 and C-13. This six-membered
ring is attached to a 2-acyl-4-ylidene tetronic acid deriva-
tive at C-7 and C-15.
The unusual structure of 1 and its biological activity
profile have attracted the attention of synthetic chemists
and five synthetic studies of this natural product have ap-
peared in the literature.3 In 2006, the Tatsuta group report-
ed the first total synthesis of 14 in 27 steps from a known
lactone and this still remains the only completed synthesis
O
O
1
6
17
O
2
3
H
9
H
O
18
7
10
11
4
O
8
16
13
12
14
O
15
5
O
15
HO
OH
2
Tetrodecamycin (1)
7-membered-
ring formation
O
O
O
O
H
H
H
O
O
O
HO
4
H
H
OMe
3
CHO
CHO
CHO
H
7
6
5
Scheme 1 Retrosynthetic analysis of tetrodecamycin (1)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
J. He et al.
Letter
Synlett
The synthesis of aldehyde 7 was first reported by Snid-
er5 and subsequently by the Paintner group.3b In each of
these syntheses, the crucial C–C bond-forming step was
achieved through the use of a Li2CuCl4-catalysed cross-cou-
pling reaction between a protected Grignard reagent and
the commercially available (2E,4E)-2,4-hexadien-1-yl ace-
tate. Both the Snider and Paintner groups observed that
these coupling reactions proceeded with modest yields. To
avoid a significant material loss at an early stage of a multi-
step synthesis, we devised a more efficient and protecting-
group-free synthesis of aldehyde 7.
Treatment of commercially available 1,6-hexanediol (8)
with hydrogen bromide (48% aq.) in toluene under reflux
afforded monobrominated alcohol 9 in high yield.6 Reaction
of 9 with triphenylphosphine in acetonitrile gave phospho-
nium salt 10 in almost quantitative yield after heating to
reflux overnight (Scheme 2).
Table 1 Schlosser–Wittig Reaction between Phosphonium Salt 10 and
Aldehyde 11
OH
Conditions
OH
Ph3P
Br
10
12
CHO
11
Entry
1
Conditions
Yield (%) E/Z ratio
MeLi·LiBra (2 equiv), THF, –78 °C; r.t., 30
min; 11, –78 °C; MeLi·LiBr (1.2 equiv),
–30 °C; r.t., 30 min; HClc (1.1 equiv), –78 °C,
30 min; KOtBu (1.24 equiv) –78 °C to r.t.
53
25:1
2
3
MeLi·LiBr (2 equiv), THF, –78 °C; r.t., 30 min; 62
11, –78 °C; MeLi·LiBr (1.2 equiv), –78 °C; r.t.,
30 min; CF3CO2H (1.1 equiv), –78 °C,
9:1
30 min; KOtBu (1.24 equiv) –78 °C to r.t.
MeLi·LiBr (2 equiv), LiClb (3 equiv), THF,
–78 °C; r.t., 30 min; 11, –78 °C; MeLi·LiBr
(1.2 equiv), –78 °C; r.t., 30 min; CF3CO2H
(1.1 equiv), –78 °C, 30 min; KOtBu (1.24
equiv), –78 °C to r.t.
71
19:1
HBr (48% aq.),
toluene, reflux
OH
OH
HO
Br
94%
9
8
MeCN, reflux, 24 h
99%
a MeLi·LiBr used as a 1.5 M solution in Et2O.
b Lithium chloride was dried at 150 °C in vacuo overnight.
OH
c HCl used as a 1.0 M solution in Et2O.
Ph3P
Br
10
reactive organolithium species. Investigation of the E-olefi-
nation of phosphonium salt 10 with aldehyde 11 is summa-
rized in Table 1.
Scheme 2 Synthesis of phosphonium salt 10 from diol 8
Our aim was to conduct a Schlosser-modified Wittig re-
action7 of 10 with aldehyde 11. A number of factors affect
the outcome of a Schlosser-Wittig reaction. Extensive in-
vestigations by the Schlosser group demonstrated that
'homemade' phenyllithium is the reagent of choice for the
Schlosser-Wittig reaction, due to its low tendency to aggre-
gate.7d The same investigation also reported that methyl-
lithium, despite of existing as a tight tetramer,7d also per-
formed satisfactorily as a base in the same reaction to give
the olefination product in good E/Z ratio and yield. Schloss-
er also observed that the E/Z ratio of olefination product
was also affected by the amount of lithium salts in the reac-
tion. It was proposed that the presence of an excess amount
of lithium salts in the reaction would suppress the dissocia-
tion of the α-lithiated betaine ylide to an α-metal-free beta-
ine ylide. This dissociative pathway would result in a loss of
stereoselectivity between threo and erthro forms of the
betaine ylide.7e
Experimentally the preparation of phenyllithium is haz-
ardous and it also has a limited shelf life, making the utili-
zation of 'homemade' phenyllithium in large quantity rath-
er unappealing. We wondered if the standard Schlosser–
Wittig procedure could be simplified by substituting
'homemade' phenyllithium with the commercially available
methyllithium·lithium bromide complex. We postulated
that the addition of an excess lithium salts in the reaction
could break up the methylithium clusters to form a more
Initially, the double deprotonation of 10 using two
equivalents of methyllithium·lithium bromide complex –78 °C
followed by stirring at room temperature resulted in the
formation of the corresponding ylide. The ylide was then
treated with aldehyde 11 to form the betaine adduct. Fur-
ther deprotonation of the betaine at low temperature using
methyllithium·lithium bromide complex followed by
sequential addition of HCl in diethyl ether and then potassi-
um tert-butoxide gave the desired product 12 in 53% yield
with an E/Z ratio of 25:1 (Table 1, entry 1). We observed
that commercial sources of HCl in diethyl ether varied in
quality and often affected the reproducibility of this reac-
tion. When trifluoroacetic acid was used as a substitute for
HCl in diethyl ether the reaction became more reproduc-
ible, and a 62% yield of 12 with an E/Z ratio of 9:1 was ob-
tained (Table 1, entry 2). Overall the original conditions
gave the best ratio of E/Z, but were neither the highest
yielding nor most consistent. Finally, the reaction was con-
ducted in the presence of additional lithium chloride (three
equivalents) and with trifluoroacetic acid as the proton
source. This gave a 71% yield of 12 with a respectable E/Z
ratio of 19:1 (entry 3). Further investigations will be carried
out to examine the general applicability of this modified
protocol.
Compound 12 was oxidized with 2-iodoxybenzoic acid
(IBX)8 to aldehyde 7, which was olefinated with phospho-
nate 13 using the Masamune–Roush conditions9 (LiCl and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
J. He et al.
Letter
Synlett
1,8-diazabicyclo[5.4.0]undec-7-ene [DBU]) to form ester
14. Reduction of 14 with diisopropylaluminium hydride10
(DIBAL-H) afforded allylic alcohol 15. Oxidation of 15 to
aldehyde 6 was best performed using catalytic tetra-n-butyl-
ammonium perruthenate (TPAP) with N-methylmorpholine
N-oxide (NMO) as co-oxidant11 (Scheme 3).
methane at 0 °C for 3 h only resulted in the formation of a
complex mixture (Table 2, entry 1). No reaction was
observed when the reaction temperature was lowered to
–78 °C, despite an extended reaction time (Table 2, entry 2).
Switching the reaction medium to toluene and gradually
raising the reaction temperature also resulted in the forma-
tion of a complex mixture, together with unreacted 6
(Table 2, entry 3). When ZnCl2 in tetrahydrofuran was used
as Lewis acid,13 the desired product 5 was formed in 25%
yield, together with recovered 6 in 53% yield after stirring at
room temperature for 3 d (Table 2, entry 4). Finally, it was
found that, by extending the duration of reaction to 4 d, and
with ZnCl2 in diethyl ether as Lewis acid, a 66% yield of 5
could be obtained14 (Table 2, entry 5). The spectroscopic
data of 5 were consistent with those reported by Kobayashi
et al.12
O
EtO
P
CO2Et
CHO
CO2Et
OH
EtO
IBX
13
DMSO
THF, r.t.
84%
LiCl, DBU,
MeCN, r.t.,
overnight
12
7
14
93%
DIBAL-H
Et2O
95%
–78 °C
TPAP, NMO,
molecular sieves,
CH2Cl2, r.t.
CHO
OH
Table 2 Lewis Acid Mediated Intramolecular Diels–Alder Reaction of 6
89%
CHO
6
15
CHO
H
Conditions
Scheme 3 Synthesis of aldehyde 6 from alcohol 12
H
5
6
With good quantities of aldehyde 6 in hand, the intra-
molecular Diels–Alder reaction of 6 was investigated (Table
2).
Entry Conditions
Results
Kobayashi et al. previously reported that treatment of 6
with Et2AlCl resulted in the formation of 5 via an endo-
selective intramolecular Diels–Alder reaction. However,
they observed that 5 could not be isolated as it underwent
an Et2AlCl-mediated Meerwein–Ponndorf–Verley reduction
in situ to form the corresponding alcohol. A separate oxida-
tion step was performed on this alcohol in order to obtain
aldehyde 5.12 However, our attempts to repeat this reaction
were unsuccessful. Treatment of 6 with Et2AlCl in dichloro-
1
2
3
Et2AlCl (1.3 equiv), CH2Cl2, 0 °C, 3 h
complex mixture
Et2AlCl (1.02 equiv), CH2Cl2, –78 °C, 6 h mostly unreacted 6
Et2AlCl (0.95 equiv), toluene, –78 °C to
r.t., overnight
unreacted 6 + complex
mixture
4
5
ZnCl2 (1.0 M in THF, 1.2 equiv), CH2Cl2,
r.t., 3 d
5 (25%) + 6 (53%)
ZnCl2 (1.0 M in Et2O, 1.2 equiv), CH2Cl2, 5 (66%)
r.t., 4 d
OH
O
O
O
CHO
H
H
H
OEt
OEt
EtOAc
IBX
B(OH)2
DMSO, THF, r.t.
75%
LDA, THF, –78 °C
85%
OH
H
H
H
(2.5 mol%)
O
17
16
5
NO2
OMe
18
toluene, reflux overnight
82%
O
O
O
O
H
H
O
O
O
HO
O
H
OMe
H
TBAF (3 equiv), THF
3a
4a
+
+
O
40 °C, 5 d
78%
O
O
H
H
O
O
O
HO
H
H
OMe
3b
4b
Scheme 4 Synthesis of tetronic acids 3a,b from aldehyde 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
J. He et al.
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Synlett
With the trans-decalin 5 available, the construction of
the tetronic acid moiety was examined. Compound 5 was
subjected to an aldol reaction with deprotonated ethyl ace-
tate15 to afford condensation product 16. Oxidation of 16
with IBX gave β-keto ester 17 in good yield. A transesterifi-
cation reaction was performed on 17 with methyl S-lactate
18, using 3-nitrobenzeneboronic acid as catalyst.16 This re-
action delivered 4a,b as a diastereomeric mixture. This mix-
ture was not separated but was utilized directly for
Dieckmann cyclization. However, this transformation was
far from trivial. A number of base/solvent combinations was
examined and, eventually, it was found that stirring 4a,b
with tetra-n-butylammonium fluoride16 in THF at 40 °C for
5 d, led to a combined yield of 78% for 3a,b (Scheme 4)
Next the intramolecular cyclisation of 3a,b to form a
seven-membered ring was examined. It was envisaged that
an electrophile induced ring closure of the tetonic acid onto
the trans-decalin double bond would result in the forma-
tion of the desired seven-membered ring. This step could be
followed by either a concomitant or sequential elimination
of the electrophile in the cyclised product to install a double
bond at the ring junction. This double bond could then be
dihydroxylated to give dihydrotetrodecamycin (19a) and its
diasteroisomer 19b. It was hoped that 19a could eventually
be converted into tetrodecamycin (1).
pected cyclisation, even after the reaction was left stirring
for one week. Again, unreacted 3a,b was recovered (Scheme
5).
We apportioned that the failure of 3a,b to undergo
cyclisation was partly due to their low solubilities but
mainly due to the difficulty in the direct formation of the
medium sized seven-membered ring through a ring closure
process.
In conclusion, we have completed the synthesis of the
cis-decalin skeleton and the tetronic acid ring of tetrodeca-
mycin (1). Although our attempts to close the seven-mem-
bered ring to form the basic skeleton of 1 did not come to
fruition, this venture allowed us to achieve a protecting-
group-free synthesis of compound 12 through the develop-
ment and application of a practically convenient version of
the Schlosser–Wittig reaction. We hope that this 'practical-
ly friendly' protocol will make the application of this reac-
tion more appealing to synthetic organic chemistry com-
munity. Finally, we have also developed a route using mild
conditions for the intramolecular Diels–Alder reaction of
compound 6 to synthesise the trans-decalin ring system of
tetrodecamycin (1).
Funding Information
Attempts to perform a palladium(II)-catalysed oxidative
cyclisation18 on 3a,b only resulted in the recovery of unre-
acted starting material. Treatment of 3a,b with phenyl-
selenyl chloride19 and triethylamine did not induce the ex-
J.H. thanks the Clarendon Fund bursary, Oxford for financial support. )(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609303.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
O
O
O
O
O
O
O
H
O
H
H
H
O
O
Pd(OAc)2 or Pd(CF3CO2)2,
NaOAc, molecular sieves
DMSO, O2, r.t. to 80 °C
HO
O
H
PhSeCl, Et3N, CH2Cl2,
r.t., 1 week
3a
SePh
+
+
+
O
O
O
O
O
O
H
H
H
O
O
O
HO
O
O
H
H
3b
SePh
O
O
O
O
O
O
O
O
O
H
H
H
+
O
O
O
HO
OH
HO
HO
OH
OH
19b
Tetrodecamycin (1)
Dihydrotetrodecamycin (19a)
Scheme 5 Attempted cyclization reactions of 3a,b
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Synlett
References and Notes
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bined organic layers were dried (Na2SO4), filtered, concentrated,
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give 5 as a yellowish oil (360.4 mg, 66%). 1H NMR (500 MHz,
CDCl3): δ = 1.03 (3 H, s, H-12), 1.06 (3 H, d, J = 7.0 Hz, H-13),
1.11–1.21 (2 H, m, 1 × H-7 and 1 × H-10), 1.30–1.50 (3 H, m, 1 ×
H-7, 1 × H-8, and 1 × H-9), 1.71–1.86 (5 H, m, H-1, H-6, 1 × H-8,
1 × H-9, and 1 × H-10), 2.02–2.05 (1 H, m, H-3), 5.40–5.43 (1 H,
m, 1 × H-5), 5.47–5.52 (1 H, m, H-4), 9.62 (1 H, s, H-11).13C NMR
(125.8 MHz, CDCl3): δ = 14.4 (C-12), 17.3 (C-13), 26.9 (C-9), 26.9
(C-8), 27.2 (C-7), 32.5 (C-10), 37.8 (C-6), 38.7 (C-1), 39.7 (C-3),
49.7 (C-2), 130.0 (C-4), 130.2 (C-5), 209.2 (C-11). GC–MS: m/z
calcd for C13H24NO [MNH4+]: 210.1858; found: 210.1858. IR
(thin film): νmax = 3012 (w, C=C–H), 2925 (str, C–H stretch),
2855 (m, C–H stretch), 1725 (str, s, C=O), 1654 (w, C=C), 1448
(m, C–H deformation), 1374 (w), 1041 (w) cm–1
.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E