Chemoenzymatic Synthesis of Advanced Intermediates for Formal Total Syntheses of Tetrodotoxin

Article abstract of DOI:10.1002/anie.201804602

Advanced intermediates for the syntheses of tetrodotoxin reported by the groups of Fukuyama, Alonso, and Sato were prepared. Key steps include the toluene dioxygenase mediated dihydroxylation of either iodobenzene or benzyl acetate. The resulting diene diols were transformed into Fukuyama's intermediate in six steps, into Alonso's intermediate in nine steps, and into Sato's intermediate in ten steps.

Full text of DOI:10.1002/anie.201804602

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Accepted Article
Title: Chemoenzymatic Approach to Tetrodotoxin: Synthesis of
Fukuyama's, Alonso's, and Sato's Advanced Intermediates
Authors: Daler Baidilov, Lukas Rycek, John F. Trant, Jordan Froese,
Brennan Murphy, and Tomas Hudlicky
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10.1002/anie.201804602
Angewandte Chemie International Edition
Chemoenzymatic Approach to Tetrodotoxin: Synthesis of Fukuyama’s, Alonso’s, and
Sato’s Advanced Intermediates
Daler Baidilov, Lukas Rycek, John F. Trant, Jordan Froese, Brennan Murphy and Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way, St.
Catahrines, ON L2S 3A1, Canada
thudlicky@brocku.ca
Abstract: The advanced intermediates in the syntheses of tetrodotoxin reported by Fukuyama, Alonso,
and Sato were prepared. The key steps in the synthesis of the title compounds involved the toluene
dioxygenase–mediated dihydroxylation of either iodobenzene or benzyl acetate. The resulting diene
diols were transformed to Fukuyama’s intermediate in six steps, to Alonso’s intermediate in nine steps
and to Sato’s intermediate in ten steps, respectively.
Tetrodotoxin (1), (TTX),[1] Figure 1, was first isolated by Tahara in 1909[2] and eluded precise structural
determination for half a century. Following the successful preparation of the toxic principle in analytically
pure crystalline form in the early 1950s,[3] a race broke out to elucidate the structure of this marine toxin.
In 1964,[4] no fewer than four research groups reported successful elucidation.[5]
Figure 1. Chemoenzymatic approach to advanced precursors of TTX.
1
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10.1002/anie.201804602
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The structure of TTX contains nine contiguous stereogenic centers in a molecule of only eleven carbons
with the molecular weight slightly exceeding 300. The most intriguing structural feature is a
dioxaadamantane skeleton with a cyclic guanidine containing a hemiaminal moiety, Figure 1. TTX
naturally occurs in several species of pufferfish and some other aquatic animals, but it is believed to be
produced by symbiotic bacteria.[6] The toxin is a potent inhibitor of voltage-gated sodium channels (Nav).
At very low dosages it has a potential to treat cancer pain or relieving the symptoms of withdrawal in
opiate addicts.[7] The important clinical applications and the intricate structure of TTX have attracted the
attention of synthetic community and several syntheses were reported since the attainment of the
racemate by Kishi in 1972.[8] The interest in this fascinating molecule continues unabated and many
creative total syntheses have been published.[9] Additionally, various approaches to TTX have also been
summarized.[10] In this paper, we report a chemoenzymatic synthesis of the title advanced intermediates
from diene diols 5 or 6, Figure 1, obtained by toluene dioxygenase-mediated dihydroxylation of
iodobenzene or benzyl acetate, respectively.
Fukyama’s synthesis of Boc-protected amine 2 proceeded in 13 steps from benzoquinone (see Scheme 1
in the Appendix of the Supplemental Information Section for detailed description of the synthesis).
Alonso’s approach started with furfural, which was converted in 12 steps to alcohol 4, Figure 1 (see
Scheme 2 in the Appendix of the Supplemental Information Section for detailed description of the
synthesis). Sato prepared the advanced intermediate 3 in 21 steps from D-glucose (see Scheme 3 in the
Appendix of the Supplemental Information Section for detailed description of the synthesis).
2
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Our approaches to the advanced precursors of TTX shown in Figure 1 share the common intermediate
enone 7, Scheme 1. We envisioned access to compounds of this type via enzymatic dihydroxylation of
suitable aromatic substrates. This highly regio- and enantioselective dihydroxylation was discovered in
1968 by Gibson[11a] who also later provided a robust recombinant organism, E. coli JM109 (pDTG601A),
that overexpresses toluene dioxygenase.[11b] The use of this strain in whole-cell fermentations[11c] allows
access to large amounts (>20 g/L) of the homochiral diene diols (such as 5 or 6, Scheme 1) that serve as
ideal starting materials for enantioselective synthesis of highly oxygenated targets. To date many
examples of efficient chemoenzymatic syntheses of natural products from diols of type 5 have been and
continue to be published.[11d-f]
Scheme 1. Synthesis of the key intermediate 7. a) p-TsOH·H2O, 2,2-DMP, rt; b) Pd(OAc)2, NEt3, CO (1 atm), MeOH,
40°C; c) DIBAL (neat), benzene : n-hexane = 1 : 1, 0 °C; d) p-TsOH·H2O, 2,2-DMP, rt; K2CO3, MeOH, rt; e) O2
(bubbling), TPP, hv, CH2Cl2; Et3N, rt (11: 46% from 5, 4 steps; 11: 68% from 6, 2 steps; 13: 42% from 6, 2 steps); f)
LiOH, THF/H2O, 0°C, 50%; g) p-TsOH·H2O, 2,2-DMP, 50°C, 80%.
Ts = tosyl, DMP = dimethoxypropane, Ac = acyl, DIBAL = diisobutylaluminium hydride, TPP = tetraphenylporphyrin,
THF = tetrahydrofuran.
Several generations of approaches to the synthesis of enone 7 were pursued in our group with the most
efficient one proceeding in four steps from benzyl acetate 9. The 1st generation employed iodobenzene 8
as a substrate for chemoenzymatic dihydroxylation by toluene dioxygenase.[11] The resulting iodo diol 5
was converted to the key enone 7 in a five-step sequence. Acetonide protection, palladium catalyzed
methoxycarbonylation,[12] and DIBAL reduction produced allylic alcohol 10. Construction of the
tetrasubstituted carbon at C-6 (TTX numbering) was realized through [4+2] hetero-Diels-Alder
3
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10.1002/anie.201804602
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cycloaddition with singlet oxygen followed by Kornblum-DeLaMare rearrangement,[13] utilized recently
in our synthesis of pleiogenone.[14] The singlet oxygen cycloaddition took place exclusively from the less
sterically hindered face of the diene moiety. The intermediate endo-peroxide was rearranged by means of
triethylamine in the same reaction pot to furnish enone 11. Protection of the diol in 11 provided efficient
access to 7 in an overall yield of 36% from diene diol 5. In the 2nd generation approach we used benzyl
acetate 9 as a starting material, as this compound already contains the C-11 hydroxymethyl moiety of
TTX. Acetonide protection of the diol in 6 furnished the photooxygenation precursor 12. Following the
cycloaddition of singlet oxygen and the subsequent rearrangement furnished enone 13, whose
deacetylation yielded shorter synthetic route to diol 11 and hence to the key enone 7 (33% overall yield
from 6). Finally, in the 3rd generation approach, we realized that allylic alcohol 10 can be obtained
directly from 6 in a one-pot fashion. Thus, acetonide protection of the diol in 6 followed by deacetylation
provided rapid access to diene 10, which was then converted to enone 7 (54% from 6) in two subsequent
synthetic operations as described above.
With the rapid access to 7 in hand, we turned our
attention to the synthesis of Fukuyama’s intermediate
2. Allylic alcohol 14 was accessed in high yields via
Peterson olefination/DIBAL reduction sequence and
the precursor to rearrangement was prepared through
carbamoylation of 14, as shown in Scheme 2. The
Scheme 2. Synthesis of Fukuyama’s carbamate 2. a)
TMSCH2CO2Et, LDA, THF, -78 to 0 °C; b) DIBAL,
allylic alcohol moiety in 14 can also be installed
toluene, -78 to 0 °C, 80% (2 steps); c) n-BuLi,
directly on 7 via means of Wittig olefination,[15] albeit
in a lower yield. Upon dehydration of 15 with TFAA
and Hunig’s base,[16] a facile [3,3]-sigmatropic
rearrangement took place to yield isocyanate
intermediate, which, upon treatment with lithium tert-
Ph3P+CH2CH2OH Br-, THF, -30 °C to rt, 64% (E : Z =
8 : 1); d) Cl3CC(O)NCO, CH2Cl2, rt; Et3N, MeOH, rt,
96%; e) TFAA, i-Pr2NEt, CH2Cl2, -78 °C to rt; LiOt-
Bu, -78 to 0 °C, 56%.
DIBAL = diisobutylaluminium hydride, LDA = lithium
diisopropylamide, t-Bu = tert-butyl, THF =
tetrahydrofuran, TMS = trimethylsilyl, Boc = tert-
butyloxycarbonyl, TFAA = trifluoroacetic anhydride.
butoxide, furnished Fukuyama’s carbamate 2 in 56%
22
yield, Scheme 2, in 6 steps from 6 (Fukuyama’s work: [훼]퐷24 + 10° (c 0.97, CHCl3); This work: [훼]퐷
+
9.8° (c 1.0, CHCl3)). Both E and Z isomers of 14 converge to the same Boc-amine 2. Fukuyama in his
approach to TTX utilized the Z isomer of 15 as the rearrangement precursor (see Scheme 1 in the
Appendix of the Supplemental Information Section for detailed description of the synthesis).
4
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10.1002/anie.201804602
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The construction of the key cyclohexanone 3
commenced
with
the
bromination/
dehydrobromination sequence of 7 to furnish the
vinyl bromide 16.[17] Introduction of the C-4 carbon
proved possible by utilizing Stille coupling with an
oxygenated stannane to provide TBDPS-silyl ether
17,[18] whose DIBAL reduction gave efficient access
to allylic alcohol 18, Scheme 3. The desired
stereochemistry at C-5 of TTX can be accessed
Scheme 3. Synthesis of allylic alcohol 18. a) Br2, CH2Cl2,
0°C; Et3N, 0 °C, 68%; b) Pd(OAc)2, Bu3SnCH2OTBDPS,
1,4-dioxane, 90 °C, 64%; c) DIBAL, toluene, -78 to 0 °C,
94%.
DIBAL = diisobutylaluminium hydride, TBDPS = tert-
butyldiphenylsilyl, Bu = butyl, Ac = acyl.
through
hydroxyl
directed
epoxidation of 18. Oxidation of
the intermediate epoxy alcohol
19 with IBX provided the α,β-
epoxy ketone 21 as a precursor
for
reductive
epoxide
opening.[19] Unfortunately, the
latter procedure gave 4 and its
α-position epimer, 4’, as an
Scheme 4. Reductive epoxide opening approach to 4. a) mCPBA, CHCl3, reflux; b)
IBX, EtOAc, reflux, 82% (21 : 22 = 3 : 7, 2 steps); c) Zn, Cp2TiCl2, THF/MeOH, -78 to
0 °C, 20 %; d) Zn, Cp2TiCl2, THF/MeOH, 50 °C, 10-30 %.
TBDPS = tert-butyldiphenylsilyl, mCPBA = meta-chloroperbenzoic acid, IBX = 2-
iodoxybenzoic acid, Cp = cyclopentadienyl, THF = tetrahydrofuran.
inseparable
diastereomers, Scheme 4. The
stereochemistry of the
intermediate epoxy alcohol was
mixture
of
validated by subjecting the undesired epoxide 20 to a base-promoted Payne rearrangement, Scheme 5.
Scheme 5. Payne rearrangement. a) KOt-Bu, THF :
HOt-Bu = 1 : 1, rt, 95%.
THF = tetrahydrofuran, t-Bu = tert-butyl.
5
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10.1002/anie.201804602
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Clearly, this process requires
the trans arrangement of the
oxirane
and
hydroxyl
functionalities.
Moreover,
reductive epoxide opening was
also performed with keto-
Figure 2. Hydride shift approach.
epoxide 22, as shown in Scheme 4, which could not have resulted in inversion of stereochemistry at C-5.
In considering the problem of
the undesired epimer formation,
it seemed that a possible
solution might involve
suprafacial delivery of
a
a
hydrogen
by
“hydride”
migration of an already α-
configured hydrogen in 19 in an
intramolecular fashion as shown
Figure 3. Stereoelectronic arguments.
in Figure 2. The key argument in favour of this manoeuvre assumed that it ought to be possible to prompt
the rearrangement of 19 to 4 by either
Lewis acid activation of the oxirane,[20] or
deprotonation of an alcohol, so that the
alkoxide would provide the necessary
electron push,[21] wherein suprafacial
hydride shift of the α-hydrogen from C-
8a would deliver it to the desired α-face
at C-4a, thereby restoring the carbonyl
moiety and producing
stereospecific fashion.
4
in
a
To
our
Scheme 6. Synthesis of Alonso’s (4) and Sato’s (3)
intermediates. a) mCPBA, CHCl3, reflux; b) TMSCl, imidazole,
CH2Cl2, 85% (25 : 26 = 3 : 7, 2 steps); c) TiCl4, CH2Cl2, -78 °C,
52% (27 : 4 = 4 : 1); d) BF3·Et2O, CH2Cl2, 0°C, 93%; e)
CH2(OMe)2, P2O5, CH2Cl2, rt, 79%.
disappointment, 19 was completely inert
to any kind of Lewis acid or base
activation. Assuming that the resident
TBDPS = tert-butyldiphenylsilyl, TMS = trimethylsilyl, mCPBA
= meta-chloroperbenzoic acid.
“hydride”
lacks
the
optimal
6
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10.1002/anie.201804602
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stereoelectronic alignment with the σ*(C–O) of the oxirane, we prepared the TMS ether 25, from the free
alcohol 19. The introduction of the steric hindrance between the TMS group and the adjacent acetonides
forced the resident hydrogen to accommodate pseudoaxial orientation, as shown in Figure 3. Indeed, upon
exposure of 25 to TiCl4,[22] the desired hydride shift took place smoothly producing 27 and 4 in 4 : 1 ratio
as the major products, with the required stereochemistry at the newly formed C-4a tertiary carbon center,
as shown in Scheme 6. Removal of the TMS group in 27 provided the Alonso’s intermediate 4 in 49%
yield from epoxy silyl ether 25 over two steps. Sato’s intermediate 3 (Sato’s work: [훼]퐷25 - 5.5° (c 4.09,
CHCl3); This work: [훼]퐷24 - 3.5° (c 0.44, CHCl3))[23] was then obtained by MOM protection of 4 with
dimethoxymethane in the presence of phosphorus(V) oxide. Thus, Sato’s intermediate was synthesized in
ten steps from 6.
Finally, the undesired epoxide 26
was also converted to Sato’s
intermediate as shown in Scheme 7.
TMS removal, Payne rearrangement,
followed
by
inversion
of
stereochemistry at C-5 by oxidation-
reduction sequence provided epoxy
alcohol 28. Alkylation of 28 with
MOMCl and subsequent cleavage of
the silyl ether moiety in 29 furnished
primary alcohol 30. Iodination[24] of
30 and reductive cleavage of the
resulting 2,3-epoxyalkyliodide 31 by
the sonochemically generated zinc-
copper couple[25] gave Sato’s allylic
alcohol 32 (see Scheme 4 in the
Scheme 7. The end game: conversion of 26 to Sato’s intermediate 32.
a) K2CO3, MeOH, rt; b) KOt-Bu, THF : HOt-Bu = 1 : 1, rt; c) IBX,
EtOAc, reflux; d) NaBH4, MeOH, rt, 64% (4 steps); e) NaHMDS,
MOMCl, THF, 0 °C to rt, 88%; f) TBAF, THF, rt, 92%; g) I2, PPh3,
imidazole, CH2Cl2, rt, 78%; h) Zn, CuI, EtOH/H2O/MeOH/THF,
sonication, rt, 91%.
THF = tetrahydrofuran, t-Bu = tert-butyl, TBDPS = tert-
butyldiphenylsilyl, TMS = trimethylsilyl, IBX = 2-iodoxybenzoic acid,
HMDS = hexamethyldisilizide, MOM = methoxymethyl, TBAF =
tetrabutylammonium fluoride.
Appendix of the Supplemental Information Section for detailed description of the synthesis). This last
approach corrected the lack of stereoselectivity in the epoxidation of 18; both epoxy alcohols 19 and 20
can now be used to access Sato’s intermediate.
7
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10.1002/anie.201804602
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In summary, two short chemoenzymatic routes to known advanced intermediates for (–)-TTX are
described in this paper and were accomplished in just six and nine steps from 6, to Fukuyama’s and
Alonso’s intermediates, respectively (these compounds can also be attained from 5). Alkylation of
Alonso’s intermediate also formalized the preparation of Sato’s ketone 3 in ten steps from benzyl acetate.
If our approach were to be used for the completion of (–)-TTX by the known methods the overall step
count would be 21 or 22 steps from 6 via Fukuyama’s or Sato’s intermediate, respectively.
Acknowledgements
We are grateful to the following agencies for financial support of this work: Natural Sciences and Engineering
Research Council of Canada (NSERC) (Idea to Innovation and Discovery Grants), Canada Research Chair
Program, Canada Foundation for Innovation (CFI), TDC Research, Inc., TDC Research Foundation, the Ontario
Partnership for Innovation and Commercialization (OPIC), and The Advanced Biomanufacturing Centre (Brock
University). We are thankful to Helen Endoma (Brock University) for her skillful assistance in the fermentations.
We thank to Razvan Simionescu and Dr. Liqun Qui for their help with NMR and mass spectrometry analyses,
respectively.
[1] German: “tetrodongift”, meaning tetrodon poison. The name was assigned by Tahara (vide infra, ref. 2) who pioneered the
isolation of the marine toxin.
[2] a) Y. Tahara, J. Pharm. Soc. Japan 1909, 29, 587; b) Y. Tahara, Biochem. Z. 1911, 10, 255.
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8
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9
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