Construction of Iterative Tetrahydrofuran Ring Units and Total Synthesis of (+)-Goniocin

Article abstract of DOI:10.1021/acs.orglett.6b00877

Cytotoxic acetogenin (+)-goniocin has been synthesized in 17 steps from (R)-O-tritylglycidol. The core structure of the contiguous C₂₂-C₁₀ threo-trans-threo-trans-threo-trans-tris-tetrahydrofuran (THF) ring involving an iterative THF-ring unit was synthesized. An iterative THF ring unit was constructed from an alkenyl-substituted THF ring in four steps including a Pd(II)-catalyzed ring-closing reaction and cross-metathesis. This method is general and allows the preparation of both trans-threo-trans- and trans-threo-cis-THF ring units flexibly.

Full text of DOI:10.1021/acs.orglett.6b00877

Letter
pubs.acs.org/OrgLett
Construction of Iterative Tetrahydrofuran Ring Units and Total
Synthesis of (+)-Goniocin
Ai Suzuki, Mai Sasaki, Tetsuya Nakagishi, Tsuyoshi Ueda, Naoyuki Hoshiya, and Jun’ichi Uenishi*
Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8412, Japan
*
S Supporting Information
ABSTRACT: Cytotoxic acetogenin (+)-goniocin has been synthesized in 17 steps from (R)-O-tritylglycidol. The core structure
of the contiguous C −C threo-trans-threo-trans-threo-trans-tris-tetrahydrofuran (THF) ring involving an iterative THF-ring unit
2
2
10
was synthesized. An iterative THF ring unit was constructed from an alkenyl-substituted THF ring in four steps including a
Pd(II)-catalyzed ring-closing reaction and cross-metathesis. This method is general and allows the preparation of both trans-
threo-trans- and trans-threo-cis-THF ring units flexibly.
nnonaceae acetogenins are a class of natural lipophilic
and its biological activity. Herein, we present a short synthetic
route to (+)-goniocin along with a new method for the
stereocontrolled construction of the bis- and tris-THF ring units.
The contiguous bis-THF ring unit has often been observed in
A
polyketides with C32 or C34 unbranched fatty acid chains,
1
and they are isolated from the Annonaceous plant family. They
display a wide array of biological activities including anticancer,
anti-inflammatory, pesticidal, antimalarial, immunosuppressive,
and neurotoxic. Goniocin (1) was isolated from the bark of
1g−j
the structure of many acetogenins,
and in fact, numerous
syntheses have been reported for acetogenins possessing a bis-
7
,8
Goniothalamus giganteus in Thailand by the McLaughlin group in
THF ring unit. Nonetheless, flexible and efficient stereo-
controlled synthesis of the bis-THF ring unit is desired not only
for the synthesis of 1 but also for the synthesis of other members
of bis-THF acetogenins. Our synthetic plans for the trans-threo-
trans-bis-THF (IA) and trans-threo-cis-bis-THF (IB) rings are
depicted in Scheme 1. The alkene-substituted bis-THF ring of IA
could, in principle, be constructed by Pd(II)-catalyzed stereo9-
specific ring formation from chiral ε-hydroxy allylic alcohol IIA.
This precursor IIA could be derived by cross-metathesis of chiral
2
1
994. They discovered the unique structure and potent
cytotoxic activity of 1. The structure of 1 consists of a core
contiguous tris-trans-tetrahydrofuran (THF) ring unit, a left
linear hydrocarbon chain unit, and a methyl-substituted γ-
butenolactone unit on the right.
1
-tetrahydrofurylpentenol III with chiral allylic alcohol possess-
ing an (S)-chiral center. Meanwhile, the trans-cis-bis-THF ring
isomer IB could be derived from III via the same two steps,
except that (R)-allylic alcohol is used instead of (S)-allylic
alcohol. The common intermediate III is provided from the 1-
alkenyl THF compound V in two steps (ozonolysis followed by
stereoselective butenylation). This method would provide an
additional stereodefined THF ring unit from a simple alkene V or
an aldehyde IV. Thus, the stereodivergent synthesis of the 2-
alkenyl-5,2′-bis-THF ring from the 2-alkenyl-mono-THF ring
could be achieved in four steps.
The chiral γ-butenolactone moiety is a common pharmaco-
phore of acetogenins. Bioenergetic production has been reported
3
,1b,k
to be hindered by the inhibition of mitochondrial complex I.
In fact, 1 displays remarkable profiles of potent growth inhibition
1
,4
of cancer cells. Goniocin is the only acetogenin that has an all-
trans tris-THF ring unit in the C −C chain. Although the
1
0
21
intriguing structure and potent cytotoxic activity of 1 against
cancer cell lines at very low concentrations are attractive, this
compound has not been fully investigated. Only one landmark
total synthesis has been reported by Sinha and Keinan et al. in
5
,6
1
998. However, no additional report for the synthesis of 1 has
Received: March 25, 2016
appeared since then. We are interested in the total synthesis of 1
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Strategy for trans-trans- and trans-cis-Bis-
THF Ring Units IA and IB
Scheme 2. Stereocontrolled Synthesis of trans-threo-trans- and
trans-threo-cis-Bis-THF Rings
On the basis of this idea, we began the synthesis with (R)-O-
1
0
tritylglycidol 2 (Scheme 2). Ring opening of 2 with
allylmagnesium bromide gave 3 in 96% yield, which was
subjected to cross-metathesis with (S)-5-phenylpent-1-en-3-ol
1
1
(
S)-4 in the presence of Grubbs’ II catalyst (0.5 mol %) to
obtain 5 in 71% yield. Catalytic cyclization of 5 with
9
PdCl (MeCN) (5 mol %) gave the desired trans-THF product
2
2
6
in 90% yield along with cis-THF ring isomer 6′ in 5% yield. The
second THF ring for trans isomer 10 was constructed via the
following four steps: (i) ozonolysis of 6 afforded THF−aldehyde
7
in 86% yield; (ii) addition of butenylmagnesium bromide to 7
in THF gave the chelation-controlled product 8 in 51% yield and
12
its diastereomer 8′ in 24% yield; (iii) cross-metathesis of 8 with
S)-4 in the presence of Grubbs’ II catalyst (0.1 mol %) gave diol
in 81% yield; and (iv) Pd(II)-catalyzed cyclization of 9
(
9
furnished the trans-threo-trans-bis-THF ring product 10 in 88%
yield and the trans-threo-cis ring isomer 11 in 4% yield. However,
cross-metathesis of 8 with (R)-4 under the same conditions gave
diol the 12 in 84% yield. Pd(II)-catalyzed cyclization of 12
afforded 11 in 86% yield and 10 in 5% yield.
The facial selectivity in the butenylation of 7 was improved
through the addition of a chelate complex of 7 with MgBr −
2
13
etherate complex into an excess of the butenylmagnesium
bromide in ether. The ratio of isomers became 6.5:1 favoring of
the chelation product 8 (65%) over its isomer 8′ (10%).
Additionally, the diastereomeric isomer 8′ was converted into the
(
R)-isomer 8 in 68% yield by Mitsunobu inversion followed by
C bond. The C -hydroxy group could be created by the
9
22
hydrolysis of the resulting p-nitrobenzoate ester. In the four-step
reaction sequence starting from 7 and resulting in either 10 or 11,
we efficiently constructed a bis-THF ring system in a
stereocontrolled manner. This methodology was then used for
the total syntheses of goniocin.
addition of a dodecyl unit to the C -formyl group derived from
22
15. The consecutive tris-trans-THF ring unit in 15 could be
installed following the same strategy described for the formation
of the bis-THF intermediate 10. The preparation of 10 via the
mono-THF intermediate 6 is shown in Scheme 2.
Scheme 4 shows the synthesis of 1 from 10. First, oxidative
cleavage of alkenyl bond of 10 by ozonolysis gave aldehyde 16 in
86% yield. Addition of butenylmagnesium bromide to 16 in THF
Scheme 3 summarizes our retrosynthetic plan for goniocin.
The C −C unit 13 could be assembled from a right γ-
9
34
14
butenolide unit (R)-14 by alkene cross-metathesis at the C −
8
B
DOI: 10.1021/acs.orglett.6b00877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Retrosynthetic Plan for (+)-Goniocin
Scheme 4. Synthesis of (+)-Goniocin
gave the desired product 17 and the undesired isomer 17′ in a
1
:1.2 ratio and in 33% and 37% yields, respectively. However, the
formation of a MgBr complex of bis-THF aldehyde 16 and the
2
addition by butenylmagnesium bromide resulted in a worse ratio
of 1:1.7, with 17 and 17′ in 28% and 47% yields, respectively.
This result suggests that chelation control in the addition to the
aldehyde was not exerted because of the formation of the MgBr2
complex with the bis-THF ring of 16 and, instead, control
opposite to that expected occurred through the Felkin−Anh
model. The influence of the unexpected stereoselectivity by the
15
existence of a neighboring THF group was reported. The
undesired (S)-isomer 17′ was transformed into the (R)-isomer
17 in 68% overall yield via the Mitsunobu method. Cross-
metathesis of 17 with (S)-4 gave 18 in 82% yield. Compound 18
underwent Pd(II)-catalyzed tris-THF ring formation in THF for
2
0 min at rt, producing 15 in 75% yield along with the cis product
5′ in 6% yield. Deprotection of the O-Tr group of 15 followed
1
by Swern oxidation provided the aldehyde 20 via alcohol 19 in
9
1% overall yield. Addition of the MgBr complex of aldehyde 20
2
to a large excess of dodecylmagnesium bromide in ether gave the
1
6
desired isomer 13 in 43% yield and its isomer 13′ in 28% yield.
Coupling of 13 with an excess of 14 via cross-metathesis gave 21
in 90% yield. HF-promoted deprotection of the O-silyl group and
reduction of the alkene with diimide furnished the total synthesis
of 1 in 52% yield in two steps. The spectroscopic data for
synthetic 1 (i.e., H and C NMR and mass spectra) are identical
to those previously reported in the literature. In particular, the
1
13
2
2
4
specific degree of optical rotation was [α]
CHCl3).
+8.2 (c 0.42,
D
1
7
Subsequently, the effect of the synthetic goniocin 1 was
measured on the proliferation of four cancer cell lines. The IC50
values of cytotoxicity against HL-60, Paca 2, MCF-7, and A 549
were 2.3, 9.4, 21.8, and 6.6 μM/mL, respectively.
paper can be applied for the synthesis of acetogenins and their
analogues possessing a multi-THF ring unit.
In conclusion, we have accomplished the total synthesis of
+)-goniocin. The synthesis comprises 17 linear steps from (R)-
O-tritylglycidol. The four-step reaction sequence from an alkenyl
unit provides short access to the installation of an additional THF
unit. The synthetic strategy and technologies developed in this
ASSOCIATED CONTENT
Supporting Information
(
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00877.
C
DOI: 10.1021/acs.orglett.6b00877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Synthesis protocols and characterization of all new
Letter
M. M.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 580−584.
(n) Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 10818−
1
13
compounds including H and C NMR spectra (PDF)
1
2
0819. (o) Wang, Z.-M.; Tian, S.-K.; Shi, M. Eur. J. Org. Chem. 2000,
000, 349−356. (p) Emde, U.; Koert, U. Eur. J. Org. Chem. 2000, 1889−
AUTHOR INFORMATION
Corresponding Author
■
1904. (q) Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha, S.
C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279−11284. (r) Trost, B.
M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1997, 36,
*E-mail: juenishi@mb.kyoto-phu.ac.jp.
2
632−2635. (s) Towne, T. B.; McDonald, F. E. J. Am. Chem. Soc. 1997,
119, 6022−6028. (t) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118,
801−1802. (u) Sinha, S. C.; Sinha, A.; Yazbak, A.; Keinan, E. J. Org.
Notes
1
The authors declare no competing financial interest.
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Maeda, M.; Sasaki, S. J. Org. Chem. 1995, 60, 4419−4427. (w) Hoye, T.
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ACKNOWLEDGMENTS
■
We are grateful to the Sanyo Fine Co. Ltd. for kindly providing us
optically pure (S)-glycidol. We thank Dr. Hiromi Ii (Kyoto
Pharmaceutical University) for the measurement of cytotoxic
activity toward cancer cells.
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D
DOI: 10.1021/acs.orglett.6b00877
Org. Lett. XXXX, XXX, XXX−XXX