Total synthesis of muconin

Article abstract of DOI:10.1016/S0040-4039(02)02182-2

An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF-THP segment and a terminal butenolide. The key reactions include 6-exo cyclization of an epoxy tetraol, regioselective cyclization of hydroxy tosylate, and stereoselective reduction of an acyclic ketone adjacent to the 2,6-cis THP ring with Zn(BH₄)₂.

Full text of DOI:10.1016/S0040-4039(02)02182-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8661–8664
Total synthesis of muconin
Shunya Takahashi,a,* Akemi Kubotab and Tadashi Nakataa,b
aRIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama, 351-0198, Japan
bGraduate School of Science and Engineering, Saitama University, Saitama, Saitama 338-8570, Japan
Received 30 August 2002; revised 24 September 2002; accepted 27 September 2002
Abstract—An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF–THP segment and a
terminal butenolide. The key reactions include 6-exo cyclization of an epoxy tetraol, regioselective cyclization of hydroxy tosylate,
and stereoselective reduction of an acyclic ketone adjacent to the 2,6-cis THP ring with Zn(BH4)2. © 2002 Elsevier Science Ltd.
All rights reserved.
Since the discovery of a powerful antitumor agent,
mucocin, several annonaceous acetogenins carrying a
tetrahydropyran (THP) ring have been isolated from
the Annonaceae plant species.1 These compounds have
attracted much attention among synthetic organic
chemists because of their structural diversity and strong
antitumor activities.2 Muconin (1), which was isolated
from the leaves of Rollinia mucosa by McLaughlin et al.
in 1996, is a rare type of acetogenin bearing a THP ring
along with a tetrahydrofuran (THF) ring (Fig. 1).3
Compound 1 is reported to show potent and selective in
vitro cytotoxicity against PACA-2 (pancreatic cancer)
and MCF-7 (breast cancer) in a panel of six human
solid tumor cell lines. Recently, we have been engaged
in the synthetic studies on the THP-acetogenins, result-
ing in the total synthesis of mucocin and jimenezin.4 As
part of our continuing studies in this field, we describe
herein the total synthesis5 of 1 in a stereocontrolled
manner.
Our synthetic strategy directed toward 1 was based on
a convergent process which involves a Pd-catalyzed
cross-coupling reaction of the THF-THP segment 2 and
a vinyl iodide 3, as illustrated in Scheme 1. Disconnec-
tion of the acetylene unit and cleavage of the THF ring
in 2 lead to a THP derivative 4, which would be
synthesized from an epoxy alcohol 5 through a 6-exo
cyclization and stereoinversion at the C-8 position. For
effective inversion, we planned to utilize a stereoselec-
tive reduction of an acyclic ketone adjacent to the
2,6-cis THP ring. The usefulness of the method has
been already demonstrated in our total synthesis of
mucocin and jimenezin.4a–c
An unsaturated ester 6, which was prepared by Keinan
and Sinha’s procedure,6 was reduced, and then sub-
jected to tosylation to afford the corresponding tosyl-
ate. Treatment of this with sodium cyanide gave a
nitrile 77 in 84% overall yield from 6 (Scheme 2). The
nitrile 7 was converted into an allyl alcohol 8 by the
following sequence: (1) reduction of the nitrile function
with DIBAL; (2) Wittig reaction; (3) DIBAL reduction
of ester carbonyl (85% overall yield). Installation of the
requisite oxygen function into the carbon backbone was
accomplished by the Sharpless protocol.8 Initially, 8
was epoxidized with Ti(Oi-Pr)4 and t-BuO2H in the
presence of D-diethyl tartrate to give an epoxide9 in
91% yield. After silylation with chloro t- butyldiphenyl-
silane and imidazole, the resulting silylether reacted
with AD-mix b in the presence of methanesulfonamide
(2.0 equiv.) in aq. t-BuOH to give the tetraol 5 in
almost quantitative yield.10 Upon treatment of 5 with
d-camphorsulfonic acid in CH2Cl2, 6-exo cyclization
occurred to produce a THP derivative 9 in 86% yield.
From a practical point of view, isolation after the
Figure 1.
* Corresponding author. Fax: +81-48-462-4666; e-mail: shunyat@
riken.go.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02182-2

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S. Takahashi et al. / Tetrahedron Letters 43 (2002) 8661–8664
Scheme 1. Retrosynthetic scheme of muconin (1).
Scheme 2. (a) LiAlH4, THF, 0°C; (b) p-TsCl, pyridine, 0°C; (c) NaCN, DMSO, rt; (d) DIBAL, CH2Cl2, −78°C; (e)
(MeO)2P(O)CH2CO2Me, NaH, THF, 0°C; (f)
D-DET, Ti(Oi-Pr)4, t-BuO2H, MS4A, CH2Cl2, −23°C; (g) TBDPSCl, imidazole,
DMF, rt; (h) AD-mix b, MeSO2NH2, aq. t-BuOH, 0°C; (i) CSA, CH2Cl2, rt, then MeOH, concd., and (MeO)2CMe2–CH2Cl2, rt.
following hydroxy protection was found to be more
efficient. Hence, after completion of the cyclization, the
reaction mixture was treated with methanol in order to
hydrolyze the TBDPS ether, concentrated in vacuo and
then reacted with 2,2-dimethoxypropane in CH2Cl2 in one
pot to give a diacetonide 10 in 85% overall yield. The
optical purity of 10 was determined to be >98% e.e. by
the 1H NMR analyses of the corresponding MTPA esters.
The alcohol 10 was oxidized with Dess–Martin periodi-
nane to give a ketone, which was reduced with
11
Zn(BH4)2 in ether at −10°C (Scheme 3). As expected,
the reduction proceeded stereoselectively to afford a 93:7
mixture of the desired b-alcohol and its epimer 11 in 98%
yield. This high stereoselectivity would be explained by
the a-chelation as shown in Fig. 2. As separation of these
isomers was found to be difficult at this stage, 11
Scheme 3. (a) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt; (b) Zn(BH4)2, Et2O, −10°C; (c) p-TsCl, DMAP, Et3N, CH2Cl2,
0°C; (d) AcOH–H2O, rt; (e) NaOMe, MeOH, rt–50°C; (f) (MeO)2CMe2, CSA, CH2Cl2, rt; (g) MOMBr, i-Pr2NEt, CH2Cl2, rt; (h)
BzCl, pyridine, CH2Cl2, −20°C, and then MsCl; (i) aq. NaOH, MeOH–THF, −20–5°C; (j) TMSꢀLi, BF3·Et2O, THF, −78°C; (k)
K2CO3, MeOH, rt; (l) (Ph3P)2PdCl2, CuI, Et3N, rt; m) (Ph3P)3RhCl, H2, benzene–EtOH, rt; (n) 10% HCl–MeOH, CH2Cl2.

S. Takahashi et al. / Tetrahedron Letters 43 (2002) 8661–8664
8663
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Figure 2.
was transformed into a C-8 epimeric mixture of tetraols
4a via the corresponding monotosylates (97% yield).
Formation of the second ether-ring was achieved by
heating 4a with sodium methoxide (2.0 eq.) in methanol
at 50°C to provide the desired cyclic ether 12 in 78%
yield after isopropylidenation. The remaining task was
introduction of an ethynyl group through a stereoinver-
sion at the C-2 position. Prior to the transformation,
the 12-hydroxyl group was protected as a methoxy-
methyl (MOM) ether, and subsequent hydrolysis gave a
diol 13 in 89% yield. Successive treatment of 13 with
benzoyl chloride and methanesulfonyl chloride in pyri-
dine provided a mesyl benzoate. Exposure of the ben-
zoate to alkaline conditions led to an oxirane formation
to give 14 in 83% yield from 13. The epoxide 14 reacted
with lithium trimethylsilylacetylide in the presence of
BF3·E2O to produce a terminal acetylene 2 in 97% yield
after de-silylation (potassium carbonate, MeOH).
3. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K.
V.; MacDougal, J. M.; McLaughlin, J. L. J. Org.
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4. (a) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999,
40, 723–726 and 727–730; (b) Takahashi, S.; Nakata, T.
J. Org. Chem. 2002, 67, 5739–5752; (c) Takahashi, S.;
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2025–2028; (d) Takahashi, S.; Kubota, A.; Nakata, T.
Abstracts of Papers, 43rd Tennen Yuki Kagobutsu
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5. (a) Schaus, S. E.; Branalt, J.; Jacobsen, E. N.
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7. All new compounds have been fully characterized spec-
troscopically and the elemental composition established
by combustion analysis or high-resolution mass
spectroscopy.
The complete carbon skeleton of 1 was assembled by
joining 2 and 34d,12 under Hoye’s conditions,13 to give
enyne 15 in 79% yield. This underwent regioselective
reduction with Wilkinson’s catalyst to give a partially
protected muconin, in which all protecting groups were
subsequently cleaved by hydrogen chloride in
methanol–CH2Cl2 to give muconin (1).14 The spectro-
scopic and physical properties of 1 were identical those
of natural 1.
In summary, we have succeeded in a convergent synthe-
sis of 1 via successive ether-ring formation reaction
under acidic and basic conditions and stereoselective
reduction of acyclic ketone as the key steps.
8. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S.
Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc.
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9. The optical purity was determined to be >94% e.e. by
the 1H NMR analyses of the corresponding MTPA
esters.
Acknowledgements
10. Although this compound included a trace amount of
the diastereomers, undesired isomers could be separated
at a later stage (vide infra).
11. Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338–
344.
12. This compound was prepared from the corresponding
aldehyde through a vinyl iodide formation.15 For an
alternative synthesis of the aldehyde, see: Sinha, S. C.;
Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1997, 119, 12014–12015.
We are grateful to Dr. J. L. Mclaughlin for providing
us copies of the NMR spectra of natural muconin. We
also thank Ms. K. Harata (RIKEN) for mass spectral
measurements, and Dr. T. Chihara and his collabora-
tors in RIKEN for the elemental analyses.
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8664
S. Takahashi et al. / Tetrahedron Letters 43 (2002) 8661–8664
14. [h]2D3 +12.9° (c=0.21, CHCl3); IR (neat) 3421, 2925, 1755,
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;
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J=6.8 Hz), 2.30–2.62 (3H, m), 2.38 (1H, dd, J=15.1, 8.2
Hz), 2.51 (1H, ddd, J=15.1, 2.0, 1.5 Hz), 3.16 (1H, m),
3.30 (1H, m), 3.37 (1H, m), 3.42 (1H, m), 3.80 (1H, m),
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