Total synthesis of a cytotoxic acetogenin, pyranicin

Article abstract of DOI:10.1021/ol034323m

(Matrix presented) The first total synthesis of a new cytotoxic acetogenin, pyranicin (1), is described. Sml₂-induced reductive cyclization of β-alkoxy acrylate 4 proceeded stereoselectively to give 16,20-syn-19,20-trans-THP derivative 14, whic

Full text of DOI:10.1021/ol034323m

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1353-1356
Total Synthesis of a Cytotoxic
Acetogenin, Pyranicin
,†
,†,‡
Shunya Takahashi,* Akemi Kubota,‡ and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako,
Saitama 351-0198, Japan, and Graduate School of Science and Engineering,
Saitama UniVersity, Saitama, Saitama 338-8570, Japan
shunyat@postman.riken.go.jp; nakata@postman.riken.go.jp
Received February 24, 2003
ABSTRACT
The first total synthesis of a new cytotoxic acetogenin, pyranicin (1), is described. SmI2-induced reductive cyclization of â-alkoxy acrylate 4
proceeded stereoselectively to give 16,20-syn-19,20-trans-THP derivative 14, which was efficiently transformed into the 19,20-cis-THP derivative
18 through Mitsunobu lactonization. Wittig reaction of the phosphonium salt 2 obtained therefrom with butenolide 3 at −78 °C followed by
reduction and deprotection afforded 1 in good overall yield.
Annonaceous acetogenins are a relatively new class of natural
polyketides which have promising anticancer, antiinfective,
immunosuppressive, pesticidal, and antifeedant properties.1
On the basis of the number of tetrahydrofuran (THF) rings
within the molecule and their connection patterns, these
natural products have been classified into three major
groups: mono-THF, adjacent bis-THF, and nonadjacent bis-
THF subclasses. Their structural diversity and remarkable
biological activities have attracted much attention of synthetic
organic chemists.2
(1), which was isolated from the stem bark of Goniothalamus
giganteus Hook. f. & Thomas (Annonaceae), is the first
mono-THP acetogenin.4 Structurally, 1 is related to substi-
tuted THP acetogenin such as mucocin and jimenejin,
differing remarkably in the absolute configuration of the THP
moiety and the presence of an axial hydroxyl group on the
THP ring. The acetogenin 1 was quite active in the BST
assay5 and showed selective inhibitory effects against
PACA-2 (pancreatic cancer) cell lines with potency 10 times
that of adriamycin. Recently, we have been engaged in
synthetic studies on the THP-acetogenins, resulting in the
total synthesis of mucocin, jimenezin, and muconin.6 As part
of our continuing studies in this field, we describe herein
the first total synthesis of 1 in a stereocontrolled manner.
Our retrosynthetic analysis of 1 is illustrated in Scheme
1. Thus, 1 would be synthesized by Wittig reaction of a
phosphonium salt 2 with an aldehyde 3.7,6f Construction of
Recently, several new types of acetogenins bearing a
tetrahydropyran (THP) ring have been discovered.3 Pyranicin
† RIKEN.
‡ Saitama University.
(1) For recent reviews see: (a) Zafra-Polo, M. C.; Gonzalez, M. C.;
Estornell, E.; Sahpaz, S.; Cortes, D. Phytochemistry 1996, 42, 253-271.
(b) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275-306. (c) Zafra-Polo, M.
C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
1998, 48, 1087-1117. (d) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J.
Nat. Prod. 1999, 62, 504-540 and references therein.
(2) For recent total synthesis, see: (a) Harcken, C.; Bruckner, R. New J.
Chem. 2001, 40-54. (b) Hu, T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J. Org.
Chem. 2001, 66, 853-861. (c) Maezaki, N.; Kojima, N.; Sakamoto, A.;
Iwata, C.; Tanaka, T. Org. Lett. 2001, 3, 429-432. (d) Burke, S. D.; Jiang,
L. Org. Lett. 2001, 3, 1953-1955. (e) Dixon, D. J.; Ley, S. V.; Reynolds,
D. J. Chem. Eur. J. 2002, 8, 1621-1636. (f) Makabe, H.; Hattori, Y.;
Tanaka, A.; Oritani, T. Org. Lett. 2002, 4, 1083-1085 and references
therein.
(3) (a) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Zhao,
G.-X.; He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc.
1995, 117, 10409-10410. (b) Shi, G.; Kozlowski, J. F.; Schwedler, J. T.;
Wood, K. V.; MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996,
61, 7988-7989. (a) Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod.
1998, 61, 419-421
(4) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833-5844.
(5) Alali, F.; Zeng, L.; Zhang, Y.; Ye, Q.; Hopp, D. C.; Schewedler, J.
McLaughlin J. L. Bioorg. Med. Chem. 1997, 5, 549-555.
10.1021/ol034323m CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003

Scheme 1
Scheme 2a
the 16,20-syn-19,20-cis-THP ring system in 2 would be
achieved by SmI2-induced reductive cyclization8 of â-alkoxy
acrylate 4 having a formyl group followed by stereoinversion
at the C-19 position. The acrylate 4 should be prepared
through a two-directional chain extension of 2,3-O-isopro-
pylidene-D-threitol (5) reported by Kotsuki et al.9 For this
purpose, allylmagnesium bromide and chiral acetylene 610,11
were designed as synthons for the chains.
a Reagents and conditions: (a) TBDMSCl, NaH, DME, THF, 0
°C to room temperature, 90%; (b) Tf2O, Et3N, CH2Cl2, -15 °C;
(c) 6, n-BuLi, DMPU, THF, -15 °C; (d) TBAF, THF, room
temperature, 70% (three steps from 7); (e) (Ph3P)3RhCl, H2,
benzene, room temperature, 95%; (f) allylMgBr, CuBr, Et2O, -15
°C to room temperature, 74% (two steps); (g) OsO4, NaIO4, THF/
H2O, room temperature; (h) CSA, CH(OMe)3, MeOH, 0 °C, 76%
(two steps); (i) BnBr, NaH, Bu4NI, DMF, 0 °C to room temperature,
98%; (j) 1,3-propanedithiol, Zn(OTf)2, (CH2Cl)2, 50 °C, 97%; (k)
ethylpropiolate, N-methylmorpholine, CH2Cl2, room temperature,
94%; (l) MeI, NaHCO3, CH3CN/H2O, 0 °C to room temperature,
92%; (m) SmI2, MeOH, THF, 0 °C, 95%.
Synthesis of 2 began with triflation12 of threitol derivative
7 (Scheme 2).13 The resulting triflate 8 was coupled with a
lithium acetylide derived from terminal acetylene 6 in the
(6) (a) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 723-726.
(b) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 727-730. (c)
Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025-
2028. (d) Takahashi, S.; Fujisawa, K.; Sakairi, N.; Nakata, T. Heterocycles
2000, 53, 1361-1370. (e) Takahashi, S.; Nakata, T. J. Org. Chem. 2002,
67, 5739-5752. (f) Takahashi, S.; Kubota, A.; Nakata, Angew. Chem., Int.
Ed. 2002, 41, 4751-4754 (g) Takahashi, S.; Kubota, A.; Nakata, T.
Tetrahedron Lett. 2002, 43, 8661-8664. (h) Takahashi, S.; Kubota, A.;
Nakata, T. Tetrahedron 2003, 59, 1627-1638.
presence of N,N′-dimethylpropyleneurea (DMPU),9b and
subsequent de-silylation with TBAF afforded alcohol 9 in
70% overall yield from 7. Reduction of the triple bond in 9
was performed by using the Wilkinson catalyst (5.0 mol %)
in benzene to give saturated compound 10 in 95% yield. The
alcohol 10 was, again, converted into the corresponding
triflate, which reacted with allylmagnesium bromide in the
presence of cuprous bromide in ether to give a terminal olefin
1114 in 74% yield from 10. For introduction of the â-alkoxy
acrylate residue into the C-16 position of 11, discrimination
of two oxygen functions at the C-15 and 16 positions was
needed. Therefore, olefin 11 was oxidized under Lemieux-
Johnson conditions and then treated with CSA and HC-
(7) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1997, 119, 12014-12015.
(8) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811-2814. (b) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron
Lett. 1999, 40, 8859-8863. (c) Hori, N.; Matsukura, H.; Nakata, T. Org.
Lett. 1999, 1, 1099-1101. (d) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata,
T. Tetrahedron 2002, 58, 1853-1864. (e) Matsuo, G.; Kadohama, H.;
Nakata, T. Chem. Lett. 2002, 148-149.
(9) (a) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55, 4417-
4422. (b) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 32,
4609-4612.
(10) This compound was prepared from (R)-1,2-anhydro-4-O-benzylbu-
tane-1,2,4-triol11 in three steps as follows: (i) lithium (trimethylsilyl)-
acetylide, BF3‚Et2O, THF, -78 °C; (ii) K2CO3, MeOH, room temperature,
91% (two steps); (iii) BnBr, NaH, n-Bu4NI, DMF, 0 °C, 99%.
(11) Nakata, T.; Suenaga, T.; Oishi, T. Tetrahedron Lett. 1989, 30, 6525-
6528.
(13) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52,
3337-3342.
(14) Attempts for a one-pot double alkylation into the tosyltriflate of 5
gave unsatisfactory results.
(12) Mukai, C.; Kim, J. S.; Uchiyama, M.; Sakamoto, S.; Hanaoka, M.
J. Chem. Soc., Perkin Trans. 1 1998, 2903-2915.
1354
Org. Lett., Vol. 5, No. 8, 2003

Scheme 3a
a Reagents and conditions: (a) 5%NaOH, EtOH, room temperature, 97%; (b) PPh3, DEAD, THF, 0 °C, 92%; (c) DIBAL, CH2Cl2, -78
°C; (d) C10H21PPh3Br, n-BuLi, THF, -15 °C, 87% (two steps from 16); (e) MOMBr, i-Pr2NEt, (CH2Cl)2, 0-50 °C; (f) 10% Pd/C, H2,
EtOH, room temperature, 89% (two steps from 17); (g) Ac2O, DMAP, pyridine, room temperature (quant); (h) TBDPSCl, i-Pr2NEt, CH2Cl2,
room temperature, 97%; (i) TBAF, THF, room temperature, 97% (two steps from 19); (j) I2, PPh3, imidazole, benzene, 0 °C, 98%; (k)
PPh3, CH3CN, 60 °C, 93%; (l) 3, NaHMDS, THF, -78 °C, 69%; (m) (Ph3P)3RhCl, H2, benzene, room temperature, 88%; (n) HCl-MeOH,
CH2Cl2, room temperature, 95%; (o) (R)- or (S)-MTPACl, DMAP, Et3N, CH2Cl2, room temperature.
(OMe)3 in methanol to provide acetal 12 in 76% yield. After
benzylation of 12, the benzyl ether was subjected to
transacetalization15 to give thioacetal 13 in 97% yield. Oxy-
Michael addition of 13 to ethyl propiolate followed by de-
thioacetalization afforded the key intermediate 4 in 86%
yield. SmI2-induced reductive cyclization of 4 was effected
by treatment with 3.5 equiv of SmI2 in the presence of
methanol (4.4 equiv) in THF at 0 °C to give a 16,20-cis-
19,20-anti-THP derivative 14 in 95% yield. The stereochem-
istry around the THP ring system was established by the
NMR analyses including NOE experiments. Thus, irradiation
of H20 results in enhancement of the H16 peak. In the 1H NMR
(C6D6) spectra of 14, the signal corresponding to the proton
of C-19 was observed at 3.09 ppm as triplets of doublet
(J19,20) 9.2 Hz). These data are consistent with the proposed
structure for 14. The high stereoselectivity would be ex-
plained by the transition state via a cyclic chelate.6f
lyzed under basic conditions, giving carboxylic acid 15 in
97% yield. Treatment of this with diethyl azodicarboxylate
in the presence of Ph3P led to formation of a γ-lactone ring,
affording bicyclic compound 16 in 92% yield. After DIBAL
reduction of 16, the resulting hemiacetal underwent Wittig
reaction to give olefin 17 in 87% yield. Methoxymethylation
of 17 and subsequent hydrogenation provided triol 18 in 89%
yield from 17. The stereochemistry of the C-19 position in
1
18 was confirmed mainly by H NMR analyses of the
triacetate 18a including decoupling experiments; the spec-
trum of 18a revealed the C-19 proton at δ 3.40 as a broad
singlet (WH ) 6.0 Hz) and the C-20 proton at δ 3.27 as a
broad doublet of doublets with J20,21 ) 8.7 Hz and J20,21′
)
4.4 Hz. The small coupling constant of the protons at C-19
and 20 indicates the presence of an axially oriented meth-
oxymethoxy group in the THP ring of 18a.
Direct iodination of 18 followed by methoxymethylation
(methylal-phosphorus pentaoxide) furnished iodide 21 in a
low yield (31%). Therefore, a stepwise procedure was
adopted for preparation of 21. The primary hydroxyl group
in 18 was temporarily protected to give silyl ether 19 in 97%
yield. Hydroxy protection-deprotection sequence to 19
provided alcohol 20 in 97% yield. Iodination of 20 proceeded
As we could secure the key intermediate in high yield,
our attention was then turned to stereoinversion at the C-19
position (Scheme 3). To accomplish the transformation
efficiently, we planned utilization of Mitsunobu lactoniza-
tion.16 Prior to the transformation, the ester 14 was hydro-
(15) Corey, E. J. Shimoji, K. K. Tetrahedron Lett. 1983, 24, 1289-
1292.
(16) Mitsunobu, O. Synthesis 1981, 1-28.
Org. Lett., Vol. 5, No. 8, 2003
1355

nicely to give the desired iodide 21 in 98% yield. Preparation
of the phosphonium salt 2 from 21 was accomplished by
heating the latter with 2.0 equiv of triphenylphosphine in
acetonitrile at 60 °C, giving the phosphonium salt 2 in high
yield.
optical rotation of natural product was measured at very low
concentration, the difference may be due to experimental
error or the presence of impurities.19 To clarify this, a direct
comparison of our synthetic sample with the authentic natural
product would be necessary.20
In summary, we have succeeded in a convergent synthesis
of 1 employing SmI2-induced radical cyclization reaction of
4 and coupling reaction between 2 and 3 as the key steps.
This procedure would also be useful for preparation of a
variety of analogues of 1.
Construction of the complete carbon skeleton of 1 relied
on the Wittig reaction as follows. Generation of the Wittig
reagent derived from 1.0 equiv of 2 and 0.95 equiv of sodium
hexamethyldisilazide in THF at 0 °C followed by addition
of 3 at -78 °C cleanly provided a coupling product 22 in
69% yield. The reaction at higher temperature (-20 to 0
°C) caused destruction, giving 22 in a low yield (∼35%).
Finally, hydrogenation of 22 using the Wilkinson catalyst
afforded a fully protected pyranicin 23 in which all the
hydroxy protecting groups were removed by HCl in MeOH-
CH2Cl2 to produce pyranicin 1 (mp 82-83 °C)17 in high
Acknowledgment. We are grateful to Dr. J. L. McLaugh-
lin (Purdue University) for providing us copies of the NMR
spectra of natural pyranicin. We also express our thanks to
Dr. H. Koshino for measurement of 2D-NMR spectra, Ms.
K. Harata for mass spectral measurements, and Dr. T.
Chihara and his staff in RIKEN for the elemental analyses.
1
yield. H and 13C NMR spectral data of synthetic 1 were
Supporting Information Available: Physical and spec-
troscopic data for compounds 1, 2, 4, 6, and 9-23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
identical with those of the natural product. On the other hand,
their specific optical rotations showed sharp contrast. While
synthetic 1 showed [R]24D +19.5 (c 0.55, CHCl3), the [R]23
D
value of natural 1 was reported to be -9.7 (c 0.008, CHCl3).
The discrepancy suggested synthetic 1 to be an enantiomer
of the natural product. Therefore, we prepared the corre-
sponding MTPA esters (24 and 25) from synthetic 1 and
carried out extensive NMR analyses. Consequently, NMR
data of the corresponding MTPA esters (24 and 25) were
revealed to be well matched with those reported.18 These
results made us conclude that synthetic 1 should not be an
enantiomer of natural product. Taking into account that the
OL034323M
(18) Differences in the chemical shifts (∆δ) between 24 and 25 are as
follows: H2-3 (-0.03, -0.07), H2-5 (+0.04, +0.05), H2-6 (+0.10), H2-14
(+0.08, +0.08), H-16 (-0.03), H2-17 (+0.10, +0.29), H2-18 (+0.01,
+0.01), H-20 (-0.07), H2-21 (-0.19, -0.20), H-33 (-0.23), H-34 (-0.04),
H-35 (-0.02).
(19) The discrepancy with the optical rotation value of synthetic product
with that reported for the natural product has been reported so far: (a)
Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067-7073.
(b) ref 2c.
(20) Natural pyranicin was unavailable (personal communication by Dr.
McLaughlin).
(17) The melting point of natural 1 is not denoted.
1356
Org. Lett., Vol. 5, No. 8, 2003