Structural determination of montanacin D by total synthesis

Article abstract of DOI:10.1021/ol801576z

(Chemical Equation Presented) The first total syntheses of acetogenin 3 and its 4S,8R-isomer are described. The key step involves intermolecular metathesis of an α,β-unsaturated ketone carrying a tetrahydropyranyl lactone with a tetrahydrofuran derivative

Full text of DOI:10.1021/ol801576z

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4223-4226
Structural Determination of Montanacin
D by Total Synthesis
Shunya Takahashi,* Yayoi Hongo, Yuki Tsukagoshi, and Hiroyuki Koshino
RIKEN (The Institute of Physical and Chemical Research), Wako,
Saitama 351-0198, Japan
shunyat@riken.go.jp
Received July 11, 2008
ABSTRACT
The first total syntheses of acetogenin 3 and its 4S,8R-isomer are described. The key step involves intermolecular metathesis of an r,ꢀ-
unsaturated ketone carrying a tetrahydropyranyl lactone with a tetrahydrofuran derivative. Compound 3 has spectroscopic and physical data
consistent with those of natural montanacin D, suggesting that the absolute configuration of the natural product is as shown in 3.
The Annonaceous acetogenins from the Annonaceae plants
comprise a class of almost 400 natural products that exhibit
a remarkably broad spectrum of biological properties such
as anticancer, antiinfective, immunosuppressive, pesticidal,
and antifeedant activities.1 Structurally, most of these
compounds belong to several classic types with an unsub-
stituted tetrahydrofuran (THF) ring: the mono-THF, the
adjacent bis-THF, and the nonadjacent bis-THF acetogenins.
Recently, several nonclassical acetogenins have been dis-
covered bearing a tetrahydropyran (THP) ring.2
THF ring (Figure 1).4 However, the absolute configuration
of the THP ring part was not determined. Unlike the other
In 1999, Qin and Cheng et al. isolated montanacin D from
the ethanolic extract of the leaves of Annona montana.3 The
structure was elucidated by chemical and spectral means to
be 1 possessing a 4,8-cis THP ring along with a 16,19-trans
Figure 1. Proposed structure of montanacin D.
approximately 420 acetogenins, the presence of the THP ring
adjacent to the butenolide moiety in 1 provides a confor-
(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 cited therein.
(3) (a) Wang, L.-Q.; Zhao, W.-M.; Qin, G.-W.; Cheng, K.-F.; Yang,
R.-Z. Nat. Prod. Lett. 1999, 14, 83–90. (b) Wang, L.-Q.; Nakamura, N.;
Meselhy, M. R.; Hattori, M.; Zhao, W.-M.; Cheng, K.-F.; Yang, R.-Z.; Qin,
G.-W. Chem. Pharm. Bull. 2000, 48, 1109–1113.
(4) For recent syntheses of THP-THF acetogenins, see: (a) Evans, P. A.;
Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc.
2003, 125, 14702–14703. (b) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J.
Org. Chem. 2004, 69, 1993–1998. (c) Zhu, L.; Mootoo, D. R. Org. Biomol.
Chem. 2005, 3, 2750–2754. (d) Hwang, C. H.; Keum, G.; Sohn, K.; Lee,
D. H.; Lee, E. Tetrahedron Lett. 2005, 46, 6621–6623. (e) Crimmins, M. T.;
Zhang, Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369–2372. (f) Bandur, N. G.;
Bru¨ckner, D.; Hoffmann, R. W.; Koert, U. Org. Lett. 2006, 8, 3829–3831.
(g) Criso´stomo, F. R. P.; Carrillo, R.; Leo´n, L. G.; Mart´ın, T.; Padro´n, J. M.;
Mart´ın, V. S. J. Org. Chem. 2006, 71, 2339–2345.
(2) (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. (c) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L.
Tetrahedron 1998, 54, 5833–5844. (d) Chavez, D.; Acevedo, L. A.; Mata,
R. J. Nat. Prod. 1998, 61, 419–421. (e) Fall, D.; Duval, R. A.; Gleye, C.;
Laurens, A.; Hocquemiller, R. J. Nat. Prod. 2004, 67, 1041–1043.
10.1021/ol801576z CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

mational rigidity around the lactone ring, an essential domain
for several biological activities.1d Therefore, compound 1 is
regarded as a unique member of this family and is expected
to have interesting activity. Recently, we have been engaged
in synthetic studies on THP-acetogenins, resulting in the total
synthesis of mucocin, jimenezin, muconin, pyranicin, and
pyragonicin.5 As part of our continuing studies in this field,
we describe herein the structural determination of montanacin
D by total synthesis of (4R,8S)-montanacin D (3) and its
4S,8R-isomer 27 and a comparison of their analytical data
with those reported for montanacin D.
tathesis6 of olefin 47 and enone 5 as illustrated in Scheme 1.
The latter might be prepared from γ-lactone 69 and THP
derivative 7. The THP core in 7 would be constructed by an
intramolecular oxy-Michael addition of R,ꢀ-unsaturated ester
8 having a hydroxyl group. To synthesize 8, we selected
chiral alcohol 9 as the starting material. As 9 and ent-9 are
commercially available compounds, this strategy enabled us
to prepare both enantiomers of a THP compound such as 7
easily.
Synthesis of 3 began with allylation of the tosylate10
obtained from 9 (Scheme 2). The resulting olefin 10 was
Along with montanacin D, montanacin B (2)3 was also
isolated from the same origin by the same authors (Scheme
1). This report prompted us to suppose that montanacin D
Scheme 2
Scheme 1
might be biosynthetically obtained through ꢀ-elimination of
the C-8 hydroxyl group of 2 followed by oxy-Michael
addition of the 4-OH to the resulting olefin. Hence, we
initially started synthesis of 3 with the stereochemistry of
4R,8S. Our synthetic strategy directed toward 3 was based
on a convergent process that involved intermolecular me-
ozonolized and then subjected to Wittig-Horner-Emmons
reaction to give E-olefin 11. Acid hydrolysis of 11 furnished
diol 12. Cyclization of 12 with NaH at rt for 1.5 h resulted
in the stereoselective formation of cis-isomer 15, but partial
hydrolysis of the ester moiety decreased the yield of 15
(∼50%). The stereochemistry was established by the NMR
analyses including NOE experiments. Thus, irradiation of
H8 results in enhancement of the H4 peak.11 In the 1H NMR
(5) (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, T. 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. (i) Takahashi, S.; Kubota,
A.; Nakata, T. Org. Lett. 2003, 6, 1353–1356. (j) Takahashi, S.; Ogawa,
N.; Koshino, H.; Nakata, T. Org. Lett. 2005, 7, 2783–2786. (k) Takahashi,
S.; Hongo, Y.; Ogawa, N.; Koshino, H.; Nakata, T. J. Org. Chem. 2006,
71, 6305–6308.
(6) Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH: Weinheim,
2003; Vols. 1-3.
(7) This was prepared from a known lactone 198 in three steps (vide
infra).
(8) Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 119, 4891–4892.
(9) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991–4998.
(10) Koert, U.; Wagner, H.; Pidun, U. Ber. Chem. 1994, 127, 1447–
1457.
(11) The numbering system in ref 3 was adopted.
4224
Org. Lett., Vol. 10, No. 19, 2008

Scheme 3
(CDCl3) spectrum of 15, the signal corresponding to the
The left-half-segment 4 was prepared from the known
lactone 19 in three steps: (1) DIBALH reduction of 19, (2)
Wittig reaction, and (3) silylation of 20 (Scheme 3).
Intermolecular olefin metathesis of 4 with the major lactone
5b in the presence of Grubbs second generation catalyst
proceeded nicely to give E-olefin 22 in 84% yield. The
coupling reaction of TBS ether 18 or its corresponding
alcohol with 4 gave unsatisfactory results. Hydrogenation
of the enone moiety in 22 was achieved by using PtO2 in
THF to afford saturated ketone 25 in 82% yield. Oxidation
of the phenyl sulfide moiety with m-CPBA followed by
thermolysis and a final deprotection provided the target
molecule 3 in 83% overall yield. Similarly, minor isomer
5a was smoothly coupled with 4, affording 21 (82%). The
enone 21 was hydrogenated and the resulting ketone 24 was
transformed into 3 in good overall yield. The physical and
proton of C-8 was observed at 3.80 ppm as a doublet of
doublet of doublets (J7,8 ) 11.1 Hz). These data are consistent
with the proposed structure for 15. In a similar oxy-Michael
reaction, Banwell et al.12 conducted re-esterification of crude
products after cyclization reaction to recover the desired ester.
Thus, we introduced a triisopropylsilyl group into the primary
OH in 12 in order to suppress the hydrolysis by neighboring
group participation and examined the cyclization. Brief
treatment (5 min) of silyl ether 8 with t-BuOK (0.25 molar
equiv) in toluene at 0 °C afforded trans-isomer 13 stereo-
selectively (13/14 ) 70/30),13 while on exposure of 8 to the
base for a longer period of time (3 h), the thermodynamic
isomer 14 became more prominent (13/14 ) 3/97).14 The
isomers could be separated by chromatography on silica gel,
and the stereochemistries were confirmed by 1H NMR
analyses including NOE experiments.15 The cis-isomer 14
thus obtained was reduced with DIBALH and then alkylated
with vinylmagnesium chloride to give alcohol 16 as a
diastereomeric mixture (ca. 1:1). Upon treatment with TBAF,
16 led to diol 17. This was treated successively with triflic
anhydride and TBDMSOTf in the presence of 2,6-lutidine
at -78 f 0 °C to afford unstable triflate 7, which reacted
with the sodium enolate derived from 6, giving lactone 18.
Desilylation of 18 and oxidation provided 2S-lactone 5b and
2R-isomer 5a after chromatography on silica gel (5a/5b )
ca. 1/4).16
18
spectral data ([R]D, H and 13C NMR) of 3 were well
matched with those of natural montanacin D. The THP core
is located apart from the other stereogenic regions so that
the effect of this domain on the chemical shift seemed to be
small in the NMR spectra. Hence, for unambiguous estab-
lishment of the structure of montanacin D, the data of 4S,8R-
isomer 27 was also required.
1
In a similar manner, enone 5c19 was prepared from ent-
diol 17 in 36% overall yield. Cross-metathesis of 5c with 4
afforded 23, which was reduced to give 26 in 62% yield
(2 steps). Finally, butenolide formation in 26 and desilylation
(12) Banwell, M. G.; Bui, C. T.; Simpson, G. W. J. Chem. Soc., Perkin
Trans. 1 1998, 791–799.
1
(13) The ratio was determined by H NMR analysis.
(14) For an example of oxy-Michael cyclization by using NaH as a base,
see: Edmunds, A. J. F.; Trueb, W. Tetrahedron Lett. 1997, 38, 1009–1012.
(15) Irradiation of CHCO2Et in 13 caused an NOE of the proton at the
C-4 position. In 14, a strong NOE was observed for the signal of H8 upon
irradiation of H4.
(17) Sinha, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem.
1999, 64, 2381–2386, references cited therein.
(18) Physical and spectroscopic data for 3: [R]24 ) +14.3 (c 0.12,
D
MeOH); 13C NMR (150 MHz, CDCl3) δ 209.29, 174.14, 151.27, 130.57,
82.70, 82.53, 77.78, 75.59, 74.05, 74.03, 73.72, 49.13, 43.78, 33.49, 33.26,
31.91, 31.78, 31.15, 31.06, 29.70, 29.66, 29.64, 29.63, 29.61, 29.58, 29.34,
28.71, 28.70, 25.60, 25.20, 23.54, 23.28, 22.67, 19.09, 14.10.
(19) This compound was obtained as an inseparable mixture of diaster-
eomers with regard to the SPh group.
(16) The stereochemistries of each were deduced by the 1H NMR
analyses. In the 1H NMR spectra, the methyl group of 5b was observed at
δ 1.16 (d, J ) 6.3 Hz) while the minor isomer 5a showed a doublet at 1.39
ppm. The data were consistent with those reported in the literature.8,17
Org. Lett., Vol. 10, No. 19, 2008
4225

1
Table 1. Selected H NMR data (δ) for Natural Compound, 3, 27, and Their MTPA Esters
(S)-MTPA ester
(R)-MTPA ester
position
natural
3
27
2.36 (m)b
3.56 (m)
3.82 (m)
2.63 (dd, 15.9, 8.8)
2.37 (dd, 15.9, 3.3)
2.41 (t, 7.2)
1.39 (m)
natural
28
30
natural
29
31
3
4
8
9
2.36 (d, 6.0)a
3.59 (m)
3.85 (m)
2.63 (dd, 15.0, 9.0)
2.41 (dd, 15.0, 6.6)
2.37 (m)
2.35 (m)b
3.58 (m)
3.82 (m)
3.566
3.818
2.600
2.360
3.570
3.810
2.600
2.340
3.561
3.810
2.603
2.355
3.564
3.813
2.589
2.342
3.568
3.809
2.587
2.340
3.557
3.805
2.590
2.337
2.62 (dd, 15.9, 8.8)
2.37 (dd, 15.9, 3.9)
2.41 (t, 7.2)
1.39 (m)
11
14
1.40 (m)
1.562
1.580
1.580
1.519
1.530
1.530
15
3.40 (m)
3.38 (m)
3.38 (m)
16
17,18
3.80 (m)
3.79 (m)
3.79 (m)
3.918
1.650
1.382
3.918
3.919
1.650
1.370
3.919
3.918
1.650
1.370
3.918
3.998
1.890
1.560
3.998
3.999
1.910
1.570
3.999
4.001
1.920
1.560
4.001
19
20
21
32
33
34
35
3.80 (m)
3.40 (m)
1.40 (m)
0.88 (t, 7.0)
7.14 (d, 1.6)
4.99 (dq, 6.8, 1.6)
1.41 (d, 6.8)
3.79 (m)
3.40 (m)
1.39 (m)
0.87 (t, 6.9)
7.14 (m)
3.79 (m)
3.40 (m)
1.39 (m)
0.87 (t, 7.1)
7.17 (m)
1.562
1.540
1.550
1.519
1.530
1.530
7.136c
4.962c
1.390c
7.130
4.954
1.384
7.149
4.958
1.360
7.132c
4.959c
1.390c
7.126
4.959
1.384
7.154
4.959
1.364
4.98 (brq, 6.6)
1.40 (d, 6.6)
4.98 (brq, 6.6)
1.38 (d, 6.6)
a 500 MHz. b 600 MHz. c Obtained from the copies of the original NMR spectra kindly provided by Prof. Qin.
yielded the second target 27 (78% yield).20 The spectroscopic
and physical properties of the synthetic material 27 were
found to differ from those of natural montanacin D. In
particular, the specific rotation of 27 [[R]24D ) +26.9 (c 0.12,
MeOH)] was higher than the reported value of natural
montanacin D [[R]25D ) +12.4 (c 0.1, MeOH)]. In addition,
the synthetic product 27 contained three signals at δ 1.38
(H-35), 3.56 (H-4), and 7.17 (H-33), which were observed
of these synthetic studies, we concluded that the structure
of natural montanacin D is 3.
In summary, we succeeded in a convergent synthesis of
two possible isomers proposed to montanacin D based on
cross-metathesis as a key step, showing that the structure of
natural montanacin D is 3 not 27.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture of Japan and in part by
the Chemical Genomics Project (RIKEN). We are grateful
to Prof. G.-W. Qin (Shanghai Institute of Materia Medica)
and Prof. M. Hattori at Toyama University for providing us
copies of the original spectra of natural montanacin D and
the MTPA esters.
1
at 1.41, 3.59, and 7.14 ppm, respectively, in the H NMR
spectrum of the natural product (Table 1).
We also prepared MTPA esters of 3 and 27 and carried
out extensive NMR analyses of the compounds 28-31. Table
1
1 lists the comparisons of H NMR data. In analogy with
the case of OH-free compounds, we found that the data from
MTPA derivatives of 3 closely resembled those of natural
montanacin D. In contrast, the two signals for H-33 and -35
of the synthetic materials 30 and 31 deviated by 0.01-0.03
ppm compared to the respective signals of the natural
Supporting Information Available: Experimental pro-
cedures, NMR spectra of 3-5c, 8, 10-18, and 20-31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
21
1
compounds in the H NMR spectra. Based on the results
(20) Spectroscopic data for 27: 13C NMR (150 MHz, CDCl3) δ 209.27,
174.15, 151.43, 130.55, 82.69, 82.51, 77.76, 75.66, 74.02, 73.97, 73.69,
49.17, 43.70, 33.48, 33.23, 31.90, 31.74, 31.17, 31.05, 29.70, 29.66, 29.64,
29.63, 29.61, 29.58, 29.34, 28.70, 25.59, 25.19, 23.50, 23.28, 22.67, 19.03,
14.10.
OL801576Z
(21) The difference seemed to be due to the THP ring not flanking both
MTPA esters since the butenolide unit and the THF region are separated
by a long carbon chain.
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