Synthesis of two possible diastereomers of reticulatain-1

Article abstract of DOI:10.1016/j.tetlet.2003.11.109

A convergent synthesis of two possible diastereomers of reticulatain-1 (1a and 1b) was accomplished. Comparison of the specific optical rotations of 1a and 1b did not allow for the strict determination of the absolute configuration. However, bis-(R)-MTPA

Full text of DOI:10.1016/j.tetlet.2003.11.109

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 973–977
Synthesis of two possible diastereomers of reticulatain-1
Hidefumi Makabe,a,* Aya Miyawaki,a Ryoko Takahashi,a Yasunao Hattori,a
Hiroyuki Konno,b Masato Abec and Hideto Miyoshic
aSciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minami-minowa, Kamiina,
Nagano 399-4598, Japan
bDepartment of Biological Science and Technology, Faculty of Engineering University of Tokushima, 2-1 Minamijosanjimacho,
Tokushima 770-8506, Japan
cDivision of Applied Sciences, Graduate School of Agriculture, Kyoto University, Kita-shirakawa, Sakyo-ku, Kyoto 606-8502, Japan
Received 25 September 2003; revised 20 November 2003; accepted 21 November 2003
Abstract—A convergent synthesis of two possible diastereomers of reticulatain-1 (1a and 1b) was accomplished. Comparison of the
specific optical rotations of 1a and 1b did not allow for the strict determination of the absolute configuration. However, bis-(R)-
MTPA esters of 1a and 1b showed a clear difference in chemical shifts in the 1H NMR spectra. If the bis-(R)-MTPA ester of natural
reticulatain-1 (1) is available, the absolute configuration of 1 will be determined. Inhibitory action of these compounds was
examined with bovine heart mitochondrial complex I. Both compounds showed almost the same activity.
Ó 2003 Elsevier Ltd. All rights reserved.
Annonaceous acetogenins, that have been isolated from a
number of tropical or subtropical plants of the Annona-
ceae, have attracted much attention due to a wide
variety of biological activities, for example, cytotoxic,
antitumoral, antimalarial, antibiotic, antiparasitic, and
antifeedant. So far, more than 350 compounds have
been isolated.1 Most of them possess one or more tetra-
hydrofuran (THF) rings, together with an a,b-unsatu-
rated c-lactone part on a C-35 or C-37 carbon chain.
Reticulatain-1 (1) is a mono-THF acetogenin,2 isolated
from Annona reticulata in 1995.3 A similar compound
corresponding to the well-known reticulatacin (2)4 was
synthesized by Keinan5 and us.6 The absolute configu-
ration of natural 1 has not been reported yet. However,
because the erythro-trans-threo stereochemistry of the
trans
O
O
erythro
C12H25
threo
O
OH
OH
reticulatain-1 (1)
21
18
21
18
O
O
17
22
22
17
OH
OH
OH
OH
1a
1b
O
O
C
12H25
O
reticulatacin (2)
OH
OH
OH
trans
OH
O
O
threo
C12H25
tetrahydrofuran ring of 1 has been determined by
3
Figadere et al., and the (S) configuration of the sec-
threo
ꢀ
O
ondary methyl group of the c-lactone moiety is well
known, it follows that the absolute stereochemistry of 1
is (17R,18R,21R,22S) or (17S,18S,21S,22R) (Fig. 1).
(8'R)-corossoline (3)
OH
Figure 1. The structure of reticulatain-1.
The two possible structures, 1a and 1b, would be very
difficult to differentiate by 1H NMR or 13C NMR
spectroscopic data, because two stereogenic centers, that
is, the THF ring part and the c-lactone moiety are
separated by a long carbon chain. In a previous paper,
we prepared chiral building block 4 for synthesizing
(80R)-corossoline (3), mono-THF acetogenins, which
possess the threo-trans-threo stereochemistry of the
Keywords: Annonaceous acetogenin; Antitumor; Mitochondrial com-
plex I.
* Corresponding author. Tel.: +81-265-77-1630; fax: +81-265-77-1700;
e-mail: makabeh@gipmc.shinshu-u.ac.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.109

974
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
Ref. 7
AD mix β
+
C12H25
OH
C12H25MgBr
CHO
O
Ref. 7
Ref. 7
3
C
12H25
O
C12H25
OMOM
OMOM
O
O
5
OH
O
C12H25
4
C
12H25
O
O
O
Mitsunobu Inversion
and Hydrolysis
OH
O
OMOM
7a
OMOM
6
I
C12H25
O
+
O
O
OMOM
OMOM
8
7a
trans
O
O
erythro
C12H25
threo
O
OH
OH
1a
Scheme 1. Synthetic strategy of reticulatain-1.
tetrahydrofuran ring. In this paper, we prepared another
chiral building block 6 for synthesizing mono-THF
acetogenins, which possess erythro-trans-threo stereo-
chemistry by using the Mitsunobu inversion from 4
(Scheme 1). To utilize this methodology, we planned to
synthesize two candidates of reticulatain-1 (1), 1a and 1b.
acrolein and laurylmagnesium bromide. Grignard reac-
tion of acrolein with laurylmagnesium bromide gave
allylic alcohol 9. Johnson–Claisen rearrangement with
1,1,1-triethoxyethane and a catalytic amount of prop-
ionic acid gave ester 10, which was then submitted to
reduction with diisobutylaluminum hydride (DIBALH)
to afford 11. The conversion of compound 11 to 4 was
performed using the Sharpless epoxidation and dihydr-
oxylation according to our previously published method.7
As shown in Scheme 2, the THF part 15 of 1a was
constructed via a multi-step process starting from
OH
a
c
b
CO2Et
CHO
C12H25
C12H25
10
acrolein
9
Ref. 7
d
C12H25
C
12H25
O
O
O
C12H25
OH
O
O-p-NBA
O
OH
f
O
4
11
12
C
12H25
C12H25
g
e
O
O
O
O
OH
OH
O
OMOM
13
O
6
h
i
C
12H25
C
12H25
OH
OTBS
k
O
O
OMOM
OMOM
15
OH
14
j
C12H25
C12H25
C12H25
O
O
O
O
OMOM
OMOM
17
OH
OMOM
7a
OMOM
16
Scheme 2. Synthesis of tetrahydrofuran part of 1a. Reagents: (a) C12H25MgBr, Et2O (95%); (b) CH3C(OEt)3, propionic acid (86%); (c) DIBALH,
CH2Cl2 (95%); (d) p-nitrobenzoic acid, DEAD, THF (85%); (e) NaOH, MeOH (91%); (f) MOMCl, i-Pr2NEt, CH2Cl2 (92%); (g) 60% AcOH, (96%);
(h) TBSCl, Et3N, DMAP, CH2Cl2 (100%); (i) 1) MsCl, Et3N, CH2Cl2 2) TBAF, THF(96%); (j) lithium acetylide, ethylenediamine complex, DMSO
(83%); (k) MOMCl, i-Pr2NEt, CH2Cl2 (94%).

H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
975
The spectral data (1H NMR, 13C NMR, EIMS) of the
synthetic 1a and 1b were in good agreement with those
reported for natural 1.3 This indicates that the relative
Table 1. Variation of the carboxylic acids in the Mitsunobu inversion
of 4a
Acid
pKa
Yield (%)
stereochemistry of natural 1 is erythro-trans-threo as
3
Acetic acid
Benzoic acid
p-Nitrobenzoic acid
4.76
4.19
3.41
0
17
85
ꢀ
reported by Figadere et al. The two synthetic samples
(1a, 1b) could not be differentiated by the spectral data
(1H NMR, 13C NMR, MS). On the other hand, their
a The reaction was carried out in THF at room temperature for 12 h.
optical rotations showed different values. The specific
30
D
lower than the reported value of natural occurring
rotation of synthetic 1a (½aꢀ +9.68°, c 1.00, CHCl3) is
Compound 4 was then subjected to the Mitsunobu
reaction.8 In this reaction, the yields of products were
highly dependent on the pKa values of acids perhaps due
to the steric hindrance of the acetonide group.9 p-Ni-
trobezoate gave a good result. On the other hand, acetic
acid or benzoic acid afforded the product in low yield
(Table 1).
reticulatain )13 (½aꢀ +22°, c 1, CHCl3). On the other
D
27
hand, that of 1b (½aꢀ +2.34°, c 1.00, CHCl3) showed
D
a very small value.13 Judging from the specific optical
rotations of 1a and 1b, it is difficult to determine the
absolute configuration of natural reticulatain-1.2e;14 We
also prepared the corresponding bis-(R)-MTPA esters
from synthetic 1a and 1b. The chemical shifts of H-17,
H-18, H-21, and H-22 of both 1a and 1b showed a clear
difference and they were in good agreement with those
of the methine protons of Fujimotoꢀs stereochemically
defined model compounds (Fig. 2, Table 2).15
Hydrolysis of p-nitrobezoate 12 with methanolic NaOH
gave building block 6. The inverted secondary hydroxyl
group of 12 was protected as the methoxymethyl
(MOM) ether to afford 13. Selective deprotection of the
acetonide group of 13 with 60% AcOH gave diol 14.
Silylation of the primary hydroxyl group of 14 with
t-butyldimethylchlorosilane (TBSCl), Et3N, and 4-di-
methylaminopyridine (DMAP) afforded 15. Successive
treatment with methanesulfonyl chloride (MsCl), tetra-
butylammonium fluoride (TBAF) furnished terminal
epoxide 16. Alkynylation with lithium acetylide, an
ethylene diamine complex, afforded alkyne 17. Protec-
tion of the secondary hydroxyl group gave the THF
moiety 7a.
This indicates that if the bis-(R)-MTPA ester of natural
1 is available, the absolute configuration of reticulatain-
1 will be definitely established.
Compounds 1a and 1b were tested as inhibitors of
bovine-heart mitochondrial complex I. Both compounds
exhibited almost the same activity (1a: IC50 ¼ 16 nM, 1b:
IC50 ¼ 17 nM). This observation is in agreement with the
results reported by Miyoshi et al., who found that the
stereochemistry around the THF rings was of minor
importance.16 Compared to the most potent acetogenin
like bullatacin (IC50 0.8 nM), the activity is much
weaker. One reason is that the spacer moiety between
the THF ring and the c-lactone moiety (about 15 carbon
atoms) is longer than the optimal length of the spacer
(about 13 carbon atoms).17 Another reason is the length
of the tail that links the THF ring. Compounds 1a and
1b possess 13 carbon atoms while bullatacin has 11
carbon atoms. As Miyoshi et al. reported,16 increase in
hydrophobicity of the tail has a rather adverse effect
on the activity due to some sort of trapping in the
hydrophobic lipid bilayer of the mitochondria mem-
brane. This would weaken the inhibition of mitochon-
drial complex I.
As shown in Scheme 3, c-lactone 19 was constructed as
we had reported earlier starting from 18.6 Oxidation
with mCPBA followed by thermal elimination afforded
the c-lactone moiety 8.
Both segments were coupled by the Sonogashira cross-
coupling10 reaction. The most effective catalyst system in
this reaction is 5 mol % of Cl2Pd(PPh3)2, 10 mol % of
CuI in Et3N to furnish cross-coupled product 20 in 85%
yield. Diimide reduction11 with p-TsNHNH2 and
NaOAc in ethylene glycol diethyl ether under reflux
afforded saturated product 21. When ethylene glycol
dimethyl ether was used in this reaction, the reduction
did not proceed smoothly. Finally, deprotection of
MOM ethers with BF3ÆEt2O afforded candidate 1a.12 On
the other hand, the other candidate 1b was synthesized
from 7b using the same procedure as that employed for
1a (Scheme 4).
In conclusion, we have achieved total synthesis of two
possible diastereomers of reticulatain-1 from building
block 6. On the basis of the present data, it is difficult to
SPh
SPh
O
I
Ref. 6
a
O
O
O
19
18
I
O
O
8
Scheme 3. Synthesis of the c-lactone part of 1a. Reagents: (a) mCPBA, toluene, reflux (78%).

976
H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
I
C12H25
+
O
O
O
OMOM
OMOM
7a
8
a
O
O
C12H25
O
OMOM
OMOM
20
O
O
b
c
C12H25
O
OMOM
OMOM
OH
21
1a
O
O
C12H25
O
OH
C
12H25
O
OMOM
OMOM
7b
O
O
C12H25
O
OH
OH
1b
Scheme 4. Synthesis of 1a. Reagents: (a) 5 mol % Cl2Pd(PPh3)2, 10 mol % CuI, Et3N (85%); (b) p-TsNHNH2, NaOAc, ethylene glycol diethyl ether
(61%); (c) BF3ÆEt2O, DMS (87%).
O
pounds was examined with bovine heart mitochondrial
complex I. Both compounds showed almost the same
activity.
21
21
18
22
17
C12H25
O
O
O
MTPA-(R)-O
O-(R)-MTPA
(R)-MTPA-1a
O
O
18
22
C12H25
17
Acknowledgements
MTPA-(R)-O
O-(R)-MTPA
(R)-MTPA-1b
This work was supported in part by a Grant-in-aid from
the Japan Society for the Promotion of Science
(15780084). We thank Ms. Keiko Hashimoto, Ms.
Moemi Mizu, and Ms. Megumi Miyazawa of the Fac-
ulty of Agriculture, Shinshu University, for the
500 MHz NMR measurements. We also thank Prof. Dr.
Mitsuru Hirota of the Faculty of Agriculture, Shinshu
University, for obtaining Mass spectra.
O
O
MTPA-(R)-O
O-(R)-MTPA
MTPA-(R)-O
O-(R)-MTPA
22a
22b
Figure 2. Bis-(R)-MTPA esters of 1a, 1b, and Fujimotoꢀs model
compounds 22a and 22b.
Table 2. 1H NMR chemical shifts of the bis-(R)-MTPA esters of 1a
and 1b
References and notes
MTPA ester
(R)-MTPA-1a 4.98
22a 4.98
(R)-MTPA-1b 5.02
22b 5.03
17-H
18-H
21-H
22-H
3.76
3.77
3.93
3.94
3.98
3.98
3.93
3.94
5.26
5.27
5.22
5.22
1. For recent reviews for Annonaceous acetogenins, see: (a)
Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod.
ꢀ
1999, 62, 504–540; (b) Zafra-Polo, M. C.; Figadere, B.;
Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
1998, 48, 1087–1117.
2. For recent total synthesis of mono-THF acetogenins, see:
(a) Maezaki, N.; Kojima; Sakamoto, A.; Tominaga, H.;
Iwata, C.; Tanaka, T.; Monden, M.; Damdinsuren, B.;
Nakamori, S. Chem. Eur. J. 2003, 9, 389–399; (b) Cecil,
A. R. L.; Brown, R. C. D. Org. Lett. 2002, 4, 3715–3718;
(c) Makabe, H.; Hattori, Y.; Tanaka, A.; Oritani, T. Org.
Lett. 2002, 4, 1083–1085; (d) Hu, T.-S.; Yu, Q.; Wu, Y.-L.
J. Org. Chem. 2001, 66, 853–861; (e) Maezaki, N.; Kojima;
determine the absolute configuration of natural reticu-
latain-1. The 1H NMR chemical shifts of bis-(R)-MTPA
esters of 1a and 1b showed a clear difference. This
indicates that if the bis-(R)-MTPA ester of natural 1 is
available, the absolute configuration of reticulatain-1
will be determined. Inhibitory action of these com-

H. Makabe et al. / Tetrahedron Letters 45 (2004) 973–977
977
Sakamoto, A.; Tominaga, H.; Iwata, C.; Tanaka, T. Org.
Lett. 2001, 3, 429–432.
J ¼ 7:5 Hz), 2.31 (1H, br –OH), 3.39 (1H, m), 3.80–3.90,
(3H, m), 4.98 (1H, qd, J ¼ 6:6, 1.5 Hz), 6.98 (1H, d,
J ¼ 1:5 Hz). 13C NMR (CDCl3, Me4 Si) d: 14.09, 19.22,
22.68, 25.19, 25.60, 25.97, 27.43, 28.61, 29.19, 29.31, 29.35,
29.52, 29.56, 29.61, 29.65, 29.67, 29.69, 29.73, 31.92, 32.63,
33.32, 71.65, 74.33, 77.36, 82.17, 83.22, 134.41, 148.77,
173.84. HREIMS (M)H2O): Calcd for C37H66O4
574.4961, found 574.4930.
ꢀ
3. Tam, V. T.; Hieu, P. Q. C.; Chappe, B.; Robolt, F.; Figadere,
ꢁ
B.; Cave, A. Bull. Soc. Chim. Fr. 1995, 132, 324–329.
4. Saad, J. M.; Hui, Y. H.; Rupprecht, J. K.; Anderson, J. E.;
Kozlowski, J. F.; Zhao, G. X.; Wood, K. V.; McLaughlin,
J. L. Tetrahedron 1991, 47, 2751–2756.
5. Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1993, 115,
4891–4892.
13. The data for 1b: mp 87–90 °C, ½aꢀ28 +2.34° (c 1.00, CHCl3).
D
6. Makabe, H.; Tanaka, A.; Oritani, T. J. Chem. Soc., Perkin
Trans. 1 1994, 1975–1981.
The IR, 1H NMR, 13C NMR, HREIMS data were
identified with those of 1a.
7. Makabe, H.; Tanimoto, H.; Tanaka, A.; Oritani, T.
Heterocycles 1996, 43, 2229–2248.
8. Mitsunobu, O. Synthesis 1981, 1–28.
9. Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem.
1994, 59, 234–236.
14. The discrepancy in the optical rotation value of the
synthetic product with that reported for the natural
product has been reported: (a) Sinha, S. C.; Sinha, S. C.;
Keinan, E. J. Org. Chem. 1999, 64, 7067–7073; (b)
Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003,
5, 1353–1356.
15. Shimada, H.; Nishioka, S.; Singh, S.; Sahai, M.; Fujimoto,
Y. Tetrahedron Lett. 1994, 35, 3961–3964.
16. Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.;
Iwamura, H.; McLaughlin, J. L. Biochim. Biophys. Acta
1998, 1365, 443–452.
10. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467–4470.
11. Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F.
J. Org. Chem. 2003, 68, 1780–1785.
12. The data for 1a: mp 85–87 °C, ½aꢀ30 +9.68° (c 1.00, CHCl3).
D
IR (KBr) mmax cmꢁ1: 3444, 3076, 2917, 2849, 1741, 1470,
1321, 1121, 1075, 1022, 950, 877, 718. H NMR (CDCl3,
1
17. Takada, M.; Kuwabara, K.; Nakato, H.; Tanaka, A.;
Iwamura, H.; Miyoshi, H. Biochim. Biophys. Acta 2000,
1460, 302–310.
Me4Si) d: 0.88 (3H, t, J ¼ 6:8 Hz), 1.20–2.00 (52H, m),
1.40 (3H, d, J ¼ 6:6 Hz), 2.00 (1H, br –OH), 2.26 (2H, t,