First total synthesis of mosin B.

Article abstract of DOI:10.1021/ol006938e

[figure: see text] The first total synthesis of mosin B and a diastereomer was accomplished using asymmetric desymmetrization of the sigma-symmetric diol and the Nozaki-Hiyama-Kishi reaction as the key steps. The THF core segment was stereoselectively con

Full text of DOI:10.1021/ol006938e

ORGANIC
LETTERS
2001
Vol. 3, No. 3
429-432
First Total Synthesis of Mosin B
Naoyoshi Maezaki, Naoto Kojima, Atsunobu Sakamoto, Chuzo Iwata, and
Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received November 29, 2000
ABSTRACT
The first total synthesis of mosin B and a diastereomer was accomplished using asymmetric desymmetrization of the σ-symmetric diol and
the Nozaki−Hiyama−Kishi reaction as the key steps. The THF core segment was stereoselectively constructed employing a stereodivergent
synthesis starting from a common intermediate, 4-cyclohexene-1,2-diol, based on a desymmetrization strategy. By virtue of these synthetic
results, it is suggested that the absolute configuration is 1a.
Mosin B (1) is a mono-tetrahydrofuran acetogenin1,2 isolated
by McLaughlin’s group from the bark of Annona squamosa
and shows selective cytotoxic activity against the human
pancreatic tumor cell line, PACA-2, with potency 100 times
that of adriamycin.3 The structure of 1, which possesses a
mono-THF ring and a carbonyl group at the C9 position, was
elucidated by spectroscopic and chemical methods. Although
the absolute configuration of the γ-lactone moiety was
established as 4R,34S and the relative stereochemistry of the
THF part was determined as threo/trans/erythro in 1997,1c
the absolute configuration remained unknown. Two possible
structures 1a and 1b would be difficult to differentiate by
1H or 13C NMR spectroscopic data, since two stereogenic
(1) Reviews for annonaceous acetogenins: (a) Alali, F. Q.; Liu, X.-X.;
McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (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) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J.
L. J. Nat. Prod. 1990, 53, 237-278. (d) Cave´, A.; Figade´re, B.; Laurens,
A.; Cortes D. In Progress in the Chemistry of Organic Natural Products:
Acetogenins from Annonaceae; Herz, W., Eds.; Springer-Verlag: New York,
1997; Vol. 70, pp 81-288.
Figure 1.
regions, that is, the THF ring core part (C15-C20) and the
butenolide segment (C4 and C34), are separated by a long
carbon chain. Moreover, the absolute stereochemical assign-
ment of the threo/trans/erythro-type acetogenin using the
advanced Mosher ester methodology is generally difficult
since the protons of the THF part experienced shielding
effects of both flanking MTPA esters.3,4 X-ray analysis is
(2) Recent total syntheses of mono-THF acetogenins: (a) Ba¨urle, S.;
Peters, U.; Friedrich, T.; Koert, U. Eur. J. Org. Chem. 2000, 2207-2217.
(b) Dixon, D. J.; Ley, S. V.; Reynolds, D. J. Angew. Chem., Int. Ed. 2000,
39, 3622-3626. (c) Hu, T.-S.; Wu, Y.-L.; Wu, Y. Org. Lett. 2000, 2, 887-
889. (d) Yu, Q.; Wu, Y.; Ding, H.; Wu, Y.-L. J. Chem. Soc., Perkin Trans.
1 1999, 1183-1188. (e) Yu, Q.; Yao, Z.-J.; Chen, X.-G.; Wu, Y.-L. J.
Org. Chem. 1999, 64, 2440-2445. (f) Hu, T.-S.; Yu, Q.; Lin, Q.; Wu,
Y.-L.; Wu, Y. Org. Lett. 1999, 1, 399-401. (g) Kuriyama, W.; Ishigami,
K.; Kitahara, T. Heterocycles 1999, 50, 981-988. (h) Wang, Z.-M.; Tian,
S.-K.; Shi, M. Tetrahedron: Asymmetry 1999, 10, 667-670.
(3) Hopp, D. C.; Zeng, L.; Gu, Z.-M.; Kozlowski, J. F.; McLaughlin, J.
L. J. Nat. Prod. 1997, 60, 581-586.
(4) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Tetrahedron: Asymmetry 2000,
11, 2781-2791.
10.1021/ol006938e CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

also very difficult due to the waxy nature of this compound.
To establish the absolute configuration of mosin B, we
planned to synthesize two candidates 1a and 1b, employing
a stereodivergent synthesis starting from a common inter-
mediate, 4-cyclohexene-1,2-diol 3, based on a desymmetri-
zation strategy.5
Scheme 2
The σ-symmetric diol 3 can be readily converted into
desymmetrized alcohols 4a and 4b with very high enantio-
selectivity (>98% ee) by means of diasteroselective acetal
fission using a C2-symmetric bis-sulfoxide 2, a new chiral
auxiliary for asymmetric desymmetrization recently devel-
oped in our laboratory (Scheme 1).5 The resulting chiral
Scheme 1
Synthesis of THF core segment 21 was started from
optically pure alcohol 4a, which was converted into lactol
11 by dihydroxylation of the double bond followed by
oxidative cleavage of 1,2-diol (Scheme 3). An alkyl chain
was introduced into the free aldehyde by Wittig reaction,
and the lactol was reduced with NaBH4 to give diol 12.
Hydrogenation of the double bond accompanied with de-
benzylation afforded triol 13. After the 1,2-diol was selec-
tively protected as an acetonide,10 iodination of the primary
alcohol was carried out via mesylation, giving the iodide
15. The coupling reaction of 15 and the acetylide generated
from the TBS ether of propargyl alcohol11 using n-BuLi
afforded the alkyne 16, which was converted into the
E-allylic alcohol 7 by deprotection of the TBS ether to give
alcohol 17 followed by E-selective reduction of the triple
7
alcohols 4a and 4b are versatile chiral building blocks for
the construction of stereogenic centers at the C19 and C20
positions in both 1a and 1b.
bond. Upon treatment of 7 with I(coll)2ClO4 in MeCN-
H2O, iodoetherification proceeded highly stereoselectively
to give epoxide 18 as a single isomer after subsequent base
treatment. The epoxide 18 was subjected to Grignard
reaction7b,12 using 6-hexenylmagnesium bromide in the
presence of CuBr to give diol 19.13 Silylation of the diol
followed by oxidative cleavage of the terminal olefin to the
aldehyde gave the THF core segment 21.
Scheme 2 outlines our synthetic strategy. One of the key
steps is a coupling of the THF core segment 5 and the
γ-lactone segment 6 by the Nozaki-Hiyama-Kishi reac-
tion.6 The THF core segment 5 is stereoselectively con-
structed by iodoetherification7 of E-allylic alcohol 7, which
is prepared from chiral alcohol 4a.5 On the other hand, the
γ-lactone segment 6 is synthesized by R-alkylation of
R-sulfenyl γ-lactone 98 with 8 prepared from the known
aldehyde 10.9
(10) Hayashi, H.; Nakanishi, K.; Brandon, C.; Marmur, J. J. Am. Chem.
Soc. 1973, 95, 8749-8757.
(11) Araki, Y.; Konoike, T. J. Org. Chem. 1997, 62, 5299-5309.
(12) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J. Org.
Chem. 1995, 60, 4419-4427.
(5) (a) Maezaki, N.; Sakamoto, A.; Nagahashi, N.; Soejima, M.; Li, Y.-
X.; Imamura, T.; Kojima, N.; Ohishi, H.; Sakaguchi, K.; Iwata, C.; Tanaka,
T.; J. Org. Chem. 2000, 65, 3284-3291. (b) Maezaki, N.; Sakamoto, A.;
Soejima, M.; Sakamoto, I.; Li, Y.-X.; Tanaka, T.; Ohishi, H.; Sakaguchi,
K.; Iwata, C.; Tetrahedron: Asymmetry 1996, 7, 2787-2790.
(6) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644-5646. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, K.; Nozaki, H. Ibid. 1986, 108, 6048-6050.
(7) (a) Zhang, H.; Seepersaud, M.; Seepersaud, S.; Mootoo, D. R. J.
Org. Chem. 1998, 63, 2049-2052. (b) Zhang, H.; Mootoo, D. R. Ibid. 1995,
60, 8134-8135.
(13) Relative stereochemistry of threo/trans/erythro was confirmed by
comparison with the chemical shifts around the THF ring in 13C NMR
spectroscopic data of Fujimoto’s synthetic model compounds. Fujimoto,
Y.; Murasaki, C.; Shimada, H.; Nishioka, S.; Kakinuma, K.; Singh, S., Singh,
M.; Gupta, Y.; Sahai, M. Chem. Pharm. Bull. 1994, 42, 1175-1184.
(14) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(15) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158-8159.
(16) Although an alkylation of the thiophenyl lactone 9 is a convenient
method and was often used to construct the γ-lactone moiety of
acetogenins,2g,17 this method has not been applied to a synthesis of
4-hydroxylated acetogenins except for Jacobsen’s synthesis of muconin.18
The attempted coupling of the iodide 24b with 9 in the Jacobsen’s conditions
was failed due to the low reactivity of 24b.
(8) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991-4998.
(9) Smith, A. B. III; Rano, T. A.; Chida, N.; Sulikowski, G. A.; Wood,
J. L. J. Am. Chem. Soc. 1992, 114, 8008-8022.
430
Org. Lett., Vol. 3, No. 3, 2001

Scheme 3a
a Reagents and conditions: (a) cat. OsO4, NMO, acetone-THF, rt; (b) NaIO4, acetone-H2O, rt; (c) Ph3PC10H21Br, KHMDS, THF, -78
°C to rt; (d) NaBH4, MeOH, rt (20% in four steps); (e) H2, Pd-C, 3 atm, MeOH, rt (quant.); (f) TsOH, acetone, rt (93%); (g) MsCl, Et3N,
CH2Cl2, rt; (h) NaI, NaHCO3, acetone, reflux (88% in two steps); (i) 1-tert-butyldimethylsilyloxy-2-propyne, n-BuLi, THF-HMPA, 0 °C
(74%); (j) TBAF, THF, rt (quant.); (k) LiAlH4, THF, reflux (90%); (l) I(coll)2ClO4, MeCN-H2O, rt; (m) K2CO3, MeOH, rt (80% in two
steps); (n) 6-bromo-1-hexene, Mg, CuBr, THF, 0 °C (89%); (o) TBSOTf, 2,6-lutidine, CH2Cl2, rt (83%); (p) cat. OsO4, NMO, THF-
acetone-H2O (1:1:1), rt (79%); (q) NaIO4, CH2Cl2-acetone-H2O (10:6:1), rt (75%).
Scheme 4 shows the synthesis of the γ-lactone segment
26. Takai’s olefination14 followed by deacetalization of the
known aldehyde 10 prepared from D-glutamic acid afforded
diol 23 in a 9:1 mixture of E/Z isomers. Selective triflation
of the primary alcohol in 23 with Tf2O and subsequent
silylation of the secondary alcohol was carried out in a one-
pot reaction.15 Coupling reaction of 24a and lactone 9
provided 25 in 79% yield. It is noteworthy that a combination
of the leaving group (OTf) and the protecting group (TBS)
in 24a is important to achieve high yield.16,19 Other leaving
groups (iodide, chloromethanesulfonate20) or protecting group
(MOM) resulted in a poor yield or gave no product. This
methodology would be useful for the synthesis of other
acetogenins having a hydroxy group at the C4 position.
Oxidation of the sulfide 25 into sulfoxide followed by
thermal elimination afforded the γ-lactone segment 26.
Both segments were coupled by the Nozaki-Hiyama-
Kishi reaction mediated by CrCl2/NiCl2 in DMF-Me2S
solvent system21 to give E-allylic alcohol 2222 in good yield
(Scheme 5). Oxidation of 22 with SO3‚pyridine complex and
Scheme 5a
Scheme 4a
a Reagents and conditions: (a) 26, CrCl2, cat. NiCl2, DMF-
Me2S, rt (71%); (b) SO3•pyridine, DMSO, Et3N, CH2Cl2, 0 °C to
rt (72%); (c) H2, (Ph3P)3RhCl, benzene, rt (78%); (d) HF (aq),
MeCN-THF, rt (72%).
DMSO followed by selective reduction of the resulting enone
with Wilkinson’s catalyst afforded the tri-TBS ether of mosin
a Reagents and conditions: (a) CrCl2, CHI3, THF, rt; (b) Dowex
50W, MeOH, rt (58% in two steps); (c) Tf2O, 2,6-lutidine, CH2Cl2,
-50 °C then TBSOTf, 0 °C (92%); (d) 9, KHMDS, THF, 0 °C
then 24a, rt (79%); (e) (i) m-CPBA, CH2Cl2, 0 °C; (ii) toluene,
reflux (85% in two steps).
(17) (a) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T. D.;
Zhuang, Z. J. Am. Chem. Soc. 1991, 113, 9369-9371. (b) Sinha, S. C.;
Keinan, E. Ibid. 1993, 115, 4891-4892. (c) Makabe, H.; Tanaka, A.; Oritani,
T. J. Chem. Soc., Perkin Trans. 1 1994, 1975-1994. (d) Makabe, H.;
Tanaka, A.; Oritani, T. Tetrahedron Lett. 1997, 38, 4247-4250. (e) Yazbak,
A.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1998, 63, 5863-5868.
Org. Lett., Vol. 3, No. 3, 2001
431

B. Finally, deprotection of these TBS ethers with HF afforded
the candidate 1a.23 On the other hand, the other candidate
1b24 was synthesized from 4b using the same procedure for
1a.
optical rotations of acetogenins sometimes show smaller
values than their actual ones when they are measured at low
concentrations presumably owing to experimental error or
the presence of impurities,2c-d,25 we suggest strongly that
natural mosin B is 1a, not 1b.
In conclusion, the first total synthesis of mosin B (1a) and
the diastereomer 1b was accomplished using asymmetric
desymmetrization of the s-symmetric diol 3 and the Nozaki-
Hiyama-Kishi reaction as key steps. The overall yield was
1.1% through 20 steps from desymmetrized alcohol 4a. On
the basis of the present data, it is suggested that mosin B is
1a.
The two synthetic samples (1a, 1b) could not be dif-
ferentiated by the spectral data (1H NMR, 13C NMR, MS).
On the other hand, their specific rotations showed sharp
contrast. While the specific rotation of synthetic 1a ([R]25
D
) +18.7, c 0.50, CH2Cl2) is higher than the reported value
of the naturally occurring mosin B3 ([R]23D ) +11.5, c 0.005,
CH2Cl2), that of 1b ([R]26D ) +2.2, c 0.39, CH2Cl2) showed
a very small value. Taking into account that the reported
(18) Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
4876-4877.
(19) During the course of our study, Kitahara reported another solution
employing a less hindered MeS group instead of a PhS group as an anion-
stabilizing group. (a) Yang, W.-Q.; Kitahara, T. Tetrahedron Lett. 1999,
40, 7827-7830. (b) Yang, W.-Q.; Kitahara, T. Tetrahedron 2000, 56, 1451-
1461.
(20) Shimizu, T.; Hiranuma, S.; Nakata, T. Tetrahedron Lett. 1996, 37,
6145-6148.
(21) Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989,
111, 2735-2737.
Acknowledgment. We thank Prof. J. L. McLaughlin and
Dr. D. C. Hopp for providing spectral data of mosin B.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
of key intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL006938E
(22) Although a 9:1 mixture of (E/Z)-26 isomers was used for the Nozaki-
Hiyama-Kishi reaction, the coupling reaction gave the only E-allylic alcohol
22 presumably due to E/Z-isomerization of organochromium reagent and
the low reactivity of Z-isomer.
(24) Physical and spectroscopic data for 1b: [R]26 ) +2.2 (c 0.39,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J )D1.2 Hz, 1H), 5.04
(qd, J ) 6.7, 1.2 Hz, 1H), 3.84-3.87 (m, 2H), 3.76-3.83 (m, 2H), 3.34-
3.38 (m, 1H), 2.47-2.51 (m, 1H), 2.39 (t, J ) 7.3 Hz, 2H), 2.38 (t, J ) 7.3
Hz, 2H), 2.36-2.41 (m, 1H), 1.94-2.00 (m, 1H), 1.79-1.92 (m, 2H), 1.51-
1.64 (m, 1H), 1.45-1.49 (m, 2H), 1.41 (d, J ) 6.7 Hz, 3H), 1.33-1.38
(m, 4H), 1.23 (br s, 30H), 0.86 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 211.4, 174.6, 152.0, 131.0, 83.2, 82.2, 78.0, 74.2, 71.4, 69.5,
42.6, 42.5, 37.0, 33.3, 32.9, 32.5, 31.9, 29.6, 29.61, 29.59 (2C), 29.55, 29.5,
29.3, 29.1, 28.6, 26.0, 25.23, 25.16, 25.1, 23.6, 23.4, 22.6, 19.0, 14.1; IR
(KBr) 3439, 2918, 2850, 1740, 1720, 1716, 1705, 1072 cm-1; MS (FAB)
m/z 595 [M+ + H]; HRMS (FAB) calcd for C35H63O7 [M+ + H] 595.4574,
found 595.4561.
(23) Physical and spectroscopic data for 1a: [R]25 ) +18.7 (c 0.50,
D
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J ) 1.2 Hz, 1H), 5.06
(qd, J ) 6.7, 1.2 Hz, 1H), 3.85-3.89 (m, 2H), 3.79-3.84 (m, 2H), 3.36-
3.40 (m, 1H), 2.52 (ddd, J ) 15.3, 3.1, 1.8 Hz, 1H), 2.42 (t, J ) 7.3 Hz,
2H), 2.40 (t, J ) 7.3 Hz, 2H), 2.38-2.43 (m, 1H), 1.97-2.02 (m, 1H),
1.82-1.94 (m, 2H), 1.56-1.65 (m, 1H), 1.46-1.51 (m, 2H), 1.44 (d, J )
6.7 Hz, 3H), 1.35-1.41 (m, 4H), 1.26 (br s, 30H), 0.88 (t, J ) 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 211.4, 174.7, 152.0, 131.0, 83.2, 82.1,
78.0, 74.2, 71.5, 69.6, 42.7, 42.5, 37.0, 33.4, 32.9, 32.5, 31.9, 29.7 (2C),
29.63 (2C), 29.59, 29.5, 29.3, 29.2, 28.6, 26.0, 25.3, 25.2, 25.1, 23.6, 23.4,
22.7, 19.1, 14.1; IR (KBr) 3444, 2953, 2918, 2850, 1767, 1755, 1743, 1703,
1072 cm-1; MS (FAB) m/z 595 [M+ + H]. HRMS (FAB) calcd for
C35H63O7 [M+ + H] 595.4574, found 595.4556.
(25) Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067-
7073.
432
Org. Lett., Vol. 3, No. 3, 2001