Stereoselective synthesis of the cytotoxic macrolide aspergillide B

Article abstract of DOI:10.1016/j.tetlet.2009.04.026

A total, stereoselective synthesis of the cytotoxic macrolide aspergillide B has been performed. A cross metathesis and a C-glycosidation via a Mukaiyama-type aldol reaction were key features of the synthesis. The macrocyclic lactone ring was created by m

Full text of DOI:10.1016/j.tetlet.2009.04.026

Tetrahedron Letters 50 (2009) 3783–3785
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Tetrahedron Letters
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Stereoselective synthesis of the cytotoxic macrolide aspergillide B
Santiago Díaz-Oltra a, César A. Angulo-Pachón a, María N. Kneeteman b, Juan Murga a,
c,
Miguel Carda a, , J. Alberto Marco
*
*
a Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, E-12080 Castellón, Spain
b Depart. de Química, Fac. Ing. Química, Univ. del Litoral, Santa Fe, Argentina
c Depart. de Q. Orgánica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A total, stereoselective synthesis of the cytotoxic macrolide aspergillide B has been performed. A cross
metathesis and a C-glycosidation via a Mukaiyama-type aldol reaction were key features of the synthesis.
The macrocyclic lactone ring was created by means of the Yamaguchi procedure.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 March 2009
Revised 30 March 2009
Accepted 3 April 2009
Available online 14 April 2009
Keywords:
Macrolides
Aspergillides
Mukaiyama C-glycosidation
Cross metathesis
Yamaguchi macrolactonization
Brown asymmetric allylation
The aspergillides A, B and C (1–3) are three 14-membered mac-
rolides isolated the last year from a strain of the marine-derived
fungus Aspergillus ostianus cultivated in a bromine-modified med-
ium.1,2 The structures of these new compounds were determined
by analyses of their 1D and 2D NMR spectra and reported to be
as depicted in Figure 1. Their absolute configurations were eluci-
dated by means of the modified Mosher’s method as well as with
the aid of chemical conversions. Macrolides 1–3 were found to
show cytotoxic activities in the micromolar range against mouse
lymphocytic leukaemia cells (L1210).
The structures of these natural lactones show some unusual fea-
tures which deserve comment. In a literature perusal, we have
found only two examples of naturally occurring, very recently iso-
lated 14-membered macrolides that possess a tetrahydropyran
ring not forming part of a hemiacetal or acetal moiety.3,4 This
and the aforementioned bioactivities prompted us to initiate the
total synthesis of these compounds.
thesis of aspergillide C and confirmed it to have structure 3.6 Struc-
ture 2 therefore does not correspond to any natural compound
isolated so far.5
In the present manuscript, we wish to publish our own synthe-
sis of aspergillide B, now known to have structure 1.7 The retrosyn-
thetic concept is depicted in Scheme 1. Hydrolytic opening of the
lactone ring gives the protected seco acid 4. Inverse cross metath-
esis (CRM) yields the known alcohol 58 and tetrahydropyran 6. We
planned to obtain 6 by means of an anomeric Mukaiyama-type
alkylation of a suitable lactol derivative prepared through reduc-
tion of lactone 7. The latter was to be obtained by functional mod-
ification of 8, in turn derived from 9 through a metal-catalyzed
double bond migration. Following this, inverse asymmetric allyla-
tion to aldehyde 10 and oxidative retro-cleavage of the olefinic
bond finally led to the known compound 11.9
In the beginning of this year, Uenishi et al. published a synthesis
of a compound having structure 1, then assumed to correspond to
aspergillide A.5 However, these authors found that their synthetic
compound had spectral properties identical with those reported
for aspergillide B. The latter compound was thus reassigned struc-
ture 1, which led to the need of a new structure assignment for
aspergillide A. Still more recently, Kuwahara et al. published a syn-
13
1
O
O
O
O
O
O
3
O
O
O
7
H
H
H
4
HO
HO
HO
1
3
2
* Corresponding authors. Tel.: +34 96 3544337; fax: +34 96 3544328 (J.A.M.).
E-mail address: alberto.marco@uv.es (J.A. Marco).
Figure 1. Structures of the aspergillides A–C as reported in the initial publication.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.026

3784
S. Díaz-Oltra et al. / Tetrahedron Letters 50 (2009) 3783–3785
OBn
OR
H
H
b
c
TPSO
TPSO
10
OH
O
O
HOOC
BnO
OR
O
O
11
R = H
a
13 R = H
d
H
+
H
12 R = Bn
9
R = TES
HO
e
1
4
OBn
BnO
H
g
CRM
RO
OH
BnO
BnO
R
O
5
OR´
8
R = TPS R´ = TES
14 R = R´ = H
H
7
R = O
O
h
f
O
O
H
15 R = H,OAc
H
COOH
7
6
i
BnO
OH
OBn
H
OBn
H
Mes
Cl
Cl
N
N Mes
k
HOOC
BnO
TPSO
TPSO
Ph
O
H
3
Ru
O
H
18
8
OTES
9
PCy3
OTES
COR
16 R = StBu
j
4 (E +Z )
6
R = OH
OH
H
OBn
H
TPSO
11
l
TPSO
CHO
10
Scheme 1. Retrosynthetic analysis of aspergillide B (1).
O
O
O
O
O
O
m
+
O
O
O
H
H
H
Scheme 2 shows the details of the synthesis. Alcohol 119 was
benzylated to 12 under mild, nonbasic conditions.10 Ozonolytic
cleavage of the olefinic bond yielded aldehyde 10, which was first
purified and then subjected to Brown’s asymmetric allylbora-
tion.11 This gave homoallyl alcohol 13 in a very high diastereo-
meric purity (dr >95:5 by NMR), which was subsequently
protected as its triethylsilyl derivative 9. Isomerization of the ter-
minal olefinic bond to the internal position was achieved by
means of the catalytic method of Wipf et al.12 With the aid of this
procedure, compound 9 was converted into its isomer 8 in high
yield.13 Compound 8 was obtained as a ꢀ9:1 E/Z mixture14,15
which proved to be difficult to separate and was thus carried as
such until the last step of the synthesis. Cleavage of the two silyl
groups and selective oxidation of the primary alcohol with
PhI(OAc)2/TEMPO16 afforded d-lactone 7. Reduction of 7 (DIBAL)
followed by acetylative quenching yielded the acetylated lactol
15 as a mixture of stereoisomers,17 which were not separated.
The mixture was subsequently treated with the trimethylsilyl
enolate of tert-butyl thioacetate18 in the presence of BF3-etherate
and TMSOTf.19 This furnished the trans-2,6-disubstituted20 tetra-
hydropyran 16 in 55% yield, accompanied by its epimer at C-3
(21%, not depicted in Scheme 2). Alkaline hydrolysis of 16 pro-
vided acid 6 in high yield.
BnO
BnO
HO
(Z)-17
(E)-17
1
Scheme 2. Reagents and conditions: (a) BnBr, Ag2O, Et2O, rt, 3 d (83%); (b) O3,
CH2Cl2, ꢁ80 °C, 30 min, then Ph3P, rt, 2 h (78%); (c) allylBIpc2 from (ꢁ)-DIP-Cl and
allylmagnesium bromide, Et2O, ꢁ90 °C, 2 h (dr >95:5); (d) TESOTf, Et3N, CH2Cl2,
ꢁ80 °C, 2 h (77% overall from 10); (e) cat. 18 (5% molar), N-trityl allylamine, EtNiPr2,
CH2Cl2,
D, 16 h (96%, E/Z 9:1); (f) TBAF, THF, rt, 16 h (98%); (g) PhI(OAc)2, TEMPO
(cat.), 0 °C, 16 h (84%); (h) DIBAL, CH2Cl2, ꢁ80 °C, 2 h, then addition of Ac2O, py,
DMAP, 14 h (93%); (i) CH2@C(OTMS)StBu, 4 Å MS, BF3ꢂEt2O, TMSOTf, MeCN, 16 h,
ꢁ18 °C (55%); (j) NaOH, aq MeOH, rt, 16 h (94%); (k) 5 (5 equiv), cat. 18 (20% molar),
CH2Cl2,
D, 6 h (89%, E/Z 7:3); (l) Cl3C6H2COCl, Et3N, THF, rt, 1.5 h, then DMAP,
toluene, 50 °C, 6 h (57%); (m) DDQ, CH2Cl2/H2O 10:1, rt, 20 h (51%). Abbreviations:
Bn, benzyl; TPS, tert-butyldiphenylsilyl; TES, triethylsilyl.
Acknowledgements
Financial support has been granted by the Spanish Ministry of
Science and Technology (Projects CTQ2005-06688-C02-01 and
CTQ2005-06688-C02-02), the Conselleria de Educación, Ciencia y
Empresa de la Generalitat Valenciana (Project ACOMP07/023)
and the BANCAJA-UJI Foundation (Project P1-1B-2008-14). M.N.K.
thanks the BANCAJA-UJI Foundation for a grant.
Treatment of 6 with 5 equiv of olefinic alcohol 5 in the presence
of 20% of ruthenium catalyst 18 caused cross metathesis21 and
afforded hydroxy acid 4 in 89% yield as a 7:3 E/Z mixture. Macrol-
actonization was performed on the mixture by means of the Yam-
aguchi procedure22 and gave a separable mixture of (E)- and (Z)-17.
Cleavage of the benzyl group in the former was performed with
DDQ23 in wet CH2Cl2 and yielded lactone 1, which showed physical
and spectral properties24 identical to those published for aspergil-
lide B.1,5
In summary, the cytotoxic macrolide aspergillide B has been
synthesized in a stereoselective way. As recently reported by
Hande and Uenishi,5 its actual structure has been found to be 1
(Fig. 1), the structure initially and erroneously proposed for asper-
gillide A.
References and notes
1. Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi, T. Org. Lett.
2008, 10, 225–228.
2. These compounds must not be confused with a group of other structurally
unrelated metabolites of the same name isolated from Aspergillus terreus. See:
Holding, B. T.; Rickards, R. W.; Vanek, Z. J. Chem. Soc. Perkin Trans. I 1975, 1961–
1963.
3. Neopeltolide (14-membered macrolide containing
a cis-2,6-disubstituted
tetrahydropyran ring): Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.;
Linley, P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod. 2007,
70, 412–416; The structure reported in this Letter has been later corrected as a
consequence of synthetic efforts of several groups. See the most recent
synthesis in: Vintonyak, V. V.; Kunze, B.; Sasse, F.; Maier, M. E. Chem. Eur. J.
2008, 14, 11132–11140. and references therein to previous syntheses.
4. Pochonin
J (benzofused 14-membered macrolide containing a trans-2,6-
disubstituted tetrahydropyran ring): Shinonaga, H.; Kawamura, Y.; Ikeda, A.;

S. Díaz-Oltra et al. / Tetrahedron Letters 50 (2009) 3783–3785
3785
Aoki, M.; Sakai, N.; Fujimoto, N.; Kawashima, A. Tetrahedron Lett. 2009, 50, 108–
110.
5. Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009, 50, 189–192. The compound
with structure 2 was also synthesized by these authors and found to be
different from aspergillide A.
6. Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761–764.
7. When we started our synthetic efforts, the synthesis of Hande and Uenishi had
not yet appeared. Our initial synthetic target therefore was aspergillide A,
assumedly having structure 1.
17. Compound 15 is a ca. 2:1 mixture of anomers, each of which being a ca. 9:1
mixture of E/Z geometric isomers. The 1H NMR spectrum shows four doublets
in the d 6.50–5.50 range with the expected coupling constant values. Major
anomer: d 5.64 (d, J = 7.9 Hz; E isomer) and 5.59 (d, J = 7.9 Hz; Z isomer); minor
anomer: d 6.38 (d, J = 3.1 Hz; E isomer) and 6.33 (d, J = 3.1 Hz; Z isomer).
18. (a) Simchen, G.; West, W. Synthesis 1977, 247–248; (b) Evans, D. A.; Scheidt, K.
A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480–4491.
19. (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976–4978; (b)
Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749–3754.
8. Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc. Perkin Trans. I 2000, 2385–2394.
9. Dixon, D. J.; Ley, S. V.; Reynolds, D. J. Chem. Eur. J. 2002, 8, 1621–1636.
10. (a) Mislow, K.; OBrien, R. E.; Schaefer, H. J. Am. Chem. Soc. 1962, 84, 1940–1944;
20. We have found one precedent of this Mukaiyama-type C-glycosidation method
using
a ketene O,S-acetal: Vitale, J. P.; Wolckenhauer, S. A.; Do, N. M.;
´
Rychnovsky, S. D. Org. Lett. 2005, 7, 3255–3258.
(b) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247–3251; (c) Marshall, J.
A.; Seletsky, B. M.; Luke, G. P. J. Org. Chem. 1994, 59, 3413–3420; (d) Chen, M.-
D.; He, M.-Z.; Zhou, X.; Huang, L.-Q.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron 2005,
61, 1335–1344; (e) Yokokawa, F.; Inaizumia, A.; Shioiri, T. Tetrahedron 2005, 61,
1459–1480.
21. (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923; (b)
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370; (c) Vernall, A. J.; Abell, A. D. Aldrichim. Acta 2003, 36, 93–
105; (d) Schrodi, Y.; Pederson, R. L. Aldrichim. Acta 2007, 40, 45–52.
22. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
23. (a) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 2524–2536; (b)
Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029–2032.
24. Compounds (E)-17 and (Z)-17 were separated on a silica gel column using
hexanes–EtOAc mixtures as the eluent (gradient from 95:5 to 90:10).
Compound 1 was purified on a silica gel column using a 70:30 mixture of
hexanes–EtOAc. Physical and spectral data of (E)-17, (Z)-17 and 1:(E)-17: oil; Rf
11. (a) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahedron Lett. 1997, 38,
2417–2420; (b) Ramachandran, P. V. Aldrichim. Acta 2002, 35, 23–35.
12. (a) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848–
14849; (b) Sieng, B.; Ventura, O. L.; Bellosta, V.; Cossy, J. Synlett 2008, 1216–
1218.
13. Protection of the free OH group in compound 13 was crucial. Attempts at
double bond isomerization in 13 under various conditions gave only ketone i in
low yield.
on a silica gel TLC plate (hexanes–EtOAc, 80:20): 0.21; [
a
]
D
ꢁ56.3 (c 1.5;
CHCl3); IR mmax 1732 (lactone C@O) cmꢁ1 1H NMR (500 MHz, CDCl3) d 7.35–
;
OBn
H
7.25 (5H, br m, arom. H), 6.19 (1H, dddd, J = 15.5, 10.8, 4.8, 1.8 Hz; H-9), 5.64
(1H, br dd, J = 15.5, 4 Hz; H-8), 5.06 (1H, m; H-13), 4.72 (1H, d, J = 12.5 Hz;
benzyl), 4.49 (1H, m; H-7), 4.40 (1H, d, J = 12.5 Hz; benzyl), 4.18 (1H, br d,
J = 11 Hz; H-3), 3.32 (1H, br s; H-4), 2.64 (1H, dd, J = 14, 11 Hz; H-2), 2.25–2.15
(2H, m; H-6, H-10), 2.10 (1H, dd, J = 14, 1.7 Hz; H-20), 2.05–1.90 (2H, m; H-5,
H-100), 1.85–1.75 (2H, m; H-11, H-12), 1.70–1.55 (2H, br m; H-50, H-120),
1.45–1.30 (2H, br m; H-60, H-110), 1.17 (3H, d, J = 6.5 Hz; Me-C13); 13C NMR
(125 MHz, CDCl3) d 170.6 (C-1), 138.6 (aromatic quat. C), 137.7 (C-9), 128.8 (C-
8), 128.3, 127.9, 127.6 (aromatic), 73.1 (C-4), 71.2 (C-7), 70.5 (benzyl CH2), 69.9
(C-13), 69.0 (C-3), 39.9 (C-2), 31.7 (C-12), 30.6 (C-10), 24.8 (C-11), 23.0 (C-6),
22.9 (C-5), 19.1 (Me-C13).
TPSO
O
i
14. Both E/Z isomers were synthetically productive. In order to avoid working with
mixtures, however, we tried to convert compound into its nor-methyl
8
derivative (vinyl instead of propenyl) by means of cross metathesis under an
ethylene atmosphere.12a This goal was achieved but yields were not
satisfactory (50–55% at <1 mmol scale) and difficult to reproduce at a larger
scale.
(Z)-17: oil; Rf on a silica gel TLC plate (hexanes–EtOAc, 80:20): 0.33; [
a]D ꢁ28.4
15. We also made attempts at obtaining the aforementioned vinyl derivative by
means of asymmetric ethynylation of aldehyde 10 (Frantz, D. E.; Fässler, R.;
Carreira, E. M., J. Am. Chem. Soc. 2000, 122, 1806–1807) followed by
semihydrogenation of the triple bond. Unfortunately, the ethynylation step
proved to be too slow (mainly starting materials in the reaction mixture after
4 days) and was abandoned.
(c 0.5; CHCl3); IR mmax 1729 (lactone C@O) cmꢁ1 1H NMR (500 MHz, CDCl3) d
;
7.35–7.25 (5H, br m, arom. H), 5.69 (1H, br tt, J ꢀ 10.2, 2.5 Hz; H-9), 5.46 (1H,
br d, J = 10.5 Hz; H-8), 4.88 (1H, m; H-13), 4.68 (1H, d, J = 12.2 Hz; benzyl), 4.63
(1H, m; H-7), 4.40 (1H, d, J = 12.2 Hz; benzyl), 4.16 (1H, dt, J = 11.8, 2.2 Hz; H-
3), 3.30 (1H, br s; H-4), 2.86 (1H, dd, J = 15.2, 11.8 Hz; H-2), 2.76 (1H, m; H-10),
2.20–2.10 (2H, m; H-20, H-6), 2.00 (1H, dq, J = 14, 3.5 Hz; H-5), 1.90 (1H, br d,
J ꢀ 15 Hz; H-100), 1.80–1.50 (5H, br m; H-50, H-11, H-110, H-12, H-120), 1.34
(1H, br dq, J ꢀ 13, 2.5 Hz; H-60), 1.18 (3H, d, J = 6.3 Hz; Me-C13); 13C NMR
Me3Si
(+)-N-methylephedrine
H
OBn
H
(125 MHz, CDCl3)
d 170.6 (C-1), 138.5 (C-9 + aromatic quat. C), 128.3
TPSO
(aromatic), 128.2 (C-8), 127.8, 127.6 (aromatic), 72.5 (C-4), 72.1 (C-13), 70.5
(benzyl CH2), 69.4 (C-3), 69.3 (C-7), 38.4 (C-2), 32.8 (C-12), 27.2 (C-11), 24.7 (C-
10), 24.6 (C-6), 22.1 (C-5), 21.7 (Me-C13).
CHO
10
Zn(OTf)2
, NEt3, tol, RT, 4d
1: oil; Rf on a silica gel TLC plate (hexanes–EtOAc, 60:40): 0.15; [
a
]
ꢁ88.2 (c
D
0.26; MeOH), lit.1
[a
]
D
ꢁ97.2 (c 0.27; MeOH), lit.5
[a
]
D
ꢁ90 (c 0.1; MeOH); IR
m
max 3400 (br, OH), 1732 (lactone C@O) cmꢁ1 1H NMR (500 MHz, C6D6) d 6.19
;
OBn
H
SiMe3
(1H, dddd, J = 15.5, 10.8, 4.8, 1.8 Hz; H-9), 5.64 (1H, br dd, J = 15.5, 4 Hz; H-8),
5.09 (1H, m; H-13), 4.30 (1H, m; H-7), 4.08 (1H, br d, J = 11.4 Hz; H-3), 3.22
(1H, br s; H-4), 2.71 (1H, dd, J = 13.8, 11.6 Hz; H-2), 2.12 (1H, dd, J = 14, 1.7 Hz;
H-20), 2.04 (1H, dddd, J = 13.5, 10.5, 4.8, 2.2 Hz; H-10), 1.85–1.75 (2H, br m; H-
6, H-100), 1.65–1.50 (3H, br m; H-5, H-11, H-12), 1.45–1.30 (3H, br m; H-50, H-
110, H-120), 1.07 (3H, d, J = 6.4 Hz; Me-C13), 1.00 (1H, dddd, J = 14, 4.5, 2.5,
1.3 Hz; H-60); 13C NMR (125 MHz, C6D6) d 169.9 (C-1), 138.2 (C-9), 129.1 (C-8),
71.6 (C-7), 69.9 (C-3), 69.7 (C-13), 67.3 (C-4), 39.9 (C-2), 32.1 (C-12), 30.7 (C-
10), 27.8 (C-5), 25.3 (C-11), 22.6 (C-6), 19.2 (Me-C13).
TPSO
OH
16. (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org.
Chem. 1997, 62, 6974–6977; (b) Paterson, I.; Tudge, M. Tetrahedron 2003, 59,
6833–6849; (c) Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.;
Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem.
Soc. 2006, 128, 14042–14043.