Efficient synthesis of the 6,6-spiroacetal of spirofungin A

Article abstract of DOI:10.1016/S0040-4039(03)01184-5

The 6,6-spiroacetal segment of spirofungin A, an antifungal antibiotic isolated from Streptomyces violaceusniger Tü 4113, was efficiently prepared via the coupling reaction of the Weinreb amide and the alkyne which are readily available from the common in

Full text of DOI:10.1016/S0040-4039(03)01184-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4965–4968
Efficient synthesis of the 6,6-spiroacetal of spirofungin A
Takeshi Shimizu,* Junichi Kusaka, Haruaki Ishiyama and Tadashi Nakata
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan
Received 14 April 2003; revised 9 May 2003; accepted 9 May 2003
Abstract—The 6,6-spiroacetal segment of spirofungin A, an antifungal antibiotic isolated from Streptomyces violaceusniger Tu¨
4113, was efficiently prepared via the coupling reaction of the Weinreb amide and the alkyne which are readily available from the
common intermediate. The synthesis includes the unsymmetrization through a stereoinversion at the C11 position and the
transacetalization as the key steps. © 2003 Elsevier Science Ltd. All rights reserved.
Spirofungins A (1) and B (2) are novel polyketide-type
antibiotics isolated from Streptomyces violaceusniger Tu¨
4113 as a 4:1 mixture of 1:2 and show various antifun-
gal activities, particularly against yeasts.1 The molecu-
lar structures of 1 and 2 are characterized by a
6,6-spiroacetal core bearing two unsaturated side chains
ending in carboxylic acid units and two methyl groups.
The relative configuration of the spiroacetal core in 1 is
quite similar to reveromycin A (3), a potent inhibitor of
mitogenic activity induced by the epidermal growth
factor.2 The absolute configuration depicted for 1 was
proposed by analogy with 3 and remains unconfirmed
(Fig. 1).3,4 We have already reported the first asymmet-
ric total synthesis of 3 (Fig. 2).5 In connection of our
studies concerning the chemical modifications and
structure–activity relationships of 3,6 we planned to
synthesize 1 and to confirm the relative and absolute
configuration of 1.
Our retrosynthetic analysis of spirofungin A (1) is
shown in Scheme 1. The unsaturated left and right side
chains should be produced by the Horner–Wadsworth–
Emmons reaction and Negishi coupling reaction.5,7 The
Figure 1. Provisional structures of spirofungins A (1) and B
(2).
Figure 2. Structure of reveromycin A (3).
Keywords: spirofungin A; antifungal; 6,6-spiroacetal; Weinreb amide.
* Corresponding author. Tel.: +81-48-467-9375; fax: +81-48-462-4666;
e-mail: tshimizu@postman.riken.go.jp
Scheme 1. Retrosynthetic analysis of spirofungin A (1).
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01184-5

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T. Shimizu et al. / Tetrahedron Letters 44 (2003) 4965–4968
Scheme 2. Reagents and conditions: (a) (+)-DET, Ti(Oi-Pr)4,
t-BuOOH, MS-4A, CH2Cl2, −25°C (88%); (b) (COCl)2,
DMSO, CH2Cl2, −78°C; Et3N, −78°C to rt; (c)
Ph3PꢀCHCO2Me, benzene, rt (82%, two steps); (d)
Pd2(dba)3·CHCl3, n-Bu3P, HCO2H–Et3N, dioxane, rt (96%).
construction of 5 could be achieved by the intramolecu-
lar acetalization of the ketone 6 derived from ketone 7
through a stereoinversion at the C11 position. The
symmetrical ketone 7 would be synthesized via the
coupling reaction of the lactone 8 or Weinreb amide 9
and alkyne 10, which in turn might be prepared from a
common precursor 11. The vinyl iodide 4 for the
Negishi coupling could also be prepared from 11.
Scheme 3. Reagents and conditions: (a) H2, Pd/C, AcOEt, rt
(99%); (b) CSA, benzene, 70°C (72%); (c) Me2AlCl,
(MeO)MeNH·HCl, CH2Cl2, 0°C to rt; (d) TESCl, imidazole,
DMAP, DMF, rt (92%, two steps); (e) TBSCl, imidazole,
DMF, 0°C to rt (99%); (f) OsO4, NMO, acetone-H2O-t-
BuOH, rt; (g) Pb(OAc)4, toluene, rt; (h) CBr4, Ph3P, Et3N,
CH2Cl2, 0°C to rt (93%, three steps); (i) n-BuLi, THF, −78°C
to rt (91%).
First, the common precursor 11 was prepared. The
Sharpless epoxidation8 of the allyl alcohol 129, which
was readily prepared from cis-2-buten-1,4-diol, with
t-BuOOH in the presence of (+)-DET and Ti(Oi-Pr)4
gave the epoxide 13 in 88% yield (90% ee).10 The Swern
oxidation of 13 followed by the Wittig reaction with
Ph3PꢀCHCO2Me afforded the ester 15 in 82% yield in
two steps. The palladium-catalyzed hydrogenolysis of
15 was performed with Pd2(dba)3·CHCl3 in the presence
of n-Bu3P–HCO2H–Et3N to stereoselectively afford the
syn-alcohol 11 (96%) (Scheme 2).11
95% yield. It is important to note that the C19-hydroxyl
group forms the acetal with the C15-carbonyl group
distinguished from the C11-hydroxyl group. The next
task is the introduction of propyne through a stereo-
inversion at the C11 position. The TBS group in 22 was
deprotected with n-Bu4NF to give the alcohol, which
was immediately treated with MsCl in pyridine to
afford the mesylate 23. The treatment of 23 with DDQ
effected deprotection of both MPM groups and simul-
taneous transacetalization to give the stable hydroxyl
bicyclic acetal 24 (80%, three steps). The mesylate was
treated with K2CO3 in MeOH to provide the epoxide
25 in 93% yield. The epoxide 25 was reacted with
propyne and n-BuLi in the presence of BF3·OEt2 to
afford the alcohol 26 with the desired configuration at
the C11 position.14 The remaining task is formation of
the 6,6-spiroacetal core by the transacetalization of 26.
The treatment of 26 with CSA in CH2Cl2 at room
temperature gave an equilibrium mixture of 26 and the
6,6-spiroacetal alcohols 5a and 27a (3:3:2) which was
selectively acetylated by an addition of collidine and
AcCl at −78°C to provide a mixture of the secondary
alcohol 26 and the 6,6-spiroacetal acetates 5b and 27b.15
These successive treatments were repeated four times in
one pot and the desired 6,6-spiroacetal 5b16 and the
isomer 27b were obtained in 46 and 30% yields, respec-
tively (Scheme 4). The stereostructures of 5b and 27b
were confirmed by the extensive NMR analyses (1H,
13C NMR, NOE and HMBC). The vicinal coupling
constant between H11 and H12 (J=10.8 Hz) in 5b
reflects the diaxial position of the two protons. The
vicinal coupling constant between H18 and H19 (J=4.4
Hz) as well as the chemical shift of the C18-Me (15.0
ppm) indicate that H18 is axial and H19 is equatorial.
The NOEs between H20 and H11, H17 axial also
proved that 5b has the same conformation as that of
spirofungin A (1) as shown in Figure 3.
Next, all of the segments 8, 9 and 10 were prepared
from 11. The hydrogenation of 11 on Pd/C gave the
saturated alcohol 16 (99%), which was then treated with
CSA to afford the lactone 8 (72%). The methyl ester 16
was converted into the Weinreb amide 9 by treatment
with Me2AlCl–(MeO)MeNH·HCl12 followed by silyla-
tion with TESCl. The alkyne 10 was synthesized from
11. After protection of the hydroxyl group in 11 as the
TBS ether (99%), the olefin 18 was oxidatively cleaved
by successive treatment with OsO4-NMO and Pb(OAc)4
to afford the aldehyde 19. The aldehyde 19 was then
treated with CBr4–Ph3P in the presence of Et3N to
produce the dibromoolefin (93%, three steps), which
was converted into the alkyne 10 by treatment with 2
equiv. of n-BuLi (Scheme 3).13
The stage was then set for the construction of the
6,6-spiroacetal. The treatment of 10 with n-BuLi fol-
lowed by the addition of 8 afforded the coupling
product 20a in 23% yield together with the recovered 10
(65%). On the other hand, 9 produced 20 in 81% yield
by a similar treatment with 10. Then, 20b was hydro-
genated on Pd/C to give the saturated ketone 21 (99%),
which is a latent C2 symmetric compound. Selective
cleavage of the TES group in 21 followed by simulta-
neous acetalization was performed with PPTS in
MeOH at room temperature to give the acetal 22 in

T. Shimizu et al. / Tetrahedron Letters 44 (2003) 4965–4968
4967
Scheme 4. Reagents and conditions: (a) LHMDS, THF, −78°C to rt (20a from 8, 23%; 20b from 9, 91%); (b) H2, Pd/C, AcOEt,
rt (99%); (c) PPTS, MeOH, rt (95%); (d) TBAF, DMF, rt; (e) MsCl, pyridine, 0°C to rt; (f) DDQ, CH2Cl2–H2O, rt (80%, three
steps); (g) K2CO3, MeOH, rt (93%); (h) propyne, n-BuLi, BF3·OEt2, THF, −78°C to rt (99%); (i) CSA, CH2Cl2, rt then AcCl,
collidine, −78°C (four times repeated) (5b, 46%; 27b, 30%).
2. (a) Takahashi, H.; Osada, H.; Koshino, H.; Kudo, T.;
Amano, S.; Shimizu, S.; Yoshihama, M.; Isono, K. J.
Antibiot. 1992, 45, 1409–1413; (b) Takahashi, H.; Osada,
H.; Koshino, H.; Sasaki, M.; Onose, R.; Nakakoshi, M.;
Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414–
1419; (c) Koshino, H.; Takahashi, H.; Osada, H.; Isono,
K. J. Antibiot. 1992, 45, 1420–1427.
3. Ubukata, M.; Koshino, H.; Osada, H.; Isono, K. J.
Chem. Soc., Chem. Commun. 1994, 1877–1878.
4. Shimizu, Y.; Kiyota, H.; Oritani, T. Tetrahedron Lett.
2000, 41, 3141–3144.
5. Shimizu, T.; Masuda, T.; Hiramoto, K.; Nakata, T. Org.
Lett. 2000, 2, 2153–2156.
6. Shimizu, T.; Usui, T.; Machida, K.; Furuya, K.; Osada,
H.; Nakata, T. Bioorg. Med. Chem. Lett. 2002, 12, 3363–
Figure 3. 1H, 13C NMR and NOE data of spiroacetals 5b and
3366.
27b.
7. (a) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912–
4913; (b) Drouet, K. E.; Theodorakis, E. A. J. Am.
Chem. Soc. 1999, 121, 456–457.
In summary, the segments, Weinreb amide 9 and
alkyne 10, were readily prepared from the common
intermediate 11. In turn, the 6,6-spiroacetal core 5b was
efficiently synthesized via the coupling reaction of 9 and
10, the unsymmetrization by the reaction of the epoxide
with propyne through a stereoinversion at the C11
position and the transacetalization to form the 6,6-
spiroacetal.
8. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5976–5978; (b) Gao, Y.; Hanson, R. M.; Klunder, J.
M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765–5780; (c) Kolb, H. C.; Van-
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9. (a) Terashima, S.; Hashimoto, M.; Matsumoto, M.;
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10. The optical purity was determined to be >90% ee by the
1H NMR analyses of the corresponding MTPA esters.
11. Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji,
J. J. Am. Chem. Soc. 1989, 111, 6280–6287.
12. Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett.
1997, 38, 2685–2688.
Acknowledgements
We thank Dr. H. Koshino for the NMR measurements
and Ms. K. Harata for the mass spectral measurements.
13. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–
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T. Shimizu et al. / Tetrahedron Letters 44 (2003) 4965–4968
16. Data for 5b: [h]D24: −69.1 (c 1.17, C6D6); IR (neat):
H19), 3.91 (ddd, J=10.8, 5.4, 2.4 Hz, H11), 4.27 (dd,
J=11.2, 4.4 Hz, H20), 4.47 (dd, J=11.2, 8.3 Hz, H20);
13C NMR (150 MHz, C6D6) l 3.6, 15.0, 18.0, 24.1, 25.4,
27.8, 31.2, 33.7, 34.2, 34.7, 64.8, 74.2, 74.5, 76.3, 76.9,
96.8, 170.0; HRMS (FAB) calcd for C18H29O4 (M++H+)
309.2066, found 309.2084.
1
wmax=2930, 1743, 1458, 1370, 1239 cm−1; H NMR (600
MHz, C6D6) l 0.72 (d, J=7.3 Hz, C18-Me), 0.81 (d,
J=6.9 Hz, C12-Me), 1.58 (t, J=2.4 Hz, C8-Me), 1.75 (s,
Ac), 2.40 (ddq, J=17.1, 5.4, 2.4 Hz, H10), 2.55 (ddd,
J=17.1, 2.4, 2.4 Hz, H10), 3.81 (ddd, J=8.3, 4.4, 4.4 Hz,