Synthesis of the spiroacetal parts of spirofungin A and B

Article abstract of DOI:10.1016/S0040-4039(00)00371-3

The C9-C20 spiroacetal parts of spirofungin A and B, antifungal antibiotics from Streptomyces violaceusniger Tu 4113, were synthesized simultaneously from (S)-citronellyl bromide and (±)-epoxy alcohol via alkyne-lactone coupling reaction and diastereomeric separation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00371-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3141–3144
Synthesis of the spiroacetal parts of spirofungin A and B
Yuko Shimizu, Hiromasa Kiyota ∗ and Takayuki Oritani
Department of Applied Bioorganic Chemistry, Division of Life Science, Graduate School of Agricultural Science,
Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Received 27 January 2000; revised 21 February 2000; accepted 25 February 2000
Abstract
The C9–C20 spiroacetal parts of spirofungin A and B, antifungal antibiotics from Streptomyces violaceusniger
Tü 4113, were synthesized simultaneously from (S)-citronellyl bromide and (±)-epoxy alcohol via alkyne–lactone
coupling reaction and diastereomeric separation. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: spiro compounds; antibiotics; lactonization; polyketides.
Spirofungin A and B were isolated from the culture extracts of Streptomyces violaceusniger Tü 4113
as new polyketide-type antibiotics (Fig. 1).1 These compounds showed various antifungal activities
especially against yeasts.1 The relative configuration of them quite resembles reveromycin A,2 an
inhibitor of the mitogenic activity of epidermal growth factor (EGF), except C18 position: spirofungins
lack succinate residue and have methyl group instead of n-butyl group. As homologues of promising
anticancer agents reveromycins, total synthesis and structure confirmation of spirofungins are to be
expected. For the total synthesis of spirofungins, we planned that the whole structures were disconnected
to a core spiroacetal part and two side chains. Here we describe the synthesis of the spiroacetal cores of
spirofungin A and B.
Fig. 1.
Our synthetic plan is shown in Scheme 1. We assumed the absolute configurations of the spiroacetal
cores of spirofungin A (1) and B (2) to be (11R,12S,15S,18S,19R) and (11R,12S,15S,18R,19S), respec-
∗
Corresponding author. Tel/fax: +81-22-717-8783; e-mail: kiyota@biochem.tohoku.ac.jp (H. Kiyota)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00371-3
tetl 16651

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tively, by analogy to reveromycin A.3 As our targets 1 and 2 were expected to be normally separable due
to the diastereomeric nature, we planned to synthesize these cores as a diastereomeric mixture from a
coupling reaction of a racemic part [(±)-3] and an optically active counterpart (4).4 The racemic alkyne
(±)-3 was to be prepared from the known epoxy alcohol (±)-5 according to the literature,5,6 and the
lactone 4 could be converted from (S)-citronellyl bromide (6).
Scheme 1. Retrosynthetic plan for spirofungin A and B
Synthesis of the alkyne part [(±)-3] started from (±)-5 (Scheme 2). The epoxy ring was substituted
with methyl group5 and the resulting 1,2- and 1,3-diols were converged to a single triol (±)-76 after the
removal of benzyl group. The vicinal diol part was selectively protected as dioxolane acetal7 to give (±)-
8. The remaining hydroxy group was converted to the desired alkyne [(±)-3] via Corey–Fuchs method.8
The yield from (±)-5 was 40% in six steps.
Scheme 2. Synthesis of racemic alkyne part. (a) (i) MeMgI, CuI, THF, −78∼20°C (86%, 1,3-/1,2-diol=3.5/1); (ii) H2, Pd–C,
EtOH. (b) 3-Pentanone, TsOH, rt (83%, two steps). (c) (i) Dess–Martin oxidation, 0°C; (ii) Ph3P, CBr4, Zn, CH2Cl2 (70%, two
steps); (iii) n-BuLi, THF, −78°C (81%)
The asymmetric center of the lactone part (4) was derived from (S)-citronellyl bromide (6) (Scheme
3).9 The double bond of 6 was cleaved to give bromoaldehyde 9.10 Dehydrobromination of 9 to form
the olefin with t-BuOK was successful only after conversion to the corresponding trityl ether (10). In the
cases of ethylene acetal and O,O0-xylenedioxy acetal of 9, undesired t-butoxy ether formation competed.
After the double bond was oxidized with OsO4 and cleaved with NaIO4, the resulting aldehyde was
coupled with Wittig reagent (Ph3P_CHCO2Me) to afford unsaturated ester 12. The ester group was
reduced and the formed hydroxy group was protected as benzyl ether. Then, removal of trityl group
and Jones oxidation gave carboxylic acid 14. This was subjected to thermodynamically controlled
iodolactonization to give 15. Undesired cis-isomer was easily separated by silica gel chromatography.
Finally, the iodo group was removed to give the lactone 4 {[α]D +84° (c 1.0, i-Pr2O)}. The yield from 6
was 19% in 14 steps.
As the required segments were prepared, coupling reaction was examined. Alkynyl anion derived from
(±)-3 was treated with the lactone (+)-4 to afford the desired alkynyl ketone 16 in 78% yield (Scheme
4). Since direct reduction of the triple bond to single bond was unsuccessful (giving a complex mixture),
we did this reduction step by step. Treatment of 16 with hydrogen in the presence of Lindlar catalyst

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Scheme 3. Synthesis of lactone part [(+)-4]. (a) (i) MCPBA, CHCl3; (ii) NaIO4, THF/H2O. (b) (i) NaBH4, MeOH; (ii) TrCl,
pyridine, DMAP, DMF (74% from 6). (c) t-BuOK, DMSO, pentane (95%). (d) (i) OsO4, NMO, THF–H2O; (ii) NaIO4 (pH 6);
(iii) methyl (triphenylphosphoranylidene)acetate, toluene (79%, E/Z=95/5; and 20% of 11); (iv) separation (SiO2 column). (e)
(i) DIBAL, THF; (ii) BnBr, NaH, THF (93%). (f) (i) 1 M HCl aq.–THF; (ii) Jones oxidation (70%). (g) (i) I2, CH3CN, 0°C; (ii)
separation (SiO2) (42%). (h) (n-Bu)3SnH, toluene (quant.)
gave enone 17. Spiroacetalization from this enone also failed in the formation of a tricyclic compound by
the initial 1,4-addition of the primary hydroxy group to the enone moiety followed by spiroacetalization
with the remaining secondary hydroxy group. Thus, the double bond was further hydrogenated over
Pd–BaSO4 catalyst. In this reaction, acetal exchange with MeOH occurred to form monocyclic acetal 18.
Finally, treatment with TsOH afforded the desired spiroacetals 111 and 2,12 which were easily separated
by silica gel column chromatography: the Rf of 1 was 0.71 while that of 2 was 0.43 (SiO2 coated TLC,
hexane:EtOAc=1:1). The stereochemistry of 1 and 2 was confirmed by 1H–1H COSY, HMQC and NOE
experiments. The total yields were 6.7% for 1 and 3.4% for 2 from (S)-citronellyl bromide. Preparation
of other side chain parts and total synthesis of spirofungin A and B are in progress.
Scheme 4. Synthesis of spiroacetal parts of spirofungin A and B. (a) n-BuLi, Et2O, −20°C, 30 min, then (+)-4 (78%). (b) H2,
Lindlar cat., MeOH (quant.). (c) H2, Pd–BaSO4, MeOH (quant.). (d) TsOH, CHCl3, rt 24 h (45% for 1 and 23% for 2)
Acknowledgements
Our thanks are due to Takasago International Corporation for the gift of (S)-citronellal.

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References
1. Höltzel, A.; Kempter, C.; Metzger, J. W.; Jung, G.; Groth, I.; Fritz, T.; Fiedler, H.-P. J. Antibiot. 1989, 51, 699–707.
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, T.; Osada, H.; Koshino, H.; Sasaki, M.; Onose, R.; Nakakoshi, M.; Yoshihama, M.; Isono, K.
J. Antibiot. 1992, 45, 1414–1419.
3. (a) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J. Antibiot. 1992, 45, 1420–1427. (b) Ubukata, M.; Koshino, H.; Osada,
H.; Isono, K. J. Chem. Soc., Chem. Commun. 1994, 1877–1878.
4. Constructions of spiroacetal compounds by an analogous methodology were reported: (a) Phillip, C.; Jacobson, R.;
Abrahams, B.; Williams, H. J.; Smith, L. R. J. Org. Chem. 1980, 45, 1920–1924. (b) Baker, R.; Herbert, R. H.; Parton,
A. H. J. Chem. Soc., Chem. Commun. 1982, 601–603. For a review on the construction of spiroacetals, see: (c) Vaillancourt,
V.; Pratt, N. E.; Perron, F.; Albizati, K. F. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley & Sons:
New York, 1992; Vol. 8, pp. 533–691.
5. Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131–4132.
6. Preparation of both enantiomers of 7 was reported: Mori, K.; Nomi, H.; Chuman, T.; Kohno, M.; Kato, K.; Noguchi, M.
Tetrahedron 1982, 38, 3705–3711.
7. Lavalée, P.; Ruel, R.; Grenier, L.; Bissonnette, M. Tetrahedron Lett. 1986, 27, 679–682.
8. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–3772.
9. (S)-Citronellyl bromide was prepared from (S)-citronellal in three steps [(i) NaBH4, MeOH; (ii) TsCl, Et3N; (iii) NaBr, DMF
(total 80%)].
10. Preparation of racemic 9 was reported: Molander, G. A.; Harris, C. R. J. Org. Chem. 1997, 62, 7418–7429.
19
1
11. Compound 1: [α]D +68° (c 0.14, i-Pr2O). H NMR (500 MHz, CDCl3) δ 0.85 (d, 3H, J=6.5 Hz, 12-Me), 0.89 (d, 3H,
J=7.0 Hz, 18-Me), 1.33 (m, 1H, H-12), 1.35 (m, 1H, H-13), 1.41 (m, 1H, H-14), 1.48 (m, 1H, H-16), 1.52 (m, 1H, H-17),
1.55 (m, 1H, H-17), 1.57 (m, 1H, H-10), 1.63 (m, 1H, H-14), 1.65 (m, 1H, H-18), 1.66 (m, 1H, H-16), 2.03 (m, 1H, H-13),
2.06 (m, 1H, H-10), 3.39 (m, 1H, H-20), 3.43 (m, 1H, H-11), 3.56 (m, 1H, H-20), 3.65 (m, 1H, H-9), 3.74 (m, 1H, H-9),
3.77 (m, 1H, H-19), 4.50 (s, 2H, CH2OPh), 7.26–7.38 (m, 5H, Ph). 13C NMR (125 MHz, CDCl3) δ 11.57 (18-Me), 17.76
(12-Me), 26.59 (C-13), 28.09 (C-17), 28.15 (C-18), 30.25 (C-14), 33.17 (C-10), 35.15 (C-12), 35.64 (C-16), 64.57 (C-20),
67.11 (C-9), 71.26 (C-12), 71.69 (C-19), 73.05 (CH2OPh), 95.51 (C-15), 127.57, 127.71, 128.36, 138.45 (Ph). FABMS
(NOBA) m/z: 349 (M+H)+; HR-EIMS calcd for C21H32O4: 348.2301, found: 348.2303.
19
1
12. Compound 2: [α]D +35° (c 0.10, i-Pr2O). H NMR (500 MHz, CDCl3) δ 0.86 (d, 3H, J=6.5 Hz, 12-Me), 0.92 (d, 3H,
J=7.0 Hz, 18-Me), 1.31 (m, 1H, H-13), 1.33 (m, 1H, H-17), 1.37 (m, 1H, H-12), 1.37 (m, 1H, H-16), 1.56 (m, 1H, H-14),
1.64 (m, 1H, H-14), 1.65 (m, 1H, H-10), 1.65 (m, 1H, H-13), 1.73 (m, 1H, H-18), 1.82 (m, 1H, H-17), 2.03 (m, 1H, H-10),
2.07 (m, 1H, H-16), 3.25 (dd, 1H, J=9.5, 10.5 Hz, H-11), 3.48 (m, 1H, H-20), 3.63 (m, 1H, H-20), 3.65 (m, 1H, H-9), 3.72
(m, 1H, H-9), 4.24 (m, 1H, H-19), 4.51 (s, 2H, CH2OPh), 7.28–7.40 (m, 5H, Ph). 13C NMR (125 MHz, CDCl3) δ 12.38
(18-Me), 18.15 (12-Me), 23.36 (C-16), 26.48 (C-17), 28.97 (C-18), 30.21 (C-13), 34.54 (C-10), 36.07 (C-12), 37.19 (C-14),
65.17 (C-20), 67.82 (C-9), 73.52 (C-19), 75.55 (C-11), 73.84 (CH2OPh), 98.11 (C-15), 128.25, 128.51, 129.07, 139.35 (Ph).
FABMS (NOBA) m/z: 349 (M+H)+; HR-EIMS calcd for C21H32O4: 348.2301, found: 348.2298.