ring-formation strategy to the tricyclic core of the targeted
natural product by an intramolecular alkyne cyclotrimerisation
applying Wilkinson’s catalyst. Furthermore, the option that the
underlying tethered triyne is accessible through a simple
esterification keeps the overall approach very flexible and
should allow syntheses of other members of the alcyopterosin
family—studies that are currently under investigation.
Notes and references
‡ A solution of diyne ester (R)-11 (128 mg, 0.32 mmol) in dry CH2Cl2 (8
mL) was purged with argon for 15 min. After addition of 10 mol% of
[RhCl(PPh3)3] (29 mg, 0.03 mmol) the solution was stirred at 40 °C for 24
h. The reaction was quenched by filtration through a plug of silica gel, that
was thereafter rinsed twice with CH2Cl2 (15 mL). Column chromatography
(silica gel, hexanes–diethyl ether = 7+3 (v/v)) afforded (R)-12 (91 mg,
22
1
71%) as a solid. M.p. 80–82 °C; [a]D 289.2 (c 1.00, CHCl3); H NMR
(400 MHz, CDCl3): d 1.14 (s, 3 H), 1.19 (s, 3 H), 2.31 (s, 3 H), 2.45 (s, 3
H), 2.74 (d, J = 3.6 Hz, 2H), 2.99 (br s, 2H), 4.25 (dd, J = 5.4 and 11.5 Hz,
1H), 4.57 (dd, J = 2.4 and 11.5 Hz, 1H), 5.56 (dd, J = 1.9 and 5.2 Hz, 1H),
7.22 (br s, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 17.9, 21.6, 28.7, 40.9, 44.7, 47.0, 68.2, 78.1, 122.4,
127.9, 129.9, 130.2, 131.9, 132.3, 140.7, 141.3, 145.2, 147.3, 169.8; MS
(EI, 70 eV); m/z (%): 400 (M+, 14); Anal. Calc. for C22H24O5S: C, 65.98;
H, 6.04. Found: C, 66.10; H, 6.17%.
§ NaNO3 (123 mg, 1.45 mmol) and tetrabutylammonium nitrate (228 mg,
0.75 mmol) were added to a solution of (R)-12 (58 mg, 0.15 mmol) in
toluene (5 mL). The reaction mixture was heated to 110 °C for 5 h. Filtration
and subsequent flash chromatography gave (R)-(1) (31 mg, 69%) as a
colourless oil. All spectroscopic data of synthetic (R)-1 were identical to
those of natural alcyopterosin E.1 1H NMR (400 MHz, CDCl3) d 1.16 (s,
3H), 1.19 (s, 3H), 2.40 (s, 3H), 2.75 (br s, 2H), 3.04 (br s, 2H), 4.57 (dd, J
= 12.7 and 6.8 Hz, 1H), 5.06 (dd, J = 12.6 and 2.2 Hz, 1H), 5.66 (dd, J =
6.8 and 2.2 Hz, 1H), 7.27 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 18.0,
28.7, 28.7, 41.0, 169.7, 147.6, 141.8, 140.5, 132.1, 130.2, 122.3, 76.9, 71.6,
47.0, 44.7.
Scheme 1 Reagents and conditions: (i) LDA, THF, 278 °C, add
SiClMe2Ph, 98%; (ii) LDA, THF, 278 °C, add POCl(OEt)2, then addition
of LDA, 278 °C to r.t., 70%; (iii) n-BuLi, THF, 240 °C, add CO2 (gas),
89%; (iv) TBAF, THF, 0 °C, 94%; (v) Zn, CBr4, PPh3, CH2Cl2, 61%; (vi)
n-BuLi (2.2 equiv.), THF, 278 °C, then add MeI; (vii) p-TsOH, MeOH,
61% over two steps; (viii) p-TsCl, pyridine–CH2Cl2, 69%; (ix) DCC,
DMAP, CH2Cl2, 278 °C to rt, 70%; (x) 10 mol% [RhCl(PPh3)3], CH2Cl2,
40 °C, 72%; (xi) NaNO3 (10 equiv.), Bu4NNO3, toluene, 110 °C, 69%.
1 J. A. Palermo, M. F. Rodríguez Brasco, C. Spagnuolo and A. M. Seldes,
J. Org. Chem., 2000, 65, 4482.
2 For a very recent synthesis of alcyopterosin A by metalative Reppe
reactions using stoichiometric amounts of Ti(O-i-Pr)4/2 i-PrMgCl, see:
R. Tanaka, Y. Nakano, D. Suzuki, H. Urabe and F. Sato, J. Am. Chem.
Soc., 2002, 124, 9682.
3 E. Müller, Synthesis, 1974, 761; R. Grigg, R. Scott and P. Stevenson,
Tetrahedron Lett., 1982, 23, 2691; R. Grigg, R. Scott and P. Stevenson,
J. Chem. Soc., Perkin Trans. 1, 1988, 1357; P. Magnus, D. Witty and A.
Stamford, Tetrahedron Lett., 1993, 34, 23; F. E. McDonald, H. Y. H.
Zhu and C. R. Holmquist, J. Am. Chem. Soc., 1995, 117, 6605; B.
Witulski and T. Stengel, Angew. Chem., Int. Ed., 1999, 38, 2426; R.
Grigg, V. Sridharan, J. Wang and J. Xu, Tetrahedron, 2000, 56, 8967;
S. Kotha, K. Mohanraja and S. Durani, Chem. Commun., 2000, 1909; B.
Witulski, T. Stengel and J. M. Fernández-Hernández, Chem. Commun.,
2000, 1965; F. E. McDonald and V. Smolentsev, Org. Lett., 2002, 4,
745.
4 Pterosin Z and calomelanolactone: S. J. Neeson and P. J. Stevenson,
Tetrahedron, 1989, 45, 6239.
5 Clausine C and the marine carbazole alkaloid hyellazole: B. Witulski
and C. Alayrac, Angew. Chem., Int. Ed., 2002, 41, 3281.
6 (S)-3-n-butylphtalide: B. Witulski and A. Zimmermann, Synlett, 2002,
1855.
7 For the syntheses of natural products by cobalt mediated [2+2+2]
cycloadditions, see: (±)-strychnine: M. J. Eichberg, R. L. Dorta, K.
Lamottke and K. P. C. Vollhardt, Org. Lett., 2000, 2, 2479; (±)-LSD: C.
Saá, D. D. Crotts, G. Hsu and K. P. C. Vollhardt, Synlett, 1994, 487;
(+)-g-lycorane: D. B. Grotjahn and K. P. C. Vollhardt, Synthesis, 1993,
579; (±)-illudol: E. P. Johnson and K. P. C. Vollhardt, J. Am. Chem.
Soc., 1991, 113, 381; dl-estrone: R. L. Funk and K. P. C. Vollhardt, J.
Am. Chem. Soc., 1980, 102, 5253.
mol% Wilkinson’s catalyst.‡ Although smooth heating to 40 °C
was required for completion of the reaction, high dilution
conditions appeared to be unnecessary. Treatment of a 0.04 M
solution of (R)-11 (128 mg in 8 mL CH2Cl2) with 10 mol%
[RhCl(PPh3)3] gave (R)-12 as a single product in 72% yield.
Finally, the first synthesis of alcyopterosin E (1) was
completed by nucleophilic displacement of the tosyl protective
group against a nitrate ester functionality. Such a nucleophilic
substitution became feasible in toluene under phase transfer
conditions using both an excess of sodium nitrate and tetrabutyl
ammonium nitrate. Thus synthetic (R)-1 was gained in 69%
yield and showed NMR spectroscopic data which were
superimposable on those of natural alcyopterosin E isolated
from Alcyonium paessleri.§ The optical rotation of the synthetic
25
(R)-configured material ([a]D = 230.5 (c 2.35, CHCl3)) was
25
in agreement with that of the natural product ([a]D = 231.28
(c 2.35, CHCl3)1 and thereby confirming its absolute config-
uration.
Notably, the reported strategy for the synthesis of (R)-
alcyopterosin E (1) also allowed the synthesis of its non-natural
(S)-enantiomer, because glyceraldehyde acetonide 8 is available
8 For intramolecular alkyne cyclotrimerisations mediated by stoichio-
metric amounts of a nickel(0)-complex, see: P. Bhatarah and E. H.
Smith, J. Chem. Soc., Perkin Trans 1, 1992, 2163.
9 D. Felix, J. Schreiber, G. Ohloff and A. Eschenmoser, Helv. Chim. Acta,
1971, 54, 2896.
10 I. Fleming and E. Martínez de Marigorta, J. Chem. Soc., Perkin. Trans
1, 1999, 889.
11 C. Hubschwerlen, Synthesis, 1986, 962; S. Takano, H. Numata and K.
Ogasawara, Heterocycles, 1982, 19, 327.
in either enantiomeric form.12 By starting from
D-mannitol, the
synthesis of (R)-8, (S)-9, (S)-10 and finally the synthesis of the
25
non-natural (S)-alcyopterosin E ([a]D
= +31.1 (c 2.35,
CHCl3)) was realised by applying the same synthesis sequence
as outlined in Scheme 1 for (R)-1.
In conclusion, we have achieved an expedient, asymmetric
synthesis of alcyopterosin E (1) from simple starting materials.
The salient features of our synthesis includes a concise ABC
12 M. E. Jung and T. J. Shaw, J. Am. Chem. Soc., 1980, 102, 6304; D. Y.
Jackson, Synth. Commun., 1988, 18, 337.
CHEM. COMMUN., 2002, 2984–2985
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