ketone 6 in 28% yield. Compound 6 is the sole reaction
product (92% isolated yield) when the reaction of 3b is
carried out in refluxing toluene using the same catalyst.21
The R,â-unsaturated ketone 3a failed to give dimer 5a in
acceptable yields (4%). In fact, the tricyclic ketone 7 was
the main reaction product (72% yield) in this case. Tricyclic
ketone 7 was formed by the RCM reaction of 3a. Minute
amounts of ketone 7, which has a weak woody odor, have
been isolated from the mixture of products obtained in the
treatment of (R)-(+)-sclareolide with Eaton’s reagent (Scheme
3).22 Finally, alkene 3d did not produce the desired ho-
9 in very low yields. Therefore, the terminal double bond,
required for the metathesis reaction, was built in two steps
from the corresponding intermediates 10 and 11. Thus, amide
2 was reacted with 4-lithiobenzaldehyde dimethyl acetal,
yielding 10 in 99% yield. Treatment of 10 with PTSA
monohydrate afforded the corresponding aldehyde, which
was submitted to Lebel’s methylenation conditions ([RhCl(P-
Ph3)3]/Ph3P, i-PrOH/TMSCHN2) to yield ketone 8 in 64%
overall yield from amide 2 (Scheme 4). A similar procedure
Scheme 4
Scheme 3
was used to anchor the ferrocenyl fragment of ketone 9.23
This time, the reaction of amide 2 with lithioferrocene-1,3-
dioxolane gave ketone 11.24 Without further purification, 11
was treated with PTSA affording the corresponding keto
aldehyde, wich was submitted to methylenation using Lebel’s
(20) Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy. High-
Resolution Methods and Applications in Organic Chemistry and Biochem-
istry; VCH: New York, 1987; pp 192-195.
(21) The γ,δ- to R,â-unsaturated ketone isomerization (3b to 6) may be
due to the active participation of Grubbs’ catalyst in the hydride transfer.
However, this process requires the addition of alcohols and bases to the
reaction mixture. See: Schmidt, B. Chem. Commun. 2004, 742 and the
pertinent references therein. In our case, the increased yield of 6 in toluene
pointed to an uncatalyzed thermal isomerization rather to the participation
of Grubbs’ catalyst.
(22) Fra´ter, G.; Helmlinger, D.; Kraft, P. HelV. Chim. Acta 2003, 86,
678.
modimer. Unreacted starting material was recovered in all
reaction conditions tested.
(23) The following procedure was used to prepare compound 9: To a
solution of [RhCl(PPh3)3] (95 mg, 0.10 mmol) and PPh3 (370 mg, 1.4 mmol)
in THF at rt were sequentially added i-PrOH (8.8 mL, 1.4 mmol) and 570
mg, (1.3 mmol) of the corresponding aldehyde in 8 mL of THF. The mixture
was stirred for 10 min to dissolve the catalyst, treated with TMSCHN2 (0.90
mL, 1.8 mmol, 2.0 M solution in Et2O), and stirred at rt during 45 min.
The reaction mixture was diluted with water and extracted with AcOEt.
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified by
The direct addition of 4-lithiostyrene or lithium vinylfer-
rocene to Weinreb’s amide 2 gave the desired ketones 8 and
(18) The following procedure for the metathesis of compound 3b is
representative for the reactions of compounds 3a and 3c: To a previously
degassed DCM (8.8 mL) solution (0.05 M) of the ketone 3b (120 mg, 0.44
mmol) was added the catalyst 4b (19 mg, 0.02 mmol, 5%). The flask was
fitted with a condenser and refluxed for 6 h. The reaction mixture was then
reduced in volume to 0.5 mL and purified by silica gel chromatography
(hexanes/AcOEt ranging from 100:0 to 95:5) to give pure 6 (34 mg, 28%)
as a clear oil and 5b (42 mg, 37%, E/Z ratio 5:1). Data for 5b: IR (film)
νmax 3078, 2928, 2862, 2840, 1716, 1644, 1459, 1441, 1385, 1364, 1202,
silica gel chromatography to yield 220 mg (39%) of 9 as a red oil: [R]22
D
) +140.6 (c 0.34, CHCl3); IR (film) νmax 3085, 2929, 2868, 2844, 1673,
1452, 1380, 1066 cm-1; 1H NMR (CDCl3, 300 MHz) δ 6.34 (dd, J ) 17.5,
10.7 Hz, 1H), 5.35 (d, J ) 17.5 Hz, 1H), 5.13 (d, J ) 10.7 Hz, 1H), 4.75
(br s, 1H), 4.72 (br s, 2H), 4.44 (br s, 1H), 4.41 (br s, 2H), 4.34 (br s, 2H),
4.23 (br s, 2H), 2.83 (dd, J ) 16.7, 9.4 Hz, 1H), 2.67 (dd, J ) 16.7, 3.4
Hz, 1H), 2.61 (br d, J ) 9.4 Hz, 1H), 2.39 (ddd, J ) 11.4, 3.7, 2.3 Hz,
1H), 2.14 (td, J ) 12.9, 5.6 Hz, 1H), 1.75 (m, 1H), 1.65-1.10 (m, 7H),
0.90 (s, 3H), 0.83 (s, 3H), 0.76 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
199.4, 149.2, 141.7, 136.6, 135.9, 128.3, 126.3, 116.5, 106.4, 55.3, 51.5,
41.9, 39.2, 39.0, 37.5, 34.2, 33.6, 33.5, 23.9, 21.7, 19.3, 14.8; MS (EI) m/z
(relative intensity) 444 [M+] (100), 426 (2), 411 (3), 254 (6), 239 (35),
211 (21), 153 (5), 121 (6), 91 (12). Anal. Calcd for C28H36FeO: C, 75.67;
H, 8.16. Found: C, 75.73; H, 8.10.
1093, 971 cm-1 1H NMR (CDCl3, 300 MHz) δ 5.78 (br t, J ) 4.5 Hz,
;
2H), 5.65 (m, 2H), 4.71 (br s, 4H), 4.29 (br s, 4H), 3.18 (m, 8H), 2.61 (dd,
J ) 18.5, 6.7 Hz, 4H), 2.41 (m, 12H), 2.10 (m, 4H), 1.72 (m, 4H), 1.60-
1.00 (m, 28H), 0.88 (s, 12H), 0.80 (s, 12H), 0.68 (s, 12H); 13C NMR (CDCl3,
100 MHz) δ 208.6, 207.7, 149.2, 149.1, 126.5, 124.8, 106.4, 55.1, 51.2,
46.4, 41.9, 41.7, 39.1, 38.9, 38.8, 37.4, 33.5, 33.4, 24.4, 22.1, 19.7, 15.0;
MS (EI) m/z (relative intensity) 502 [M+] (3), 487 (3), 287 (14), 233 (57),
215 (17), 191 (100), 175 (21), 161 (8), 137 (52). Anal. Calcd for
C36H56O2: C, 83.02; H, 10.84. Found: C, 82.93; H, 10.81.
(24) Regioisomeric derivatives were also detected in the crude reaction
mixture.
1
(19) Determined by H NMR.
Org. Lett., Vol. 8, No. 4, 2006
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