overall yield) by exposure to powdered potassium hydroxide,
iodomethane, and catalytic 18-crown-6 in THF.5 The 2:1
mixture of R and â anomers was separated, and the individual
diastereomers were isomerized to the corresponding allenes
5 and 29 by treatment with potassium tert-butoxide at 60
°C for 1 h.6
A series of amides was examined to determine the scope
of the method.11 Table 1 summarizes our results.12 Product
Table 1
Equation 2 summarizes the first cyclization reaction, which
we performed with the R anomer of the asymmetric allene
reagent. R-Deprotonation of the allene ether took place with
n-butyllithium in THF; however, the resulting allenyllithium
species was quite unreactive compared to 1-lithio-1-(meth-
oxy)methoxyallene. Addition of 4 equiv of LiCl7 to the
solution of the anion improved the nucleophilicity so that
addition to morpholino amide 6 took place.8 Cyclization was
induced by transferring the reaction mixture to a solution of
HCl in ethanol at -78 °C. The solution was warmed to room
temperature, worked up, and chromatographed to provide
cyclopentenone 7 in 67% yield with 67% ee.9 Cyclopenten-
one 7 is a key intermediate in our roseophilin synthesis.10
(5) Bessodes, M.; Shamsazar, J.; Antonakis, K. Synthesis 1988, 560-
562.
(6) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1968,
87, 916-924.
(7) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-1654.
(8) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997,
1414-1416.
(9) The enantioselectivities were determined by HPLC on a Daicel
Chiralcel OD (250 mm × 10 mm) chiral column with mixtures of 2-propanol
and hexanes as eluant, with a flow rate of 1 mL/min with UV detection at
254 nm; co-injection with racemate confirmed the peak assignment in the
chromatogram.
(10) Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649-651.
(11) Amides 10, 14, and 16 were prepared by Horner-Emmons condensa-
tion of the corresponding aldehydes with triethyl 2-phosphonopropionate
followed by conversion to the amide; see: Basha, A.; Lipton, M.; Weinreb,
S. M. Tetrahedron Lett. 1977, 18, 4171-4174. Amides 8, 12, 18. and 20
were prepared from the corresponding commercially available acids via
the acid chlorides.
(12) Typical Procedure (entry 1, EtOH quench). To a solution of LiCl
(63 mg, 1.5 mmol) and allene 5 (100 mg, 0.365 mmol) in 1.5 mL of THF
at -78 °C was added n-BuLi (160 µL, 2.28 M in hexanes, 0.365 mmol).
After 30 min, a solution of amide 6 (38 mg, 0.16 mmol) in 1.5 mL of THF
was added at -78 °C via cannula. After 1 h the reaction mixture was
quenched by rapid addition through a large bore cannula to 5% (v/v) aqueous
HCl in 3 mL of EtOH at -78 °C. The flask was removed from the cooling
bath and diluted with pH 7 buffer, brine, and EtOAc. The aqueous phase
was extracted with EtOAc (3×), and the combined aqueous extracts were
washed with brine and dried (MgSO4). Purification by flash column
chromatography on silica (5% EtOAc in hexanes) gave cyclopentenone 7
(22 mg, 67% yield, 67% ee) as a colorless oil: Rf ) 0.35 (20% EtOAc in
hexanes); 1H NMR (300 MHz, CDCl3) δ 6.89 (br s, 1H), 6.10 (s, 1H),
5.83 (ddt, J ) 17.1, 10.5, 6.1 Hz, 1H), 5.41 (s, 1H), 5.07 (dd, J ) 17.1, 1.5
Hz, 1H), 4.99 (br d, J ) 10.5 Hz, 1H), 3.20 (br s, 1H), 2.77 (m, 1H),
2.45-2.22 (m, 3H), 2.15 (sept d, J ) 7.1, 2.9 Hz, 1H), 1.10 (d, J ) 7.1
Hz, 3H), 0.65 (d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 189.8,
151.1, 144.4, 141.7, 137.4, 116.7, 115.3, 47.1, 30.7, 29.1, 25.9, 21.7, 16.3;
IR (neat) 3310 (br), 2965, 1680, 1625, 1395, 1095, 915, 820 cm-1; MS
m/z 206 (M+, 35), 164 (79), 163 (100), 135 (65), 123 (91), 122 (43), 117
(36); exact mass calcd for C13H18O2 206.1307, found 206.1283; chiral HPLC
(2.5% 2-propanol in hexanes) tR ) 23.7 min (major), tR ) 25.3 min (minor);
yields varied between 42% and 71%, whereas enantiomeric
excesses varied between 41% and 67%, with no clear trends
in evidence. In one case (entry 9) racemic product was
obtained (vide infra). The absolute stereochemistry of 11 was
[R]27D +5° (c 0.0080, CHCl3). Typical Procedure (entry 1, HFIP quench).
To a solution of LiCl (83 mg, 2.0 mmol) and allene 5 (155 mg, 0.565 mmol)
in 3 mL of THF at -78 °C was added n-BuLi (245 µL, 2.44 M in hexanes,
0.598 mmol). After 30 min, a solution of amide 6 (71 mg, 0.30 mmol) in
3 mL of THF at -78 °C was added via cannula. After 1 h, the reaction
mixture was quenched by rapid addition through a large bore cannula to
HCl (generated by addition of 750 µL of acetyl chloride) in 6 mL of HFIP
at 0 °C. The flask was removed from the cooling bath and diluted with pH
7 buffer, brine, and EtOAc. The aqueous phase was extracted with EtOAc
(3×), and the combined organic extracts were washed with brine and dried
(MgSO4). Purification by flash column chromatography on silica (5% EtOAc
in hexanes) gave cyclopentenone 7 (32 mg, 52% yield, 68% ee) as a
colorless oil.
2448
Org. Lett., Vol. 2, No. 16, 2000