SCHEME 4. Tentative Mechanism for Pd(II)-Mediated
Alkynediol Spiroketalization
(3S,4S,6S,9R) and (3S,4S,6R,9R), respectively. As a result of
convergence at an advanced stage and the late stage installation
of the key spirocyclic core, the present approach leaves ample
room for the synthesis of related natural products.
Experimental Section
Coupling of 10 and 11. At -40 °C, a solution of 10 (1.6 g,
5.37 mmol) in THF (40 mL) and HMPA (5 mL) was treated with
n-BuLi (4 mL, 1.6 M in hexanes, 6.44 mmol) and stirred for 20
min. A solution of compound 11 (2.0 g, 6.44 mmol) in THF (5
mL) was added dropwise and the mixture was stirred for 1 h at
-30 °C. The reaction was quenched by saturated NH4Cl solution
(10 mL) then the mixture was extracted with ethyl acetate. The
combined organic phase was washed with brine, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The purification
of residue by silica gel column chromatography (7% ethyl acetate
in petroleum ether) gave 17 (1.77 g, 68% yield) as a colorless oil.
[R]25D +15.3 (c 1.7, CHCl3). IR (CHCl3) ν 2956, 2931, 2828, 2238,
A tentative mechanism for Pd-mediated spiroketalization of
9 is given in Scheme 4. The reaction will be initiated by the
π-activation of the alkyne. A 5-exo-dig mode of addition of
the C(9)-OH and subsequent protodepalladation of the resulting
vinylpalladium intermediate leads to the formation of the exo-
enol ether intermediate and thus regenerates the Pd(II) catalyst.10
The regiochemistry of the nucleophilic addition could be
explained by considering the -I effect of the furanosyl ring.8i
The exo-enol ether intermediate upon exposure to in situ
generated acid leads to the formation of an oxy-carbenium
cation. The addition of the C(3)-OH to the incipient oxy-
carbenium cation affords the spiroketals 8. The lack of regi-
oselectivity in spiroketalization is indicative of the conforma-
tional flexibility along the C(5)-C(6) bond.
After examining a set of reaction conditions, the deprotection
of 1,2-acetonide could be conducted successfully by using 40%
acetic acid at 80 °C (oil bath temperature) for 4 h to obtain a
mixture of lactols 18 in 65% yield along with 20% of unreacted
8. Selective oxidation of lactols 18 under Fe´tizon’s conditions15
employing Ag2CO3/Celite gave lactones 19 and 20 which were
separated and characterized. The relative configuration of the
newly created spiro center in compounds 19 and 20 was assigned
by comparing the multiplicity and coupling constants of H-C(4)
and H-C(5) with the reported values of 1, 2, and 4 - 7 (Table
1, Supporting Information). The assigned configuration of
compound 19 was further confirmed with the help of single
crystal X-ray analysis (Supporting Information).16,17 The R-hy-
droxy function of 19 and 20 was subjected to Barton-McCombie
deoxygenation18 through the phenylthionocarbonate intermedi-
ates to afford 21 and 22, respectively.
1
1472, 1376, 1256, 1218, 1131, 1082, 1018, 838 cm-1. H NMR
(CDCl3, 500 MHz) δ 0.03 (2s, 6H), 0.12, 0.13 (2s, 6H), 0.86 (s,
9H), 0.91 (s, 9H), 1.10 (d, J ) 6.1 Hz, 3H), 1.29 (s, 3H), 1.46 (s,
3H), 1.60 (dd, J ) 1.7, 5.9 Hz, 1H), 1.62 (d, J ) 17.4 Hz, 1H),
2.22 (ddt, J ) 2.0, 8.0, 16.8 Hz, 1H), 2.31 (ddt, J ) 2.0, 7.2, 16.8
Hz, 1H), 3.86 (sextet, J ) 6.1 Hz, 1H), 4.12 (d, J ) 2.5 Hz, 1H),
4.37 (d, J ) 3.6 Hz, 1H), 4.78 (dd, J ) 2.1, 4.3 Hz, 1H), 5.93 (d,
J ) 3.6 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ -5.0 (q), -4.9
(q), -4.8 (q), -4.4 (q), 15.2 (t), 18.0 (s), 18.3 (s), 23.5 (q), 25.7
(3q, 3C), 25.8 (3q, 3C), 26.2 (q), 26.8 (q), 38.0 (t), 67.1 (d), 72.5
(d), 74.1 (s), 77.3 (d), 85.2 (d), 88.7 (s), 104.5 (d), 111.6 (s) ppm.
ESI-MS m/z 485 (6%, [M + 1]+), 502 (21%, [M + NH4]+), 507
(100%, [M + Na]+), 523 (13%, [M + K]+). Anal. Calcd for
C25H48O5Si2: C, 61.93; H, 9.98. Found: C, 61.84; H, 10.03.
Cycloisomerization of Alkynediol 9. A solution of 9 (300 mg,
1.17 mmol) and PdCl2(CH3CN)2 (15 mg, 0.06 mmol) in dry CH3CN
(25 mL) under argon atmosphere was stirred at rt for 4 h. The
reaction mixture was concentrated and the crude was purified by
silica gel column chromatography (10% ethyl acetate in petroleum
ether) to afford 8 (186 mg, 62% yield) as a viscous, colorless oil.
1
IR (CHCl3) ν 2980, 1458, 1383, 1218, 1164, 1058, 891 cm-1. H
NMR (CDCl3, 200 MHz) δ 1.19, 1.26 (2d, J ) 6.2 Hz, 3H), 1.29,
1.32 (2s, 3H), 1.45, 1.46 (2s, 3H), 1.70-2.37 (m, 6H), 4.05-4.21
(m, 1H), 4.52-4.61 (m, J ) 3.3, 4.2 Hz, 2H), 4.87 (ddd, J ) 1.5,
3.3, 5.2 Hz, 0.5H), 5.00 (t, J ) 5.2 Hz, 0.5H), 5.88 (d, J ) 3.8 Hz,
0.5H), 6.02 (d, J ) 3.6 Hz, 0.5H). 13C NMR (CDCl3, 50 MHz) δ
21.0 (q), 22.7 (q), 26.6 (q), 27.1 (q, 2C), 27.7 (q), 31.1 (t), 32.5 (t),
35.0 (t), 38.0 (t), 42.3 (t), 43.0 (t), 74.9 (d), 76.2 (d), 83.1 (d), 83.2
(d), 83.7 (d), 85.3 (d), 86.2 (d), 86.4 (d), 106.7 (d), 106.8 (d), 111.6
(s), 112.3 (s), 115.5 (s), 116.5 (s) ppm. ESI-MS m/z 257 (19%, [M
+ 1]+), 279 (100%, [M + Na]+), 295 (18%, [M + K]+). Anal.
Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 60.84; H, 7.94.
Oxidation of Lactols 18. A suspension of lactols 18 (150 mg,
0.69 mmol) and Ag2CO3 impregnated on Celite (1.19 g, 2.08
mmol, contains 1 mmol of Ag2CO3 per 0.57 g of prepared
reagent) in toluene (15 mL) was heated at reflux for 3 h. The
reaction mixture was cooled to room temperature and filtered
through a pad of Celite and the Celite pad was washed with
ethyl acetate (2 × 10 mL). The combined filtrate was concen-
trated under reduced pressure and purified by silica gel column
chromatography (25% ethyl acetate in petroleum ether) to afford
19 (78 mg, 53%) as a white crystalline solid and 20 (36 mg,
24% yield) as a colorless oil. 19: Mp 106-108 °C (EtOAc/n-
The spectral and analytical data of synthetic cephalosporolide
E (21) were in agreement with the reported data and the
observed optical rotation {[R]25 -48.2 (c 0.50, CHCl3); lit.1
D
[R]30 +51.3 (c 0.42)} indicated that the enantiomer of the
D
cephalosporolide E has been synthesized. While the spectral
data for 22 were found to be in excellent agreement with that
for cephalosporolide F, the opposite sign and a large deviation
in the magnitude of specific rotation {[R]25 synthetic +95.2
D
(c 0.9, CHCl3); lit.2 [R]25D -33.3 (c 0.79, CHCl3)} was noticed.
The constitution and the relative stereochemistry of compound
22 were further established by single crystal X-ray analysis
(Supporting Information),16,17 which, along with the observed
opposite sign of specific rotation, confirmed that it was the
enantiomer of the natural cephalosporolide F.
hexane). [R]25 +5.2 (c 0.5, CHCl3). IR (CHCl3) ν 3430, 3020,
D
2929, 1774, 1403, 1216, 1050, 970 cm-1. 1H NMR (CDCl3, 400
MHz) δ 1.17 (d, J ) 6.2 Hz, 3H), 1.43-1.47 (m, 1H), 2.06-2.14
(m, 4H), 2.39 (d, J ) 14.3 Hz, 1H), 3.06 (br s, 1H), 4.10-4.18
(m, 1H), 4.35 (s, 1H), 4.71 (d, J ) 6.2 Hz, 1H), 5.23 (t, J ) 6.2
Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 20.8 (q), 31.3 (t), 33.8
(t), 41.2 (t), 74.3 (d), 75.3 (d), 82.2 (d), 83.6 (d), 115.2 (s),
In summary, a Pd-mediated alkynediol cycloisomerization
approach to the central tricyclic core of cephalosporolides E/F
and related congeners has been developed. A concise synthesis
of cephalosporolide E (1) and cephalosporolide F (2) has been
executed, which established their absolute configurations as
2844 J. Org. Chem. Vol. 74, No. 7, 2009