Nonanomeric [6.5]-Spiroketals in Aqueous Media
9H) ppm; 13C NMR (acetonitrile-d3, 400 MHz) δ 136.2, 135.9,
134.1, 130.1, 128.1, 116.5, 99.6, 71.4, 70.9, 67.8, 46.8, 42.2, 32.7,
32.5, 30.9, 27.0, 26.6, 19.2, 18.8 ppm. HRMS (ESI) calcd for
C29H42O4NaSi 505.2750, found 505.2759, ∆ 1.8 ppm.
The allyl alcohol 14b was prepared similarly (see Supporting
Information).
General Procedure for the Spiroketalizations. To a solution
of the alcohol 8, 9, 10, 11, 14a, 14b, 22a, or 22b (0.03-0.06 mmol
in 2-3 mL of solvent, see Supporting Information for details) was
added the appropriate amount of acid catalyst at room temperature.
The resulting solution was stirred at room temperature until the
reaction was completed as indicated by TLC. The reaction was
quenched by the addition of saturated aqueous NaHCO3 (2 mL)
and H2O (2 mL). The separated aqueous phase was extracted with
EtOAc (3 × 5 mL), and the combined organic phases were dried
over Na2SO4, filtered, and concentrated. The crude product was
purified by flash column chromatography (SiO2) using 1:4 Et2O/
hexanes as the eluent.
of nonanomeric spiroketals as the major products when the
reaction is performed under kinetic conditions. We are tempted
to speculate that these kinetic spiroketalizations may be suf-
ficient to explain the formation of most nonanomeric spiroketals
in nature, especially in view of the fact that nearly all
thermodynamically unstable nonanomeric [6.5]-spiroketals in
natural products appear to be accompanied by their anomeric
congeners. As such, the presence of nonanomeric spiroketals
in natural products may simply reflect the kinetic preference to
form the nonanomeric spiroketal rather than a specifically
directed spirocyclization reaction.
Further studies are in progress to apply these methods to the
synthesis of nonanomeric natural products, such as pecteno-
toxins.
Experimental Section
Anomeric Spiroketal 13a. Rf ) 0.88 (1:1 Et2O/hexanes, vanillin
General methods and the synthesis of 3-7, 9-11, and 17-23
are described in the Supporting Information.
stain), [R]20D ) + 1.4 (c ) 0.5, CH2Cl2); IR (thin film, cm-1) 3054,
1
2987, 1718, 1424, 1266; H NMR (acetonitrile-d3, 400 MHz) δ
Primary Alcohol 8. A solution of the crude aldehyde 6 (33 mg,
0.076 mmol) in THF (3.0 mL) was cooled to -78 °C, and
DIBAL-H (0.15 mL of a 1 M solution in toluene, 0.153 mmol)
was added dropwise over a period of 10 min. The resulting solution
was stirred at -78 °C for an additional 20 min and then warmed
to 0 °C. After another 20 min, the reaction was quenched with
aqueous saturated Rochelle’s salt (1 mL). The mixture was warmed
to room temperature and stirred for an additional 20 min before
the solution was extracted with EtOAc (3 × 40 mL). The combined
organic phases were washed pH 7 buffer, dried over MgSO4,
filtered, and concentrated. The crude product was purified by flash
column chromatography (SiO2) using 2:1 Et2O/hexanes as the eluent
to yield the primary alcohol 8 (23 mg, 67%) as a viscous bright
8.06-8.03 (d, 2H, J ) 7.8 Hz), 7.75-7.71 (m, 4H), 7.66-7.64
(m, 1H), 7.55-7.51 (m, 2H), 7.47-7.40 (m, 6H), 4.41-4.38 (m,
2H), 4.31-4.26 (dd, 1H, J ) 6.4 Hz, 12.4 Hz), 3.94-3.90 (ddt,
1H, J ) 2.2, 5.1, 11.7 Hz), 3.64-3.63 (d, 2H, J ) 5.2 Hz), 2.17
(m, 1H), 1.95-1.96 (m, 7H), 1.31-1.22 (m, 2H), 1.05 (s, 9H);
13C NMR (acetonitrile-d3, 400 MHz) δ 166.7, 135.8, 134.1, 133.4,
130.3, 129.7, 128.9, 128.1, 128.0, 119.5, 107.0, 75.9, 71.7, 67.9,
67.0, 37.4, 33.0, 27.1, 26.1, 20.0, 19.1 ppm. HRMS (ESI) calcd
for C33H40O5NaSi 567.2543, found 567.2535, ∆ 1.4 ppm.
Anomeric Spiroketal 13b. Rf ) 0.73 (1:1 Et2O/hexanes, vanillin
stain), [R]20D ) -5.8 (c ) 0.8, CH2Cl2); IR (thin film, cm-1) 3054,
1
2987, 1712, 1421, 1265; H NMR (acetonitrile-d3, 400 MHz) δ
yellow oil. Rf ) 0.29 (2:1 Et2O/hexanes, UV/vanillin stain); [R]20
8.04-8.01 (d, 2H, J ) 7.8 Hz), 7.75-7.71 (m, 4H), 7.64-7.60
(m, 1H), 7.49-7.39 (m, 8H), 4.45-4.28 (m, 2H), 4.02 (m, 1H),
3.94-3.90 (m, 1H), 3.64-3.56 (m, 2H), 2.12 (m, 1H), 1.84-1.58
(m, 7H), 1.32-1.28 (m, 2H), 1.03 (s, 9H); 13C NMR (acetonitrile-
d3, 400 MHz) δ 166.2, 135.9, 134.1, 133.4, 130.7, 130.1, 129.6,
128.9, 128.0, 117.7, 106.8, 78.0, 71.3, 68.8, 67.8, 38.4, 33.2, 27.0,
26.6, 20.2, 19.2 ppm. HRMS (ESI) calcd for C33H40O5NaSi
567.2543, found 567.2546, ∆ 0.5 ppm.
D
) +19.9 (c ) 1.39, CH2Cl2); IR (thin film, cm-1) 3401, 3071,
1
2931, 2858, 1472, 1462, 1113, 1082, 1010, 824, 702; H NMR
(acetonitrile-d3, 400 MHz) δ 7.75-7.69 (m, 4 H), 7.48-7.38 (m,
6 H), 3.71-3.64 (m, 1H), 3.61 (dd, 2H, J ) 5.1, 1.2 Hz), 3.49 (br
m, 2 H), 3.13 (s, 3 H), 2.58 (br s, 1 H), 1.81-1.41 (m, 10 H), 1.03
(s, 9 H) ppm; 13C NMR (acetonitrile-d3, 100 MHz) δ 135.9, 135.9,
134.1, 130.1, 128.1, 128.0, 99.6, 71.4, 67.8, 62.1, 46.8, 33.0, 32.5,
27.0, 26.5, 19.2, 18.8 ppm. HRMS (ESI) calcd for C26H38O4NaSi
465.2437, found 465.2435, ∆ 0.4 ppm.
Nonanomeric Spiroketal 13c. Rf ) 0.63 (1:1 Et2O/hexanes,
vanillin stain), [R]20 ) +2.8 (c ) 1.0, CH2Cl2); IR (thin film,
D
Allyl Alcohol 14a. Brown’s reagent (+)-B-allyldiisopinocam-
phenylborane was prepared according to a literature procedure.3 A
solution of (+)-Brown’s reagent freshly prepared (0.16 mmol) in
dry Et2O (1 mL) was cooled at -100 °C. A solution of the aldehyde
6 (74 mg, 0.16 mmol) in dry Et2O (2 mL) was added dropwise to
the previous solution via a syringe. The resulting mixture was
further stirred at the same temperature for 5 h. The reaction mixture
was then quenched through the addition of MeOH (3 mL), 3 M
NaOH solution (5 mL), and H2O2 30% (5 mL). After being stirred
overnight, the mixture was poured into saturated aqueous NaHCO3,
extracted with Et2O (3 × 10 mL), dried (Na2SO4) and concentrated.
The crude product was purified by flash column chromatography
(SiO2) using 1:5 Et2O/hexanes as the eluent to yield alcohol 14a
(82%, 66 mg) as a 6:1 mixture of diastereomers as revealed by 1H
NMR data. Spectroscopic data of the major diastereomer are
reported. Spectroscopic data of the minor diastereomer are reported
in the Supporting Information. Rf ) 0.26 (1:1 Et2O/hexanes, UV/
vanillin stain), [R]20D ) + 15.1 (c ) 0.55, CH2Cl2); IR (thin film,
cm-1) 3691, 3054, 2987, 1422, 1264; 1H NMR (acetonitrile-d3, 400
MHz) δ 7.77-7.73 (m, 4H), 7.48-7.43 (m, 6H), 5.87 (m, 1H),
5.10 (dd, 1H, J ) 1.2 Hz, 17.2 Hz), 5.05 (dd, 1H, J ) 1.2 Hz, 9.2
Hz), 3.72 (m, 1H), 3.64 (m, 2H), 3.56 (m, 1H), 3.15 (s, 3H), 2.68
(d, 1H, J ) 5.2 Hz), 2.20 (m, 2H), 1.76-1.23 (m, 10H), 1.06 (s,
cm-1) 3054, 2987, 1712, 1420, 1265; 1H NMR (acetonitrile-d3, 400
MHz) δ 8.01-7.98 (d, 2H, J ) 7.8 Hz), 7.72-7.69 (m, 4H), 7.64-
7.57 (m, 3H), 7.47-7.40 (m, 6H), 4.36-4-32 (m, 2H), 4.27-4.22
(m, 1H), 3.68-3.63 (m, 3H), 2.38 (ddd, 1H, J ) 1.3, 7.1, 12.6
Hz), 2.12-2.02 (m, 1H), 1.81-1.79 (m, 2H), 1.68-1.57 (m, 6H),
1.04 (s, 9H); 13C NMR (acetonitrile-d3, 400 MHz) δ 160.4, 135.8,
134.0, 133.4, 130.6, 130.1, 129.6, 128.9, 128.1, 117.7, 108.5, 77.8,
75.3, 68.6, 67.4, 34.4, 32.6, 27.1, 26.6, 21.0, 19.1 ppm. HRMS
(ESI) calcd for C33H40O5NaSi 567.2543, found 567.2537, ∆ 1.1
ppm.
Acknowledgment. Financial support from the Academy of
Finland (Academy Decisions 108793 and 107453), Tekes, and
Helsinki University of Technology is gratefully acknowledged.
We thank Dr. Jari Koivisto for assistance with the NMR
experiments and Terhi Rissa for early experimental contribu-
tions.
Supporting Information Available: Full experimental proce-
dures, compound characterization, and copies of NMR spectra. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702022U
J. Org. Chem, Vol. 72, No. 26, 2007 10087