Preparation of the 5/5-spiroketal of the ritterazines

Article abstract of DOI:10.1021/jo0626461

(Chemical Equation Presented) The enantiomerically pure 5/5-spiroketal required for the synthesis of the ritterazines has been prepared with high diastereocontrol by ring closure followed by equilibration.

Full text of DOI:10.1021/jo0626461

Preparation of the 5/5-Spiroketal of the Ritterazines
Douglass F. Taber* and Jean-Michel Joerger
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
taberdf@udel.edu
ReceiVed December 22, 2006
The enantiomerically pure 5/5-spiroketal required for the synthesis of the ritterazines has been prepared
with high diastereocontrol by ring closure followed by equilibration.
SCHEME 1
Introduction
The ritterazines (represented by ritterazine O 1), found in
small quantities in the lipophilic extract of the tunicate Ritterella
tokioka, induce apoptosis in apoptosis-resistant malignant cells.1
With the closely related cephalostatins, which show the same
activity, they form a unique class of trisdecacyclic molecules
featuring a pyrazine as the core ring, steroid-related structures,
and spiroketal edge rings (E and F). Partial syntheses from
steroid precursors of several of the 6-6-6-5 cephalostatins and
derivatives have been accomplished.2 There has been no report
of efforts other than our own toward the 6-6-5-5 ritterazines or
cephalostatins. In a preceding paper,3 we described the prepara-
tion of the A-B-C carbocyclic core of these ritterazines via
an intramolecular diene cyclozirconation-carbonylation process.
Here we present our synthesis of the 5/5-spiroketals (rings E
and F, rings E′ and F′) of 1.
Results and Discussion
Synthetic Approach: To prepare ritterazine O 1, we planned
to alkylate the ketone 2 with the triflate 3 (Scheme 1). We
envisioned preparing 3 by the acid-catalyzed deprotection,
cyclization, and equilibration of the ketone 4 to give 5a.
Although many 5/5-spiroketals have been prepared,4 little is
known about stereocontrol.5 Under acid-catalyzed conditions,
(1) For the isolation and activity of the ritterazines and cephalostatins,
see: (a) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997,
62, 4484. (b) Komiya, T.; Fusetani, N.; Matsunaga, S.; Kubo, A.; Kaye, F.
J.; Kelley, M. J.; Tamura, K.; Yoshida, M.; Fukuoka, M.; Nakagawa, K.
Cancer Chemother. Pharmacol. 2003, 51, 202. (c) Pettit, G. R.; Tan, R.;
Xu, J.; Ichihara, Y.; Williams, M. D.; Boyd, M. R. J. Nat. Prod. 1998, 61,
955.
10.1021/jo0626461 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/31/2007
3454
J. Org. Chem. 2007, 72, 3454-3457

Ritterazine Spiroketal
SCHEME 2
FIGURE 1. Calculated relative stabilities (MOPAC PM3, kcal/mol)
of diastereomers 6a-6d.
6/5- and 6/6-spiroketals generally equilibrate toward a particular
diastereoisomer due to anomeric or substituent stabilization in
the six-membered rings,6 but 5/5-spiroketals typically equilibrate
to nearly a 1:1 mixture of epimers.4c An advantage in the
synthesis of 5a is the presence of the methyl group adjacent to
the spiro carbon, which we expected to exert significant
stereocontrol. It was reasonable to expect that the methyl group
on the E ring which is cis to the vinyl group in 5c and 5d would
equilibrate to the trans form. MOPAC PM3 calculations7 with
model compounds 6a-6d (Figure 1) further encouraged us to
adopt this route to 5a.
Preparation of the Spiroketal Precursor: The synthesis of
4 (Scheme 2) began with 2-butyne-1,4-diol, which was con-
verted into enantiomerically pure 8 following literature prece-
dents8,9 and modifications thereof.10a Opening of epoxides is
known to be particularly difficult with nitrile-stabilized anions,11
but the presence of the vinyl group in 8 promoted attack by the
propionitrile anion, leading to the desired alcohol 9. Protection
of the alcohol 9 was required, as addition of the side chain
Grignard reagent to 9 led to lactone formation. Reduction of
10 to the aldehyde, Grignard addition,12 and oxidation delivered
the desired ketone 4.
Spiroketal Formation and Equilibration: The crucial
deprotection/cyclization of 4 was carried out with aqueous HCl
in THF. The spiroketal 5a was obtained along with notable
amounts of the other diastereomers 5b-5d (Table 1, entry 1).
The four diastereomers were separable by silica gel chroma-
tography, and their structures could be assigned spectroscopi-
cally.
TABLE 1. Equilibration of Diastereomers 5a-d
Yield (%)
entry
from
conditions
5a
5b
5c
33d
5d
1
2
3
4
5
6
4
Aa
Bc
B
37d
74b
62b
81b
0f
3d
17b
3d
15d
entry 1 mix
5c:5d ) 71:29
of 5b-d
8d
3d
1b
5a
5c
5d
B
6b
3b
Ce
C
0f
54f
46f
60f
0f
0f
40f
a Aqueous 1 M HCl/THF (1:4), rt, 3 h. b Isolated yield. c PPTS (0.1 M),
CH2Cl2, 80 °C (sealed flask), 5-7 h. d Determined by NMR ratios from
partially separated mixtures. e In CDCl3 for 4 weeks. f NMR ratio.
(2) For leading references, see: (a) Lee, J. S.; Fuchs, P. L. J. Am. Chem.
Soc. 2005, 127, 13122. (b) Nawasreh, M.; Winterfeldt, E. Curr. Org. Chem.
2003, 7, 649.
(3) Taber, D. F.; Taluskie, K. V. J. Org. Chem. 2006, 71, 2797.
(4) For a review, see: (a) Perron, F.; Albizati, K. F. Chem. ReV. 1989,
89, 1617. For a selection of recent work on 5/5-spiroketals, see: (b) Hirai,
K.; Ooi, H.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5,
857. (c) Doubsky´, J.; Streinz, L.; Sˇaman, D.; Zedn´ık, J.; Koutek, B. Org.
Lett. 2004, 6, 4909.
(5) For stereoselective 5/5-spiroketal formation, see: (a) Sharma, G. V.
M.; Subash Chander, A.; Goverdan Reddy, V.; Krishnudu, K.; Ramana Rao,
M. H. V.; Kunwar, A. C. Tetrahedron Lett. 2000, 41, 1997. (b) Betancor,
C.; Freire, R.; Pe´rez-Martin, I.; Prange´, T.; Sua´rez, E. Org. Lett. 2002, 4,
1295. (c) Lee, S.; LaCour, T. G.; Lantrip, D.; Fuchs, P. L. Org. Lett. 2002,
4, 313. (d) Lee, J. S.; Fuchs, P. L. Org. Lett. 2003, 5, 2247. (e) Sartillo-
Piscil, F.; Vargas, M.; Anaya de Parrodi, C.; Quintero, L. Tetrahedron Lett.
2003, 44, 3919. (f) Jeong, J. U.; Fuchs, P. L. Tetrahedron Lett. 1994, 35,
5385.
(6) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: New York, 1983.
(7) Structures 6a-6d were first minimized with Mechanics before they
were evaluated with MOPAC PM3. Both Mechanics and MOPAC PM3
were used as implemented on the Fujitsu CAChe workstation.
(8) Organ, M. G.; Cooper, J. T.; Rogers, L. R.; Soleymanzadeh, F.; Paul,
T. J. Org. Chem. 2000, 65, 7959.
Further equilibration of the mixture of 5a-5d obtained in
entry 1 was observed when the reaction time was prolonged,
but this also led to decomposition. It was better to equilibrate
the mixture with PPTS in CH2Cl2 (entry 2), which delivered
5a in 74% yield accompanied by 17% of a mixture of the other
three diastereomers. The recovered mixture of ketals 5b-5d
could be subjected again to equilibration. For example (entry
3), under PPTS-catalyzed conditions, a mixture of 5c and 5d
can be converted to 5a in 70% yield, based on starting material
not recovered. Entries 5 and 6 show that, under careful acid-
catalyzed conditions, 5c and 5d can be equilibrated, without
going on to 5a. This can be rationalized by a low activation
barrier for the inversion at the spiro center. By contrast, the
inversion of the methyl substituent requires more drastic
conditions. Entry 4 shows the result of a PPTS-catalyzed
equilibration that started from pure 5a.
Structure Assignments: The relative configurations of the
secondary methyl groups of 5a-5d were assigned unambigu-
ously using NMR NOE techniques, which showed clear
correlations between this methyl and the methine proton of the
(9) Mori, Y.; Asai, M.; Kawade, J.-i.; Furukawa, H. Tetrahedron 1995,
51, 5315.
(10) (a) Roush, W. R.; Straub, J. A.; VanNieuwenhze, M. S. J. Org.
Chem. 1991, 56, 1638. (b) Nacro, K.; Zedde, C.; Escudier, J.-M.; Baltas,
M.; Gorrichon, L.; Neier, R. Chirality 1998, 10, 804.
(11) (a) Larcheveˆque, M.; Debal, A. Synth. Commun. 1980, 10, 49. (b)
Taylor, S. K.; DeYoung, D.; Simons, L. J.; Vyvyan, J. R.; Wemple, M. A.;
Wood, N. K. Synth. Commun. 1998, 28, 1691.
(12) Andrews, D. R.; Barton, D. H. R.; Hesse, R. H.; Pechet, M. M. J.
Org. Chem. 1986, 51, 4819.
J. Org. Chem, Vol. 72, No. 9, 2007 3455

Taber and Joerger
SCHEME 3
vinyl group for 5c and 5d (Scheme 3). A NOE between the
methyl group of the E ring and the nearest methyl in the F ring
was observed in 5c and was very weak in 5d. The calculated
distances between the carbons of those methyls were 3.5 and
4.1 Å, respectively, which allowed unequivocal assignment of
5c and 5d. The differentiation of 5a and 5b was less clear, so
we converted 5a into the crystalline bis-dinitrobenzoate 12 under
careful nonacidic conditions (Scheme 4). This derivative
delivered a crystal that was suitable for X-ray analysis (Figure
2).
FIGURE 2. Molecular structure of compound 12. The dinitrobenzoyl
groups have been omitted for clarity. ORTEP drawings are shown at
the 50% probability level.
Experimental Section
(3S)-3-((R)-2-(tert-Butyldiphenylsilyloxy)-1-hydroxyethyl)-2-
methyl-4-pentenenitrile (9). To a solution of propionitrile (2.24
g, 40.6 mmol) in THF (57 mL) was added n-BuLi (1.9 M, 19 mL)
at -78 °C. After this solution was stirred for 1 h at -78 °C, a
solution of epoxide 8 (2.75 g, 8.12 mmol) in THF (10 mL) was
added over 3 min at -78 °C. The temperature of the solution was
progressively increased over 2 h, and when it reached -10 °C, the
reaction was quenched with saturated aqueous NH4Cl (40 mL). The
mixture was partitioned between ether and brine. The combined
organic extracts were dried (Na2SO4) and concentrated. The residue
was chromatographed to give the alcohol 9 as a mixture of two
diastereomers as a colorless oil (1.66 g, 52% yield in a ratio of
SCHEME 4
1
54:46): TLC Rf (MTBE/PE ) 40:60) ) 0.84 and 0.62; H NMR
of mixture δ 1.06 (s), 1.07 (s), 1.25 (d, J ) 7.2 Hz), 1.29 (d, J )
7.1 Hz), 2.10-2.21 (m, 1H), 2.36 (br s), 2.43 (br s), 2.78-2.95
(m, 1H), 3.52-3.70 (m, 2H), 3.81-3.87 (m), 4.14-4.23 (m), 5.03
(dd, J ) 17.2, 1.4 Hz), 5.16 (dd, J ) 17.1, 1.4 Hz), 5.18 (dd, J )
10.2, 1.6 Hz), 5.30 (dd, J ) 10.2, 1.5 Hz), 5.61 (dd, J ) 17.2, 10.0
Hz), 5.82 (dd, J ) 17.1, 10.0 Hz), 7.37-7.49 (m, 6H), 7.61-7.68
(m, 4H); 13C NMR13 of mixture δ u 132.9, 132.9, 132.8, 122.3,
121.8, 121.0, 120.7, 66.4, 65.9, 19.2, 19.2, d 135.5, 133.0, 132.8,
130.0, 129.9, 129.9, 127.9, 127.8, 127.8, 127.8, 71.6, 71.1, 49.5,
49.5, 27.0, 26.8, 26.8, 26.7, 16.5, 16.2; IR of mixture (cm-1) 3454
(br), 2929, 2857, 2240, 1113; MS m/z (%) 394 (M + H, 100), 362
(13), 307 (11); HRMS calcd for C24H31NO2SiNa (M + Na)
416.2022, obsd 416.2032.
The three-dimensional structure of 12 was instructive. The
more highly substituted five-membered ring adopts a half-chair
conformation. Following the expected anomeric affect,6 the more
stable diastereomer 5a of the spiroketal then has the oxygen
branch, rather than the carbon branch, axial on that half chair.
This may be a general principle contributing to conformational
preferences in five-membered ring spiroketals.
(3S)-3-((R)-2-(tert-Butyldiphenylsilyloxy)-1-(triethylsilyloxy)-
ethyl)-2-methyl-4-pentenenitrile (10). To a solution of the alcohol
9 (1.56 g, 3.96 mmol) in pyridine (20 mL) were added DMAP (97
mg, 0.79 mmol) and triethylsilyl chloride (2.0 mL, 11.9 mmol) at
rt. The reaction mixture was stirred at rt for 20 h, then partitioned
between ether, and sequentially a 1:1 mixture of water and saturated
aqueous NH4Cl and brine. The combined organic extracts were
dried (Na2SO4) and concentrated. The residue was chromatographed
to give the nitrile 10 as a mixture of two diastereomers as a slightly
yellow oil (1.90 g, 95% yield): TLC Rf (MTBE/PE ) 5:95) )
Conclusion
1
0.53 and 0.41; H NMR of mixture δ 0.39-0.49 (m, 6H), 0.79-
0.86 (m, 9H), 1.05 (s, 9H), 1.30 (d, J ) 7.1 Hz), 1.33 (d, J ) 7.1
Hz), 2.44-2.50 (m), 2.54-2.62 (m), 2.68-2.77 (m), 2.80-2.89
(m), 3.44-3.59 (m, 2H), 3.74-3.80 (m), 4.09-4.15 (m), 5.16-
5.35 (m, 2H), 5.49-5.60 (m), 5.77-5.88 (m), 7.33-7.47 (m, 6H),
The preparation of the key building block 5a has been
accomplished, using a δ,δ′-dihydroxyketone spiroketalization
as the key step, followed by equilibration. These results make
the enantiomerically pure spiroketal 5a available in sufficient
quantity to support our efforts toward the total synthesis of the
ritterazines. The correlation between the experimental results
and the MOPAC PM3 calculations is encouraging.
(13) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d”
from methylene and quaternary carbons as “u”.
3456 J. Org. Chem., Vol. 72, No. 9, 2007

Ritterazine Spiroketal
7.61-7.70 (m, 4H); 13C NMR of mixture δ u 133.2, 133.1, 122.4,
122.4, 120.7, 120.5, 65.2, 64.7, 19.1, 4.9, 4.8, d 135.6, 135.5, 135.5,
133.5, 133.3, 129.8, 129.8, 129.6, 129.5, 127.7, 127.7, 127.7, 127.7,
72.7, 72.2, 50.3, 50.2, 27.2, 26.8, 16.8, 6.8, 6.7; IR of mixture
(cm-1) 2956, 2934, 2877, 2859, 2239, 1472, 1462, 1428, 1113;
MS m/z (%) 508 (M + H, 100), 462 (18), 394 (13); HRMS calcd
for C30H45NO2Si2Na (M + Na) 530.2887, obsd 530.2890.
give the spiroketals 5a-5d as a mixture of four diastereomers as
a colorless oil (2.44 g, 87% yield).
(2R,3S,4S,5S)-2-tert-Butyldiphenylsilyloxymethyl-3-ethenyl-
4,7,7-trimethyl-1,6-dioxaspiro[4.4]nonane (5a): TLC Rf (MTBE/
PE ) 5:95) ) 0.48; 1H NMR δ 0.92 (d, J ) 6.8 Hz, 3H), 1.04 (s,
9H), 1.18 (s, 3H), 1.39 (s, 3H), 1.67-1.76 (m, 1H), 1.95-2.20
(m, 4H), 2.72-2.83 (m, 1H), 3.61 (dd, J ) 11.1, 3.0 Hz, 1H), 3.76
(dd, J ) 11.3, 3.5 Hz, 1H), 4.10-4.16 (m, 1H), 5.05-5.13 (m,
2H), 5.89-6.00 (m, 1H), 7.32-7.44 (m, 6H), 7.66-7.78 (m, 4H);
13C NMR δ u 133.7, 133.5, 81.7, 64.4, 37.4, 34.0, 19.2, d 137.4,
135.8, 135.7, 129.6, 129.5, 127.6, 127.5, 79.4, 52.5, 44.8, 29.8,
28.3, 26.8, 11.7; IR (cm-1) 2963, 2930, 2858, 1112; MS m/z (%)
387 (100), 309 (10); HRMS calcd for C29H40O3SiNa (M + Na)
487.2644, obsd 487.2658; [R]D -77 (c 1.00, CH2Cl2).
(2R,3S,4S,5R)-2-tert-Butyldiphenylsilyloxymethyl-3-ethenyl-
4,7,7-trimethyl-1,6-dioxaspiro[4.4]nonane (5b): TLC Rf (MTBE/
PE ) 5:95) ) 0.60. Although 5b could be separated from the other
diastereomers, its conversion to 5a in CDCl3 or in a PE/MTBE
mixture was fast. Selection of 1H NMR signals: δ 0.94 (d, J ) 8.1
Hz, 3H), 1.04 (s, 9H), 1.16 (s, 3H), 1.35 (s, 3H); 13C NMR δ u
133.9, 133.7, 117.3, 116.5, 81.0, 64.6, 36.9, 32.3, 19.2, d 137.0,
135.8, 135.7, 129.4, 127.5, 127.5, 117.3, 116.5, 79.3, 53.2, 43.8,
29.8, 28.6, 26.8, 13.8.
(3S)-3-((R)-2-(tert-Butyldiphenylsilyloxy)-1-(triethylsilyloxy)-
ethyl)-2-methyl-4-pentenal (11). To a solution of the nitrile 10
(2.00 g, 3.93 mmol) in toluene (25 mL) was added a 20 wt %
solution of Dibal in toluene (10.2 mmol, 8.4 mL) at -78 °C. The
temperature of the solution was progressively increased over 2.5
h, and when it reached -5 °C, the reaction was poured in a well-
stirred mixture of saturated aqueous NH4Cl (100 mL) and ether
(500 mL). After partition, the aqueous phase was re-extracted with
ether (2 × 100 mL). The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed to
give the aldehyde 11 as a mixture of two diastereomers as a slightly
yellow oil (1.72 g, 86% yield): TLC Rf (MTBE/PE ) 4:96) )
1
0.51 and 0.46; H NMR of mixture δ 0.37-0.78 (m, 6H), 0.79-
0.86 (m, 9H), 1.02-1.13 (m, 12H), 2.51-2.65 (m), 2.74-2.82 (m),
3.43-3.58 (m), 3.73-3.79 (m), 3.82-3.88 (m), 5.09-5.25 (m, 2H),
5.68-5.69 (m, 1H), 7.34-7.47 (m, 6H), 7.60-7.68 (m, 4H), 9.63-
9.66 (m, 1H); 13C NMR of mixture δ u 133.4, 133.3, 119.2, 188.7,
65.2, 64.7, 19.2, 19.1, 4.9, 4.9, d 205.5, 205.3, 135.5, 135.5, 135.5,
129.8, 129.7, 129.7, 129.6, 127.7, 127.0, 73.2, 72.3, 49.0, 48.4,
47.1, 4.9, 26.8, 26.8, 12.7, 12.6, 6.7; IR of mixture (cm-1) 3072,
2957, 2876, 2858, 1726, 1428, 1112; MS m/z (%) 511 (M + H,
13), 333 (100); HRMS calcd for C30H46O3Si2Na (M + Na)
533.2883, obsd 533.2866.
(2R,3S,4R,5R)-2-tert-Butyldiphenylsilyloxymethyl-3-ethenyl-
4,7,7-trimethyl-1,6-dioxaspiro[4.4]nonane (5c): TLC Rf (MTBE/
PE ) 5:95) ) 0.71; 1H NMR δ 0.86 (d, J ) 7.0 Hz, 3H), 1.03 (s,
9H), 1.09 (s, 3H), 1.27 (s, 3H), 1.60-1.68 (m, 1H), 1.84-2.02
(m, 4H), 2.19-2.29 (m, 1H), 2.69-2.79 (m, 1H), 3.64-3.75 (m,
2H), 4.04-4.13 (m, 1H), 4.95-5.04 (m, 2H), 5.92-6.04 (m, 1H),
7.31-7.42 (m, 6H), 7.65-7.71 (m, 4H); 13C NMR δ u 134.1, 134.0,
116.9, 115.3, 82.0, 64.7, 37.0, 35.6, 19.3, d 135.9, 135.7, 135.7,
(3S)-3-((R)-2-(tert-Butyldiphenylsilyloxy)-1-(triethylsilyloxy)-
ethyl)-4,8-dimethyl-8-(triethylsilyloxy)1-nonen-5-one (4). A solu-
tion of BrCH2CH2C(CH3)2OTES (2.10 g, 7.5 mmol) and iodine
(17 mg) in THF (19 mL) was added to magnesium turnings (200
mg, 8.25 mmol) over 10 min at rt.12 Stirring was continued for an
additional 2.5 h at rt. The resulting Grignard solution was cooled
to 0 °C, then cannulated over 5 min into a solution of the preceding
aldehyde (1.28 g, 2.5 mmol) in THF (5 mL) at 0 °C. After 10 min,
the mixture was partitioned between ether (50 mL) and saturated
aqueous NH4Cl (10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was dissolved in CH2Cl2
(30 mL) and the Dess-Martin reagent (3.18 g, 7.5 mmol) was
added. After 2 h at rt, the mixture was poured into a 1:1 mixture
of 20 wt % aqueous Na2S2O3 (50 mL) and saturated aqueous NH4-
Cl (50 mL) and stirred at rt for 5 min. This mixture was then
partitioned with ether (100 mL). The combined organic extracts
were dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give the ketone 4 as a mixture of two diastereomers as
a slightly yellow oil (1.54 g, 86% yield): TLC Rf (MTBE/PE )
3:97) ) 0.37 and 0.23; 1H NMR of mixture δ 0.37-0.49 (m, 6H),
0.51-0.62 (m, 6H), 0.78-0.88 (m, 9H), 0.90-0.98 (m, 9H), 1.01-
1.13 (m, 12H), 1.16-1.24 (m, 3H), 1.58-1.75 (m, 2H), 2.43-
2.86 (m, 4H), 3.38-3.53 (m, 2H), 3.65-3.71 (m), 3.81-3.88 (m),
4.95-5.18 (m, 2H), 5.57-5.77 (m, 1H), 7.33-7.46 (m, 6H), 7.60-
7.69 (m, 4H); 13C NMR of mixture δ u 214.8, 214.3, 133.6, 133.6,
133.5, 118.5, 118.4, 72.6, 72.5, 65.8, 65.2, 38.4, 38.2, 37.7, 36.7,
19.2, 19.2, 6.7, 5.2, 5.1, d 135.7, 135.6, 135.6, 135.6, 135.5, 129.7,
129.7, 129.6, 129.6, 127.7, 127.7, 127.6, 73.5, 71.2, 49.5, 48.7,
129.4, 127.5, 81.0, 50.6, 43.4, 30.1, 28.2, 26.8, 10.4; IR (cm-1
)
2965, 2930, 2857, 1112; MS m/z (%) 387 (100), 309 (11); [R]D
+8 (c 1.00, CH2Cl2).
(2R,3S,4R,5S)-2-tert-Butyldiphenylsilyloxymethyl-3-ethenyl-
4,7,7-trimethyl-1,6-dioxaspiro[4.4]nonane (5d): TLC Rf (MTBE/
PE ) 5:95) ) 0.54; 1H NMR δ 0.89 (d, J ) 7.4 Hz, 3H), 1.02 (s,
9H), 1.19 (s, 3H), 1.37 (s, 3H), 1.68-1.86 (m, 2H), 1.91-2.06
(m, 2H), 2.40-2.49 (m, 1H), 2.86-2.94 (m, 1H), 3.60-3.70 (m,
2H), 4.21-4.27 (dd, J ) 11.5, 5.7 Hz, 1H), 5.00-5.04 (m, 1H),
5.04-5.08 (m, 1H), 5.55-5.67 (m, 1H), 7.30-7.44 (m, 6H), 7.64-
7.75 (m, 4H); 13C NMR δ u 134.0, 133.8, 117.9, 116.7, 80.4, 64.3,
37.5, 33.7, 19.2, d 135.7, 135.0, 134.3, 129.4, 127.5, 127.5, 79.3,
50.2, 44.5, 29.8, 28.8, 26.7, 12.2; IR (cm-1) 2964, 2931, 2858,
1112; MS m/z (%) 387 (100), 309 (12); [R]D -40 (c 1.00, CH2-
Cl2).
Procedure for the Equilibration of the Spiroketals. A solution
of the mixed spiroketals 5a-5d (1.24 g, 2.67 mmol) and PPTS
(338 mg, 1.33 mmol) in CH2Cl2 (13.3 mL) was stirred at 80 °C in
a sealed flask for 5 h. To the reaction mixture was added 8 g of
silica gel. The solvent was evaporated, and the residue was
chromatographed directly to give spiroketals 5a (920 mg, 74%)
and 5b-5c (206 mg, 17%).
Acknowledgment. We thank Zhe Zhang for preliminary
experiments, John Dykins for recording mass spectra, Steve Bai
for NMR assistance, Glenn Yap for the X-ray structure, and
the NIH (GM 60287) for financial support of this work.
47.1, 46.6, 30.0, 29.9, 29.8, 26.9, 16.2, 15.0; IR of mixture (cm-1
)
2957, 2934, 2911, 2876, 1715, 1113; MS m/z (%) 579 (52), 447
(100), 387 (46); HRMS calcd for C42H70O4Si3 (M + H) 711.4660,
obsd 711.4640.
Spiroketals 5a-d. A solution of the ketone 4 (4.28 g, 6.02
mmol) in aqueous HCl (48 mL, 1 M) and THF (190 mL) was stirred
at rt for 3 h. The solution was then partitioned between ether (500
mL) and sequentially saturated aqueous NaHCO3 (120 mL), water
(120 mL), and brine. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed to
Supporting Information Available: General experimental
1
procedures, H and 13C spectra, X-ray data for 12, and other data
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0626461
J. Org. Chem, Vol. 72, No. 9, 2007 3457