Diyl trapping reactions to synthesize taxol analogs

Article abstract of DOI:10.1021/jo970042e

A new and efficient entry to the ABC-ring system common to taxol and related materials has been developed. Highlights include the use of a regioselective intramolecular diyl trapping reaction to synthesize tricyclic alkene 5, the creation and oxidative cleavage of the tetrasubstituted olefin found in ketal 20a,b to afford a highly functionalized eight-membered ring (21a), and cyclization of 22, thereby providing the tricyclic core.

Full text of DOI:10.1021/jo970042e

1610
J . Org. Chem. 1997, 62, 1610-1616
Diyl Tr a p p in g Rea ction s To Syn th esize Ta xol An a logs
Michael M. Ott and R. Daniel Little*
Department of Chemistry, University of CaliforniasSanta Barbara, Santa Barbara, California 93106
Received J anuary 6, 1997X
A new and efficient entry to the ABC-ring system common to taxol and related materials has been
developed. Highlights include the use of a regioselective intramolecular diyl trapping reaction to
synthesize tricyclic alkene 5, the creation and oxidative cleavage of the tetrasubstituted olefin found
in ketal 20a ,b to afford a highly functionalized eight-membered ring (21a ), and cyclization of 22,
thereby providing the tricyclic core.
Sch em e 1
The importance of taxol (1) and related materials in
the treatment of a variety of forms of cancer is exception-
ally clear.1 While many ingenious approaches to the
skeleton have been developed, only three total syntheses
have been published.2 As indicated recently by Dan-
ishefsky and co-workers, the availability of a renewable
source of baccatin III (2) reduces the impact new total
synthesis might have upon the supply problem.2h The
development of general strategies that will allow the
construction of a wide range of analogs whose bioactivity
might equal or exceed that of the naturally occurring
materials clearly represents a laudable and noteworthy
objective. In this paper, we report the results of our
initial investigations dealing with the possible applicabil-
ity of the intramolecular diyl trapping reaction to the
assembly of the ABC ring system of the natural materi-
als.3 Our target structure was tricycle 3, a system
possessing much of the functionality found in the B-ring.
We believe that the methodology described herein can
readily be adapted to allow the incorporation of much of
the functionality deemed necessary for bioactivity.
3 was predicated upon being able to move the C-C
π-bond from its original tri- to the tetrasubstituted
position located between carbons Ca and Cb, as in 4.
Subsequent oxidative cleavage of that bond promised to
afford the [5.3.1] ring system common to the natural
materials.
THF served as an inexpensive, readily available start-
ing material. Ring opening using sodium iodide and
benzoyl chloride in acetone,4 followed by alkylation of
acetyl acetone, the addition of paraformaldehyde, and
deacylative methylenation in DMSO, afforded vinyl
ketone 10 (Scheme 2).5 This material was most conve-
niently used without purification in a sequence consisting
(2) (a) Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R.
J .; Boatman, D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile,
L. S.; Liu, J . H. J . Am. Chem. Soc. 1994, 116, 1597. (b) Holton, R. A.;
Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. J .; Boatman, D.; Shindo,
M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.;
Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. S.; Liu, J . H. J . Am.
Chem. Soc. 1994, 116, 1599. (c) Nicolaou, K. C.; Zang, Z.; Liu, J . J .;
Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J .;
Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J . Nature 1994, 357,
630. (d) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.;
Couladouros, E. A.; Sorensen, E. J . J . Am. Chem. Soc. 1995, 117, 624.
(e) Nicolaou, K. C.; Liu, J . J .; Yang, Z.; Ueno, H.; Sorensen, E. J .;
Claiborne, C. F.; Guy, R. K.; Hwang, C. K.; Nakada, M.; Nantermet,
P. G. J . Am. Chem. Soc. 1995, 117, 634. (f) Nicolaou, K. C.; Yang, Z.;
Liu, J . J .; Nantermet, P. G.; Claiborne, C. F.; Renaud, J .; Guy, R. K.;
Shibayama, K. J . Am. Chem. Soc. 1995, 117, 645. (g) Nicolaou, K. C.;
Ueno, H.; Liu, J . J .; Nantermet, P. G.; Yang, Z.; Renaud, J .; Paul-
vannan, K.; Chadha, R. J . Am. Chem. Soc. 1995, 117, 653. (h) Masters,
J . J .; Link, J . T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J . Angew.
Chem., Int. Ed. Engl. 1995, 34, 1723.
Key to the successful implementation of the plan was
the construction of aldehyde 7 and its conversion to the
bicyclic diazene 6 in a manner that would allow the
subsequent diyl trapping reaction to be conducted on a
multigram scale; see Scheme 1. Previous studies indi-
cated that cycloaddition ought to preferentially afford the
bridged adduct 5 rather than the linearly fused regioi-
somer.3 The ketal, which is critical to guarantee forma-
tion of the bridged cycloadduct, is designed to serve as a
synthon for the hydroxyl group appended to C1 of the
natural products. Conversion of 5 to the target structure
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) Taxane Anticancer Agents; Georg, G. I., Chen, T. T., Ojima, I.,
Vyas, D. M., Eds.; American Chemical Society: San Diego, 1995; Vol.
583.
(3) Little, R. D. Chem. Rev. 1996, 96, 93.
(4) Nystro¨m, J . E.; McCanna, T. D.; Helquist, P.; Amouroux, R.
Synthesis 1988, 56.
S0022-3263(97)00042-X CCC: $14.00 © 1997 American Chemical Society

Diyl Trapping Reactions To Synthesize Taxol Analogs
J . Org. Chem., Vol. 62, No. 6, 1997 1611
Sch em e 2
Sch em e 4
Sch em e 3
Our next objective was to move the double bond in
preparation for oxidative cleavage leading to the eight-
membered ring.9 In principle, both stereoisomers 5a and
5b can be converted to the same enone 4. Despite
considerable effort, only 5a has proven useful. Corrective
measures continue to be explored. As shown in Scheme
4, the operation could conveniently be carried out via the
addition of phenylselenyl trifluoroacetate (93%),10 Swern
oxidation of the hydroxyl group in 13 (90%), and elimina-
tion of the selenoxide derived from 14 (>95%), in the
usual manner, to afford enone 4.
The regiochemical outcome of the oxyselenation step
is of interest as it led exclusively to the adduct wherein
selenium was appended to the more highly substituted
carbon of the alkene. Presumably this is a consequence
of the need to form a cis, rather than a highly strained
trans-fused bicyclo[3.3.0] subunit.11 Once the presumed
selenonium ion intermediate 15 is formed, ring opening
occurs by nucleophilic attack at the less substituted
carbon to afford the cis-fused adduct. An alternative
pathway involving the development of a partial positive
charge at the quaternary bridgehead carbon is unlikely
given the increase in strain that would accompany
rehybridization.
of ketalization, removal of the benzoate, and Doering
oxidation6 to provide aldehyde 7 in a 60% yield overall.
Treatment of 7 with cyclopentadiene and diethylamine
in methanol afforded fulvene 11 in a 90% yield.7
A
subsequent Diels-Alder reaction with diethyl azodicar-
boxylate, followed by reduction of the ∆-5,6 π bond of the
adduct using diimide generated in situ, led efficiently
(>95%) to the biscarbamate 12 (Scheme 3). The diazene
linkage was unveiled in a customary fashion, to provide
20 g of diazene 6 in an overall yield, from THF, of 35%.
We were delighted to discover that the intramolecular
diyl trapping reaction could conveniently be carried out
on this scale, a point that is of obvious practical signifi-
cance. This was achieved simply by adding a solution of
6 in acetonitrile to the solvent at reflux via addition
funnel over 48 h.8 An 80% isolated yield of a 1:1 mixture
of stereoisomeric bridged cycloadducts 5a and 5b was
obtained consistently.
A first indication of the viability of the proposed route
to the eight-membered ring was obtained after selective
1,2-reduction and protection of enone 4 to obtain the
allylic silyl ether 16b in a 77% yield as a separable 4:1
mixture of diastereomers. Ozonolytic cleavage of the
(6) Parikh, J . R.; Doering, W. E. J . Am.Chem. Soc. 1967, 89, 5505.
(7) Stone, K. J .; Little, R. D. J . Org. Chem. 1984, 41, 1849.
(8) The dimethyl ketal analog of diazene 6 proved too labile toward
conversion to the corresponding ketone and was not useful.
(9) (a) Blechert, S.; Mu¨ller, R.; Beitzel, M. Tetrahedron 1992, 48,
6953. (b) Galatsis, P.; Manwell, J . J . Tetrahedron 1995, 51, 665. (c)
Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757.
(10) (a) Reich, H. J .; J . Org. Chem. 1974, 39, 428. (b) Reich, H. J .;
Wollowitz, S.; Trend, J . E.; Chow, F.; Wendelborn, D. F. J . Org. Chem.
1978, 43, 1697.
(5) The sequence leading from 9 to 10 was originally explored and
developed by Mr. Scott Meehan of UCSB. The use of DMSO allowed
the chemistry to be conducted at room temperature, made the process
very convenient to conduct, and led to significantly improved yields.
Details concerning the general procedure will be published elsewhere.
(11) Van Hijfte, L.; Little, R. D.; Petersen, J . L.; Moeller, K. D. J .
Org. Chem. 1987, 52, 4647.

1612 J . Org. Chem., Vol. 62, No. 6, 1997
Ott and Little
major isomer afforded diketone 17 (70%), a material that
displays two carbonyl absorptions in the infrared (1702
and 1698 cm-1) and in the 13C NMR spectrum (215.7 and
213.4).9a,b
With 20 in hand, the stage was set to produce the
eight-membered ring. Oxidative cleavage of the double
bond was accomplished to afford an 80% yield of diketone
21a by using ruthenium tetraoxide, generated in situ
from sodium periodate (3 equiv) and 10 mol % ruthenium
dioxide at 0 °C.12 It was important to carefully monitor
the course of this reaction, and in particular, to avoid
prolonged reaction times; in this instance, 20 min proved
optimal.
Completion of the sequence was initiated by removing
the silyl ether, separating the major diastereomer, and
converting the resulting alcohol 21b to the corresponding
iodide 22. Closure to afford the C-ring was accomplished
by treating 22 with a fivefold excess of LDA at -78 °C
(0.5 h) and allowing the reaction mixture to gradually
warm to room temperature. Workup, isolation, and
characterization indicated, much to our delight, that the
desired product 3 had been produced in a 63% yield. To
ensure that the thermodynamically preferred trans ring
fusion had been obtained, the product was treated for 8
h at room temperature with KOBu-t/t-BuOH. The start-
ing material was recovered unchanged; isomerization did
not occur.13
Verification of structure was obtained by NMR using
HMQC TOCSY. A particularly remarkable observation
was that the chemical shift difference between the
methylene protons, Hs and Ha, of the one-carbon bridge
was 1.9 ppm! This suggests that the material exists in
a conformation wherein the carbonyl units are oriented
as shown in 18, with syn proton, Hs, resonating at 3.76,
and the anti, Ha, at 1.89 ppm. A similar difference was
observed for the methylene protons located at C3 (taxol
numbering), one appearing at 1.89, the other deshielded
considerably, appearing at 3.83 ppm. This helps to define
the conformation of the eight-membered ring and sug-
gests that one of the protons is aligned properly to allow
removal in subsequent acid-base chemistry.
The formation of a highly functionalized central ring
and the annulation of ring C was achieved in the
following manner. The enolate of enone 4 was regiose-
lectively alkylated using iodo ether 19 to afford a 2.5:1
mixture of diastereoisomers that were separated by
column chromatography and fully characterized. Decou-
pling and NOE experiments were used to determine that
the R-alkylated material was the major product. Molec-
ular mechanics calculations (SYBYL) strengthened this
notion, consistently placing it at a slightly lower energy
than its stereoisomer. It proved advantageous to use the
mixture in the ketalization step, since the use of either
of the pure forms met with epimerization. In fact, each
isomer independently afforded the same 2.5:1 ratio of
isomeric ketals, suggesting that the initial alkylation
ratio reflected a thermodynamic product distribution.
In closing, we note the ample opportunity to add key
functionality to our second generation efforts, those
designed to provide bioactive materials. For example,
incorporation of a protected hydroxyl group at the central
carbon of the tether that links diazene to diylophile (Cr
in 6, Scheme 1), would provide the important functional-
ity at C13 of the taxol framework, and the use of a
functionally more elaborate alkylating unit in conjunction
with the addition of the C-ring would allow the incorpo-
ration of the oxetane. Other options exist, and several
(12) (a) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936. (b) Mehta, G.; Krishnamurthy, N. J .
Chem. Soc., Chem. Commun. 1986, 1319.
(13) (a) Blechert, S.; Kleine-Klausing, A. Angew. Chem., Int. Ed.
Engl. 1991, 30, 412. (b) Magnus, P.; Ujjainwalla, F.; Westwood, N.;
Lynch, V. Tetrahedron Lett. 1996, 37, 6639. (c) SYBYL calculations
consistently placed the trans-fused isomer at a substantially lower
energy than the cis (>2 kcal/mol).

Diyl Trapping Reactions To Synthesize Taxol Analogs
J . Org. Chem., Vol. 62, No. 6, 1997 1613
in vacuo. Chromatography on silica gel (60% ether/pentane)
afforded 35.38 g (189.2 mmol) of aldehyde 7 (88%). TLC (SiO2,
60% ether/pentane, vanillin) Rf ) 0.54; 1H NMR (500 MHz,
CDCl3) δ 9.78 (t, J ) 1.5 Hz, 1H), 5.30 (s, 1H), 4.89 (d, J ) 1.5
Hz, 1H), 3.94 (m, 2H), 3.81 (m, 2H), 2.46 (td, J ) 7.3, 1.5 Hz,
2H), 2.08 (t, J ) 7.8 Hz, 2H), 1.82 (tt, J ) 7.7, 7.3 Hz, 2H),
1.45 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 201.6, 148.0, 110.1,
108.7, 63.8, 43.0, 29.5, 23.8, 20.2; FTIR (neat/NaCl) 3096, 2989,
2952, 2884, 2721, 1726, 1651, 1444, 1041 cm-1; HRMS (CI/
NH3) calcd for C10H16O3 [M + H]+: 185.1177, found: 187.1171.
2-[1-(4-Cyclop en ta -2,4-d ien ylid en ebu tyl)vin yl]-2-m eth -
yl-1,3-d ioxola n e (11). To a solution of aldehyde 7 (5.5 g, 30.2
mmol) and cyclopentadiene (5.0 g, 75.5 mmol) in MeOH (64
mL) at 0 °C was added diethylamine (3.31 g, 45.3 mmol)
dropwise via syringe. The resulting homogeneous mixture was
allowed to warm to room temperature. After 5 h, the reaction
mixture was cooled to 0 °C, and glacial acetic acid (9.06 g, 151
mmol) was added in one portion. After 20 min the solution
was diluted with water (50 mL), and the aqueous layer was
extracted with ether (5 × 50 mL). The combined organic layers
were washed with saturated NaHCO3 (100 mL) and brine (100
mL), dried over magnesium sulfate, and concentrated in vacuo.
Chromatography on silica gel (5% ether/pentane) afforded 6.09
g (26.3 mmol) of fulvene 11 as a bright yellow oil (87%). TLC
(SiO2, 5% ether/pentane, UV, vanillin) Rf ) 0.28; 1H NMR (500
MHz, CDCl3) δ 6.53 (m, 2H), 6.44 (m, 2H), 6.21 (m, 1H), 5.30
(d, J ) 0.7 Hz, 1H), 4.90 (bd, J ) 1.5 Hz, 1H), 3.94 (m, 2H),
3.81 (m, 2H), 2.57 (dt, J ) 7.7 Hz, 2H), 2.14 (t, J ) 8.0 Hz,
2H), 1.74 (tt, J ) 8.0, 7.7 Hz, 2H), 1.48 (s, 3H); 13C NMR (50
MHz, CDCl3) δ 148.6, 146.1, 142.3, 132.9, 130.6, 125.4, 118.9,
110.2, 109.2, 64.2, 30.7, 30.2, 27.9, 24.2; FTIR (neat/NaCl)
3095, 3068, 2990, 2935, 2886, 1645, 1474, 1040 cm-1; HRMS
(EI) calcd for C15H20O2: 232.1463, found: 232.1452.
are under investigation. The results will be reported in
due course.
Exp er im en ta l Section
4-Iod o-1-(ben zoyloxy)bu ta n e (9). To a stirring solution
of benzoyl chloride (105.4 g, 0.75 mol) and THF (175.1 g, 2.74
mol) in acetone (1.5 L) was added sodium iodide (224.8 g, 1.5
mol). The orange reaction mixture was stirred at room
temperature for 10 h and then turned clear after being
quenched with saturated NaHSO3 (500 mL). The water layer
was extracted with ether (3 × 250 mL), and the combined
organic layers were washed with saturated NaHCO3 (300 mL)
and brine (300 mL), dried (MgSO4), and concentrated in vacuo.
The crude oil was filtered through silica gel (ether) to yield
207 g (0.69 mol) of pure alkyl iodide 9 (93%). TLC (SiO2, 100%
1
ether, UV, vanillin) Rf ) 0.50; H NMR (400 MHz, CDCl3) δ
8.03 (m, 2H), 7.55 (app dd, J ) 7.4, 1.6 Hz, 1H), 7.43 (m, 2 H),
4.34 (t, J ) 6.2 Hz, 2H), 3.24 (t, J ) 6.8 Hz, 2H), 1.98 (tt, 2H),
1.89 (tt, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 132.8, 130.1,
129.4, 128.3, 63.6, 30.0, 29.6, 5.9; FTIR (neat/NaCl) 3064, 2952,
2895, 2854, 1717, 1595, 1452, 1273, 1110 cm-1; HRMS (CI/
CH4) calcd for C11H13O2I [M - 57(C4H9)]: 305.0039, found:
305.0040.
1-(Ben zoyloxy)-5-m eth ylid en eh ep ta n -6-on e (10). A 3
L round-bottom flask equipped with an overhead stirrer was
charged with 2,4-pentanedione (75 g, 0.75 mol) and potassium
carbonate (207.3 g, 1.5 mol) in DMSO (1.5 L). To the mixture
was added 4-iodo-1-(benzoyloxy)butane (9) (222 g, 0.75 mol).
After stirring for 10 h at room temperature, paraformaldehyde
(100 g, 7.5 mol) was added in one portion. The reaction
mixture was stirred for 3 h and quenched with saturated
NaHCO3 (300 mL). The aqueous layer was extracted with
ether (5 × 250 mL), and the combined organic layers were
dried (MgSO4) and concentrated in vacuo. The crude oil was
filtered through silica gel (ether) to yield 156.8 g (0.63 mol) of
enone 10 (85%). TLC (SiO2, 30% ether/pentane, UV, vanillin)
Rf ) 0.57; 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H), 7.50
(app tt, J ) 7.4, 1.2, 2.0 Hz, 1H), 7.43 (m, 2 H), 5.99 (s, 1H),
5.75 (bt, J ) 1.2 Hz, 1H), 4.28 (t, J ) 6.4 Hz, 2H), 2.31 (s, 3H),
1.74 (m, 2H), 1.54 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 199.4,
166.4, 132.7, 130.2, 128.3, 128.2, 125.1, 64.6, 30.0, 28.3, 25.7,
24.8; FTIR (neat/NaCl) 3063, 2952, 2867, 1718, 1677, 1274,
7-[5-(2-Met h yl-1,3-d ioxola n -2-yl)h ex-5-en ylid en e]-2,3-
d ia za bicyclo[2.2.1]h ep t-2-en e (6). To a solution of fulvene
11 (4.90 g, 21.1 mmol) in methylene chloride (84 mL) was
added diethyl azodicarboxylate (3.83 g, 22 mmol) at room
temperature. The solution was placed in the refrigerator (4
°C) for 8 h. To the solution of crude carbamate (Rf ) 0.74
[100% ether], UV, vanillin) was added dipotassium azodicar-
boxylate (41 g, 211 mmol), and the mixture was stirred with
an overhead stirrer. The reaction mixture was cooled to 0 °C,
and glacial acetic acid (18.1 mL, 316 mmol) was added
dropwise via addition funnel over 45 min. A vigorous gas
evolution took place. After 4 h, the reaction mixture was
1115 cm-1
.
5-(2-Meth yl-1,3-dioxolan -2-yl)h ex-5-en al (7). A 3 L round-
bottom flask equipped with an overhead stirrer was charged
with enone 10 (156.8 g, 637.5 mmol), ethylene glycol (1000
mL), and trimethyl orthoformate (500 mL). p-Toluenesulfonic
acid (12 g, 63 mmol) was then added to this biphasic mixture.
The solution immediately became clear and slowly became
dark red upon stirring for 10 h at room temperature. A 26.5
M solution of KOH/H2O (200 mL) was then added over 1 h.
The dark red solution initially turned cloudy orange and then
clear orange. After stirring for 2 h, the aqueous layer was
extracted with methylene chloride (7 × 300 mL), and the
combined organic layers were dried (MgSO4) and concentrated
in vacuo. Distillation under reduced pressure (120-125 °C/
0.1 Torr) afforded 89.2 g (471.7 mmol) of 5-(2-methyl-1,3-
dioxolan-2-yl)hex-5-en-1-ol (74%). TLC (SiO2, 70% ether/
pentane, vanillin) Rf ) 0.20; 1H NMR (500 MHz, CDCl3) δ 5.24
(d, J ) 1.0 Hz, 1H), 4.89 (dd, J ) 1.0, 2.5 Hz, 1H), 3.95 (m,
2H), 3.83 (m, 2H), 3.67 (bt, J ) 5.5 Hz, 2H), 2.09 (t, J ) 7.5
Hz, 2H), 1.56 (m, 4H), 1.45 (s, 3H); 13C NMR (50 MHz, CDCl3)
δ 148.5, 109.6, 109.0, 63.8, 61.7, 32.1, 29.9, 23.9, 23.8; FTIR
(neat/NaCl) 3428, 3090, 2988, 2937, 2909, 1652, 1646, 1041
cm-1; HRMS (CI/NH3) calcd for C10H18O3 [M + H]+: 187.1334,
found: 187.1337.
filtered through
a sintered glass funnel with ether and
concentrated in vacuo. The crude reduced carbamate 12 (Rf
) 0.74 [100% ether], UV, vanillin) was dissolved in ethanol
(192 mL), the solution was degassed with argon for 20 min,
and potassium hydroxide (21.3 g, 380 mmol) was added. The
resulting mixture was refluxed for 2.5 h and then cooled to 0
°C. The reflux condenser was removed and replaced with an
overhead stirrer. Potassium ferricyanide (21.53 g, 65.41 mmol)
in water (172 mL) was added via addition funnel over 30 min..
After 2.5 h, the cloudy brown mixture was poured into a
separatory funnel containing water (1 L) and ether (300 mL).
The aqueous layer was extracted with ether (7 × 150 mL),
and the combined organic layers were dried (MgSO4) and
concentrated in vacuo. Chromatography on silica gel (50%
ether/pentane) afforded 5.14 g (19.6 mmol) of diazene 6 (93%).
TLC (SiO2, 50% ether/pentane, vanillin) Rf ) 0.4; 1H NMR (400
MHz, CDCl3) δ 5.38 (bs, 1H), 5.26 (d, J ) 1.0, 1H), 5.12 (m,
2H), 4.83 (q, J ) 1.5 Hz, 1H), 3.94 (m, 2H), 3.80 (m, 2H), 2.00
(m, 4H), 1.70-1.46 (m, 4H), 1.45 (s, 3H), 1.10 (d, J ) 9.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 148.7, 145.0, 117.2, 110.3,
109.4, 76.8, 72.6, 64.4, 30.1, 28.9, 28.0, 24.4, 21.5, 21.1; FTIR
(neat/NaCl) 3092, 2984, 2941, 2888, 1645, 1455, 1039 cm-1
;
HRMS (CI/NH3) calcd for C15H22O2N2 [M + H]+: 263.1759,
found: 263.1748.
Sulfur trioxide-pyridine complex (100 g, 500 mmol) was
added at room temperature to a stirring solution of the alcohol
(40 g, 215 mmol, obtained as described above) in triethylamine
(536 mL) and DMSO (536 mL). After 20 min the reaction was
complete. The solution was cooled to 0 °C, and water (500
mL) was added. Upon warming to room temperature, the
aqueous layer was extracted with ether (5 × 100 mL), and the
combined organic layers were dried (MgSO4) and concentrated
Diyl Tr a p p in g Rea ction : Dia zen e 6 in MeCN. A 2 L
round-bottom flask was charged with acetonitrile (1000 mL)
and degassed with argon for 30 min. A reflux condenser was
then attached to the round-bottom flask. To the top of the
reflux condenser was attached a 500 mL addition funnel, and
the system was purged with argon. The addition funnel was
charged with a solution of diazene 6 (15.30 g, 58.4 mmol) in

1614 J . Org. Chem., Vol. 62, No. 6, 1997
Ott and Little
previously degassed acetonitrile (500 mL) via cannula. The
addition funnel was wrapped in aluminum foil to prevent light-
induced deazotization of the substrate, and the acetonitrile in
the round-bottom flask was heated to reflux. The solution of
diazene was slowly added dropwise (1 drop/4 s) through the
condenser into the refluxing acetonitrile over 40 h. After 40
h, the empty addition funnel was rinsed with previously
degassed acetonitrile (25 mL) which was allowed to drop into
the reluxing reaction mixture over a period of 15 min. The
solution was refluxed another 2 h and cooled to room temper-
ature, and the solvent was removed in vacuo. The crude oil
was purified by chromatography on silica gel (5% ether/
pentane) to afford 11.1 g (47.3 mmol) of trapped products 5a
and 5b (81%). The mixture contained endo and exo bridged
products in a ratio of 1:1, as well as a trace amount of linearly
fused tricyclopentanoid product. The ratio of bridged to linear
products was 10:1. The spectral data were the following:
(3a â,4r,8r)-2-(3,3a ,5,6,7,8-Hexa h ydr o-2H-4,8-m eth a n oa -
zu len -4-yl)-2-m eth yl-1,3-d ioxola n e (5a ). TLC (SiO2, 10%
ether/pentane, vanillin) Rf ) 0.42; 1H NMR (400 MHz, CDCl3)
δ 5.49 (t, J ) 4.0 Hz, 1H), 3.97-3.75 (m, 4H), 2.64 (br t, J )
2.5 Hz, 1H), 2.59 (br t, J ) 8.0 Hz, 1H), 2.36 (m, 1H), 2.15 (m,
1H), 1.94 (m, 2H), 1.79 (m, 1H), 1.68 (m, 1H), 1.58 (m, 5H),
1.44 (m, 1H), 1.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.6,
120.7, 112.7, 65.1, 63.8, 53.7, 49.4, 40.3, 37.6, 35.1, 34.8, 34.0,
29.7, 20.7, 19.8; FTIR (neat/NaCl) 3045, 2936, 2871, 1451,
1375, 1154, 1080, 1040 cm-1; HRMS (EI) calcd for C15H22O2:
234.1619, found: 234.1611.
(3ar,4r,8r)-2-(3,3a,5,6,7,8-Hexah ydr o-2H-4,8-m eth an oa-
zu len -4-yl)-2-m eth yl-1,3-d ioxola n e (5b). TLC (SiO2, 10%
ether/pentane, vanillin) Rf ) 0.34; 1H NMR (400 MHz, CDCl3)
δ 5.12 (t, J ) 1.5 Hz, 1H), 3.93-3.80 (m, 4H), 3.05 (br t, J )
7.5 Hz, 1H), 2.68 (br s, 1H), 2.63 (m, 1H), 2.50 (m, 1H), 2.11
(m, 1H), 1.85-1.58 (m, 5H), 1.52-1.36 (m, 4H), 1.20 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 157.7, 115.4, 112.4, 65.0, 64.8,
56.5, 49.0, 43.9, 37.0, 33.7, 33.6, 27.2, 27.1, 20.7, 18.6; FTIR
(neat/NaCl) 3045, 2947, 2874, 1440, 1352, 1210, 1151, 1046
cm-1; HRMS (EI) calcd for C15H22O2: 234.1619, found: 234.1620.
(3a â,4r,8r)-4-(2-Meth yl-1,3-dioxola n -2-yl)-8a -(p h en ylse-
len yl)d eca h yd r o-4,8-m eth a n oa zu len -1-ol (13). To a solu-
tion of bromine (1.36 g, 17.0 mmol) and propylene oxide (1.0
mL) in benzene (20 mL) was added diphenyl diselenide (7.95
g, 25.5 mmol) at room temperature. The mixture immediately
turned black. After stirring 20 min, the mixture was trans-
ferred to a 100 mL round-bottom flask containing silver
trifluoroacetate (7.5 g, 34.0 mmol). The resulting bright yellow
reaction mixture was stirred for 20 min, and alkene 5a (5.0 g,
21.5 mmol) dissolved in benzene (10.0 mL) was added dropwise
via syringe. The mixture was allowed to stir for 3 h leading
to the formation of the addition product (Rf ) 0.42 [10% ether/
pentane], UV, vanillin). Hydrolysis of the trifluoroacetate
group was accomplished by the addition of potassium hydrox-
ide (50 g, 890 mmol) in ethanol (117 mL). After stirring at
room temperature for 5 min, the reaction was complete. Brine
(100 mL) was added to the reaction mixture, the aqueous layer
was extracted with ether (5 × 100 mL), and the combined
organic layers were dried (MgSO4) and concentrated in vacuo.
The crude product was purified by chromatography on silica
gel (60% ether/pentane) to afford 8.07 g (20.0 mmol) of pure
product 13 (93%). TLC (SiO2, 60% ether/pentane, UV, vanillin)
Rf ) 0.36; 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, 2H, J ) 7.0,
2.0 Hz), 7.29 (m, 3H), 4.63 (bt, J ) 7.0 Hz, 1H), 3.97-3.73 (m,
4H), 2.57 (br d, J ) 3.1 Hz, 1H), 2.15-1.99 (m, 5H), 1.90 (m,
1H), 1.78-1.56 (m, 7H), 1.30 (s, 3H), 1.14 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 135.3, 129.9, 129.1, 127.8, 112.8, 84.0,
68.7, 65.4, 63.6, 56.4, 54.3, 38.0, 37.7, 35.4, 35.1, 31.4, 26.5,
20.9, 19.2; FTIR (neat/NaCl) 3461, 3437, 3045, 2949, 2873,
1477, 1376, 1055 cm-1; HRMS (EI) calcd for C21H28O3Se:
408.1203, found: 408.1191.
solution of the alcohol 13 (8.07 g, 20.0 mmol) in methylene
chloride (10 mL) was then slowly added via syringe. After
stirring at -78 °C for 2 h, triethylamine (9.71 g, 96.0 mmol)
was slowly added (again exotherm occurred), and the reaction
mixture was allowed to warm to room temperature. After
stirring at room temperature for 2 h, the reaction mixture was
quenched with saturated NH4Cl (100 mL). The aqueous layer
was extracted with methylene chloride (5 × 100 mL), and the
combined organic layers were dried (MgSO4) and concentrated
in vacuo. The crude product was purified by chromatography
on silica gel (60% ether/pentane) to afford 7.26 g (18.0 mmol)
of pure ketone 14 (90%). TLC (SiO2, 60% ether/pentane, UV,
vanillin) Rf ) 0.50; 1H NMR (400 MHz, CDCl3) δ 7.63 (m, 2H),
7.35 (app tt, J ) 7.0, 1.3 Hz, 1H), 7.43 (m, 2 H), 3.96-3.70 (m,
4H), 2.45 (d, J ) 9.0 Hz, 1H), 2.41 (m, 1H), 2.23-2.15 (m, 3H),
2.0 (m, 2H), 1.66 (m, 4H), 1.53 (m, 1H), 1.47 (dd, J ) 11.5, 5.5
Hz, 1H), 1.30 (s, 3H), 1.24 (d, J ) 12.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 217.9, 137.0, 128.8, 128.7, 126.6, 111.7, 66.0,
65.2, 63.7, 55.4, 52.3, 40.2, 37.2, 36.3, 35.2, 28.2, 22.5, 20.9,
18.9; FTIR (neat/NaCl) 3063, 2950, 2875, 1719, 1469, 1438,
1375, 1044 cm-1; HRMS (EI) calcd for C21H26O3Se: 406.1047,
found: 406.1029.
(4r,8r)-4-(2-Meth yl-1,3-dioxolan -2-yl)-3,4,5,6,7,8-h exah y-
d r o-2H-4,8-m eth a n oa zu len -1-on e (4). To a stirring solution
of ketone 14 (7.26 g, 17.9 mmol) in methylene chloride (90 mL)
was added m-CPBA (50%, 3.71 g, 21.5 mmol) at -78 °C. The
homogeneous yellow solution turned to a heterogeneous orange
mixture which was allowed to stir at -78 °C for 2 h. The
reaction mixture was then transferred into a solution of
refluxing triethylamine (6 mL) and carbon tetrachloride (200
mL). The dark orange solution was maintained at reflux for
8 h. The reaction mixture was then cooled to room tempera-
ture and quenched with saturated NaHCO3 (100 mL). The
aqueous layer was extracted with methylene chloride (5 × 100
mL), and the combined organic layers were dried (MgSO4) and
concentrated in vacuo. The crude product was purified by
chromatography on silica gel (70% ether/pentane) to afford 4.22
g (17.0 mmol) of pure enone 4 (95%). TLC (SiO2, 70% ether/
1
pentane, UV, vanillin) Rf ) 0.30; H NMR (400 MHz, CDCl3)
δ 4.04-3.95 (m, 4H), 2.87 (br s, 1H), 2.79-2.51 (m, 4H), 2.46
(m, 1H), 1.63 (m, 4H), 1.48 (m, 1H), 1.39 (app tdd, J ) 11.9,
5.1, 1.8 Hz, 1H), 1.28 (s, 3H), 1.0 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 203.8, 186.8, 149.3, 110.6, 64.5, 57.0, 48.0, 40.1, 33.6,
25.0, 24.6, 24.0, 20.2, 19.5; FTIR (neat/NaCl) 2942, 2872, 1686,
1613, 1445, 1380, 1146, 1103, 1041 cm-1; HRMS (EI) calcd for
C15H20O2: 248.1412, found: 248.1416.
2-[(4r,8r)-1-[(ter t-Bu tyld ip h en ylsilyl)oxy]d eca h yd r o-
4,8-m eth a n oa zu len -4-yl]-2-m eth yl-1,3-d ioxola n e (16b). To
a solution of enone 4 (250 mg, 1.0 mmol) in CH2Cl2 (3 mL) at
-78 °C was added DIBAL-H (1 M in hexanes, 1.5 mL, 1.5
mmol). After 15 min, saturated sodium potassium tartrate
(10 mL) was added, and the mixture was allowed to warm to
room temperature where it stirred for 30 min. Brine (3 mL)
was added, and the aqueous layer was extracted with CH2
Cl2
(5 × 15 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo. The crude mixture of allylic
alcohols 16a were protected without further purification. TLC
(SiO2, 60% ether/pentane, UV, vanillin) Rf ) 0.40 (major
diastereomer), 0.55 (minor diastereomer).
To a stirring solution of allylic alcohols 16a (250 mg, 1.0
mmol), DMAP (5 mg), and tert-butylchlorodiphenylsilane
(302.3 mg, 1.1 mmol) in CH2Cl2 (3 mL) was added NEt3 (0.417
mL, 3.0 mmol) at 0 °C. The cloudy mixture was allowed to
warm to room temperature and stir for 8 h. The reaction was
quenched with saturated NH4Cl (3 mL), and the water layer
was extracted with CH2Cl2 (5 × 6 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
crude products were purified by chromatography on silica gel
(10% ether/pentane) to afford 376 mg (0.77 mmol) of diaster-
eomers 16b (77%) in a ratio of 4:1. TLC (SiO2, 10% ether/
pentane, UV, vanillin) Rf ) 0.30 (major diastereomer), 0.40
(minor diastereomer). Major diastereomer 16b: 1H NMR (400
MHz, CDCl3) δ 7.66 (m, 4H), 7.38 (m, 6H), 4.95 (app dt, J )
6.5, 2.0 Hz, 1H), 4.00-3.85 (m, 4H), 2.37 (m, 2H), 2.20 (m,
2H), 2.08 (ddt, J ) 16.3, 8.0, 2.4 Hz, 1H), 1.99 (ddt, J ) 13.5,
8.0, 2.4 Hz, 1H), 1.68-1.56 (m, 5H), 1.47-1.37 (m, 2H), 1.26
(3a â,4r,8r)-4-(2-Meth yl-1,3-dioxola n -2-yl)-8a -(ph en ylse-
len yl)octa h yd r o-4,8-m eth a n oa zu len -1-on e (14). To a stir-
ring solution of DMSO (3.75 g, 48.0 mmol) in methylene
chloride (100 mL) at -78 °C was added oxalyl chloride (2 M
solution in methylene chloride, 12.0 mL, 24.0 mmol) via
syringe. The reaction is slightly exothermic. The resulting
pale yellow solution was stirred at -78 °C for 20 min.
A

Diyl Trapping Reactions To Synthesize Taxol Analogs
J . Org. Chem., Vol. 62, No. 6, 1997 1615
(m, 2H), 1.19 (s, 3H), 1.05 (s, 9H); FTIR (neat/NaCl) 3070,
3050, 2941, 2857, 1958, 1898, 1824, 1472, 1427, 1389, 1112,
129.3, 127.7, 127.5, 110.6, 64.6, 63.6, 57.0, 51.6, 47.8, 33.6, 32.5,
31.8, 31.2, 26.8, 24.8, 24.0, 23.5, 20.4, 19.5, 19.1; FTIR (neat/
1048 cm-1
.
NaCl) 3061, 2940, 2864, 1686, 1615, 1460, 1381, 1104 cm-1
;
exact mass [HRMS (CI/CH4)] calcd for C35H46O4Si [M + H]+:
559.3243, found: 559.3250.
(1r,5r,7r)-5-[(ter t-Bu tyld ip h en ylsilyl)oxy]-1-(2-m eth yl-
1,3-d ioxola n -2-yl)bicyclo[5.3.1]u n d eca n e-2,6-d ion e (17).
To a solution of silyl ether 16b (100 mg, 0.2 mmol) in CH2-
Cl2/MeOH (2 mL, 3:1) at -78 °C was bubbled ozone until a
pale blue color persisted (10 min). The excess ozone was
removed by bubbling nitrogen through the solution until the
reaction maintained a clear color (10 min). Excess methyl
sulfide (124 mg, 2.0 mmol) was added at -78 °C, and the
reaction was allowed to warm to room temperature where it
stirred for 3 h. The solvents were removed in vacuo, and the
crude product was purified by chromatography on silica gel
(30% ether/pentane) to afford 72 mg (0.14 mmol) of pure dione
(70%). TLC (SiO2, 30% ether/pentane, UV, vanillin) Rf ) 0.50;
1H NMR (400 MHz, CDCl3) δ 7.67-6.78 (m, 10H), 4.54 (t, J )
3.5 Hz, 1H), 4.08-3.92 (m, 4H), 3.89 (m, 1H), 3.76 (dd, J )
14.7, 2.2 Hz, 1H), 2.39 (br s, 1H), 2.14 (m, 1H), 1,94 (m, 4H),
1.34-1.20 (m, 5H), 1.10 (s, 9H), 1.06 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 215.6, 213.5, 154.2, 135.1, 130.7, 130.4, 129.7,
129.6, 128.1, 122.1, 119.7, 119.5, 110.9, 80.2, 65.5, 64.6, 60.4,
43.0, 34.5, 33.9, 27.0, 25.8, 25.6, 25.1, 20.5, 18.9, 18.0; FTIR
(neat/NaCl) 2979, 2955, 2933, 2890, 2859, 1702, 1698, 1596,
For (2â,4R,8R)-2-[4-[(tert-Butyldiphenylsilyl)oxy]butyl]-4-
(2-methyl-1,3-dioxolan-2-yl)-3,4,5,6,7,8-hexahydro-2H-4,8-meth-
anoazulen-1-one: TLC (SiO2, 50% Et2O/pentane, UV, vanillin)
1
Rf ) 0.28; H NMR (400 MHz, CDCl3) δ 7.66 (app d, J ) 6.5,
4H), 7.39 (m, 6H), 4.04-3.95 (m, 4H), 3.67 (t, J ) 6.4 Hz, 2H),
2.86 (br s, 1H), 2.79-2.67 (m, 2H), 2.43 (m, 1H), 2.20 (d, J )
17.2 Hz, 1H), 1.86 (m, 1H), 1.60 (m, 6H), 1.49-1.26 (m, 6H),
1.27 (s, 3H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 205.8,
184.7, 148.7, 135.5, 134.0, 129.5, 127.6, 110.7, 64.6, 63.6, 57.0,
51.1, 47.9, 33.7, 32.5, 31.4, 26.8, 24.9, 24.0, 23.6, 20.3, 19.6,
19.2; FTIR (neat/NaCl) 3059, 2940, 2864, 1689, 1615, 1460,
1380, 1104 cm-1
; exact mass [HRMS (CI/CH4)] calcd for
C35H46O4Si [M + H]+: 559.3243, found: 559.3224.
A 250 mL round-bottom flask was charged with a mixture
of enones (2.20 g, 3.93 mmol; prepared as described above),
camphorsulfonic acid (10 mg), ethylene glycol (100 mL), and
benzene (100 mL). The biphasic mixture was heated to reflux,
and water was azeotropically removed by using a Dean-Stark
trap. After 12 h, the reaction mixture was cooled to room
temperature and diluted with 200 mL of saturatated NaHCO3,
and the aqueous layer was extracted with ether (3 × 100 mL).
The combined organic layers were washed with brine, dried
(MgSO4), and concentrated in vacuo. Chromatography on
silica gel (30% ether/pentane) afforded 1.54 g (2.55 mmol, 65%)
of inseparable ketals 20a and 20b (2.5:1) and recovered
starting material (400 mg, 0.71 mmol, 83% based on recovered
starting material). TLC (SiO2, 50% Et2O/pentane, UV, vanil-
1492, 1251, 1112 cm-1
.
4-Iod o-1-(ter t-bu tyld ip h en ylsiloxy)bu ta n e (19). To a
stirring solution of tert-Butylchlorodiphenylsilane (105.4 g,
0.75 mol) and THF (175.1 g, 2.74 mol) in acetone (1.5 L) was
added sodium iodide (224.8 g, 1.5 mol). The orange reaction
mixture was stirred at room temperature for 10 h and then
quenched with saturated NaHSO3 (500 mL). The water layer
was extracted with ether (3 × 250 mL), the combined organic
layers were washed with saturated NaHCO3 (300 mL) and
brine (300 mL), dried (MgSO4), and concentrated in vacuo. The
crude oil was filtered through silica gel (ether) to yield 207 g
(0.70 mol) of pure alkyl iodide 19 (93%). TLC (SiO2, 100%
1
lin) Rf ) 0.55; H NMR (500 MHz, CDCl3) δ 7.67 (app d, J )
6.5, 4H), 7.39 (m, 6H), 4.04-3.95 (m, 8H), 3.68 (t, J ) 6.5 Hz,
2H, 20b), 3.67 (t, J ) 6.5 Hz, 2H, 20a ), 2.60 (br m, 1H), 2.40
(m, 1H), 2.32 (m, 1H), 2.00 (dd, J ) 15.5, 3.6 Hz, 1H, 20b),
1.88 (dd, J ) 16.5, 7.0 Hz, 1H, 20a ), 1.68-1.53 (m, 6H), 1.50-
1.31 (m, 8H), 1.22 (s, 3H, 20a ), 1.21 (s, 3H, 20b), 1.05 (s, 9H);
13C NMR (125 MHz, CDCl3) major diastereomer 20a δ 152.0,
146.3, 135.5, 134.1, 129.4, 127.5, 117.3, 111.5, 65.6, 65.0, 64.9,
64.8, 64.0, 54.7, 50.7, 48.2, 36.2, 32.9, 31.8, 29.1, 26.8, 25.5,
24.4, 20.7, 19.8, 19.6, 19.2; minor diastereomer 20b δ 152.0,
145.9, 135.5, 134.1, 129.4, 127.5, 116.7, 111.6, 65.4, 64.8, 64.4,
64.0, 54.5, 51.3, 48.7, 35.9, 32.8, 32.0, 30.0, 26.8, 25.2, 24.9,
24.3, 20.6, 19.8, 19.7, 19.2; FTIR (neat/NaCl) 3059, 2940, 2864,
1689, 1615, 1460, 1380, 1104 cm-1; exact mass [HRMS (CI/
CH4
1
pentane, UV, vanillin) Rf ) 0.50; H NMR (400 MHz, CDCl3)
δ 7.71 (app dd, J ) 8.0, 1.5 Hz, 4H), 7.44 (m, 6H), 3.72 (t, J )
6.0 Hz, 2H), 3.22 (t, J ) 7.0 Hz, 2H), 1.99 (tt, J ) 14.0, 7.0 Hz,
2H), 1.69 (tt, J ) 14.0, 6.0 Hz, 2H), 1.10 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 135.5, 133.7, 129.6, 127.6, 62.6, 33.2, 30.1,
26.8, 19.2, 7.1; FTIR (neat/NaCl) 3069, 2949, 2857, 1958, 1896,
1824, 1472, 1427, 1224, 1112 cm-1; exact mass [HRMS(CI/
CH4)] calcd for C20H26OSiI [M - H]+: 437.0798, found:
437.0792.
Syn th esis of Alk yla ted En on es 20a a n d 20b. 2-[1,1-O-
E t h ylen e-1,1-d ih yd r oxy-2-[4-[(ter t-b u t yld ip h en ylsilyl)-
oxy]bu tyl]d eca h yd r o-4,8-m eth a n oa zu len -4-yl]-2-m eth yl-
1,3-d ioxola n e (20a a n d 20b). To a stirring solution of n-BuLi
(2.5 M solution in hexanes, 4.0 mL, 10.0 mmol) in THF (34
mL) was added diisopropylamine (1.40 mL, 10.0 mmol) at -78
°C. After 20 min the enone (2.0 g, 8.1 mmol) in THF (3 mL)
was added dropwise via syringe and stirred at -78 °C for 1 h.
The solution was warmed to 0 °C for 30 min and then cooled
back to -78 °C for 30 min. Alkyl iodide 9 (6.0 g, 26.2 mmol)
was added via syringe and the reaction was allowed to warm
to room temperature. After stirring at room temperature for
3 h, the reaction was quenched with saturated NH4Cl (20 mL).
The aqueous layer was extracted with ether (5 × 100 mL),
the combined organic layers were dried (MgSO4) and concen-
trated in vacuo. The crude products were purified and
separated on silica gel (50% ether/pentane) to afford 3.49 g
(6.24 mmol) of pure enones (77%) and recovered starting
material (250 mg, 1.01 mmol, 89% based on recovered starting
material). The product mixture contained the 2R,4R,8R and
2â,4R,8R-diastereomers in a ratio of 2.5:1; their spectral date
follows.
)] calcd for C37H50O5Si [M + H]+: 603.3505, found:
603.3495.
4-[4-[(ter t-Bu tyldiph en ylsilyl)oxy]bu tyl]-5,5-O-eth ylen e-
5,5-dih ydr oxy-1-(2-m eth yl-1,3-dioxolan -2-yl)bicyclo[5.3.1]-
u n d eca n e-2,6-d ion e (21a ). To a stirring mixture of ketals
20a and 20b (256 mg, 0.40 mmol) and sodium periodate (263
mg, 1.23 mmol) in carbon tetrachloride (2 mL), acetonitrile (2
mL), and water (2 mL) was added ruthenium tetraoxide (10
mg) at 0 °C. The mixture turned black (with green overtones).
After 20 min the reaction was complete by TLC. The mixture
was transferred directly onto a premade column of silica gel
and eluted with ether. The crude products were collected and
concentrated in vacuo. Purification on silica gel (40% ether/
pentane) afforded 205 mg (0.32 mmol, 80%) of inseparable
diastereomers 21a (2.5:1). TLC (SiO2, 50% Et2O/pentane, UV,
vanillin) Rf ) 0.30; 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 4H),
7.39 (m, 6H), 4.11-3.87 (m, 7H,), 3.77-3.63 (m, 4H), 3.52-
3.38 (m, 1H), 2.67 (br m, 1H), 2.22-2.05 (m, 4H), 2.01 (dd, J
) 15.2, 5.5 Hz, 1H, minor diastereomer), 1.95 (dd, J ) 14.8,
5.5 Hz, 1H, major diastereomer), 1.74-1.43 (m, 5H), 1.40-
1.09 (m, 5H), 1.06 (s, 3H, minor diastereomer) and 1.05 (s, 3H,
major diastereomer), 1.04 (s, 9H, major diastereomer) and 1.03
(s, 9H, minor diastereomer); 13C NMR (50 MHz, CDCl3) major
diastereomer δ 214.2, 212.8, 135.5, 134.2, 129.5, 127.5, 112.2,
110.7, 66.4, 65.3, 65.0, 64.5, 63.7, 60.6, 45.6, 44.6, 39.7, 32.6,
27.6, 27.1, 26.8, 25.6, 23.5, 20.3, 19.2, 18.6, 17.6; minor
diastereomer 212.8, 210.1, 135.5, 134.0, 129.3, 127.5, 111.1,
110.7, 65.6, 65.0, 64.0, 60.4, 45.2, 44.2, 35.9, 32.5, 27.4, 26.7,
25.4, 23.2, 20.0, 19.2, 18.6, 17.6; FTIR (neat/NaCl) 3067, 3047,
2950, 2932, 2880, 2856, 1732, 1707, 1690, 1460, 1424, 1377,
For (2R,4R,8R)-2-[4-[(tert-Butyldiphenylsilyl)oxy]butyl]-4-
(2-methyl-1,3-dioxolan-2-yl)-3,4,5,6,7,8-hexahydro-2H-4,8-meth-
anoazulen-1-one: TLC (SiO2, 50% Et2O/pentane, UV, vanillin)
1
Rf ) 0.30; H NMR (500 MHz, CDCl3) δ 7.66 (app d, J ) 6.5,
4H), 7.39 (m, 6H), 4.04-3.89 (m, 4H), 3.67 (t, J ) 6 Hz, 2H),
2.86 (br s, 1H), 2.71 (dd, J ) 19.0, 6.2 Hz, 1H), 2.63 (br s, 1H),
2.42 (m, 1H), 2.27 (d, J ) 19.0 Hz, 1H), 1.84 (m, 1H), 1.60 (m,
6H), 1.44 (m, 6H), 1.27 (s, 3H), 1.0 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 205.8, 185.2, 148.6, 135.5, 135.4, 134.0, 133.9, 129.4,

1616 J . Org. Chem., Vol. 62, No. 6, 1997
Ott and Little
1136 cm-1; exact mass [HRMS (CI/CH4)] calcd for C37H50O7Si
[M + H]+: 635.3404, found: 635.3385.
3H), 1.14 (m, 2H), 1.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
214.1, 212.7, 112.2, 110.7, 66.5, 65.4, 65.1, 64.5, 60.5, 44.3, 44.2,
39.9, 33.5, 27.9, 27.1, 26.7, 26.6, 25.6, 20.4, 17.6, 6.8; FTIR
(neat/NaCl) 2945, 2890, 1702, 1698, 1596, 1485, 1230, 1150
4-(4-Hyd r oxylbu tyl)-5,5-O-eth ylen e-5,5-d ih yd r oxy-1-(2-
m et h yl-1,3-d ioxola n -2-yl)b icyclo[5.3.1]u n d eca n e-2,6-d i-
on e (21b). To neat mixed diones 21a (200 mg, 0.31 mmol)
was added TBAF (1 M solution in THF, 1 mL, 1 mmol) at room
temperature. The reaction was complete by TLC after stirring
for 3 h. Water (1 mL) was added, and the aqueous layer was
extracted with methylene chloride (5 × 100 mL). The com-
bined organic layers were washed with brine, dried (MgSO4),
and concentrated in vacuo. Chromatography on silica gel (20%
ethyl acetate/pentane) afforded 117 mg (0.29 mmol, 95%) of
separable alcohols (2.5:1). Major diastereomer 21b: TLC
(SiO2, 20% ethyl acetate/pentane, vanillin) Rf ) 0.20; 1H NMR
(400 MHz, CDCl3) δ 4.12-3.88 (m, 7H), 3.75 (m, 1H), 3.63 (t,
J ) 6.5 Hz, 2H), 3.47 (dd, J ) 14.7, 2.4 Hz, 1H), 3.41 (app t,
J ) 13 Hz, 1H), 2.68 (br s, 1H), 2.09 (m, 3H), 1.94 (dd, J )
14.7, 5.5 Hz, 1H), 1.75 (m, 2H), 1.55 (m, 4H), 1.42-1.23 (m,
4H), 1.15 (m, 2H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
214.3, 212.8, 112.2, 110.7, 66.5, 65.4, 65.0, 64.4, 62.8, 60.5, 44.5,
44.2, 39.8, 32.7, 27.4, 27.1, 26.7, 25.6, 23.2, 20.3, 17.6; FTIR
(neat/NaCl) 3422, 2936, 2879, 1731, 1708, 1693, 1460, 1378,
1101 cm-1; exact mass [HRMS (CI/NH3)] calcd for C21H32O7
[M + H]+: 396.2226, found: 396.2227.
4-(4-Iodobu tyl)-5,5-O-eth ylen e-5,5-dih ydr oxy-1-(2-m eth -
yl-1,3-dioxolan -2-yl)bicyclo[5.3.1]u n decan e-2,6-dion e (22).
To a stirring solution of alcohol 21b (8 mg. 0.02 mmol),
methanesulfonyl chloride (2.3 µL, 0.03 mmol), and DMAP (2
mg) in CH2Cl2 (0.5 mL) at 0 °C was added NEt3 (4.3 µL, 0.03
mmol). After 1 h, saturated NH4Cl (0.5 mL) was added, the
aqueous layer was extracted with CH2Cl2 (5 × 1 mL), and the
combined organic layers were dried (MgSO4) and concentrated
in vacuo. The crude mesylate was carried on without further
purification. TLC (SiO2, 100% ether, vanillin) Rf ) 0.20.
To a stirring solution of crude mesylate (9 mg, 0.02 mmol)
in acetone (0.5 mL) at 0 °C was added sodium iodide (4.5 mg,
0.03 mmol). The reaction was allowed to warm to room
temperature where it stirred for 8 h. Saturated NaHCO3 (0.5
mL) was added, and the aqueous layer was extracted with
ether (5 × 1 mL). The combined organic layers were washed
with sodium bisulfite (3 mL), dried (MgSO4), and concentrated
in vacuo. Chromatography on silica gel (100% ether) afforded
8 mg (0.016 mmol) of pure iodide 22 (80%). TLC (SiO2, 100%
ether, vanillin) Rf ) 0.55; 1H NMR (400 MHz, CDCl3) δ 4.10-
3.88 (m, 7H), 3.75 (m, 1H), 3.44 (m, 2H), 3.16 (t, J ) 7 Hz,
2H), 2.66 (br s, 1H), 2.14-2.01 (m, 4H), 1.94 (dd, J ) 14.7, 5.3
Hz, 1H), 1.88-1.67 (m, 3H), 1.58-1.50 (m, 2H), 1.42-1.23 (m,
cm-1
.
9,9-O-Eth ylen e-9,9-dih ydr oxy-1-(2-m eth yl-1,3-dioxolan -
2-yl)tr icyclo[9.3.1.03,8]p en ta d eca n e-2,10-d ion e (3). To a
stirring solution of n-BuLi (1.6 M solution in hexanes, 18 µL,
0.03 mmol) in THF (0.5 mL) was added diisopropylamine (4.2
µL, 0.03 mmol) at -78 °C. After 20 min the dione 22 (4 mg,
0.008 mmol) in THF (0.25 mL) was added and stirred at -78
°C for 1 h. The solution was warmed to 0 °C for 5 min and
then allowed to warm to room temperature for 5 min. The
reaction was quenched with saturated NH4Cl (1 mL), and the
layers were separated. The aqueous layer was extracted with
ether (5 × 1 mL), and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. The crude product was
purified on silica gel (100% ether/pentane) to afford 2 mg (0.005
mmol) of pure tricyclic dione 3 (63%). TLC (SiO2, 100% ether,
vanillin) Rf ) 0.7; 1H NMR (400 MHz, CDCl3) δ 4.22-3.88 (m,
7H), 3.70 (app q, J ) 6.5 Hz, 1H,), 3.46 (m, 2H), 2.67 (br s,
1H), 2.09 (m, 2H), 2.00 (m, 1H), 1.92 (dd, J ) 14.6, 5.5 Hz,
1H), 1.75-1.60 (m, 3H), 1.48-1.11 (m, 9H), 1.05 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 216.5, 212.9, 112.0, 110.7, 66.8, 65.5,
64.9, 64.4, 60.3, 46.9, 46.6, 44.0, 30.6, 29.7, 27.5, 26.1, 25.5,
24.8, 24.0, 20.7, 17.4; FTIR (neat/NaCl) 3054, 2928, 2855, 1733,
1714, 1692, 1463, 1265, 1040 cm-1; exact mass [HRMS (CI/
CH4)] calcd for C21H30O6 [M + H]+: 379.21206, found:
379.21169.
Ack n ow led gm en t. We are exceptionally grateful to
the National Institutes of Health (NIH) for their support
of our research. We also express our sincere thanks to
Dr. Andre D’Avignon of Washington University for
performing the HMQC-TOCSY experiments.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds 3, 4, 5a , 5b, 6, 7, 9, 10, 11, 12, 13, 14, 16a , 16b,
17, 19, 20, 21a , 21b, and 22, as well as HMQC TOCSY for 17
and decoupling and NOE data for the R-alkylated isomer of
enone 4 [alkyl group ) (CH2)4OTBDPS] (94 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O970042E