Synthesis of novel simplified sarcodictyin/eleutherobin analogs with potent microtubule-stabilizing activity, using ring closing metathesis as the key-step

Article abstract of DOI:10.1016/j.tet.2003.08.057

The synthesis of a number of novel simplified eleutheside analogs with potent tubulin-assembling and microtubule-stabilizing properties is described, using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in 6 steps on a multigram scale from R-(-)-carvone in 30% overall yield] via multiple stereoselective Brown allylations. Second generation RCM catalyst 13 gave the desired ring closed 10-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) likely reflects thermodynamic control. The crucial role of the protecting groups of the homoallylic and allylic substituents for the efficiency of the RCM reactions is discussed. These simplified analogs of the natural product (lacking inter alia the C-4/C-7 ether bridge) retain potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma and human colon carcinoma cell lines, IC₅₀ in the μM range given in Table 2), three orders of magnitude less than paclitaxel (IC₅₀ in the nM range).

Full text of DOI:10.1016/j.tet.2003.08.057

Tetrahedron 59 (2003) 8803–8820
Synthesis of novel simplified sarcodictyin/eleutherobin analogs
with potent microtubule-stabilizing activity, using ring closing
metathesis as the key-step
†
‡
b
,
a
a
Raphael Beumer,a Pau Bayon, Piergiuliano Bugada, Sylvie Ducki, Nicola Mongelli,b
,
´
Federico Riccardi Sirtori,b Joachim Telsera § and Cesare Gennaria
,
,
*
aDipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I., Istituto CNR di Scienze e Tecnologie Molecolari,
Universita’ di Milano, via Venezian 21, I-20133 Milan, Italy
bPharmacia, viale Pasteur 10, I-20014 Nerviano, Italy
Received 28 June 2003; revised 5 August 2003; accepted 29 August 2003
Abstract—The synthesis of a number of novel simplified eleutheside analogs with potent tubulin-assembling and microtubule-stabilizing
properties is described, using ring closing metathesis as the key-step for obtaining the 6–10 fused bicyclic ring system. The RCM precursors
were synthesized starting from aldehyde 3 [prepared in 6 steps on a multigram scale from R-(2)-carvone in 30% overall yield] via multiple
stereoselective Brown allylations. Second generation RCM catalyst 13 gave the desired ring closed 10-membered carbocycles as single Z
stereoisomers in good yields. The RCM stereochemical course (100% Z) likely reflects thermodynamic control. The crucial role of the
protecting groups of the homoallylic and allylic substituents for the efficiency of the RCM reactions is discussed. These simplified analogs of
the natural product (lacking inter alia the C-4/C-7 ether bridge) retain potent microtubule-stabilizing activity. However, the cytotoxicity tests
did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three
common tumor cell lines (human ovarian carcinoma and human colon carcinoma cell lines, IC50 in the mM range given in Table 2), three
orders of magnitude less than paclitaxel (IC50 in the nM range).
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
cell lines and therefore hold potential as second generation
microtubule-stabilizing anticancer agents.4,5 The scarce
availability of 1–2 from natural sources makes their total
syntheses vital for further biological investigations.5 To
date, sarcodictyins A and B have been synthesized
successfully by Nicolaou et al.,6 who have also exploited
a similar route for accessing eleutherobin.7 A subsequent
report by Danishefsky and co-workers details an elegant
alternative access to eleutherobin.8 A number of partial
syntheses and approaches have also been described.9
Sarcodictyins A (1a) and B (1b) (Fig. 1) were isolated in
1987 by Pietra et al. from the Mediterranean stoloniferan
coral Sarcodictyon roseum,1 while their antitumor activity
was recognized about a decade later, and their paclitaxel-
like mechanism of action uncovered (1996).2 In the mean-
time, the diterpene glycoside eleutherobin (2) was reported
by Fenical et al. from an Eleutherobia species of australian
soft coral, accompanied by disclosure of its potent
cytotoxicity (1995).3 Two years later, in 1997, it was
shown that eleutherobin, similarly to sarcodictyins, acted by
mitotic arrest through induced tubulin polymerization.4
Both sarcodictyins and eleutherobin (the ‘eleutheside’
family of microtubule-stabilizing drugs) are characterized
by an activity profile different from that of paclitaxel; in
particular, they are active against paclitaxel resistant tumor
The total syntheses of the eleuthesides have generated very
Keywords: allylation; antitumor compounds; metathesis; stereocontrol.
*
Corresponding author. Tel.: þ39-0250314091; fax: þ39-0250314072;
e-mail: cesare.gennari@unimi.it
Present address: Roche Vitamins Ltd, VFK R&D Actives, CH-4070
†
Basel, Switzerland.
Present address: Centre for Molecular Drug Design, Kidscan
‡
Laboratories, University of Salford, Salford M5 4WT, UK.
Present address: Medicinal Chemistry PH-R EU CR MC6, Bayer AG,
Pharma Research, D-42096 Wuppertal, Germany.
§
Figure 1. Marine diterpenoids sarcodictyin A (1a), B (1b) and eleutherobin
(2).
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.057

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R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
Scheme 1. Reagents and conditions: (a) (i) AllMgBr, lIpc2BOMe, Et2O–THF, 08C to rt; (ii) 3, 2788C to rt, 6 h; (iii) 6N NaOH, H2O2, rt, 15 h, 77% (.95%
diastereomeric purity). (b) TBDPS–Cl, excess imidazole, CH2Cl2, rt, 16 h, quant. (c) AcOH/THF/H2O (3:1:1), rt, 16 h, 99%. (d) NaBH4, EtOH, rt, 15 min,
98%. (e) MsCl, Et3N, CH2Cl2, 08C to rt, 1 h, quant. (f) KCN, 18-crown-6, MeCN, 808C, 5 h, 95%. (g) DIBAl-H, hexane/toluene (2:1), 2788C, 40 min, quant.
(h) (i) AllMgBr, lIpc2BOMe, Et2O-THF, 08C to rt; (ii) 10, 2788C to rt, 3 h; (iii) 6N NaOH, H2O2, rt, 15 h, 55% (.95% diastereomeric purity). (i) Ac2O, cat.
DMAP, Py, rt, 94%.
limited diversity in the diterpenoid core, with major
variations reported only in the C-15 functionality and C-8
side-chain.5–8 As part of our ongoing program aimed at the
synthesis of simplified analogs of the eleutheside natural
products, ideally showing improved synthetic accessibility
and retaining microtubule-stabilizing properties, we
describe in this full account of our work the synthesis of
a number of eleutheside analogs with potent tubulin-
assembling and microtubule-stabilizing activity, using ring
closing metathesis (RCM) as the key-step for obtaining
the 6–10 fused bicyclic ring system.10 We also report
the cytotoxicity tests (IC50 values) performed on these
compounds using several different tumor cell lines.
Z stereoisomer in 88% yield (95% considering the recovered
starting material, Scheme 2).
As expected, entropic support (by virtue of the cis fusion
to the cyclohexyl ring) made ring closure of diene 12
extremely smooth. Despite the known effectiveness of RCM
in the synthesis of rings of all sizes, no control over the E/Z
stereochemistry of the double bond generated is usually
possible for ring sizes .8.12 Luckily, and delightfully, the
stereochemistry of the double bond created by this RCM
reaction was fully controlled in the desired sense (100% Z)
by the structure of the new 10-membered carbocycle.14 This
stereochemical course, which was found to be common to
the cyclization of all the substrates reported in the present
manuscript (vide infra), likely reflects thermodynamic
control.15 The Z stereochemistry of the double bond was
2. Results and discussion
3
unequivocally assigned by detection of the olefinic Jcis
coupling constant (11.5 Hz between the protons at d¼5.51
Aldehyde 3 (prepared in 6 steps on a multigram scale from
R-(2)-carvone in 30% overall yield)9a,g was submitted to the
allyl borane derived from (2)-a-pinene,11 generating the
homoallylic oxygenated stereocenter (alcohol 4, Scheme 1).
and 5.86 ppm, respectively) in a 400 MHz H,H-COSY
The allylation reaction proceeded with complete stereo-
control in favor of the desired stereoisomer (diastereomeric
purity .95% by 1H- and 13C NMR). After standard alcohol
protection, an efficient and well established sequence of
steps8c led to the homologated aldehyde 10, on which the
same allylation procedure described above was applied.
Addition of the allyl borane derived from (2)-a-pinene to
aldehyde 10 was again completely stereoselective (dia-
stereomeric purity of 11 .95%). Homoallylic alcohol 11
was acetylated to 12, and this diene was subjected to ring
closing metathesis12 using a variety of catalysts. After a
number of attempts, the ‘second generation’ RCM-cata-
lyst13 13 gave the desired ring closed product 14 as a single
Scheme 2.

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8805
Scheme 3. Reagents and conditions: (a) TBAF, THF, rt, 94%. (b) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 59% (87% considering the recovered starting material).
(c) K2CO3, MeOH, 94%. (d) (COCl)2, DMSO, Et3N, CH2Cl2, 260 to 08C, 81% (95% considering the recovered starting material). (e) TBAF, THF, rt, quant.
(f) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 52%. (g) Ph3PvCH2, THF, 508C, 94%. (h) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 47%.
experiment, and by detection of a NOE contact between
these protons in a 400 MHz NOESY experiment.
The major diastereomer 25 was isolated by flash chroma-
tography and transformed into the allylic alcohol 28 via a
simple protection/deprotection sequence. Second genera-
tion RCM catalyst 1313 gave the desired ring closed product
29 as a single Z stereoisomer in 73% yield.
A first series of simple eleutheside analogs (17, 21 and 24)
was then synthesized from compound 14 using standard,
high-yielding transformations (Scheme 3).
The reports that describe application of the RCM to medium
sized—particularly ten-membered—rings, are still very
rare, especially when dense functionality close to the
reaction centre is involved.14,16 The crucial role of the
protecting groups in the cyclization precursor 28 is
noteworthy: (a) the large TBDPS group in the homoallylic
With the goal of synthesizing more functionalized eleuthe-
side analogs, aldehyde 10 was oxyallylated using Brown’s
methodology [(Z)-g-(methoxymethoxy) allyldiisopinocam-
pheyl-borane from (2)-a-pinene]11d in high yield (77%)
and with good stereoselectivity (25/26¼91:9, Scheme 4).
Scheme 4. Reagents and conditions: (a) (i) lIpc2BOMe, AllO-MOM, s-BuLi, BF3·Et2O, THF, 2788C; (ii) 6N NaOH, H2O2, rt, 15 h, 77% (84% considering the
recovered starting material, de¼82%, 25/26¼10:1). (b) t-BuCOCl (PivCl), cat. DMAP, Py, rt, 80%. (c) BF3·Et2O, PhSH, CH2Cl2, 278 to 2108C, 64%. (d) 13
(9 mol%), CH2Cl2, rt, 120 h, 73% (100% Z).

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R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
Scheme 5. Reagents and conditions: (a) MeOTf, 2,6-di-t-Bu-Py, CH2Cl2, 408C, 96%. (b) TBAF, THF, rt, 89%. (c) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 66%.
Scheme 6. Reagents and conditions: (a) Ac2O, cat. DMAP, Py, rt, 71%. (b) TBAF, THF, rt, 92%. (c) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 80%.
Scheme 7. Reagents and conditions: (a) DHP, PPTS, CH2Cl2, 77%. (b) TBAF, THF, rt, quant. (c) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 61%. (d) PTSA,
EtOH/H2O (8:2), 82%.
position helps to suppress the undesired dimerization
reaction;17 (b) a free alcohol18 in the allylic position is
important to promote the cyclization (the RCM reaction did
not occur on dienes with variously protected alcohols in the
allylic position, e.g. OMe, OMOM).19
than PhSH, BF3·Et2O for deprotecting the allylic alcohol
from the MOM group).20 Treatment with catalyst 13 gave
the desired ring closed product 42 as a single Z stereoisomer
in 60% yield. By comparing this RCM reaction with the one
described above leading to 29, a relatively minor effect of
the stereochemistry of the homoallylic and allylic sub-
stituents on the RCM performance can be observed.21
Finally, a standard sequence of reactions transformed
compound 42 into the eleutheside analogs 45 and 49
(Schemes 9 and 10).
Compound 29 was transformed into a second set of
eleutheside analogs 32, 35 and 39, using standard, high-
yielding transformations (Schemes 5–7).
Aldehyde 10 was also oxyallylated using Brown’s enantio-
meric reagent [(Z)-g-(methoxymethoxy)allyldiisopino-
campheyl-borane from (þ)-a-pinene]11d in high yield
(78%) and with excellent stereoselectivity (26/25¼
98.7:1.3, Scheme 8). The major diastereomer 26 was
isolated by flash chromatography and transformed into the
allylic alcohol 41 via a simple protection/deprotection
sequence (in this case Me2S, BF3·Et2O proved more reliable
The effect of these new eleutheside analogs on the assembly
of tubulin and on the stability of the formed microtubules
was assessed at Pharmacia (Nerviano, Italy) and at Salford
(UK), using the potent microtubule-stabilizing agent
paclitaxel as a reference (Table 1).2b
Eleutheside analogs 21 and 45 were shown to be at least as

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8807
d
Scheme 8. Reagents and conditions: (a) (i) Ipc2BOMe, AllO-MOM, s-BuLi, BF3·Et2O, THF, 2788C; (ii) H2O2, 6N NaOH, rt, 15 h, 78% (de¼97.4%, 25/
26¼1.3:98.7). (b) t-BuCOCl (PivCl), cat. DMAP, Py, rt, 94%. (c) BF3·Et2O, Me2S, CH2Cl2, 2208C, 78%. (d) 13 (10 mol%), CH2Cl2, rt, 120 h, 60% (86%
considering the recovered starting material, 100% Z).
Scheme 9. Reagents and conditions: (a) MeOTf, 2,6-di-t-Bu-Py, CH2Cl2, 408C, 99%. (b) TBAF, THF, rt, 67%. (c) 16 (Ref. 6b), Et3N, DMAP, ClCH2CH2Cl,
79%.
Scheme 10. Reagents and conditions: (a) DHP, PPTS, CH2Cl2, 91%. (b) TBAF, THF, rt, 96%. (c) 16 (Ref. 6b), Et3N, DMAP, CH2Cl2, 75%. (d) PTSA,
EtOH/H2O (8:2), 40%.
Table 1. Tubulin polymerizing activities
Compound
ED50 (mM)
ED90 (mM)
Paclitaxel ED50 (mM)
Paclitaxel ED90 (mM)
17
21
24
32
35
39
45
49
2.0
0.2
5.0
3.0
1.0
1.0
,0.5
,0.5
10.0
1.2
16.0
7.0
1.7
1.8
1.0
3.0
,0.5
0.5
,0.5
0.5
,0.5
,0.5
,0.5
,0.5
0.5
3.0
0.5
3.0
0.5
0.5
1.0
1.0
ED50, effective dose that induces 50% tubulin polymerization; ED90, effective dose that induces 90% tubulin polymerization (see Ref. 2b). ED values may vary
depending on the tubulin batch (from pig brain): the same batch is used for the paclitaxel reference assay.

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R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
Table 2. Cytotoxicity assays: IC50 values on A2780, HCT116, HT29 tumor
cell lines
analytical thin-layer chromatography (TLC) using silica
gel 60 F254 precoated glass plates (0.25 mm thickness). TLC
Rf values are reported. Visualization was accomplished
by irradiation with a UV lamp and/or staining with ceric
ammonium molybdate (CAM) solution. Flash column
Compound
IC50
(mM)
(A2780)
IC50
(mM)
(HCT116)
IC50
(mM)
(HT29)
˚
chromatography was performed using silica gel 60 A,
17
21
24
32
35
39
45
49
4a
12b
n.d.c
30a
6a
particle size 40–64 mm. Proton NMR spectra were recorded
on 400, 300, or 200 MHz spectrometers. Proton chemical
shifts are reported in ppm (d) with the solvent reference
relative to tetramethylsilane (TMS) employed as the internal
standard (CDCl3 d 7.26 ppm; d6-DMSO d 2.50 ppm).
Carbon NMR spectra were recorded on 400 (100 MHz),
300 (75 MHz) or 200 (50 MHz) spectrometers with
complete proton decoupling. Carbon chemical shifts are
reported in ppm (d) relative to TMS with the respective
solvent resonance as the internal standard (CDCl3, d 77.0).
Infrared spectra were recorded on a standard Infrared
Spectrophotometer; peaks are reported in cm21. Optical
rotation values were measured on an automatic polarimeter
at the sodium D line. High resolution mass spectra (HRMS)
were performed on a hybrid quadrupole time of flight mass
spectrometer equipped with an ESI ion source. A Reserpine
solution 100 pg/mL (about 100 counts/s), 0.1% HCOOH/
CH3CN 1:1, was used as reference compound (Lock Mass).
40a
4a
35–60b
5b
,5a
n.d.c
4a
10a
10a
10–25b
n.d.c
4b
7b
7b
7a
n.d.c
5a
n.d.c
n.d.c
IC50 values: concentration inhibiting cell growth by 50%. A2780: human
ovarian carcinoma cell line. HCT116 and HT29: human colon carcinoma
cell lines.
a
Paclitaxel IC50,5 nM.
Paclitaxel IC50#5 nM.
Not determined.
b
c
potent as paclitaxel. Microtubules were generated in the
presence of CaCl2 at 378C and were stable (did not
depolymerize) at 108C. Although there is a general
agreement that the (E)-N-methylurocanic side chain, the
C-4/C-7 ether bridge, and the cyclohexene ring are
important determinants of antimitotic activity,5 it is
interesting to note that these simplified analogs of the
natural product (lacking inter alia the C-4/C-7 ether bridge)
retain potent microtubule-stabilizing activity. Given the
dramatic impact that the furanose oxygen deletion is likely
to have on the conformation of the ring system, the fact that
some of these compounds retain activity comparable to
paclitaxel in the tubulin polymerization assay is remarkable.
3.1.1. (2R)-1-[(1R,5R,6R)-6-Dimethoxymethyl-5-isopro-
pyl-2-methyl-cyclohex-2-enyl]-pent-4-en-2-ol (4). To
AllMgBr (0.61 mL, 0.61 mmol, 1.0 M in Et2O) was slowly
added lIpc2BOMe (0.83 mL, 0.71 mmol, 0.86 M in THF) at
08C. The mixture was stirred at ambient temperature for 1 h,
then cooled to 2788C and aldehyde 3 [prepared from
R-(2)-carvone in 30% overall yield according to Ref. 9g;
149 mg, 0.51 mmol] in THF (2 mL) was added. The
reaction mixture was stirred at 2788C for 6 h, warmed to
room temperature and an aqueous NaOH solution (0.25 mL,
6.0 M) and H2O2 (0.20 mL, 35%) were added. The mixture
was stirred at room temperature overnight. The layers were
separated, the aqueous layer was extracted with Et2O
(3£10 mL) and the combined organic extracts were dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the residue was purified by flash chromatog-
raphy (hexane/EtOAc 4:1) to give compound 4 (117 mg,
77%, de$95%) as a colorless oil. Rf¼0.43 (hexane/EtOAc
However, the cytotoxicity assays did not parallel the potent
tubulin-assembling and microtubule-stabilizing properties:
limited cytotoxicity was observed against three common
tumor cell lines (human ovarian carcinoma and human
colon carcinoma cell lines, IC50 in the mM range, Table 2),
three orders of magnitude less than paclitaxel (IC50 in the
nM range). This might be due to an easy esterase-mediated
hydrolytic cleavage of the N-methylurocanic ester side-
chain in living cells (it is known that the natural eleuthesides
are devoid of any cytotoxicity when the N-methylurocanic
ester side-chain is lacking in position 8).5 Natural eleuthe-
sides have a fully substituted quaternary carbon in position
7, adjacent to the ester, which is likely to hinder its
hydrolysis.
1
4:1); H NMR (200 MHz, CDCl3): d¼5.98–5.77 (m, 1H),
5.36 (m, 1H), 5.16–5.12 (m, 1H), 5.07 (br s, 1H), 4.36 (d,
J¼5.4 Hz, 1H), 3.95–3.86 (m, 1H), 3.38 (s, 6H), 2.46–1.19
(m, 14H), 0.94 (d, J¼6.6 Hz, 3H), 0.84 (d, J¼6.6 Hz, 3H);
13C NMR (50.3 MHz, CDCl3): d¼136.7, 135.6, 121.1,
116.8, 106.9, 68.4, 54.7, 54.4, 42.9, 40.2, 37.1, 36.0, 34.7,
27.0, 24.4, 22.2, 21.0, 17.1; IR (CCl4): n¼3590, 3480, 3064,
2945, 2919, 2820, 1516, 1457, 1438, 1380, 1361, 1155,
1105, 1065, 910; [a]2D0¼þ63.6 (c¼1.16, EtOAc); HRMS
(ESI): m/z: calcd for C18H32NaO3: 319.2249 [MþNa]þ;
found: 319.2241.
Work is in progress to synthesize more potent eleutheside
analogs (substituted at C-7), investigate the interaction with
tubulin and establish their cytotoxicity.
3. Experimental
3.1.2. tert-Butyl-{(1R)-1-[(1R,5R,6R)-6-dimethoxy-
methyl-5-isopropyl-2-methyl-cyclohex-2-enyl-methyl]-
but-3-enyloxy}-diphenyl-silane (5). Alcohol 4 (184 mg,
0.62 mmol) was dissolved in CH2Cl2 (5 mL) and cooled
to 08C. Imidazole (211 mg, 3.11 mmol) and TBDPSCl
(341 mg, 1.24 mmol) were added. The reaction mixture
stirred for 90 min at 08C and at room temperature overnight.
The solvent was evaporated under reduced pressure and the
3.1. General procedures
All reactions were carried out in flame-dried glassware
under argon atmosphere. All commercially available
reagents were used as received. The solvents were dried
by distillation over the following drying agents and were
transferred under nitrogen: CH3CN (CaH2), CH2Cl2 (CaH2),
THF (Na), Et2O (Na). Reactions were monitored by

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8809
residue was purified by flash chromatography (hexane/
EtOAc 25:1) to yield compound 5 (332 mg, quant.) as a
colorless oil. Rf¼0.40 (hexane/EtOAc 25:1); 1H NMR
(200 MHz, CDCl3): d¼7.78–7.76 (m, 4H), 7.72–7.49 (m,
6H), 5.76–5.59 (m, 1H), 5.24 (m, 1H), 4.90–4.73 (m, 2H),
4.09 (d, J¼5.6 Hz, 1H), 4.06–3.98 (m, 1H), 3.19 (s, 3H),
3.17 (s, 3H), 2.47–2.41 (m, 1H), 2.14–2.07 (m, 2H), 1.93–
1.72 (m, 6H), 1.65 and 1.64 (s, 3H), 1.42–1.22 (m, 1H), 1.06
(s, 9H), 0.84 (d, J¼6.8 Hz, 3H), 0.75 (d, J¼6.6 Hz, 3H); 13C
NMR (50.3 MHz, CDCl3): d¼138.6, 136.1 (2C), 136.0
(2C), 135.3, 135.1, 134.8, 129.2 (2C), 127.3 (2C), 127.2
(2C), 120.5, 116.1, 107.6, 72.5, 54.7, 54.6, 42.3, 41.3, 38.1,
35.5, 35.1, 27.1, 27.1 (3C), 24.1, 22.9, 21.5, 19.4, 16.3; IR
(CCl4): n¼3060, 3040, 2943, 2917, 2840, 1465, 1420, 1381
1320, 1105, 1075, 905; [a]2D0¼þ46.4 (c¼1.04, EtOAc);
HRMS (ESI): m/z: calcd for C34H50NaO3Si: 557.3427
[MþNa]þ; found: 557.3413.
(4C), 121.5, 117.2, 72.3, 62.4, 41.7, 41.3, 36.9, 36.0, 34.7,
27.1 (4C), 24.1, 23.4, 21.2, 19.4, 16.2; IR (CCl4): n¼3615,
3060, 2945, 2918, 2880, 2842, 1422, 1381, 1363, 1105,
1058; [a]2D0¼þ67.5 (c¼0.99, EtOAc); HRMS (ESI): m/z:
calcd for C32H47O2Si: 491.3345 [MþH]þ; found: 491.3341.
3.1.5. Methanesulfonic acid {(1R,2R,6R)-(2-[(2R)-2-(tert-
butyl-diphenyl-silanyloxy)-pent-4-enyl]-6-iso-propyl-3-
methyl-cyclohex-3-enyl}-methyl ester (8). Alcohol 7
(218 mg, 0.44 mmol) was dissolved in CH2Cl2 (4 mL) and
cooled to 08C. NEt3 (135 mg, 1.33 mmol) and MsCl (76 mg,
0.66 mmol) were added. The reaction mixture was stirred
for 1 h at 08C and for 1 h at room temperature. The solvent
was evaporated under reduced pressure and the residue was
taken up in EtOAc (10 mL) and H2O (10 mL). The aqueous
layer was extracted with EtOAc (3£10 mL) and the
combined organic extracts were dried over Na2SO4. The
solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography (hexane/
EtOAc 4:1) to yield mesylate 8 (250 mg, quant.) as a
colorless oil. Rf¼0.63 (hexane/EtOAc 4:1); 1H NMR
(200 MHz, CDCl3): d¼7.65–7.59 (m, 4H), 7.44–7.30 (m,
6H), 5.88–5.67 (m, 1H), 5.23 (br s, 1H), 5.02–4.88 (m, 2H),
4.21 (dd, J¼10.0, 6.5 Hz, 1H), 3.98 (dd, J¼10.0, 8.5 Hz,
2H), 2.86 (s, 3H), 2.31–2.26 (m, 3H), 2.04–0.99 (m, 19H),
0.82 (d, J¼6.0 Hz, 3H), 0.80 (d, J¼6.0 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3): d¼136.3, 135.9 (4C), 134.7, 134.4
(2C), 129.6 (2C), 127.6 (4C), 121.5, 117.5, 72.1, 70.1, 41.3,
39.0, 37.3, 37.0, 36.3, 34.8, 27.3, 27.1 (3C), 23.7, 23.2, 21.0,
19.4, 17.0; IR (CCl4): n¼3070, 2960, 2930, 2858, 1471,
1428, 1389, 1368, 1348, 1329, 1180, 1110, 1062; [a]2D0¼
þ58.1 (c¼0.92, EtOAc); HRMS (ESI): m/z: calcd for
C33H52NO4SiS: 586.3386 [MþNH4]þ; found: 586.3368.
3.1.3. {(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-diphenyl-silanyl-
oxy)-pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-3-
ene}-carbaldehyde (6). Compound 5 (332 mg, 0.62 mmol)
was dissolved in a mixture of AcOH/H2O/THF (15 mL, v/v/
v, 3:1:1) and stirred at room temperature for 21 h. The
solution was transferred to a separatory funnel charged with
a saturated aqueous NaHCO3 solution (30 mL). Solid
NaHCO3 was added until no more gas was evolved and
the solution was neutralized to pH¼7. EtOAc (20 mL) was
added and after separation of the layers, the aqueous layer
was extracted with EtOAc (3£20 mL) and the combined
organic extracts were dried over Na2SO4. Evaporation of the
solvent under reduced pressure yielded pure aldehyde 6
(299 mg, 99%) as a colorless oil. 1H NMR (200 MHz,
CDCl3): d¼9.55 (d, J¼3.6 Hz, 1H), 7.71–7.58 (m, 4H),
7.48–7.29 (m, 6H), 5.72–5.51 (m, 1H), 5.30 (m, 1H), 4.99–
4.79 (m, 2H), 3.79–3.69 (m, 1H), 2.43–1.01 (m, 22H), 0.88
(d, J¼6.7 Hz, 3H), 0.74 (d, J¼6.6 Hz, 3H); 13C NMR
(50.3 MHz, CDCl3): d¼206.5, 136.1, 135.9 (4C), 134.2,
134.1, 134.0, 129.7, 129.6, 127.6 (2C), 127.5 (2C), 121.6,
117.5, 72.1, 53.1, 41.6, 36.9, 35.7, 35.3, 27.1 (3C), 26.3,
23.8, 22.3, 20.6, 19.3, 16.9; IR (CCl4): n¼3060, 2945, 2918,
2842, 2700, 1713, 1465, 1458, 1420, 1382, 1363, 1105,
1061, 910; [a]2D0¼þ28.4 (c¼1.22, EtOAc); HRMS (ESI):
m/z: calcd for C32H44NaO2Si: 511.3008 [MþNa]þ; found:
511.2996.
3.1.6. {(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-diphenyl-silanyl-
oxy)-pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-3-
enyl}-acetonitrile (9). Compound 8 (162 mg, 0.29 mmol),
KCN (56 mg, 0.86 mmol) and 18-crown-6 (226 mg,
0.86 mmol) were dissolved in CH3CN (3 mL). The reaction
mixture was heated to 808C for 6 h. The solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography (hexane/EtOAc 14:1) to
yield compound 9 (136 mg, 95%) as a colorless oil. Rf¼0.40
(hexane/EtOAc 14:1); 1H NMR (200 MHz, CDCl3): d¼
7.71–7.69 (m, 4H), 7.47–7.33 (m, 6H), 5.84–5.70 (m, 1H),
5.22 (br s, 1H), 5.05–4.92 (m, 2H), 3.95–3.86 (m, 1H),
2.27–1.27 (m, 15H), 1.05 (s, 9H), 0.83 (d, J¼6.8 Hz, 3H),
0.79 (d, J¼6.8 Hz, 3H); 13C NMR (50.3 MHz, CDCl3):
d¼135.8 (4C), 135.4, 134.3, 134.2, 134.1, 129.5 (2C), 127.4
(4C), 121.2, 119.4, 117.6, 71.8, 40.9, 38.5, 36.3, 36.1, 35.9,
27.2, 27.0 (3C), 23.4, 22.8, 20.8, 19.2, 17.8, 17.5; IR (CCl4):
n¼3070, 2955, 2922, 2890, 2856, 1715, 1470, 1460,
1425, 1388, 1369, 1110, 1070, 915; [a]2D0¼þ66.4 (c¼
1.28, EtOAc); HRMS (ESI): m/z: calcd for C33H45NaNOSi:
522.3168 [MþNa]þ; found: 522.3179.
3.1.4. {(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-diphenyl-silanyl-
oxy)-pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-3-
enyl}-methanol (7). Aldehyde 6 (834 mg, 1.71 mmol) was
dissolved in EtOH (7 mL) and NaBH4 (129 mg, 3.41 mmol)
was added. The reaction mixture was stirred at room
temperature for 15 min. Solid NH4Cl (919 mg) was then
added and the mixture was stirred for 30 min, was then
diluted with Et2O and dried over Na2SO4. The solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography (hexane/EtOAc 25:1) to
yield alcohol 7 (818 mg, 98%) as a colorless oil. Rf¼0.21
(hexane/EtOAc 25:1); 1H NMR (200 MHz, CDCl3): d¼
7.77–7.57 (m, 4H), 7.45–7.34 (m, 6H), 5.92–5.75 (m, 1H),
5.26 (br s, 1H), 5.05–4.92 (m, 2H), 4.08–3.95 (m, 1H), 3.65
(dd, J¼10.9, 5.6 Hz, 1H), 3.48–3.38 (m, 1H), 2.30 (t, J¼
5.8 Hz, 2H), 1.90–0.91 (m, 21H), 0.85 (d, J¼6.8 Hz, 3H),
0.79 (d, J¼6.8 Hz, 3H); 13C NMR (75.5 MHz, CDCl3):
d¼137.4, 136.0 (4C), 135.2, 134.7, 134.4, 129.6 (2C), 127.5
3.1.7. {(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-diphenyl-silanyl-
oxy)-pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-3-
enyl}-acetaldehyde (10). Compound
9
(185 mg,
0.37 mmol) was dissolved in toluene/n-hexane (6 mL, v/v,
1:2) and cooled to 2788C. DIBAL-H (3.7 mL, 3.70 mmol,
1.0 M in hexanes) was added and the solution was stirred for
45 min at 2788C. EtOAc (3 mL) and an aqueous tartaric

8810
R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
acid solution (3 mL, 1.0 M) were added and the mixture was
warmed to room temperature and stirred for 1 h at room
temperature. The aqueous layer was extracted with CH2Cl2
(3£5 mL), the combined organic extracts were washed with
an aqueous Na,K-tartrate solution (2£5 mL, 1.0 M) and
dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by flash
chromatography (hexane/EtOAc 14:1) to yield aldehyde 10
(186 mg, quant.) as a colorless oil. Rf¼0.39 (hexane/EtOAc
14:1); 1H NMR (200 MHz, CDCl3): d¼9.66 (s, 1H), 7.78–
7.71 (m, 4H), 7.45–7.35 (m, 6H), 5.91–5.71 (m, 1H), 5.26
(br s, 1H), 5.07–4.90 (m, 2H), 3.91 (q, J¼5.9 Hz, 1H),
2.38–2.03 (m, 5H), 1.99–0.93 (m, 19H), 0.87 (d, J¼6.7 Hz,
3H), 0.75 (d, J¼6.7 Hz, 3H); 13C NMR (75.5 MHz, CDCl3):
d¼203.1, 136.6, 135.9 (4C), 134.6, 134.5, 134.3, 129.6
(2C), 127.5 (4C), 121.3, 117.4, 72.1, 44.2, 41.2, 38.9, 37.0,
36.4, 34.3, 27.4, 27.1 (3C), 23.7, 23.1, 21.2, 19.4, 17.2;
IR (CCl4): n¼3060, 2943, 2917, 2880, 2842, 2695, 1720,
1465, 1455, 1420, 1382, 1365, 1103, 1095, 1060, 910;
[a]2D0¼þ53.3 (c¼1.14, EtOAc).
organic extracts were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography (hexane/EtOAc 14:1) to
give compound 12 (237 mg, 94%) as a colorless oil. Rf¼
1
0.58 (hexane/EtOAc 14:1); H NMR (200 MHz, CDCl3):
d¼7.99–7.65 (m, 4H), 7.45–7.28 (m, 6H), 5.91–5.62 (m,
2H), 5.19–4.87 (m, 6H), 3.91 (q, J¼5.7 Hz, 1H), 2.30–2.01
(m, 5H), 1.97 (s, 3H), 1.85–1.14 (m, 11H), 1.06 (s, 9H),
0.95–0.84 (m, 1H), 0.76 (d, J¼6.6 Hz, 3H), 0.72 (d, J¼
6.6 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): d¼170.4,
135.8 (4C), 135.0, 134.5, 134.4 (2C), 133.6, 129.4 (2C),
127.3 (4C), 121.1, 117.6, 117.0, 71.9, 71.2, 41.4, 39.2,
39.0, 36.6, 34.8, 33.5, 31.5, 27.2, 27.0 (3C), 23.6, 22.9,
21.1, 20.9, 19.3, 19.2; IR (CCl4): n¼3050, 2934, 2911,
2831, 1726, 1460, 1450, 1415, 1375, 1359, 1096, 1090,
1052, 900; [a]2D0¼þ27.9 (c¼1.26, EtOAc); HRMS (ESI):
m/z: calcd for C38H54NaO3Si: 609.3740 [MþNa]þ; found:
609.3746.
3.1.10. Acetic acid [(4R,4aR,6R,11R,12aR)-11-(tert-butyl-
diphenyl-silanyloxy)-4-isopropyl-1-methyl-3,4,4a,5,
6,7,10,11,12,12a-decahydro-benzocyclodecen-6-yl] ester
(14). Compound 12 (67 mg, 0.12 mmol) was dissolved in
degassed CH2Cl2 (12 mL). Second generation RCM catalyst
13 (5 mg, 6 mmol) in degassed CH2Cl2 (2 mL) was slowly
added. The mixture stirred for 2 days at room temperature.
Additional catalyst 13 (2 mg, 2 mmol) in degassed CH2Cl2
(1 mL) was slowly added. The mixture stirred for additional
3 days at room temperature. The solvent was evaporated
under reduced pressure and the residue was purified by flash
chromatography (hexane/EtOAc 14:1) to recover unreacted
12 (6 mg) and to provide the bicyclic product 14 (57 mg,
88% yield, 95% considering the recovered starting material)
3.1.8. (2R)-1-{(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-diphenyl-
silanyloxy)-pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-
3-enyl}-pent-4-en-2-ol (11). To AllMgBr (0.15 mL,
0.15 mmol, 1.0 M in Et2O) lIpc2BOMe was added
(0.17 mL, 0.17 mmol, 1.0 M in THF) at 08C. The mixture
was stirred at room temperature for 1 h, then cooled to
2788C and a solution of aldehyde 10 (25 mg, 0.05 mmol) in
THF (0.2 mL) was added. The mixture was stirred at 2788C
for 3 h, then warmed to room temperature and an aqueous
NaOH solution (0.25 mL, 6.0 M) and H2O2 (0.20 mL, 35%)
were added. Stirring was continued at ambient temperature
for 40 min, then H2O (5 mL) and Et2O (10 mL) were added.
The aqueous layer was extracted with Et2O (3£5 mL) and
the combined organic extracts were dried over Na2SO4. The
solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography (hexane/
EtOAc 4:1) to yield compound 11 (15 mg, 55%, de$95%
1
as colorless oils. Rf¼0.43 (hexane/EtOAc 14:1); H NMR
(400 MHz, CDCl3): d¼7.72–7.62 (m, 4H), 7.44–7.33 (m,
6H), 5.86 (dt, J¼11.1, 4.7 Hz, 1H), 5.51 (ddd, J¼11.7,
3.9 Hz, 1H), 5.20 (m, 1H), 5.13 (m, 1H), 4.17 (m, 1H),
2.77–2.49 (m, 2H), 2.29–2.25 (m, 1H), 2.15 (m, 1H), 2.05–
0.85 (m, 23H), 0.89–0.85 (m, 1H), 0.81 (d, J¼6.6 Hz, 3H),
0.77–0.65 (m, 1H), 0.61 (d, J¼6.6 Hz, 3H); 13C NMR
(50.3 MHz, CDCl3): d¼170.4, 138.5, 135.7 (4C), 134.4
(2C), 129.5 (2C), 127.5 (4C), 126.9 (2C), 120.4, 72.8 (2C),
37.8, 37.0, 36.6, 34.7, 31.9, 31.6, 26.9 (4C), 26.2, 24.2, 23.9,
21.2, 20.9, 19.2, 14.9; IR (CCl4): n¼3070, 2958, 2926,
2856, 1740, 1460, 1427, 1368, 1110, 1067; [a]2D0¼þ41.0
(c¼1.26, EtOAc); HRMS [EI (70 eV)]: m/z: calcd for
C36H50O3Si: 558.3529 [M]þ; found: 558.3532.
1
by H- and 13C NMR) as a colorless oil. Rf¼0.59 (hexane/
1
EtOAc 4:1); H NMR (200 MHz, CDCl3): d¼7.73–7.56
(m, 4H), 7.46–7.27 (m, 6H), 5.91–5.70 (m, 2H), 5.49–4.92
(m, 5H), 4.17–3.89 (m, 1H), 3.67–3.62 (m, 1H), 2.51–1.92
(m, 5H), 1.82–1.19 (m, 13H), 1.09 (s, 9H), 0.82 (d, J¼
6.7 Hz, 3H), 0.76 (d, J¼6.7 Hz, 3H); 13C NMR (50.3 MHz,
CDCl3): d¼136.9, 135.9 (4C), 135.0, 134.9, 134.6, 134.5,
129.5 (2C), 127.4 (4C), 121.1, 118.0, 117.0, 72.2, 68.3,
41.9, 41.5, 38.5, 37.1, 35.8, 35.4, 35.2, 27.1, 27.0 (3C), 23.9,
23.1, 21.2, 19.3, 17.5; IR (CCl4): n¼3595, 3078, 2960,
2934, 2899, 2860, 1642, 1475, 1465, 1430, 1389, 1371,
1110, 1069, 917; [a]2D0¼þ38.8 (c¼0.84, EtOAc); HRMS
(ESI): m/z: calcd for C36H52NaO2Si: 567.3634 [MþNa]þ;
found: 567.3665.
3.1.11. Acetic acid [(4R,4aR,6R,11R,12aR)-11-hydroxy-
4-isopropyl-1-methyl-3,4,4a,5,6,7,10,11,12,12a-deca-
hydro-benzocyclodecen-6-yl] ester (15). Compound 14
(19 mg, 0.04 mmol) was dissolved in THF (0.55 mL) and
TBAF (0.17 mL, 0.17 mmol, 1.0 M in THF) was added. The
reaction mixture was stirred for 16 h at room temperature.
EtOAc (10 mL) was added, the organic layer was washed
with an aqueous phosphate buffer solution (2£5 mL, pH¼7)
and then dried over Na2SO4. The solvent was evaporated
under reduced pressure and the residue was purified by flash
chromatography (hexane/EtOAc 4:1) to yield compound 15
(10 mg, 94%) as a colorless oil. Rf¼0.27 (hexane/EtOAc
3.1.9. Acetic acid {(1R)-1-{(1R,2R,6R)-2-[(2R)-2-(tert-
butyl-diphenyl-silanyloxy)-pent-4-enyl]-6-isopropyl-3-
methyl-cyclohex-3-enylmethyl}-but-3-enyl} ester (12).
Compound 11 (234 mg, 0.43 mmol) was dissolved in
pyridine (1.5 mL). Ac2O (88 mg, 0.86 mmol) and DMAP
(6 mg, 0.05 mmol) were added and the reaction mixture was
stirred for 24 h at room temperature. EtOAc (20 mL) was
added and the organic layer was washed with a saturated
aqueous KHSO4 solution (2£15 mL), the aqueous layer was
back extracted with EtOAc (3£20 mL) and the combined
1
4:1); H NMR (200 MHz, CDCl3): d¼5.72 (dt, J¼11.2,
3.9 Hz, 1H), 5.53 (dt, J¼11.7, 4.0 Hz, 1H), 5.31–5.12 (m,
2H), 4.26–4.19 (m, 1H), 2.85–2.66 (m, 2H), 2.42–1.16 (m,

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8811
19H), 0.85 (d, J¼6.8 Hz, 3H), 0.67 (d, J¼6.8 Hz, 3H); 13
C
3.1.14. (4R,4aR,11R,12aR)-11-(tert-Butyl-diphenyl-sila-
noxy)-4-isopropyl-1-methyl-3,4a,5,7,10,11,12,12a-octa-
hydro-4H-benzocyclodecen-6-one (19). (COCl)2 (91 mg,
0.72 mmol) was dissolved in CH2Cl2 (0.5 mL) and cooled to
2608C. DMSO (77 mg, 0.98 mmol) was added and the
solution stirred for 10 min at 2608C. Compound 18 (62 mg,
0.12 mmol) in CH2Cl2 (0.5 mL) was added and the solu-
tion stirred for further 30 min at 2608C. NEt3 (199 mg,
1.97 mmol) was added, the solution was allowed to warm
to 08C over 1 h and stirred additional 10 min at 08C. An
aqueous phosphate buffer solution (3 mL, pH¼7) was
added, the layers were separated and the aqueous layer
was extracted with CH2Cl2 (3£5 mL) and the combined
organic extracts were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the resulting residue
was purified by flash chromatography (hexane/EtOAc 9:1)
to provide unreacted 18 (9 mg) and ketone 19 (50 mg, 81%
yield, 95% considering the recovered starting material) as
colorless oils. Rf¼0.55 (hexane/EtOAc 9:1); 1H NMR
(200 MHz, CDCl3): d¼7.77–7.59 (m, 4H), 7.47–7.29
(m, 6H), 6.19–6.06 (m, 1H), 5.97–5.84 (m, 1H), 5.06 (br
s, 1H), 3.96–3.82 (m, 1H), 3.20–2.87 (m, 3H), 2.32–1.95
(m, 4H), 1.89–1.61 (m, 5H), 1.41–1.18 (m, 5H), 1.07
(s, 9H), 0.87 (d, J¼6.8 Hz, 3H), 0.69 (d, J¼6.8 Hz, 3H);
13C NMR (50.3 MHz, CDCl3): d¼213.0, 139.2, 135.8
(4C), 134.0 (2C), 131.4, 129.7, 129.6, 127.6 (2C), 127.5
(2C), 123.7, 116.7, 73.0, 44.1, 38.7, 36.0, 36.7 (2C),
36.5, 32.1, 27.0 (3C), 26.6, 24.1, 22.6, 21.1, 19.2, 14.3; IR
(CCl4): n¼3022, 2955, 2922, 2899, 2860, 1708, 1705, 1469,
1427; [a]2D0¼þ49.0 (c¼0.79, EtOAc); HRMS (ESI): m/z:
calcd for C34H46NaO2Si: 537.3165 [MþNa]þ; found:
537.3139.
NMR (50.3 MHz, CDCl3): d¼170.4, 138.4, 127.9, 126.2,
121.1, 72.6, 71.3, 38.0, 37.4, 36.8, 34.7, 31.9, 31.8, 27.0,
26.4, 24.4, 24.3, 21.2, 21.0, 15.1; IR (CCl4): n¼3634, 3621,
2924, 2843, 1739, 1460, 1382, 1364; [a]2D0¼þ4.6 (c¼0.46,
EtOAc); HRMS (ESI): m/z: calcd for C20H32NaO3:
343.2249 [MþNa]þ; found: 343.2241.
3.1.12. (E)-3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,11R,12aR)-11-acetoxy-1-isopropyl-4-
methyl-1,2,4a,5,6,7,10,11,12,12a-decahydro-benzocyclo-
decen-6-yl] ester (17). Compound 15 (11 mg, 0.04 mmol)
was dissolved in CH2Cl2 (2 mL) and added to mixed
anhydride 16 (prepared according to Ref. 6b; 123 mg,
0.52 mmol). NEt3 (52 mg, 0.52 mmol) and DMAP (4 mg,
0.04 mmol) were added and the solution stirred for 3 days
at room temperature. The solvent was evaporated under
reduced pressure and the resulting residue was purified by
flash chromatography (hexane/EtOAc 1:4) to recover
unreacted 15 (4 mg) and to yield compound 17 (9 mg,
59% yield, 87% considering the recovered starting material)
1
as a colorless oil. Rf¼0.25 (hexane/EtOAc 1:4); H NMR
(400 MHz, CDCl3): d¼7.55 (d, J¼15.6 Hz, 1H), 7.47 (s,
1H), 7.09 (s, 1H), 6.54 (d, J¼15.6 Hz, 1H), 5.74–5.66 (m,
1H), 5.62–5.55 (m, 1H), 5.45–5.39 (m, 1H), 5.34 (br s, 1H),
5.24–5.18 (m, 1H), 3.72 (s, 3H), 2.88–2.77 (m, 2H), 2.40–
2.25 (m, 2H), 2.23–2.18 (m, 1H), 2.07 (s, 3H), 2.05–1.26
(m, 12H), 0.87 (d, J¼6.7 Hz, 3H), 0.70 (d, J¼6.7 Hz, 3H);
13C NMR (50.3 MHz, CDCl3): d¼170.4, 166.7, 137.9,
138.4, 135.9, 127.9, 126.4, 122.2, 121.0, 116.4, 73.6, 72.5,
37.5, 37.3, 34.6, 33.5, 32.7, 31.6, 29.6, 29.2, 26.9, 26.2,
24.3, 24.2, 21.2, 20.9, 15.1; IR (CCl4): n¼2960, 2850, 1745,
1705, 1640, 1450, 1440, 1380, 1345, 1295, 905; [a]2D0¼
229.0 (c¼0.71, EtOAc); HRMS [EI (30 eV)]: m/z: calcd for
C27H38N2O4: 454.2832 [M]þ; found: 454.2802.
3.1.15. (4R,4aR,11R,12aR)-11-Hydroxy-4-isopropyl-1-
methyl-3,4a,5,7,10,11,12,12a-octahydro-4H-benzocyclo-
decen-6-one (20). Compound 19 (16 mg, 0.03 mmol)
was dissolved in THF (0.50 mL) and TBAF (0.06 mL,
0.06 mmol, 1.0 M in THF) was added. The reaction mixture
was stirred 23 h at room temperature. Additional TBAF
(0.06 mL, 0.06 mmol, 1.0 M in THF) was then added and
the solution stirred for further 5 h at room temperature. An
aqueous phosphate buffer solution (1.0 mL, pH¼7) was
added and the layers were separated. The aqueous layer was
extracted with EtOAc (3£5 mL) and the combined organic
extracts were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography (hexane/EtOAc 8:2) to
yield compound 20 (10 mg, quant.) as a colorless oil. Rf¼
0.17 (hexane/EtOAc 8:2); 1H NMR (200 MHz, CDCl3):
d¼6.01–5.84 (m, 2H), 5.23 (br s, 1H), 4.07–3.93 (m, 1H),
3.24–2.87 (m, 3H), 2.42–2.08 (m, 4H), 1.92–1.01 (m,
11H), 0.87 (d, J¼6.9 Hz, 3H), 0.71 (d, J¼6.9 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3): d¼212.8, 139.0, 130.3, 124.6,
119.5, 71.9, 44.2, 39.0, 38.0, 37.1, 37.0, 36.9, 32.1, 26.6,
24.2, 23.3, 21.2, 14.4; IR (CCl4): n¼3627, 2960, 2951,
2904, 1709, 1460, 1442, 1389, 1371, 909; [a]2D0¼24.7
(c¼0.51, EtOAc).
3.1.13. (4R,4aR,6R,11R,12aR)-11-(tert-Butyl-diphenyl-
silanoxy)-4-isopropyl-1-methyl-3,4,4a,5,6,7,10,11,12,12a-
decahydro-benzocyclodecen-6-ol (18). Compound 14
(30 mg, 0.05 mmol) was dissolved in MeOH (1 mL).
K2CO3 (17 mg, 0.10 mmol) was added and the solution
stirred for 15 h at room temperature. H2O (2 mL) was
added, the layers were separated and the aqueous layer was
extracted with EtOAc (3£5 mL), the combined organic
extracts were washed with a saturated aqueous NaCl
solution (2£5 mL) and the combined organic extracts
were dried over Na2SO4. The solvent was evaporated
under reduced pressure and the resulting residue was
purified by flash chromatography (hexane/EtOAc 9:1) to
give compound 18 (26 mg, 94%) as a colorless oil. Rf¼0.25
(hexane/EtOAc 9:1); 1H NMR (200 MHz, CDCl3): d¼
7.74–7.61 (m, 4H), 7.46–7.31 (m, 6H), 5.82 (dt, J¼11.3,
5.1 Hz, 1H), 5.52 (dt, J¼11.3, 5.1 Hz, 1H), 5.13 (br s, 1H),
4.23–4.04 (m, 2H), 2.70–2.49 (m, 2H), 2.33–2.04 (m, 3H),
1.99–1.18 (m, 13H), 1.08 (s, 9H), 0.84 (d, J¼6.8 Hz, 3H),
0.72 (d, J¼6.8 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): d¼
138.5, 135.7 (4C), 134.5, 134.4, 129.4 (2C), 127.9, 127.5
(4C), 126.6, 120.4, 72.7, 71.0, 37.9, 37.3, 36.6, 35.5, 33.7,
32.0, 29.1, 27.0 (4C), 24.3, 23.9, 21.0, 19.2, 15.3; IR (CCl4):
n¼3611, 2942, 2921, 2842, 1472, 1458, 1427, 1389, 1369,
1109, 1067, 909; [a]2D0¼þ25.3 (c¼0.73, EtOAc); HRMS
(ESI): m/z: calcd for C34H48NaO2Si: 539.3321 [MþNa]þ;
found: 539.3306.
3.1.16. (E)-3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,12aR)-1-isopropyl-4-methyl-11-oxo-1,2,
4a,5,6,7,10,11,12,12a-decahydro-benzocyclodecen-6-
enyl] ester (21). Compound 20 (9 mg, 0.03 mmol) was
dissolved in CH2Cl2 (2 mL) and added to mixed anhydride

8812
R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
16 (prepared according to Ref. 6b; 110 mg, 0.47 mmol).
NEt3 (48 mg, 0.47 mmol) and DMAP (4 mg, 0.03 mmol)
were added and the solution was stirred for 3 days at 408C.
The solvent was evaporated under reduced pressure and the
resulting residue was purified by flash chromatography
(hexane/EtOAc 1:5) to yield compound 21 (7 mg, 52%) as a
colorless oil. Rf¼0.18 (hexane/EtOAc 1:5); 1H NMR
(400 MHz, CDCl3): d¼7.55 (d, J¼15.6 Hz, 1H), 7.47 (s,
1H), 7.09 (s, 1H), 6.55 (d, J¼15.6 Hz, 1H), 5.97–5.88 (m,
2H), 5.26 (br s, 1H), 5.15 (d, J¼12.0 Hz, 1H), 3.72 (s, 3H),
3.25–3.15 (m, 1H), 3.09–2.96 (m, 2H), 2.46–2.14 (m, 4H),
1.94–1.55 (m, 7H), 1.48–1.17 (m, 3H), 0.89 (d, J¼6.9 Hz,
3H), 0.75 (d, J¼6.9 Hz, 3H); 13C NMR (100.8 MHz,
CDCl3): d¼212.7, 166.6, 139.1, 139.0. 138.6, 136.0,
130.6, 124.7, 122.3, 119.2, 116.3, 73.7, 44.1, 39.1, 37.0,
36.8 (2C), 34.1, 33.5, 29.7, 26.7, 24.2, 23.1, 21.1, 14.4; IR
(CCl4): n¼2945, 2920, 2890, 1703, 1640, 1452, 1381, 1390,
1153, 1104, 905; [a]2D0¼215.6 (c¼0.34, EtOAc); HRMS
(ESI): m/z: calcd for C25H35N2O3: 411.2648 [MþH]þ;
found: 411.2648.
EtOAc 9:1) to yield compound 23 (4 mg, quant.) as a
colorless oil. Rf¼0.28 (hexanes/EtOAc 9:1); 1H NMR
(200 MHz, CDCl3): d¼5.76–5.62 (m, 2H), 5.26 (br s,
1H), 4.98 (s, 1H), 4.80 (s, 1H), 4.08–3.97 (m, 1H), 3.24–
3.12 (m, 1H), 2.98–2.74 (m, 2H), 2.29–1.67 (m, 9H), 1.61–
1.34 (m, 5H), 0.87 (d, J¼6.7 Hz, 4H), 0.77 (d, J¼6.7 Hz,
3H); 13C NMR (50.3 MHz, CDCl3): d¼133.8, 129.8, 127.0,
123.3, 120.0, 111.7, 72.0, 39.7, 37.7, 37.5, 36.9, 36.7, 32.2,
31.1, 26.8, 24.6, 23.6, 21.1 (2C); IR (CCl4): n¼3632, 3080,
3024, 2967, 2930, 1461, 1455, 1440, 1389, 1370; [a]2D0¼
þ36.4 (c¼0.17, EtOAc).
3.1.19. (E)-3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,12aR)-(1-isopropyl-4-methyl-11-methylene-
1,2,4a,5,6,7,10,11,12,12a-decahydro-benzocyclodecen-6-
yl] ester (24). Compound 23 (4 mg, 0.0091 mmol) was
dissolved in CH2Cl2 (1.0 mL) and added to mixed anhydride
16 (prepared according to Ref. 6b; 51 mg, 0.137 mmol).
NEt3 (22 mg, 0.219 mmol) and DMAP (1 mg, 0.008 mmol)
were added and the solution was stirred for 3 days at room
temperature. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 1:4) to yield compound 24
(3 mg, 47%) as a colorless oil. Rf¼0.30 (hexane/EtOAc
1:4); 1H NMR (200 MHz, CDCl3): d¼7.62 (br s, 1H), 7.54
(d, J¼15.7 Hz, 1H), 7.08 (br s, 1H), 6.59 (d, J¼15.7 Hz,
1H), 5.74–5.62 (m, 2H), 5.30–5.11 (m, 2H), 5.04 (br s, 1H),
4.72 (br s, 1H), 3.73 (s, 3H), 3.25–2.73 (m, 3H), 2.34–1.55
(m, 7H), 1.44–1.21 (m, 6H), 0.87 (d, J¼6.7 Hz, 4H), 0.77
(d, J¼6.7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): d¼164.3,
148.2, 138.2, 135.4, 131.5, 131.3, 129.6, 127.6, 119.7,
113.8, 111.6, 74.7, 39.3, 37.4, 36.9, 36.2, 34.8, 33.7, 30.9,
29.7, 29.5, 26.5, 24.5, 23.4, 21.0 (2C); IR (CCl4): n¼3380,
3075, 2956, 2922, 2856, 1766, 1709, 1645, 1460, 1428,
1382, 1368, 1305, 1159, 1099; [a]2D0¼þ6.0 (c¼0.05,
EtOAc); HRMS (ESI): m/z: calcd for C26H37N2O2:
409.2855 [MþH]þ; found: 409.2855.
3.1.17. (1R,4aR,6R,12aR)-tert-Butyl-(1-isopropyl-4-
methyl-11-methylene-1,2,4a,5,6,7,10,11,12,12a-deca-
hydro-benzocyclodecen-6-yloxy)-diphenyl-silane (22).
Ph3PCH3Br (17 mg, 0.047 mmol) was dissolved in THF
(0.2 mL). n-BuLi (13 mL, 0.020 mmol, 1.6 M in n-hexane)
was added and the solution was stirred for 1 h at room
temperature. Compound 19 (8 mg, 0.016 mmol) was added
in THF (600 mL) and the solution was heated to 508C
for 12 h. H2O (2.0 mL) was added and the layers were
separated. The aqueous layer was extracted with EtOAc
(3£5 mL) and the combined organic extracts were dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the residue was purified by flash chroma-
tography (hexane) to yield compound 22 (8 mg, 94%) as a
colorless oil. Rf¼0.32 (hexane); 1H NMR (200 MHz,
CDCl3): d¼7.72–7.65 (m, 4H), 7.46–7.33 (m, 6H), 6.03–
5.87 (m, 1H), 5.73–5.61 (m, 1H), 5.11 (br s, 1H), 4.94 (br s,
1H), 4.75 (br s, 1H), 4.04–3.93 (m, 1H), 3.08 (dd, J¼16.1,
5.9 Hz, 1H), 2.84–2.70 (m, 2H), 2.19–1.44 (m, 8H),
1.41–1.17 (m, 6H), 1.09 (s, 9H), 0.88 (d, J¼5.8 Hz, 3H),
0.75 (d, J¼5.8 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): d¼
138.4, 135.9 (4C), 134.5 (2C), 133.8, 129.6, 129.5, 128.8,
128.6 (2C), 127.6, 127.5 (2C), 119.2, 111.1, 73.3, 39.4,
37.7, 37.3, 37.1, 36.3, 32.1, 30.7, 27.1 (3C), 26.6, 24.5, 23.1,
21.1 (2C), 19.3; IR (CCl4): n¼3070, 3018, 2955, 2925,
2856, 1470, 1459, 1423, 1385, 1366, 1308, 1108, 1071;
[a]2D0¼þ68.4 (c¼0.25, EtOAc).
3.1.20. (2S,3S)-1-{(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-
diphenyl-silanyloxy)-pent-4-enyl]-6-isopropyl-3-methyl-
cyclohex-3-enyl}-3-methoxymethoxy-pent-4-en-2-ol (25)
and (2R,3R)-1-{(1R,2R,6R)-2-[(2R)-2-(tert-butyl-diphenyl-
silanyloxy)-pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-
3-enyl}-3-methoxymethoxy-pent-4-en-2-ol (26). Meth-
oxymethyl allyl ether (180 mg, 1.75 mmol) in THF
(4.0 mL) was cooled to 2788C and sec-BuLi (1.10 mL,
1.45 mmol, 1.3 M in cyclohexane) was added. The reaction
l
solution was stirred at 2788C for 30 min and Ipc2BOMe
(1.60 mL, 1.45 mmol, 0.93 M in THF) was then added.
Stirring was maintained for 1 h, BF3·Et2O (263 mg,
1.86 mmol) was then added, followed by aldehyde 10
(293 mg, 0.58 mmol) in THF (2.0 mL). The mixture was
stirred at 2788C for 5 h and then slowly warmed to room
temperature. An aqueous NaOH solution (4.0 mL, 6.0 M)
and H2O2 (4.0 mL, 35%) were then added and the mixture
was left stirring overnight. H2O (5 mL) was added and the
aqueous layer was extracted with EtOAc (3£10 mL) and
the combined organic extracts were dried over Na2SO4. The
solvent was evaporated under reduced pressure and the
resulting residue was purified by flash chromatography
(hexane/EtOAc 6:1) to provide unreacted 10 (56 mg), 25
(246 mg, 70%) and 26 (25 mg, 7%) as colorless oils (total
yield¼77%, 84% considering the recovered starting
3.1.18. (1R,4aR,6R,12aR)-1-Isopropyl-4-methyl-11-
methylene-1,2,4a,5,6,7,10,11,12,12a-decahydro-benzo-
cyclodecen-6-ol (23). Compound 22 (8 mg, 0.015 mmol)
was dissolved in THF (1.0 mL) and TBAF (73 mL,
0.075 mmol, 1.0 M in THF) was added. The reaction
mixture was stirred 12 h at room temperature. Additional
TBAF (73 mL, 0.075 mmol, 1.0 M in THF) was added and
the reaction mixture was stirred for another 12 h at room
temperature. An aqueous phosphate buffer solution (1.0 mL,
pH¼7) was added, the layers were separated and the
aqueous layer was extracted with EtOAc (3£5 mL) and
the combined organic extracts were dried over Na2SO4. The
solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography (hexanes/

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8813
material, de¼82%, 25/26 10:1). 25: Rf¼0.43 (hexane/
3.1.22. 2,2-Dimethyl-propionic acid {(1S,2S)-1-{(1R,
2R,6R)-2-[(2R)-2-(tert-butyl-diphenyl-silanoxy)-pent-4-
enyl]-6-isopropyl-3-methyl-cyclohex-3-enylmethyl}-2-
hydroxy-but-3-enyl} ester (28). Compound 27 (10 mg,
0.015 mmol) was dissolved in CH2Cl2 (0.3 mL) and cooled
to 2788C. PhSH (2 mg, 0.015 mmol) and BF3·Et2O (4 mg,
0.029 mmol) were added and the solution was allowed
to warm to 2108C and stirred at 2108C for 2 h. Then a
saturated aqueous NaHCO3 solution (2 mL) was added and
the solution was warmed up to room temperature. The layers
were separated, the aqueous layer was extracted with EtOAc
(3£5 mL) and the combined organic extracts were dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 8:2) to give compound 28
(6 mg, 64%) as a colorless oil. Rf¼0.54 (hexane/EtOAc
1
EtOAc 6:1); H NMR (200 MHz, CDCl3): d¼7.95–7.66
(m, 4H), 7.45–7.30 (m, 6H), 5.91–5.51 (m, 2H), 5.32–5.16
(m, 3H), 5.01–4.90 (m, 2H), 4.72 (d, J¼6.7 Hz, 1H), 4.56
(d, J¼6.7 Hz, 1H), 3.95 (q, J¼5.9 Hz, 1H), 3.79–3.72 (m,
1H), 3.58–3.47 (m, 1H), 3.38 (s, 3H), 2.35–2.14 (m, 5H),
1.93–1.14 (m, 11H), 1.05 (s, 9H), 0.79 (d, J¼6.6 Hz, 3H),
0.77 (d, J¼6.6 Hz, 3H); 13C NMR (50.3 MHz, CDCl3):
d¼136.4, 135.9 (4C), 135.1, 134.9, 134.7, 134.6, 129.4
(2C), 127.4 (4C), 120.9, 119.9, 117.0, 93.9, 81.9, 72.2, 71.4,
55.7, 41.3, 39.3, 37.1, 35.8, 34.3, 31.3, 27.5, 27.1 (3C), 23.9,
22.9, 21.2, 19.3, 19.2; IR (CCl4): n¼3590, 3078, 2955,
2893, 2860, 1473, 1462, 1430, 1390, 1369, 1152, 1108, 935,
915; [a]2D0¼þ43.8 (c¼0.90, EtOAc); HRMS (ESI): m/z:
calcd for C38H56NaO4Si: 627.3845 [MþNa]þ; found:
627.3828; 26: Rf¼0.37 (hexane/EtOAc 6:1); 1H NMR
(200 MHz, CDCl3): d¼7.71–7.60 (m, 4H), 7.47–7.30 (m,
6H), 5.96–5.77 (m, 1H), 5.65–5.49 (m, 1H), 5.38–5.21 (m,
2H), 5.16 (br s, 1H), 5.07–4.92 (m, 2H), 4.73 (d, J¼6.7 Hz,
1H), 4.58 (d, J¼6.7 Hz, 1H), 3.98–3.83 (m, 1H), 3.81–3.69
(m, 1H), 3.65–3.50 (m, 1H), 3.39 (s, 3H), 2.46–1.95
(m, 4H), 1.90–0.98 (m, 20H), 0.90–0.87 (m, 1H), 0.83
(d, J¼6.8 Hz, 3H), 0.69 (d, J¼6.8 Hz, 3H); 13C NMR
(50.3 MHz, CDCl3): d¼137.3, 135.9 (4C), 135.1, 134.8,
134.7 (2C), 129.4 (2C), 127.4 (4C), 121.9, 120.2, 117.0,
93.7, 82.4, 72.1, 70.3, 55.8, 40.8, 37.5, 37.1, 35.8, 35.4,
31.3, 29.7, 27.0 (3C), 26.8, 24.3, 23.9, 21.1, 19.3; IR (CCl4):
n¼3600, 3080, 2960, 2938, 2899, 2862, 1475, 1432, 1391,
1372, 1158, 1108, 912; [a]2D0¼þ48.1 (c¼1.09, EtOAc);
HRMS (ESI): m/z: calcd for C38H56NaO4Si: 627.3846
[MþNa]þ; found: 627.3860.
1
8:2); H NMR (200 MHz, CDCl3): d¼7.71–7.67 (m, 4H),
7.41–7.31 (m, 6H), 5.89–5.72 (m, 2H), 5.34 (br s, 1H),
5.25–5.14 (m, 2H), 5.03–4.91 (m, 3H), 4.08 (br s, 1H),
3.93–3.87 (m, 1H), 2.27–2.16 (m, 3H), 2.01–1.22 (m,
14H), 1.18 (s, 9H), 1.04 (s, 9H), 0.93–0.88 (m, 1H), 0.82
(d, J¼6.4 Hz, 3H), 0.72 (d, J¼6.4 Hz, 3H); 13C NMR
(50.3 MHz, CDCl3): d¼176.1, 137.1 (2C), 136.4, 135.9
(2C), 135.0 (2C), 134.7, 129.5 (2C), 127.4 (4C), 121.0,
117.2, 116.4, 74.4, 73.4, 72.3, 41.4, 39.2, 36.7, 35.0, 33.3,
28.0, 27.5, 27.3 (3C), 27.0 (3C), 23.8, 22.6, 20.9 (2C), 20.0,
19.3 (2C); IR (CCl4): n¼3618, 3582, 3060, 2942, 2918,
2842, 1724, 1472, 1465, 1458, 1421, 1382, 1363, 1149,
1101, 1060, 908; [a]2D0¼þ6.1 (c¼0.56, EtOAc); HRMS
(ESI): m/z: calcd for C41H62NaO4Si: 669.4315 [MþNa]þ;
found: 669.4299.
3.1.21. 2,2-Dimethyl-propionic acid {(1S,2S)-1-
{(1R,2R,6R)-2-[(2R)-2-(tert-butyl-diphenyl-silanyloxy)-
pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-3-enyl-
methyl}-2-methoxymethoxy-but-3-enyl} ester (27). Com-
pound 25 (173 mg, 0.29 mmol) was dissolved in pyridine
(2.0 mL). DMAP (4 mg, 0.03 mmol) and PivCl (172 mg,
1.43 mmol) were added and the mixture was stirred at
room temperature for 72 h. EtOAc (10 mL) was added, the
organic layer was washed with a saturated aqueous KHSO4
solution (2£10 mL), the combined aqueous layers were
back extracted with EtOAc (3£10 mL) and the combined
organic extracts were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the resulting residue
was purified by flash chromatography (hexane/EtOAc 9:1)
to give compound 27 (158 mg, 80%) as a colorless oil. Rf¼
0.52 (hexane/EtOAc 9:1); 1H NMR (300 MHz, CDCl3):
d¼7.71–7.66 (m, 4H), 7.45–7.28 (m, 6H), 5.85–5.59
(m, 2H), 5.29–5.17 (m, 3H), 5.03–4.90 (m, 3H), 4.65 (d,
J¼ 6.3 Hz, 1H), 4.56 (d, J¼6.3 Hz, 1H), 4.09–3.87 (m, 2H),
3.35 (s, 3H), 2.30–2.12 (m, 3H), 1.85 (br s, 1H), 1.72–1.22
(m, 11H), 1.18 (s, 9H), 1.04 (s, 9H), 0.82 (d, J¼6.3 Hz, 3H),
0.72 (d, J¼6.3 Hz, 3H); 13C NMR (50.3 MHz, CDCl3):
d¼177.6, 135.9 (4C), 135.3, 134.8, 134.6 (2C), 134.1,
129.5 (2C), 127.5 (4C), 121.0, 119.0, 117.2, 94.4, 77.8,
72.2, 71.7, 55.6, 41.4, 39.4, 36.8, 34.8, 32.7, 27.4, 27.3
(3C), 27.2, 27.0 (3C), 23.6, 22.5, 21.0, 20.6, 19.3 (2C);
IR (CCl4): n¼3061, 2942, 2920, 2882, 2842, 1722, 1455,
1467, 1458, 1423, 1392, 1385, 1362, 1150, 1107, 1098,
909; [a]2D0¼þ25.5 (c¼0.78, EtOAc); HRMS (ESI): m/z:
calcd for C43H64NaO5Si: 711.4420 [MþNa]þ; found:
711.4412.
3.1.23. 2,2-Dimethyl-propionic acid [(4R,4aR,6S,7S,11-
R,12aR)-11-(tert-butyl-diphenyl-silanoxy)-7-hydroxy-4-
isopropyl-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahydro-
benzocyclodecen-6-yl] ester (29). Compound 28 (33 mg,
0.05 mmol) was dissolved in degassed CH2Cl2 (5.1 mL).
Second generation RCM catalyst 13 (2 mg, 2.5 mmol) in
degassed CH2Cl2 (0.5 mL) was slowly added. The reaction
mixture was stirred for 2 days at room temperature.
Additional catalyst 13 (1 mg, 1.3 mmol) in degassed
CH2Cl2 (0.2 mL) was slowly added and the mixture stirred
for further 2 days at room temperature. Additional catalyst
13 (1 mg, 1.3 mmol) in degassed CH2Cl2 (0.2 mL) was
slowly added and the mixture stirred for further 1 day at
room temperature. The solvent was evaporated under
reduced pressure and the residue was purified by flash
chromatography (hexane/EtOAc 8:2) to give compound 29
(23 mg, 73%) as a colorless oil. Rf¼0.44 (hexane/EtOAc
1
8:2); H NMR (400 MHz, CDCl3): d¼7.73–7.65 (m, 4H),
7.47–7.35 (m, 6H), 5.99 (dt, J¼11.5, 5.2 Hz, 1H), 5.58
(t, J¼10.5 Hz, 1H), 5.14 (br s, 1H), 5.05–4.96 (m, 1H), 4.77
(t, J¼9.9 Hz, 1H), 4.23–4.16 (m, 1H), 2.65–2.57 (m, 1H),
2.32–2.27 (m, 1H), 1.89–1.54 (m, 9H), 1.40–1.05 (m,
23H), 0.84 (d, J¼6.8 Hz, 3H), 0.64 (d, J¼6.8 Hz, 3H); 13C
NMR (50.3 MHz, CDCl3): d¼178.1, 137.1, 135.8 (4C),
135.4, 134.8, 134.5 (2C), 129.4 (2C), 127.4 (4C), 121.0,
117.2, 116.4, 74.4, 73.3, 72.2, 41.3, 39.2, 36.6, 34.6, 33.1,
27.7, 27.3 (3C), 26.9 (3C), 23.6, 22.6, 20.9 (2C), 20.0; IR
(CCl4): n¼3630, 2958, 2925, 2852, 1730, 1425, 1367, 1155,
1112, 908; [a]2D0¼þ17.5 (c¼0.60, EtOAc); HRMS (ESI):
m/z: calcd for C39H56NaO4Si: 639.3846 [MþNa]þ; found:
639.3855.

8814
R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
3.1.24. 2,2-Dimethyl-propionic acid [(4R,4aR,6S,7S,11-
R,12aR)-11-(tert-butyl-diphenyl-silanyloxy)-4-isopropyl-
7-methoxy-1-methyl-3,4,4a,5,6,7,10,11,12,12a-deca-
hydro-benzocyclodecen-6-yl] ester (30). Compound 29
(14 mg, 0.023 mmol) was dissolved in CH2Cl2 (0.2 mL).
2,6-Di-tert-butyl-pyridine (44 mg, 0.23 mmol) and MeOTf
(19 mg, 0.12 mmol) were added and the solution stirred for
18 h at 408C. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 9:1) to give compound 30
(14 mg, 96%) as a colorless oil. Rf¼0.28 (hexane/EtOAc
(6 mg, 66%) as a colorless oil. Rf¼0.22 (hexane/EtOAc
1
1:5); H NMR (400 MHz, CDCl3): d¼7.56 (d, J¼15.6 Hz,
1H), 7.48 (s, 1H), 7.10 (s, 1H), 6.53 (d, J¼15.6 Hz, 1H),
5.96–5.89 (m, 1H), 5.52–5.38 (m, 2H), 5.32 (br s, 1H), 5.12
(d, J¼7.3 Hz, 1H), 4.27 (t, J¼9.9 Hz, 1H), 3.73 (s, 3H), 3.26
(s, 3H), 2.88–2.76 (m, 1H), 2.54–2.46 (m, 1H), 2.13–1.14
(m, 24H), 0.99–0.87 (m, 2H), 0.85 (d, J¼5.1 Hz, 3H), 0.65
(d, J¼5.1 Hz, 3H); 13C NMR (100.8 MHz, CDCl3): d¼
177.7, 166.6, 139.2, 138.5, 136.1, 135.7, 130.3, 129.6,
122.3, 121.1, 116.3, 79.7, 74.7, 72.9, 56.7, 37.4 (2C), 35.3,
33.5, 33.2, 30.7, 29.6, 29.3, 27.2 (3C), 26.9, 26.6, 24.3, 24.4,
21.0 (2C); IR (CCl4): n¼2960, 2931, 2889, 2861, 1731,
1712, 1645, 1481, 1460, 1389, 1300, 1157, 1103; [a]2D0¼
217.0 (c¼0.33, EtOAc); HRMS (ESI): m/z: calcd for
C32H50NaN2O5: 565.3617 [MþNa]þ; found: 565.3611.
1
9:1); H NMR (200 MHz, CDCl3): d¼7.74–7.60 (m, 4H),
7.54–7.27 (m, 6H), 6.08 (dt, J¼11.4, 5.3 Hz, 1H), 5.40
(t, J¼10.7 Hz, 1H), 5.16–5.01 (m, 2H), 4.29–4.08 (m, 2H),
3.18 (s, 3H), 2.68–2.49 (m, 1H), 2.35–2.17 (m, 1H), 2.09–
0.84 (m, 31H), 0.80 (d, J¼6.8 Hz, 3H), 0.57 (d, J¼6.8 Hz,
3H); 13C NMR (75.5 MHz, CDCl3): d¼177.7, 138.6, 135.8
(4C), 134.3 (2C), 130.9, 129.6 (2C), 129.2, 127.6 (4C),
120.5, 78.8, 74.8, 72.2, 56.2, 37.6, 37.1, 36.4, 35.3, 32.6,
29.7, 27.2 (3C), 27.0 (3C), 26.9, 26.7, 24.3, 24.1, 21.0 (2C),
19.2; IR (CCl4): n¼2948, 2920, 2848, 1723, 1475, 1422,
1385, 1363, 1279, 1155, 1099, 1059; [a]2D0¼þ7.8 (c¼0.77,
EtOAc); HRMS (ESI): m/z: calcd for C40H58NaO4Si:
653.4002 [MþNa]þ; found: 653.3986.
3.1.27. 2,2-Dimethyl-propionic acid [(4R,4aR,6S,7S,11-
R,12aR)-7-acetoxy-11-(tert-butyl-diphenyl-silanyloxy)-4-
isopropyl-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahydro-
benzocyclodecen-6-yl] ester (33). Compound 29 (16 mg,
0.026 mmol) was dissolved in pyridine (0.5 mL). Ac2O
(5 mg, 0.052 mmol) and DMAP (cat.) were added and the
reaction mixture was stirred for 24 h at room temperature.
EtOAc (5 mL) was added and the organic layer was washed
with a saturated aqueous KHSO4 solution (2£5 mL), the
aqueous layer was back extracted with EtOAc (3£5 mL)
and the combined organic extracts were dried over Na2SO4.
The solvent was evaporated under reduced pressure and the
residue was purified by flash chromatography (hexane/
EtOAc 9:1) to give compound 33 (12 mg, 71%) as a
colorless oil. Rf¼0.69 (hexane/EtOAc 9:1); 1H NMR
(200 MHz, CDCl3): d¼7.69–7.61 (m, 4H), 7.46–7.30 (m,
6H), 6.11–5.87 (m, 2H), 5.45 (t, J¼10.7 Hz, 1H), 5.22–
5.10 (m, 2H), 4.24–4.18 (m, 1H), 2.88–2.74 (m, 1H), 2.32–
2.25 (m, 1H), 2.12–1.95 (m, 4H), 1.84–0.89 (m, 30H), 0.82
(d, J¼6.9 Hz, 3H), 0.57 (d, J¼6.9 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3): d¼177.5, 170.0, 138.8, 135.7 (4C),
134.1 (2C), 132.1, 129.6, 129.5, 127.6 (2C), 127.5 (2C),
126.5, 120.3, 73.6, 72.0, 71.5, 37.7, 37.3, 36.4, 35.3, 32.9,
29.6, 27.0 (7C), 26.5, 24.3, 24.0 (2C), 21.0, 19.2, 14.5;
IR (CCl4): n¼3078, 2959, 2938, 2860, 1739, 1732, 1482,
1460, 1430, 1371, 1155, 1112, 1070; [a]2D0¼þ0.6 (c¼0.51,
EtOAc); HRMS (ESI): m/z: calcd for C41H58NaO5Si:
681.3951 [MþNa]þ; found: 681.3967.
3.1.25. 2,2-Dimethyl-propionic acid [(4R,4aR,6S,7S,11-
R,12aR)-11-hydroxy-4-isopropyl-7-methoxy-1-methyl-
3,4,4a,5,6,7, 10,11,12,12a-decahydro-benzocyclodecen-6-
yl] ester (31). Compound 30 (14 mg, 0.022 mmol) was
dissolved in THF (0.50 mL) and TBAF (0.044 mL,
0.044 mmol, 1.0 M in THF) was added. The reaction
mixture was stirred 14 h at room temperature. An aqueous
phosphate buffer solution (1.0 mL, pH¼7) was added, the
layers were separated and the aqueous layer was extracted
with EtOAc (3£5 mL) and the combined organic extracts
were dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by flash
chromatography (hexanes/EtOAc 8:2) to yield compound
31 (8 mg, 89%) as a colorless oil. Rf¼0.11 (hexanes/EtOAc
1
8:2); H NMR (400 MHz, CDCl3): d¼5.87 (dt, J¼11.6,
5.4 Hz, 1H), 5.44 (t, J¼10.8 Hz, 1H), 5.32 (br s, 1H), 5.12–
5.08 (m, 1H), 4.34–4.23 (m, 2H), 3.26 (s, 3H), 2.80–2.74
(m, 1H), 2.48–2.2.31 (m, 1H), 2.25–1.12 (m, 20H), 1.05–
0.89 (m, 3H), 0.86 (d, J¼6.8 Hz, 3H), 0.64 (d, J¼6.8 Hz,
3H); 13C NMR (100.8 MHz, CDCl3): d¼177.6, 137.5,
130.0, 129.5, 121.0, 78.3, 74.7, 70.7, 56.2, 37.8, 37.3, 36.9,
36.6, 35.3, 32.4, 29.6, 27.2 (3C), 26.9, 26.7, 24.4, 21.0 (2C);
IR (CCl4): n¼3620, 2954, 2923, 2864, 1728, 1478, 1451,
1395, 1386, 1367, 1280, 1160, 1099, 905; [a]2D0¼28.4 (c¼
0.37, EtOAc).
3.1.28. 2,2-Dimethyl-propionic acid [(4R,4aR,6S,7S,11-
R,12aR)-7-acetoxy-11-hydroxy-4-isopropyl-1-methyl-
3,4,4a,5,6,7,10,11,12,12a-decahydro-benzocyclodecen-6-
yl] ester (34). Compound 33 (11 mg, 0.0167 mmol) was
dissolved in THF (0.30 mL) and TBAF (0.033 mL,
0.0334 mmol, 1.0 M in THF) was added. The reaction
mixture was stirred 20 h at room temperature. An aqueous
phosphate buffer solution (1.0 mL, pH¼7) was added, the
layers were separated and the aqueous layer was extracted
with EtOAc (3£5 mL) and the combined organic extracts
were dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by flash
chromatography (hexanes/EtOAc 8:2) to yield compound
34 (7 mg, 92%) as a colorless oil. Rf¼0.15 (hexanes/EtOAc
3.1.26. (E)-3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,10S,11S,12aR)-11-(2,2-dimethyl-propionyl-
oxy)-1-isopropyl-10-methoxy-4-methyl-1,2,4a,5,6,7,
10,11,12,12a-decahydro-benzocyclodecen-6-yl] ester
(32). Compound 31 (6 mg, 0.0153 mmol) was dissolved in
CH2Cl2 (1.8 mL) and added to mixed anhydride 16
(prepared according to Ref. 6b; 76 mg, 0.325 mmol). NEt3
(33 mg, 0.325 mmol) and DMAP (2 mg, 0.0153 mmol)
were added and the solution stirred for 15 days at room
temperature. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 1:5) to yield compound 32
1
8:2); H NMR (200 MHz, CDCl3): d¼6.01 (t, J¼10.3 Hz,
1H), 5.91 (dt, J¼11.4, 5.4 Hz, 1H), 5.47 (t, J¼10.7 Hz, 1H),
5.29 (br s, 1H), 5.19 (dd, J¼10.1, 6.9 Hz, 1H), 4.46–4.24
(m, 1H), 3.08–2.91 (m, 1H), 2.44–2.33 (m, 1H), 2.18–1.22

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8815
(m, 17H), 1.18 (s, 9H), 0.84 (d, J¼6.8 Hz, 3H), 0.61 (d,
J¼6.8 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d¼177.4,
171.1, 138.8, 130.9, 127.3, 120.9, 73.5, 71.3, 70.5, 37.9,
37.4, 36.6, 35.3, 32.7, 29.7, 27.1 (3C), 26.9, 26.4, 24.4, 21.0
(2C), 14.5; IR (CCl4): n¼3622, 2957, 2935, 2870, 1745,
1730, 1479, 1452, 1395, 1388, 1369, 1280, 1155;
[a]2D0¼233.5 (c¼0.39, EtOAc); HRMS (ESI): m/z: calcd
for C25H40NaO5: 443.2773 [MþNa]þ; found: 443.2761.
24.3, 23.9, 21.0 (2C), 19.2, 16.7þ16.3, 14.6; IR (CCl4):
n¼3062, 2945, 2918, 2844, 1722, 1474, 1465, 1448, 1422,
1381, 1362, 1151, 1107, 1059, 902; [a]2D0¼27.2 (c¼1.16,
EtOAc); HRMS (ESI): m/z: calcd for C44H64NaO5Si:
723.4421 [MþNa]þ; found: 723.4416.
3.1.31. 2,2-Dimethyl-propionic acid {(4R,4aR,6S,7S,11R,
12aR)-11-hydroxy-4-isopropyl-1-methyl-[(20*)-7-(tetra-
hydro-pyran-20-yloxy)]-3,4,4a,5,6,7,10,11,12,12a-deca-
hydro-benzocyclodecen-6-yl} ester (37). Compound 36
(23 mg, 0.033 mmol) was dissolved in THF (2.0 mL) and
TBAF (165 mL, 0.165 mmol, 1.0 M in THF) was added.
The reaction mixture was stirred 20 h at room temperature.
An aqueous phosphate buffer solution (1.0 mL, pH¼7) was
added, the layers were separated and the aqueous layer was
extracted with EtOAc (3£5 mL). The combined organic
extracts were dried over Na2SO4 and, after filtration, the
solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography (hexanes/EtOAc 4:1)
to yield compound 37 (15 mg, quant.) as a colorless oil.
Rf¼0.10 (hexanes/EtOAc 4:1); 1H NMR (200 MHz, CDCl3,
signal doubling due to diastereomers): d¼5.97þ5.78 (dt,
J¼9.3, 5.8 Hz, 1H), 5.60þ5.35 (t, J¼10.3 Hz, 1H), 5.29–
5.01 (m, 2H), 4.93–4.65 (m, 2H), 4.39–4.15 (m, 1H), 4.02–
3.73 (m, 1H), 3.55–3.33 (m, 1H), 2.93–2.71 (m, 1H), 2.40–
2.22 (m, 1H), 2.17–1.09 (m, 29H), 0.82 (d, J¼6.7 Hz, 3H),
0.62þ0.59 (d, J¼6.7 Hz, 3H); 13C NMR (100.8 MHz,
CDCl3, signal doubling due to diastereomers): d¼177.5,
133.8, 129.2, 126.6, 120.9þ120.8, 99.3þ93.1, 76.5, 74.9þ
74.7, 70.7þ70.4, 61.5þ60.6, 37.9þ37.8, 37.4, 36.6, 35.5,
32.4, 30.4þ30.2, 27.4, 27.3 (3C), 27.2, 26.9, 26.7þ26.3,
25.5þ25.4, 24.5, 21.1 (2C), 18.7þ18.4; IR (CCl4): n¼3620,
3440, 2950, 2865, 1723, 1477, 1451, 1392, 1385, 1365,
1279, 1155, 1110, 1072, 1050, 905; [a]2D0¼236.1 (c¼0.75,
EtOAc); HRMS (ESI): m/z: calcd for C28H46NaO5:
485.3243 [MþNa]þ; found: 485.3238.
3.1.29. (E)-3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,10S,11S,12aR)-10-acetoxy-11-(2,2-di-
methyl-propionyloxy)-1-isopropyl-4-methyl-1,2,4a,5,6,
7,10,11,12,12a-decahydro-benzocyclodecen-6-yl] ester
(35). Compound 34 (6 mg, 0.014 mmol) was dissolved in
CH2Cl2 (1.6 mL) and added to mixed anhydride 16
(prepared according to Ref. 6b; 50 mg, 0.21 mmol). NEt3
(21 mg, 0.21 mmol) and DMAP (2 mg, 0.014 mmol) were
added and the solution was stirred for 2 days at room
temperature. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 1:4) to yield compound 35
(6 mg, 80%) as a colorless oil. Rf¼0.20 (hexane/EtOAc
1:4); 1H NMR (400 MHz, CDCl3): d¼7.60 (s, 1H), 7.54 (d,
J¼15.7 Hz, 1H), 7.11 (s, 1H), 6.59 (d, J¼15.7 Hz, 1H), 6.04
(t, J¼10.4 Hz, 1H), 5.89 (dt, J¼11.6, 5.6 Hz, 1H), 5.55–
5.45 (m, 2H), 5.32 (s, 1H), 5.23 (dd, J¼10.1, 6.8 Hz, 1H),
3.75 (s, 3H), 3.13–3.03 (m, 1H), 2.54–2.48 (m, 1H), 2.22–
1.17 (m, 25H), 0.85 (d, J¼6.9 Hz, 3H), 0.63 (d, J¼6.9 Hz,
3H); 13C NMR (75.5 MHz, CDCl3): d¼177.6, 170.1, 166.7,
138.6, 138.4, 136.1, 130.9, 127.5 (2C), 122.3, 120.9, 116.3,
73.4, 72.8, 71.1, 37.5, 36.5, 35.3, 33.7, 33.5, 30.0, 29.7, 27.2
(3C), 26.8, 26.3, 24.5, 21.0 (3C), 14.5; IR (CCl4): n¼2961,
2935, 1742, 1733, 1712, 1648, 1390, 1371, 1155;
[a]2D0¼239.6 (c¼0.24, EtOAc); HRMS (ESI): m/z: calcd
for C32H47N2O6: 555.3434 [MþH]þ; found: 555.3425.
3.1.30. 2,2-Dimethyl-propionic acid {(4R,4aR,6S,7S,11-
R,12aR)-11-(tert-butyl-diphenyl-silanyloxy)-4-isopropyl-
1-methyl-7-[(20*)-tetrahydro-pyran-20-yloxy)]-3,4,4a,5,6,
7,10,11,12,12a-decahydro-benzocyclodecen-6-yl} ester
(36). Compound 29 (29 mg, 0.047 mmol) was dissolved in
CH2Cl2 (0.4 mL). Dihydropyran (6 mg, 0.071 mmol) and
PPTS (1 mg, 0.005 mmol) were added and the solution was
stirred for 11 h at room temperature. i-Pr2O (5 mL) was
added, the organic layer was washed with a semisaturated
NaCl solution (2£5 mL) and the organic layer was dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 14:1) to yield compound
36 (25 mg, 77%) as a colorless oil. Rf¼0.33 (hexane/EtOAc
3.1.32. 3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
{(1R,4aR,6R,10S,11S,12aR)-11-(2,2-dimethyl-propionyl-
oxy)-1-isopropyl-4-methyl-10-[(20*)-(tetrahydro-pyran-
2-yloxy)]-1,2,4a,5,6,7,10,11,12,12a-decahydro-benzo-
cyclodecen-6-yl} ester (38). Compound 37 (15 mg,
0.032 mmol) was dissolved in CH2Cl2 (2.0 mL) and added
to mixed anhydride 16 (prepared according to Ref. 6b;
118 mg, 0.494 mmol). NEt3 (50 mg, 0.494 mmol) and
DMAP (4 mg, 0.032 mmol) were added and the solution
was stirred for 3 days at room temperature. The solvent was
evaporated under reduced pressure and the resulting residue
was purified by flash chromatography (hexane/EtOAc 1:4)
to yield compound 38 (12 mg, 61%) as a colorless oil. Rf¼
0.15 (hexane/EtOAc 1:4); 1H NMR (400 MHz, CDCl3,
signal doubling due to diastereomers): d¼7.62 (s, 1H),
7.57þ7.53 (d, J¼15.7 Hz, 1H), 7.10 (s, 1H), 6.56 (d, J¼
15.7 Hz, 1H), 5.94þ5.75 (dt, J¼9.1, 6.2 Hz, 1H), 5.65 (t,
J¼10.4 Hz, 1H), 5.45–5.37 (m, 2H), 5.30 (s, 1H), 5.23–
5.08 (m, 1H), 4.92þ4.78 (t, J¼10.2 Hz, 1H), 4.90–4.85þ
4.68–4.65 (m, 1H), 3.99–3.92þ3.84–3.77 (m, 1H), 3.74
(s, 3H), 3.57–3.47þ3.45–3.38 (m, 1H), 2.97–2.83 (m, 1H),
2.48–2.41 (m, 1H), 2.17–1.38 (m, 15H), 1.33–1.18 (m,
12H), 0.84 (d, J¼6.8 Hz, 3H), 0.67–0.61 (m, 3H); 13C
NMR (50.3 MHz, CDCl3, signal doubling due to dia-
stereomers): d¼177.2, 166.5, 137.9, 135.2, 130.9þ130.8,
129.4, 126.7, 122.1, 120.8, 117.0, 99.3þ93.3, 74.7þ74.5,
1
14:1); H NMR (200 MHz, CDCl3, signal doubling due to
diastereomers): d¼7.68–7.61 (m, 4H), 7.38–7.28 (m, 6H),
6.08þ5.93 (dt, J¼11.6, 5.5 Hz, 1H), 5.59þ5.32 (t, J¼
10.4 Hz, 1H), 5.18–5.01 (m, 2H), 4.88–4.61 (m, 2H),
4.23–4.10 (m, 1H), 3.94–3.72 (m, 1H), 3.51–3.33 (m, 1H),
2.76–2.57 (m, 1H), 2.35–2.17 (m, 1H), 2.13–1.95 (m, 1H),
1.91–0.95 (m, 36H), 0.80 (d, J¼5.8 Hz, 3H), 0.61–0.55
(m, 3H); 13C NMR (50.3 MHz, CDCl3, signal doubling due
to diastereomers): d¼177.6þ177.4, 138.9þ138.8, 135.7
(4C), 134.4þ134.2 (2C), 132.0, 130.0þ129.5 (2C), 128.4,
127.9þ127.5þ127.4 (4C), 120.2, 99.2þ93.0, 76.5, 74.9þ
74.6, 72.1þ70.5, 61.5þ60.4, 37.7, 37.3, 36.5, 35.4, 32.6,
30.4þ30.1, 29.6, 27.3 (3C), 27.0þ26.6 (3C), 26.3, 25.4,

8816
R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
73.1, 70.2, 61.5þ60.8, 37.4, 36.6, 35.4, 33.7, 30.3, 29.6,
27.3 (3C), 27.0, 26.8, 26.5, 26.2, 25.4, 24.5, 24.3, 21.0 (2C),
19.0þ18.7, 14.6; IR (CCl4): n¼2959, 2877, 1725, 1709,
1645, 1481, 1452, 1385, 1398, 1156, 1113, 909; [a]2D0¼
244.4 (c¼0.59, EtOAc); HRMS (ESI): m/z: calcd for
C32H53N2O6: 597.3904 [MþH]þ; found: 597.3900.
4-enyl]-6-isopropyl-3-methyl-cyclohex-3-enylmethyl}-2-
methoxymethoxy-but-3-enyl} ester (40). Compound 26
(160 mg, 0.271 mmol) was dissolved in pyridine (1.8 mL).
DMAP (4 mg, 0.03 mmol) and PivCl (161 mg, 1.33 mmol)
were added and the mixture was stirred at room temperature
for 18 h. EtOAc (9 mL) was added, the organic layer
was washed with a saturated aqueous KHSO4 solution
(2£10 mL), the combined aqueous layers were back
extracted with EtOAc (3£10 mL) and the combined organic
extracts were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the resulting residue
was purified by flash chromatography (hexane/EtOAc 9:1)
to give compound 40 (172 mg, 94%) as a colorless oil.
Rf¼0.71 (hexane/EtOAc 9:1); 1H NMR (200 MHz, CDCl3):
d¼7.67–7.59 (m, 4H), 7.42–7.28 (m, 6H), 6.03–5.91 (m,
1H), 5.87–5.76 (m, 1H), 5.31–4.95 (m, 6H), 4.63 (d, J¼
6.7 Hz, 1H), 4.55 (d, J¼6.7 Hz, 1H), 4.04–3.89 (m, 2H),
3.35 (s, 3H), 2.23–2.15 (m, 3H), 1.96–1.91 (m, 2H), 1.87–
0.80 (m, 28H), 0.75 (d, J¼6.7 Hz, 3H), 0.62 (d, J¼6.7 Hz,
3H); 13C NMR (50.3 MHz, CDCl3): d¼173.7, 137.4, 135.9
(4C), 135.1, 134.9, 134.6, 134.3, 129.4, 129.3, 127.4 (2C),
127.3 (2C), 121.8, 119.2, 117.2, 94.3, 78.5, 71.8, 71.5, 55.7,
40.3, 37.2, 37.0, 35.8, 35.6, 29.7, 28.8, 27.3 (3C), 27.1 (4C),
24.3, 23.8, 21.0 (2C), 19.3; IR (CCl4): n¼2935, 2905, 2867,
2830, 1728, 1431, 1372, 1159, 1107, 910; [a]2D0¼þ52.7
(c¼0.77, EtOAc); HRMS (ESI): m/z: calcd for
C43H64NaO5Si: 711.4421 [MþNa]þ; found: 711.4406.
3.1.33. 3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,10S,11S,12aR)-11-(2,2-dimethyl-propionyl
oxy)-10-hydroxy-1-isopropyl-4-methyl-1,2,4a,5,6,7,
10,11,12,12a-decahydro-benzocyclodecen-6-yl] ester
(39). Compound 38 (13 mg, 0.022 mmol) was dissolved in
EtOH (2.0 mL, 80%). PTSA (0.8 mg, 0.0044 mmol) was
added and the solution was stirred for 72 h at room
temperature. EtOAc (5 mL) was added, the organic layer
was washed with a saturated aqueous NaHCO3 solution
(2£5 mL), with a saturated aqueous NaCl solution (5 mL)
and then the organic layer was dried over Na2SO4. The
solvent was evaporated under reduced pressure and the
resulting residue was purified by flash chromatography
(EtOAc) to yield compound 39 (7 mg, 82%) as a colorless
oil. Rf¼0.16 (EtOAc); 1H NMR (400 MHz, CDCl3): d¼7.67
(s, 1H), 7.54 (d, J¼5.2 Hz, 1H), 7.09 (s, 1H), 6.58 (d, J¼
5.2 Hz, 1H), 5.77 (dt, J¼11.5, 5.3 Hz, 1H), 5.60 (t, J¼
10.5 Hz, 1H), 5.43–5.37 (m, 1H), 5.29 (s, 1H), 5.11–5.00
(m, 1H), 4.84 (t, J¼9.8 Hz, 1H), 3.74 (s, 3H), 2.87–2.78 (m,
1H), 2.51–1.71 (m, 11H), 1.62–1.36 (m, 3H), 1.35–1.15
(m, 10H), 0.84 (d, J¼6.8 Hz, 3H), 0.64 (d, J¼6.8 Hz, 3H);
13C NMR (100.8 MHz, CDCl3): d¼178.5, 166.5, 138.9,
137.7, 135.1, 131.4, 128.2, 122.4, 121.1, 117.2, 77.7, 73.1,
70.4, 69.5, 37.4, 33.9, 33.1, 30.1, 29.7, 27.3 (3C), 27.2, 26.9,
26.8, 24.4, 24.3, 21.0 (2C), 19.1; IR (CCl4): n¼3620, 3240,
2957, 2922, 2865, 1709, 1643, 1478, 1455, 1385, 1367,
1322, 1297, 1155, 1109, 1043, 908; [a]2D0¼245.0 (c¼0.28,
EtOAc); HRMS (ESI): m/z: calcd for C30H45N2O5:
513.3329 [MþH]þ; found: 513.3321.
3.1.36. 2,2-Dimethyl-propionic acid {(1R,2R)-1-
{(1R,2R,6R)-2-[(2R)-2-(tert-butyl-diphenyl-silanoxy)-
pent-4-enyl]-6-isopropyl-3-methyl-cyclohex-3-enyl-
methyl}-2-hydroxy-but-3-enyl} ester (41). Compound 40
(100 mg, 0.015 mmol) was dissolved in CH2Cl2 (0.5 mL)
and cooled to 2788C. Me2S (42 mg, 0.068 mmol) and
BF3·Et2O (11 mg, 0.079 mmol) were added and the solution
was allowed to warm to 2208C for 0.5 h. Then, a saturated
aqueous NaHCO3 solution (1 mL) was added and the
solution was warmed up to room temperature. The layers
were separated, the aqueous layer was extracted with EtOAc
(3£5 mL) and the combined organic extracts were dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 9:1) to give compound 41
(7 mg, 78%) as a colorless oil. Rf¼0.40 (hexane/EtOAc
3.1.34. (2R,3R)-1-{(1R,2R,6R)-2-[(2R)-2-(tert-Butyl-
diphenyl-silanyloxy)-pent-4-enyl]-6-isopropyl-3-methyl-
cyclohex-3-enyl}-3-methoxymethoxy-pent-4-en-2-ol
(26). Methoxymethyl allyl ether (136 mg, 1.33 mmol) in
THF (2.7 mL) was cooled to 2788C and sec-BuLi (854 mL,
1.11 mmol, 1.3 M in cyclohexane) was added. The reaction
d
solution was stirred at 2788C for 30 min and Ipc2BOMe
1
(1.11 mL, 1.11 mmol, 1.0 M in THF) was then added.
Stirring was maintained for 1 h, BF3·Et2O (213 mg,
1.50 mmol) was then added, followed by aldehyde 10
(279 mg, 0.55 mmol) in THF (3.9 mL). The mixture was
stirred at 2788C for 14 h and then slowly warmed to room
temperature. An aqueous NaOH solution (1.8 mL, 6.0 M)
and H2O2 (1.8 mL, 35%) were then added and the mixture
was left to warm up to room temperature for 5 h. H2O
(5 mL) was added and the aqueous layer was extracted with
EtOAc (3£30 mL) and the combined organic extracts were
dried over Na2SO4. The solvent was evaporated under
reduced pressure and the resulting residue was purified
by flash chromatography (from hexane/EtOAc 7.5:1 to
hexane/EtOAc 6:1) to give compound 26 (251 mg, 77%) as
a colorless oil (26/25¼98.7:1.3). The characterization of
compounds 25 and 26 is reported above.
9:1); H NMR (200 MHz, CDCl3): d¼7.74–7.63 (m, 4H),
7.48–7.28 (m, 6H), 6.05–5.68 (m, 2H), 5.36–4.88 (m, 6H),
4.08–3.89 (m, 2H), 2.41–2.18 (m, 2H), 2.09–1.95 (m, 1H),
1.84–0.82 (m, 31H), 0.78 (d, J¼6.7 Hz, 3H), 0.66 (d,
J¼6.7 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d¼178.3,
137.3, 137.1, 135.9 (4C), 135.1, 134.6 (2C), 129.5 (2C),
127.4 (4C), 121.7, 117.3, 116.3, 74.3, 73.1, 71.6, 40.5, 37.4,
36.7, 35.6, 35.3, 29.7, 28.7, 27.2 (3C), 27.1 (4C), 24.0, 23.7,
21.0 (2C), 19.3; IR (CCl4): n¼3580, 3066, 2951, 2922,
2850, 1724, 1425, 1384, 1365, 1152, 1107, 905; [a]2D0¼
þ70.7 (c¼0.81, EtOAc); HRMS (ESI): m/z: calcd for
C41H60NaO4Si: 667.4159 [MþNa]þ; found: 667.4128.
3.1.37. 2,2-Dimethyl-propionic acid [(4R,4aR,6R,7R,11-
R,12aR)-11-(tert-butyl-diphenyl-silanoxy)-7-hydroxy-4-
isopropyl-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahydro-
benzocyclodecen-6-yl] ester (42). Compound 41 (50 mg,
0.077 mmol) was dissolved in degassed CH2Cl2 (6.4 mL).
Second generation RCM catalyst 13 (5.5 mg, 6 mmol) in
3.1.35. 2,2-Dimethyl-propionic acid {(1R,2R)-1-{(1R,
2R,6R)-2-[(2R)-2-(tert-butyl-diphenyl-silanyloxy)-pent-

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8817
1
degassed CH2Cl2 (2.7 mL) was slowly added. The reaction
mixture stirred for 12 h at room temperature. Additional
RCM catalyst 13 (3 mg, 3.5 mmol) in degassed CH2Cl2
(1.5 mL) was slowly added and the mixture stirred for
further 12 h at room temperature. The solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography (hexane/EtOAc 9:1) to
provide unreacted 41 (15 mg) and compound 42 (29 mg,
60%, 86% considering the recovered starting material) as
colorless oils. Rf¼0.20 (hexane/EtOAc 9:1); 1H NMR
(400 MHz, CDCl3): d¼7.66–7.63 (m, 4H), 7.44–7.32
(m, 6H), 6.10–5.91 (m, 2H), 5.75–5.70 (m, 1H), 5.55–
5.49 (m, 1H), 5.14–5.05 (m, 2H), 4.40–4.36 (m, 1H), 4.30–
3.80 (m, 4H), 2.81–2.73 (m, 1H), 2.38–2.25 (m, 2H),
2.15–2.10 (m, 1H), 1.82–1.10 (m, 16H), 1.06 (s, 9H), 0.85
(d, J¼6.8 Hz, 3H), 0.67 (d, J¼6.8 Hz, 3H); 13C NMR
(100.8 MHz, CDCl3): d¼173.9, 136.3, 135.9 (2C), 135.8
(2C), 133.9 (2C), 130.3, 129.8, 129.7, 127.7, 127.6 (2C),
127.5 (2C), 119.3, 75.3, 73.1, 72.3, 37.2, 36.5, 35.1, 34.7,
30.5, 27.7, 27.2 (3C), 27.0 (3C), 26.4, 24.4, 22.7, 21.0 (2C),
20.8, 19.2; IR (CCl4): n¼3618, 3070, 2955, 2923, 2850,
1725, 1477, 1459, 1425, 1384, 1365, 1155, 1100, 1080;
[a]2D0¼þ4.0 (c¼0.35, EtOAc); HRMS (ESI): m/z: calcd for
C39H56NaO4Si: 639.3846 [MþNa]þ; found: 639.3860.
8:2); H NMR (400 MHz, CDCl3): d¼5.97 (dt, J¼16.5,
4.6 Hz, 1H), 5.85 (m, 1H), 5.65 (br s, 1H), 5.24 (br s, 1H),
4.08 (m, 1H), 3.74 (dd, J¼9.0, 7.4 Hz, 1H), 3.29 (s, 3H),
2.98 (m, 1H), 2.39 (m, 1H), 1.88–1.19 (m, 23H), 0.85
(d, J¼6.8 Hz, 3H), 0.68 (d, J¼6.8 Hz, 3H); 13C NMR
(100.8 MHz, CDCl3): d¼177.7, 144.6, 132.2, 129.1, 119.8,
80.8, 72.3, 72.1, 57.0, 37.5, 37.2, 36.5, 34.9, 31.5, 30.2,
27.2, 27.1 (3C), 26.5, 24.4, 23.2, 21.0 (2C); IR (CCl4):
n¼3622, 3019, 2961, 2932, 2904, 2874, 2291, 2004, 2003,
1848, 1729, 1558, 1480, 1461, 1397, 1388, 1369, 1283,
1255, 1218, 1159, 1107; [a]2D0¼262.6 (c¼0.70, EtOAc);
HRMS (ESI): m/z: calcd for C28H46O5: 393.3005; found:
393.3015.
3.1.40. (E)-3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid
[(1R,4aR,6R,10R,11R,12aR)-11-(2,2-dimethyl-propionyl-
oxy)-1-isopropyl-10-methoxy-4-methyl-1,2,4a,5,6,7,
10,11,12,12a-decahydro-benzocyclodecen-6-yl] ester
(45). Compound 44 (7 mg, 0.018 mmol) was dissolved in
ClCH2CH2Cl (1.0 mL) and added to mixed anhydride 16
(prepared according to Ref. 6b; 120 mg, 0.509 mmol). NEt3
(33 mg, 0.325 mmol) and DMAP (2 mg, 0.0164 mmol)
were added and the solution stirred for 64 h at room
temperature and refluxed for 2 h. The solvent was evapo-
rated under reduced pressure and the resulting residue was
purified by flash chromatography (from 100% hexanes to
hexanes/EtOAc 1:4) to yield compound 45 (7 mg, 79%) as a
colorless oil. Rf¼0.23 (hexane/EtOAc 1:5); 1H NMR
(400 MHz, CDCl3): d¼7.53 (d, J¼15.6 Hz, 1H), 7.46 (s,
1H), 7.06 (s, 1H), 6.53 (d, J¼15.6 Hz, 1H), 5.99–5.41 (br s,
2H), 5.94 (dt, J¼16.1, 4.5 Hz, 1H), 5.32–5.00 (br s, 2H),
3.76 (t, J¼7.7 Hz, 1H), 3.70 (s, 3H), 3.28 (s, 3H), 3.04 (m,
1H), 2.46 (m, 1H), 2.17–1.19 (m, 20H), 0.89 (m, 2H), 0.84
(d, J¼6.7 Hz, 3H), 0.69 (d, J¼6.7 Hz, 3H); 13C NMR
(50.3 MHz, CDCl3): d¼176.9, 166.6, 138.7, 138.6, 136.0,
135.9, 132.4, 129.2, 122.3, 80.8, 74.0, 72.4, 56.9 (2C), 37.6,
36.3, 33.5 (2C), 30.2, 27.1 (3C), 26.6 (3C), 24.4, 23.1, 21.0
(2C); IR (CCl4): n¼2961, 2932, 2873, 2821, 2291, 2003,
1848, 1729, 1708, 1646, 1544, 1480, 1461, 1387, 1253,
1217, 1159; [a]2D0¼2 43.8 (c¼0.70, EtOAc); HRMS (ESI):
m/z: calcd for C31H46N2O5: 527.3485 [MþH]þ; found:
527.3499.
3.1.38. 2,2-Dimethyl-propionic acid [(4R,4aR,6R,7R,11-
R,12aR)-11-(tert-butyl-diphenyl-silanyloxy)-4-isopropyl-
7-methoxy-1-methyl-3,4,4a,5,6,7,10,11,12,12a-decahy-
dro-benzocyclodecen-6-yl] ester (43). Compound 42
(10 mg, 0.016 mmol) was dissolved in CH2Cl2 (0.2 mL).
2,6-Di-tert-Butyl-pyridine (31 mg, 0.16 mmol) and MeOTf
(13 mg, 0.08 mmol) were added and the solution was stirred
for 7 h at 408C. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 9:1) to give compound 43
(10 mg, 99%) as a colorless oil. Rf¼0.66 (hexane/EtOAc
1
8:2); H NMR (400 MHz, CDCl3): d¼7.66–7.64 (m, 4H),
7.51–7.34 (m, 6H), 6.14–5.60 (br s, 2H), 5.06 (br s, 2H),
3.97 (br s, 1H), 3.71 (m, 1H), 3.25 (s, 3H), 2.77 (m, 1H),
2.20 (m, 1H), 2.07–0.95 (m, 31H), 0.83 (d, J¼6.7 Hz, 3H),
0.65 (d, J¼6.5 Hz, 3H); 13C NMR (100.8 MHz, CDCl3):
d¼183.1, 135.9, 135.8 (4C), 134.1, 134.0, 130.2, 129.7,
129.6, 128.3, 127.6 (2C), 127.5 (2C), 119.0, 115.1, 80.8,
73.2, 72.4, 56.9, 50.5, 38.5, 37.5, 37.2, 36.3, 30.1 (3C), 27.0
(3C), 26.4, 24.8, 24.3, 22.6, 21.0, 19.2; IR (CCl4): n¼2962,
2935, 2901, 2867, 2293, 2000, 1729, 1558, 1429, 1368,
1261, 1160; [a]2D0¼223.5 (c¼1.00, EtOAc); HRMS (ESI):
m/z: calcd for C40H58O4Si: 631.4183; found: 631.4200.
3.1.41. 2,2-Dimethyl-propionic acid {(4R,4aR,6R,7R,11-
R,12aR)-11-(tert-butyl-diphenyl-silanyloxy)-4-isopropyl-
1-methyl-7-[(20*)-tetrahydro-pyran-20-yloxy)]-3,4,4a,5,
6,7,10,11,12,12a-decahydro-benzocyclodecen-6-yl} ester
(46). Compound 42 (20 mg, 0.032 mmol) was dissolved in
CH2Cl2 (0.3 mL). Dihydropyran (4 mg, 0.048 mmol) and
PPTS (1 mg, 0.005 mmol) were added and the solution was
stirred for 12 h at room temperature. i-Pr2O (5 mL) was
added, the organic layer was washed with a semisaturated
NaCl solution (2£5 mL) and the organic layer was dried
over Na2SO4. The solvent was evaporated under reduced
pressure and the resulting residue was purified by flash
chromatography (hexane/EtOAc 14:1) to yield compound
46 (20 mg, 91%) as a colorless oil. Rf¼0.40 (hexane/EtOAc
3.1.39. 2,2-Dimethyl-propionic acid [(4R,4aR,6R,7R,11-
R,12aR)-11-hydroxy-4-isopropyl-7-methoxy-1-methyl-
3,4,4a,5,6,7,10,11,12,12a-decahydro-benzocyclodecen-6-
yl] ester (44). Compound 43 (10 mg, 0.016 mmol) was
dissolved in THF (0.40 mL) and TBAF (0.034 mL,
0.034 mmol, 1.0 M in THF) was added. The reaction
mixture stirred 14 h at room temperature. An aqueous
phosphate buffer solution (1.0 mL, pH¼7) was added, the
layers were separated and the aqueous layer was extracted
with EtOAc (3£5 mL) and the combined organic extracts
were dried over Na2SO4. The solvent was evaporated under
reduced pressure and the residue was purified by flash
chromatography (hexanes/EtOAc 8:2) to yield compound
44 (4 mg, 67%) as a colorless oil. Rf¼0.10 (hexanes/EtOAc
1
14:1); H NMR (250 MHz, CDCl3, signal doubling due to
diastereomers): d¼7.68–7.64 (m, 4H), 7.44–7.34 (m, 6H),
6.20þ6.02 (m, 1H), 5.86þ5.70 (m, 2H), 4.80–4.60 (m, 2H),
4.07–3.92 (m, 1H), 3.90–3.75 (m, 1H), 3.50–3.35 (m, 1H),
2.90–2.75 (m, 1H), 2.35–2.20 (m, 1H), 2.20–2.10 (m, 1H),
1.95–1.05 (m, 36H), 0.84 (d, J¼6.7 Hz, 3H), 0.66–0.63 (m,

8818
R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
3H); 13C NMR (50.3 MHz, CDCl3, signal doubling due to
diastereomers): d¼178.0, 135.9þ135.8, 131.0þ134.1 (2C),
130.0, 129.7þ129.6 (2C), 128.3, 127.6þ127.5 (4C), 119.0,
100.7þ93.4, 78.4þ77.2, 73.3þ72.7, 68.6, 62.1þ60.8, 38.6,
37.1, 36.4þ36.3, 34.8, 30.5þ30.4, 27.4, 27.2, 27.1 (2C),
27.0, 26.4, 25.5þ25.4, 24.8, 24.4, 22.9þ22.7, 21.0þ20.7,
19.2þ19.1, 18.3; IR (CCl4): n¼3072, 3052, 2961 2859,
2290, 2003, 1848, 1742, 1728, 1558, 1480, 1462, 1428,
1390, 1371, 1261, 1219, 1159, 1105, 1011; [a]2D0¼22.8
(c¼8.75, EtOAc); HRMS (ESI): m/z: calcd for C44H64
NaO5Si: 723.4421 [MþNa]þ; found: 723.4420.
4.29 (m, 1H), 4.10–3.97 (m, 1H), 3.90–3.77 (m, 1H),
3.72þ3.70 (s, 3H), 3.55–3.39 (m, 2H), 3.20–3.05 (m, 1H),
2.61–2.50þ2.49–2.35 (m, 1H), 2.21 (br s, 1H), 2.10–1.15
(m, 23H), 2.17–1.38 (m, 15H), 0.84þ0.83 (d, J¼6.8 Hz,
3H), 0.75–0.64 (m, 3H); 13C NMR (50.3 MHz, CDCl3,
signal doubling due to diastereomers): d¼178.1, 166.6,
139.7, 138.4, 135.8þ135.7, 131.1, 129.9, 123.9, 122.4,
116.5, 114.6, 100.3þ93.5, 78.2, 73.2, 72.7, 70.3, 61.7þ
60.8, 38.5, 37.4, 36.3, 36.1, 34.4, 33.7, 33.6 (3C), 30.5, 27.3
(3C), 27.2, 27.1, 26.6, 26.5, 26.4, 23.2, 21.0, 18.5þ18.0; IR
(CCl4): n¼2961, 2873, 1727, 1708, 1645, 1480, 1460, 1387,
1368, 1159, 1159, 909; [a]2D0¼223.6 (c¼0.32, EtOAc);
HRMS (ESI): m/z: calcd for C32H53N2O6: 597.3904
[MþH]þ; found: 597.3909.
3.1.42. 2,2-Dimethyl-propionic acid {(4R,4aR,6R,7R,11R,
12aR)-11-hydroxy-4-isopropyl-1-methyl-[(20*)-7-(tetra-
hydro-pyran-20-yloxy)]-3,4,4a,5,6,7,10,11,12,12a-deca-
hydro-benzocyclodecen-6-yl} ester (47). Compound 46
(18 mg, 0.025 mmol) was dissolved in THF (1.5 mL) and
TBAF (125 mL, 0.125 mmol, 1.0 M in THF) was added.
The reaction mixture was stirred 12 h at room temperature.
An aqueous phosphate buffer solution (1.0 mL, pH¼7) was
added, the layers were separated and the aqueous layer
was extracted with EtOAc (3£5 mL) and the combined
organic extracts were dried over Na2SO4. The solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography (hexanes/EtOAc 8:2) to
yield compound 47 (11 mg, 96%) as a colorless oil. Rf¼0.11
3.1.44. 3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid [(1R,
4aR,6R,10R,11R,12aR)-11-(2,2-dimethyl-propionyloxy)-
10-hydroxy-1-isopropyl-4-methyl-1,2,4a,5,6,7,10,11,12,
12a-decahydro-benzocyclodecen-6-yl] ester (49). Com-
pound 48 (13 mg, 0.022 mmol) was dissolved in EtOH
(1.5 mL, 80%). PTSA (1 mg, 0.0049 mmol) was added and
the solution was stirred for 4 days at room temperature.
EtOAc (5 mL) was added, the organic layer was washed
with a saturated aqueous NaHCO3 solution (2£5 mL), with
a saturated aqueous NaCl solution (5 mL) and then the
organic layer was dried over Na2SO4. The solvent was
evaporated under reduced pressure and the resulting residue
was purified by flash chromatography (hexanes/EtOAc, 1:5)
to yield compound 49 (5 mg, 40%) as a colorless oil. Rf¼
1
(hexanes/EtOAc 8:2); H NMR (200 MHz, CDCl3, signal
doubling due to diastereomers): d¼6.04–5.91 (m, 1H), 5.85
(dt, J¼12.2, 4.5 Hz, 1H), 5.73 (m, 2H), 5.24 (br s, 2H),
4.90–4.62 (m, 2H), 4.39–4.25 (m, 1H), 4.20–3.97 (m, 1H),
3.97–3.77 (m, 1H), 2.55–2.39 (m, 1H), 3.10–2.95 (m, 1H),
2.50–2.27 (m, 1H), 2.15 (br s, 1H), 2.00–1.15 (m, 27H),
0.85 (d, J¼6.8 Hz, 3H), 0.69þ0.67 (d, J¼6.8 Hz, 3H); 13C
NMR (100.8 MHz, CDCl3, signal doubling due to dia-
stereomers): d¼139.7, 132.8, 130.8, 129.6, 128.9, 119.6,
100.4þ93.3, 78.1, 73.0, 72.5þ72.0 (2C), 68.1þ60.7, 37.5,
37.2, 37.0 (2C), 36.5, 34.8, 30.6, 30.4þ30.3, 27.3, 27.1
(3C), 26.3, 25.4, 24.8, 24.4, 23.2, 21.0 (2C), 20.7,
18.9þ18.2; IR (CCl4): n¼3622, 3449, 2961, 2931, 2873,
2290, 2003, 1848, 1728, 1558, 1480, 1460, 1441, 1397,
1388, 1369, 1322, 1261, 1218, 1159, 1099, 1014, 978;
[a]2D0¼264.3 (c¼1.04, EtOAc); HRMS (ESI): m/z: calcd
for C28H46O5þNH4: 480.3689 [MþNH4]þ; found:
480.3690.
1
0.23 (hexanes/EtOAc, 1:5); H NMR (400 MHz, CDCl3):
d¼7.91 (s, 1H), 7.50 (d, J¼15.6 Hz, 1H), 7.10 (s, 1H), 6.68
(d, J¼15.6 Hz, 1H), 6.09–5.61 (m, 3H), 5.37–5.13 (m, 2H),
4.93–4.66 (m, 1H), 3.78 (s, 3H), 3.60–3.37 (m, 1H), 4.23–
3.02 (m, 1H), 2.67–1.07 (m, 23H), 0.84 (d, J¼5.2 Hz, 3H),
0.67 (d, J¼5.2 Hz, 3H); 13C NMR (100.8 MHz, CDCl3):
d¼178.7, 166.3, 140.5, 136.4, 135.1, 131.8, 121.3, 119.2,
78.0, 73.1, 70.2, 69.0, 37.1, 36.2, 33.4, 30.4, 27.3 (2C),
27.1, 26.4, 24.4, 23.2, 22.9, 22.8; IR (CCl4): n¼3405, 3135,
3022, 2960, 2991, 1708, 1646, 1542, 1480, 1442, 1387,
1369, 1298, 1262, 1115, 1024, 909; [a]2D0¼235.5 (c¼0.23,
EtOAc); HRMS (ESI): m/z: calcd for C30H45N2O5:
513.3328 [MþH]þ; found: 513.3337.
3.2. Tubulin polymerization assay
3.1.43. 3-(1-Methyl-1H-imidazol-4-yl)-acrylic acid {(1R,
4aR,6R,10R,11R,12aR)-11-(2,2-dimethyl-propionyloxy)-
1-isopropyl-4-methyl-10-[(20*)-(tetrahydro-pyran-2-
yloxy)]-1,2,4a,5,6,7,10,11,12,12a-decahydro-benzocyclo-
decen-6-yl} ester (48). Compound 47 (10 mg, 0.022 mmol)
was dissolved in ClCH2CH2Cl (1.2 mL) and added to mixed
anhydride 16 (prepared according to Ref. 6b; 190 mg,
0.807 mmol). NEt3 (41 mg, 0.402 mmol) and DMAP
(2.5 mg, 0.020 mmol) were added and the solution was
stirred for 40 h at room temperature and 3 h at 508C. The
solvent was evaporated under reduced pressure and the
resulting residue was purified by flash chromatography
(hexane/EtOAc 1:4) to yield compound 48 (10 mg, 75%) as
a colorless oil. Rf¼0.23 (hexane/EtOAc from 1:3 to 1:2); 1H
NMR (400 MHz, CDCl3, signal doubling due to dia-
stereomers): d¼7.63þ7.52 (d, J¼15.5 Hz, 1H), 7.49þ7.48
(s, 1H), 7.16þ7.06 (s, 1H), 6.55þ6.53 (d, J¼15.5 Hz, 1H),
6.09þ5.75 (m, 4H), 5.24 (s, 2H), 4.85–4.65 (m, 2H), 4.40–
The samples were prepared directly in 1.5 mL optical glass
cuvettes at 08C which contained aqueous ‘Mes buffer’
[0.900 mL (0.1 M MES, 1 mM EGTA, 0.5 mM MgCl2,
pH¼6.6)], GTP (10 mL, 100 mM in doubly distilled water)
and tubulin (100 mL, 8–10 mg/mL of aqueous ‘Mes
buffer’). The cuvettes were thoroughly agitated and
immediately placed in a spectrophotometer, preheated at
378C, alongside a blank sample containing aqueous ‘Mes
buffer’ (0.990 mL) and GTP (10 mL, 100 mM in doubly
distilled water) and the absorbance at l¼350 nm was
recorded. When the absorbance reached a plateau (after
15 min), CaCl2 (10 mL, 400 mM in doubly distilled water)
was added to each cuvette. After another 15 min, a
minimum absorbance was reached and the tubulin-poly-
merizing-agent in DMSO (2.5 mM) was added to the
cuvettes in portions (2, 2, 4, 12, 20 and 40 mL) every 15 min
and thoroughly shaken to give final concentrations of 0.5,
1.0, 2.0, 5.0, 10 and 20 mM, respectively (final concen-

R. Beumer et al. / Tetrahedron 59 (2003) 8803–8820
8819
Soc. 1998, 120, 8661. (c) Nicolaou, K. C.; Kim, S.;
Pfefferkorn, J.; Xu, J.; Ohshima, T.; Hosokawa, S.; Vourlou-
mis, D.; Li, T. Angew. Chem. Int. Ed. 1998, 37, 1418.
7. (a) Nicolaou, K. C.; van Delft, F.; Ohshima, T.; Vourloumis,
D.; Xu, J.; Hosokawa, S.; Pfefferkorn, J.; Kim, S.; Li, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2520. (b) Nicolaou,
K. C.; Ohshima, T.; Hosokawa, S.; van Delft, F. L.;
Vourloumis, D.; Xu, J. Y.; Pfefferkorn, J.; Kim, S. J. Am.
Chem. Soc. 1998, 120, 8674.
trations of the tubulin-polymerizing-agent in the assay). The
results were compared to the untreated control (using the
same quantities of DMSO without the tubulin-polymeriz-
ing-agent) to assess the relative change in absorbance due to
microtubule assembly. The results are presented as ED50
and ED90 which correspond to the dose of tubulin-
polymerizing-agent required to induce 50 and 90% micro-
tubule assembly (MES, 2-(morpholino)ethane sulphonic
acid; EGTA, ethyleneglycol-bis-(b-ami0noethylether)-
N,N,N0,N0-tetraacetic acid; GTP, guanosine 5 -triphosphate).
8. (a) Chen, X.-T.; Gutteridge, C. E.; Bhattacharya, S. K.; Zhou,
B.; Pettus, T. R. R.; Hascall, T.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 1998, 37, 185. (b) Chen, X.-T.; Zhou, B.;
Bhattacharya, S. K.; Gutteridge, C. E.; Pettus, T. R. R.;
Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 789. (c)
Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.;
Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 6563.
Acknowledgements
We thank the European Commission for financial support
(IHP Network grant ‘Design and synthesis of microtubule-
stabilizing anticancer agents’ HPRN-CT-2000-00018) and
for postdoctoral fellowships to R. Beumer (HPRN-CT-
9. (a) Ceccarelli, S.; Piarulli, U.; Gennari, C. Tetrahedron Lett.
1999, 40, 153. (b) Baron, A.; Caprio, V.; Mann, J. Tetrahedron
Lett. 1999, 40, 9321. (c) Carter, R.; Hodgetts, K.; McKenna, J.;
Magnus, P.; Wren, S. Tetrahedron 2000, 56, 4367. (d)
Ceccarelli, S.; Piarulli, U.; Gennari, C. J. Org. Chem. 2000,
65, 6254. (e) Xu, Q.; Weeresakare, M.; Rainier, J. D.
Tetrahedron 2001, 57, 8029. (f) Ceccarelli, S.; Piarulli, U.;
Telser, J.; Gennari, C. Tetrahedron Lett. 2001, 42, 7421. (g)
Ceccarelli, S.; Piarulli, U.; Gennari, C. Tetrahedron 2001, 57,
8531. (h) Sandoval, C.; Redero, E.; Mateos-Timoneda, M. A.;
Bermejo, F. A. Tetrahedron Lett. 2002, 43, 6521. (i)
Kaliappan, K. P.; Kumar, N. Tetrahedron Lett. 2003, 44,
379. (j) Winkler, J. D.; Quinn, K. J.; MacKinnon, C. H.;
Hiscock, S. D.; McLaughlin, E. C. Org. Lett. 2003, 5, 1805. (k)
Scalabrino, G.; Sun, X.-W.; Mann, J.; Baron, A. Org. Biomol.
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´
2000-00018), S. Ducki (HPRN-CT-2000-00018), P. Bayon
(‘Marie Curie’ HPMF-CT-2000-00838) and J. Telser
(‘Marie Curie’ HPMF-CT-1999-00001). We also like to
thank Merck (Merck’s Academic Development Program
Award to C. Gennari, 2001-02) and M.U.R.S.T. COFIN
2000 (MM03155477) for financial support. We thank Dr
Paolo Cappella and Dr Aurelio Marsiglio (Pharmacia,
Nerviano, Italy) for the cytotoxicity assays on the human
tumor cell lines.
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