Stereoselective synthesis of the monomeric unit of SCH 351448

Article abstract of DOI:10.1002/ejoc.200600106

The monomeric unit of the macrodiolide SCH 351448 has been synthesized from three building blocks. Strategic disconnections were chosen between C21-C22 (Wittig) and C10-C11 (stereoselective aldol). The cis configuration of both 2,6-disubstituted tetrahydropyran rings was established by a stereoselective cationic reduction. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600106

FULL PAPER
DOI: 10.1002/ejoc.200600106
Stereoselective Synthesis of the Monomeric Unit of SCH 351448
J. René Backes[a] and Ulrich Koert*[a]
Keywords: Stereoselective synthesis / Natural product / SCH 351448 / Tetrahydropyran
The monomeric unit of the macrodiolide SCH 351448 has
been synthesized from three building blocks. Strategic dis-
connections were chosen between C21–C22 (Wittig) and
C10–C11 (stereoselective aldol). The cis configuration of both
2,6-disubstituted tetrahydropyran rings was established by a
stereoselective cationic reduction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
sity lipoprotein (LDL) receptor promoter (Figure 1, A). Its
ionophoric properties are revealed by the X-ray-structure
of the mono sodium salt (Figure 1, B). The bioactivity of
SCH 351448 brought the compound into the synthetic
focus resulting in the total syntheses of Lee,[2]
De Brabander,[3] and Leighton.[4] Here, we report our re-
sults on an efficient, stereoselective synthesis of the mono-
meric unit of SCH 351448.
Introduction
The macrodiolide SCH 351448, which was isolated in
2000 from a Micromonospora sp.,[1] received interest be-
cause of its ability to activate transcription of the low-den-
Results and Discussion
The methyl ester 2, which was chosen as a synthetic
equivalent for the seco acid, could be assembled from three
building blocks: the phosphonium salt 3,[5] the aldehyde 4,
and the ketone 5 (Scheme 1). First, a Wittig reaction be-
tween 3 and 4 was devised for the formation of the C21–
C22 bond. Thereafter, a stereoselective aldol reaction could
be used for the formation of the C10–C11 bond. Both
building blocks 4 and 5 share a cis-2,6-disubstituted tetra-
hydropyran (THP) ring as the common motif.
Scheme 1. Retrosynthetic analysis of the monomeric unit 2, Pg =
protective group.
Figure 1. A SCH 351448; B X-ray structure of the mono sodium
salt.
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Strasse, 35032 Marburg
Starting point for the synthesis of the phosphonium
salt 3 was N,N-dimethyl-3-methoxy benzylamine (6)
E-mail: koert@chemie.uni-marburg.de
Eur. J. Org. Chem. 2006, 2777–2785
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2777

J. R. Backes, U. Koert
FULL PAPER
(Scheme 2). Lithiation of 6 and subsequent treatment with configuration of 14 was assigned by NMR based on a H2–
an excess of methyl chloroformate gave the benzylchloride H6 NOE contact. Ozonolysis of the terminal double bond
7,[5] which was converted into the phosphonium salt 3.
in 14 gave the aldehyde 4.
The synthesis of the third building block 5 required the
introduction of a geminal dimethyl group adjacent to the
THP ring. Our first synthetic route towards 5 is summa-
rized in Scheme 4. Allylation of the aldehyde 15[9] gave after
acetal cleavage the lactol 16 and subsequently the acetate 17
(Scheme 4). The Lewis acid mediated addition of the TMS-
ketene acetal 18[10] led to a mixture of the two dia-
stereomers 19/20 (cis/trans), which could be separated by
chromatography. With BF3·OEt2 and TMSOTf the unde-
sired trans compound 20 was the main isomer obtained.
The relative configurations of 19 and 20 were assigned by
NMR based NOE contacts.
Scheme 2. a) nBuLi, 5.5 equiv. ClCOOMe, CH2Cl2, –78 °C, 26 %;
b) PPh3, MeCN, reflux, 94%.
The aldehyde 4 was accessible from acetoacetic acid ester
8 (Scheme 3). Allylation of 8 followed by hydrolysis/decar-
boxylation and ketalization provided compound 9.[6] Hy-
droboration of the terminal alkene and a subsequent Swern
oxidation led to the aldehyde 10. Asymmetric Brown al-
lylation[7] of 10 gave the corresponding homoallylic alcohol.
Mosher ester analysis exhibited a 88:12 enantioselectivity.
After TIPS protection and deketalization the ketone 11 was
obtained. The next task was the alkylation of 11 with the
iodide 12.[8] Initial attempts for the direct alkylation of the
ketone (LDA, LHMDS, KHMDS, addition of HMPT)
were unsatisfying. Therefore, the way over the correspond-
ing dimethyl hydrazone was chosen, which gave the desired
product 13 in 88% overall yield. Treatment of 13 with
Et3SiH, BF3·OEt2 resulted in the cleavage of the TIPS ether
followed by a cis-selective reduction of the hemiketal inter-
mediate to yield the 2,6-disubstituted THP 14. The relative
Scheme 4. a) (–)-Ipc2BAll, Et2O, –78 °C, then NaOH/H2O2, 94%;
b) 2  HCl/THF, 30 °C, 86%; c) KHMDS, Ac2O, THF, –78 °C Ǟ
20 °C, 73%; d) 18, BF3·OEt2, TMSOTf; CH2Cl2, Et2O, THF, 30–
89%.
Scheme 3. a) i: NaOEt, AllBr; ii: NaOH, reflux; iii: HCl 56%;
b) HO(CH2)2OH, pTosOH, THF, reflux, 68%; c) BH3·THF, 0 °C,
THF, H2O2/NaOH, 92%; d) (COCl)2, DMSO, NEt3, CH2Cl2,
–78 °C, 90%; e) (–)-Ipc2BAll, Et2O, H2O2/NaOH, –78 °C, 92 %;
d) TIPSOTf, 2,6-lutidine, CH2Cl2, 98%; g) acetone, pTosOH, re-
flux, 87%; h) Me2N-NH2, TMSCl, 0 °C, 94%; i) LDA, HMPT,
THF, 12, –78 °C; Amberlyst 50, 20 °C, 94%; j) BF3·OEt2, HSiEt3,
MeCN, –35 °C, 93%; k) O3, CH2Cl2, –78 °C, PPh3, 86%.
Scheme 5. a) 18, CH2Cl2, –78 °C, 75%; b) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 °C, 99%; c) O3, CH2Cl2, –78 °C, PPh3, 82%; d) AllBpin-
acol, THF, 0 °C, e) Dess–Martin periodinane, pyridine, CH2Cl2,
0 °C Ǟ 20 °C, 72%; f) HSiEt3, BF3·OEt2, MeCN, –35 °C, 98 %,
g) PdCl2, CuCl, O2, DMF/H2O, 20 °C, 89 %.
2778
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2777–2785

Stereoselective Synthesis of the Monomeric Unit of SCH 351448
FULL PAPER
The lack of stereoselectivity in the addition of the ketene stereoselective aldol reaction with the methyl ketone 5 pro-
acetal 18 to the acetate 17 led to development of an im- ceeded with a 1,5-induction from the ketone and an anti-
proved second synthetic route for compound 5 (Scheme 5). Felkin mode with respect to the aldehyde.[13] Using Et3N as
This time, the introduction of the first stereocenter was a base only the stereoisomer 28 was obtained in 55% yield.
achieved by an asymmetric aldol reaction of the aldehyde
The stereochemical assignment of the anti-Felkin config-
21[11] and the ketene actetal 18. Using the oxazaborolid- uration in 28 was possible according to the NMR-analysis
inone 22[12] as chiral promoter the product 23 was obtained of Roush et al.[14] Table 1 shows representative chemical
in 75% yield. NMR-analysis of the corresponding Mosher shifts and coupling constants for γ-methyl-β-hydroxy
ester showed an enantioselectivity of Ͼ 95:5. Compound 23 ketones. The experimental data for 28 are J(HbHβ) = 9.5 Hz
was converted via TBS-protection and subsequent ozonoly- and J(HaHβ) Ͻ 2.5 Hz and thus indicate the anti-Felkin
sis into the aldehyde 24. The latter was allowed to react configuration.
with 2-allyl-4,4,5,5-tetramethyl-1,3-dioxa-2-borolane to
The final step of the synthesis was the stereoselective re-
yield the corresponding homoallylic alcohol which was oxi- duction of the β-hydroxy ketone 28 to the anti-1,3-diol 29
dized following the Dess–Martin protocol to the ketone 25. using NMe4B(OAc)3H (Scheme 7).[15]
A cis selective cationic reduction of 25 with Et3SiH and
BF3·OEt2 gave the 2,6-disubstituted THP 19 in 98% yield
as the exclusive stereoisomer. The Wacker oxidation of 19
led to the desired methyl ketone 5 in 89% yield.
Having all three building blocks at hand, we addressed
their assembly into the target compound (Scheme 6). First,
the Wittig reaction of the phosphonium salt 3 with the alde-
hyde 4 was used for the formation C21–C22 bond. The sub-
sequent hydrogenation of the double bond and the simulta-
neous hydrogenolysis of the benzyl ether gave the alcohol
26 in 83% yield from 4. A Dess–Martin oxidation of 26
produced the aldehyde 27. The following boron mediated
Scheme 7. a) Me4NB(OAc)3H, AcOH, Me2CO, 20 °C, 85 %.
Conclusions
An efficient, stereoselective synthesis of the monomeric
unit of the macrodiolide SCH 351448 has been achieved. A
modular strategy was applied with three building blocks 3,
4 and 5 and disconnections between C21–C22 (Wittig) and
C10–C11 (stereoselective aldol). The cis-2,6-disubstituted
tetrahydropyran rings were synthesized by a stereoselective
cationic reduction. This work paves the way for a total syn-
thesis of the natural product provided that a protective
group differentiation between OH(C9) and OH(C11) will
be possible. Derivatives of SCH 351448 with interesting ef-
fects on blood-cholesterol level should also be accessible.
Experimental Section
General: All reactions sensitive to air or moisture were conducted
in flame-dried glassware under an atmosphere of dry Argon. THF
and Et2O were distilled from sodium benzophenone. CH2Cl2, tolu-
ene, hexanes, pyridine, and Et3N were distilled from CaH2. All
starting materials and reagents were used as received unless noted
Scheme 6. a) LiHMDS, THF, –78 °C, 84%; b) H2, Pd(OH)2/C,
MeOH, 99%; c) Dess–Martin periodinane, pyridine, CH2Cl2, 0 °C
Ǟ 20 °C, 84%; d) 5, NEt3, Bu2BOTf, then 27, Et2O, 55 %.
Table 1. J (Ha/Hb, Hβ) in γ-methyl-β-hydroxy ketones from Roush et al.[14]
syn-Felkin
Ha
Hb
anti-Felkin
Ha
Hb
δ [ppm]
J [Hz] with β-H
2.64–2.88
7.8–10.0
2.20–2.52
1.1–5.4
δ [ppm]
J [Hz] with β-H
2.58–2.84
1.5–2.8
2.16–2.65
9.2–12.5
Eur. J. Org. Chem. 2006, 2777–2785
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2779

J. R. Backes, U. Koert
FULL PAPER
otherwise. Thin layer chromatography was performed on glass-sup-
ported Merck silica gel 60 F254 plates. Spots were visualized by
UV light and by heat staining with 2% molybdophosphoric acid
in ethanol. Column chromatography was performed on Merck sil-
ica gel 60 (63–200 µm). The eluent for the preparative separations
was chosen according to the TLC eluent. Melting points were mea-
sured with a Büchi Melting Point Apparatus and are not corrected.
of the combined organic layers with NaHCO3 and brine (100 mL
each), drying with MgSO4 and fractional distillation yielded the
corresponding hexenone (37.8 g, 385 mmol, 56%) as a colourless
liquid, which was dissolved in toluene (200 mL) and treated with
ethylene glycol (25 mL, 462 mmol) and pTosOH (1.33 g, 7.7 mmol)
and refluxed at a Dean–Stark apparatus. The solution was washed
with NaHCO3 (100 mL) and H2O (100 mL), dried with MgSO4
and fractional distilled to yield the ketal 9 (35.9 g, 253 mmol, 66%)
1
IR-Spectra were measured with a Bruker FT-IR spectrometer. H-
and 13C-NMR spectra were recorded with Bruker spectrometers
as a
colourless liquid. b.p. 75 °C (1013 mbar). 1H NMR
ARX-200, AC-300, AV-300, AMX-400, DRX-400, DRX-500, (300 MHz): δ = 1.29 (s, 3 H, HMe), 1.67–1.76 (m, 2 H, HCH2),
DRX-600. CDCl3 was used as normal solvent. TMS was used as
internal standard. Optical rotations: Perkin–Elmer polarimeter
241, cuvette path length 10 cm, T = 22 °C. CHCl3 for spectroscopy
was filtered through basic aluminium oxide before use. Microanaly-
sis: CHN rapid, Heraeus. HRMS: Finnigan LTQ FT (ESI). MTBE
= tert-butyl methyl ether.
2.09–2.14 (m, 2 H, HCH2), 3.87–3.95 (m, 4 H, O-CH2-CH2-O),
4.91 (dd, J = 10.2, 1.5 Hz, 1 H, H2C=C), 4.99 (dd, J = 17.1, 1.5 Hz,
1 H, H2C=CHR), 5.81 (ddt, J = 17.1, 10.2, 6.6 Hz, 1 H,
H2C=CHR) ppm. 13C NMR (75 MHz): δ = 23.8, 28.3, 38.2, 64.6
(2C), 109.7, 114.1, 138.4 ppm.
Aldehyde 10. Hydroboration: Olefin 9 (10.0 g, 70.3 mmol) was dis-
solved in THF (100 mL) at 0 °C and BH3·THF (23.4 mL, 1  in
THF, 23.4 mmol) was added dropwise. The solution was warmed
to 20 °C and stirred for 3 h, whereafter it was cooled to 0 °C and
treated with 30% H2O2/3  NaOH (70 mL, 1:3). After vigorous
stirring at 20 °C for 1 h the layers were separated and the aqueous
layer was extracted with MTBE (5×50 mL). The combined organic
layers were dried with MgSO4 and the solvent was removed in
vacuo. Purification by silica gel chromatography gave the corre-
sponding alcohol (10.3 g, 64.3 mmol, 91%) as a colourless liquid;
b.p. 96 °C (1013 mbar). 1H NMR (200 MHz): δ = 1.31 (s, 3 H,
HMe), 1.40–1.72 (m, 6 H, HAlk), 3.64 (t, J = 6.1 Hz, 2 H, CH2-
OH), 3.90–3.97 (m, 4 H, O-C2H4-O) (OH not detected) ppm. 13C
NMR (50 MHz): δ = 20.2 (CMe), 23.7, 32.8, 38.8 (3×CH2), 62.8
(CH2OH), 64.6 (2C, O-C2H4-O), 110.0 (Cq) ppm. HRMS (EI)
calcd. 160.1094 [M+]; found 160.1089. Swern Oxidation: To oxalyl
chloride (1.53 g, 12.0 mmol) in CH2Cl2 (150 mL) at –78 °C was
added dropwise DMSO (1.88 g, 24.0 mmol) in CH2Cl2 (5 mL). The
reaction mixture was stirred for 10 min before the alcohol (1.75 g,
10.9 mmol) in CH2Cl2 (5 mL) was added dropwise. After 5 min
stirring at –78 °C, Et3N (5.53 g, 55.0 mmol) was added. 5 min later
the solution was warmed to 20 °C. It was poured into H2O
(100 mL). The aqueous layer was extracted with CH2Cl2
(3×75 mL) and the combined organic layers were washed with
brine (100 mL) and dried with MgSO4. The solvent was removed
and the residue purified by chromatography to yield the aldehyde
10 (1.55 g, 9.80 mmol, 90%) as a colourless oil. Rf = 0.31 (50%
General Procedure 1 (GP1). Ozonolysis: At –78 °C ozone was
bubbled through a solution of the olefin (5 g/100 mL) in CH2Cl2
until the colour change to blue was observed. After the removal of
excess O3 with O2, 1 equiv. of solid PPh3 was added and the reac-
tion was warmed to 20 °C. The solvents were removed and the
residue purified by chromatography on silica.
Methyl 2-Chloromethyl-6-methoxybenzoate (7): A solution of N,N-
dimethyl-3-methoxybenzylamine (15.0 g, 90.8 mmol) at –10 °C was
treated with nBuLi (49 mL, 2.5  in hexane, 123 mmol) and stirred
for 30 min. At –78 °C, methyl chloroformate (39 mL, 500 mmol)
was added. The solution was kept at –78 °C for another 30 min
and warmed to 20 °C overnight. Washing of the solution with water
(2×200 mL), extraction of the aqueous layer with CH2Cl2
(2×150 mL), drying of the combined organic layers with MgSO4
and fractional distillation afforded the methyl ester 7 (5.00 g,
23.3 mmol, 26%) as
a colourless liquid; b.p. 108–115 °C
(1013 mbar); Rf = 0.26 (17% MTBE in pentane). 1H NMR
(300 MHz): δ = 3.83 (s, 3 H, OMe), 3.95 (s, 3 H, COOMe), 4.59
(s, 2 H, Bn), 6.91 (d, J = 8.4 Hz, 1 H, H5), 7.02 (d, J = 7.8 Hz, 1
H, H3), 7.35 (dd, J = 8.4, 7.8 Hz, 1 H, H4) ppm. 13C NMR
(75 MHz): δ = 43.3 (CBn), 52.4 (COMe), 56.1 (CCOOMe), 111.5
(C3), 121.7 (C5), 123.0 (C2), 131.0 (C4), 136.2 (C1), 156.8
(CCOMe), 167.4 (CCOOR) ppm. C10H11ClO3 (214.65): calcd. C
55.96, H 5.17; found C 55.84, H 5.22.
Phosphonium Chloride 3:
A solution of chloride 7 (2.00 g,
1
9.32 mmol) and triphenylphosphane (2.40 g, 9.32 mmol) in MeCN
(15 mL) was refluxed for 72 h. After removal of the solvent the
residue was triturated with Et2O (20 mL) to yield the phosphonium
salt 8 (4.20 g, 8.81 mmol, 94%) as a transparent solid. m.p. 211 °C
CH2Cl2/n-hexane; 1H NMR (500 MHz, 31P-decoupled): δ = 3.46
(s, 3 H, OMe), 3.68 (s, 3 H, COOMe), 5.30 (d, J = 14.4 Hz, 2 H,
Bn), 6.84 (dd, J = 8.3, 2.1 Hz, 1 H, HAr), 6.89 (dd, J = 7.7, 2.4 Hz,
1 H, HAr), 7.16 (ddd, J = 8.3, 7.7, 0.6 Hz, 1 H, HAr), 7.24–7.56
(m, 12 H, PPh3), 7.68–7.72 (m, 3 H, PPh3) ppm. 13C NMR
(125 MHz, 31P-decoupled): δ = 28.8, 52.1, 56.3, 112.2, 117.6 (3C),
123.1, 123.8, 128.4, 129.9 (6C), 132.0, 134.1 (6C), 134.9 (3C), 158.4,
167.1 ppm. 31PNMR (202 MHz): δ = 22.36 ppm.
MTBE in hexane); b.p. 68 °C (0.01 mbar). H NMR (200 MHz): δ
= 1.27 (s, 3 H, CH3), 1.56–1.78 (m, 4 H, 2×CH2), 2.42 (td, J =
6.8, 1.4 Hz, 2 H, CH2CHO), 3.85–3.96 (m, 4 H, O-C2H4-O), 9.71
(t, J = 1.4 Hz, 1 H, CHO) ppm. 13C NMR (50 MHz): δ = 16.5
(Me), 23.7, 38.2 (2×CH2), 43.7 (CH2CHO), 64.5 (2C, O-C2H4-O),
109.5 (Cq), 202.3 (CHO) ppm.
Methyl Ketone 11. Brown Allylation: (–)-Bis(isopinocampheyl)-
methoxyborane (4.67 g, 14.7 mmol) in Et2O 70 mL was cooled to
0 °C and treated with allylmagnesium bromide (7.8 mL, 1.63  in
Et2O, 12.7 mmol). After stirring for 45 min, the solution was co-
oled to –78 °C, the solids deposited and the supernatant was trans-
ferred through a cannula to aldehyde 10 (1.55 g, 9.77 mmol) in
Et2O (20 mL) at –78 °C. After 1.5 h the solution was warmed to
20 °C and poured into 30% H2O2/3  NaOH (75 mL, 1:2). After
1 h at 20 °C and 3 h at 40 °C the aqueous layer was extracted with
MTBE (3×50 mL), the combined organic layers were dried with
MgSO4 and the solvents removed in vacuo. Chromatographic puri-
fication delivered the homoallyl alcohol (1.80 g, 8.99 mmol, 92%)
2,2-Ethylendioxy-5-hexene (9):[6] To a solution of acetoacetic acid
ester 8 (117 mL, 0.92 mol) in ethanol (300 mL) sodium (17.3 g,
0.76 mol) was added and the resulting solution was cooled to 0 °C.
Allylbromide (59 mL, 0.69 mol) was added over 30 min and the
solution was stirred for 3 h at 20 °C and 4 h at 60 °C. The suspen-
sion was filtered and the solvent removed in vacuo. The residue
was dissolved in NaOH (200 mL, 10% aq.) and heated to 60 °C for as a colourless oil. Rf = 0.17 (50% MTBE in hexane). 1H NMR
3 h. After cooling to 20 °C, the solution was acidified to pH Ͻ 3.
Extraction of the aqueous layer with Et2O (3×100 mL), washing
(500 MHz): δ = 1.32 (s, 3 H, CH3), 1.42–1.71 (m, 7H, 3×CH2,
OH), 2.15 (dt, J = 14.0, 7.9 Hz, 1 H, CH2-CH=C), 2.30 (dddt, J =
2780
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2777–2785

Stereoselective Synthesis of the Monomeric Unit of SCH 351448
FULL PAPER
= 0.50 (10% MTBE in hexane). H NMR (400 MHz): δ = 0.92 (d,
1
14.0, 6.5, 4.3, 1.3 Hz, 1 H, CH2-CH=C), 3.63–3.68 (m, 1 H,
CHOH), 3.90–3.97 (m, 4 H, O-C2H4-O), 5.11–5.15 (m, 2 H, J = 6.6 Hz, 3 H, CH3), 1.06 (br. s, 21 H, TIPS), br. 1.38–1.53 (m,
H2C=CH-), 5.78–5.87 (m, 1 H, H2C=CH-) ppm. 13C NMR 3 H, 2×H8, H3), 1.57–1.65 (m, 2 H, H7), 1.68–1.81 (m, 2 H, H3,
(125 MHz): δ = 20.2 (CMe), 23.7, 36.9, 39.0 (C3×CH2), 41.9
H2), 2.22–2.30 (m, 2 H, H10), 2.32–2.48 (m, 4 H, H6,H4), 3.25–
(CCH2-CH=C), 64.6 (2C, O-C2H4-O), 70.6 (CC-O), 110.0 (Cq), 3.33 (m, 2 H, H1), 3.87 (quint, J = 5.4 Hz, 1 H, H9), 4.49 (s, 2 H,
118.1 (CH =C-), 134.8 (CH =C-) ppm. IR: ν = 3445 (br. s), 3075
OBn), 5.01–5.08 (m, 2 H, H12), 5.82 (ddt, J = 17.2, 10.2, 7.1 Hz,
1 H, H11), 7.25–7.37 (m, 5 H, Bn) ppm. 13C NMR (100 MHz): δ
= 12.6 (3C, TIPS), 17.0 (CH3), 18.2 (6C, TIPS), 19.2 (C7), 27.7
(C3), 33.1 (C2), 35.9 (C8), 40.3 (C4), 41.2 (C10), 42.9 (C6), 71.7
(C9), 73.0 (Bn), 75.6 (C1), 116.8 (C12), 127.5 (CarH), 127.5 (2C,
˜
2
2
(m), 2947 (s), 1641 (m), 1220 (s), 1142 (s), 1065 (br. s) cm–1. [α]D
=
+4.8, c = 4.04. C11H20O3 (200.27): calcd. C 65.97, H 10.07; found
C 65.81, H 10.10. TIPS-Protection: TIPSOTf (9.4 mL, 67.4 mmol)
was added dropwise to a solution of the alcohol (5.4 g, 27.0 mmol)
and 2,6-lutidine (7.2 mL, 67.4 mmol) in CH2Cl2 (150 mL) at 0 °C. Car), 128.3 (2C, Car), 134.9 (Car, q), 139.0 (C11), 211.1 (C=O) ppm.
After stirring for 1 h at 20 °C, the reaction mixture was poured into
NH4Cl (100 mL). The aqueous layer was extracted with MTBE
(3×75 mL), the combined organic layers were dried with MgSO4
evaporated and purified by chromatography to yield the silyl ether
ketal (9.40 g, 26.3 mmol, 98%) as a colourless oil. Rf = 0.40 (10%
MTBE in hexane). 1H NMR (300 MHz): δ = 1.06 (br. s, 21 H,
TIPS), 1.31 (s, 3 H, CH3), 1.38–1.54 (m, 4 H, 2×CH2), 1.57–1.66
(m, 2 H), 2.20–2.35 (m, 2 H, CH2CH=CH2), 3.82–3.97 (m, 5 H,
O-C2H4-O, R2CHOR), 5.00–5.08 (m, 2 H, CH2=CH-), 5.77 (ddt,
J = 17.2, 10.2, 7.1 Hz, 1 H, CH2=CH-) ppm. 13C NMR (75 MHz):
δ = 12.6 (3C, TIPS), 18.2 (6C, TIPS), 19.5 (Me), 23.7, 36.7, 39.4
(3×CH2), 41.3 (C-CH=C), 64.6 (2C, O-C2H4-O), 71.9 (CO), 110.1
(Cq), 116.7 (CH=CH2), 135.1 (CH=CH2) ppm. [α]D = +5.25, c =
2.42 (CHCl3). HR-MS (ESI) [C20H40SiO3 +Na]+ calcd. 357.2819;
found 357.2824. Deketalization: Silyl ether ketal (2.99 g,
8.37 mmol) and pTosOH (117 mg) were dissolved in acetone/H2O
(125 mL, 9:1), and refluxed until TLC control showed complete
conversion. After washing with NaHCO3 (50 mL), the aqueous
layer was extracted with MTBE (3×50 mL), the combined organic
layers were dried with MgSO4 and after removal of solvents in
vacuo chromatographic purification yielded the ketone 11 (2.27 g,
7.27 mmol, 87%) as a colourless oil. Rf = 0.36 (10% MTBE in
IR: ν = 3071 (w), 3030 (w), 2942 (s), 2866 (s), 1715 (s), 1641 (w),
˜
1460 (s), 1103 (s), 1063 (s), 998 (m) cm–1. [α]D = +0.70, c = 2.00
(CHCl3). C29H50O3Si (474.79): calcd. C 70.36, H 10.61; found C
70.31, H 10.61.
(2R,6S,3ЈS)-2-Allyl-6-(4-benzyloxy-3-methylbutyl)tetrahydropyran
(14) cis-THP Ether (14): Triethylsilane (2.57 g, 22.09 mmol) and
dodecenone 13 (2.62 g, 5.52 mmol) were dissolved in MeCN
(40 mL) at –35 °C. Boron trifluoride–diethyl ether (1.57 g,
11.05 mmol) was added. The solution was warmed to 25 °C and
poured into water (40 mL). The aqueous layer was extracted with
MTBE and (3×40 mL) and the combined organic layers were dried
with MgSO4. Chromatographic purification gave the cis THP 14
(1.55 g, 5.12 mmol, 93%) as a colourless liquid. Rf = 0.63 (10%
1
MTBE in hexane). H NMR (500 MHz): δ = 0.94 (d, J = 6.9 Hz,
3 H, Me), 1.10–1.20 (m, 3 H, H2Ј, H3, H5), 1.42–1.51 (m, 3 H,
2H1Ј, H4), 1.54–1.60 (m, 3 H, H2Ј, H3, H5), 1.74–1.84 (m, 2 H,
H3Ј, H4), 2.14 (ddd, J = 14.0, 7.3, 6.4 Hz, 1 H, HAll), 2.28 (ddd,
J = 14.0, 6.7, 6.6 Hz, 1 H, HAll), 3.19–3.25 (m, 1 H, H6), 3.24 (dd,
J = 9.1, 6.8 Hz, 1 H, H4Ј), 3.30 (dtd, J = 11.0, 6.4, 1.8 Hz, 1 H,
H2), 3.35 (dd, J = 9.1, 5.8 Hz, 1 H, H4Ј), 4.50 (s, 2 H, Bn), 5.01
(d, J = 10.1 Hz, 1 H, HAll), 5.06 (d, J = 17.2 Hz, 1 H, HAll), 5.85
(dddd, J = 17.2, 10.1, 7.3, 6.7 Hz, 1 H, HAll), 7.25–7.35 (m, 5 H,
Bn) ppm. 13C NMR (75 MHz): δ = 17.1 (CMe), 23.7 (C4), 29.5,
31.2 (C3,5), 31.5 (C2Ј), 33.5 (C3Ј), 33.9 (C1Ј), 41.0 (CAll), 72.9
(Bn), 75.9 (C4Ј), 77.4 (C2), 78.3 (C6), 116.2 (CAll), 127.4 (CarH),
127.5 (2CarH), 128.3 (2CarH), 135.4 (CAll), 138.9 (Car, q) ppm. IR:
1
hexane). H NMR (400 MHz): δ = 1.06 (br. s, 21 H, TIPS), 1.39–
1.54 (m, 2 H, H4), 1.57–1.68 (m, 2 H, H5), 2.12 (s, 3 H, H1), 2.23–
2.34 (m, 2 H, H3), 2.37–2.46 (m, 2 H, H7), 3.85–3.90 (m, 1 H, H6),
5.01–5.08 (m, 2 H, H9), 5.77 (ddt, J = 17.2, 10.2, 7.1 Hz, 1 H, H8)
ppm. 13C NMR (100 MHz): δ = 12.6 (3C, TIPS), 18.2 (6C, TIPS),
19.1 (C4), 29.7 (C5), 35.8 (C1), 41.2 (C3), 44.0 (C7), 71.9 (C6),
116.9 (C9), 134.8 (C8), 208.9 (C=O) ppm. C18H36O2Si (312.56):
calcd. C 69.17, H 11.61; found C 68.87, H 11.70.
ν = 3069 (m), 3030 (m), 2934 (s), 2852 (s), 1641 (w), 1455 (m), 1368
˜
(m), 1199 (m), 1087 (s), 911 (m), 736 (s), 697 (s) cm–1. C20H30O2
(302.45): calcd. C 79.42, H 10.00; found C 79.36, H 10.01. HR-MS
(ESI) [C20H30O2 +Na]+ calcd. 325.2144; found 325.2142.
THP-Aldehyde 4. Ozonolysis: Following GP1 the alkene 14
(530 mg, 1.75 mmol) was converted into aldehyde 4 (458 mg,
1.50 mmol, 86%). Rf = 0.30 (10% MTBE in hexane). 1H NMR
(300 MHz): δ = 0.92 (d, J = 6.8 Hz, 3 H, Me) 1.05–1.32 (m, 3 H,
H2Ј, 3, 5), 1.38–1.63 (m, 6 H, 2H1Ј, 2Ј, 3–5), 1.69–1.78 (m, 1 H,
H3Ј), 1.80–1.88 (m, 1 H, H4), 2.43 (ddd, J = 16.2, 4.6, 2.2 Hz, 1
H, H1ЈЈ), 2.58 (ddd, J = 16.2, 8.2, 2.7 Hz, 1 H, H1ЈЈ), 3.22 (dd, J
= 9.1, 6.8 Hz, 1 H, H4Ј), 3.16–3.34 (m, 1 H, H2), 3.32 (dd, J = 9.1,
6.0 Hz, 1 H, H4Ј), 3.83 (dddd, J = 10.9, 8.2, 4.6, 2.0 Hz, 1 H, H6),
4.49 (s, 2 H, Bn), 7.09–7.37 (m, 5 H, Ar), 9.79 (dd, J = 2.2, 2.7 Hz,
1 H, CHO) ppm. 13C NMR (125 MHz): δ = 17.1 (Me), 23.5 (C4),
29.5, 31.1, 31.5 (C5), 33.4 (C3Ј), 33.7, 50.0 (C1ЈЈ), 72.3 (Bn), 73.1
(C2), 75.8 (C2Ј), 78.5 (C5), 127.4 (CarH), 127.5 (2Car), 128.3 (2Car),
(2S,9R)-1-Benzyloxy-2-methyl-9-triisopropylsiloxy-11-dodecen-5-
one (13). Hydrazone Formation: To a solution of ketone 11 (2.48 g,
7.93 mmol) in N,N-dimethylhydrazine (20 mL) at 0 °C was added
dropwise chlorotrimethylsilane (1.30 g, 11.9 mmol). The solution
was kept at 0 °C for 30 min and not converted hydrazine was vola-
tilised in an argon stream. The residue was dissolved in a small
amount of solvent and filtered through a short pad of silica gel to
give recovered starting material (213 mg) and hydrazone (2.43 g,
6.84 mmol, 94 %). Alkylation: To freshly prepared LDA
(5.70 mmol) in THF (20 mL) at –78 °C was added the hydrazone
(2.04 g, 5.70 mmol) in THF (5 mL) over 5 min. The solution was
kept at –78 °C for 45 min and treated successively with HMPT
(2.04 g, 11.4 mmol) in THF (5 mL) and iodide 12 in THF (5 mL).
The solution was kept at –78 °C for additional 15 min and then
allowed to reach 20 °C during 3 h. The reaction mixture was
poured into NH4Cl (45 mL). The aqueous phase was extracted
with MTBE (3×30 mL), the combined organic layers dried with
MgSO4 and the solvents removed in vacuo. Hydrazone Cleavage:
The residue was dissolved in acetone (30 mL). Amberlyst 15
(1.00 g) was added and the suspension was vigorously stirred for
1 h. The filtrate was concentrated and purified by chromatography
to give ketone 13 (2.68 g, 5.64 mmol, 94%) as a colourless oil. Rf
138.8 (Car, q), 201.8 (CHO) ppm. IR: ν = 3063 (w), 3030 (w), 2934
˜
(s), 2854 (s), 2724 (m), 1726 (s), 1456 (m), 1370 (m), 1200 (m), 1099
(s), 739 (m), 699 (m) cm–1. [α]D = +3.7, c = 2.00 (CHCl3). HR-MS
(ESI) [C19H28O3 +Na]+ calcd. 327.1936; found 327.1934.
(6S)-6-Allyltetrahydropyran-2-ol 16. Allylation: To a solution of
(+)-diisopinocampheylmethoxyborane (10.2 g, 31.2 mmol) at 0 °C
in Et2O (140 mL) was added a solution of allylmagnesium bromide
(16.7 mL, c = 1.67  in Et2O, 27.5 mmol). After 45 min stirring at
0 °C the solution was cooled to –78 °C and aldehyde 15[10] (3.00 g,
Eur. J. Org. Chem. 2006, 2777–2785
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2781

J. R. Backes, U. Koert
FULL PAPER
20.8 mmol) in Et2O (10 mL) was added dropwise. The reaction was
kept at –78 °C for 1.5 h and quenched with a mixture of 30% H2O2/
H2b), 1.19–1.30 (m, 1 H), 1.24 (t, J = 7.1 Hz, 3 H, OEt), 1.42–1.56
(m, 3 H), 1.82–1.88 (m, 1 H), 2.11 (dt, J = 13.9, 6.7 Hz, 1 H, H8),
3 NaOH (150 mL, 1:2). Stirring for 30 min at 20 °C, extraction of 2.21 (dt, J = 13.9, 6.9 Hz, 1 H, H8), 3.31 (dddd, J = 11.0, 7.1, 5.4,
the aqueous layer with Et2O (3×75 mL), drying of the combined
organic layers with MgSO4 and subsequent column chromatog-
raphy of the crude product delivered the homoallyl alcohol (3.65 g,
19.6 mmol, 94%) as a colourless oil. Rf = 0.15 (50% MTBE in
1.7 Hz, 1 H, H7), 3.50 (dd, J = 11.4, 1.9 Hz, 1 H, H3), 4.09 (dq, J
= 10.8, 7.1 Hz, 1 H, OEt), 4.14 (dq, J = 10.8, 7.1 Hz, 1 H, OEt),
4.97 (dd, J = 10.2, 1.5 Hz, 1 H, H10), 5.01 (dd, J = 17.2, 1.5 Hz,
1 H, H10), 5.78 (dddd, J = 17.2, 10.2, 6.9, 6.7 Hz, 1 H, H9) ppm.
hexane). 1H NMR (200 MHz): δ = 1.43–1.75 (m, 6 H, H4–H6), 13C NMR (125 MHz): δ = 14.2 (OEt), 20.4 (C2a), 21.0 (C2b), 23.6,
2.06–2.38 (m, 2 H, H8), 3.66 (br. s, 1 H, H7), 3.78–4.04 (m, 4 H, 25.1, 31.1 (C4–C6), 40.8 (C8), 46.5 (C2), 60.2 (OEt), 77.7 (C7),
O-C2H4-O), 4.86 (t, J = 4.63 Hz, 1 H, H3), 5.08–5.19 (m, 2 H, 82.2(C3), 115.9 (C10), 135.5 (C9), 177.0 (C1) ppm. [α]D = +5.4, c
H10), 5.82 (dddd, J = 17.6, 9.6, 7.9, 6.4 Hz, 1 H, H9) ppm. 13C
NMR (50 MHz): δ = 20.0, 33.6, 36.4 (C4–C6), 41.8 (C8), 64.7 (C7),
70.4 (2C, O-C2H4-O), 104.4 (C3), 117.9 (C10), 134.8 (C9) ppm.
[α]D = +0.40, c = 1.00 (CHCl3). HRMS (EI) calcd. 186.1250 [M+];
found 186.1209. Lactol Formation: The homoallyl alcohol (0.90 g,
4.83 mmol) was dissolved in THF/2  HClaq (60 mL, 5:1) and
stirred at 30 °C for 8 h. NaHCO3 (30 mL) was added and the aque-
ous layer was extracted with MTBE (3 ×30 mL). Drying of the
combined organic layers with MgSO4 and subsequent column
chromatography furnished the lactol 16 (590 mg, 41.5 mmol, 86%)
as a colourless liquid. Rf = 0.40 (50% MTBE in hexane). 1H NMR
(200 MHz): δ = 1.10–2.00 (m, 6 H), 2.10–2.40 (m, 2 H), 3.39 (dtd,
J = 11.3, 6.2, 1.8 Hz, 1 H, α-ds), 3.63 (br. s, 1 H, β-OH), 3.94 (dtd,
J = 11.4, 6.3, 1.7 Hz, 1 H, β-ds), 4.35 (br. s, 1 H, α-OH), 4.65 (dd,
J = 6.4, 4.7 Hz, 1 H, α-ds), 4.99–5.09 (m, 2 H), 5.19–5.30 (m, 1 H,
β-ds), 5.67–5.90 (m, 1 H) ppm. 13C NMR (75 MHz): δ = 17.7 (β),
22.3 (α), 30.1 (β), 30.3 (α), 31.1 (β), 32.9 (α), 40.3 (α), 40.5 (β), 68.2
(β), 75.8 (α), 91.7 (β), 96.4 (α), 116.7 (β), 116.9 (α), 134.5 (α), 134.7
= 2.38 (CHCl3). C14H24O3 (240.34): calcd. C 69.96, H 10.07; found
C 70.10, H 10.11.
(2ЈS,6ЈS)-2-(6Ј-Allyl-2Ј-tetrahydropyranyl)-2-methylethylpropionate
1
(20): Rf = 0.62 (10% MTBE in hexane). H NMR (300 MHz): δ =
1.09 (s, 3 H, H2a), 1.15 (s, 3 H, H2b), 1.25 (t, J = 7.1 Hz, 3 H,
OEt), 1.29–1.38 (m, 1 H), 1.42–1.53 (m, 2 H), 1.61–1.69 (m, 3 H),
2.26 (dt, J = 14.2, 7.4 Hz, 1 H, H8), 2.55 (ddd, J = 14.2, 7.4, 6.5 Hz,
1 H, H8), 3.77 (dd, J = 11.4, 1.8 Hz, 1 H, H3), 3.93–3.99 (m, 1 H,
H7), 4.09 (dq, J = 10.5, 7.1 Hz, 1 H, OEt), 4.14 (dq, J = 10.5,
7.1 Hz, 1 H, OEt), 5.01 (d, J = 10.3 Hz, 1 H, H10), 5.05 (d, J =
17.2 Hz, 1 H, H10), 5.76 (dddd, J = 17.2, 10.3, 7.4, 6.5 Hz, 1 H,
H9) ppm. 13C NMR (50 MHz): δ = 14.6, 18.8, 20.5, 21.2, 25.8,
27.7, 34.4, 46.8, 60.9, 73.3, 76.8, 116.4, 135.9, 177.1 ppm.
Hydroxy Ester 23: A solution of N-Tos--valine (25.4 g, 93.7 mmol)
in CH2Cl2 (250 mL) was treated with borane/THF solution
(80 mL, 1  in THF, 80 mmol). After 30 min at 0 °C and 30 min at
20 °C the solution was cooled to –78 °C. The aldehyde 21 (8.00 g,
81.5 mmol) and subsequently TMS-ketene acetal 18 (16.5 g,
89.7 mmol) were added dropwise. After 30 min pH7 buffer (75 mL)
was added. The reaction mixture was vigorously stirred for 15 min
and poured into a two-layer system of NaCl (150 mL) and MTBE
(75 mL). The layers were separated and the aqueous layer was ex-
tracted with MTBE (3×100 mL). The combined organic layers
were dried with MgSO4. Chromatographic purification yielded the
alcohol 23 (9.12 g, 42.6 mmol, 52%) and its TMS ether (5.33 g,
18.6 mmol, 23%) as colourless liquids. Acidic treatment converted
the TMS ether into 23.
Hydroxy Ester 23: Rf = 0.16 (17% MTBE in hexane). 1H NMR
(500 MHz): δ = 1.16 (s, 3 H, H2a), 1.19 (s, 3 H, H2b), 1.27 (t, J =
7.1 Hz, 3 H, OEt), 1.27–1.32 (m, 1 H), 1.39–1.50 (m, 2 H), 1.66–
1.74 (m, 1 H), 2.02–2.15 (m, 2 H, H6), 2.44 (d, J = 7.0 Hz, 1 H,
OH), 3.60 (dd, J = 10.5, 7.0, 1.7 Hz, 1 H, H3), 4.16 (q, J = 7.1 Hz,
2 H, OEt), 4.95 (bd, J = 10.3 Hz, 1 H, H8), 5.01 (dq, J = 17.1,
1.6 Hz, 1 H, H8), 5.81 (ddt, J = 17.1, 10.3, 6.7 Hz, 1 H, H7) ppm.
13C NMR (125 MHz): δ = 14.1 (OEt), 20.4 (C2a), 22.4 (C2b), 25.9,
31.1, 33.(C6), 47.0 (C2), 60.6 (OEt), 76.6 (C3), 114.6 (C7), 138.7
(C8), 177.7 (COOR) ppm. [α]578 = +15.00, c = 3.06 (CHCl3).
C12H22O3 (214.30): calcd. C 67.26, H 10.35; found C 67.07, H
10.44. TMS Ether of 23: Rf = 0.40 (5% MTBE in hexane). 1H
NMR (500 MHz): δ = 0.11 (s, 9 H, TMS), 1.07 (s, 3 H, H2a), 1.14
(s, 3 H, H2b), 1.25 (t, J = 7.13 Hz, 3 H, OEt), 1.28–1.40 (m, 3 H),
1.51–1.60 (m, 1 H), 1.97–2.12 (m, 2 H, H6), 3.88 (dd, J = 8.8,
2.3 Hz, 1 H, H3), 4.11 (dq, J = 11.0, 7.1 Hz, 1 H, OEt), 4.17 (dq,
(β) ppm. IR: ν = 3405 (br. s), 1031 (s), 980 (s), 914 (s) cm–1. [α]
˜
D
= +24.4, c = 3.20 (CHCl3).
(6S)-2-Acetoxy-6-allyltetrahydropyran (17): To the lactol 16
(380 mg, 2.70 mmol) in THF (10 mL) was added at –78 °C
KHMDS (559 mg, 3.20 mmol) in THF (10 mL) and after 15 min
Ac2O (0.30 mL, 2.80 mmol). After stirring for 60 min at –78 °C the
reaction was warmed to 20 °C and quenched with NH4Cl (15 mL).
The aqueous layer was extracted with Et2O (3×15 mL) and the
combined organic layers were dried with Na2SO4. Purification by
silica gel chromatography yielded the acetate 17 (356 mg,
1.93 mmol, 73%) as a colourless liquid. Rf = 0.47 (50% MTBE in
hexane) 1H NMR (500 MHz): δ = 1.15–1.26 (m, 1 H), 1.40–1.61
(m, 3 H), 1.75–1.91 (m, 2 H), 2.08 (s, 3 H), 2.17–2.25 (m, 1 H),
2.33–2.40 (m, 1 H), 3.56 (dtd, J = 10.9, 6.7, 2.0 Hz, 1 H), 5.02 (d,
J = 10.0 Hz, 1 H), 5.06 (d, J = 17.1 Hz, 1 H), 5.63 (dd, J = 9.5,
2.1 Hz, 1 H), 5.79 (ddt, J = 17.1, 10.0, 6.7 Hz, 1 H) ppm. 13C NMR
(125 MHz): δ = 21.2, 21.5, 29.6, 29.8, 40.1, 76.5, 94.8, 117.0, 134.2,
169.3 ppm.
(2ЈS,6ЈR)-2-(6Ј-Allyl-2Ј-tetrahydropyranyl)-2-methylethylpropionate
(19): A solution of the acetate 17 in the given solvent at –78 °C was
subsequently treated with 2 equiv. of the ketene acetal 18 and
1 equiv. of Lewis acid (Table 2). The reaction was quenched with
pH7 buffer and the aqueous layer extracted with Et2O. Drying of
the combined organic layers with MgSO4, and chromatographic
purification led to the cis THP 19 and the trans THP 20.
(2ЈR,6ЈS)-2-(6Ј-Allyl-2Ј-tetrahydropyranyl)-2-methylethylpropionate J = 11.0, 7.1 Hz, 1 H, OEt) 4.95 (d, J = 10.4 Hz, 1 H, H8), 5.00
1
(19): Rf = 0.64 (10% MTBE in hexane). H NMR (500 MHz): δ =
1.10 (s, 3 H, H2a), 1.13 (dd, J = 11.2, 3.9 Hz, 1 H), 1.17 (s, 3 H,
(dq, J = 17.1, 1.6 Hz, 1 H, H8), 5.79 (ddt, J = 17.1, 10.4, 1.6 Hz,
1 H, H7) ppm. 13C NMR (125 MHz): δ = 0.7 (3C, TMS), 14.1
Table 2. Selected reaction conditions for the addition of 18 to 17.
Scale
Solvent
Lewis acid
Time
Yield
cis/trans
47 mg (0.26 mmol)
44 mg (0.24 mmol)
CH2Cl2
Et2O
BF3·OEt2
TMSOTf
8 h
24 h
48 mg, 78%
38 mg, 66%
2:3
1:20
2782
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2777–2785

Stereoselective Synthesis of the Monomeric Unit of SCH 351448
(OEt), 19.8 (C2a), 21.9 (C2b), 26.2, 32.4, 33.7 (C6), 48.0 (C2), 60.2
FULL PAPER
(100 MHz): δ = –4.2 (TBS), –3.7 (TBS), 14.1 (OEt), 18.3 (OEt),
(OEt), 77.4 (C3), 114.5 (C7), 138.5 (C8), 177.1 (COOR) ppm. [α]D 19.6 (Me), 21.2 (C5), 22.5 (Me), 26.0 (3C, TBS), 33.6 (C4), 42.4
= +9.2, c = 3.08 (CHCl3). C15H30O3Si (286.48): calcd. C 62.89, H
10.55; found C 62.73, H 10.47.
(C6), 47.7 (C8), 48.2 (C2), 60.3 (OEt), 76.2 (C3), 118.7 (C10), 130.6
(C9), 177.1 (COOR), 208.1 (C8) ppm. C20H38O4Si (370.60): calcd.
C 64.82, H 10.34; found C 64.52, H 10.20.
Aldehyde 24. TBS Protection: The alcohol 23 (3.00 g, 14.0 mmol)
was dissolved in THF (50 mL) at 0 °C. 2,6-Lutidine (3.8 mL,
35.0 mmol) and TBS-triflate (4.20 g, 16.8 mmol) were added drop-
wise subsequently. After 2h stirring at 0 °C the reaction mixture
was warmed to 20 °C and quenched with NH4Cl (40 mL). The
aqueous layer was extracted with MTBE (3×25 mL), the combined
organic layers were dried with MgSO4. Chromatographic purifica-
tion gave the corresponding TBS ether (4.55 g, 13.9 mmol, 99%)
as a colorless oil. Rf = 0.63 (10% MTBE in hexane). 1H NMR
(300 MHz): δ = 0.03 (s, 3 H, TBS), 0.07 (s, 3 H, TBS), 0.87 (s, 9
H, TBS), 1.07 (s, 3 H, CH3), 1.15 (s, 3 H, CH3), 1.24 (t, J = 7.0 Hz,
3 H, OEt), 1.29–1.42 (m, 3 H), 1.47–1.63 (m, 1 H), 1.93–2.09 (m,
2 H, H6), 3.87 (t, J = 5.3 Hz, 1 H, H3), 4.07 (dq, J = 11.1, 7.0 Hz,
1 H, OEt), 4.12 (dq, J = 11.1, 7.0 Hz, 1 H, OEt), 4.91–5.02 (m, 2
H, H8), 5.77 (ddt, J = 17.0, 10.3, 6.7 Hz, 1 H, H7) ppm. 13C NMR
(75 MHz): δ = –4.2 (TBS), –3.7 (TBS), 14.1 (OEt), 18.3 (TBS), 19.7
(C2a), 22.5 (C2b), 26.0 (3C, TBS), 26.4, 33.6, 34.0 (C6), 48.3 (C2),
60.2 (OEt), 77.0 (C3), 114.5 (C8), 138.5 (C7), 177.2 (COOR) ppm.
[α]D = –1.30, c = 1.00 (MTBE). C18H36O3Si (328.56): calcd. C
65.80, H 11.04; found C 65.51, H 10.96. Ozonolysis: Following GP1
the alkene (2.00 g, 6.09 mmol) was converted into the aldehyde 24
cis THP Ester 19 (from 25): Triethylsilane (2.45 g, 21.05 mmol) and
the ketone 25 (1.95 g, 5.26 mmol) were dissolved in MeCN (25 mL)
at –35 °C. Boron trifluoride–diethyl ether (1.49 g, 10.52 mmol) was
added. The solution was warmed to 20 °C and poured into water
(25 mL). The aqueous layer was extracted with MTBE (3×25 mL)
and the combined organic layers were dried with MgSO4. Chroma-
tographic purification gave the cis THP ester 19 (1.24 g, 5.15 mmol,
98%) which was identical with respect to its analytical data with
the compound prepared from 17.
Methyl Ketone 5: CuCl (62 mg, 624 µmol) was suspended in DMF/
H2O (8 mL, 7:1), and the solvent was thoroughly saturated with
argon gas. PdCl2 (11 mg, 62.4 µmol) was added. The suspension
was saturated with oxygen until the colour changed back to green.
The olefin 19 (150 mg, 624 µmol) was added and the suspension
was vigorously stirred under oxygen until the black colour changed
back to green. The suspension was poured into NH4Cl (20 mL)
and extracted with MTBE (3×20 mL). The combined organic lay-
ers were dried with MgSO4. Purification by chromatography gave
the methyl ketone 5 (143 mg, 448 mmol, 89%) as a colourless oil.
1
1
Rf = 0.17 (17% MTBE in hexane). H NMR (400 MHz): δ = 1.08
(1.66 g, 5.01 mmol, 82%). H NMR (300 MHz): δ = 0.03 (s, 3 H,
(s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.15–1.19 (m, 1 H, H6), 1.23 (t
J = 7.2 Hz, 3 H, OEt), 1.22–1.30 (m, 1 H, H4), 1.44–1.62 (m, 3 H,
H4–6), 1.83–1.90 (m, 1 H, H5), 2.14 (s, 3 H, H10), 2.34 (dd, J =
14.5, 4.1 Hz, 1 H, H8), 2.58 (dd, J = 14.5, 8.8 Hz, 1 H, H8) 3.54
(dd, J = 11.4, 1.7 Hz, 1 H, H3), 3.75 (dddd, J = 11.0, 8.8, 4.1,
2.0 Hz, 1 H, H7), 4.02 (q, J = 7.2 Hz, 2 H, OEt) ppm. 13C NMR
(100 MHz): δ = 14.1 (OEt), 20.0 (Me), 21.2 (Me), 23.4 (C5), 24.7
(C6), 31.2 (C10), 31.4 (C4), 46.4 (C2), 50.1 (C8), 60.3 (OEt), 75.2
(C7), 82.3 (C3), 176.7 (COOR), 208.2 (C=O) ppm. [α]D = +13.2, c
= 3.70 (CHCl3). HR-MS (ESI): [C14H24O4 +Na]+ calcd. 279.1567;
found 279.1565. C14H24O4 (256.34): calcd. C 65.60, H 9.44; found
C 65.15, H 9.59.
TBS), 0.07 (s, 3 H, TBS), 0.87 (s, 9 H, TBS), 1.06 (s, 3 H, CH3),
1.14 (s, 3 H, CH3), 1.23 (t, J = 7.2 Hz, 3 H, OEt), 1.34–1.42 (m, 2
H, H4), 1.47–1.62 (m, 1 H, H5), 1.71–1.85 (m, 1 H, H5), 2.40 (ddd,
J = 8.1, 6.9, 1.2 Hz, 2 H, H6), 3.88 (t, J = 5.3 Hz, 1 H, H3), 4.07
(dq, J = 11.2, 7.0 Hz, 1 H, OEt), 4.11 (dq, J = 11.2, 7.0 Hz, 1 H,
OEt), 9.73 (t, J = 1.6 Hz, 1 H, CHO) ppm. 13C NMR (75 MHz):
δ = –4.2 (TBS), –3.7 (TBS), 14.1 (OEt), 18.3 (TBS), 19.6, 19.7 (Me,
C5), 22.6 (Me), 26.0 (3C, TBS), 33.6 (C4), 44.0 (C6), 48.2 (C2),
60.3 (OEt), 76.6 (C3), 177.0(C1), 201.9 (CHO) ppm. [α]D = –1.1, c
= 2.14 (CHCl3).
Ketone 25. Allylation: To a solution of the aldehyde 24 (3.34 g,
10.1 mmol) in THF (50 mL) was added 2-allyl-4,4,5,5-tetramethyl-
1,3-dioxa-2-borolane (1.88 g, 11.1 mmol) in THF (2 mL) at 0 °C.
The reaction mixture was warmed to 20 °C and stirred for another
12 h. It was poured into NaHCO3/H2O (50 mL, 1:1) and stirred
for 1h. The aqueous layer was extracted with MTBE (3×40 mL)
and the combined organic layers were dried with Na2SO4. Removal
of the solvents and purification by chromatography led to the cor-
responding homoallylic alcohol 3.38 g (9.09 mmol, 90%). Dess–
Martin Oxidation: To a solution of the homoallylic alcohol (2.70 g,
7.25 mmol) in CH2Cl2 (50 mL) at 20 °C was added pyridine
(2.35 mL, 28.94 mmol) followed by Dess–Martin periodinane
(6.15 g, 14.49 mmol). The clear solution was stirred for 12 h at
20 °C and poured into a solution of 2.5 g Na2S2O3 in 30 mL satd.
aq. NaHCO3, which was vigorously stirred for another 1 h. The
aqueous layer was extracted with MTBE (3×25 mL) and the com-
bined organic layers were dried with Na2SO4. Purification by
chromatography gave the ketone 25 (2.15 g, 5.80 mmol, 80%) as a
colorless oil. Rf = 0.20 (17% MTBE in pentane). 1H NMR
(2S,6S,3ЈS)-2-(4-Hydroxy-3-methylbutyl)-6-[3-(3-methoxy-2-meth-
oxycarbonylphenyl)propyl]tetrahydropyran (26). Wittig Reaction:
Wittig salt 3 (3.69 g, 7.74 mmol) suspended in THF (150 mL) at
0 °C was treated with LiHMDS (7.8 mmol, 1  in THF). After
30 min at 0 °C, the solution was cooled to –78 °C. The aldehyde 4
(1.57 g, 5.15 mmol) was added. After 30 min the reaction was
warmed to 20 °C (overnight). The solvents were removed in vacuo
and the residue chromatographically purified to deliver the olefin
(2.02 g, 4.33 mmol, 84%) as a 1:1 mixture of the isomers, which
could not be separated. Rf = 0.28 (17% MTBE in hexane). HR-
MS (ESI) [C29H38O5 +Na]+ calcd.: 489.2605 found: 489.2611. Hy-
drogenation: The olefin (1.52 g, 3.26 mmol) was dissolved in THF
(50 mL) and treated with a catalytic amount of Pd(OH)2/C (10%,
wet). The suspension was vigorously stirred under H2-Atmosphere
for 2 h. The filtrate was concentrated and chromatographically
purified to furnish alcohol 26 (1.22 g, 3.22 mmol, 99%) as a colour-
1
less oil. Rf = 0.20 (50% MTBE in pentane). H NMR (400 MHz):
(400 MHz): δ = 0.03 (s, 3 H, TBS), 0.07 (s, 3 H, TBS), 0.87 (s, 9 δ = 0.91 (d, J = 6.7 Hz, 3 H, Me), 1.09–1.19 (m, 3 H, H3, 6, 8),
H, TBS), 1.06 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.24 (t, J = 7.1 Hz, 1.31–1.67 (m, 10H, OH), 1.71–1.82 (m, 2 H, H2, 7), 2.49–2.61 (m,
3 H, OEt), 1.31–1.38 (m, 2 H, H4), 1.43–1.55 (m, 1 H, H5), 1,67– 2 H, H12), 3.16–3.25 (m, 2 H, H5,9), 3.43 (dd, J = 10.7, 6.7 Hz, 1
1.78 (m, 1 H, H5), 2.40 (t, J = 7.3 Hz, 2 H, H6), 3.14 (d, J = H, H1), 3.49 (dd, J = 10.7, 5.7 Hz, 1 H, H1), 3.81 (s, 3 H, OMe),
7.1 Hz, 2 H, H8), 3.86 (dd, J = 6.1, 4.6 Hz, 1 H, H3), 4.07 (dq, J 3.90 (s, 3 H, OMe), 6.75 (d, J = 8.3 Hz, 1 H, H16), 6.82 (d, J =
= 10.4, 7.3 Hz, 1 H, OEt), 4.11 (dq, J = 10.4, 7.3 Hz, 1 H, OEt),
7.6 Hz, 1 H, H14), 7.26 (dd, J = 8.3, 7.6 Hz, 1 H, H15) ppm. 13C
5.12 (dd, J = 17.1,1.0 Hz, 1 H, H10), 5.17 (dd, J = 10.4,1.0 Hz, 1 NMR (100 MHz): δ = 16.7 (Me), 23.7 (C7), 27.2 (11), 29.1 (C4),
H, H10) 5.90 (ddt, J = 17.1, 10.2, 7.1 Hz, 1 H, H9) ppm. 13C NMR 31.7 (2C, C6, C8), 33.4 (C12), 33.8 (C3), 35.8 (C2), 36.3 (C10), 52.2
Eur. J. Org. Chem. 2006, 2777–2785
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2783

J. R. Backes, U. Koert
FULL PAPER
(OMe), 55.9 (OMe), 68.2 (C1), 77.6, 78.3 (C5,9), 108.4 (C16), 121.5
(C14), 123.5 (C13), 130.2 (C15), 141.1 (C18), 156.3 (C17), 168.9
Diol 29: Tetramethylammonium triacetoxyboronhydride (1.62 g,
6.16 mmol) in acetone (20 mL) was treated with acetic acid
(740 µL, 12.3 mmol) and stirred at 0 °C for 30 min. To the clear
(C19) ppm. IR: ν = 3430 (br. s), 2934 (s), 2863 (s), 1733 (s), 1585
˜
(s), 1469 (s), 1267 (s), 1076 (s), 755 (s) cm–1. [α]D = –5.50, c = 2.00 solution hydroxy ketone 28 (390 mg, 616 µmol) in acetone (10 mL)
(CHCl3). HR-MS (ESI) [C22H34O5 +Na]+ calcd. 401.2298; found
401.2297.
was added via a cannula. After 4 h at 0 °C the solution was warmed
to 20 °C and stirred for another 8 h. The reaction was poured into
satd. aq. Na/K tartrate (30 mL) and vigorously stirred for 15 min.
Satd. aq. NaHCO3 (20 mL) was added, the aqueous layer was ex-
tracted with MTBE (5×40 mL), the combined organic layers dried
with Na2SO4 and concentrated. Chromatographic purification gave
1,3-anti-diol 29 (334 mg, 526 µmol, 55%) as a colourless oil. Rf =
Aldehyde 27: To a solution of alcohol 26 (238 mg, 0.63 mmol) in
CH2Cl2 (10 mL) were added every 30 min 5 mL of a solution of
pyridine (300 mg) and Dess–Martin periodinane (800 mg,
1.89 mmol) in CH2Cl2 (25 mL). After three amounts the clear solu-
tion was poured into a solution of 5 g Na2S2O3 in 50 mL satd. aq.
NaHCO3, which was vigorously stirred for another 30 min. The
aqueous layer was extracted with CH2Cl2 (3×25 mL) and the com-
bined organic layers were dried with MgSO4. Purification by
chromatography gave the aldehyde 27 (200 mg, 0.53 mmol, 84%)
1
0.10 (50% MTBE in hexane); 0.25 (EtOAc). H NMR (500 MHz):
δ = 0.86 (d, J = 6.7 Hz, 3 H, H12a), 1.08–1.14 (m, 2 H), 1.12 (s, 3
H, H2a), 1.15 (s, 3 H, H2b), 1.24 (t, J = 7.1 Hz, 3 H, OEt), 1.20–
1.33 (m, 3 H), 1.26–1.67 (m, 15 H), 1.69–1.80 (m, 4 H), 1.83–1.88
(m, 1 H), 2.52 (ddd, J = 13.9, 9.0, 6.2 Hz, 1 H, H22), 2.56 (ddd, J
= 13.9, 9.0, 6.3 Hz, 1 H, H22), 3.16–3.24 (m, 2 H, H15,19), 3.28
(br. s, 1 H, OH), 3.57 (dd, J = 11.3, 1.2 Hz, 1 H, H3), 3.55–3.61
(m, 1 H, H7), 3.70–3.75 (m, 1 H, H9), 3.80 (s, 3 H, H29a), 3.86
(br. s, 1 H, OH), 3.89 (s, 3 H, H27a), 4.10 (dq, J = 10.8, 7.1 Hz, 1
H, OEt), 4.09–4.14 (m, 1 H, H11), 4.15 (dq, J = 10.8, 7.1 Hz, 1 H,
OEt), 6.74 (d, J = 8.3 Hz, 1 H, H26), 6.82 (d, J = 7.6 Hz, 1 H,
H24), 7.25 (dd, J = 8.3, 7.6 Hz, 1 H, H25) ppm. 13C NMR
(125 MHz): δ = 14.1 (OEt), 15.2 (C12a), 19.9 (C2a), 21.8 (C2b),
23.2 (C5), 23.7 (C17), 24.8 (C4), 27.1 (C21), 28.1 (C14), 31.5, 31.7
(C16, C18), 32.0 (C6), 33.4 (C20), 34.1 (C13), 36.3 (C22), 38.7
(C12), 38.9, 42.5 (C8, C10), 46.4 (C2), 52.1 (C29a), 55.9 (C27a),
60.7 (OEt), 70.4 (C11), 72.3 (C9), 77.6, 78.3 (C15, C19), 80.1 (C7),
83.0 (C3), 108.4 (C26), 121.5 (C24), 123.6 (C23), 130.2 (C25), 141.2
(C28), 156.2 (C27), 168.9 (C29), 176.7 (C1) ppm. [α]D = –1.45, c =
2.75 (CHCl3). HR-MS (ESI) [C36H58O9 +H]+ calcd. 635.4154;
found 635.4148.
1
as a colourless oil. Rf = 0.44 (50% MTBE in pentane). H NMR
(500 MHz): δ = 1.08 (d, J = 6.9 Hz, 3 H, Me), 1.12–1.20 (m, 2 H),
1.36–1.6 (m, 9 H, H3, 4, 6, 7, 8, 10, 11), 1.71–1.82 (m, 2 H, H11,7),
1.87–1.94 (m, 1 H, H3), 2.34 (ddq, J = 6.7, 6.7, 6.7 Hz, 1 H, H2),
2.53 (dt, J = 13.6, 6.2 Hz, 1 H, H12), 2.57 (dt, J = 13.6, 6.2 Hz, 1
H, H12), 3.18–3.25 (m, 2 H, H5,9), 3.81 (s, 3 H, OMe), 3.90 (s, 3
H, OMe), 6.75 (d, J = 8.3 Hz, 1 H, H14), 6.82 (d, J = 7.8 Hz, 1 H,
H16), 7.26 (dd, J = 8.3, 7.8 Hz, 1 H, H15), 9.61 (d, J = 1.6 Hz, 1
H, CHO) ppm. 13C NMR (125 MHz): δ = 13.2 (Me), 23.6 (C7),
26.5 (C3), 27.1 (C11), 31.6, 31.7 (C6, 8), 33.3 (C12), 33.7 (C10),
36.2 (C4), 46.1 (C2), 52.1 (OMe), 55.8 (OMe), 77.4, 77.5 (C5,9),
108.4 (C16), 121.4 (C14), 123.5 (C13), 130.2 (C15), 141.0 (C18),
156.2 (C17), 168.8 (C19), 205.2 (CHO) ppm. IR: ν = 2936 (s), 2981
˜
(s), 1732 (s), 1585 (m), 1470 (m), 1268 (s), 1111 (s), 1075 (s), 755
(m) cm–1. [α]D = +11.4, c = 0.50 (CHCl3). C22H32O5 (376.49): calcd.
C 70.18, H 8.57; found C 69.74, H 8.43.
γ-Methyl-β-anti-hydroxy Ketone 28: Methyl ketone 5 (337 mg,
1.32 mmol) was dissolved in Et2O at –78 °C and treated with NEt3
(145 mg, 1.43 mmol). After 20 min dibutylboron triflate
(1.38 mmol, 1  in Et2O) was added. After 10 min aldehyde 27
(450 mg, 1.20 mmol) was added. The reaction was kept at –78 °C
for 5 h, treated with MeOH/pH7buffer/H2O2 (40 mL, 2:2:1) and
warmed to 20 °C. After vigorous stirring for 30 min the aqueous
layer was extracted with MTBE (3×50 mL) and the combined or-
ganic layers were dried with MgSO4. Purification by chromatog-
raphy gave the β-hydroxy ketone 28 (414 mg, 664 µmol, 55%) as a
colourless oil. Rf = 0.20 (50% MTBE in pentane). 1H NMR
(500 MHz): δ = 0.89 (d, J = 6.7 Hz, 3 H, Me), 0.86–0.93 (m, 1 H),
1.07 (s, 3 H, Me), 1.12 (s, 3 H, Me), 1.10–1.20 (m, 3 H), 1.23 (t, J
= 7.1 Hz, 3 H, OEt), 1.33–1.66 (m, 12 H), 1.68–1.88 (m, 5 H), 2.34
(dd, J = 14.7, 7.1 Hz, 1 H, H8), 2.49 (dd, J = 16.9, 9.5 Hz, 1 H,
H10), 2.52–2.64 (m, 4 H, H8,10, H22), 3.11 (d, J = 3.2 Hz, 1 H,
OH), 3.16–3.24 (m, 2 H, H15,19), 3.51 (dd, J = 11.1, 1.1 Hz, 1 H,
H3), 3.75–3.79 (m, 1 H, H7), 3.80 (s, 3 H, H27a), 3.85–3.88 (m, 1
H, H11), 3.89 (s, 3 H, H29a), 4.09 (q, J = 7.1 Hz, 2 H, OEt), 6.74
(d, J = 8.0 Hz, 1 H, H24), 6.82 (d, J = 8.0 Hz, 1 H, H26), 7.25 (dd,
J = 8.0, 8.0 Hz, 1 H, H25) ppm. 13C NMR (125 MHz): δ = 14.1
(OEt), 15.1 (C12a), 20.4 (C2a), 21.0 (C2b), 23.4 (C5), 23.7 (C17),
24.8 (C4), 27.2 (C21), 28.0 (C14), 31.3 (C6), 31.6, 31.7 (C18, C16),
33.4 (C20), 34.0 (C13), 36.3 (C22), 38.1 (C12), 46.3 (C2), 47.3
(C10), 49.9 (C8), 52.1 (C29a), 55.8 (C27a), 60.3 (OEt), 71.1 (C11),
74.9 (C7), 77.6, 78.2 (C15, C19), 82.3 (C3), 108.4 (C26), 121.5
(C24), 123.6 (C23), 130.2 (C25), 141.1 (C28), 156.3 (C27), 168.8
Acknowledgments
Generous support by the Pinguin foundation, the Deutsche For-
schungsgemeinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged.
[1] V. R. Hedge, M. S. Puar, P. Dai, M. Patel, V. P. Gullo, P. R.
Das, R. W. Bond, A. T. McPhail, Tetrahedron Lett. 2000, 41,
1351–1354.
[2]
a) E. J. Kang, E. J. Cho, Y. E. Lee, M. K. Ji, D. M. Shin, Y. K.
Chung, E. Lee, J. Am. Chem. Soc. 2004, 126, 2680–2681; b)
E. J. Kang, E. J. Cho, M. K. Ji, Y. E. Lee, D. M. Shin, S. Y.
Choi, Y. K. Chung, J.-S. Kim, H.-J. Kim, S.-G. Lee, M. S. Lah,
E. Lee, J. Org. Chem. 2005, 70, 6321–6329.
[3]
[4]
[5]
O. Soltani, J. K. De Brabander, Org. Lett. 2005, 7, 2791–2793.
S. Bolshakov, J. L. Leighton, Org. Lett. 2005, 7, 3809–3812.
Y. Yamagiwa, K. Ohashi, Y. Sakamoto, S. Hirakawa, T. Kami-
kawa, I. Kubo, Tetrahedron 1987, 43, 3387–3394.
H. Knust, R. W. Hoffmann, Helv. Chim. Acta 2003, 86, 1871–
1893.
H. C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 5919–
5923.
B. G. Vong, S. Abraham, A. X. Xiang, E. A. Theodorakis, Org.
Lett. 2003, 5, 1617–1620.
[6]
[7]
[8]
[9]
[10]
H. O. House, L. F. Lee, J. Org. Chem. 1976, 41, 863–869.
E. Juaristi, J. S. Cruz-Sanchez, J. Org. Chem. 1988, 53, 3334–
3338.
(C29), 176.6 (C1), 211.3 (C9) ppm. IR: ν = 3464 (br. s), 2936 (s),
˜
2864 (s), 1732 (s), 1585 (m), 1470 (s), 1269 (s), 1079 (s), 1047 (s),
756 (s) cm–1. [α]D = +8.2, c = 2.00 (CHCl3). HR-MS (ESI)
[C36H56O9 +Na]+ calcd. 655.3817; found 655.3820.
[11]
[12]
N. Y. Grigorieva, O. N. Yudina, A. M. Moiseenkov, Synthesis
1989, 591–595.
S.-I. Kiyooka, M. A. Hena, J. Org. Chem. 1999, 64, 5511–5523.
2784
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2777–2785

Stereoselective Synthesis of the Monomeric Unit of SCH 351448
FULL PAPER
[13] a) D. A. Evans, P. J. Coleman, B. Côté, J. Org. Chem. 1997, 62,
788–789; b) M. Berger, J. Mulzer, J. Am. Chem. Soc. 1999, 121,
8393–8394.
[14] W. R. Roush, T. D. Bannister, M. D. Wendt, M. S.
Van Nieuwenhze, D. J. Gustin, G. J. Dilley, G. C. Lane, K. A.
Scheidt, W. J. Smith III, J. Org. Chem. 2002, 67, 4284–4289.
[15] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem.
Soc. 1988, 110, 3560–3578.
Received: February 7, 2006
Published Online: April 10, 2006
Eur. J. Org. Chem. 2006, 2777–2785
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2785