Synthetic studies directed toward the phorboxazoles: Preparation of the C3-C15 bisoxane segment and two stereoisomers

Article abstract of DOI:10.1016/S0040-4020(02)00613-0

A synthetic approach to the C3-C15 segment of the cytotoxic marine metabolite phorboxazoles is described. This segment consists of a methylene linked bisoxane structure. The first pyran ring was constructed by a Lewis acid catalyzed diene-aldehyde cyclocondensation. The β-C-glucoside substitution pattern of this ring was established by a stereoselective allylation. Ozonolysis of vinyl group and enantioselective allylation of the racemic aldehyde generated two separable homoallylic alcohols (-)-22 and (+)-23. The Mosher's esters of each alcohol were determined to be >90% de. Reaction of (-)-22 with acryloyl chloride, followed by ring closing metathesis gave the dihydro-2-pyrone target (-)-5. Mitsunobu inversion of (+)-23 with p-nitrobenzoic acid, hydrolysis, and esterification with acryloyl chloride and ring closing metathesis gave pseudoenantiomeric segment (+)-6.

Full text of DOI:10.1016/S0040-4020(02)00613-0

TETRAHEDRON
Pergamon
Tetrahedron 58 02002) 6009±6018
Synthetic studies directed toward the phorboxazoles: preparation
of the C3±C15 bisoxane segment and two stereoisomers
Patrick B. Greer and William A. Donaldsonp
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA
Received 22 April 2002; accepted 10 June 2002
AbstractÐA synthetic approach to the C3±C15 segment of the cytotoxic marine metabolite phorboxazoles is described. This segment
consists of a methylene linked bisoxane structure. The ®rst pyran ring was constructed by a Lewis acid catalyzed diene±aldehyde cyclo-
condensation. The b-C-glucoside substitution pattern of this ring was established by a stereoselective allylation. Ozonolysis of vinyl group
and enantioselective allylation of the racemic aldehyde generated two separable homoallylic alcohols 02)-22 and 01)-23. The Mosher's
esters of eachalcohol were determined to be .90% de. Reaction of 02)-22 with acryloyl chloride, followed by ring closing metathesis gave
the dihydro-2-pyrone target 02)-5. Mitsunobu inversion of 01)-23 with p-nitrobenzoic acid, hydrolysis, and esteri®cation with acryloyl
chloride and ring closing metathesis gave pseudoenantiomeric segment 01)-6. q 2002 Published by Elsevier Science Ltd.
O
The phorboxazoles A and B 01a and b) are isomeric
macrolides isolated from the marine sponge Phorbas sp.1a
In addition to exhibiting antifungal activity against Candida
albicans, both phorboxazoles inhibit the growth of most of
the 60 tumor cell lines in the NCI panel at concentrations
,8£10210 M. This level of activity places phorboxazole
among the most potent cytostatic agents known. While the
exact mechanism of action is unknown, the phorboxazoles
do not interfere withtubulin polymerization/depolymeriza-
tion as is the case for many other antitumor agents 0e.g.
epothiolone, taxol). Initial results indicate that 1a arrests
Burkitt lymphoma CA46 cells in the S phase.1c
X
MeO
15
Y
Br
N
H
H
O
H
O
H
Me
Me
H
O
OH
H
O
N
HO
O
H
O
Me
Me
3
O
OMe
1a, X = OH, Y = H
1b, X = H, Y = OH
HO
H2N
OP13
MeO
15
Br
O
The complex structure of 1 consists of four oxane rings, two
oxazole rings, 15 asymmetric centers, and a conjugated
diene segment. The complete structure was assigned on
the basis of NMR spectral studies, Mosher ester data, degra-
dation, and model synthesis.1 The outstanding biological
activity of 1a/b, combined withtheir complex structural
architecture, has led to signi®cant activity by a number of
H
O
CO2Me
PPh3
H
Me
38O
H
O
H
O
P
H
OP20
3
P3O
2
4
OMe
Me
H
Me
O
2
3
researchgroups, and three total syntheses.3 The three
HO2C
P(O)(OCH2CF3)2
H
syntheses are all convergent, with the initial preparation of
fragments roughly encompassing the C3±C15 bisoxane
portion, the C20±C27 oxane ring, and the C31±C46
diene±oxane fragment. Our retrosynthetic strategy dis-
connects the target into three major fragments, 2±4
0Scheme 1), with connections similar to those reported by
Forsyth3a and by Evans.3b±d We herein report our detailed
study on the enantioselective synthesis of a C3±C15
N
OP24
O
Me
Me
Scheme 1.
segment 02)-5, its pseudoenantiomer 01)-6, and the dia-
stereomer 01)-7 0Fig. 1).4
1. Results and discussion
Keywords: phorboxazoles; C3±C15 bisoxane segment; stereoisomers;
phorboxazoles.
Corresponding author. Tel.: 11-414-288-7374; fax: 11-414-288-7066;
e-mail: donaldsonw@marquette.edu
Lewis acid catalyzed diene±aldehyde cyclocondensation5
of 8 with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene 09)
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020002)00613-0

6010
P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
glycoside 12 0Scheme 2). Compound 12 was assigned the
b-stereochemistry on the basis of the 1H NMR signal for the
anomeric proton 0d 4.54, dd, Jˆ2.7, 9.0 Hz). The larger
coupling constant is consistent withan axial±axial orienta-
tion of the anomeric proton with one on the adjacent carbon.
Reduction of 12 withLiAlH0O tBu)3 gave the equatorial
alcohol 13, while reduction of 12 with l-selectride gave a
mixture of 13 and the axial alcohol 14 0Scheme 2). The
H
R
H
S
H
S
S
R
O
O
H
O
O
H
S
O
O
H
H
H
H
O
S
O
R
O
R
OAc
O
OAc
BPSO
BPSO
O
BPSO
(+)-6
(+)-7
(–)-5
1
structural assignments for 13 and 14 are based on their H
Figure 1.
NMR spectral data. In particular, the signals for H9 and H7
0phorboxazole numbering) of 13 0d 4.26, dd, Jˆ1.9, 9.5 Hz
and d 3.60, br m, 1/2Wˆ26 Hz) are consistent withatetra-
hydropyran bearing all equatorial substituents, while these
signals for 14 0d 4.69, dd, Jˆ2.1, 9.9 Hz and d 4.31, pentet,
Jˆ3.0 Hz) are consistent witha C7 axial hydroxyl group.
The diastereoselectivity for reduction of b-pyranoside
ketones under these conditions has been previously
reported.8
in the presence of BF3´Et2O, followed by brief treatment
withCF CO2H gave dihydropyrone rac-10 0Eq. 01), Table
3
1). In a similar fashion, cyclocondensation in the presence
of ZnCl2, or TiCl4, or MgBr2 gave the same product. Asym-
metric cyclocondensation6a of 8 with the chiral auxiliary
modi®ed diene 1-l-menthyloxy-3-tert-butyldimethylsilyl-
oxy-1,3-butadiene 011)6b in the presence of 01)-Eu0hfc)3
0hexane), followed by elimination of methanol gave 05S)-
10 in good yield. Unfortunately, comparison of the optical
rotation of this product with the literature value2e indicated
that it was only 10% ee. Cyclocondensation of 8 with 9 in
the presence of the Keck's R-BINOL/Ti0iPrO)4/CF3CO2H
catalyst7 likewise gave 05S)-10 withgood enantioselectivity
0.90% ee) albeit in low isolated yield 019%). Unfortunately
in our hands, attempts to optimize the yield of this reaction
were unsuccessful.
Acylation of 13 gave 15 0Scheme 3). Treatment of 15 with
allyl trimethylsilane/BF3´Et2O gave a separable mixture of
1
16 and 17 0Scheme 3). The H NMR spectrum of 17 is
conspicuous in its absence of a signal for the acetate
group and by the presence of signals for 5 ole®nic protons.
In contrast, the 1H NMR spectrum of 16 contains signals at
d 5.77 0tdd, 1H) and 5.07±4.80 0m, 3H) corresponding to
the vinyl group and the C7 proton, and a singlet at d 2.04
03H) corresponding to the acetate methyl. The trans- stereo-
chemistry of the allyl substituent in both 16 and 17 was
assigned on the basis of the expected9 axial attack of nucleo-
philes on the cyclic oxonium ion generated from 15. Th e
formation of 17 presumably arises from elimination of
methanol from 15 to generate the pseudoglycal 18. A
carbon-Ferrier rearrangement of 18 would give the product
17. Changing the Lewis acid from BF3´Et2O to TMSOTf10
suppressed the formation of 17; the desired allylpyran 16
was isolated in 73% yield.
ꢀ1†
Table 1. Lewis acid catalyzed diene±aldehyde cyclocondensation
Lewis acid/rxn conditions
Yield 0%)
Ozonolysis of 16, followed by treatment of the ozonide with
triphenylphosphine, gave the aldehyde rac-19 0Scheme 4).
Cyclocondensation of 19 with 9 in the presence of TiCl4
gave an inseparable mixture of dihydropyrones 20, which
are diastereomeric at C11. The structural assignment for 20
BF3´Et2O/Et2O/2788C to rt/9 h71
ZnCl2/Et2O/2788C/9 h, 238C/12 h70
TiCl4/Et2O/788C/9 h, 238C/12 h50
MgBr2/Et2O/788C/9 h, 238C/12 h31
01)-Eu0hfc)3/hexane/rt/24 ha
52 05S, 10% ee)
19 05S, 95% ee)
1
Ti0iPrO)4/R-BINOL/CF3CO2H/Et2O
is based on its H NMR spectral data. In particular, the
signals corresponding to the C15 proton of the two diaster-
eomers appear at d 7.20 0d) and 7.17 0d), while the signals
corresponding to the C14 proton appear at d 5.36 0d) and
5.35 0d) ppm. Integration of the C15 signals indicated that
a
1-01-l-Menthyloxy)-3-0tert-butyldimethylsilyloxy)-1,3-butadiene
was used instead of 9.
011)
Reaction of rac-10 withmercuric acetate in metahnol,
followed by treatment withNaBH CN gave the methyl
3
MeO
Ac2O
H
H
Hg(OAc)2
TMS
NaOAc
O
O
O
rac-13
H
H
H
MeOH;
NaBH3CN
THF
MeO
O
OMe
OMe
OAc
OAc
(92%)
9
O
O
rac-10
H
H
H
OBPS
OBPS
OBPS
O
OH
OH
7
rac-15
rac-16
rac-17
(69%)
rxn conditions
OBPS
OBPS
OBPS
O
rac-12
rac-13
rac-14
H
35%
0%
26%
73%
BF3:Et2O, CH2Cl2
TMSOTf, CH3CN
rxn conditions
ratio (yield)
OAc
100:0 (92%)
1:1 (72%)
OBPS
LiAl(OtBu)3H/THF
L-selectride/THF
rac-18
Scheme 2.
Scheme 3.

P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
6011
OTMS
O
14
S
R
H
HO
H
HO
H
MeO
OAc
OHC
H
H
15
O
H
11
ZnCl2
Et2O
H
H
S
S
O
O
O3/CH2Cl2
-78; PPh3
O
H
O
9
–78oC
S
R
R
OTIPS
S
OTIPS
rac-16
OAc
(45%)
(89%)
OTBS
OTBS
BPSO
BPSO
25
24
rac-19
rac-20
2:1 dr
Figure 2.
H
O
M
OAc
In comparison, the spectrum of 24 contains signals at d 71.2,
69.5, and 67.6 ppm, while the spectrum of 25 contains
signals at d 67.8, 67.0, and 66.3 ppm.
O
21
OBPS
Scheme 4.
Analysis of the 1H NMR spectra 0CDCl3) of th e 0R)- and 0S)-
MTPA esters of 22 indicated separation of the H-13 signals;
integration of these signals indicated that the Mosher's
esters were .90% de. The absolute con®guration of 22 at
C11 0S) is based on the relative chemical shifts for H-13
signals of the 0R)- and 0S)-MTPA esters; this signal for the
0R) ester appears down®eld of that for the 0S) ester.14 In a
similar fashion, integration of the H-13 signals of the 0R)-
and 0S)-MTPA esters of 23 indicated eachto be .90% de.
The absolute con®guration of 23 at C11 0S) is based on the
relative chemical shifts of these signals; the signal for the
0R) ester appears down®eld of that for the 0S) ester.14
the diastereomers were formed in a 2:1 ratio. Cyclo-
condensation of 19 with 9 in the presence of ZnCl2 or
BF3´Et2O in place of TiCl4 gave a similar 2:1 mixture of
diastereomers 20. It was not possible to assign the relative
stereochemistry of the major diastereomer of 20 at C11.
Pyranyl aldehydes similar to 19 are known to undergo
cyclocondensation with 9 withmodest diastereoselectivity
04:1±5:1).11 In these cases, the major diastereomer
possesses the 9Sp,11Rp relative stereochemistry. One ratio-
nalization for this stereoselectivity is approach of the silyl-
oxydiene 9 to the less hindered face of a chelated structure
0c.f. 21). It should be noted that the 9Sp,11Rp relative stereo-
chemistry is opposite to that desired for the phorboxazoles.
Reaction of the diastereomeric alcohols 02)-22 or 01)-23
with acryloyl chloride gave the diastereomeric unsaturated
esters 02)-26 or 01)-27 0Scheme 5).15 The structures of
acrylate esters 26 and 27 were assigned on the basis of
their NMR spectral data. In particular, doublet of doublets
signals present at ca. d 6.37, 6.09, and 5.79 ppm in their 1H
NMR spectra and resonances at ca. d 165.5, 130.5, and
128.7 ppm in their 13C NMR spectra are characteristic
of the acrylate group. Ring closing metathesis16 of 02)-26
or 01)-27 in the presence of Grubbs' catalyst gave the
Due to the lack of any signi®cant diastereoselectivity in the
cyclocondensation of 19, it was decided to introduce the
C11±C15 pyran ring via sequential allylation±esteri®ca-
tion-ring-closing metathesis.12 Toward this end, reaction
of rac-19 with B-allyldiisopinocampheylborane 0prepared
from 02)-0IPC)2BOMe) under salt-free conditions,13
followed by oxidative work up withNaBO , gave a separ-
3
able mixture of the diastereomers 02)-22 and 01)-23 041
and 42%, respectively, Eq. 02)). The relative stereo-
chemistry of 22 and 23 were assigned by comparison of
their 13C NMR spectral data with that of the diastereomeric
compounds 24 and 25 0Fig. 2), previously reported by
Hoffmann's group.2m In particular, the spectrum of 22
contains signals at d 70.6, 69.7, and 67.2 ppm 0C5, C9,
C11, phorboxazole numbering, speci®c assignments not
intented) while the spectrum of 23 contains signals at d
67.6, 67.0, and 66.8 ppm.
PCy3
Cl
Ru CHPh
H
Cl
PCy3
O
O
H
H2C=CHCOCl
NEt3, DMAP
H
(0.2 equiv)
Ti(iPrO)4
(73%)
O
(–)-5
(–)-22
(52%)
OAc
BPSO
(–)-26
PCy3
Cl
Ru CHPh
PCy3
H
H
Cl
O
O
H
H2C=CHCOCl
NEt3, DMAP
(0.97 equiv)
Ti(iPrO)4
O
(+)-7
(+)-23
ꢀ2†
(52%)
OAc
BPSO
(89%)
(+)-27
Scheme 5.

6012
P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
tography was performed on silica gel 60 060±200 mesh,
Aldrich). Melting points were obtained on a Mel-Temp
1
H
H
melting point apparatus and are uncorrected. All H and
13C NMR spectra were recorded at 300 and 75 MHz,
respectively. Elemental analyses were obtained from
Midwest Microlabs, Indianapolis, IN and high resolu-
tion mass spectra were obtained from the Washington
University Resource for Biomedical and Bioorganic Mass
Spectrometry.
RO
H
O
O
H
H
H
a
d
(+)-6
(+)-23
O
O
OR'
OR'
OBPS
OBPS
(+)-28, R = PNB, R' = Ac
b
2.1.1. Dihydropyrone -10). To a solution of 3-0tert-butyldi-
phenylsilyloxy)propanal20 08, 11.42 g, 36.5 mmol) in ether
075 mL) cooled to 2788C was added dropwise 1-methoxy-
3-trimethylsilyloxy-1,3-butadiene 09, 10.0 g, 5.80 mmol) in
ether 025 mL). After stirring for 5 min, BF3´Et2O 07 mL,
56.9 mmol) was added dropwise over a 5 min period. The
mixture was stirred for 9 hduring whichit was slowly
warmed to rt. Saturated aqueous NaHCO3 was added, the
reaction was stirred for 30 min, and then extracted with
ether 03£75 mL). The combined organic layers were dried
0MgSO4) and the solvent evaporated to afford a reddish
brown oil. This residue was dissolved in CH2Cl2
0100 mL), tri¯uoroacetic acid 07 drops) was added, and
the mixture stirred for 18 h at rt. Saturated aqueous
NaHCO3 was added, the mixture stirred for 30 min, the
layers separated, and the aqueous layer extracted with
CH2Cl2 04£75 mL). The combined organic layers were
dried 0MgSO4) and the solvent evaporated. The residue
was puri®ed by chromatography 0hexane±ethyl
acetateˆ9:1) to give 10 as a colorless oil 09.879 g, 71%);
1H NMR 0CDCl3) d 7.66±7.63 0m, 4H), 7.47±7.37 0m, 6H),
7.29 0d, Jˆ6.0 Hz, 1H), 5.40 0d, Jˆ6.2 Hz, 1H), 4.67 0tdd,
Jˆ4.4, 8.6, 12.7 Hz, 1H), 3.90±3.74 0m, 2H), 2.59±2.42 0m,
2H), 2.08±1.97 0m, 1H), 1.93±1.83 0m, 1H), 1.04 0s, 9H);
13C NMR 0CDCl3) d 192.8, 163.3, 135.7, 133.6, 130.0,
127.9, 107.3, 76.6, 59.3, 42.2, 37.4, 27.0, 19.4; FAB-
HRMS m/z 387.1980 0calcd for C23H28O3SiLi [M1Li]1
m/z 387.1968).
(+)-30, R' = COCH=CH2
(+)-29, R = R' = H
c
b
(–)-22
(–)-29, R = R' = H (5S,7R,9S,11S)
Scheme 6. Reagents 0a) p-NO2PhCO2H, DEAD, PPh3 051%); 0b) K2CO3,
MeOH 072±88%); 0c) H2CvCHCOCl, NEt3, DMAP 043%);
0d) Ru0CHPh)0PCy3)2Cl2 00.07 equiv.), Ti0iPrO)4, CH2Cl2 079%).
dihydropyran-2-ones 02)-5 or 01)-7, respectively.17 The
structures of 5 and 7 were assigned on the basis of their
NMR spectral data. In particular, signals present at ca. d
6.7±6.8 0ddd) and 6.0±5.9 0dd) ppm in their 1H NMR spec-
tra and at ca. d 144.9 and 121.4 ppm in their 13C NMR
spectra are characteristic of the ole®n of the dihydro-
pyran-2-one ring.
The enantiomers of certain naturally occurring substances
fortuitously exhibit interesting biological activity.18 It was
envisioned that inversion of the C11 stereocenter present in
01)-23 would generate a molecule enantiomeric with0 2)-
22. To this end, reaction of 28 alcohol 01)-23 with p-nitro-
benzoic acid in the presence of DEAD/PPh3 proceeded with
inversion19 to give 01)-28 0Scheme 6). Hydrolysis of both
the p-nitrobenzoate and acetate esters of 01)-28 gave diol
01)-29. In a similar fashion, hydrolysis of 02)-22 gave the
enantiomeric diol 02)-29. Th e1H and 13C NMR spectra of
01)-29 and 02)-29 were identical. Reaction of 01)-29 with
2 equiv. of acryloyl chloride gave the bis-acrylate ester 01)-
30. Ring closing metathesis of the bis-acrylate 01)-30
proceeded only via formation of the six-membered dihydro-
pyran-2-one ring to give 01)-6.
Effect of Lewis acid: ZnCl2. The reaction of aldehyde 8
withdiene
9 in the presence of ZnCl2 01.0 M in
ether, 1 equiv.) was carried out in ether at 2788C for 9 h,
followed by 12 hat room temperature. Reaction of teh
residue withtri¯uoroacetic acid in CH 2Cl2 was carried
out as previously described. Puri®cation of the crude
product by chromatography gave 10 as a pale yellow oil
070%).
In summary, the C3±C15 segment of the phorboxazoles 0in
the form of optically active dihydropyran-2-one 02)-5) was
prepared in 9 steps from the known aldehyde 8 via the
alcohol 02)-22. The presence of the a,b-unsaturated lactone
should allow for introduction of the requisite C13 hydroxyl
substituent12b and the C15±C16 bond in a stereoselective
fashion. Additionally, the enantiomeric segment 01)-6
was prepared from 01)-23.
Effect of Lewis acid: TiCl4. The reaction of aldehyde 8 with
diene 9 in the presence of TiCl4 01 equiv.) was carried out in
ether at 2788C for 9 h, followed by 12 h at room tempera-
ture. Reaction of the residue with tri¯uoroacetic acid in
CH2Cl2 was carried out as previously described. Puri®cation
of the crude product by chromatography gave 10 as a pale
yellow oil 050%).
2. Experimental
2.1. General data
Effect of Lewis acid: MgBr2. The reaction of aldehyde 8 with
diene 9 in the presence of MgBr2 01 equiv.) was carried out
in ether at 2788C for 9 h, followed by 12 h at room tempera-
ture. Reaction of the residue with tri¯uoroacetic acid in
CH2Cl2 was carried out as previously described. Puri®cation
of the crude product by chromatography gave 10 as a pale
yellow oil 031%).
Spectrograde solvents were used without puri®cation with
the exception of dry ether and dry THF which were distilled
from sodium benzophenone ketyl and dichloromethane
which was distilled from P2O5 and then stored
over molecular seives. Anhydrous hexane and anhydrous
toluene were purchased from Aldrich. Column chroma-

P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
6013
Effect of chiral Lewis acid and chiral auxillary modi®ed
butadiene. The reaction of aldehyde 8 with1-01- l-menthyl-
oxy)-3-0tert-butyldimethylsilyloxy)-1,3-butadiene6b in the
presence of 01)-Eu0hfc)3 00.05 equiv.) was carried out in
anhydrous hexane at room temperature. After 24 h, NEt3
04 mL) and methanol 02 mL) were added and the mixture
was concentrated under vacuum. Reaction of the residue
withtri¯uoroacetic acid in CH 2Cl2 was carried out as
previously described. Puri®cation of the crude product by
chromatography gave 10 as a pale yellow oil 052%). The 1H
NMR spectrum of this product was identical with that of
rac-10: [a]Dˆ24.1 0c 1.32, CHCl3) [lit.2e [a]Dˆ235.8 0c
1.0, CHCl3) 88%ee].
in small portions over a 15 min period, solid LiAlH0OtBu)3
01.358 g, 5.341 mmol). The reaction mixture was stirred at
rt for 3 h, at which time TLC analysis indicated complete
consumption of 12. Water 010 mL) was cautiously added
dropwise, the mixture was extracted with ether 04£50 mL)
and the combined extracts were dried 0MgSO4) and the
solvent evaporated. The residue was puri®ed by chromato-
graphy 0hexane±ethyl acetateˆ4:1) to give 13 as a colorless
oil 01.640 g, 92%): Rf 0.12 0hexane±ethyl acetateˆ4:1); IR
1
0CHCl3, cm21) 3440; H NMR 0CDCl3) d 7.68±7.63 0m,
4H), 7.46±7.34 0m, 6H), 4.26 0dd, Jˆ1.9, 9.5 Hz, 1H),
3.92±3.73 0m, 3H), 3.60 0br m, 1/2Wˆ26 Hz, 1H), 3.42
0s, 3H), 2.17 0tdd, Jˆ1.9, 4.6, 12.0 Hz, 1H), 1.92±1.78
0m, 3H), 1.54 0d, Jˆ5.1 Hz, OH), 1.42±1.33 0m, 2H), 1.05
0s, 9H); 13C NMR 0CDCl3) d 135.7, 134.0, 129.8, 127.8,
101.2, 68.6, 67.2, 60.2, 56.5, 41.1, 40.9, 38.6, 27.0, 19.4;
FAB-HRMS m/z 421.2381 0calcd for C24H34O4SiLi
[M1Li]1 m/z 421.2386). Anal. calcd for C24H34O4Si: C,
69.52; H, 8.26. Found: C, 69.45; H, 8.17.
Effect of Lewis acid: BINOL±Ti0iPrO)4. To a solution of
0R)-1,10-binaphthol 075.3 mg, 0.263 mmol) in ether
Ê
010 mL) was added 4 A molecular sieves 0526 mg). To
this suspension was added dropwise, by syringe, Ti0iPrO)4
00.0374 mL, 0.127 mmol). The reaction mixture turned a
reddish-brown in color. To the mixture was added a solution
of CF3CO2H in CH2Cl2 03 mL, 0.5 M, 0.15 mmol) and the
reaction mixture was heated at re¯ux for 1 h. After the
mixture was cooled to room temperature, a solution of 8
0411 mg, 1.32 mmol) in ether 05 mL) was added dropwise.
The resultant mixture was cooled to 278 8C and 9
00.313 mL) was added dropwise. The reaction mixture
was stirred at 2788C for 30 min, and then stored in the
freezer 0258C) for 48 h. Saturated aqueous NaHCO3
015 mL) was added and the mixture was stirred for
45 min. The mixture was ®ltered through ®lter-aid, the ®lter
bed was washed with ether 04£25 mL) and the combined
organic layers dried 0MgSO4) and concentrated. Reaction of
the residue with tri¯uoroacetic acid in CH2Cl2 was carried
out as previously described. Puri®cation of the crude
product by chromatography gave 10 as a pale yellow oil
019%). [a]Dˆ239 0c 0.84, CHCl3) [lit.2e [a]Dˆ235.8 0c
1.0, CHCl3) 88%ee].
2.1.4. Reduction of 12 with l-selectride. A solution of
l-selectride 02 mL, 1.0 M THF, 2.0 mmol) in dry THF
08 mL) was cooled to 2788C. To the cooled solution was
added dropwise via syringe, over a period of 10 min, a
solution of 12 0371 mg, 0.900 mmol) in dry THF 05 mL).
The reaction mixture was stirred for 3 h, during which time
the mixture was allowed to come to room temperature and
TLC analysis indicated completion. Water 08 mL) was
cautiously added dropwise, followed by 6N NaOH
00.6 mL), 30% H2O2 00.6 mL) and aqueous K2CO3
010 mL). The mixture was extracted with ether 03£15 mL)
and the combined extracts were dried 0MgSO4) and the
solvent evaporated. The residue was puri®ed by chromato-
graphy 0hexane±ethyl acetateˆ4:1) to give a 1:1 mixture of
13 and 14 as a colorless oil 0267 mg, 72%). The axial
alcohol 14 was only characterized as a mixture with 13.
1
14: Rf 0.12 0hexane±ethyl acetateˆ4:1); H NMR 0CDCl3,
2.1.2. b-Methyl glycoside -12). To a solution of dihydro-
pyrone 10 03.00 g, 7.89 mmol) in dry methanol 025 mL) was
added, in one portion, Hg0OAc)2 03.1 g, 9.7 mmol). The
reaction mixture was stirred at rt for 6 h, and the solvent
was evaporated. The residue was dissolved in dry THF
025 mL) and cooled to 2788C. To the cooled solution was
added, via syringe, a solution of NaBH3CN 00.2181 g,
3.471 mmol) in THF 02 mL). The reaction mixture was stir-
red for 4 h, diluted with pentane and the solvent evaporated.
The residue was puri®ed by chromatography 0hexane±ethyl
acetateˆ19:1) to give 12 as a colorless oil 02.204 g, 69%):
partial) d 7.68±7.63 0m, 4H), 7.46±7.34 0m, 6H), 4.69 0dd,
Jˆ2.1, 9.9 Hz, 1H), 4.31 0pentet, Jˆ3.0 Hz, 1H), 4.22 0dd,
Jˆ4.4, 6.3 Hz, 1H), 3.42 0s, 3H), 1.92±1.20 0m, 7H), 1.05
0s, 9H).
2.1.5. Acetoxy b-methyl glycoside -15). To a solution of 13
01.90 g, 4.582 mmol) in acetic anhydride 020 mL) was
added sodium acetate 00.3758 g, 4.582 mmol). The reaction
mixture was heated at re¯ux for 30 min, diluted with water
and extracted withether 04 £20 mL). The combined ethereal
extracts were repeatedly washed with saturated NaHCO3,
followed by brine, dried 0MgSO4) and the solvent evapo-
rated. The residue was puri®ed by chromatography
0hexane±ethyl acetateˆ9:1) to give 15 as a colorless oil
01.924 g, 92%); IR 0CHCl3, cm21) 1740; 1H NMR
0CDCl3) d 7.69±7.64 0m, 4H), 7.46±7.34 0m, 6H), 4.93
0tt, Jˆ5.0, 11.5 Hz, 1H), 4.33 0dd, Jˆ1.9, 9.8 Hz, 1H),
3.89 0ddd, Jˆ5.4, 8.1, 10.1 Hz, 1H), 3.76 0td, Jˆ5.1,
10.2 Hz, 1H), 3.68 0br m, 1/2Wˆ21 Hz, 1H), 3.43 0s, 3H),
2.19 0tdd, Jˆ2.3, 4.8, 11.8 Hz, 1H), 2.05 0s, 3H), 1.96 0br dd,
Jˆ5.0, 12.2 Hz, 1H), 1.87±1.79 0m, 2H), 1.43 0dt, Jˆ9.7,
11.9 Hz, 1H), 1.29 0q, Jˆ12.1 Hz, 1H), 1.06 0s, 9H); 13C
NMR 0CDCl3) d 171.0, 135.7, 134.0, 129.8, 127.8, 101.0,
69.1, 68.4, 60.0, 56.5, 38.6, 37.3, 37.0, 27.0, 21.4, 19.4;
FAB-HRMS m/z 463.2489 0calcd for C26H36O5SiLi
1
Rf 0.49 0hexane±ethyl acetateˆ4:1); H NMR 0CDCl3) d
7.67±7.61 0m, 4H), 7.46±7.34 0m, 6H), 4.54 0dd, Jˆ2.7,
9.0 Hz, 1H), 3.95±3.85 0m, 2H), 3.79 0td, Jˆ5.1, 10.2 Hz,
1H), 3.46 0s, 3H), 2.66 0ddd, Jˆ2.6, 3.9, 14.8 Hz, 1H), 2.43
0dd, Jˆ9.7, 14.8 Hz, 1H), 2.38 0br d, Jˆ15.1 Hz, 1H), 4H),
2.28 0dd, Jˆ11.3, 15.1 Hz, 1H), 1.92±1.84 0m, 2H), 1.04 0s,
9H); 13C NMR 0CDCl3) d 205.9, 135.7, 133.8, 129.9, 127.9,
101.2, 68.2, 59.7, 56.6, 48.1, 47.1, 38.9, 27.1, 19.4; FAB-
HRMS m/z 419.2238 0calcd for C24H32O4SiLi [M1Li]1 m/z
419.2230). Anal. calcd for C24H32O4Si: C, 69.86; H, 7.82.
Found: C, 69.85; H, 7.79.
2.1.3. Reduction of 12 with LiAlH-tBuO)3. To a solution
of 12 01.764 g, 4.275 mmol) in dry THF 020 mL) was added,

6014
P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
[M1Li]1 m/z 463.2492). Anal. calcd for C26H36O5Si: C,
68.38; H, 7.95. Found: C, 68.38; H, 7.92.
9:1±4:1 gradient) to give 19 as a colorless oil 00.4632 g,
1
89%); H NMR 0CDCl3) d 9.70 0dd, Jˆ1.7, 2.4 Hz, 1H),
7.68±7.63 0m, 4H), 7.45±7.35 0m, 6H), 5.07 0br m,
1/2Wˆ26 Hz, 1H), 4.54 0m, 1H), 4.00 0tt, Jˆ4.1, 8.1 Hz,
1H), 3.81±3.65 0m, 2H), 2.77 0ddd, Jˆ2.5, 8.4, 16.4 Hz,
1H), 2.50 0ddd, Jˆ1.7, 5.5, 16.4 Hz, 1H), 2.04 0s, 3H),
2.01±1.90 0m, 2H), 1.80±1.64 0m, 3H), 1.45 0td, Jˆ8.3,
14.2 Hz, 1H), 1.04 0s, 9H). Anal. calcd for C27H36O5Si: C,
69.19; H, 7.74. Found: C, 69.07; H, 7.79.
2.1.6. Allylation of 15 with TMSOTf. A solution of 15
00.2244 g, 0.4913 mmol) in anhydrous CH3CN 05 mL)
was cooled to 08C. To the cooled solution was added allyl-
trimethylsilane 05 mL, 3.6 g, 31 mmol). After stirring for
10 min, trimethylsilyl tri¯ate 00.048 mL, 0.055 g,
0.246 mmol) was added dropwise via syringe. The reaction
mixture was stirred for ca. 15 min, diluted withwater, and
extracted with ether. The combined ether extracts were
dried 0MgSO4) and the solvent evaporated. The residue
was puri®ed by chromatography 0hexane±ethyl
acetateˆ9:1) to give 16 as a pale yellow oil 00.1684 g,
73%): Rf 0.65 0hexane±ethyl acetateˆ9:1); 1H NMR
0CDCl3) d 7.68±7.64 0m, 4H), 7.46±7.35 0m, 6H), 5.77
0tdd, Jˆ7.0, 10.3, 17.0 Hz, 1H), 5.07±4.80 0m, 3H), 4.05±
3.92 0m, 2H), 3.84±3.67 0m, 3H), 2.46 0td, Jˆ7.2, 14.4 Hz,
1H), 2.23 0td, Jˆ7.0, 14.2 Hz, 1H), 2.04 0s, 3H), 1.90±1.78
0m, 2H), 1.72±1.62 0m, 2H), 1.38 0td, Jˆ9.3, 13.0 Hz, 1H),
1.05 0s, 9H); 13C NMR 0CDCl3) d 170.8, 135.8, 134.9,
134.1, 129.8, 127.9, 117.3, 70.9, 67.7, 66.0, 60.5, 38.5,
37.1, 36.6, 33.9, 27.0, 21.6, 19.4; FAB-HRMS m/z
473.2730 0calcd for C28H38O4SiLi [M1Li]1 m/z
473.2699). Anal. calcd for C28H38O4Si: C, 72.05; H, 8.21.
Found: C, 71.65; H, 8.07.
2.1.9. Bis-pyran -20). To a solution of aldehyde 19
00.2101 g, 0.4489 mmol) in ether 010 mL) cooled to
2788C was added dropwise 1-methoxy-3-trimethylsilyl-
oxy-1,3-butadiene 00.127 g, 0.735 mmol) in ether 05 mL).
After stirring for 5 min, a solution of ZnCl2 00.73 mL,
1.0 M in ether, 0.73 mmol) was added. The mixture was
stirred for 3 hat 2788C, then warmed to room temperature
and stirring was continued for 4 h. Saturated aqueous
NaHCO3 was added, the reaction was stirred for 30 min,
and then extracted with ether 03£10 mL). The combined
organic layers were dried 0MgSO4) and the solvent evapo-
rated to afford a reddishbrown oil. Tihs residue was
dissolved in CH2Cl2 015 mL), tri¯uoroacetic acid 03 drops)
was added, and the mixture stirred for 8 h at rt. Saturated
aqueous NaHCO3 was added, the mixture stirred for 30 min,
the layers separated, and the aqueous layer extracted with
CH2Cl2 04£10 mL). The combined organic layers were
dried 0MgSO4) and the solvent evaporated. The residue
was puri®ed by chromatography 0hexane±ethyl
acetateˆ9:1) to give 20 as a pale orange oil 00.1092 mg,
2.1.7. Allylation of 15 with BF3´Et2O. A solution of 15
095.4 mg, 0.209 mmol) in dry CH2Cl2 03 mL) was cooled
to 08C. To the cooled solution was added allyltrimethyl-
silane 00.1 mL, 0.63 mmol). After stirring for 10 min,
BF3´Et2O 00.04 mL, 0.4 mmol) was added dropwise via
syringe. The reaction mixture was stirred for 20 min at
08C, and then warmed to room temperature and stirred for
3 h, diluted with saturated aqueous NaHCO3, and extracted
withCH 2Cl2 02£10 mL). The combined extracts were dried
0MgSO4) and the solvent evaporated. The residue was puri-
®ed by chromatography 0hexane±ethyl acetateˆ19:1) to
give 17 030.1 mg, 35%) followed by 16 025.3 mg, 26%)
bothas colorless oil.
1
45%). Analysis by H NMR spectroscopy indicated that
1
this is a mixture of diastereomers at C11 0ca. 2:1); H
NMR 0CDCl3) d 7.65±7.60 0m, 4H), 7.46±7.33 0m, 6H),
7.20 0d, Jˆ6.1 Hz, 0.65H) and 7.17 0d, Jˆ5.7 Hz, 0.35H),
5.36 0d, Jˆ6.1 Hz) and 5.35 0d, Jˆ6.2 Hz, total 1H), 5.08
0m, 1H), 4.53 0m, 1H), 4.26 0m, 1H), 3.99 0m, 1H), 3.81±
3.62 0m, 2H), 2.53±2.32 0m, 2H), 2.05 0s, 3H), 2.01±1.92
0m, 2H), 1.84±1.64 0m, 3H), 1.45 0td, Jˆ8.3, 13.1 Hz, 1H),
1.02 0s, 9H); EI-HRMS m/z 479.1887 0calcd for C27H31O6Si
[M2tBu]1 m/z 479.1890).
17: Rf 0.78 0hexane±ethyl acetateˆ19:1); 1H NMR 0CDCl3)
d 7.72±7.65 0m, 4H), 7.46±7.35 0m, 6H), 5.91±5.77 0m,
2H), 5.72 0br d, Jˆ10.2 Hz, 1H), 5.10±5.00 0m, 2H), 4.16
0br s, 1H), 3.98 0dddd, Jˆ4.2, 4.2, 8.4, 8.4 Hz, 1H), 3.89±
3.71 0m, 2H), 2.41 0td, Jˆ7.2, 14.1 Hz, 1H), 2.24 0td, Jˆ7.1,
14.1 Hz, 1H), 2.07±1.65 0m, 4H), 1.06 0s, 9H). This product
was not further characterized.
2.1.10. Chiral allylation of 19. To a solution of 02)-b-
methoxydiisopinocampheylborane 04.00 g, 12.6 mmol) in
anhydrous toluene 030 mL) at 2788C was added via syringe
a solution of allylmagnesium bromide 012.4 mL, 1.0 M in
ether, 12.4 mmol). The reaction mixture was stirred at
2788C for 15 min and then warmed to room temperature
over 1.5 h. A white precipitate of magnesium salts formed
during this time. The reaction mixture was transferred, via
syringe, into four equal portions in four centrifuge tubes.
After centrifugation, the salt-free solution was transferred
into a second ¯ask containing a solution of 19 02.26 g,
2.1.8. Aldehyde -19). A solution of 16 00.5200 g,
1.114 mmol) in dry CH2Cl2 015 mL) was cooled to 2788C
in a dry ice/acetone bath. The system was purged with
carrier gas 0compressed air) for 20 min, and then ozone
0generated from the compressed air with a Welsbach appa-
ratus) was bubbled through the solution until a blue color
persisted 0ca. 15 min). The system was purged with carrier
gas until the blue color disappeared. Triphenylphosphine
01.39 g, 5.31 mmol) was added and the mixture was stirred
and allowed to warm to rt over a period of 2.5 h. The
reaction mixture diluted withbrine and stirred for 10 min.
The mixture was extracted with CH2Cl2 02£10 mL) and the
combined extracts dried 0MgSO4), and concentrated. The
residue was puri®ed by chromatography 0hexane±acetone,
Ê
4.81 mmol) and 4 A molecular sieves in anhydrous toluene
010 mL) at 2788C. The reaction mixture was stirred at
2788C for 6 h, and then slowly warmed to room tempera-
ture overnight. Proton NMR monitoring indicated dis-
appearance of the starting aldehyde. Solid sodium
perborate 03.4 g) and water 05 mL) were added and the
resultant mixture was heated at re¯ux for 1 h. After cooling
to room temperature, brine was added and the reaction
mixture stirred for 20 min. The mixture was ®ltered through
®lter-aid and the ®lter bed washed with ether 03£100 mL).
The combined organic phases were dried 0MgSO4) and

P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
6015
concentrated. The residue was puri®ed by column chroma-
tography 0hexane±ethyl acetateˆ19:1) to give 22 01.044 g,
42%) followed by 23 01.009 g, 41%) bothas colorless oils.
66.8, 66.5, 60.5, 55.4, 38.0, 37.4, 35.9, 34.2, 26.9, 26.8,
21.2, 19.2. This product was not further characterized.
2.1.13. -R)-MTPA ester of 23. The preparation of the 0R)-
MTPA ester of 01)-23 was carried out in the same fashion
as the preparation of the 0R)-MPTA ester 02)-22 047%).
Analysis by 1H NMR spectroscopy indicated that the
product was .90% de: Rf 0.35 0hexane±ethyl acetateˆ4:1);
1H NMR 0CDCl3) d 7.68±7.63 0m, 4H), 7.52±7.50 0m, 2H),
7.41±7.34 0m, 9H), 5.71 0tdd, Jˆ7.1, 10.0, 17.0 Hz, 1H),
5.35±5.22 0m, 1H), 5.10±4.95 0m, 3H), 3.93±3.76 0m, 3H),
3.71 0td, Jˆ5.3, 10.6 Hz, 1H), 3.54 0s, 3H), 2.42 0m, 2H),
2.01 and 2.06±1.75 0s and m, 5H), 1.88±1.65 0m, 4H),
1.45±1.20 0m, 2H), 1.06 0s, 9H). This product was not
further characterized.
02)-22: Rf 0.60 0hexane±ethyl acetateˆ1:1); [a]Dˆ26.9 0c
0.94, CHCl3); IR 0neat) 3483, 3068, 1736, 1639, 989,
1
912 cm21; H NMR 0CDCl3) d 7.65±7.60 0m, 4H), 7.46±
7.33 0m, 6H), 5.82 0tdd, Jˆ7.1, 10.8, 16.5 Hz, 1H), 5.15±
5.05 0m, 3H), 4.21±4.07 0m, 2H), 3.84±3.67 0m, 3H), 3.16
0OH), 2.23 0t, Jˆ6.4 Hz, 2H), 2.03 and 2.06±1.94 0s and m,
5H), 1.88±1.65 0m, 4H), 1.52 0td, Jˆ3.3, 14.2 Hz, 1H), 1.48
0td, Jˆ7.7, 13.2 Hz, 1H), 1.06 0s, 9H); 13C NMR 0CDCl3) d
170.2, 135.5, 134.7, 133.8, 129.6, 127.6, 117.4, 70.6, 69.7,
67.2, 66.9, 60.4, 41.7, 38.9, 37.5, 35.2, 35.1, 26.8, 21.2,
19.1. Anal. calcd for C30H42O5Si: C, 70.55; H, 8.29.
Found: C, 70.51; H, 8.34.
2.1.14. -S)-MTPA ester of 23. The preparation of the 0S)-
MTPA ester of 01)-23 was carried out in the same fashion
as the preparation of the 0R)-MPTA ester of 02)-22 057%).
Analysis by 1H NMR spectroscopy indicated that the
product was .90% de: Rf 0.29 0hexane±ethyl acetateˆ4:1);
1H NMR 0CDCl3) d 7.68±7.63 0m, 4H), 7.52±7.50 0m, 2H),
7.41±7.34 0m, 9H), 5.60 0tdd, Jˆ7.2, 10.1, 17.4 Hz, 1H),
5.35±5.22 0m, 1H), 5.10±4.95 0m, 3H), 4.08 0qd, Jˆ3.7,
11.3 Hz, 1H), 3.99±3.80 0m, 2H), 3.71 0m, 1H), 3.58 0s,
3H), 2.50±2.30 0m, 2H), 2.03 and 2.12±1.90 0s and m,
5H), 1.88±1.50 0m, 6H), 1.07 0s, 9H). This product was
not further characterized.
01)-23: Rf 0.55 0hexane±ethyl acetateˆ1:1); [a]Dˆ121.9
0c 1.00, CHCl3); IR 0neat) 3457, 3068, 1736, 1644, 994,
1
917 cm21; H NMR 0CDCl3) d 7.65±7.60 0m, 4H), 7.46±
7.33 0m, 6H), 5.73 0tdd, Jˆ7.3, 9.9, 17.4 Hz, 1H), 5.13±5.02
0m, 3H), 4.27 0m, 1H), 3.98 0tt, Jˆ4.2, 8.4 Hz, 1H), 3.86±
3.77 0m, 2H), 3.70 0m, 1H), 2.27±2.10 0m, 2H), 2.04 0s, 3H),
2.00±1.85 0m, 3H), 1.77±1.64 0m, 3H), 1.47±1.35 0m, 2H),
1.04 0s, 9H), OH not observed; 13C NMR 0CDCl3) d 170.3,
135.5, 134.5, 133.8, 129.6, 127.6, 117.9, 67.6, 67.0, 66.8,
66.1, 60.4, 42.3, 38.8, 37.9, 35.8, 34.9, 26.8, 21.1, 19.1.
Anal. calcd for C30H42O5Si: C, 70.55; H, 8.29. Found: C,
70.25; H, 8.35.
2.1.15. Acrylate -2)-26. To a solution of 02)-22 0105 mg,
0.206 mmol) in CH2Cl2 05 mL) at 08C was triethylamine
00.09 mL, 0.62 mmol) and DMAP 02.5 mg, 0.021 mmol).
Acryloyl chloride 00.02 mL, 0.25 mmol) was added via
syringe and the solution was stirred at 08C for 20 min, and
then warmed to room temperature and stirred for 2 h. The
reaction mixture was poured into a separatory funnel with
saturated aqueous NaHCO3. The layers were separated and
the aqueous layer was washed with methylene chloride
03£20 mL). The combined organic layers were dried
0MgSO4) and concentrated. The residue was puri®ed by
column chromatography 0hexane±ethyl acetateˆ4:1) to
give 02)-26 as a colorless oil 060.3 mg, 52%): Rf 0.27
0hexane±ethyl acetateˆ4:1), [a]Dˆ24.0 0c 1.26, CHCl3);
IR 3073, 3042, 1788, 1726, 1636, 1619, 998, 989, 939,
2.1.11. -R)-MTPA ester of 22. To a solution of 02)-22
052.9 mg, 0.104 mmol) in CH2Cl2 08 mL) was added 0R)-
a-methoxy0tri¯uoromethyl)phenyl acetic acid 073.0 mg,
0.310 mmol), DMAP 05.0 mg, 0.04 mmol) and DCC
00.35 mL, 0.35 mmol). The reaction mixture was stirred
for 3 h, and then washed with 3% aqueous HCl, followed
by brine, dried 0MgSO4) and concentrated. The residue was
puri®ed by column chromatography 0hexane±ethyl ace-
tateˆ19:1) to give a colorless oil 045.4 mg, 60%). Analysis
1
by H NMR spectroscopy indicated that the product was
1
.90% de: Rf 0.55 0hexane±ethyl acetateˆ7:3); H NMR
0CDCl3) d 7.68±7.63 0m, 4H), 7.53±7.50 0m, 2H), 7.41±
7.34 0m, 9H), 5.76±5.62 0m, 1H), 5.18±4.99 0m, 4H), 4.01±
3.90 0m, 2H), 3.82±3.66 0m, 3H), 3.51 0s, 3H), 2.46±2.39
0m, 2H), 2.03 and 2.12±1.80 0s and m, 5H), 1.76±1.62 0m,
4H), 1.37 0td, Jˆ9.0, 13.1 Hz, 1H), 1.03 0s, 9H); 13C NMR
0CDCl3) d 170.3, 166.0, 135.5, 133.9, 133.8, 132.9, 132.2,
129.6, 128.3, 127.6, 127.4, 118.6, 73.9, 67.2, 66.7, 66.4,
60.4, 55.4, 38.1, 37.5, 36.0, 35.4, 34.1, 26.9, 26.8, 21.3,
21.2, 19.1. This product was not further characterized.
1
919 cm21; H NMR 0CDCl3) d 7.65±7.60 0m, 4H), 7.46±
7.33 0m, 6H), 6.38 0dd, Jˆ1.3, 17.4 Hz, 1H), 6.09 0dd,
Jˆ10.1, 17.4 Hz, 1H), 5.79 0dd, Jˆ1.5, 10.1 Hz, 1H), 5.73
0tdd, Jˆ6.9, 11.0, 16.5 Hz, 1H), 5.10±4.95 0m, 4H), 4.07 0br
m, 1H), 3.97 0dddd, Jˆ2.9, 4.9, 7.9, 9.8 Hz, 1H), 3.85±3.67
0m, 2H), 2.37 0m, 2H), 2.03 0s, 3H), 2.10±1.64 0m, 7H), 1.34
0td, Jˆ9.4, 12.6 Hz, 1H), 1.05 0s, 9H); 13C NMR 0CDCl3) d
170.3, 165.5, 135.5, 133.7, 133.2, 130.6, 129.5, 128.6,
127.6, 118.1, 70.9, 68.1, 67.3, 66.2, 60.4, 38.3, 38.2, 36.4,
35.7, 34.0, 26.8, 21.2, 19.1; FAB-HRMS m/z 507.2187
0calcd for C29H35O6Si [M2tBu]1 m/z 507.2203).
2.1.12. -S)-MTPA ester of 22. The preparation of the 0S)-
MTPA ester of 02)-22 was carried out in the same fashion
as the preparation of the 0R)-MPTA ester 093%). Analysis
1
by H NMR spectroscopy indicated that the product was
1
.90% de: Rf 0.55 0hexane±ethyl acetateˆ7:3); H NMR
0CDCl3) d 7.68±7.63 0m, 4H), 7.52±7.49 0m, 2H), 7.41±
7.33 0m, 9H), 5.62±5.48 0m, 1H), 5.18±4.94 0m, 4H), 4.10±
3.92 0m, 2H), 3.84±3.68 0m, 2H), 3.51 0s, 3H), 2.45±2.27
0m, 2H), 2.10 0m, 1H), 2.03 and 2.03±1.82 0s and m, 5H),
1.78±1.55 0m, 4H), 1.45±1.32 0m, 1H), 1.04 0s, 9H); 13C
NMR 0CDCl3) d 170.5, 165.9, 135.5, 133.9, 133.8, 132.9,
132.5, 132.2, 129.6, 128.3, 127.6, 127.4, 118.6, 73.8, 67.2,
2.1.16. Acrylate -1)-27. Reaction of acryloyl chloride with
01)-23 was carried out in a fashion similar to the prepara-
tion of acrylate ester of 02)-22 052%): Rf 0.53 0hexane±
ethyl acetateˆ7:3), [a]Dˆ130.2 0c 1.06, CHCl3); IR
1
3073, 3037, 1739, 1726, 1634, 1614, 983, 917 cm21; H
NMR 0CDCl3) d 7.69±7.64 0m, 4H), 7.43±7.34 0m, 6H),
6.37 0dd, Jˆ1.8, 17.3 Hz, 1H), 6.09 0dd, Jˆ10.2, 17.3 Hz,

6016
P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
1H), 5.78 0dd, Jˆ1.8, 10.3 Hz, 1H), 5.70 0tdd, Jˆ7.1, 10.4,
17.3 Hz, 1H), 5.14 0m, 1H), 5.08±4.96 0m, 3H), 4.12±4.04
0m, 1H), 3.95±3.80 0m, 2H), 3.67 0td, Jˆ5.9, 10.0 Hz, 1H),
2.35 0m, 2H), 2.02 and 2.09±1.90 0s and m, 5H), 1.84±1.55
0m, 5H), 1.33 0td, Jˆ9.7, 12.7 Hz, 1H), 1.04 0s, 9H); 13C
NMR 0CDCl3) d 170.4, 165.4, 135.5, 133.9, 133.1, 130.4,
129.5, 128.7, 127.6, 118.1, 70.5, 67.6, 67.5, 65.6, 60.2, 39.1,
38.3, 36.4, 35.8, 34.9, 26.8, 21.2, 19.2; FAB-HRMS
m/z 571.3072 0calcd for C33H44O6SiLi [M1Li]1 m/z
571.3067).
NaHCO3 was added and the layers were separated. The
aqueous layer was extracted withether 04 £20 mL) and the
combined organic phases were dried 0MgSO4) and concen-
trated. Excess DEAD was removed by kugelrohr distillation
and the residue was puri®ed by column chromatography
0hexane±ethyl acetateˆ7:3), to give 01)-28 00.286 g,
51%) as a pale yellow oil: Rf 0.77 0hexane±ethyl
acetateˆ1:1); [a]Dˆ18.1 0c 0.94, CHCl3); IR 3067, 3048,
1726, 1639, 1608, 1521, 1352, 921 cm21; 1H NMR 0CDCl3)
d 8.25 and 8.16 0AA0BB0, Jˆ9.0 Hz, 4H), 7.68±7.63 0m,
4H), 7.42±7.34 0m, 6H), 5.78 0tdd, Jˆ7.1, 10.1, 17.1 Hz,
1H), 5.24 0tt, Jˆ5.7, 6.7 Hz, 1H), 5.13±5.01 0m, 3H), 4.16±
4.08 0m, 1H), 4.02±3.92 0m, 1H), 3.81±3.64 0m, 2H), 2.57±
2.40 0m, 2H), 2.23 0ddd, Jˆ7.1, 8.6, 14.5 Hz, 1H), 2.02 0s,
3H), 1.86±1.64 0m, 5H), 1.43±1.19 0m, 2H), 1.03 0s, 9H);
13C NMR 0CDCl3) d 170.3, 164.0, 150.4, 135.7, 135.5,
133.7, 132.9, 130.6, 129.5, 127.6, 123.4, 118.5, 72.7, 68.1,
67.2, 66.2, 60.3, 38.2, 38.0, 36.3, 35.7, 34.2, 26.7, 21.2,
19.1; FAB-HRMS m/z 666.3054 0calcd for C37H45O8NSiLi
[M1Li]1 m/z 666.3075).
2.1.17. Dihydropyran-2-one -2)-5. To a solution of 02)-
26 057.2 mg, 0.101 mmol) in degassed CH2Cl2 050 mL) was
added, via syringe, Ti0iPrO)4 00.01 mL, 0.03 mmol). The
reaction mixture was heated at re¯ux for 1 h, and then
cooled to room temperature. A solution of `Grubbs'
catalyst' 016.7 mg, 0.020 mmol) in CH2Cl2 010 mL) was
added via cannula transfer at room temperature and the
reaction mixture was stirred for 20 h. The mixture was
®ltered through a small bed of silica gel and the ®lter bed
washed with ethyl acetate 03£10 mL). The combined
organic layers were washed with brine, dried 0MgSO4)
and concentrated. The residue was puri®ed by column chro-
matography 0hexane±ethyl acetateˆ7:3) to give 02)-5 as a
colorless oil 039.9 mg, 73%): Rf 0.065 0hexane±ethyl
acetateˆ7:3); [a]Dˆ238 0c 1.0, CHCl3); IR 1731,
2.1.20. Hydrolysis of -1)-28. A solution of 01)-28
078.5 mg, 0.119 mmol) in saturated methanolic K2CO3
010 mL) was stirred at rt until TLC monitoring indicated
complete comsumption of starting material. Aqueous HCl
01% by volume) was added until the solution was neutral.
The reaction mixture was extracted with ether 04£25 mL),
and the combined organic layers were dried 0MgSO4) and
concentrated. The residue was puri®ed by column chroma-
tography 0hexane±ethyl acetateˆ1:1) to give 01)-29
040.3 mg, 72%) as a colorless oil: Rf 0.17 0hexane±ethyl
acetateˆ1:1); [a]Dˆ19.4 0c 0.73, CHCl3); IR 3396,
1
704 cm21; H NMR 0CDCl3) d 7.68±7.61 0m, 4H), 7.46±
7.32 0m, 6H), 6.77 0ddd, Jˆ3.3, 5.3, 9.6 Hz, 1H), 5.97 0br d,
Jˆ10.1 Hz, 1H), 5.06 0tt, Jˆ4.5, 9.0 Hz, 1H), 4.52 0m, 1H),
4.24 0dq, Jˆ4.6, 9.1 Hz, 1H), 3.97 0tt, Jˆ4.2, 8.4 Hz, 1H),
3.81±3.63 0m, 2H), 2.36 0m, 2H), 2.28 0ddd, Jˆ5.5, 9.3,
15.3 Hz, 1H), 2.03 0s, 3H), 1.97 0td, Jˆ3.1, 12.7 Hz, 1H),
1.86±1.62 0m, 5H), 1.39 0td, Jˆ9.2, 12.9 Hz, 1H), 1.02 0s,
9H); 13C NMR 0CDCl3) d 170.3, 164.1, 144.9, 135.5, 133.8,
129.6, 127.7, 121.4, 75.0, 67.2, 66.4, 65.9, 60.2, 38.1, 36.8,
36.2, 34.4, 28.7, 26.8, 21.2, 19.2; FAB-HRMS m/z 479.1882
0calcd for C27H31O6Si [M2tBu]1 m/z 479.1890).
1107 cm21 1H NMR 0CDCl3) d 7.69±7.64 0m, 4H),
;
7.45±7.36 0m, 6H), 5.89±5.75 0m, 1H), 5.13±5.07 0m,
2H), 4.26±4.21 0m, 1H), 4.05±3.97 0m, 2H), 3.85±3.69
0m, 3H), 3.24 0OH), 2.23 0t, Jˆ6.5 Hz, 1H), 2.00±1.57
0m, 8H), 1.46 0br d, Jˆ14.4 Hz, 1H), 1.35 0td, Jˆ7.9,
13.0 Hz, 1H), 1.05 0s, 9H); 13C NMR 0CDCl3) d 135.5,
134.8, 133.7, 129.6, 127.6, 117.4, 70.8, 70.4, 67.0, 64.2,
60.4, 41.7, 38.9, 38.7, 38.5, 37.7, 26.8, 19.1. This
product was used in the next reaction without further
characterizaton.
2.1.18. Dihydropyran-2-one -1)-7. The reaction of 01)-27
with Grubbs' catalyst 00.97 equiv.) in methylene chloride
was carried out in a fashion similar to the ring closing
metathesis of 02)-26, except that the reaction was run at
room temperature for 20 h. Work-up and puri®cation as
before gave 01)-7 as a colorless oil 089%): Rf 0.14 0hexane±
ethyl acetateˆ7:3); [a]Dˆ17.7 0c 1.16, CHCl3); IR 3067,
2.1.21. Hydrolysis of -2)-22. The hydrolysis of 02)-22 in
saturated methanolic K2CO3 was carried out in a fashion
similar to the hydrolysis of 01)-28 to give 02)-29 088%):
The 1H and 13C NMR spectra of 02)-29 were identical with
01)-29. [a]Dˆ25.7 0c 0.88, CHCl3).
1
1726, 1235 cm21; H NMR 0CDCl3) d 7.64±7.59 0m, 4H),
7.44±7.33 0m, 6H), 6.70 0ddd, Jˆ3.0, 5.5, 9.6 Hz, 1H), 5.94
0dd, Jˆ2.5, 9.7 Hz, 1H), 5.08 0tt, Jˆ4.3, 8.7 Hz, 1H), 4.57
0m, 1H), 4.34 0m, 1H), 4.02 0tt, Jˆ4.1, 8.4 Hz, 1H), 3.84
0ddd, Jˆ4.0, 9.5, 9.8 Hz, 1H), 3.68 0td, Jˆ4.9, 10.2 Hz, 1H),
2.31±2.11 0m, 2H), 2.04 0s, 3H), 2.04±1.62 0m, 7H), 1.44
0td, Jˆ8.2, 13.4 Hz, 1H), 1.02 0s, 9H); 13C NMR 0CDCl3) d
170.4, 164.0, 144.8, 135.4, 133.9, 133.6, 129.6, 127.6,
121.3, 74.4, 67.3, 65.5, 65.4, 60.0, 38.0, 37.7, 35.8, 35.0,
29.8, 26.8, 21.3, 19.2. This product was not further
characterized.
2.1.22. Bisacrylate -1)-30. The bisacrylate ester 01)-30
043%) of 01)-29 was prepared in the same fashion as the
acrylate ester of 02)-22: Rf 0.78 0hexane±ethyl
acetateˆ1:1), [a]Dˆ115.5 0c 0.976, CHCl3); IR 3068,
1726 cm21 1H NMR 0CDCl3) d 7.69±7.64 0m, 4H),
;
7.43±7.34 0m, 6H), 6.40 and 6.38 02£dd, Jˆ1.6, 17.2 Hz,
2H), 6.09 02£dd, Jˆ10.3, 17.3 Hz, 2H), 5.83 and 5.79
02£dd, Jˆ1.6, 10.3 Hz, 1H), 5.74 0m, 1H), 5.17±5.00 0m,
2H), 4.15±4.05 0m, 1H), 4.03±3.95 0m, 1H), 3.85±3.68 0m,
2H), 2.38 0m, 2H), 2.07 0td, Jˆ7.5, 14.5 Hz, 1H), 2.00 0br d,
Jˆ12.9 Hz, 1H), 1.90±1.65 0m, 5H), 1.40 0td, Jˆ9.5,
12.7 Hz, 1H), 1.04 0s, 9H); 13C NMR 0CDCl3) d 165.6,
165.4, 135.5, 133.8, 133.7, 132.2, 130.7, 130.6, 129.5,
128.7, 128.6, 127.6, 118.2, 70.9, 68.0, 67.5, 66.2, 60.3,
2.1.19. Mitsunobu inversion of -1)-23. To a stirred slurry
of 01)-23 0358 mg, 0.702 mmol), triphenylphosphine
0442 mg, 1.68 mmol), and p-nitrobenzoic acid 0282 mg,
1.68 mmol) in toluene 05 mL) at 2308C was added diethyl
azodicarboxylate 00.26 mL, 1.7 mmol). The reaction
mixture was warmed to rt overnight. Saturated aqueous

P. B. Greer, W. A. Donaldson / Tetrahedron 58 02002) 6009±6018
6017
Lett. 1998, 39, 7185±7188. 0s) Rychnovsky, S. D.; Thomas,
C. R. Org. Lett. 2000, 2, 1217±1219. 0t) Schaus, J. V.; Panek,
J. S. Org. Lett. 2000, 2, 469±471. 0u) White, J. D.;
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4006.
38.2, 36.3, 35.8, 34.0, 26.8, 19.1. This product was used in
the next reaction without further characterizaton.
2.1.23. Dihydropyran-2-one -1)-6. The reaction of 01)-30
withGrubbs' catalyst 00.07 equiv.) in CH Cl2 was carried
2
out in a fashion similar to the ring closing metathesis of 02)-
22, except that the reaction was run at room temperature for
48 h. Work-up and puri®cation as before gave 01)-6 as a
colorless oil 079%): Rf 0.56 0hexane±ethyl acetateˆ1:1);
3. 0a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 120, 5597±5598. 0b) Evans, D. A.; Cee,
V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem.,
Int. Ed. Engl. 2000, 39, 2533±2536. 0c) Evans, D. A.; Fitch,
D. M. Angew. Chem., Int. Ed. Engl. 2000, 39, 2536±2540.
0d) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J.
J. Am. Chem. Soc. 2000, 122, 10033±10046. 0e) Smith, III,
A. B.; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am.
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1
[a]Dˆ145.0 0c 0.732, CHCl3); IR 1721 cm-1; H NMR
0CDCl3) d 7.66±7.61 0m, 4H), 7.45±7.34 0m, 6H), 6.77
0ddd, Jˆ3.3, 5.1, 9.5 Hz, 1H), 6.41 0dd, Jˆ1.5, 17.4 Hz,
1H), 6.10 0dd, Jˆ10.7, 17.4 Hz, 1H), 5.98 0td, Jˆ1.9,
9.6 Hz, 1H), 5.85 0dd, Jˆ1.6, 10.4 Hz, 1H), 5.16 0tt,
Jˆ4.8, 8.7 Hz, 1H), 4.53 0m, 1H), 4.25 0dq, Jˆ9.6,
4.9 Hz, 1H), 4.00 0tt, Jˆ4.1, 8.0 Hz, 1H), 3.81±3.64 0m,
2H), 2.39±2.24 0m, 3H), 2.01 0td, Jˆ3.5, 13.0 Hz, 1H),
1.90±1.69 0m, 5H), 1.45 0td, Jˆ9.0, 12.9 Hz, 1H), 1.03 0s,
9H); 13C NMR 0CDCl3) d 165.5, 164.2, 144.9, 135.5, 133.7,
133.6, 131.0, 128.5, 127.7, 121.4, 75.0, 67.4, 66.3, 65.8,
60.1, 38.0, 36.8, 36.0, 34.3, 28.6, 26.8, 19.1; FAB-HRMS
m/z 555.2747 0calcd for C32H40O6SiLi [M1Li]1 m/z
555.2754).
4. Preliminary communication: Greer, P. B.; Donaldson, W. A.
Tetrahedron Lett. 2000, 41, 3801±3803.
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Financial support for this work was provided by the
National Institutes of Health 0GM-42641). The high resolu-
tion mass-spectral determinations were made at the
Washington University Resource for Mass Spectrometry.
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