Synthetic studies toward C3-C9 segment of Soraphen A1α

Article abstract of DOI:10.1080/00397910801929358

The ring-closure metathesis of the diene (2S,3R,4S)-1-(tert- butyldiphenylsilyloxy)-2,4-dimethylhex-5-en-3-yl acrylate produced the dihydropyrone with the correct stereochemistry for Soraphen A1α synthesis. The C2,C3 stereocenters were introduced by the a

Full text of DOI:10.1080/00397910801929358

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Synthetic Studies toward C3‐C9 Segment of
Soraphen A1α
Ahmad Farouk Eweas a
a Medicinal Chemistry Department , National Research Center , Dokki, Cairo,
Egypt
Published online: 24 Apr 2008.
To cite this article: Ahmad Farouk Eweas (2008) Synthetic Studies toward C3‐C9 Segment of Soraphen A1α
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Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:10, 1541-1552, DOI: 10.1080/00397910801929358
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Synthetic Communicationsw, 38: 1541–1552, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801929358
Synthetic Studies toward C3-C9 Segment of
Soraphen A1a
Ahmad Farouk Eweas
Medicinal Chemistry Department, National Research Center, Dokki,
Cairo, Egypt
Abstract: The ring-closure metathesis of the diene (2S,3R,4S)-1-(tert-butyldiphenylsi-
lyloxy)-2,4-dimethylhex-5-en-3-yl acrylate produced the dihydropyrone with the
correct stereochemistry for Soraphen A1a synthesis. The C2,C3 stereocenters were
introduced by the addition of the (Z)-crotyl-n-butylstannane to the b-alkoxyalde-
hyde(S)-3-(benzyloxy)-2-methylpropanal in presence of TiCl4 as a chelating catalyst
to give the desired anti,syn homoallyic alcohol (2S,3R,4S)-1-(tert-butyldiphenylsily-
loxy)-2,4-dimethylhex-5-en-3-ol.
Keywords: Soraphen A1a, ring-closure metathesis, (Z)-crotyl-n-butylstannane
INTRODUCTION
Soraphen A 1 is a macrolide isolated from myxobacterium Sorangium
cellulosum, which exhibits potent antifungal activity against various patho-
genic plant fungi.[1,2] Soraphen A has highly efficient and specific inhibitory
action on acetyl CoA carboxylase. The structure was well defined by X-ray
crystallographic study. This 18-membered macrolide with an unsubstituted
phenyl ring has received considerable attention as a synthetic target.
Numerous synthetic studies have been reported.[3] The only total synthesis
of Soraphen A was reported by Giese in 1999.[3b] We reported the synthesis
of C11–C17 fragment 2 of Soraphen A.[4] See Fig. 1.
Received in Poland August 8, 2007
Address correspondence to Ahmad Farouk Eweas, Medicinal Chemistry Depart-
ment, National Research Center, Eltahrir st., Dokki 12311, Egypt. E-mail: eweas1@
gawab.com
1541

1542
A. F. Eweas
Figure 1. Soraphen A1a
.
RESULTS AND DISCUSSION
Our design for the synthesis of C1-C9 fragment of Soraphen A1a was essen-
tially based on the Lewis acid–catalyzed diene-aldehyde cycloaddition
(LACDAC) reaction[5] of diene 3 with aldehyde[6] 4 (Fig. 2). It was antici-
pated that this would establish the C6 and C7 stereocenters of the dihydro-
pyran ring.
However, because of problems in obtaining the correct stereochemistry at
C6, C7 of Soraphen A1a, our focus was shifted to an alternative route for the
preparation of the vital dihydropyrone with the correct stereochemistry for
Soraphen A1a (Fig. 3).
The key step in this route is a ring-closing metathesis[7] of the acylate
ester 5. The requisite 2(S),4(S)-dimethyl-hex-5-en-3(R)-ol 7a,b was
prepared by the chelation-controlled addition of (Z)-crotyl-n-butylstannane
to the b-alkoxy aldehydes 4a or b using titanium tetrachloride.
Reaction of crotyl bromide and tributyltin chloride in the presence of zinc
powder in the mixed cosolvent tetrahydrofuran (THF) and saturated NH4Cl
gave but-2-enyl-tributyl-stannane 8[8] as mixture of (Z/E isomers 8:1) in
Figure 2. C3-C9 Soraphen A1a segment synthesis.

C3-C9 Segment of Soraphen A1a
1543
Figure 3. Retero synthesis of C3-C9 soraphen A1a segment.
79% yield (Scheme 1). Addition of (Z)-crotyltri-n-butylstannane 8 to the
b-alkoxyaldehydes 4a or b in the presence of TiCl4 gave the desired
anti,syn homoallylic alcohol 7a or b[8] in good yields.
Scheme 1. a, P ¼ TBDPS; b, P ¼ Bn.
The stereochemistry of this product is the result of two factors: attack of
the crotyl stannane occurs on the re-face of the chelated aldehyde 4 because of
the steric hindrance of the a-methyl group on approach to the si-face (Fig. 4).
Figure 4. Selective facial approach to chelated aldehydes 4.

1544
A. F. Eweas
The C3,C4 erythro stereochemistry is due to approach of the si-face of the
crotyl stannane (i.e., A) in comparison to approach of the re-face of this
reagent (i.e., B, Fig. 5).
Figure 5. Chelation-controlled addition of b-alkoxy aldehydes to (Z)-crotyl-n-
butylstannane.
The produced alcohols 7a or b were subjected to reaction with acryloyl
chloride in the presence of diisopropylethylamine in anhydrous dichloro-
methane to afford acryloate ester 5a or b in good yields (Scheme 2). The
produced terminal dienes 5a or b were subjected to ring-closing metathesis
(RCM) using 15% Grubbs’s catalyst[7] in anhydrous dichloromethane. The
reaction mixture was then treated with lead tetracetate to remove the
colored ruthenium by-products[9] to afford the unsaturated lactones 6a or b
in good yields.
Scheme 2.
Dihydropyrone 6a was subjected to reduction using diisobutylaluminum
hydride (DIBAL) in anhydrous dichloromethane to afford lactols 8 (93%)
(Scheme 3). The produced lactol 8 was treated with p-toluenesulfonic
acid using isopropyl alcohol in the presence of a catalytic amount of p-tolue-
nesulfonic acid to afford the (1S)-tert-butyl-[(5S,6R)-2-(6-isopropoxy-3-
methyl-3,6-dihydro-2H-pyran-2-yl)-propoxy]-diphenylsilane 9 (82%) via
mixed acetalization. The epoxidation of
9 was carried out with

C3-C9 Segment of Soraphen A1a
1545
m-chloroperoxybenzoic acid (CPBA) in anhydrous dichloromethane to give
tert-butyl-[(2S,5R,6S)-2-(2-isopropoxy-5-methyl-3,7-dioxa-bicyclo[4.1.0]-
hept-4-yl)-propoxy]-diphenylsilane 10 (73%).
Scheme 3.
All attempts for the diaxial cleavage of the epoxides 10 to get the target
C3-C9 1,2-diaxial diol fragment 11 were unsuccessful (Scheme 4).
Scheme 4.
EXPERIMENTAL
General Data
Unless otherwise noted, reactions were carried out in oven-dried glassware.
Spectrograde solvents were used without purification with the exception of tetra-
hydrofuran, which was distilled from sodium benzophenone ketyl, and CH2Cl2,
which was distilled from P2O5. Anhydrous toluene was purchased from the
Aldrich Chemical Co. Elemental analyses were obtained from Midwest
Microlabs, Ltd., Indianapolis, and high-resolution mass spectral (HRMS) deter-
minations were made at the Washington University Resource for Biomedical
and Bio-organic Mass Spectrometry. Melting points were determined for
samples in open capillaries and are uncorrected. All 1H and 13C NMR spectra
were recorded in CDCl3 solution at 300 MHz and 75 MHz respectively. All
chemical shifts are reported in parts per million (ppm) downfield from tetra-
methylsilane signal. All IR spectral data were collected on a Nicolet Magna
IR 560 spectrophotometer. Optical rotations were measured on a Perkin-Elmer

1546
A. F. Eweas
polarimeter 341 at 589 nm and 20 8C. Thin-layer chromatography (TLC) was
performed on Merck Kiesegel 60 F254 and detected by one of the following
methods: ultraviolet visualization, iodine, or vanillin solution [vanillin (8 g),
sulfuric acid (2.5 mL, 96 wt%), ethanol (100 mL)]. Most iron complexes were
stored refrigerated at less than 4 8C.
But-2-enyl-tributyl-stannane (8)
In an oven-dried two-necked round-bottom flask equipped with a magnetic stir
bar and a condenser, Tributyltin chloride (4.17 g, 12.8 mmol) was added to
saturated aqueous NH4Cl (25 mL) and THF (25 mL). An excess amount of
zinc powder (2 g, 2 eq) was added to the reaction mixture. The mixture was
stirred at room temperature for 5 min before crotyl bromide (5.0 g, 3.7
mmol, 2 eq) was slowly added over a period of 30 min using a pressure,
relief dropping funnel. The reaction mixture was stirred at room temperature
for an additional 45 min after addition was completed. The reaction mixture
was then extracted with petroleum ether (40–60 8C, 3 ꢀ 100 mL). The
combined organic layer were dried (MgSO4), and the solvent was evaporated
under reduced pressure to give a crude oil, which was found to be mixture of
Z- and E- isomers (8:1). The spectroscopic data of this product was consistent
with the literature values.[8]
1-Benzyloxy-2(S),4(S)-dimethyl-hex-5-en-3(R)-ol (7a)
Titanium tetrachloride (1.07 g, 5.67 mmol) was added dropwise via a syringe
to a solution of (R)-3-benzyloxy-2-methylpropanal 8 (1.08 g, 5.78 mmol) in
dry CH2Cl2 (60 mL) at 285 8C. The color of the reaction mixture turned
bright yellow. After stirring the solution at 285 8C for 10 min, tributylcrotyl-
stannane (2.0 g, 5.8 mmol) was slowly added via a syringe down the side walls
of the reaction flask. The reaction mixture became colorless. After completion
of the addition, the reaction mixture was stirred at 285 8C for 5 min before
being quenched by addition of a saturated aqueous solution of NaHCO3
(10 mL). The resulting mixture was warmed to room temperature with
stirring. The mixture was then diluted with ether (100 mL); the layers were
separated, and the aqueous layer was extracted with ether (3 ꢀ 50 mL). The
combined ethereal layer were washed with water and brine (10 mL each)
and dried (MgSO4), and the solvent was evaporated under reduced pressure.
The crude product was purified by column chromatography (ethyl acetate/
1
hexanes ¼ 1:19) to afford pure alcohol 7a as a colorless oil (2.78, 89%). H
NMR (CDCl3) d 7.37–7.27 (m, 5H), 5.85 (ddd, J ¼ 17.4, 9.7, 7.3 Hz, 1H),
4.94–5.06 (m, 2H), 4.51 (s, 2H), 3.66 (dd, J ¼ 9.7, 4.6 Hz, 1H), 3.40
(m, 1H), 3.16 (d, J ¼ 4.5 Hz, 1H), 2.31 (m, 1H), 1.96 (m, 1H), 1.04
(d, J ¼ 7.6 Hz, 3H), 0.96 (d, J ¼ 7.6 Hz, 3H). The signal for OH was not
observed. 13C NMR (CDCl3) d 142.3, 138.2, 128.4, 128.1, 127.7, 114.4,

C3-C9 Segment of Soraphen A1a
1547
78.70, 74.40, 73.5, 41.15, 38.0, 14.6, 13.6. The spectroscopic data of this
product were consistent with the literature values.[10]
1-(tert-Butyl-diphenyl-silanyloxy)-2(S),4(S)-dimethyl-hex-5-en-
3(R)-ol (7b)
To a solution of (S)-3-(tert-butyl-diphenylsilyloxy)-2-methyl-propionalde-
hyde, (3.0 g, 10 mmol) in dry CH2Cl2, (50 mL) at 285 8C under nitrogen,
titanium tetrachloride (1.8 mL, 9.5 mmol) was added dropwise via a syringe
(mixture turned bright yellow upon addition). The reaction mixture was
stirred at 285 8C for 10 min before tributyl crotyl stannane 8 (3.35 g,
9.67 mmol) was slowly added over a 10-min period via a syringe down the
side walls of the round-bottom flask. The reaction mixture turned clear
during addition. Upon completion of the addition, the reaction was
quenched by addition of a saturated solution of NaHCO3 (10 mL). The
solution was warmed to room temperature with stirring. The reaction
mixture was diluted with ether (100 mL), the layers were separated, and the
aqueous layer was extracted with ether (3 ꢀ 20 mL). The combined ethereal
extracts were washed with brine (10 mL) and dried (MgSO4), and the
solvent was evaporated under reduced pressure. The resultant crude yellow
oil was purified by column chromatography (ethyl acetate/hexanes ¼ 1:10)
to afford 1-(tert-butyldiphenylsilyloxy)-2(S),4(S)-dimethyl-hex-5-en-3(R)-ol
1
as a colorless oil (3.4 g, 93%). Rf ¼ 0.28 (ethyl acetate/hexanes 1:5); H
NMR (CDCl3) d 7.70–7.66 (m, 4H), 7.45–7.37 (m, 6H), 5.62 (ddd,
J ¼ 17.0, 9.9, 7.0 Hz, 1H), 5.05 (dd, J ¼ 17.0, 1.2 Hz, 1H), 4.96 (dd, 10.0,
1.8 Hz, 1H), 3.78 (dd, J ¼ 9.9, 3.5 Hz, 1H), 3.68–3.62 (m, 2H), 2.95
(d, J ¼ 3 Hz, 1H), 2.32 (bs, 1H), 1.81 (m, 1H), 1.12 (d, J ¼ 7.0 Hz, 3H),
1.07 (s, 9H), 0.98 (d, J ¼ 7.0 Hz, 3H); 13C NMR d 141.8, 135.6, 133.3,
133.1, 129.7, 127.6, 115.3, 76.1, 68.4, 41.7, 36.7, 26.8, 19.1, 16.7, 9.5; IR
(CH2Cl2) n 3512, 1647, 1590 cm21
.
4(R)-Acroyloxy-6-benzyloxy-3(S),5(S)-dimethyl-1-hexane (5a)
A solution of 1-benzyloxy-2(S),4(S)-dimethyl-hex-5-en-3(R)-ol 7a (0.43 g,
1.8 mmol) in dry CH2Cl2 (7 mL) and a catalytic amount of DMAP (10 mg)
were added to an oven-dried round-bottom flask equipped with a magnetic
stirbar. The reaction mixture was cooled to 278 8C and then diisopropylethy-
lamine (Hunig’s base) (1.0 mL, 5.7 mmol) was added dropwise via a syringe
immediately followed by acryloyl chloride (0.21 g, 2.3 mmol). The reaction
mixture was stirred at 278 8C for 2 h. The reaction was diluted with CH2Cl2
(25 mL) and quenched by addition of brine solution (10 mL). The reaction
mixture was warmed to room temperature with stirring. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 ꢀ 30 mL).
The combined organic layers were dried (MgSO4), and the solvent was

1548
A. F. Eweas
evaporated under reduced pressure. The resultant crude oil was purified by
column chromatography (ethyl acetate/hexanes ¼ 1:4) to afford (5a) as a
colorless oil (0.50 g, 95%). Rf ¼ 0.18 (ethyl acetate/hexanes ¼ 1:4); [a]
¼ þ23 (c ¼ 0.01 CHCl3). Elemental analysis: calculated: C, 74.97; H,
D
1
8.39; O, 16.64; found C, 74.95; H, 8.37; O, 16.65. H NMR (CDCl3) d 7.32
(s, 5H), 6.37 (dd, J ¼ 17.6, 1.7 Hz, 1H), 6.10 (dd, J ¼ 17.6, 10.5 Hz, 1H),
5.82 (dd, J ¼ 9.9, 1.2 Hz, 1H), 5.76–5.70 (m, 1H), 5.09–4.90 (m, 2H), 4.46
(s, 2H), 3.55 (dd, J ¼ 8.8, 4.7 Hz, 1H), 3.48 (m, 1H), 3.26 (dd, J ¼ 9.4,
7.6 Hz, 1H), 2.56 (m, 1H), 2.17 (m, 1H), 1.01 (d, J ¼ 7.3 Hz, 3H), 0.99
(d, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3) d 166.2, 140.3, 138.5, 130.8, 128.6,
128.4, 127.7, 127.6, 115.3, 78.3, 73.2, 71.8, 39.5, 35.7, 12.8, 10.1.
4(R)-Acryloxy-6-[(tert-butyldiphenylsilyloxy]-3(S),5(S)-dimethyl-1-
hexane (5b)
A solution of 1-(tert-butyl-diphenylsilyloxy)-2(S),4(S)-dimethyl-hex-5-en-
3(R)-ol 7b (1.3 g, 3.4 mmol) in anhydrous CH2Cl2 (25 mL) and a catalytic
amount of DMAP (25 mg) was added to an oven-dried round-bottom flask
equipped with a magnetic stirbar. The reaction mixture was cooled to 278 8C
(dry ice/acetone). The solution was stirred at 278 8C for 5 min before diisopro-
pylethyl amine (0.83 g, 6.4 mmol) was added dropwise, followed by slow
addition of acryloyl chloride (0.61 g, 6.7 mmol). The reaction mixture was
stirred for 2 h, diluted with CH2Cl2 (30 mL), and quenched with brine (5 mL).
The reaction mixture was quickly warmed to room temperature. The layers
were separated, and the aqueous layer was extracted with CH2Cl2
(3 ꢀ 50 mL). The combined organic layers were washed with brine and dried
(MgSO4), and the solvent evaporated under reduced pressure. The resultant
crude oil was purified by column chromatography (ethyl acetate/
hexanes ¼ 1:9) to afford pure product as a colorless oil (1.17 g, 79%),
Rf ¼ 0.73 (ethyl acetate/hexanes ¼ 1:4), Elemental analysis: calculated: C,
1
74.27; H, 8.31; O, 10.99; found: C, 74.28; H, 8.30; O, 11.00. H NMR
(CDCl3) d 7.71–7.64 (m, 4H), 7.43–7.32 (m, 6H), 6.38 (dd, J ¼ 15.8, 1.2 Hz,
1H), 6.10 (dd, J ¼ 17.0, 11.1 Hz, 1H), 5.82 (dd, J ¼ 11.7, 1.2 Hz, 1H), 5.17
(dd, J ¼ 7.6, 3.5 Hz, 1H), 5.10–4.98 (m, 2H), 3.53–3.37 (m, 3H), 2.58–2.47
(m, 1H), 2.10–1.98 (m, 1H), 1.02 (s, 9H), 0.98 (d, J ¼ 5.8 Hz, 3H), 0.89
(d, J ¼ 7.0 Hz, 1H); 13C NMR (CDCl3) d 165.6, 139.3, 135.4, 133.8, 129.9,
128.9, 128.7, 128.1, 127.5, 115.2, 76.6, 66.3, 37.6, 27.1, 19.2, 17.3, 11.7.
(5S,6R)-6-[(1S)-2-Benzyloxy-1-methyl-ethyl]-5-methyl-5,6-dihydro-
pyran-2-one (6a)
To an oven-dried round-bottom flask equipped with a magnetic stirbar
under nitrogen atmosphere, a solution of 4(R)-acroyloxy-6-benzyloxy-3(S),

C3-C9 Segment of Soraphen A1a
1549
5(S)-dimethyl-1-hexane 5a (0.5 g, 1.7 mmol) in CH2Cl2 (50 mL) was added
followed by addition of titanium(IV) isopropoxide (0.15 g, 0.52 mmol). The
reaction mixture was heated to reflux for 1 h and then cooled to room temp-
erature. A solution of Grubbs’s catalyst (0.21 g, 0.25 mmol) in dry CH2Cl2
(5 mL) was added in three portions over a 1- h period. The reaction mixture
was heated at reflux for 18 h before cooling to room temperature. Lead tetra-
cetate (0.9 g) was added, and the reaction mixture was stirred at room temp-
erature overnight. The reaction mixture was filtered through a pad of silica gel
and the filter bed was washed with CH2Cl2 (100 mL). The filtrate was concen-
trated under reduced pressure, and the crude product was purified by column
chromatography (ethyl acetate/hexanes ¼ 1:4) to afford the product as a
colorless oil (0.35 g, 78%). Rf ¼ 0.19 (ethyl acetate/hexanes ¼ 1:4); [a]
¼ þ21 (c ¼ 0.1, CH2Cl2). Elemental analysis: calculated: C, 73.82; H,
D
1
7.74; O, 18.44; found: C, 73.82; H, 7.74; O, 18.45. H NMR (CDCl3) d
7.35–7.30 (m, 5H), 6.66 (dd, J ¼ 9.9, 2.9 Hz, 1H), 5.94 (dd, J ¼ 9.9,
2.3 Hz, 1H), 4.51 (s, 2H), 4.31 (dd, J ¼ 10.5, 2.9 Hz, 1H), 3.71 (dd,
J ¼ 9.4, 7.0 Hz, 1H), 3.39 (dd, J ¼ 9.4, 5.8 Hz, 1H), 2.90–2.84 (m, 1H),
2.46–2.40 (m, 1H), 1.09 (d, J ¼ 7.0 Hz, 3H), 1.03 (d, J ¼ 7.0 Hz, 3H).
(5S,6R)-6-[(1S)-2-(tert-Butyl-diphenylsilanyloxy)-1-methyl-ethyl]-5-
methyl-5,6-dihydro-pyran-2-one (6b)
To an oven-dried round-bottom flask equipped with a magnetic stirbar under
nitrogen atmosphere, a solution of 4(R)-acryloxy-6-[(tert-butyl diphenylsily-
loxy]-3(S),5(S0-dimethyl-1-hexane 5b (1.5 g, 4.1 mmol) in CH2Cl2
(150 mL) was added followed by addition of titanium(IV) isopropoxide
(0.34 g, 1.23 mmol). The reaction mixture was heated to reflux for 1 h and
cooled to room temperature. A solution of Grubbs’s catalyst (0.5 g,
0.6 mmol) in dry CH2Cl2 (5 mL) was added in three portions over a 1- h
period. The reaction mixture was heated at reflux overnight before cooling
to room temperature. Lead tetracetate (2.7 g, 1.5 eq) was added, and the
reaction mixture was stirred at room temperature overnight. The reaction
mixture was filtered through a pad of silica gel, and the filter bed was
washed with CH2Cl2 (250 mL). The filtrate was concentrated under reduced
pressure, and the crude product was purified by column chromatography
(ethyl acetate/hexanes ¼ 1:4) to afford the product as a colorless oil
(1.09 g, 78%). Rf ¼ 0.21 (ethyl acetate/hexanes ¼ 1:4); [a]D ¼ þ18
(c ¼ 0.7 MeOH). Elemental analysis: calculated: C, 73.49; H, 7.89; O,
1
11.75; found: C, 73.48; H, 7.88; O, 11.76. H NMR (CDCl3) d 7.67–7.61
(m, 4H), 7.48–7.36 (m, 5H), 6.90 (dd, J ¼ 9.3, 6.4 Hz, 1H), 5.9
(d, J ¼ 9.4 Hz, 1H), 4.28 (dd, J ¼ 9.9, 2.9 Hz, 1H), 3.59 (dd, J ¼ 4.7, 1.8 Hz,
2H), 2.34 (m, 1H), 2.19–1.98 (m, 1H), 1.20 (d, J ¼ 6.4 Hz, 3H), 1.05
(s, 9H), 0.92 (d, J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3) d 165.2, 152.2, 135.8,
133.7, 130.0, 127.9, 120.0, 82.5, 65.4, 36.8, 31.3, 27.2, 19.7, 14.3, 11.9.

1550
A. F. Eweas
(5S,6R)-6-[(1S)-2-(tert-Butyl-diphenylsilanyloxy)-1-methyl-ethyl]-5-
methyl-5,6-dihydro-2H-pyran-2-ol (8)
A solution of diisobutyl aluminum hydride (DIBAL-H) (1.53 mL, 1 M in
hexanes) was added slowly via a syringe to a solution of (5S,6R)-6-[(1S)-2-
(tert-butyl-diphenylsilyloxy)-1-methyl-ethyl]-5-methyl-5,6-dihydro-pyran-2-
one 6b (0.52 g, 1.3 mmol) in dry CH2Cl2 (15 mL) at 278 8C. After completion
of addition, the reaction mixture was stirred at 278 8C under nitrogen for 1 h
before quenching by addition of 10% aqueous sodium potassium tartrate
(5 mL). The resulting solution was warmed to room temperature with
stirring, and stirring was continued for an extra hour. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 ꢀ 25 mL).
The combined organic layers were washed with brine (10 mL) and dried
(MgSO4), and the solvent was evaporated under reduced pressure. The
resultant crude product was purified by column chromatography (ethyl
acetate/hexanes ¼ 1:4) to afford the alcohol as a colorless oil (0.45 g,
89%), [a]
¼ þ11 (c ¼ 0.07, CH2Cl2); Rf ¼ 0.16 (ethyl acetate/
D
hexanes 1:4). Elemental analysis: found: C, 73.13; H, 8.35; O, 11.69;
1
calculated: C, 73.14; H, 8.36; O, 11.71. H NMR (CDCl3) d 7.70–7.64
(m, 4H), 7.50–7.42 (m, 6H), 5.74–5.66 (m, 1H), 4.90 (m, 1H), 3.82–3.78
(m, 1H), 3.60 (d, J ¼ 7.8 Hz, 2H), 3.25–3.20 (m, 1H), 2.40–2.32 (m, 1H),
2.0–1.78 (br m, 2H), 1.06 (s, 9H), 0.97 (d, J ¼ 7.0 Hz, 3H), 0.79
(d, J ¼ 6.4 Hz, 3H).
(1S)-tert-Butyl-[(5S,6R)-2-(6-isopropoxy-3-methyl-3,6-dihydro-2H-
pyran-2-yl)-propoxy]-diphenyl-silane (9)
Camphorsulphonic acid (10 mg) was added to a solution of (5S,6R)-6-[(1S)-
2-(tert-butyl-diphenylsilanyloxy)-1-methyl-ethyl]-5-methyl-5,6-dihydro-2H-
pyran-2-ol 8 (0.42 g, 1.0 mmol) in isopropyl alcohol (10 mL). The reaction
mixture was stirred at room temperature. The reaction was monitored by
thin-layer chromatography (TLC). After 3 h, the reaction was quenched by
addition of a few drops of triethyl amine. The solvent was evaporated under
reduced pressure, and the resultant crude product was purified by column
chromatography (ethyl acetate/hexanes ¼ 1:10) to afford (1S)-tert-butyl-
[(5S,6R)-2-(6-isopropoxy-3-methyl-3,6-dihydro-2H-pyran-2-yl)-propoxy]-
diphenylsilane 9 as a colorless oil (0.36 g, 79%). Rf ¼ 0.65 (ethyl acetate/
hexanes ¼ 1:4); [a] D ¼ þ13 (c ¼ 0.12, CH2Cl2). Elemental analysis: calcu-
lated: C, 74.29; H, 8.91; O, 10.60; found: C, 74.31; H, 8.93; O, 10.62. 1H NMR
(CDCl3) d 7.70–7.67 (m, 4H), 7.46–7.38 (m, 6H), 5.98 (dd, J ¼ 10.5, 9.3 Hz,
1H), 5.58 (dd, J ¼ 10.3, 3.5 Hz, 1H), 5.03 (d, J ¼ 2.9 Hz, 1H), 3.81 (dd,
J ¼ 9.9, 2.3 Hz, 1H), 3.50 (m, 2H), 3.18 (m, 1H), 2.32 (m, 1H), 2.10
(m, 1H), 1.16 (d, J ¼ 5.9 Hz, 6H), 1.02 (s, 9H), 0.91 (d, J ¼ 7.0 Hz, 3H),
0.79 (d, J ¼ 7.0 Hz, 3H).

C3-C9 Segment of Soraphen A1a
1551
tert-Butyl-[(2S,5R,6S)-2-(2-isopropoxy-5-methyl-3,7-dioxa-
bicyclo[4.1.0]hept-4-yl)-propoxy]-diphenyl-silane (10)
m-Chloroperbenzoic acid (80–85%, 0.23 g, 1.23 mmol) was added to a stirred
solution of (1S)-tert-butyl-[(5S,6R)-2-(6-isopropoxy-3-methyl-3,6-dihydro-
2H-pyran-2-yl)-propoxy]-diphenyl-silane 9 (0.30 g, 0.66 mmol) in CH2Cl2
(15 mL). The reaction was stirred at room temperature overnight and then
quenched by addition of saturated aqueous solution of sodium thiosulphate
(2 mL) followed by a saturated solution of NaHCO3 (2 mL). The resultant
mixture was extracted with CH2Cl2 (3 ꢀ 15 mL). The combined organic
layers were dried (MgSO4), and the solvent was evaporated under reduced
pressure. The resultant crude product was purified by column chromatography
(ethyl acetate/hexanes ¼ 1:4) to afford tert-butyl-[(2S,5R, 6S)-2-(2-isopro-
poxy-5-methyl-3,7-dioxa-bicyclo[4.1.0]hept-4-yl)-propoxy]-diphenyl-silane 10
as colorless oil (0.22 g, 73%). Rf ¼ 0.83 (ethyl acetate/hexanes ¼ 1:4);
[a]D ¼ þ21 (c ¼ 0.12, CH2Cl2). Elemental analysis: calculated: C, 71.75; H,
1
8.60; O, 13.65; found: C, 71.77; H, 6.62; O, 13.67. H NMR (CDCl3) d
7.70–7.67 (m, 4H), 4.92 (d, J ¼ 3.0 Hz, 1H), 3.89 (dd, J ¼ 9.4, 3.5 Hz, 1H),
3.75 (dd, J ¼ 10.5, 2.9 Hz, 1H), 3.70 (dd, J ¼ 9.9, 3.5 Hz, 1H), 3.60–3.48
(m, 3H), 1.85–1.92 (m, 1H), 1.15 (d, J ¼ 5.8 Hz, 6H), 1.04 (s, 9H), 0.87
(d, J ¼ 7.0 Hz, 3H), 0.82 (d, J ¼ 7.0 Hz, 3H).
ACKNOWLEDGMENTS
Financial support for this work was provided by the National Institutes of
Health (GM-42641) and the Marquette University Graduate School. The
author thanks Dr. William A. Donaldson for his encouragement.
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