Stereoselective synthesis of Sch 642305, an inhibitor of bacterial DNA primase

Article abstract of DOI:10.1016/j.tet.2005.12.009

Sch 642305 is a fungal nonanolide, which inhibits bacterial DNA primase and HIV-1 Tat transactivation. The enantioselective synthesis of Sch 642305 was succeeded starting from useful chiral building block via stereoselective dianion alkylation of β-ketosu

Full text of DOI:10.1016/j.tet.2005.12.009

Tetrahedron 62 (2006) 2224–2230
Stereoselective synthesis of Sch 642305, an inhibitor
of bacterial DNA primase
*
Ken Ishigami, Ryo Katsuta and Hidenori Watanabe
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences,
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received 18 November 2005; revised 5 December 2005; accepted 6 December 2005
Available online 20 December 2005
Abstract—Sch 642305 is a fungal nonanolide, which inhibits bacterial DNA primase and HIV-1 Tat transactivation. The enantioselective
synthesis of Sch 642305 was succeeded starting from useful chiral building block via stereoselective dianion alkylation of b-ketosulfoxide
and lactonization.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
significant biological activities prompted us to undertake the
synthesis of this compound. During our work in progress,
Mehta and Shinde also reported the total synthesis of Sch
642305, using ring closing metathesis as a key step.7
Recently, mechanism-based drugs have been remarkably
noticed, since they will potentially provide selective
treatments for various diseases such as infections and
cancers. In 2003, Chu et al. isolated Sch 642305 from
Penicillium verrucosum as a potent inhibitor of bacterial
DNA primase.1 Because DNA primase is necessary for the
replication of chromosomal DNA,2,3 this compound is
thought to provide an alternative treatment for infectious
diseases. In addition, Jayasuriya and co-workers recently
reported that Sch 642305 potently inhibits HIV-1 Tat
transactivation.4 A number of bioactive nonanolides have
been isolated from a variety of fungal species.5,6 Sch 642305
has a structure including 10-membered lactone fused with
4-hydroxycyclohexenone. Its unique structure as well as the
2. Results and discussion
Our retrosynthesis is shown in Scheme 1. We selected
lactonization as a ring closing step. The precursor for the
lactonization A would be prepared from dianion of
b-ketosulfoxide B and iodide C. The ketosulfoxide B
would be synthesized from a chiral building block D, which
has been developed in our laboratory.8,9 The iodide C would
be obtained from chiral 3-hydroxybutylate E.10,11
O
TBSO
PhS
HO
CO2Et
TBSO
HO H
5
11
OTES
OTES
OTHP
O
4
6
3
1
H
O
2
O
O
O
O
O
A
B
D
Sch 642305 (1)
OTHP
OH
CO2Et
I
C
E
Scheme 1. Synthetic plan.
Keywords: DNA primase; Sch 642305; Lactonization.
*
Corresponding author. Tel.: C81 3 5841 5119; fax: C81 3 5841 8019; e-mail: ashuten@mail.ecc.u-tokyo.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.009

K. Ishigami et al. / Tetrahedron 62 (2006) 2224–2230
OTHP OTHP
2225
O
OH
OTHP
Ref. 10,11
CO2Et
Ref. 12
a
b
CO2Et
CO2Et
CO2Et
R
2
3
4
5
6: R = OH
7: R = I
c
Scheme 2. Reagents and conditions: (a) H2, Pd–C, EtOAc, 95%; (b) LiAlH4, ether, 98%; (c) I2, PPh3, imidazole, CH2Cl2 87%.
Preparation of iodide 7 (ZC) is shown in Scheme 2.
Optically active (S)-3-hydroxybutylate 3 (98% ee) could be
easily prepared in a large amount from ethyl acetoacetate (2)
via stereoselective reduction by baker’s yeast and enzymatic
improvement of the optical purity.10,11 This compound was
subjected to C2 elongation by the reported procedure12 to
afford a,b-unsaturated ester 4. Hydrogenation of 4 was
followed by LAH reduction to give alcohol 6,13–15 which
was converted to the corresponding iodide 7 in a usual
manner.
b-ketosulfoxide 18 was subjected to regio- and stereo-
selective alkylation with the iodide 7 by dianion pro-
cedure16–18 and subsequent thermal elimination afforded
tri-substituted cyclohexenone 19 as a single isomer in a
moderate yield. As we expected, the alkylation occurred
selectively from the less hindered b-face of the dianion.
Selective removal of TES group of 19 and two-step
oxidation were followed by removal of THP group
to give hydroxy acid 23, the lactonization precursor. It
was subjected to Yamaguchi’s method19,20 to afford
10-membered lactone 24 (73%) successfully with a small
amount of a dimeric lactone (13%). The final step, removal
of TBS group, was found to be slightly difficult.
Deprotection of 24 with TBAF or HF$NEt3 gave a
decomposed product mainly and the desired compound
was obtained only in low yield. Other conditions (p-TsOH
in MeOH, Dowexw-50 in MeOH, KF-18-crown-6 in MeCN,
or neutralized TBAF with HF in THF) resulted in a partial
epimerization at C-6 position (b:aZ3:1–1:1, see Section 3).
During our efforts as above, Mehta and Shinde reported the
successful removal of TBDPS group using TBAF–AcOH
in their synthesis of Sch 642305.7 According to their
procedure, we also succeeded in the synthesis of Sch
642305 without epimerization. The NMR data of syn-
thesized 1 were identical to those reported.1,7 Its specific
Hydroxyl group of another chiral building block 9 (99%
ee),8 which could be prepared in a large quantity via
stereoselective reduction of 8 by baker’s yeast, was
protected as TBS ether (Scheme 3) to give 10. After the
reduction of ester group in 10, resulting alcohol was
converted to the corresponding tosylate 12. Transformation
to nitrile 13 and subsequent two-step reduction gave alcohol
15 in good yield. Ketone was liberated by transacetalization
and hydroxyl group was then protected as TES ether to
afford 17. This ketone was treated with LDA and phenyl
benzenethiosulfonate to give a sulfide, which was oxidized
to corresponding sulfoxide 18 (60% as a diastereomeric
mixture) together with 0its regioisomer 180 (17%). After the
easy removal of 18 by silica gel chromatography,
O
CO2Et
O
RO
CO2Et
O
TBSO
R
TBSO
TBSO
OH
OR
ref. 8
b
f
g
i, j
O
O
O
O
O
O
O
8
9: R = H
11: R = OH
12: R = OTs
13: R = CN
14: R = CHO
15
16: R = H
a
c
h
10: R = TBS
17: R = TES
d
e
TBSO
CHO
TBSO
TBSO
PhS
TBSO
OTHP
OR
OTHP
OTES
OTES
SPh
k, l
n
o
O
O
O
O
O
O
19: R = TES
20: R = H
18
18'
21
m
O
O
O
O
O
TBSO
CO2H
RO
TBSO
HO
H
HO
H
5
O
11
q
r
4
6
3
1
H
H
2
O
O
O
O
Sch 642305 (1)
22: R = THP
23: R = H
24
6-epi-Sch 642305 (25)
p
Scheme 3. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, quant.; (b) DIBAL, CH2Cl2, 94%; (c) TsCl, TEA, DMAP, CH2Cl2, 89%; (d) NaCN,
DMSO, 93%; (e) DIBAL, CH2Cl2, 93%; (f) NaBH4, EtOH, 99%; (g) p-TsOH, Me2CO, quant.; (h) TESCl, TEA, CH2Cl2, quant.; (i) LDA, PhSO2SPh, THF;
(j) MCPBA, CH2Cl2, 60% in two steps; (k) LDA, 7, THF; (l) CaCO3, tol. 47% in two steps; (m) HF, CH3CN, 98%; (n) Dess–Martin periodinane, CH2Cl2, 84%;
(o) NaClO2, 2-methyl-2-butene, NaH2PO4$2H2O, tert-BuOH, water, 90%; (p) MgBr2$Et2O, ether, quant.; (q) 2,4,6-trichlorobenzoylchloride, TEA, THF then
DMAP, tol., 73%; (r) TBAF, AcOH, THF, 87%.

2226
K. Ishigami et al. / Tetrahedron 62 (2006) 2224–2230
rotation {[a]2D9 C74 (c 0.50, MeOH)} and mp (151–153 8C)
were slightly larger than those reported for natural Sch
642305 {[a]D C67.44 (c 0.50, MeOH), mp 143–145 8C}.1
was added iodine (3.3 g, 13 mmol) at 0 8C and the mixture
was stirred at room temperature for 3 h. This mixture was
poured into saturated NH4Cl solution and extracted with
ether. The organic layer was washed with saturated NaHCO3
solution and brine, dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with toluene–ethyl acetate (20/1) gave
7 (2.94 g, 87%) as a slightly yellow oil.
In conclusion, we have accomplished a stereoselective
synthesis of Sch 642305 starting from two chiral sources,
which were prepared by stereoselective reductions with
baker’s yeast. Alkylation of b-ketosulfoxide by dianion
procedure selectively afforded the desired stereochemistry
and Yamaguchi’s lactonization was also successful in good
yield. The overall yield was 10% in 18 steps started from
chiral building block 9. As fungal nonanolides have
interesting biological activities, we wish our syntheses21,22
of these compounds would offer any useful information for
further investigation on the related fields.
n2D7Z1.5019. [a]D26 C1.6 (c 1.0, CHCl3). IR (film): nZ1454,
1
1372, 1282, 1258, 1131, 1022, 870, 813 cmK1. H NMR
(300 MHz in CDCl3): dZ1.12 (1.5H, d, JZ6.3 Hz), 1.23
(1.5H, d, JZ6.3 Hz), 1.35–1.9 (12H, m), 3.19 (1H, t,
JZ6.9 Hz), 3.21 (1H, t, JZ6.9 Hz), 3.45–3.55 (1H, m),
3.65–3.95 (2H, m), 4.6–4.75 (1H, m). FAB-HRMS m/z
calcd for C11H22IO2 [MCH]C 313.0664, found 313.0658.
3. Experimental
3.1. General
3.2.4. Ethyl (1R,2S)-5,5-ethylenedioxy-2-(tert-butyl-
dimethylsilyloxy)cyclohexanecarboxylate (10). A sol-
ution of alcohol 9 (6.00 g, 26.1 mmol), TBSOTf (6.2 ml,
27 mmol) and 2,6-lutidine (6.1 ml, 52 mmol) in CH2Cl2
(100 ml) was stirred at room temperature for 2 h. The
reaction mixture was poured into saturated NH4Cl solution
and extracted with ether. The organic layer was washed with
1 N HCl, saturated NaHCO3 solution and brine, dried over
anhydrous magnesium sulfate and concentrated in vacuo.
The residue was chromatographed over silica gel. Elution
with hexane–ethyl acetate (4/1) gave 10 (9.03 g, quant.) as a
slightly yellow oil.
Optical rotations were recorded with a JASCO DIP-1000
polarimeter. IR spectra were measured with a JASCO FT/
IR-230 spectrophotometer. 1H and 13C NMR were recorded
on JEOL JNM AL300 or JEOL JNM GSX500. Chemical
shifts (d) were referenced to the residual solvent peak as the
internal standard (CDCl3: dHZ7.26, dCZ77.0; CD3OD:
dHZ3.30, dCZ49.0). Mass spectra were recorded on JEOL
JMS-700T. Column chromatography was performed using
Merck silica gel 60 (0.060–0.200 mm). TLC was carried out
on Merck glass plates precoated with silica gel 60 F254
(0.25 mm). Melting points are uncorrected values.
n2D7Z1.4600. [a]D26 C24 (c 1.0, CHCl3). IR (film): nZ1739,
1254, 1182, 1086, 1065, 1041, 833 cmK1 1H NMR
.
(300 MHz in CDCl3): dZK0.01 (3H, s), 0.04 (3H, s),
0.85 (9H, s), 1.25 (3H, t, JZ7.2 Hz), 1.51 (1H, m), 1.7–1.85
(3H, m), 1.95 (1H, dt, JZ6.0, 12.6 Hz), 2.16 (1H, t, JZ
13.2 Hz), 2.66 (1H, ddd, JZ13.2, 3.6, 2.4 Hz), 3.85–4.25
(6H, m), 4.42 (1H, m). FAB-HRMS m/z calcd for
C17H33O5Si [MCH]C 345.2097, found 345.2059.
3.2. Synthetic studies
3.2.1. Ethyl (S)-5-tetrahydropyranyloxyhexanoate (5).
To a solution of unsaturated ester 4 (4.97 g, 21.8 mmol) in
ethyl acetate (40 ml) was added 5% Pd/C (1.3 g) and the
mixture was stirred at room temperature for 5 h under H2.
The mixture was filtered through Celitew and concentrated
in vacuo. The residue was chromatographed over silica gel.
Elution with hexane–ethyl acetate (1/1) gave 5 (4.75 g,
95%) as a colorless oil.
3.2.5. [(1S,2S)-5,5-Ethylenedioxy-2-(tert-butyldimethyl-
silyloxy)cyclohexyl]methanol (11). To a solution of ester
10 (10.6 g, 30.9 mmol) in dry CH2Cl2 (150 ml) was added
1.01 M solution of DIBAL in toluene (67.3 ml, 68.0 mmol)
dropwise at K78 8C and the mixture was stirred at K78 8C
for 2 h under argon. The reaction mixture was quenched
with MeOH, poured into saturated Rochelle’s salt solution
and extracted with EtOAc. The organic layer was washed
with brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (2/1–1/1)
gave 11 (9.08 g, 97%) as an amorphous solid.
Spectroscopic data were identical to those reported.14
3.2.2. (S)-5-Tetrahydropyranyloxyhexan-1-ol (6). To a
solution of ester 5 (4.89 g, 21.2 mmol) in ether (60 ml) was
added LiAlH4 (0.53 g, 14 mmol) at 0 8C and the mixture
was stirred at 0 8C for 1 h under argon. The reaction mixture
was quenched with MeOH, poured into saturated NH4Cl
solution and extracted with ether. The organic layer was
washed with saturated NaHCO3 solution and brine, dried
over anhydrous magnesium sulfate and concentrated in
vacuo. The residue was chromatographed over silica gel.
Elution with hexane–ethyl acetate (1/1) gave 6 (4.19 g,
98%) as a colorless oil.
[a]2D6 C34 (c 1.0, CHCl3). IR (Nujol): nZ3479, 1253, 1108,
1076, 1032, 832 cmK1. 1H NMR (300 MHz in CDCl3): dZ
0.08 (6H, s), 0.90 (9H, s), 1.45–2.0 (7H, m), 3.55–3.7 (2H,
m), 3.9–4.0 (4H, m), 4.08 (1H, m). FAB-HRMS m/z calcd
for C15H31O4Si [MCH]C 303.1992, found 303.1969.
Spectroscopic data were identical to those reported.14
3.2.6. [(1S,2S)-5,5-Ethylenedioxy-2-(tert-butyldimethyl-
silyloxy)cyclohexyl]methyl p-toluenesulfonate (12). To a
solution of alcohol 11 (9.08 g, 30.0 mmol), triethylamine
(12.5 ml, 90.0 mmol) and DMAP (367 mg, 3.00 mmol) in
CH2Cl2 (150 ml) was added TsCl (6.86 g, 36.0 mmol) at
3.2.3. (S)-1-Iodo-5-tetrahydropyranyloxyhexane (7). To a
solution of alcohol 6 (2.19 g, 10.8 mmol), imidazole (2.94 g,
43.2 mmol) and PPh3 (2.94 g, 11.2 mmol) in CH2Cl2 (30 ml)

K. Ishigami et al. / Tetrahedron 62 (2006) 2224–2230
2227
0 8C and the mixture was stirred at room temperature for
16 h. The reaction mixture was poured into saturated NH4Cl
solution and extracted with ether. The organic layer was
washed with 1 N HCl, saturated NaHCO3 solution and
brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (3/1) gave
12 (12.2 g, 89%) as colorless crystals.
NH4Cl solution and extracted with ether. The organic layer
was washed with saturated NaHCO3 solution and brine,
dried over anhydrous magnesium sulfate and concentrated
in vacuo. The residue was chromatographed over silica gel.
Elution with hexane–ethyl acetate (5/1–1/1) gave 15
(7.96 g, 99%) as colorless needles.
Mp 51–52 8C. [a]2D6 C19 (c 1.0, CHCl3). IR (Nujol): nZ
1
3340, 1251, 1142, 1076, 1037, 996, 834 cmK1. H NMR
Mp 65–67 8C. [a]2D4 C32 (c 1.0, CHCl3). IR (Nujol): nZ
(300 MHz in CDCl3): dZ0.05 (3H, s), 0.06 (3H, s), 0.90
(9H, s), 1.4–1.95 (9H, m), 3.67 (2H, t, JZ6.3 Hz), 3.8–3.85
(1H, m), 3.85–4.0 (4H, m). FAB-HRMS m/z calcd for
C16H33O4Si [MCH]C 317.2148, found 317.2153.
1595, 1254, 1188, 1176, 1102, 1072, 957, 835, 665 cmK1
.
1H NMR (300 MHz in CDCl3): dZK0.03 (3H, s), 0.02 (3H,
s), 0.81 (9H, s), 1.35–1.8 (5H, m), 1.87 (1H, dt, JZ4.2,
12.9 Hz), 2.0–2.15 (1H, m), 2.45 (3H, s), 3.76 (1H, dd, JZ
9.0, 6.6 Hz), 3.85–4.05 (6H, m), 7.34 (2H, d, JZ8.1 Hz),
7.77 (2H, d, JZ8.1 Hz). FAB-HRMS m/z calcd for
C22H37O6SSi [MCH]C 457.2080, found 457.2079.
3.2.10. (3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-(2-
hydroxyethyl)cyclohexanone (16). A solution of acetal
15 (1.00 g, 3.16 mmol) and p-toluenesulfonic acid mono-
hydrate (59 mg, 0.31 mmol) in acetone (100 ml) was stirred
at room temperature for 2 days. The reaction mixture was
poured into saturated ammonium sulfate solution. The
organic layer was concentrated in vacuo and the residue was
dissolved in EtOAc. The aqueous layer was extracted with
EtOAc. Combined organic layers were washed with
saturated NaHCO3 solution and brine, dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue
was chromatographed over silica gel. Elution with hexane–
ethyl acetate (1/1) gave 16 (0.86 g, quant.) as a colorless oil.
3.2.7. [(1R,2S)-5,5-Ethylenedioxy-2-(tert-butyldimethyl-
silyloxy)cyclohexyl]acetonitrile (13). A mixture of tosylate
12 (19.2 g, 42.0 mmol), NaCN (3.1 g, 63 mmol) and DMSO
(150 ml) was heated to 100 8C and stirred for 4 h. After
cooling, the reaction mixture was diluted with 150 ml of
ether and washed with water and brine. The organic layer
was dried over anhydrous magnesium sulfate and concen-
trated in vacuo. The residue was recrystallized from hexane
to give 13 (12.2 g, 93%) as colorless needles.
Mp 49–51 8C. [a]2D4 C31 (c 1.0, CHCl3). IR (Nujol): nZ
n2D7Z1.4701. [a]D26 C18 (c 1.0, CHCl3). IR (film): nZ3417,
1
1
2246, 1253, 1144, 1103, 1065, 994, 838 cmK1. H NMR
1713, 1254, 1059, 837, 775 cmK1. H NMR (300 MHz in
(300 MHz in CDCl3): dZ0.09 (3H, s), 0.10 (3H, s), 0.90
(9H, s), 1.45–1.95 (6H, m), 2.12 (1H, br m), 2.25 (1H, dd,
JZ16.5, 6.9 Hz), 2.38 (1H, dd, JZ16.5, 8.4 Hz), 3.9–4.05
(5H, m). FAB-HRMS m/z calcd for C16H30NO3Si [MCH]C
312.1995, found 312.1969.
CDCl3): dZ0.11 (6H, s), 0.93 (9H, s), 1.54 (1H, m), 1.7–1.9
(2H, m), 2.0–2.15 (2H, m), 2.15–2.3 (2H, m), 2.48 (1H, t,
JZ13.2 Hz), 2.66 (1H, dt, JZ6.3, 13.5 Hz), 3.6–3.75 (2H,
m), 4.03 (1H, br m). FAB-HRMS m/z calcd for C14H29O3Si
[MCH]C 273.1886, found 273.1852.
3.2.8.
2-[(1R,2S)-5,5-Ethylenedioxy-2-(tert-butyl-
3.2.11. (3R,4S)-4-(tert-Butyldimethylsilyloxy)-3-(2-
triethylsilyloxyethyl)cyclohexanone (17). Triethylamine
(2.20 ml, 15.8 mmol) and TESCl (690 ml, 4.11 mmol) were
added to a solution of alcohol 16 (860 mg, 3.16 mmol) in
CH2Cl2 (30 ml). The reaction mixture was stirred at room
temperature for 45 min, poured into saturated NH4Cl
solution and extracted with ether. The organic layer was
washed with saturated NaHCO3 solution and brine, dried
over anhydrous magnesium sulfate and concentrated in
vacuo. The residue was chromatographed over silica gel.
Elution with hexane–ethyl acetate (20/1) gave 17 (1.23 g,
quant.) as a colorless oil.
dimethylsilyloxy)cyclohexyl]acetaldehyde (14). To a sol-
ution of nitrile 13 (1.00 g, 3.21 mmol) in dry CH2Cl2 (20 ml)
was added 1.01 M solution of DIBAL in toluene (3.4 ml,
3.4 mmol) dropwise at K78 8C and the mixture was stirred at
K78 8C for 2.5 h under argon. The reaction mixture was
quenched with MeOH, poured into saturated Rochelle’s salt
solution and extracted with EtOAc. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (4/1–2/1)
gave 14 (0.93 g, 94%) as an amorphous solid.
[a]2D4 C29 (c 1.0, CHCl3). IR (film): nZ1726, 1103, 1067,
n2D7Z1.4614. [a]D27 C1.9 (c 1.0, CHCl3). IR (film): nZ1721,
1254, 1080, 835, 742 cmK1. 1H NMR (300 MHz in CDCl3):
dZ0.11 (6H, s), 0.58 (6H, q, JZ7.8 Hz), 0.92 (9H, s), 0.94
(9H, t, JZ7.8 Hz), 1.48 (1H, m), 1.71 (1H, m), 1.81 (1H,
m), 2.0–2.15 (2H, m), 2.15–2.25 (2H, m), 2.47 (1H, t, JZ
13.5 Hz), 2.67 (1H, dt, JZ6.0, 13.5 Hz), 3.61 (1H, dt, JZ
10.5, 6.3 Hz), 3.66 (1H, dt, JZ10.5, 6.3 Hz), 4.01 (1H, br
m). FAB-HRMS m/z calcd for C20H43O3Si2 [MCH]C
387.2751, found 387.2753.
1
999, 832, 773 cmK1. H NMR (300 MHz in CDCl3): dZ
0.02 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.45–1.6 (2H, m),
1.7–1.8 (3H, m), 1.89 (1H, dt, JZ5.7, 12.0 Hz), 2.2–2.5
(2H, m), 2.56 (1H, m), 3.85 (1H, m), 3.9–3.95 (4H, m), 9.77
(1H, t, JZ1.8 Hz). FAB-HRMS m/z calcd for C16H31O4Si
[MCH]C 315.1992, found 315.1965.
3.2.9.
2-[(1R,2S)-5,5-Ethylenedioxy-2-(tert-butyl-
dimethylsilyloxy)cyclohexyl]ethanol (15). To a solution
of sodium borohydride (1.9 g, 50 mmol) in EtOH (120 ml)
was slowly added a solution of aldehyde 14 (8.00 g,
25.4 mmol) in EtOH (30 ml) at K20 8C. The reaction
mixture was stirred at 0 8C for 3 h, poured into saturated
3.2.12. (2RS,4S,5R)-4-(tert-Butyldimethylsilyloxy)-2-
phenylsulfinyl-5-(2-triethylsilyloxyethyl)cyclohexanone
(18). To a solution of diisopropylamine (701 ml, 5.00 mmol)
in THF (20 ml) was added 1.56 M solution of n-BuLi

2228
K. Ishigami et al. / Tetrahedron 62 (2006) 2224–2230
(3.3 ml, 5.0 mmol) dropwise at K20 8C and stirred for
45 min under argon. This solution was cooled down to
K78 8C and a solution of ketone 17 (1.93 g, 5.00 mmol) in
THF (5 ml) was slowly added to it. Stirring for 3 min was
followed by dropwise addition of a solution of phenyl
benzenethiosulfonate (1.25 g, 5.0 mmol) in THF (5 ml). The
reaction mixture was stirred at K78 8C for 1 h, poured into
saturated NH4Cl solution and extracted with ether. The
organic layer was washed with 1 N HCl, saturated NaHCO3
solution and brine, dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was chromato-
graphed over silica gel. Elution with hexane–ethyl acetate
(20/1) gave a diastereomeric mixture of sulfides (2.68 g) as
slightly yellow solids. This mixture was used for next
reaction without further purification.
n2D7Z1.4773. [a]D24 C147 (c 1.0, CHCl3). IR (film): nZ
1680, 1254, 1108, 1022, 837, 773 cmK1 1H NMR
.
(300 MHz in CDCl3): dZ0.11 (6H, s), 0.57 (6H, q, JZ
7.8 Hz), 0.90 (9H, s), 0.94 (9H, t, JZ7.8 Hz), 1.10 (1.5H, d,
JZ6.0 Hz), 1.21 (1.5H, d, JZ6.0 Hz), 1.2–1.7 (15H, m),
1.75–1.8 (1H, m), 1.95–2.1 (1H, m), 2.25–2.4 (1H, m),
2,45–2.6 (1H, m), 3.45–3.55 (1H, m), 3.64 (2H, t, JZ
9.9 Hz), 3.65–3.95 (1H, m), 4.65–4.8 (2H, m), 5.82 (1H, d,
JZ9.9 Hz), 6.63 (1H, d, JZ9.9 Hz). FAB-HRMS m/z calcd
for C31H61O5Si2 [MCH]C 569.4058, found 569.4055.
3.2.14. (4S,5R,6R)-4-(tert-Butyldimethylsilyloxy)-5-
(2-hydroxyethyl)-6-[(S)-5-tetrahydropyranyloxyhexyl]-
cyclohex-2-en-1-one (20). To a solution of TES ether 19
(685 mg, 1.20 mmol) in acetonitrile (40 ml) was added
0.23 N HF (1 ml) at room temperature and stirred for
15 min. The reaction mixture was diluted with ether,
washed with saturated NaHCO3 solution and brine, dried
over anhydrous magnesium sulfate and concentrated in
vacuo. The residue was chromatographed over silica gel.
Elution with hexane–ethyl acetate (2/1) gave 20 (538 mg,
98%) as a colorless oil.
A solution of MCPBA (ca. 80%, 1.1 g, 5.1 mmol) in CH2Cl2
(10 ml) was added to a mixture of crude sulfides (2.68 g) in
CH2Cl2 (20 ml) at K78 8C and stirred for 1 h. The reaction
mixture was poured into 10% Na2S2O3 solution and
extracted with ethyl acetate. The organic layer was washed
with saturated NaHCO3 solution and brine, dried over
anhydrous magnesium sulfate and concentrated in vacuo.
The residue was chromatographed over silica gel. Elution
with hexane–ethyl acetate (6/1) gave 18 (1.53 g, 60% in two
steps) and its regioisomer 180 (0.43 g, 17% in two steps).
n2D7Z1.4842. [a]D24 C99 (c 1.0, CHCl3). IR (film): nZ3486,
1680, 1112, 1022, 837, 774, 668 cmK1. 1H NMR (300 MHz
in CDCl3): dZ0.15 (6H, s), 0.93 (9H, s), 1.10 (1.5H, d, JZ
6.0 Hz), 1.21 (1.5H, d, JZ6.0 Hz), 1.3–1.95 (15H, m), 2.02
(1H, m), 2.25–2.35 (1H, m), 2.45–2.5 (1H, m), 3.45–3.55
(1H, m), 3.6–3.8 (3H, m), 3.8–3.95 (1H, m), 4.6–4.7 (1H,
m), 4.75–4.8 (1H, m), 5.85 (1H, d, JZ9.0 Hz), 6.64 (1H, d,
JZ9.0 Hz). FAB-HRMS m/z calcd for C25H47O5Si [MC
H]C 455.3193, found 455.3193.
n2D7Z1.5069. [a]D27 K2.6 (c 1.0, CHCl3). IR (film): nZ1714,
1087, 1047, 1006, 836, 776, 747 cmK1. 1H NMR (300 MHz
in CDCl3): dZK0.36, K0.11, K0.02, 0.02, 0.11, 0.22
(total 6H, 6 singlets), 0.53 (3H, q, JZ4.1 Hz), 0.58 (3H, q,
JZ4.1 Hz), 0.75–1.0 (18H, m), 1.35–1.7 (2H, m), 1.8–2.8
(5H, m), 3.5–3.7 (2H, m), 4.0–4.15 (2H, m), 7.45–7.55 (4H,
m), 7.65–7.7 (1H, m). FAB-HRMS m/z calcd for
C26H47O4SSi2 [MCH]C 511.2734, found 511.2758.
3.2.15. {(1R,2S,6R)-2-(tert-Butyldimethylsilyloxy)-6-[(S)-
5-tetrahydropyranyloxyhexyl]-5-oxocyclohex-3-en-1-
yl}acetaldehyde (21). To a solution of alcohol 20 (770 mg,
1.69 mmol) in CH2Cl2 (20 ml) was added Dess–Martin
periodinane (1.08 g, 2.54 mmol) at 0 8C and stirred for 1 h
under argon. The reaction mixture was poured into 10%
Na2S2O3 solution and extracted with ether. The organic
layer was washed with saturated NaHCO3 solution and
brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (10/1–2/1)
gave 21 (641 mg, 84%) as a colorless oil.
3.2.13. (4S,5R,6R)-4-(tert-Butyldimethylsilyloxy)-6-
[(S)-5-tetrahydropyranyloxyhexyl]-5-(2-triethylsilylo-
xyethyl)cyclohex-2-en-1-one (19). To a solution of diiso-
propylamine (463 ml, 3.30 mmol) in THF (25 ml) was added
1.56 M solution of n-BuLi (2.1 ml, 3.3 mmol) in hexane
dropwise at K20 8C and stirred for 45 min under argon. This
mixture was cooled down to K60 8C, a solution of
ketosulfoxide 18 (675 mg, 1.32 mmol) in THF (4 ml) was
slowly added to this mixture (the color of reaction mixture
was immediately changed to orange). After stirring for 5 min,
iodide 7 (478 mg, 1.53 mmol) was added to the mixture at
K60 8C and stirring was kept for 30 min until the orange color
was changed to pale yellow. The reaction mixture was poured
into saturated NH4Cl solution and extracted with ether. The
organic layer was washed with 1 N HCl, saturated NaHCO3
solution and brine, dried over anhydrous magnesium sulfate
and concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (6/1–4/1)
gave a crude oil (590 mg). This crude product was used for the
next reaction without further purification.
n2D7Z1.4837. [a]D28 C118 (c 1.0, CHCl3). IR (film): nZ
1726, 1680, 1109, 1023, 773 cmK1. 1H NMR (300 MHz in
CDCl3): dZ0.10 (3H, s), 0.13 (3H, s), 0.90 (9H, s), 1.11
(1.5H, d, JZ6.0 Hz), 1.22 (1.5H, d, JZ6.0 Hz), 1.25–1.85
(14H, m), 2.2–2.45 (2H, m), 2.8–2.95 (2H, m), 3.45–3.55
(1H, m), 3.65–3.8 (1H, m), 3.8–4.95 (1H, m), 4.6–4.65
(0.5H, m), 4.65–4.7 (0.5H, m), 4.75–4.8 (1H, m), 5.87 (1H,
d, JZ7.8 Hz), 6.61 (1H, d, JZ7.8 Hz), 9.77 (1H, t, JZ
1.2 Hz). FAB-HRMS m/z calcd for C25H45O5Si [MCH]C
453.3036, found 453.3065.
A mixture of crude product (590 mg), CaCO3 (0.5 g,
5 mmol) and toluene (20 ml) was stirred at 100 8C for 2 h.
The reaction mixture was filtered through Celitew and
concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (15/1)
gave 19 (354 mg, 47% in two steps) as a slightly yellow oil.
3.2.16. {(1R,2S,6R)-2-(tert-Butyldimethylsilyloxy)-6-[(S)-
5-tetrahydropyranyloxyhexyl]-5-oxocyclohex-3-en-1-
yl}acetic acid (22). To a solution of aldehyde 21 (600 mg,
1.33 mmol) and 2-methyl-2-butene (2 ml) in tert-BuOH
(15 ml) was added a solution of NaH2PO4$2H2O (1.04 g,
6.65 mmol) and NaClO2 (0.24 g, 2.66 mmol) in water

K. Ishigami et al. / Tetrahedron 62 (2006) 2224–2230
2229
(15 ml) at 0 8C and stirred for 1 h. The reaction mixture was
poured into 10% Na2S2O3 solution and extracted with ethyl
acetate. The organic layer was washed with 0.1 N HCl and
brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane–ethyl acetate (2/1) gave
22 (557 mg, 90%) as a colorless oil.
(300 MHz in CDCl3): dZ0.08 (3H, s), 0.11 (3H, s), 0.88
(9H, s), 1.09 (1H, m), 1.26 (3H, d, JZ6.6 Hz), 1.34 (1H, m),
1.5–1.7 (4H, m), 2.0–2.3 (2H, m), 2.4–2.9 (4H, m), 4.23
(1H, m), 5.09 (1H, m), 5.97 (1H, d, JZ9.9 Hz), 6.85 (1H,
dd, JZ9.9, 5.7 Hz). FAB-HRMS m/z calcd for C20H35O4Si
[MCH]C 367.2305, found 367.2297.
3.2.19. Sch 642305 (1). A mixture of 1.01 M solution of
TBAF in THF (600 ml, 0.6 mmol) and acetic acid (36 mg,
0.6 mmol) was added to a solution of TBS ether 24 (20 mg,
0.05 mmol) in THF (1.5 ml) and stirred at room temperature
for 3 h under argon. The reaction mixture was poured into
saturated NH4Cl solution and extracted with ether. The
organic layer was washed with saturated NaHCO3 solution
and brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The residue was purified by
preparative TLC [hexane–ether (3/1)] and recrystallization
from acetone–hexane to give 1 (12 mg, 87%) as colorless
needles.
n2D7Z1.4856. [a]D28 C131 (c 1.0, CHCl3). IR (film): nZ
1711, 1679, 1466, 1385, 1255, 1109, 1024 cmK1. 1H NMR
(300 MHz in CDCl3): dZ0.12 (3H, s), 0.13 (3H, s), 0.91
(9H, s), 1.10 (1.5H, d, JZ6.0 Hz), 1.21 (1.5H, d, JZ
6.0 Hz), 1.25–1.85 (14H, m), 2.15–2.3 (1H, m), 2.49 (1H,
m), 2.7–2.85 (2H, m), 3.45–3.55 (1H, m), 3.65–3.8 (1H, m),
3.85–4.0 (1H, m), 4.6–4.7 (1H, m), 4.74 (1H, m), 5.88 (1H,
d, JZ9.0 Hz), 6.63 (1H, d, JZ9.0 Hz). FAB-HRMS m/z
calcd for C25H45O6Si [MCH]C 469.2985, found 469.2990.
3.2.17. {(1R,2S,6R)-2-(tert-Butyldimethylsilyloxy)-6-[(S)-
5-hydroxyhexyl]-5-oxocyclohex-3-en-1-yl}acetic acid
(23). To a solution of THP ether 22 (150 mg, 0.32 mmol)
in ether (6 ml) was added MgBr2$Et2O (248 mg,
0.96 mmol) at 0 8C under argon. The reaction mixture was
stirred at room temperature for 2 h and poured into saturated
NH4Cl solution. Water was added to the mixture until dark
red precipitate was completely dissolved and the resulting
solution was extracted with EtOAc. The organic layer was
washed with 0.1 N HCl and brine, dried over anhydrous
magnesium sulfate and concentrated in vacuo. The residue
was chromatographed over silica gel. Elution with chloro-
form–methanol (50/1) gave 23 (128 mg, quant.) as a slightly
yellow oil.
Mp 151–153 8C. [a]2D9 C74 (c 0.50, CH3OH). IR (KBr): nZ
1
3472, 2933, 1703, 1659, 1255, 1201, 1083, 874 cmK1. H
NMR (500 MHz in CD3OD): dZ1.08 (1H, ddd, JZ14.0,
10.5, 3.8 Hz), 1.2–1.4 (3H, m), 1.27 (3H, d, JZ6.7 Hz),
1.54 (1H, m), 1.83 (1H, m), 2.05–2.2 (2H, m), 2.53 (1H, dd,
JZ16.8, 11.5 Hz), 2.64 (1H, dt, JZ11.5, 3.8 Hz), 2.67 (1H,
dd, JZ16.8, 2.4 Hz), 2.81 (1H, ddt, JZ3.5, 2.4, 11.5 Hz),
4.21 (1H, dd, JZ5.6, 3.5 Hz), 5.05 (1H, m), 5.96 (1H, d, JZ
9.9 Hz), 7.02 (1H, dd, JZ9.9, 5.6 Hz). 13C NMR (125 MHz
in CD3OD): dZ18.6, 22.6, 24.2, 30.8, 37.9, 39.9, 47.8, 67.2,
74.7, 130.7, 149.5, 173.8, 202.4. FAB-HRMS m/z calcd for
C14H21O4 [MCH]C 253.1440, found 253.1444.
n2D7Z1.4883. [a]D26 C88 (c 1.0, CHCl3). IR (film): nZ3454,
3.2.20. 6-epi-Sch 642305 (25). Partial epimerization at C-6
position was observed under the several conditions for the
deprotection of TBS ether 24. Treatment of 24 with
p-toluenesulfonic acid in MeOH or KF and 18-crown-6 in
acetonitrile gave about 1:1 mixture of 1 and 25. Treatment
of 24 with Dowexw-50 in MeOH gave approximately 3:1
mixture of 1 and 25. These isomers were easily separated by
preparative TLC [hexane–ether (3/1)]. The structure of 25
was confirmed by NOE experiments. NOEs were observed
between 4-H, 5-H and 6-H.
1713, 1681, 1253, 1101, 837, 779 cmK1 1H NMR
.
(300 MHz in CDCl3): dZ0.12 (3H, s), 0.13 (3H, s), 0.91
(9H, s), 1.18 (3H, d, JZ6.0 Hz), 1.25–1.75 (8H, m), 2.22
(1H, dd, JZ16.5, 7.8 Hz), 2.51 (1H, m), 2.7–2.85 (2H, m),
3.81 (1H, m), 4.75 (1H, m), 5.88 (1H, d, JZ9.9 Hz), 6.63
(1H, d, JZ9.9 Hz). FAB-HRMS m/z calcd for C20H37O5Si
[MCH]C 385.2410, found 385.2421.
3.2.18. O-(tert-Butyldimethylsilyl)Sch 642305 (24).
Triethylamine (15 mg, 0.15 mmol) and 2,4,6-trichloro-
benzoyl chloride (19 ml, 0.13 mmol) were added to a
solution of the hydroxy acid 23 (40 mg, 0.10 mmol) in
THF (1 ml). The reaction mixture was stirred at room
temperature for 3 h and then filtered through Celitew under
argon. The resultant solution was added slowly using
syringe pump to a refluxing solution of DMAP (244 mg,
2.00 mmol) in dry toluene (100 ml) over 14 h. After the
addition was complete, the reaction mixture was stirred for
additional 1 h and concentrated in vacuo. The residue was
dissolved in ether and washed with 1 N HCl, saturated
NaHCO3 solution and brine. The organic layer was dried
over anhydrous magnesium sulfate and concentrated in
vacuo. The residue was chromatographed over silica gel.
Elution with hexane–ethyl acetate (20/1) gave 24 (28 mg,
73%) as colorless crystals and a small amount of dimeric
lactone (5 mg).
1H NMR (500 MHz in CD3OD): dZ0.8–1.15 (2H, m),
1.25–1.65 (3H, m), 1.28 (3H, d, JZ6.6 Hz), 1.87 (1H, m),
2.0–2.25 (2H, m), 2.09 (1H, dd, JZ17.1, 12.3 Hz), 2.36
(1H, dt, JZ12.3, 3.3 Hz), 2.84 (1H, dd, JZ17.1, 2.4 Hz),
3.32 (1H, m), 4.90 (1H, m), 5.04 (1H, m), 5.99 (1H, dd, JZ
10.2, 2.7 Hz), 6.67 (1H, dt, JZ10.2, 1.8 Hz). FAB-HRMS
m/z calcd for C14H21O4 [MCH]C 253.1440, found
253.1444.
References and notes
1. Chu, M.; Mierzwa, R.; Xu, L.; He, L.; Terracciano, J.;
Patel, M.; Gullo, V.; Black, T.; Zhao, W.; Chan, T.-M.;
McPhail, A. T. J. Nat. Prod. 2003, 66, 1527–1530.
2. Bouche, J. P.; Zechel, K.; Kornberg, A. J. Biol. Chem. 1975,
250, 5995–6001.
Mp 104–106 8C. [a]2D7 C56 (c 1.0, CHCl3). IR (Nujol):
1
nZ1722, 1671, 1255, 1163, 1088, 1036 cmK1. H NMR

2230
K. Ishigami et al. / Tetrahedron 62 (2006) 2224–2230
3. Azai, K. I.; Kornberg, A. Proc. Natl. Acad. Sci. U.S.A. 1979,
76, 4308–4312.
13. Various other procedures had been reported for the preparation
of 6. Representative examples are listed below (see Refs.
14,15).
4. Jayasuriya, H.; Zink, D. L.; Polishook, J. D.; Bills, G. F.;
Dombrowski, A. W.; Genilloud, O.; Pelacz, F. F.; Herranz, L.;
Quamina, D.; Lingham, R. B.; Danzeizem, R.; Graham, P. L.;
Tomassini, J. E.; Singh, S. B. Chem. Biodiversity 2005, 2,
112–122.
14. Ishida, T.; Wada, K. J. Chem. Soc., Perkin Trans. 1 1979,
323–327.
15. Takahashi, S.; Hosoya, M.; Koshino, H.; Nakata, T. Org. Lett.
2003, 5, 1555–1558.
5. Ratnayake, A. S.; Yoshida, W. Y.; Moonberry, S. L.;
Hemscheidt, T. Org. Lett. 2001, 3, 3479–3481.
6. Rukachaisirikul, V.; Pramjit, S.; Pakawatchai, C.; Isaka, M.;
Supothina, S. J. Nat. Prod. 2004, 67, 1953–1955.
7. Mehta, G.; Shinde, H. M. Chem. Commun. 2005, 3703–3705.
8. Kitahara, T.; Mori, K. Tetrahedron Lett. 1985, 26, 451–452.
9. Tachihara, T.; Kitahara, T. Tetrahedron 2003, 59, 1773–1780
and references cited therein.
16. Grieco, P. A.; Pogonowski, C. S. J. Chem. Soc., Chem.
Commun. 1975, 72–73.
17. Walts, A. E.; Roush, W. R. Tetrahedron 1985, 41,
3463–3478.
18. Avery, M. A.; Chong, K. M.; Jennings-White, C. J. Am. Chem.
Soc. 1992, 114, 974–979.
19. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
20. Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. J. Org. Chem.
1990, 55, 7–9.
10. Sugai, T.; Fujita, M.; Mori, K. Nippon Kagaku Kaishi 1983,
1315–1321.
11. Sugai, T.; Ohta, H. Agric. Biol. Chem. 1989, 53, 2009–2010.
12. Tsutsui, H.; Mitsunobu, O. Tetrahedron Lett. 1984, 25,
2159–2162.
21. Ishigami, K.; Kitahara, T. Heterocycles 2004, 63, 785–790.
22. Ishigami, K.; Watanabe, H.; Kitahara, T. Tetrahedron 2005,
61, 7546–7553.