Synthesis of the spiroacetal fragments of spirofungins A and B, antibiotics isolated from Streptomyces violaceusniger Tü 4113

Article abstract of DOI:10.1515/hc-2015-0193

The spiroacetal [C(9)-C(20)] fragments of spirofungins A and B, antibiotics isolated from Streptomyces violaceusniger Tü 4113, were prepared from a known bromo alcohol derived from (S)-citronellal, using thermodynamically controlled iodolactonization and spiroacetalization as the key steps.

Full text of DOI:10.1515/hc-2015-0193

Heterocycl. Commun. 2015; 21(6): 337–343
Hiroyuki Sakauchi, Emi Higashi, Yuko Shimizu, Mikiko Kojima, Yuko Asamitsu,
SShyignefutmhi Keuswaihsaroa,fMitnhoreu IzsumpiiarndoHaircomeatsaa Kliyfortaa*gments of
spirofungins A and B, antibiotics isolated from
Streptomyces violaceusniger Tü 4113
DOI 10.1515/hc-2015-0193
Results and discussion
Received September 3, 2015; accepted October 20, 2015
Abstract: The spiroacetal [C(9)–C(20)] fragments of spiro- (S)-Citronellal was converted to the known epoxy bromide
fungins A and B, antibiotics isolated from Streptomyces 3 [14] (Scheme 1). Oxidative cleavage of the epoxy ring
violaceusniger Tü 4113, were prepared from a known bromo with NaIO4 followed by reduction with NaBH4 afforded
alcohol derived from (S)-citronellal, using thermodynami- alcohol 4 in 86% yield [15]. The resulting hydroxy group
cally controlled iodolactonization and spiroacetalization was protected with a triphenylmethyl (Tr) group to give 5,
as the key steps.
which was subjected to dehydrobromination using KOt-Bu
in DMSO, leading to the olefinic compound 6. Oxidation
of the double bond was performed by Lemieux-Johnson
oxidation or ozonolysis to afford the aldehyde, which
was treated with Ph3Pꢀ=ꢀCHCO2Me to give ester 7. The ester
carbonyl group was reduced using DIBAL to furnish 8,
and the newly formed hydroxy group was protected as
a benzyl ether to produce 9. After removal of the trityl
group, the resulting alcohol 10 was oxidized to carbox-
Keywords: acetylide; antibiotics; iodolactonization;
selenolactonization; spiroacetalization; spirofungins
A and B; Streptomyces violaceusniger Tü 4113; synthesis.
Introduction
Spirofungins A and B are antifungal polyketides bearing a ylic acid 11a, the precursor for the key halolactonization.
spiroacetal ring, isolated from culture extracts of Strepto- The corresponding p-methoxybenzyl and p-bromobenzyl
myces violaceusniger Tü 4113 (Figure 1) [1]. Total synthesis derivatives, 11b and 11c, were also prepared.
has been achieved by several groups [2–7], and other syn-
The trials of halolactonization are listed in Table 1.
thetic studies have been reported to date [8–13]. In a pre- Several reagents releasing iodonium or bromonium ions
liminary communication, we have reported the synthesis wereexaminedfor11a(entries1–6).Thedesiredtrans-isomer
of a spirofungins A C(9)–C(20) fragment (A core, 1) and was preferentially obtained using I2 under thermodynamic
incorrectly proposed B [(15S,18R,19S)-isomer of A] by addi-
tion reaction of a racemic alkyne Y to an optically active
18S
lactone X [8]. Later, an optically active alkyne Y has been
1
11
12
O
O
24
used instead for the preparation of 1 [11]. Here we describe
the synthetic details of 1 and 2 as a continuation of the
previous reports [8, 11].
O
15S
9
19R O
OH
OH
OH
Spirofungins A (15S) and B (15R)]
18S
18S
11
11
12
O
OBn
O
15R
OBn
HO
HO
15S
9
9
19R
19R
O
O
*Corresponding author: Hiromasa Kiyota, Graduate School
of Environmental and Life Science, Okayama University,
1-1-1 Tsushima-Naka, Kita, Okayama 700-8530, Japan,
e-mail: kiyota@okayama-u.ac.jp
12
A core (1)
B core (2)
15
19
11
O
O
OBn
18
Hiroyuki Sakauchi and Minoru Izumi: Graduate School
of Environmental and Life Science, Okayama University,
1-1-1 Tsushima-Naka, Kita, Okayama 700-8530, Japan
Emi Higashi, Yuko Shimizu, Mikiko Kojima, Yuko Asamitsu and
Shigefumi Kuwahara: Graduate School of Agricultural Science,
Tohoku University, Japan
O
O
X
Y
Figure 1ꢀSpirofungins A and B, and the spiroacetal fragments
prepared in this study.
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ꢀꢀꢀꢁ
338ꢀ
ꢀH. Sakauchi et al.: Synthesis of spiroacetal fragments of spirofungins A and B
TrCl
pyridine
DMF
TrO
1) NaIO4, THF-H2O
2) NaBH4, MeOH
t-BuOK
DMSO
HO
Br
Br
Br
O
O
(86%, 2 steps)
(98%)
(96%)
5
3
4
(S)-citronellal
O
OMe
OH
Br
R
OMe
Ph3P
a) OsO4, NMO, NaIO4
THF/H2O
DIBAL
THF
TrO
TrO
TrO
O
Toluene
b) O3, MeOH/DCM
then Me2S
(quant.)
NaH, THF
(R = H, quant.)
(85%)
6
7
8
R
R
R
O
O
O
1 M aq. HCl
THF
reflux
CrO3, H2SO4
acetone
TrO
HO
HO
O
a: R = H
b: R = OMe
c: R = Br
(R = H, 91%)
11a–c
(R = H, 80%)
10a–c
9a–c
Scheme 1ꢀPreparation of lactonization precursors 11a–c.
Table 1ꢀLactonization of carboxylic acid precursors 11a–c.
R
R
R
O
X
O
X
O
O
O
O
O
HO
O
X
X = I, Br, SePh
HgOAc
R
H
X
I
R
H
X
11a–c
trans-12a
cis-12a
I
a: R = H
b: R = OMe
c: R = Br
trans-12b OMe I
cis-12b OMe
cis-12c Br
I
trans-12c Br
I
I
trans-13a
trans-14a
H
H
Br
cis-13a
cis-14a
H
H
Br
SePh
SePh
Entryꢁ
R
ꢁ
Conditions
I2 (3 eq), MeCN, 0°C, 6 h
ꢁ
Yield (%)ꢁ
trans/cis
1
ꢂ
H
H
H
H
H
H
H
H
OMeꢂ
OMeꢂ
Br
Br
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
44ꢂ
23ꢂ
35ꢂ
53ꢂ
41ꢂ
13ꢂ
0ꢂ
80ꢂ
10ꢂ
70ꢂ
22ꢂ
74ꢂ
3/1
1/2.5
1.2/1
3/1
2
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
I2 (3 eq), NaHCO3, MeCN, 0°C, 3 h
3
NIS (2.3 eq), 2,6-lutidine, DCM, 0 to 20°C, 24 hꢂ
IBr (3 eq), MeCN, 0°C, 6 h
NBS (2 eq), MeCN, 0°C, 12 h
NBS (2 eq), t-BuOK (1 eq), DMF, -20 to 20°C
Hg(OAc)2 (1.1 eq), MeOH, 0°C, 12 h
PhSeCl, Et3N, DCM
4
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
5
1.3/1
2.4/1
–
6
7
8
5/1a
–
9
I2 (1.5 eq), MeCN, 0°C, 12 h
I2 (3 eq), NaHCO3, MeCN, 0°C, 24 h
I2 (1.2 eq), MeCN, 0°C, 6 h
10
11
12
1.2/1
7/1
6/1
ꢂ
ꢂ
IBr (1.2 eq), MeCN, 0°C, 6 h
aInseparable mixture: determined by 1H NMR.
conditions (entry 1), but the yield was 44%. The products (11c) substituent on the benzene ring (entries 9–12), to
trans/cis-12a were easily separated using silica gel column change the electrostatic nature of the double bond. The
chromatography. Attempted mercuriolactonization pro- yield was improved with the p-methoxy derivative 11b, but
duced no lactonic product (entry 7). Selenolactonization the stereoselectivity was lower (entry 10). The best result
[16] using PhSeCl afforded the desired lactones, trans-14a was obtained with the p-bromo derivative 11c using IBr
and cis-14a, in 80% yield (entry 8); however, these isomers under thermodynamic conditions (entry 12). However, the
were inseparable even after deselenenylation (Bu3SnH, parent Bn compound trans-12a was used in the following
Et3B, O2, THF, 85%; Scheme 2). We also tried halolactoniza- steps due to the expected difficulty in deprotection of the
tion using the substrates with p-methoxy (11b) or p-bromo p-bromobenzyl group.
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H. Sakauchi et al.: Synthesis of spiroacetal fragments of spirofungins A and Bꢃ
ꢃ339
OBn
I
corresponding p-nitrobenzoyl ester. The epoxy ring of 16
was cleaved by methylation with Me3Al and the resulting
diol [18] was isolated as an acetal 17 [8]. The benzyl group
was removed by hydrogenolysis and the deprotected
alcohol 18 was converted to the dibromo olefin 19 under
Corey-Fuchs reaction conditions. Treatment of 19 with
BuLi afforded the alkyne 20.
O
O
O
O
O
OBn
OBn
Bu3SnH, Toluene
(93%)
trans-12a
trans-15
OBn
Bu3SnH, Et3B, O2
THF, 0°C, 30 min
*
O
O
*
O
*
SePh
With both fragments, trans-15 (ꢀ=ꢀ X) and 20 (ꢀ=ꢀ Y), in
our hands, lithium acetylide derived from 20 (1.8 eq.) was
treated with trans-15 lactone to furnish hydroxy ketone
21 in 94% yield (Scheme 4). The tautomeric hemiacetal
was not observed. Selective reduction of the compound 21
triple bond using Pd/BaSO4 as a catalyst in MeOH gave the
methyl acetal 22 as a single diastereomer in quantitative
yield. The stereochemistry of the acetal carbon could not
be determined. Finally, deprotection of the terminal acetal
group under acidic conditions accompanied by spiroac-
etal formation produced the desired A core (1) and B core
(2). The ratio of two spiroacetals (A core/B core ꢀ=ꢀ 1.0:2.7
or 1.0:1.9) is similar to Diaz’s results on the correspond-
ing PMB ethers (1.0:2.3) [11]. The spectroscopic data for 2
coincides with those reported [8, 11]. Studies towards total
synthesis are underway.
(85%)
trans/cis-14a
trans/cis-15
inseparable
Scheme 2ꢀSynthesis of trans-15 (ꢂ=ꢂ X).
Deiodination of trans-12a was performed using
Bu3SnH in 93% yield to give the desired lactone trans-15
(Scheme 2). The overall yield was 18% over 10 steps from 4.
Theopticallyactivealkyne20waspreparedinasimilar
manner as described in the previous report (Scheme 3) [8],
starting from the epoxide 16 [17]. The enantiomeric purity
of 16 was increased to ꢀ>ꢀ99% ee after crystallization of the
O
1) Me3Al, DCM, rt
H2, Pd/C
OBn
OBn
O
2) Diethyl ketone
TsOH, CuSO4
(69%)
EtOH, rt
(97%)
O
HO
16 (>99% ee)
17
Experimental
1) Dess-Martin periodinane, CH2Cl2, rt
OH
O
2) PPh3, Zn, CBr4, CH2Cl2
(73%)
O
O
IR spectra were recorded using neat compounds on a Jasco IR
Report-100 spectrometer. 1H NMR spectra were recorded with a
Varian GEMINI-300 spectrometer (300 MHz) using CDCl3 as solvent
and internal standard (δH 7.26 ppm). 13C NMR spectrum was recorded
with a Varian Inova-600 spectrometer (150 MHz) using CDCl3 as sol-
vent and internal standard (δC 77.00 ppm). Mass spectra in a positive
18
Br
BuLi, THF
-78°C
Br
O
O
O
(quant.)
+
ion mode (EI ) were recorded with a Jeol JMS-700 spectrometer. Merck
19
20
silica gel 60 (70–230 mesh) was used for column chromatography.
Merck silica gel 60 F254 (0.25 mm thickness) was used for TLC analysis.
Scheme 3ꢀSynthesis of 20 (ꢂ=ꢂ Y).
H2, Pd-BaSO4
OMe
BuLi, THF, -15°C
MeOH
O
OBn
OH
O
O
O
O
OBn
(quant)
O
O
OBn
O
O
O
trans-15
20 (1.8 eq.)
21
22
(94%)
18
19
18
19
11
12
11
12
O
OBn
O
OBn
HO
HO
15S
15R
9
9
+
O
O
a) TsOH, CH2Cl2, 20°C
b) PPTS, MeOH, 20°C
A core (1)
(a: 17%)
(b: 28%)
B core (2)
(a: 46%)
(b: 54%)
17
OH
H
NOE
16
H
H
O
HO
H
11
O
O
OBn
O
OBn
13
12
Scheme 4ꢀSynthesis of spirofungins A core (1) and B core (2).
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ꢀꢀꢀꢁ
340ꢀ ꢀH. Sakauchi et al.: Synthesis of spiroacetal fragments of spirofungins A and B
silica gel (hexane/EtOAc, 100:1) to give 6 (2.30 g, 6.55 mmol, 96%)
The enantiomeric purity of compound 16 (ꢀ>ꢀ99% ee) was determined
by HPLC analysis [column Daicel Chiralcel OD (4.6ꢀ×ꢀ250 mm)] eluting
with hexane/i-PrOH, 4:1, flow rate 1.0 mL/min at 20°C, tR ꢀ=ꢀ 7.60 min
(ent-16) and 9.20 min (16)].
24
as a colorless oil; [α]D ꢀ=ꢀ +6.8° (c ꢀ=ꢀ 1.0, i-Pr2O); IR (film): νmax 3050,
3000, 2950, 2910, 2850, 1630, 1590, 1480, 1440, 1410, 1380, 1360, 1310,
1
1220, 1180, 1150, 1070, 1030, 990, 900 cm-1; H NMR: δ 0.97 (d, 3H,
J ꢀ=ꢀ 6.6 Hz, CH3), 1.33–1.38 (m, 2H), 1.57–1.65 (m, 2H), 2.02–2.11 (m, 1H,
3-H), 3.03 (t, 2H, J ꢀ=ꢀ 6.7 Hz, 6-H), 4.88–4.95 (m, 2H, 1-H), 5.67 (ddd, 1H,
J ꢀ=ꢀ 7.7, 10.4, 17.3 Hz, 2-H), 7.20–7.46 (m, 15H, Ph). EI-HR-MS. Calcd for
(S)-6-Bromo-4-methylhexan-1-ol (4) [15]
+·
C26H28O (M ): m/z 356.2140. Found: m/z 356.2141.
To a solution of epoxide 3 [14] (11 g, 47 mmol) in THF/H2O (2:1,
120 mL) was added NaIO4 (20 g, 95 mmol), and the mixture was
stirred at 50°C for 4 h. Afer removing the precipitate by filtration,
the mixture was concentrated in vacuo. The residue was diluted with
ether, washed with saturated aqueous NaHCO3 solution followed by
saturated aqueous Na2S2O3 solution, dried with MgSO4, and concen-
trated in vacuo. To a solution of the resulting crude oil in MeOH (80
mL), NaBH4 (0.62 g, 16 mmol) was gradually added at 0°C, and the
mixture was stirred at 20°C for 1 h. Afer the pH value of the solution
was adjusted to 6 with 2 m aqueous HCl, the solvent was removed in
vacuo. The residue was diluted with ether, washed with water and
brine, dried with MgSO4, and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/EtOAc, 3:1) to give 4 (7.9 g, 40
Methyl (2E,4S)-4-methyl-7-(triphenylmethyl)oxyhept-
2-enoate (7)
Method AꢁA solution of 6 (5.3 g, 15 mmol), OsO4 (catalyst) and
N-methylmorpholine N-oxide (3.0 g, 26 mmol) in THF/water (6:1,
30 mL) was stirred at room temperature for 3 h and then treated with
a solution of NaIO4 (8.1 g, 38 mmol) in THF/water (1:1, 20 mL). Afer
adjusting the pH of the solution to 7, it was stirred at room tempera-
ture for 18 h. Afer removal of precipitates by filtration, the mixture
was diluted with ether, washed twice with a saturated aqueous
Na2S2O3 solution, dried with Na2SO4 and concentrated in vacuo to
obtain crude aldehyde.
23
32
mmol, 86%) as a colorless oil, [α]D ꢀ=ꢀ +5.0° (c ꢀ=ꢀ 1.2, i-Pr2O) {[α]D ꢀ=ꢀ
+7.40 (c ꢀ=ꢀ 1.16 g/mL) [15]}; IR (film): νmax 3350, 2950, 2920, 2850, 1740,
1
1720, 1650, 1450, 1440, 1380, 1260, 1240, 1220, 1060 cm-1; H NMR:
Method BꢁOzone in oxygen gas was passed through a solution of
6 (3.4 g, 9.7 mmol) in dry MeOH/dry CH2Cl2 (5:3, 80 mL) at -78°C for
30 min. Then this solution was treated with Me2S (1.5 mL) and the
mixture was stirred until the temperature of the reaction reached
room temperature. The mixture was concentrated in vacuo and the
residue was diluted with ether, washed with water, dried with MgSO4,
and concentrated in vacuo to obtain crude aldehyde.
δ 0.92 (d, 3H, J ꢀ=ꢀ 6.6 Hz, CH3), 1.19–1.75 (m, 6H), 1.89 (m, 1H, H-4),
3.37–3.52 (m, 2H, H-6), 3.65 (t, 2H, J ꢀ=ꢀ 6.6 Hz, H-1). EI-HR-MS. Calcd for
C7H1679BrO (M+H) : m/z 195.0385. Found: m/z 195.0389.
+·
(S)-1-Bromo-3-methyl-6-(triphenylmethyl)oxyhexane (5)
A mixture of crude aldehyde and methyl triphenylphosphora-
nylideneacetate [A, 9.6 g, 30 mmol; B, 6.1 g, 19 mmol] in dry toluene
[A, 80 mL; B, 40 mL] was stirred at 50°C for 20 h. The mixture was
concentrated in vacuo and the residue was chromatographed on sil-
ica gel (hexane/EtOAc, 9:1) to give 7 [A, 5.1 g, 12 mmol, 83%; B, 3.4 g,
A solution of 4 (12.0 g, 61.5 mmol), pyridine (7.75 g, 8.00 mL, 98.0
mmol), triphenylmethyl chloride (18.1 g, 65.0 mmol) and DMAP (1.51
g, 12.0 mmol) in dry DMF (100 mL), was stirred at 70°C for 2 h. Afer
cooling to room temperature the mixture was diluted with water
and extracted with hexane. The organic layer was washed with 1 m
aqueous HCl followed by water, dried with MgSO4 and concentrated
in vacuo. The residue was chromatographed on silica gel (hexane/
EtOAc, 19:1) to give 5 (26.2 g, 60.0 mmol, 98%) as a colorless oil;
20
8.2 mmol, 85%, E/Z ꢀ=ꢀ 95:5] as a colorless oil; [α]D ꢀ=ꢀ +33° (c ꢀ=ꢀ 1.0,
i-Pr2O); IR (film): νmax 3050, 3010, 2950, 2920, 2860, 1650, 1600, 1490,
1450, 1430, 1380, 1350, 1310, 1270, 1210, 1180, 1150, 1070, 1040, 980,
1
900 cm-1; H NMR: δ 1.03 (d, 3H, J ꢀ=ꢀ 6.6 Hz, CH3), 1.39–1.48 (m, 2H),
1.57–1.64 (m, 2H), 2.25 (m, 1H, 4-H), 3.04 (dt, 2H, J ꢀ=ꢀ 1.5, 6.5 Hz, 7-H),
3.73 (s, 3H, OCH3), 5.75 (dd, 1H, J ꢀ=ꢀ 1.0, 16 Hz, 2-H), 6.84 (dd, 1H, J ꢀ=ꢀ
24
[α]D ꢀ=ꢀ -3.2° (c ꢀ=ꢀ 1.1, i-Pr2O); IR (film): νmax 3070, 3050, 3010, 2950,
2920, 2850, 1950, 1480, 1440, 1380, 1320, 1280, 1220, 1180, 1150, 1080,
1030, 1000, 900 cm-1; 1H NMR: δ 0.88 (d, 3H, J ꢀ=ꢀ 6.3 Hz, CH3), 1.15–1.69
(m, 6H), 1.73–1.82 (m, 1H, H-3), 3.05 (t, 2H, J ꢀ=ꢀ 6.6 Hz, H-6), 3.46–3.60
(m, 2H, H-1), 7.19–7.46 (m, 15H, Ph). EI-HR-MS. Calcd for C26H2979BrO
+·
8.0, 16 Hz, 3-H), 7.18–7.45 (m, 15H). EI-HR-MS. Calcd for C28H30O3 (M ):
m/z 414.2195. Found: m/z 414.2197.
+·
(M ): m/z 436.1402. Found: m/z 436.1402.
(2E,4S)-4-Methyl-7-(triphenylmethyl)oxyhept-2-en-1-ol (8)
To a solution of 7 (12.1 g, 29.1 mmol) in dry THF (100 mL) was added
DIBAL (1.0 m in toluene, 64 mL, 64 mmol) at -78°C, and the mix-
ture was stirred at this temperature for 20 min. Then MeOH (3 mL)
was added, followed by a saturated aqueous Rochelle salt solution
(10 mL), and the mixture was stirred for 2 h at room temperature.
Next, the mixture was diluted with ether, washed with a saturated
aqueous NH4Cl solution, water and then brine, dried with MgSO4 and
concentrated in vacuo. The residue was chromatographed on silica
gel (hexane/EtOAc, 10:1) to give 8 (11.2 g, 29.0 mmol, quantitative
(S)-3-Methyl-6-(triphenylmethyl)oxyhex-1-ene (6)
To a solution of 5 (3.00 g, 6.86 mmol) in pentane (15 mL) was added
a solution of KOt-Bu (1.54 g, 13.7 mmol) in DMSO (14 mL) at 0°C, and
the mixture was stirred at room temperature for 1 h. Then the mix-
ture was cooled to 0°C, and water (10 mL) was added. Afer stirring at
room temperature for 30 min., the mixture was extracted with pen-
tane. The organic layer was washed with 1 m aqueous HCl, a satu-
rated aqueous NaHCO3 solution and then water, dried with MgSO4,
and concentrated in vacuo. The residue was chromatographed on
24
yield) as a colorless oil; [α]D ꢀ=ꢀ +11°(c ꢀ=ꢀ 1.1, i-Pr2O); IR (film): νmax
3350, 3080, 3050, 3020, 2950, 2920, 2860, 1740, 1600, 1490, 1450, 1370,
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ꢁꢀꢀꢀ
H. Sakauchi et al.: Synthesis of spiroacetal fragments of spirofungins A and Bꢃ
ꢃ341
1240, 1220, 1180, 1150, 1070, 1040, 1000, 900 cm-1; 1H NMR: δ 0.98 (d,
pale green oil. This carboxylic acid was used in the next step without
3H, J ꢀ=ꢀ 6.9 Hz, CH3), 1.31–1.39 (m, 2H), 1.58–1.66 (m, 2H), 2.10 (m, 1H, further purification. IR (film): νmax 3675–3050 (br.), 3025, 2950, 2925,
4-H), 3.04 (dt, 2H, J ꢀ=ꢀ 6.7 Hz, 7-H), 4.08–4.14 (m, 3H), 5.54 (m, 2H, 2-H, 2860, 1705, 1450, 1410, 1355, 1280, 1175, 1115, 1090, 1075, 1025, 975 cm-1;
3-H), 7.23–7.46 (m, 15H, Ph). EI-HR-MS. Calcd for C27H30O2 (M ): m/z 1H NMR: δ 1.03 (d, 3H, J ꢀ=ꢀ 6.6 Hz, CH3), 1.55–1.75 (m, 2H), 2.16–2.25 (m,
+·
386.2246. Found: m/z 386.2248.
1H, 4-H), 2.31–2.37 (m, 2H, H-2), 3.98 (d, 2H, J ꢀ=ꢀ 4.8 Hz, H-7), 4.51 (s, 2H,
PhCH2), 5.57–5.60 (m, 2H, H-5, 6), 7.35–7.40 (m, 5H, Ph).
(2E,4S)-1-Benzyloxy-4-methyl-7-(triphenylmethyl)
oxyhept-2-ene (9a)
(4S,5S,6R)-7-Benzyloxy-6-iodo-4-methylheptan-5-olide
(trans-12a)
To a suspension of NaH (60% oil dispersion, washed with hexane
before use, 0.9 g, 22 mmol) in dry THF (70 mL), a solution of 8 (2.6 g,
6.7 mmol) in dry THF (15 mL) and benzyl chloride (2.9 g, 2.6 mL,
23 mmol) were added dropwise at 20°C, and the mixture was stirred
at 50°C for 12 h. Afer cooling to 0°C, water (10 mL) was added and
THF was removed in vacuo. The residue was diluted with ether,
washed with a saturated aqueous NH4Cl solution, water and then
brine, dried with MgSO4, and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/EtOAc, 10:1) to give 9a (3.2 g,
6.7 mmol, quantitative yield) as a colorless oil; [α]D23 ꢀ=ꢀ +12° (c ꢀ=ꢀ 1.0,
i-Pr2O); IR (film): νmax 3075, 3050, 3020, 2925, 2860, 1590, 1485, 1445,
To a solution of 11a (560 mg, 2.26 mmol) in dry CH3CN (5 mL) was
added I2 (1.72 g, 6.78 mmol) at 0°C, and the mixture was stirred at 0°C
for 12 h. The mixture was poured into a saturated aqueous Na2S2O3
solution (1:1, 20 mL), and stirred until the color of I2 diminished. The
aqueous layer was separated and extracted three times with EtOAc.
The combined organic layers were washed with water and then brine,
dried with MgSO4, and concentrated in vacuo. The residue was chro-
matographed twice on silica gel (hexane/EtOAc, 4:1) to give trans-12a
24
(281 mg, 0.750 mmol, 33%) as a colorless oil; [α]D ꢀ=ꢀ +22° (c ꢀ=ꢀ 0.98,
i-Pr2O); IR (film): νmax 3400, 3010, 2950, 2920, 2850, 1730, 1490, 1450,
1
1355, 1215, 1150, 1070, 1025, 970 cm-1; H NMR: δ 0.98 (d, 3H, J ꢀ=ꢀ 6.9
1
1360, 1340, 1240, 1200, 1180, 1100, 1040 cm-1; H NMR: δ 1.09 (d, 3H,
Hz, CH3), 1.31–1.42 (m, 2H), 1.57–1.66 (m, 2H), 2.11 (sep., 1H, J ꢀ=ꢀ 6.9 Hz,
H-3), 3.03 (t, 2H, J ꢀ=ꢀ 6.6 Hz, H-7), 3.96 (d, 2H, J ꢀ=ꢀ 5.0 Hz, H-1), 4.50 (s,
2H, PhCH2), 5.43–5.61 (m, 2H, H-2, 3), 7.19–7.45 (m, 15H, Tr).
J ꢀ=ꢀ 6.6 Hz, CH3), 1.49–1.62 (m, 1H, 3-H), 1.81–1.90 (m, 1H, 3-H), 2.18–
2.29 (m, 1H, 4-H), 2.38–2.65 (m, 2H, 2-H), 3.79–3.92 (m, 2H, 7-H), 4.25
(dd, 1H, J ꢀ=ꢀ 3.0, 8.5 Hz, 5-H), 4.50–4.59 (m, 3H, H-6, PhCH2), 7.27–7.36
+·
(m, 5H, Ph). EI-HR-MS. Calcd for C15H19 I O3 (M ): m/z 374.0379. Found:
m/z 374.0457.
(4E,5S)-7-Benzyloxy-4-methylhept-5-en-1-ol (10a)
(4S,5R)-7-Benzyloxy-4-methylheptan-5-olide [(4S,5R)-1
or trans-15] [8]
A solution of 9a (1.00 g, 2.10 mmol) in THF/1 M aqueous HCl (14:1,
30 mL) was stirred under reflux for 6 h. Afer removal of the solvent,
the residue was diluted with ether, washed with a saturated aque-
ous NaHCO3 solution followed by brine, dried with MgSO4 and con-
centrated in vacuo. The residue was chromatographed on silica gel
(hexane/EtOAc, 10:1) to give 10a (470 mg, 1.92 mmol, 91%) as a color-
less oil; [α]D24 ꢀ=ꢀ +19° (c ꢀ=ꢀ 1.1, i-Pr2O); IR (film): νmax 3400, 3010, 2920,
2850, 1490, 1450, 1370, 1250, 1210, 1100, 1070, 1030, 980, 910 cm-1; 1H
NMR: δ 1.02 (d, 3H, J ꢀ=ꢀ 6.9 Hz, CH3), 1.32–1.40 (m, 2H), 1.51–1.61 (m,
2H), 2.18 (m, 1H, 4- H), 3.63 (t, 2H, J ꢀ=ꢀ 1.5, 6.5 Hz, 1-H), 3.98 (d, 2H, J ꢀ=ꢀ
4.7 Hz, 7-H), 4.51 (s, 2H, PhCH2), 5.77–5.59 (m, 2H, 5, 6-H), 7.26–7.35 (m,
To a solution of trans-12a (160 mg, 0.43 mmol) in dry toluene (1 mL)
was added tributyltin hydride (0.64 mL, 400 mg, 1.37 mmol) at 0°C,
and the mixture was stirred at room temperature for 2 h. Afer the mix-
ture was diluted with ether, KF (100 mg, 1.7 mmol) was added, and
the mixture was stirred at room temperature for 24 h. Afer removal
of precipitates with a Celite pad, the filtrate was washed with brine,
dried with MgSO4, and concentrated in vacuo. The residue was chro-
matographed twice on silica gel (hexane/EtOAc, 10:1, then 4:1) to give
(4S,5R)-1 (100 mg, 0.40 mmol, 93%) as a pale yellow oil; [α]D24 ꢀ=ꢀ +84°
(c ꢀ=ꢀ 1.0, i-Pr2O); IR (film): νmax 3450, 3010, 2950, 2910, 2850, 1730, 1490,
1450, 1380, 1360, 1240, 1200, 1090, 1030 cm-1; 1H NMR: δ 1.02 (d, 3H, J ꢀ=ꢀ
6.6 Hz, CH3), 1.49–1.62 (m, 1H, H-3), 1.68–1.96 (m, 3H, H-3, 6), 2.04–2.17
(m, 1H, H-4), 2.41–2.67 (m, 2H, H-2), 3.63–3.75 (m, 2H, H-7), 4.13 (dt, 1H,
J ꢀ=ꢀ 2.5, 9.6 Hz, H-5), 4.51, 4.52 (s, s, 2H, PhCH2), 7.27–7.38 (m, 5H, Ph).
+·
5H, Ph). EI-HR-MS. Calcd for C15H22O2 (M ): m/z 234.1620. Found: m/z
234.1621.
(4E,5S)-7-Benzyloxy-4-methylhept-5-enoic acid (11a)
+·
EI-HR-MS. Calcd for C15H20O3 (M ): m/z 248.1412. Found: m/z 248.1415.
To a solution of 10a (5.39 g, 23.0 mmol) in acetone (30 mL) was titrated
with Jones reagent (2.67 M) at 0°C until the color of the solution became
pale orange, and then the mixture was stirred at room temperature for
an additional 3 h. The mixture was treated with i-PrOH until the color
of the solution changed to green. Then, solids were removed by filtra-
tion through a Celite pad, and the filtrate was concentrated in vacuo.
(2S,3R)-1-Benzyloxy-3,4-(pentane-3,3-diyl)dioxy-
2-methylbutane (17)
The residue was diluted with ether and extracted twice with a satu- To a solution of 16 (800 mg, 4.12 mmol) in dry CH2Cl2 (25 mL) was
rated aqueous NaHCO3 solution. Afer acidification with 2 m aque- added Me3Al (1.0 m in CH2Cl2, 15 mL, 15 mmol) at 20°C, and the mix-
ous HCl, the aqueous layer was extracted four times with EtOAc. The ture was stirred at 20°C for 14 h. Afer addition of 2 m aqueous HCl
combined organic layers were washed with brine, dried with MgSO4, the mixture was stirred for 30 min. Product was extracted with EtOAc
and concentrated in vacuo to give 11a (4.60 g, 18.5 mmol, 80%) as a and the extract was washed with water, a saturated aqueous NaHCO3
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342ꢀ ꢀH. Sakauchi et al.: Synthesis of spiroacetal fragments of spirofungins A and B
solution followed by brine. Final concentration in vacuo gave a pale
6H, CH3CH2 × 2), 1.10 (d, 3H, J ꢀ=ꢀ 8.2 Hz, 3-CH3), 1.56–1.70 (m, 4H,
yellow oil (0.98 g) that was used in the next step without further puri- CH3CH2 × 2), 2.66 (m, 1H, H-3), 3.68 (m, 1H, H-4), 3.92–4.02 (m, 2H,
fication. A solution of this oil (0.93 g), CuSO4 (1.5 g) and TsOH (40 mg) H-5), 6.25 (dd, 1H, J ꢀ=ꢀ 1.8, 9.6 Hz, H-2). EI-HR-MS. Calcd for C11H1979Br-
in diethyl ketone (8 mL) was stirred at 20°C for 18 h. The mixture was 81BrO2 (M+H ): m/z 342.9731. Found: m/z 342.9736.
+
filtered through a Celite pad and concentrated in vacuo. The residue
was chromatographed on silica gel (hexane/EtOAc, 10:1) to give 17
1
(750 mg, 2.69 mmol, 69%) as a colorless oil; H NMR: δ 0.89 (t, 3H,
(3S,4R)-4,5-(Pentane-3,3-diyl)dioxy-3-methylpent-
J ꢀ=ꢀ 7.4 Hz, CH3CH2), 0.90 (q, 3H, J ꢀ=ꢀ 7.4 Hz, CH3CH2), 1.04 (d, 3H, J ꢀ=ꢀ
1-yne (20)
6.9 Hz, 3-CH3), 1.55–1.70 (m, 4H, CH3CH2 × 2), 1.95 (m, 1H, H-2), 3.37
(d, 2H, J ꢀ=ꢀ 5.9 Hz, H-4), 3.64 (t, 1H, J ꢀ=ꢀ 7.9 Hz, H-3), 4.00 (m, 1H, H-3),
To a solution of 19 (590 mg, 1.72 mmol) in dry THF (7 mL) was added
4.48 (m, 2H, CH2Ph).
BuLi (1.6 m in hexane, 3.5 mL, 5.5 mmol) at -78°C and the mixture was
stirred for 30 min at -78°C. The mixture was diluted with a saturated
aqueous NH4Cl solution and extracted twice with ether. The com-
(2S,3R)-3,4-(Pentane-3,3-diyl)dioxy-2-methylbutan-
bined organic layers were washed with brine, dried with MgSO4 and
1-ol (18)
concentrated in vacuo. The residue was chromatographed on silica
gel (hexane/EtOAc, 10:1) to give 20 (314 mg, 1.72 mmol, quantitative
yield) as a colorless oil; IR (film): νmax 3300, 2950, 2920, 2860, 2100,
1640, 1460, 1370, 1350, 1330, 1290, 1280, 1260, 1200, 1170, 1120, 1080,
960, 920 cm-1; 1H NMR: δ 0.87–0.94 (m, 6H, CH3CH2 × 2), 1.27 (d, 3H, J ꢀ=ꢀ
6.9 Hz, 3-CH3), 1.57–1.70 (m, 4H, CH3CH2 × 2), 2.06 (d, 1H, H-1), 2.55–
2.65 (m, 1H, H-3), 3.84 (dd, 1H, J ꢀ=ꢀ 6.6, 8.0 Hz, H-5), 3.96 (dd, 1H, J ꢀ=ꢀ
6.5, 8.0 Hz, H-4), 4.13 (dd, 1H, J ꢀ=ꢀ 6.0, 8.0 Hz, H-5). EI-HR-MS. Calcd.
A suspension of 17 (3.12 g, 11.2 mmol) and Pd/C (10%, 300 mg) in
EtOH (100 mL) was stirred under a hydrogen atmosphere for 2 days.
The solution was filtered through a Celite pad and the filtrate was
concentrated in vacuo. The residue was chromatographed on silica
gel to separate 18 (950 mg, 5.05 mmol) and 17 as colorless oils. A sus-
pension of the recovered 17 and Pd/C (10%, ca. 150 mg) in EtOH (50
mL) was stirred under a hydrogen atmosphere for 3 days. The solu-
tion was filtered through a Celite pad and the filtrate was concen-
trated in vacuo. The residue was chromatographed on silica gel to
give 18 (1.09 g, 5.79 mmol). The combined yield was 97%; IR (film):
νmax 3400, 2950, 2920, 2850, 1740, 1720, 1450, 1370, 1350, 1260, 1200,
+
for C11H17O2 (M–H ): m/z 181.1229. Found: m/z 181.1292.
(2R,3S,9S,10R)-12-Benzyloxy-10-hydroxy-3,9-dimethyl-1,
2-(pentane-3,3-diyl)dioxydodec-4-yn-6-one (21)
1160, 1130, 1070, 1040, 960, 920 cm-1; H NMR: δ 0.88 (t, 3H, J ꢀ=ꢀ 7.4
1
Hz, CH3CH2), 0.92 (q, 3H, J ꢀ=ꢀ 7.4 Hz, CH3CH2), 0.99 (d, 3H, J ꢀ=ꢀ 6.9 Hz,
3-CH3), 1.59–1.70 (m, 4H, CH3CH2 × 2), 1.97 (m, 1H, H-2), 3.52–3.65 (m,
2H, H-1), 4.02 (dd, 1H, J ꢀ=ꢀ 6.3, 8.0 Hz, H-3), 4.10–4.17 (m, 2H, H-4).
To a solution of 20 (91.0 mg, 0.50 mmol, 1.8 equiv.) in ether (0.9 mL)
was added BuLi (1.6 m in hexane, 0.32 mL, 0.50 mmol) at -15°C and
the mixture was stirred for 15 min at this temperature. This mixture
was added dropwise to a solution of trans-15 (63.8 mg, 0.275 mmol) in
ether (1 mL) at -15°C and the resulting mixture was stirred for 20 min
at this temperature. Then the mixture was poured into a saturated
aqueous NH4Cl solution and extracted with EtOAc. The organic layer
was dried with MgSO4 and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/EtOAc,4:1) to give 21 (111 mg,
(3S,4R)-1,1-Dibromo-4,5-(pentane-3,3-diyl)dioxy-3-
methylpent-1-ene (19)
A suspension of 18 (152 mg, 0.807 mmol), NaHCO3 (140 mg, 1.75
mmol) and Dess-Martin periodinane (515 mg, 1.21 mmol) in dry CH2Cl2
(7 mL) was stirred at 20°C for 10 min. The mixture was diluted with
Et2O and washed with a saturated aqueous Na2S2O3 solution and then
a saturated aqueous NaHCO3 solution, dried with MgSO4 and concen-
trated in vacuo to give crude aldehyde; 1H NMR: δ 0.90 (t, 6H, J ꢀ=ꢀ 7.5
Hz, CH3CH2), 1.23 (m, 3H, 2-CH3), 1.59–1.65 (m, 4H, CH3CH2 × 2), 2.63
(quint, 1H, J ꢀ=ꢀ 6.6 Hz, H-2), 3.64 (t, 1H, J-7.5 Hz, H-4), 4.16 (m, 1H), 4.29
(q, 1H, J ꢀ=ꢀ 6.3 Hz), 9.74 (s, 1H, H-1).
1
0.258 mmol, 94%) as a colorless oil; H NMR: δ 0.84–0.96 (m, 12H,
CH3CH2 × 2, 3,9-CH3), 1.40–1.80 (m, 9H, H-8,9,11, CH3CH2 × 2), 2.46–1.70
(m, 2H), 2.80 (quint, 1H, J ꢀ=ꢀ 7.3 Hz), 3.07 (br. s, 1H, OH), 3.62 (m, 2H),
3.74 (m, 1H), 3.81 (m, 1H), 4.00 (m, 1H), 4.13 (dd, 1H, J ꢀ=ꢀ 8.0, 6.0 Hz),
4.53 (s, 2H, CH2Ph), 7.28–7.38 (m, 5H, Ph).
(2R,3S,9S,10R)-12-Benzyloxy-6,10-epoxy-6-methoxy-3,
9-dimethyl-1,2-(pentane-3,3-diyl)dioxydodecane (22)
A suspension of Zn powder (105 mg, 1.60 mmol) and PPh3 (420
mg, 1.60 mmol) in dry CH2Cl2 (2 mL) was stirred for 5 min at 20°C. Afer
the mixture had been cooled to 0°C, a solution of CBr4 (540 mg, 1.60
mmol) in dry CH2Cl2 (2 mL) was added, and the mixture was stirred for
30 h, during which time the temperature was gradually increased to
20°C. This mixture was treated with the aldehyde described above in
dry CH2Cl2 (2 mL), and the mixture was stirred for an additional 12 h.
Pentane was then added and the resulting crystals were removed by
filtration. The filtrate was concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/EtOAc, 10:1) to give 19 (201
A suspension of 21 (18.0 mg, 0.042 mmol) and Pd-BaSO4 (catalyst)
in MeOH (0.5 mL) was stirred under a hydrogen atmosphere for 15 h.
The mixture was filtered through a Celite pad and concentrated
in vacuo. The residue was chromatographed on silica gel (hexane/
EtOAc, 4:1) to give 22 (15.6 mg, 0.035 mmol, 83.1%) as a colorless oil;
1H NMR: δ 0.83–0.92 (m, 9H, CH3CH2 × 2, 3-CH3), 1.00 (d, 3H, J ꢀ=ꢀ 6.5
Hz, 9-Me), 1.40–1.80 (m, 11H), 2.02 (m, 1H), 3.09 (s, 3H, OCH3), 3.36 (tt,
1H, J ꢀ=ꢀ 10.2, 2.1 Hz), 3.56 (dt, 1H, J ꢀ=ꢀ 3.0, 8.0 Hz), 3.60–3.70 (m, 2H),
mg, 0.586 mmol, 73%) as a colorless oil; IR (film): νmax 2960, 2930, 3.85 (m, 1H), 4.00 (ddd, 1H, J ꢀ=ꢀ 8.0, 6.1, 4.2 Hz), 4.50 (s, 2H, CH2Ph),
+
+
2860, 1610, 1450, 1380, 1360, 1350, 1330, 1270, 1230, 1200, 1170, 1130, 7.28–7.38 (m, 5H, Ph). HR-MS (FAB ). Calcd for C27H44O5Na (M+Na ):
1
1080, 1060, 1020, 1000, 970, 940, 920 cm-1; H NMR: δ 0.86–0.95 (m, m/z 471.3086. Found: m/z 471.3093.
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ꢁꢀꢀꢀ
H. Sakauchi et al.: Synthesis of spiroacetal fragments of spirofungins A and Bꢃ
ꢃ343
[5] Marjanovic, J.; Kozmin, S. A. Spirofungin A: stereoselective
synthesis and inhibition of isoleucyl-tRNA synthetase. Angew.
Chem. Int. Ed. 2007, 46, 8854–8857.
[6] Crimmins, M. T.; O’Bryan, E. A. Enantioselective total synthesis
of spirofungins A and B. Org. Lett. 2010, 12, 4416–4419.
[7] Lynch, J. E.; Zanatta, S. D.; White, J. M.; Rizzacasa, M. A.
Stereoselective total synthesis of (-)-spirofungin A by utilising
hydrogen-bond controlled spiroketalisation. Chem. Eur. J. 2011,
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[8] Shimizu, Y.; Kiyota, H.; Oritani, T. Synthesis of the spiroacetal
parts of spirofungin A and B. Tetrahedron Lett. 2000, 41,
3141–3144.
[9] Dias, L. C.; De Oliveira, L. G. Short synthesis of the
6,6-spiroketal cores of spirofungins A and B. Org. Lett. 2004,
6, 2587–2590.
[10] La Cruz, T. E.; Rychnovsky, S. D. Synthesis of the spirofungin
B core by a reductive cyclization strategy. Org. Lett. 2005, 7,
1873–1875.
[11] de Oliveira, L. G.; Dias, L. C.; Sakauchi, H.; Kiyota, H.
Spirofungins A and B: a reassignment of Kiyota’s spiroketals.
Tetrahedron Lett. 2006, 47, 2413–2418.
[12] Shimizu, T.; Usui, T.; Fujikura, M.; Kawatani, M.; Satoh, T.;
Machida, K.; Kanoh, N.; Woo, J.-T.; Osada,.; Sodeoka, M.
Synthesis and biological activities of reveromycin A and
spirofungin A derivatives. Bioorg. Med. Chem. Lett. 2008, 18,
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187–190.
(2R,3S,6S,8R,9S)-8-(2-Benzyloxyethyl)-3,9-dimethyl-
1.7-dioxaspiro[5.5]undecane-2-methanol [spirofungin
numbering: (11R,12S,15S,19R,18S)-9-Benzyloxy-11,15:
15,19-diepoxy-12,18-dimethyldodecan-20-ol]
(spirofungin A core, 1) and its 6R-epimer
(spirofungin B core, 2)]
A solution of 22 (31.0 mg, 0.069 mmol) and TsOH (catalyst) in CH2Cl2
(1 mL) was stirred at 20°C for 5 min. A saturated aqueous NaHCO3
solution was then added, and the separated organic layer was dried
with MgSO4 and concentrated in vacuo. The residue was chroma-
tographed on silica gel (hexane/EtOAc, 4:1) to give 1 (4.0 mg, 0.011
mmol, 17%) and 2 (11 mg, 0.032 mmol, 46%) as colorless oils. Data for
1: 1H NMR: δ 0.85 (d, 3H, J ꢀ=ꢀ 6.6 Hz), 0.90 (d, 3H, J ꢀ=ꢀ 6.9 Hz), 1.2–1.35
(m, 2H), 1.4–1.7 (m, 8H), 1.9–2.1 (m, 2H), 2.13 (dd, 1H, J ꢀ=ꢀ 14.3, 3.8 Hz),
3.56–3.66 (m, 2H), 3.66–3.76 (m, 2H), 4.10 (m, 2H), 4.25 (d, 1H, J ꢀ=ꢀ 9.6
Hz), 4.50 (d, 1H, J ꢀ=ꢀ 11.8 Hz, CH2Ph), 4.56 (d, 1H, J ꢀ=ꢀ 11.8 Hz, CH2Ph),
7.4–7.2 (m, 5H, Ph); 13C NMR: δ 14.6 (Me), 17.8 (Me), 27.9, 29.6, 33.6, 34.8,
38.6, 42.1, 44.7, 66.9, 69.4, 72.3, 72.8, 77.2, 96.4 (C-15), 127.5 (p-Ph), 127.7
+
(o-Ph), 128.7 (m-Ph), 138.8 (ipso-Ph). HRMS (FAB ). Calcd for C21H33O4
+
(M+H ): m/z 359.2379. Found: m/z 349.2382. Data for 2: see refs. [8, 11].
Acknowledgments: Financial support was provided
by Grants-in-Aid from JSPS KAKENHI (No. 17580092,
19580120, 22560112 and 25450144). Support from the Agri-
cultural Chemical Research Foundation, the Intelligent
Cosmos Foundation and the Naito Foundation is gratefully
acknowledged. Our thanks are also due to the Takasago
International Corporation for the gift of (S)-citronellal.
[14] Aldred, M.; Vlachos, P.; Dong, D.; Kitney, S.; Tsoi, C. W.;
O’Neill, M.; Kelly, S. Heterocyclic reactive mesogens:
synthesis, characterisation and mesomorphic behaviour.
Liq. Cryst. 2005, 3, 951–965.
[15] Markowski, T.; Drescher, S.; Meister, A.; Hause, G.; Blume, A.;
Dobner, B. Synthesis of optically pure diglycerol tetraether
model lipids with non-natural branching pattern. Eur. J. Org.
Chem. 2011, 5894–5904.
[16] Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Halo- and selenolactonization: the two major
strategies for cyclofunctionalization. Tetrahedron 2004, 60,
5273–5308.
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