Organocatalytic asymmetric syntheses of inthomycins A, B and C

Article abstract of DOI:10.1039/c2ob26084k

The total syntheses of (+)-inthomycin A, (+)-inthomycin B and (-)-inthomycin C, the oxazole-triene antibiotics isolated from Streptomyces sp., have been accomplished via the highly enantio- and stereoselective construction of the C1-C7 (iododienyl)aldol units by taking advantage of a Cinchona alkaloid-catalyzed asymmetric β-lactone synthesis and their isomerisation-free Stille coupling with (E)-5-(3-(tributylstannyl)allyl)oxazole.

Full text of DOI:10.1039/c2ob26084k

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PAPER
Organocatalytic asymmetric syntheses of inthomycins A, B and C†
Madoka Yoshino, Kohei Eto, Keisuke Takahashi, Jun Ishihara and Susumi Hatakeyama*
Received 5th June 2012, Accepted 29th August 2012
DOI: 10.1039/c2ob26084k
The total syntheses of (+)-inthomycin A, (+)-inthomycin B and (−)-inthomycin C, the oxazole-triene
antibiotics isolated from Streptomyces sp., have been accomplished via the highly enantio- and
stereoselective construction of the C1–C7 (iododienyl)aldol units by taking advantage of a Cinchona
alkaloid-catalyzed asymmetric β-lactone synthesis and their isomerisation-free Stille coupling with
(E)-5-(3-(tributylstannyl)allyl)oxazole.
Introduction
Since Uemura and co-workers first reported the isolation of oxa-
zolomycin A and neooxazolomycin in 1985,1 many congeners
containing a methylene-interrupted oxazolyl-triene motif and a
spiro fused β-lactone/γ-lactam core have been isolated from
strains of Streptomyces sp. (Fig. 1).2 These antibiotics exhibit
wide ranging and potent antibacterial and antiviral activities as
well as in vivo antitumor activity.2 Due to such intriguing bio-
logical properties and characteristic structures, a number of
efforts have been dedicated towards the synthesis of the oxazolo-
mycin family of antibiotics.2,3 However, Kende’s total synthesis4
of neooxazolomycin had long been the only achievement until
we recently reported the syntheses of neooxazolomycin5 and
oxazolomycin A.6 In order to synthesize other members of this
family, we need to develop an efficient methodology which
allows us to secure the left hand segments having 4′Z,6′Z,8′E-,
4′E,6′E,8′E- and 4′Z,6′E,8′E-triene systems stereoselectively.
Under this situation, we became interested in the synthesis of
inthomycins A, B and C which have the structures corresponding
to the left hand segments of the oxazolomycins.
In 1990, Ōmura et al. isolated phthoxazolin A from the strain
of Streptomyces sp. OM-5714.7 Then, the following year,
Henkel and Zeek8 discovered inthomycin A together with the
geometrical isomers inthomycins B and C from the strain of
Streptomyces sp. Gö 2, and proved inthomycin A to be identical
with phthoxazolin A. These inthomycins are found to be highly
specific inhibitors of cellulose biosynthesis, displaying signifi-
cant antimicrobial9 and herbicidal activities.10 In addition, intho-
mycin A was also shown to strongly inhibit the growth of
Graduate School of Biomedical Sciences, Nagasaki University, 1-14
Bunkyo-Machi, Nagasaki 852-8521, Japan.
Fig. 1 The oxazolomycins and the inthomycins.
E-mail: susumi@nagasaki-u.ac.jp; Fax: +81-95-819-2426;
Tel: +81-95-819-2426
†Electronic supplementary information (ESI) available: 1H NMR and
13C NMR spectra for all isolated intermediates and inthomycins A, B
and C. See DOI: 10.1039/c2ob26084k
prostate cancer cells.11 Although the syntheses of ( )-inthomycin
A,12 (+)-inthomycin B12c,13 and (−)-inthomycin C14 have
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Scheme 2 Preparation of 9 and 10.
Scheme 1 Retrosynthetic analysis.
already been accomplished, there is no report of the asymmetric
synthesis of all of these three compounds based on an unified
methodology which enables us to secure the left-hand segments
of most members of the oxazolomycin family. Herein, we report
the highly enantio- and stereocontrolled total syntheses of
(+)-inthomycin A, (+)-inthomycin B and (−)-inthomycin C start-
ing with an organocatalytic asymmetric [2+2] cycloaddition
reaction of an aldehyde and a ketene.15
Results and discussion
Scheme 1 illustrates our retrosynthetic analysis of inthomycins
A, B and C. The disconnection of the C7–C8 bond by a Stille
coupling gives us (E)-5-(3-(tributylstannyl)allyl)oxazole (1)12c
and three iododienes Z,Z-2, Z,E-3 and E,E-4. We assumed that
each of these iododienes could be prepared regio- and stereo-
selectively via either iodination-semihydrogenation or hydrome-
tallation-iodination from alkyne 5 or alkyne 6. To expeditiously
access 5 and 6 we envisioned organocatalytic asymmetric syn-
thesis of β-lactones 7 and 8 from aldehydes 9 and 10 as a starting
point. Although such a chiral amine-catalyzed [2+2] cyclo-
addition reaction involving an aldol-lactonization process has
been well established by Romo et al.,16 Fu et al.,17 and Nelson
et al.,18 the reaction of a conjugated aldehyde such as 9 has
rarely been examined to-date.‡ This strategy is therefore challen-
ging, and an enantioselectivity issue of the key β-lactone for-
mations is of great interest.
Scheme 3 Unsuccessful asymmetric [2+2] cycloadditions.
Z-aldehyde 9 was synthesized by a three-step sequence involving
copper-catalyzed addition of methylmagnesium bromide fol-
lowed by iodination,12a Sonogashira coupling of 11 with ethy-
nyltrimethylsilane, and MnO2 oxidation of 12. Similarly,
E-aldehyde 10 was obtained via Negishi methylation-
iodination,19 Sonogashira coupling of 13 with ethynyltrimethyl-
silane, and MnO2 oxidation of 14.
We first examined the reaction of 9 and dimethylketene, gener-
ated by Zn-mediated reduction of 2-bromo-2-methylpropanoyl
bromide, using 15 as a catalyst under Fu’s conditions;17
however, the desired β-lactone 7 was not produced at all
(Scheme 3).
The required Z-aldehyde 9 and E-aldehyde 10 were prepared
from propargyl alcohol in geometrically pure forms (Scheme 2).
Thus, according to the procedure we previously established,5a
‡Several successful reactions using simple ynals have been reported.18a,b
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Table 1 Asymmetric [2+2] cycloadditions
LiClO4
(eq)
Catalyst
(mol%)
Yielda
(%)
eeb
(%)
deb
(%)
Entry
Scheme 4 TMSQD-catalyzed reaction of 10 with propionyl chloride.
1
2
3
4
2
4
4
4
TMSQD (10)
TMSQD (10)
TMSQD (20)
TMSQN (20)
14
87
92
84
98
97
>99
>99
>99
>99
98
−97c
a Isolated yield. b Determined by chiral HPLC analysis. c The enantiomer
of 16 was obtained.
We then investigated the Cinchona alkaloid-catalyzed reaction
of 9 with isobutyryl chloride according to Nelson’s procedure18
using quinidine TMS ether (TMSQD), LiClO4 and Hünig’s
base. This method again did not give us any encouraging results.
Alternatively, we also explored the reaction of 9 with dimethyl-
ketene under the TMSQD/LiClO4-catalyzed conditions. In this
case, the desired β-lactone 7 was obtained but the yield and the
enantioselectivity were disappointingly low. These results
suggested that the gem-dimethyl groups of the ketene hampered
this reaction, possibly because of steric hindrance. Therefore, we
alternatively planned to introduce one methyl group after an
asymmetric cycloaddition reaction using propionyl chloride
instead of isobutyryl chloride.
Table 1 illustrates the results obtained from the chiral amine-
catalyzed reaction of Z-aldehyde 9 and propionyl chloride.
When 9 was reacted with 2 equiv of propionyl chloride using 2
equiv of LiClO4 and 10 mol% of TMSQD in CH2Cl2–Et2O
(2 : 1) at −78 °C, asymmetric cycloaddition proceeded with high
enantio- and diastereoselectivity to give β-lactone 16 although
the yield was very low (entry 1). We then gratifyingly found that
when the amount of LiClO4 was increased from 2 equiv to 4
equiv, the yield was dramatically improved and both ee and de
values were again very high (entry 2). When 4 equiv of LiClO4
and 20 mol% of TMSQD were used, the best result was obtained
and β-lactone 16 was produced in 92% yield, 98% ee and 99%
de (entry 3). Similarly, when quinine TMS ether (TMSQN) was
employed as a catalyst, the corresponding enantiomer of 16 was
obtained in high yield and excellent enantio- and diastereoselec-
tivities. In addition, this method can be also applied to E-alde-
hyde 10, and β-lactone 17 was produced again in high yield and
excellent enantio- and diastereoselectivities (Scheme 4). The
stereostructure of 16 was confirmed by its NOESY spectrum and
the absolute configuration was determined by its conversion to
the known ester 5.5a
Scheme 5 Preparation of Z,Z-iododiene 2.
to Seebach’s protocol20 to afford hydroxy ester 19 in good yield.
Desilylation of 19 followed by TBS protection of 20 gave the
known ester 5 which was stereoselectively converted to Z,Z-
iododiene 2 following the previously established procedure5a
involving an iodination and a diimide reduction.
According to Baldwin’s method,12c,21 compound 2 was then
subjected to Stille coupling with stannane 1 using Pd(PPh3)4,
CuI and CsF in DMF at room temperature to give Z,Z,E-triene
21 in geometrically pure form (Scheme 6). When this coupling
was carried out using Pd(0) catalyst alone, some extent of iso-
merization of the triene system was always observed.21 After
desilylation of 21, compound 22 was successively subjected to
saponification, acetylation, and amidation to give acetate 23.
Finally, removal of the acetyl group of 23 completed the first
total synthesis of (+)-inthomycin A. The spectroscopic data and
specific rotation were identical with those reported7a,12c for
natural inthomycin A.
Synthesis of (+)-inthomycin A
Synthesis of (+)-inthomycin B
The synthesis of (+)-inthomycin A began with the preparation of
Z,Z-iododiene 2 from β-lactone 16 (Scheme 5). Thus, methano-
lysis of 16 gave methyl ester 18 which was methylated according
For the synthesis of inthomycin B, Z,E-iododiene 3 was first syn-
thesized from 5 by hydrozirconation22 followed by iodination
(Scheme 7). Thus, alkyne 5 was treated with in situ prepared
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Scheme 8 Preparation of E,E-iododiene 4.
five step-sequence involving desilylation, hydrolysis, acetylation,
amidation and removal of the acetyl group. The spectroscopic
data were in accord with those reported12c for natural
inthomycin B.
Synthesis of (−)-inthomycin C
Scheme 6 Synthesis of (+)-inthomycin A.
E-Alkyne 6 was prepared from β-lactone 17 in 80% overall yield
in the same manner as described for the synthesis of 5 from 16
(Scheme 8). E-Alkyne 6 was then subjected to hydrozirconation
followed by iodination but the transformation proceeded with
poor regioselectivity to afford a 2 : 1 mixture of 4 and its 6-iodo-
isomer in 61% yield. We then examined the hydrostannylation23
and hydrosilylation24 of 6 under various conditions. However, as
seen in Table 2, these methods did not exhibit high regioselectiv-
ity although the yields were satisfying in all cases.
After considerable experimentation, we eventually found that
a stannylcupration-iodination23a converted 26 to E,E-iododiene
29 with high regioselectivity (Scheme 9). Thus, when 26 was
treated with Bu3Sn(Bu)CuCNLi2 in THF at −78 °C followed by
iodine, a 7 : 1 mixture of 29 and its 6-iodo-isomer was obtained
in 60% yield. Stille coupling of 29 with 1 using Pd(PPh3)4, CuI,
and CsF in DMF proceeded at room temperature without isomer-
isation and geometrically pure E,E,E-triene 30 was produced in
83% yield. From coupling product 30, the total synthesis of
(−)-inthomycin C was accomplished via a four-step sequence
involving hydrolysis, acetylation, amidation and removal of the
acetyl group. The spectroscopic data§ and specific rotation were
identical with those reported12c,14 for natural inthomycin C.
Scheme 7 Synthesis of (+)-inthomycin B.
Conclusions
We have achieved highly enantio- and stereoselective syntheses
of inthomycins A, B and C in naturally occurring forms starting
with a Cinchona alkaloid-catalyzed asymmetric [2+2] cyclo-
addition of an aldehyde and a ketene. The present methodology
Schwartz’s reagent from zirconocene dichloride and DIBAL fol-
lowed by iodine to produce an inseparable 6 : 1 mixture of Z,E-
iododiene 3 and its 6-iodo-isomer in 82% yield. The mixture
was then subjected to Stille coupling with 1 under the same con-
ditions mentioned for the coupling of 2 and 1 to give Z,E,E-
triene 24 stereoselectively in moderate yield. From coupling
product 24, (+)-inthomycin B was successfully synthesized via a
§Taylor et al. reported12c that inthomycin C showed [α]2D1 +25.9 (c 0.27,
CHCl3). Recently, Ryu et al. reported14 it to be [α]D20 −34.3 (c 0.10, CHCl3)
which is close to our observation ([α]2D3 −41.5 (c 0.10, CHCl3)).
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Table 2 Hydrometallations of alkyne 6
Entry
M
Conditions
Yielda (%) 27 : 28b
1
2
3
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
Bu3SnH (1.5 eq), AIBN (5 mol%), benzene (0.1 M), reflux, 2.5 h
91
80
67
1 : 1
2 : 5
1.1 : 1
4 : 1
1.3 : 1
1.1 : 1
PdCl2(PPh3)2 (20 mol%), Bu3SnH (1.5 eq), THF (0.1 M), rt
Pd2(dba)3 (0.5 mol%), Bu3SnH (1.2 eq), Cy3PHBF4 (2 mol%), iPr2NEt, toluene (0.04 M), rt, 30 min
4
Pd2(dba)3 (0.5 mol%), Bu3SnH (1.2 eq), Cy3PHBF4 (2 mol%), iPr2NEt, toluene (0.04 M), 0 °C, 30 min 73
5c
6c
(EtO)3Si (EtO)3SiH (3 eq), Pt(dvds) (3 mol%), CH2Cl2 (0.05 M), 0 °C to rt
(EtO)3Si (EtO)3SiH (3 eq), Pt(dvds) (3 mol%), CH2Cl2 (0.05 M), −78 to −40 °C
82
80
a Isolated yield. b Determined by 1H NMR analysis. c Pt(dvds) = platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex
MgSO4 and concentrated by rotary evaporation below 30 °C at
25 Torr unless otherwise noted. Commercial reagents and sol-
vents were used as supplied with the following exceptions. N,N-
Dimethylformamide (DMF), dichloromethane (CH2Cl2), aceto-
nitrile (MeCN), benzene and toluene were distilled from CaH2.
Methanol (MeOH) was distilled from sodium. Thin-layer chrom-
atography (TLC) was performed using precoated silica gel plates
(0.2 or 0.5 mm thickness). Column chromatography was per-
formed using silica gel (particle size: 100–210 μm (regular),
40–50 μm (flash)). Optical rotations were recorded on a digital
polarimeter at ambient temperature. Infrared spectra were
measured on a Fourier transform infrared spectrometer. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were measured
using CDCl3 as solvent, and chemical shifts are reported as δ
values in ppm based on internal CHCl3 (7.26 ppm, 1H;
77.0 ppm, 13C). Mass spectra (MS and HRMS) were taken in
EI mode.
(Z)-3-Iodo-2-methylprop-2-en-1-ol (11). To a suspension of
propargyl alcohol (2.0 g, 35.6 mmol) and CuI (6.78 g,
35.6 mmol) in Et2O (100 mL) was added MeMgBr (1.65 M in
Et2O, 45 mL, 74.8 mmol) at −5 °C. The mixture was gradually
allowed to warm to room temperature and stirred for additional
2 h. ICl (5.78 g, 35.6 mmol) was then added at −5 °C, and the
mixture was allowed to warm to room temperature and stirring
was continued for 16 h. The mixture was diluted with saturated
NH4Cl (50 mL) at 0 °C and filtered through Celite®. The filtrate
was extracted with Et2O, washed with brine, dried and concen-
trated. Purification of the residue by column chromatography
(SiO2 150 g, hexane–AcOEt = 5 : 1) gave 1112b (4.60 g, 65%) as
Scheme 9 Synthesis of (−)-inthomycin C.
is of general value in approaches to the related oxazolomycins,
the syntheses of which are currently under investigation.
1
a pale yellow oil. H NMR δ 5.99 (s, 1H), 4.25 (s, 2H), 1.98 (s,
3H); 13C NMR δ 146.1, 74.9, 68.1, 21.6; FTIR (neat) 3419,
2911, 2187, 2012, 1618, 1283, 1137, 1046 cm−1; HRMS calcd
for C4H7OI (M+) 197.9541; found 197.9515.
Experimental section
General
Where appropriate, reactions were performed in flame-dried
glassware under argon atmosphere. All extracts were dried over
(Z)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-ol (12). To a
solution of 11 (4.0 g, 20.2 mmol) in degassed THF (102 mL)
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(E)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-ynal (10). Alcohol
14 (2.5 g, 14.9 mmol) was oxidized using activated MnO2
(12.9 g, 149 mmol) in the same manner as described for the
preparation of 9 from 12. Purification by column chromato-
graphy (SiO2 120 g, hexane–AcOEt = 80 : 1) gave 10 (2.32 g,
94%) as a brown oil. 1H NMR δ 9.46 (s, 1H), 6.33 (s, 1H), 1.94
(s, 3H), 0.24 (s, 9H); 13C NMR δ 194.1, 149.0, 128.6, 113.8,
100.1, 11.8, −0.4; FTIR (neat) 2961, 2821, 2713, 2137, 1689,
1604, 1092 cm−1; MS m/z 43, 151, 166 (100, M+); HRMS calcd
for C9H14OSi (M+) 166.0814, found 166.0784.
were added ethynyltrimethylsilane (5.6 mL, 40.8 mmol), diiso-
propylamine (24 mL, 153.7 mmol), PdCl2(PPh3)2 (288.2 mg,
0.4 mmol) and CuI (272 mg, 1.6 mmol) at room temperature.
After being stirred at room temperature for 1 h under sonication,
the mixture was diluted with saturated NaHCO3 (200 mL),
extracted with Et2O, washed with brine, dried and concentrated.
Purification of the residue by column chromatography (SiO2
180 g, hexane–AcOEt = 10 : 1 to 5 : 1) gave 12 (3.46 g, 100%)
1
as a reddish brown oil. H NMR δ 5.41 (s, 1H), 4.36 (d, J = 6.4
Hz, 2H), 1.88 (s, 3H), 0.19 (s, 9H); 13C NMR δ 151.9, 106.7,
101.6, 64.1, 20.3; FTIR (neat) 3393, 2143, 1629, 1448, 1254,
1100 cm−1; HRMS calcd for C9H16OSi (M+) 168.0970, found
168.0964.
(3S,4S)-3-Methyl-4-((Z)-5-(trimethylsilyl)pent-2-en-4-yn-2-yl)-
oxetan-2-one (16). To a solution of LiClO4 (1.28 g, 12.0 mmol)
and TMSQD18 (240 mg, 0.60 mmol) in CH2Cl2–hexane (1 : 1)
(10 mL) were added a solution of 9 (500 mg, 3.0 mmol) in
CH2Cl2 (2.5 mL) and diisopropylethylamine (1.32 mL,
7.50 mmol) at −78 °C. A solution of propionyl chloride
(0.50 mL, 6.0 mmol) in CH2Cl2 (2.0 mL) was then added
slowly over 2 h. After being stirred at −78 °C for 20 h, the
mixture was diluted with Et2O (50 mL) and filtered through a
short silica gel column. The filtrate was concentrated and chro-
matographed (SiO2 50 g, hexane–AcOEt = 80 : 1 to 20 : 1) to
give 16 (0.61 g, 92%) as a yellow oil. [α]2D0 −267.3 (c 0.92,
(Z)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-ynal (9). To a sus-
pension of activated MnO2 (14.4 g, 177 mmol) in hexane–
CH2Cl2 (3 : 2) (50 mL) was added a solution of 12 (2.0 g,
11.8 mmol) in CH2Cl2 (10 mL) at room temperature. The
mixture was stirred at room temperature for 24 h and filtered
through Celite® which was washed with Et2O. The combined
filtrate and washings were concentrated and the residue was
purified by column chromatography (SiO2 100 g, hexane–AcOEt
1
1
= 100 : 1) to give 9 (1.80 g, 92%) as a brown oil. H NMR δ
CHCl3); H NMR δ 5.57 (s, 1H), 5.52 (d, J = 6.8 Hz, 1H), 3.94
10.25 (s, 1H), 6.53 (s, 1H), 1.86 (s, 3H), 0.22 (s, 9H); 13C NMR
δ 192.5, 147.4, 125.8, 106.5, 92.3, 15.5, 0.3; FTIR (neat) 3557,
3357, 2138, 1697, 1257, 1100 cm−1; MS m/z 57, 131, 151
(100), 166 (M+); HRMS calcd for C9H14OSi (M+) 166.0814,
found 166.0800.
(qd, J = 7.8, 6.8 Hz, 1H), 1.87 (s, 3H), 1.18 (d, J = 7.8 Hz, 3H),
0.19 (s, 9H); 13C NMR δ 171.8, 147.0, 108.6, 101.3, 100.3,
74.9, 50.0, 19.5, 8.8, −0.3; FTIR (neat) 2138, 1836, 1763, 1446,
1253, 1102 cm−1; MS m/z 57 (100), 151, 222 (M+); HRMS
calcd for C12H18O2Si (M+) 222.1076, found 222.1096. The
enantiomeric excess and diastereomeric excess were determined
to be 98% ee and >99% de by chiral HPLC analysis: Daicel
Chiralcel AS, 2-propanol–hexane = 1 : 800 (0.5 mL min−1),
tR = 20.2 min (S,S) and 25.2 min (R,R).
(E)-3-Iodo-2-methylprop-2-en-1-ol (13). To
a solution of
Me3Al (2.0 M in hexane, 78 mL, 156 mmol) and Cp2ZrCl2
(18.2 g, 62.4 mmol) in CH2Cl2 (80 mL) was added propargyl
alcohol (3.5 g, 62.4 mmol) at 0 °C, and the mixture was stirred
at room temperature for 14 h. A solution of I2 (2.08 g,
8.21 mmol) in THF (5.0 mL) was added at −78 °C, and the
mixture was allowed to warm to room temperature. After being
stirred at room temperature for 1 h, the mixture was acidified
with 3 M HCl at 0 °C, extracted with AcOEt, washed with satu-
rated NaHCO3, saturated Na2S2O3 and brine, dried and concen-
trated. Purification of the residue by column chromatography
(SiO2 250 g, hexane–AcOEt = 3 : 1) gave 13 (6.82 g, 55%) as a
(3R,4R)-3-Methyl-4-((Z)-5-(trimethylsilyl)pent-2-en-4-yn-2-yl)-
oxetan-2-one. The reaction of 9 (50 mg, 0.30 mmol) and propio-
nyl chloride (50 μL, 0.60 mmol) was carried out using LiClO4
(1.28 g, 12.0 mmol), TMSQN18 (0.24 mg, 0.60 mmol) and di-
isopropylethylamine (0.13 ml, 0.75 mmol) at −78 °C for 20 h in
the same manner as described for the preparation of 16 from 9.
Purification by column chromatography (SiO2 6.0 g, hexane–
AcOEt = 80 : 1 to 10 : 1) to give the title compound (56 mg,
84%), an enantiomer of 16, as a yellow oil. [α]2D0 +262.9 (c 0.88,
CHCl3). The enantiomeric excess and diastereomeric excess
were determined to be 97% ee and >99% de by chiral HPLC
analysis: Daicel Chiralcel AD, 2-propanol–hexane = 1 : 800
(0.7 mL min−1), tR = 21.5 min (R,R) and 32.9 min (S,S).
1
yellow oil. H NMR δ 6.29 (s, 1H), 4.13 (d, J = 5.9 Hz, 2H),
1.85 (s, 3H); 13C NMR δ 147.1, 77.3, 66.7, 21.3; FTIR (neat)
3316, 2914, 1624, 1274, 1012 cm−1; MS m/z 71, 198 (100, M+);
HRMS calcd for C4H7OI (M+) 197.9542, found 197.9536.
(E)-2-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-ol (14). Iodide
13 (1.82 g, 9.19 mmol) was subjected to Sonogashira coupling
using ethynyltrimethylsilane (2.6 mL, 18.4 mmol), diisopropyl-
amine (9.4 mL, 68.9 mmol), PdCl2(PPh3)2 (110 mg, 0.18 mmol),
and CuI (110 mg, 0.64 mmol) in the same manner as described
for the preparation of 12 from 11. Purification by column chrom-
atography (SiO2 80 g, hexane–AcOEt = 7 : 1 to 5 : 1) afforded
(3S,4S)-3-Methyl-4-((E)-5-(trimethylsilyl)-pent-2-en-4-yn-2-yl)-
oxetan-2-one (17). The reaction of 10 (2.12 g, 12.7 mmol) with
propionyl chloride (2.22 mL, 25.4 mmol) was carried out using
LiClO4 (5.40 g, 50.8 mmol), TMSQD (1.0 g, 2.54 mmol) and
diisopropylethylamine (5.54 mL, 50.8 mmol) in the same
manner as described for the preparation of 16 from 9. Purifi-
cation by column chromatography (SiO2 120 g, hexane–AcOEt
= 80 : 1 to 20 : 1) gave 17 (2.39 g, 85%) as a yellow oil. [α]D22
1
14 (1.53 g, 99%) as a reddish brown oil. H NMR δ 5.61 (s,
1H), 4.12 (d, J = 6.3 Hz, 2H), 1.91 (s, 3H), 0.20 (s, 9H); 13C
NMR δ 151.6, 104.6, 102.4, 98.4, 66.7, 16.5, 0.0; FTIR (neat)
3329, 2138, 1252, 1098 cm−1; MS m/z 153 (100) 168 (M+);
HRMS calcd for C9H16OSi (M+) 168.0970, found 168.0961.
−123.9 (c 1.02, CHCl3); H NMR δ 5.73 (s, 1H), 4.98 (d, J =
1
6.4 Hz, 1H), 3.91 (qd, J = 7.5, 6.4 Hz, 1H), 1.89 (s, 3H), 1.21
(d, J = 7.5 Hz, 3H), 0.21 (s, 9H); 13C NMR δ 171.1, 144.3,
107.9, 100.9, 100.7, 75.7, 49.7, 16.4, 8.7, −0.1; FTIR (neat)
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2961, 2137, 1839, 1254, 1104 cm−1; MS m/z 43 (100), 163, 222
(M+); HRMS calcd for C12H18O2Si (M+) 222.1076, found
222.1091.
12.4 mmol) and TBSOTf (2.7 mL, 7.9 mmol) at 0 °C. The
mixture was allowed to warm to room temperature and stirring
was continued for 0.5 h. The mixture was diluted with saturated
NH4Cl (10 mL) at 0 °C and extracted with AcOEt. The extract
was washed with brine, dried, concentrated and chromato-
graphed (SiO2 30 g, hexane–AcOEt = 100 : 1) to give 54
(900 mg, 100%) as a colorless oil. [α]2D2 +115.3 (c 1.1, CH2Cl2);
1H NMR δ 5.44 (s, 1H), 5.15 (s, 1H), 3.66 (s, 3H), 3.13 (d, J =
1.5 Hz, 1H), 1.80 (s, 3H), 1.21 (s, 3H), 1.18 (s, 3H), 0.87 (s,
9H), 0.06 (s, 3H), −0.02 (s, 3H); 13C NMR δ 177.2, 153.1,
108.8, 82.2, 80.9, 52.0, 49.4, 25.9, 22.9, 21.0, 18.9, 18.3, −4.6,
(2S,3S,Z)-Methyl 3-hydroxy-2,4-dimethyl-7-(trimethylsilyl)-
hept-4-en-6-ynoate (18). To a solution of 16 (2.49 g, 11.2 mmol)
in MeOH (110 mL) was added NaOMe (6.0 mg, 0.112 mmol) at
0 °C. After being stirred at room temperature for 30 min, the
mixture was diluted with saturated NH4Cl (50 mL), concen-
trated, and extracted with AcOEt. The extract was washed with
brine concentrated and chromatographed (SiO2 80 g, hexane–
AcOEt = 8 : 1) to give 18 (2.71 g, 95%) as a yellow oil. [α]D24
−5.3; FTIR (neat) 3311, 1735, 1468, 1256, 1136, 1083 cm−1
;
1
HRMS calcd for C17H30O3Si (M+) 310.1965, found 310.1938.
−58.2 (c 1.02, CHCl3); H NMR δ 5.41 (s, 1H), 5.02 (d, J =
4.6 Hz, 1H), 3.70 (s, 3H), 2.95 (dq, J = 4.6, 7.1 Hz,, 1H), 2.80
(brs, 1H), 1.84 (s, 3H), 1.22 (d, J = 7.1 Hz, 3H), 0.18 (s, 9H);
13C NMR δ 175.5, 153.5, 106.5, 101.4, 100.1, 72.8, 51.8, 43.9,
19.1, 11.4, −0.2; FTIR (neat) 3495, 2136, 1730, 1445, 1254,
1201, 1093, 1032 cm−1; MS m/z 73, 167 (100), 254 (M+);
HRMS calcd for C13H22O3Si (M+) 254.1338, found 254.1329.
(R,Z)-Methyl 3-((tert-butyldimethylsilyl)oxy)-7-iodo-2,2,4-tri-
methylhept-4-en-6-ynoate. To solution of (600 mg,
a
5
1.94 mmol) in THF (10 mL) was added dropwise n-BuLi
(1.6 M in hexane, 1.34 mL, 2.14 mmol) at −78 °C. After stirring
at −78 °C for 1 h, a solution of I2 (984 mg, 3.88 mmol) in THF
(2.0 mL) was added and stirring was continued at −78 °C for
1 h. The mixture was allowed to warm to 0 °C and saturated
Na2S2O3 (10 mL) was added. The mixture was extracted with
AcOEt, washed with brine, dried, concentrated and chromato-
graphed (SiO2 50 g, hexane–AcOEt = 7 : 1) to give the corres-
ponding iodide4 (841 mg, 99%) as a pale yellow oil. [α]2D3 +93.4
(R,Z)-Methyl 3-hydroxy-2,2,4-trimethyl-7-(trimethylsilyl)hept-
4-en-6-ynoate (19). To a solution of diisopropylamine (3.9 mL,
27.7 mmol) in THF (40 mL) was added dropwise n-BuLi
(2.67 M in hexane, 8.8 mL, 24.4 mmol) at −78 °C. After stirring
at −78 °C for 45 min, a solution of 18 (1.68 g, 6.60 mmol) in
THF (10 mL) was added, and the mixture was allowed to warm
to −20 °C and stirring was continued for 20 min. Iodomethane
(4.1 mL, 66.0 mmol) was then added at −78 °C, and the mixture
was allowed to warm to −20 °C. After stirring at −20 °C for 4 h,
the reaction was quenched with saturated NH4Cl (50 mL), and
the mixture was extracted with AcOEt. The extract was washed
with brine, concentrated and purified by flash column chromato-
graphy (SiO2 60 g, CHCl3–hexane = 4 : 1) to give 19 (1.48 g,
1
(c 1.0, CH2Cl2); H NMR δ 5.55 (s, 1H), 5.10 (s, 1H), 3.67 (s,
3H), 1.80 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H), 0.88 (s, 9H), 0.06
(s, 3H), −0.03 (s, 3H); 13C NMR δ 176.7, 154.0, 109.6, 91.4,
76.5, 51.8, 49.0, 25.7, 22.4, 20.9, 18.4, 18.0, −4.9, −5.6; FTIR
(neat) 1736, 1468, 1388, 1255, 1137, 1079, 1000 cm−1; HRMS
calcd for C17H29O3SiI (M+) 436.0931, found 436.0922.
(R,4Z,6Z)-Methyl 3-(tert-butyldimethylsilyloxy)-7-iodo-2,2,4-
trimethylhepta-4,6-dienoate (2). To a solution of the iodide
(50 mg, 0.11 mmol) in THF–i-PrOH (1 : 1) (1.4 mL) were added
triethylamine (0.024 mL, 0.17 mmol) and o-nitrobenzenesulfo-
nyl hydrazide (40 mg, 0.18 mmol), and the mixture was stirred
at room temperature. Triethylamine (0.012 mL, 0.085 mmol)
and o-nitrobenzenesulfonyl hydrazide (20 mg, 0.090 mmol)
were further added each 14 h later and 20 h later. After being
stirred at room temperature for additional 6 h, the mixture was
diluted with AcOEt, washed with H2O and brine, dried and con-
centrated. Purification of the residue by flash column chromato-
graphy (SiO2 4.0 g, hexane–AcOEt = 10 : 1) gave 24 (48 mg,
1
84%) as a yellow oil. [α]2D4 −32.7 (c 1.24, CHCl3); H NMR δ
5.48 (s, 1H), 4.90 (d, J = 7.3 Hz, 1H), 3.72 (s, 3H), 3.49 (d, J =
7.3 Hz, 1H), 1.73 (s, 3H), 1.34 (s, 3H), 1.20 (s, 3H), 0.18 (s,
9H); 13C NMR δ 178.2, 151.0, 110.0, 102.3, 99.3, 77.2, 52.1,
46.9, 24.5, 20.5, 18.3, −0.2; FTIR (neat) 3506, 2132, 1727,
1464, 1260, 1137, 1045 cm−1; MS m/z 139, 151 (100), 168,
181, 195, 268 (M+); HRMS calcd for C14H24O3Si (M+)
268.1495, found 268.1500.
(R,Z)-Methyl 3-hydroxy-2,2,4-trimethylhept-4-en-6-ynoate (20).
To a solution of 19 (129 mg, 0.48 mmol) in MeOH (5.0 mL)
was added NaOMe (13 mg, 0.24 mmol) at 0 °C. After being
stirred at room temperature for 4 h, the mixture was diluted with
saturated NH4Cl (10 mL), extracted with AcOEt, washed with
brine and concentrated. Purification of the residue by column
chromatography (SiO2 5.0 g, hexane–AcOEt = 6 : 1) gave 20
1
100%) as a pale yellow oil. [α]2D3 +77.5 (c 1.35, CH2Cl2); H
NMR δ 7.00 (br, 1H), 6.25 (d, J = 6.3 Hz, 1H), 6.12 (d, J =
10.3 Hz, 1H), 4.91 (brs, 1H), 3.63 (s, 3H), 1.84 (s, 3H), 1.23 (s,
3H), 1.10 (s, 3H), 0.88 (s, 9H), 0.02 (s, 3H), −0.04 (s, 3H); 13C
NMR δ 176.8, 143.1, 133.2, 129.3, 83.0, 75.2, 51.8, 49.4, 25.6,
21.1, 18.0, −4.8, −5.6; FTIR (neat) 1741, 1469, 1386, 1260,
1091, 1012 cm−1; HRMS calcd for C17H31O3SiI (M+) 438.1087,
found 438.1072.
1
(92 mg, 98%) as a yellow oil. [α]2D4 −18.0 (c 1.20, CHCl3); H
NMR δ 5.47 (s, 1H), 4.87 (d, J = 7.5 Hz, 1H), 3.73 (s, 3H), 3.58
(d, J = 7.5 Hz, 1H), 3.08 (s, 1H), 1.75 (s, 3H), 1.35 (s, 3H), 1.20
(s, 3H); 13C NMR δ 178.1, 151.2, 108.5, 81.7, 80.3, 58.2, 52.0,
46.3, 24.3, 20.4, 18.0; FTIR (neat) 3474, 3290, 2371, 2096,
1719, 1441, 1263, 1049 cm−1; HRMS calcd for C11H16O3 (M+)
196.1099, found 196.1092.
(R,4Z,6Z,8E)-Methyl 3-((tert-butyldimethylsilyl)oxy)-2,2,4-tri-
methyl-10-(oxazol-5-yl)deca-4,6,8-trienoate (21). To a solution 2
(50 mg, 0.11 mmol) and stannane 112c (50 mg, 0.13 mmol) in
degassed DMF (4.0 mL) were added CuI (2 mg, 0.011 mmol),
CsF (35 mg, 0.23 mmol), and Pd(PPh3)4 (1 mg, 1.1 μmol) at
room temperature. The mixture was stirred at room temperature
for 5 h and concentrated. Purification of the residue by flash
(R,Z)-Methyl 3-(tert-buthyldimethylsilyloxy)-2,2,4-trimethyl-
hept-4-en-6-ynoate (5). To a solution of 20 (600 mg, 3.1 mmol)
in CH2Cl2 (13 mL) were added 2,6-lutidine (1.4 mL,
8170 | Org. Biomol. Chem., 2012, 10, 8164–8174
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column chromatography (SiO2 8.0 g, hexane–AcOEt = 1 : 1 to
5 : 1) gave 21 (40 mg, 83%) as a pale yellow oil. [α]2D3 +123.1 (c
1.25, CH2Cl2); H NMR δ 7.79 (s, 1H), 6.81 (s, 1H), 6.68 (dd,
(21 mg, 0.062 mmol) in CH2Cl2 (1.0 mL) were added SOCl2
(7.0 μL, 0.10 mmol) and one drop of DMF at 0 °C. After stirring
at room temperature for 2 h, 25% NH4OH (2 mL) was added at
0 °C and the mixture was stirred at room temperature for 1 h.
The mixture was diluted with H2O (2.0 mL) and extracted with
AcOEt. The extract was washed with brine, dried, concentrated
and purified by flash column chromatography (SiO2 3.0 g,
hexane–AcOEt = 9 : 1) to give 23 (12 mg, 58%) as a yellow oil.
1
J = 11.2, 14.2 Hz, 1H), 6.41 (d, J = 12.0 Hz, 1H), 6.25 (dd, J =
11.0, 12.0 Hz, 1H), 5.95 (dd, J = 11.2, 11.0 Hz, 1H), 5.77 (td,
J = 7.0, 14.2 Hz, 1H), 4.99 (brs, 1H), 3.62 (s, 3H), 3.52 (d, J =
7.0 Hz, 2H), 1.83 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H), 0.87 (s,
9H), 0.01 (s, 3H), −0.05 (s, 3H); 13C NMR δ 177.0, 150.7,
150.4, 139.0, 128.3, 127.5, 124.3, 124.1, 122.5, 73.7, 51.7,
49.4, 29.0, 25.6, 22.3, 21.2, 20.1, 18.0, −4.9, −5.6; FTIR (neat)
2950, 1732, 1508, 1465, 1255, 1078 cm−1; MS m/z 173, 236,
318 (100), 362, 419 (M+); HRMS calcd for C23H37NO4Si (M+)
419.2492, found 419.2493.
1
[α]2D4 +134.2 (c 0.84, CHCl3); H NMR δ 7.79 (s, 1H), 6.80 (s,
1H), 6.62 (dd, J = 11.7, 14.4 Hz, 1H), 6.49 (d, J = 11.7 Hz, 1H),
6.36 (dd, J = 11.0, 11.7 Hz, 1H), 6.04–5.98 (m, 2H), 5.86 (s,
1H), 5.79 (td, J = 6.8, 14.4 Hz, 1H), 5.86 (brs, 1H), 3.51 (d, J =
6.8 Hz, 2H), 2.10 (s, 3H), 1.82 (s, 3H), 1.23 (s, 3H), 1.20
(s, 3H); 13C NMR δ 178.2, 169.6, 151.0, 150.7, 133.4,
129.3, 128.5, 127.1, 124.2, 122.9, 46.5, 29.3, 25.1, 21.9,
21.2, 20.7; FTIR (neat) 3357, 3208, 2976, 2928, 1739,
1676, 1371, 1241, 1102, 1029 cm−1; MS m/z 43, 204 (100), 332
(M+); HRMS calcd for C18H24N2O4 (M+) 332.1736, found
332.1732.
(R,4Z,6Z,8E)-Methyl 3-hydroxy-2,2,4-trimethyl-10-(oxazol-5-
yl)deca-4,6,8-trienoate (22). To a solution of 21 (210 mg,
0.51 mmol) in MeCN (10 mL) was added 47% HF (1.0 mL) at
0 °C, and the mixture was stirred at room temperature for 6 h.
The mixture was basified with saturated NaHCO3 (20 mL) at
0 °C and extracted with AcOEt. The extract was washed with
brine, dried, concentrated and chromatographed (SiO2 10 g,
hexane–AcOEt = 2 : 1) to give 224 (137 mg, 88%) as colorless
(+)-Inthomycin A. To a solution of 23 (8.3 mg, 0.025 mmol)
in THF–MeOH–H2O (3 : 1 : 1) (1.5 mL) was added LiOH
(2.0 mg, 0.05 mmol) at room temperature. After being stirred at
room temperature for 1 h, the mixture was acidified with 1 M
HCl at 0 °C and extracted with AcOEt. The extract was washed
with brine, dried, concentrated and purified by preparative TLC
(CHCl3–MeOH = 9 : 1) to give (+)-inthomycin A (6.2 mg, 86%)
as a yellow oil. [α]D21 +37.3 (c 0.62, CHCl3) (lit.7a [α]D21 +37.4 (c
1
needles; [α]2D1 +100.6 (c 0.7, CH2Cl2); H NMR δ 7.80 (s, 1H),
6.81 (s, 1H), 6.67 (dd, J = 11.7, 14.8 Hz, 1H), 6.44 (d, J = 11.7
Hz, 1H), 6.21 (dd, J = 11.1, 11.7 Hz, 1H), 5.96 (dd, J = 11.1,
11.7 Hz, 1H), 5.77 (td, J = 6.8, 14.8 Hz, 1H), 4.77 (d, J =
6.8 Hz, 1H), 3.72 (s, 3H), 3.52 (d, J = 6.8 Hz, 2H), 3.33 (d, J =
6.8 Hz, 1H), 1.80 (s, 3H), 1.27 (s, 3H), 1.16 (s, 3H); 13C NMR δ
178.3, 150.7, 150.4, 137.7, 128.5, 128.2, 127.9, 124.9, 124.8,
122.5, 74.6, 52.2, 46.9, 29.0, 24.31, 21.0, 19.7; FTIR (neat)
3474, 2951, 2246, 1736, 1512, 1469, 1142 cm−1; HRMS calcd
for C17H23NO4 (M+) 305.1627, found 305.1621.
1
1.0, CHCl3)); H NMR δ 7.80 (s, 1H), 6.81 (s, 1H), 6.68 (dd, J
= 11.5, 14.0 Hz, 1H), 6.42 (d, J = 11.7 Hz, 1H), 6.23–6.17 (m,
2H), 5.95 (dd, J = 11.0, 11.5 Hz, 1H), 5.78 (td, J = 6.4, 14.0 Hz,
1H), 5.54 (brs, 1H), 4.65 (s, 1H), 4.05 (s, 1H), 3.52 (d, J =
6.4 Hz, 2H), 1.85 (s, 3H), 1.36 (s, 3H), 1.10 (s, 3H); 13C NMR δ
181.0, 150.7, 150.4, 138.3, 128.7, 128.2, 124.9, 123.7, 122.5,
75.4, 44.6, 29.0, 26.1, 21.7, 19.4; FTIR (neat) 3341, 2926, 1658,
1510, 1468, 1263, 1109, 1039 cm−1; MS m/z 87 (100), 290
(M+); HRMS calcd for C16H22N2O3 (M+) 290.1630, found
290.1629.
(R,4Z,6Z,8E)-3-Acetoxy-2,2,4-trimethyl-10-(oxazol-5-yl)deca-
4,6,8-trienoic acid. To a solution of 22 (60 mg, 0.196 mmol) in
THF–MeOH–H2O (3 : 1 : 1) (4.8 mL) was added LiOH (28 mg,
0.57 mmol) at 0 °C, and the mixture was stirred at room temp-
erature for 24 h. The mixture was acidified with 1 M HCl at 0 °C
and extracted with AcOEt. The extract was washed with brine,
dried and concentrated to give the corresponding carboxylic acid
(50 mg) as a yellow oil. The crude carboxylic acid (50 mg) was
dissolved in pyridine (162 μL) and Ac2O (162 μL, 1.70 mmol)
was added at 0 °C. After stirring at room temperature for 20 h, a
solution of NaHCO3 (142 mg) in MeOH (1.0 mL) was added
and stirring was continued for 1 h. The mixture was extracted
with AcOEt, washed with brine, dried and concentrated. Purifi-
cation of the residue by column chromatography (SiO2 2 g,
CHCl3–MeOH = 1 : 19) gave the acetoxy acid4 (65 mg, 100%)
as a yellow oil. 1H NMR δ 7.80 (s, 1H), 6.82 (s, 1H), 6.63 (dd, J
= 11.5, 14.4 Hz, 1H), 6.52 (d, J = 12.2 Hz, 1H), 6.36 (dd, J =
11.0, 12.2 Hz, 1H), 6.01 (s, 1H), 5.98 (dd, J = 11.0, 11.5 Hz,
1H), 5.77 (td, J = 6.8, 14.4 Hz, 1H), 3.51 (d, J = 6.8 Hz, 2H),
2.05 (s, 3H), 1.82 (s, 3H), 1.26 (s, 3H), 1.22 (s, 3H); 13C NMR
δ 180.4, 170, 150.8, 150.6, 133.2, 128.7, 128.6, 126.4, 124.3,
122.3, 75.8, 47.3, 29.0, 23.1, 21.0, 20.8, 20.7; FTIR (neat) 3528,
2923, 2532, 1749, 1512, 1471, 1370, 1271 cm−1; HRMS calcd
for C18H23NO5 (M+) 333.1603, found 333.1573.
(R,4Z,6E)-Methyl 3-(tert-butyldimethylsilyloxy)-7-iodo-2,2,4-
trimethylhepta-4,6-dienoate (3). DIBAL (1.04 M in hexane;
7.7 mL, 8.05 mmol) was placed into a 100 mL flask and most of
the hexane was evaporated. The residual DIBAL was dissolved
in THF (5.0 mL) and added dropwise to a solution of Cp2ZrCl2
(2.35 g, 8.05 mmol) in THF (5.0 mL) at 0 °C. After stirring at
0 °C for 1 h, a solution of 5 (500 mg, 1.61 mmol) in THF
(5.0 mL) was added, and the mixture was stirred at 0 °C for 1 h.
The mixture was cooled to −78 °C and a solution of I2 (2.08 g,
8.21 mmol) in THF (5.0 mL) was added. The mixture was
allowed to warm to 0 °C and stirring was continued for 2 h. The
reaction was quenched with saturated Na2S2O3 (30 mL) at 0 °C,
and the mixture was extracted with AcOEt. The extract was
washed with brine, dried, concentrated and chromatographed
(SiO2 40 g, hexane–AcOEt = 100 : 1) to give 3 (580 mg, 82%),
a yellow oil, as a 6 : 1 inseparable mixture with its 6-iodo-
1
isomer. H NMR δ 7.33–7.21 (m, 1H), 6.22 (br d, J = 13.7 Hz,
1H), 5.89 (d, J = 11.5 Hz, 1H), 4.84 (brs, 1H), 3.66 (s, 3H), 1.80
(s, 3H), 1.22 (s, 3H), 1.11 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H),
−0.05 (s, 3H); 13C NMR δ 176.6, 140.6, 133.1, 128.4, 79.0,
(R,4Z,6Z,8E)-2-Carbamoyl-2,4-dimethyl-10-(oxazol-5-yl)deca-
4,6,8-trien-3-yl acetate (23). To a solution of the acetoxy acid
This journal is © The Royal Society of Chemistry 2012
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74.1, 51.8, 49.3, 25.7, 23.5, 21.8, 18.0, −4.8, −5.4; FTIR (neat)
2952, 1736, 1467, 1256, 1080 cm−1; MS m/z 337, 381 (100),
438 (M+); HRMS calcd for C17H31O3SiI (M+) 438.1087, found
438.1103.
21.7, 19.2; FTIR (neat) 3343, 2933, 1658, 1602, 1511,
1468, 1376, 1110, 1047 cm−1; MS m/z 69 (100), 204, 290
(M+); HRMS calcd for C16H22N2O3 (M+) 290.1630, found
290.1620.
(R,4Z,6E,8E)-Methyl 3-((tert-butyldimethylsilyl)oxy)-2,2,4-tri-
methyl-10-(oxazol-5-yl)deca-4,6,8-trienoate (24). Compound 3
containing its 6-iodo-isomer (260 mg, 0.59 mmol) was dissolved
in degassed DMF (5.0 mL) and stannane 112c (260 mg,
0.65 mmol), CuI (11 mg, 0.059 mmol), CsF (180 mg,
1.18 mmol) and Pd(PPh3)4 (7 mg, 5.90 μmol) were added at
room temperature in the dark. After stirring at room temperature
for 3 h, the reaction was quenched with saturated NH4Cl
(10 mL). The mixture was extracted with AcOEt, washed with
brine, dried and concentrated. Purification of the residue by flash
column chromatography (SiO2 20 g, hexane–AcOEt = 15 : 1 to
7 : 1) gave 24 (142 mg, 57%) as a yellow oil. [α]2D7 +117.1 (c
(E,2S,3S)-Methyl 3-hydroxy-2,4-dimethyl-7-(trimethylsilyl)-
hept-4-en-6-ynoate. β-Lactone 17 (1.59 g, 0.72 mmol) was sub-
jected to methanolysis using NaOMe (4 mg, 0.072 mmol) in
MeOH (70 mL) in the same manner as described for the prep-
aration of 18 from 16. Purification by column chromatography
(SiO2 70 g, hexane–AcOEt = 8 : 1) gave the methyl ester
1
(1.82 g, 100%) as a yellow oil. [α]2D4 −24.0 (c 1.03, CHCl3); H
NMR δ 5.73 (s, 1H), 4.49 (brs, 1H), 3.72 (s, 3H), 2.70 (dq, J =
3.4, 7.1 Hz, 1H), 2.67 (d, J = 3.4 Hz, 1H), 1.86 (s, 3H), 1.09 (d,
J = 7.1 Hz, 3H), 0.20 (s, 9H); 13C NMR δ 176.0, 150.4, 106.6,
102.4, 99.0, 74.5, 52.0, 42.1, 16.3, 10.0, 0.0; FTIR (neat) 3496,
2359, 2135, 1730, 1445, 1253 cm−1; MS m/z 167 (100), 254
(M+); HRMS calcd for C13H22O3Si (M+) 254.1338, found
254.1349.
1
1.41, CHCl3); H NMR δ 7.79 (s, 1H), 6.80 (s, 1H), 6.44–6.08
(m, 3H), 5.97 (d, J = 11.5 Hz, 1H), 5.73 (td, J = 6.8, 14.9 Hz,
1H), 4.94 (brs, 1H), 3.62 (s, 3H), 3.48 (d, J = 6.8 Hz, 2H), 1.78
(s, 3H), 1.21 (s, 3H), 1.08 (s, 3H), 0.87 (s, 9H), 0.02 (s, 3H),
−0.07 (s, 3H); 13C NMR δ 177.4, 151.2, 150.7, 138.6, 133.8,
131.8, 129.8, 128.2, 127.3, 122.8, 74.5, 52.0, 50.0, 29.2, 26.0,
22.6, 21.5, 20.1, 18.3, −4.6, −5.3; FTIR (neat) 2952,
2858, 1733, 1467, 1256, 1077 cm−1; MS m/z 318 (100), 419
(M+); HRMS calcd for C23H37NO4Si (M+) 419.2492, found
419.2487.
(R,E)-Methyl 3-hydroxy-2,2,4-trimethyl-7-(trimethylsilyl)hept-4-
en-6-ynoate. The methyl ester (0.98 g, 3.85 mmol) was methyl-
ated in the same manner described for the preparation of 19 from
18. Purification by flash column chromatography (SiO2 60 g,
CHCl3–hexane = 4 : 1) gave the corresponding methylated ester
(0.82 g, 80%) as a colorless oil. [α]2D4 +17.1 (c 1.05, CHCl3); 1H
NMR δ 5.53 (s, 1H), 4.17 (d, J = 5.8 Hz, 1H), 3.71 (s, 3H), 3.04
(d, J = 5.8 Hz, 1H), 1.86 (s, 3H), 1.21 (s, 3H), 1.16 (s, 3H), 0.19
(s, 9H); 13C NMR δ 177.9, 151.1, 109.2, 102.2, 99.7, 80.8, 60.4,
52.1, 46.6, 23.4, 20.6, 16.7, 14.1, 0.0; FTIR (neat) 3501, 2959,
2360, 2135, 1724, 1253 cm−1; MS m/z 102, 167 (100), 268
(M+); HRMS calcd for C14H24O3Si (M+) 268.1494, found
268.1501.
(R,4Z,6E,8E)-Methyl 3-hydroxy-2,2,4-trimethyl-10-(oxazol-5-
yl)deca-4,6,8-trienoate (25). To a solution of 24 (90 mg,
0.21 mmol) in MeCN (4.0 mL) was added HF-pyridine
(0.2 mL) at 0 °C. After being stirred at room temperature for 4 h,
the mixture was basified with saturated NaHCO3 (30 mL) at
0 °C and extracted with AcOEt. The extract was washed with
brine, dried, concentrated and purified by flash column chrom-
atography (SiO2 6.0 g, hexane–AcOEt = 3 : 1 to 2 : 1) to give 25
(47.2 mg, 72%) as a yellow oil. [α]2D7 +81.9 (c 0.99, CHCl3); 1H
NMR δ 7.78 (s, 1H), 6.79 (s, 1H), 6.43 (dd, J = 11.5, 14.0 Hz,
1H), 6.22–6.08 (m, 2H), 6.02 (d, J = 11.5 Hz, 1H), 5.75 (td,
J = 6.8, 14.0 Hz, 1H), 4.76 (d, J = 4.9 Hz, 1H), 3.71 (s,
3H), 3.47 (d, J = 6.8 Hz, 2H), 3.29 (d, J = 6.0 Hz, 1H), 1.75
(s, 3H), 1.26 (s, 3H), 1.16 (s, 3H); 13C NMR δ 178.7,
151.1, 150.7, 132.1, 128.8, 128.4, 127.6, 125.3, 124.4, 122.8,
74.9, 52.5, 47.1, 29.3, 24.7, 21.3, 20.0; FTIR (neat) 3430, 3122,
2949, 1726, 1260, 1136 cm−1; MS m/z 102, 204 (100), 305
(M+); HRMS calcd for C17H23NO4 (M+) 305.1627, found
305.1624.
(R,E)-Methyl
3-hydroxy-2,2,4-trimethylhept-4-en-6-ynoate
(26). The methylated ester (0.57 g, 2.12 mmol) was desilylated
under methanolytic conditions using NaOMe (57 mg,
1.06 mmol) in MeOH (20 mL) at 0 °C in the same manner as
described for the preparation of 20 from 19. Purification by
column chromatography (SiO2 20 g, hexane–AcOEt = 6 : 1)
gave 26 (0.42 g, 100%) as a yellow oil. [α]2D4 −15.9 (c 1.04,
1
CHCl3); H NMR δ 5.51 (s, 1H), 4.19 (d, J = 5.8 Hz, 1H), 3.72
(s, 3H), 3.16–3.14 (m, 1H), 1.88 (s, 3H), 1.22 (s, 3H), 1.17
(s, 3H); 13C NMR δ 178.1, 152.0, 108.5, 82.6, 81.1, 80.9,
52.5, 46.9, 23.8, 21.0, 16.9; FTIR (neat) 3492, 3291, 2983,
1721, 1443, 1259, 1138, 1073 cm−1; MS m/z 102 (100), 196
(M+); HRMS calcd for C11H16O3 (M+) 196.1099, found
196.1088.
(+)-Inthomycin B. In the same manner as described for the
synthesis of (+)-inthomycin A from 22, (+)-inthomycin B
(35 mg) was obtained as a yellow oil from 25 (77 mg,
0.25 mmol) in 49% yield (4 steps) after purification by prepara-
tive TLC (CHCl3–MeOH = 9 : 1). [α]2D6 +46.8 (c 1.25, CHCl3)
(R,4E,6E)-Methyl 3-hydroxy-7-iodo-2,2,4-trimethylhepta-4,6-
dienoate (29). To a solution of CuCN (62 mg, 0.69 mmol) in
THF (1.5 mL) was added dropwise n-BuLi (2.66 M in hexane,
0.52 mL, 1.39 mmol) at −78 °C. After stirring at −40 °C for
10 min, n-Bu3SnH (0.36 mL, 1.39 mmol) was added dropwise
at −78 °C. After stirring at −40 °C for 10 min, a solution of 26
(30 mg, 0.15 mmol) in THF (1.5 mL) was added, and the
mixture was allowed to warm to −30 °C. After stirring at
−30 °C for 1 h, saturated NH4Cl (2.5 mL) and NH4OH (0.5 mL)
were added, and the mixture was allowed to warm to −10 °C.
After being stirred at −10 °C for 0.5 h, the mixture was extracted
(lit.12c [α]D +19.3 (c 1.0, CHCl3)); H NMR δ 7.79 (s, 1H),
6.80 (s, 1H), 6.46 (dd, J = 11.5, 14.0 Hz, 1H), 6.28 (brs, 1H),
6.23–6.11 (m, 2H), 6.01 (d, J = 11.5 Hz, 1H), 5.74 (td, J = 6.8,
14.0 Hz, 1H), 5.55 (brs, 1H), 4.61 (d, J = 4.4 Hz, 1H), 3.98 (brs,
1H), 3.48 (d, J = 6.8 Hz, 2H), 1.81 (s, 3H), 1.36 (s, 3H), 1.10 (s,
22
1
3H); 13C NMR
δ 181.0, 150.8, 150.4, 137.6, 133.3,
131.9, 130.1, 127.5, 127.4, 122.5, 75.8, 44.7, 28.8, 26.1,
8172 | Org. Biomol. Chem., 2012, 10, 8164–8174
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with AcOEt, washed with brine, dried and concentrated to give
the alkenylstannane (444 mg). The crude alkenylstannane
(444 mg) was dissolved in THF (2.0 mL) and a solution of I2
(240 mL, 0.94 mmol) in THF (1.0 mL) was added at −78 °C in
the dark, and the mixture was stirred at room temperature for
20 h. The reaction was quenched with saturated Na2S2O3
(10 mL), and the mixture was extracted with AcOEt. The extract
was washed with brine, dried, concentrated and purified by flash
column chromatography (SiO2 6.0 g, hexane–AcOEt = 7 : 1) to
give 29 (29 mg, 60%) as a yellow oil. [α]2D3 +8.6 (c 1.32,
Acknowledgements
This work was supported by the Grant-in-Aid for Scientific
Research (A) (22249001) from JSPS and the Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” (no. 2304) (24105526)
from MEXT.
Notes and references
1
CHCl3); H NMR δ 7.26 (dd, J = 11.2, 14.3 Hz, 1H), 6.33 (d,
1 (a) T. Mori, K. Takahashi, M. Kashiwabara, D. Uemura, C. Katayama,
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J = 14.3 Hz, 1H), 5.94 (d, J = 11.2 Hz, 1H), 4.12 (d, J = 5.5 Hz,
1H), 3.71 (s, 3H), 3.09 (d, J = 5.5 Hz, 1H), 1.70 (s, 3H), 1.21 (s,
3H), 1.15 (s, 3H); 13C NMR δ 178.1, 141.1, 137.6, 128.4, 81.7,
80.0, 52.2, 46.7, 23.6, 20.7, 14.2; FTIR (neat) 3491, 2979, 2945,
1726, 1462, 1258, 1138, 1047 cm−1; MS m/z 102 (100), 324
(M+); HRMS calcd for C17H17O3I (M+) 324.0222, found
324.0222.
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(R,4E,6E,8E)-Methyl 3-hydroxy-2,2,4-trimethyl-10-(oxazol-5-
yl)deca-4,6,8-trienoate (30). To a solution 29 (24 mg, 74 μmol)
and oxazole stannane 112c (32 mg, 81 μmol) in degassed DMF
(1.0 mL) were added CuI (1.4 mg, 1.4 μmol), CsF (22 mg,
148 μmol), and Pd(PPh3)4 (1 mg, 0.74 μmol) at room tempera-
ture in the dark. The reaction mixture was stirred at room temp-
erature for 3 h, quenched with saturated KF (1.0 mL), and
extracted with AcOEt. The extract was washed with brine, dried
and concentrated. Purification of the residue by flash column
chromatography (SiO2 6.0 g, hexane–AcOEt = 15 : 1 to 2 : 1)
gave 30 (18 mg, 79%) as a yellow oil. [α]2D2 +0.78 (c 1.39,
1
CHCl3); H NMR δ 7.79 (s, 1H), 6.80 (s, 1H), 6.43–6.37 (m,
1H), 6.27–6.18 (m, 2H), 6.02 (d, J = 11.0 Hz, 1H), 5.75 (td, J =
6.7, 13.8 Hz, 1H), 4.17 (d, J = 5.4 Hz, 1H), 3.71 (s, 3H), 3.49
(d, J = 6.7 Hz, 2H), 3.09 (d, J = 5.4 Hz, 1H), 1.74 (s, 3H), 1.21
(s, 3H), 1.15 (s, 3H); 13C NMR δ 177.8, 150.5, 150.1, 137.0,
133.1, 131.8, 128.2, 127.8, 127.0, 122.2, 81.8, 51.8, 46.7, 28.5,
23.3, 20.4, 13.6; FTIR (neat) 3383, 3128, 2982, 2949, 1727,
1510, 1463, 1257, 1134 cm−1; MS m/z 102, 204 (100), 305
(M+); HRMS calcd for C17H23NO4 (M+) 305.1627, found
305.1624.
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(−)-Inthomycin C. In the same manner as described for the
synthesis of (+)-inthomycin A from 22, (−)-inthomycin C
(19 mg) was obtained as a yellow oil from 30 (117 mg,
0.38 mmol) in 22% yield (4 steps) after purification by prepara-
tive TLC (CHCl3–MeOH = 9 : 1). [α]2D3 −41.5 (c 0.10, CHCl3)
1
(lit.14 [α]D20 −34.3 (c 0.10, CHCl3)); H NMR δ 7.79 (s, 1H),
6.79 (s, 1H), 6.39 (dd, J = 11.2, 14.2 Hz, 1H), 6.24–6.20 (m,
3H), 6.02 (d, J = 11.2 Hz, 1H), 5.75 (td, J = 6.8, 14.2 Hz, 1H),
5.40 (brs, 1H), 4.01 (d, J = 4.6 Hz, 1H), 3.72 (brs, 1H), 3.48 (d,
J = 6.8 Hz, 2H), 1.79 (s, 3H), 1.30 (s, 3H), 1.10 (s, 3H); 13C
NMR δ 180.6, 150.8, 150.4, 137.8, 133.4, 132.4, 128.8, 127.4,
122.5, 83.8, 45.0, 28.8, 25.7, 21.7, 13.3; FTIR (neat) 3341,
2925, 2849, 1739, 1658, 1510, 1469, 1372, 1103 cm−1; MS m/z
87 (100), 204, 290 (M+); HRMS calcd for C16H22N2O3 (M+)
290.1630, found 290.1629.
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8174 | Org. Biomol. Chem., 2012, 10, 8164–8174
This journal is © The Royal Society of Chemistry 2012