Synthesis of the Entomopathogenic Fungus Metabolites Militarinone C and Fumosorinone A

Article abstract of DOI:10.1021/acs.joc.8b01530

Militarinone C and fumosorinone A, 3-oligoenoyltetramic acids produced by insect pathogenic fungi, were synthesized for the first time. The pyrrolidine-2,4-dione ring was closed through a late-stage Dieckmann condensation of N-(β-ketoacyl) derivatives of tyrosine, obtained by its acylation with either thioesters or Meldrum's acid derivatives bearing the all-trans-polyene side chain. The latter was built up from (S)-citronellol via an Evans methylation and Wittig or HWE olefinations.

Full text of DOI:10.1021/acs.joc.8b01530

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of the Entomopathogenic Fungus Metabolites
Militarinone C and Fumosorinone A
Sebastian Bruckner, Marie Weise, and Rainer Schobert*
Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany
S
* Supporting Information
ABSTRACT: Militarinone C and fumosorinone A, 3-
oligoenoyltetramic acids produced by insect pathogenic
fungi, were synthesized for the first time. The pyrrolidine-
2,4-dione ring was closed through a late-stage Dieckmann
condensation of N-(β-ketoacyl) derivatives of tyrosine,
obtained by its acylation with either thioesters or Meldrum’s
acid derivatives bearing the all-trans-polyene side chain. The
latter was built up from (S)-citronellol via an Evans
methylation and Wittig or HWE olefinations.
(PTP1B), a major negative regulator6 of the insulin signaling
pathway. Such inhibitors are of interest as potential type II
diabetes drugs since Klaman et al. had confirmed a higher
sensitivity to insulin for mice deficient in PTP1B.7 Herein we
report short syntheses that procure both compounds in
quantities sufficient to study their conversion to 2-pyridones.
INTRODUCTION
■
In 2002 Hamburger et al. reported the isolation of militarinone
A (1), a neurotrophic 2-pyridone alkaloid, from the
entomogenous fungus Paecilomyces militaris.1 Shortly after,
they also identified two yellow tetramic acids, militarinone B
(2) and militarinone C (3), as cometabolites (Figure 1).2 It is
RESULTS AND DISCUSSION
■
The retrosynthetic approach is outlined in Scheme 1. Both
target compounds 3 and 4 were finished by a Dieckmann
cyclization8 of the respective functionalized β-ketoamide 5 or 6
followed by N,O-deprotection. These β-ketoamides were
obtained by reaction of N,O-bisprotected methyl tyrosinates
7 with either Meldrum’s acid derivative 8 or thioester 9 as N-
acylating agents carrying the respective unsaturated side chain.
The β-ketoesters 8 and 9 were accessible through consecutive
Wittig or HWE olefinations of key aldehyde 10 which was built
up from (S)-citronellol (11) using an Evans alkylation9 to
introduce the second methyl group and an E-selective Wittig
olefination to establish the trisubstituted double bond.
(S)-Citronellol (11) was first converted to imide 15
following a modified route by Nishida et al.10 (Scheme 2). It
was quantitatively deoxygenated to alkene 13 in two steps via
mesylation to give 12 which was reduced with LiAlH4. Olefin
13 was subjected to a ruthenium-catalyzed oxidative cleavage
according to a general procedure by Sharpless et al.11 which
afforded carboxylic acid 14. This was converted to a mixed
anhydride with pivaloyl chloride which was reacted with (R)-4-
benzyloxazolidin-2-one to yield imide 15. Its methylation at
−78 °C gave the desired (R,R)-product 16 as a separable
mixture of two diastereomers. Removal of the Evans auxiliary
with LiBH4/MeOH at 0 °C left enantiopure alcohol 17. This
was Swern oxidized to aldehyde 18 which was Wittig olefinated
Figure 1. Structures of militarinones A−C (1-3) and fumosorinone A
(4).
not uncommon that fungi produce mixtures of tyrosine-derived
tetramic acids and 2-pyridones, e.g., the family of torrubiel-
lones, metabolites of the fungus Torrubiella sp. BCC 2165,3 or
the (proto)tenellins, produced by the insect pathogenic fungus
Beauveria bassiana. For the latter, Cox et al. established a
radical oxidation−rearrangement conversion of the tetramic
acid prototenellin D to the 2-pyridone tenellin.4 In 2017,
Zhang et al.5 isolated fumosorinone A (4) from the
entomogenous fungus Isaria fumosorosea and found it to
inhibit (IC50 3.24 μM) protein tyrosine phosphatase 1B
Received: June 18, 2018
Published: July 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01530
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Article
its DIBAL-H reduction to alcohol 24, and MnO2 oxidation of
the latter to aldehyde 25 (Scheme 3). This aldehyde was
Scheme 1. Retrosynthesis of Militarinone C (3) and
Fumosorinone A (4)
Scheme 3. Synthesis of Militarinone C (3)
a
Scheme 2. Synthesis of Key Aldehyde 10
reacted with a Meldrum’s acid-derived ylide 26, applying a
recent protocol by us,13 to give β-ketoester 8. Due to its
decomposition on silica gel, the crude mixture of 8, Ph3PO,
and some residual starting material was immediately reacted
with either bisprotected methyl L-tyrosinate 7a (R3 = o-
nitrobenzyl) or 7b (R3 = 2,4-dimethoxybenzyl). The resulting
β-ketoamides 27 were treated with NaOMe in methanol to
initiate a Dieckmann cyclization affording the respective
bisprotected militarinone C 28 in quantitative yield. Unfortu-
nately, irradiation of 28a, which was previously successfully
employed for the cleavage of an oNb group on the
nonoligoenoyl tetramic acid F-14329,8 failed to give N-
unprotected tetramic acid 29. Besides requiring a longer
reaction time (4 d vs 1 d), the photolytic deprotection of 28a
also led to cis−trans isomerizations of the 3-oligoenoyl side
chain. Gratifyingly, deprotection of 28b was readily achieved
with 10% TFA in dichloromethane, leaving 29, followed by
desilylation to give militarinone C (3) in 62% over two steps
after purification by MPLC. Its NMR data are in line with
those reported2 for the natural product (cf. Supporting
Information Table S1), including the visibility of a second,
minor tautomer in the NMR spectra. The specific optical
a
Reagents and conditions: (i) MsCl, NEt3, CH2Cl2, 0 °C to rt, 3.75 h;
(ii) LiAlH4, THF, 0 °C to rt, 16 h; (iii) NaIO4 (4 equiv), RuCl3 (2
mol %), MeCN/CH2Cl2/H2O, rt, 18 h; (iv) PivCl, NEt3, THF, 0 °C,
25 min, then LiCl, (R)-Evans oxazolidinone, rt, 30 min; (v)
NaHMDS, THF, −78 °C, 15 min, then MeI, −78 °C to rt, 2.5 h;
(vi) LiBH4, MeOH, Et2O, 0 °C to rt, 5 h; (vii) (COCl)2, DMSO,
NEt3, CH2Cl2, −78 °C, 3 h; (viii) + 19, CH2Cl2, rt, 19 h; (ix) DIBAL-
H, CH2Cl2, −78 °C, 1 h; (x) MnO2, CH2Cl2, rt, 18 h.
rotation of our synthetic sample, [α]24 −310 (c 0.30,
D
CH3OH), differed distinctly from that of the natural isolate
with [α]25D −430 (c 0.17, CH3OH). However, because optical
rotations of 3-acyltetramic acids are notorious for their
volatility depending on many factors including the concen-
tration and even age of the sample solution, they are not suited
as proof of purity or identity. Although deviations between
optical rotations of otherwise identical compounds have
repeatedly been reported in the literature, e.g., lately for
without purification to furnish ester 20 in 70% yield over two
steps, following a protocol by Ding et al.12 DIBAL-H reduction
to alcohol 21 and its oxidation with MnO2 afforded aldehyde
10 (10 steps, 25% relative to 11).
For the synthesis of militarinone C (3), aldehyde 10 was
elongated, analogously to aldehyde 18, by a sequence of Wittig
olefination with stabilized ylide 22 to give ester 23, followed by
B
DOI: 10.1021/acs.joc.8b01530
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Article
14
penicillinol A2 and (−)-hymenosetin,15 our synthesis of
built up from (S)-citronellol via an Evans methylation and
consecutive Wittig or HWE olefinations. The agreement (good
in the case of 4, reasonable for 3) between NMR spectra and
optical rotations of our synthetic products and those reported
for the natural isolates at least does not rule out the origin of
the latter from L-tyrosine. Studies of the conversion of
compounds 3 and 4 to the respective 2-pyridones by means
of radical oxidants are already underway.
militarinone C supports, yet does not prove, the absolute
configuration proposed in the literature for the natural product.
An unambiguous proof would, for instance, require a
comparison of circular dichroism spectra15 of natural and
synthetic samples (for an ECD spectrum of synthetic
militarinone C (3) cf. Supporting Information).
For the synthesis of fumosorinone A (4), aldehyde 10 was
submitted to a HWE olefination with phosphonate 30,
followed by a DIBAL-H reduction of product ester 31 to
alcohol 32 and its oxidation with MnO2 to aldehyde 33,
analogously to Dash et al.16 (Scheme 4). Another HWE
EXPERIMENTAL SECTION
■
General Remarks. IR spectra were recorded with an FT-IR
spectrophotometer equipped with an ATR unit. H NMR and 13C
1
NMR spectra were obtained using a 500 MHz spectrometer.
Chemical shifts are given in parts per million using the residual
solvent peak as an internal standard 7.26 ppm (proton) and 77.16
ppm (carbon) for CDCl3, 3.31 ppm (proton), and 47.60 ppm
(carbon) for CD3OD and 2.50 ppm (proton) and 39.51 ppm
(carbon) for DMSO-d6. Coupling constants (J) are quoted in hertz
(Hz). Multiplicity abbreviation used: s singlet, d doublet, t triplet, q
quartet, m multiplet, br broad. High resolution mass spectra were
obtained with a UPLC/Orbitrap MS system in ESI mode. Optical
rotations were measured at 589 nm (Na-D line). Photolysis was
performed using a Pro Collect UV tester with 366 nm and 4 W.
Chemicals. All reagents were purchased from commercial sources
and were used without further purification. All anhydrous solvents
were used as supplied, except tetrahydrofuran, diethyl ether, and
dichloromethane which were freshly distilled according to standard
procedures. Reactions were routinely carried out under an argon
atmosphere unless stated otherwise. All glassware was flame-dried
before use.
Scheme 4. Synthesis of Fumosorinone A (4)
Chromatography. Analytical thin layer chromatography was
carried out using Merck silica gel 60GF254 precoated aluminum-
backed plates and/or Merck 60 RP-18 F254S foil plates. The
compounds were visualized with UV light (254 nm and/or 360
nm) and/or ceric ammonium molybdate (CAM) and/or potassium
permanganate and/or iodine on silica. Flash chromatography was
performed at medium pressure using dry-packed Marchery-Nagel
silica gel 60, pore size 40−63 μm, with the eluent specified. Analytical
HPLC measurements were performed on a Beckman System Gold
Programmable Solvent Module 126 using a Phenomenex Kinetex C-
18-HPLC column, length 250 × 4.6 mm, pore size 100 Å, particle size
5 μm. Detection was by a Beckman Instruments Diode Array
Detection Module 168. MPLC reversed phase chromatography was
olefination with phosphonate 34, according to Loscher et al.,17
afforded thioester 9 in excellent 95% yield as a 2:3 keto/enol
mixture. It was used to acylate aminoester 7b in a surprisingly
good yield of 89% according to Ley’s silver(I)-mediated
aminolysis protocol.18 The resulting β-ketoamide 35 was
cyclized quantitatively under mild conditions to give doubly
protected fumosorinone A 36. Due to its acid sensitivity, it had
to be deprotected in two steps. Treatment with 10% TFA for
only 30 min allowed the isolation of 30% TBS-protected
fumosorinone A 37 aside of 30% recovered 36. Desilylation of
all accumulated 37 with KF in methanol finally yielded
fumosorinone A (4) in 60% after semipreparative HPLC. It
proved identical to the natural isolate in terms of NMR spectra
(cf. Supporting Information Table S2) and also specific optical
performed using a Bu
100−50 C 18 end-capped” column, length 460 mm, diameter 49 mm.
Detection was by a Buchi UV Photometer C-635. Semipreparative
̈
chi MPLC system with a “MN Polygroprep
̈
reversed phase HPLC was performed using an Amersham Biosciences
̈
AKTAbasic10 system with a Phenomenex Gemini-NX 5u C18 110A,
250 × 10.00 mm column. Detection was by an Amersham Biosciences
̈
AKTA UV-900 module.
Militarinone C (3). A solution of protected tetramic acid 28b
(107 mg, 156 μmol) in CH2Cl2 (50 mL) was cooled to 0 °C and
treated dropwise with 20% trifluoroacetic acid in CH2Cl2 (50 mL).
The resulting mixture was stirred at ambient temperature for 1 h, sat.
aqueous phosphate buffer (pH 7, 50 mL) was added, and the phases
were separated. The organic phase was washed with the same buffer
(2 × 50 mL) and aqueous KHSO4 (5% wt, 50 mL) and then dried
(Na2SO4) and concentrated in vacuo to give a mixture of O-TBS-
protected tetramic acid 29 and militarinone C (3) as a yellow oil (93
mg) that was used in the next step without further purification.
The crude mixture of 29 and 3 was taken up in methanol p.a. (6
mL), a 10 M suspension of KF in methanol p.a. (624 μL, 6.24 mmol)
was added, and the mixture was stirred at ambient temperature for 1
h. A 1 M aqueous HCl (20 mL) solution and brine (50 mL) were
added, and the mixture was extracted with EtOAc (2 × 125 mL). The
combined organic phases were dried (Na2SO4) and concentrated in
vacuo to give a yellow oil which was purified by MPLC on an RP-18
column, eluting with 75% methanol in H2O (with 0.1% formic acid)
to 95% methanol in 10 min with a flow rate of 240 mL/min. The
rotations ([α]24 −229 (c 0.20, CH3OH) for synthetic and
D
[α]20 −207 (c 0.1, CH3OH) as reported for natural 4).
D
CONCLUSIONS
■
In summary, fumosorinone A (4) and militarinone C (3) were
each prepared in 18 steps and ca. 2% yield by N-acylating L-
tyrosine esters with thioesters or 5-enoyl Meldrum’s acids
carrying the polyene side chains, followed by Dieckmann
cyclization of the resulting β-ketoamides. The side chains were
C
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Article
product-containing fractions were collected, the methanol was
removed in vacuo, and the aqueous phase was extracted with
EtOAc (2 × 100 mL). The combined organic phases were washed
with 1 M aqueous HCl (20 mL), dried (Na2SO4), and concentrated
in vacuo to give militarinone C (3) as an orange-yellow solid foam
stirred for 19 h while reaching room temperature. The mixture was
filtered, the filtrate was taken up in CH2Cl2 (50 mL), the organic
phase was washed with sat. aqueous NH4Cl (100 mL), and the
aqueous phase was extracted with CH2Cl2 (50 mL). The combined
organic layers were washed with brine (150 mL), dried (Na2SO4),
and concentrated in vacuo to give a yellow oil that was purified by
flash chromatography (silica gel, 12% ethyl acetate in hexane) to
afford 7a as a yellow oil (746 mg, 91%); Rf = 0.74 (hexane/EtOAc
(40.9 mg, 62% over two steps); [α]24 −310 (c 0.30, MeOH) (lit.2
D
[α]24 −430.2 (c 0.17, MeOH)); IR νmax 3284, 2959, 2923, 1587,
D
1551, 1515, 1463, 1429, 1373, 1226, 1172, 1105, 1031, 1000, 895,
868, 822, 733, 626 cm−1; for NMR data cf. Supporting Information
1:1); [α]24 +26.8 (c 1.00, CHCl3); IR νmax 2954, 2931, 2858, 1737,
D
+
Table S1; HRMS (ESI) m/z [M + H]+ calcd for C26H34NO4
1609, 1580, 1527, 1510, 1471, 1444, 1346, 1255, 1200, 1170, 1131,
1
424.2482, found 424.2477.
1105, 1007, 914, 840, 782, 729, 691, 668 cm−1; H NMR (CDCl3,
Fumosorinone A (4). A solution of tetramic acid 36 (72 mg, 99
μmol) in CH2Cl2 (36 mL) was cooled to 0 °C and treated dropwise
with 20% trifluoroacetic acid in CH2Cl2 (36 mL), and the mixture was
stirred at ambient temperature for 30 min. Saturated aqueous
phosphate buffer (pH 7, 100 mL) was added at 0 °C, the phases were
separated, and the organic phase was washed with the same buffer (2
× 100 mL) and 1 M aqueous HCl (50 mL), dried (Na2SO4), and
concentrated in vacuo to afford an orange-yellow oil. It was purified
by flash chromatography on RP-18 silica gel, eluting with 95%
acetonitrile in H2O to give O-TBS-protected tetramic acid 37 (16 mg,
30%) and residual starting material 36 (22 mg, 30%); Rf = 0.36 (8%
MeOH in CH2Cl2). A solution of 37 (16 mg, 28 μmol) in MeOH
(1.8 mL) was treated with a 10 M suspension of potassium fluoride in
MeOH (199 μL, 1.99 mmol), and the mixture was stirred at ambient
temperature for 30 min. Saturated aqueous NH4Cl (20 mL) and 1 M
aqueous HCl (10 mL) were added, and the mixture was extracted
with EtOAc (2 × 50 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo to leave an orange-red oil which
was filtered over Sephadex LH-20 (MeOH) to afford an orange-red
oil upon evaporation. The oil was further purified by semipreparative
500 MHz) δ 7.91 (d, J = 8.2 Hz, 1H), 7.45−7.54 (m, 2H), 7.34−7.41
(m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 4.09 (d, J
= 15.0 Hz, 1H), 3.92 (d, J = 15.0 Hz, 1H), 3.63 (s, 3H), 3.45 (dd, J =
6.4, 7.3 Hz, 1H), 2.91 (dd, J = 6.4, 13.7 Hz, 1H), 2.86 (dd, J = 7.3,
13.7 Hz, 1H), 2.07 (br. s, 1H), 0.97 (s, 9H), 0.18 (s, 6H); 13C NMR
(CDCl3, 125 MHz) δ 174.9, 154.6, 149.1, 135.3, 133.2, 130.9, 130.3,
129.8, 128.0, 124.8, 120.1, 62.7, 51.9, 49.1, 39.1, 25.8, 18.3, −4.3;
HRMS (ESI) m /z [M + H]+ calcd for C23H33N O5Si+ 445.2153,
2
found 445.2137.
Methyl (S)-3-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-2-((2,4-
dimethoxybenzyl)amino)propanoate (7b). According to a modified
literature procedure,19 a suspension of L-tyrosine methyl ester
hydrochloride (580 mg, 2.50 mmol) in CH2Cl2 (12 mL) was treated
with imidazole (510 mg, 15.00 mmol) and TBSCl (452 mg, 6.00
mmol). The resulting mixture was stirred at room temperature for 19
h. Saturated aqueous NaHCO3 (50 mL) was added, and the jellylike
mixture was extracted with CH2Cl2 (3 × 75 mL). The combined
organic phases were washed with H2O (50 mL), dried (MgSO4), and
concentrated in vacuo to give an oil that was purified by flash
chromatography (silica gel, 90% ethyl acetate in hexane) to afford L-
Tyr(OTBS)-OMe as a clear oil (479 mg, 77%); Rf = 0.24 (hexane/
EtOAc 1:4); [α]24D +10.0 (c 1.00, CHCl3); IR νmax 2954, 2931, 2893,
2858, 1739, 1609, 1509, 1472, 1464, 1438, 1252, 1195, 1169, 1109,
̈
HPLC (AKTA system, flow rate: 5 mL/min on a Phenomenex
Gemini-NX 5u C18 110A, 250 × 10.00 mm column, one column
volume (CV) at 70% MeCN in H2O (with 0.1% formic acid), then
three CV at 90% MeCN, tret = 11.7−12.6 min, UVdet = 414 nm) to
give fumosorinone A (4) as a bright orange-yellow oil (7.7 mg, 60%);
[α]24D −229 (c 0.20, MeOH) (lit.5 [α]24D −207 (c 0.1, MeOH)); IR
νmax 3310, 2960, 2925, 1650, 1591, 1516, 1442, 1261, 1171, 988, 812,
620 cm−1; for NMR data cf. Supporting Information Table S2; HRMS
1
1102, 1008, 911, 837, 802, 779, 688 cm−1; H NMR (CDCl3, 500
MHz) δ 7.03 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 3.70 (s,
3H), 3.68 (dd, J = 5.2, 7.6 Hz, 1H), 3.00 (dd, J = 5.2, 13.7 Hz, 1H),
2.80 (dd, J = 7.6, 13.7 Hz, 1H), 1.45 (br. s., 2H), 0.97 (s, 9H), 0.18 (s,
6H); 13C NMR (CDCl3, 125 MHz) δ 175.7, 154.7, 130.3, 129.9,
120.3, 56.1, 52.1, 40.5, 25.8, 18.3, −4.3.
+
(ESI) m/z [M + H]+ calcd for C29H38NO4 464.2795, found
A solution of L-Tyr(OTBS)-OMe (881 mg, 2.85 mmol) in 3%
acetic acid in methanol (10 mL) was treated with 2,4-dimethox-
ybenzaldehyde (450 mg, 2.71 mmol), and the mixture was stirred at
room temperature for 30 min. NaBH(OAc)3 (804 mg, 3.79 mmol)
was added, stirring continued for 1.5 h, and the reaction mixture was
quenched with sat. aqueous NaHCO3 (50 mL). The mixture was
extracted with ethyl acetate (3 × 75 mL), and the combined organic
phases were washed with brine (75 mL), dried (Na2SO4), and
concentrated in vacuo to give an oil that was purified by flash
chromatography (silica gel, 15% EtOAc with 0.5% NEt3 in hexane ⇒
30% EtOAc with 0.5% NEt3) to leave 7b as a clear oil (870 mg, 71%);
Rf = 0.68 (hexane/EtOAc 1:1); [α]24D +1.98 (c 1.00, CHCl3); IR νmax
2952, 2931, 2858, 1735, 1611, 1589, 1508, 1463, 1438, 1418, 1278,
1250, 1207, 1156, 1132, 1104, 1036, 911, 835, 797, 779, 688, 634
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.02 (d, J = 8.9 Hz, 1H), 6.99
(d, J = 8.2 Hz, 2H), 6.73 (d, J = 8.2 Hz, 2H), 6.36−6.40 (m, 2H),
3.78 (s, 3H), 3.68 (s, 3H), 3.58 (s, 3H), 3.45 (t, J = 7.2 Hz, 1H), 2.89
(dd, J = 6.7, 13.4 Hz, 1H), 2.85 (dd, J = 7.6, 13.4 Hz, 1H), 1.87−2.05
(m, 1H), 0.97 (s, 9H), 0.17 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ
175.2, 160.2, 158.7, 154.5, 130.5, 130.21, 130.17, 120.2, 120.1, 103.7,
98.5, 62.4, 55.5, 55.3, 51.7, 47.3, 39.1, 25.8, 18.3, −4.3.
464.2785.
Methyl (S)-3-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-2-((2-
nitrobenzyl)amino)propanoate (7a). A solution of L-tyrosine methyl
ester hydrochloride (1.16 g, 5.00 mmol) in 3% acetic acid in methanol
(100 mL) was treated with o-nitrobenzaldehyde (1.51 g, 10.00 mmol)
and MS 3 Å (100 mg), and the resulting mixture was stirred at
ambient temperature for 1 h. NaBH3CN (781 mg, 12.50 mmol) was
added, and stirring was continued for 2 h. The molecular sieves were
filtered off, and the reaction mixture was quenched with sat. aqueous
NaHCO3 (300 mL). Ethyl acetate (300 mL) was added, the phases
were separated, and the organic phase was washed with brine (200
mL), dried (Na2SO4), and concentrated in vacuo to give a yellowish
oil that was adsorbed on silica gel (wt ratio oil/silica 1:10) and
purified by flash chromatography (silica gel, 1% MeOH in CH2Cl2 ⇒
1.5% MeOH ⇒ 2% MeOH) to give oNb-L-Tyr-OMe as a yellow oil
(1.145 g, 69%); Rf = 0.30 (4% MeOH in CH2Cl2); [α]24 +33.6 (c
D
1.00, CHCl3); IR νmax 3324, 2953, 1732, 1613, 1596, 1578, 1516,
1444, 1344, 1206, 1173, 1107, 991, 829, 789, 731, 702, 666, 556
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.90 (dd, J = 1.1, 8.1 Hz, 1H),
7.49 (ddd, J = 1.1, 7.2, 7.3 Hz, 1H), 7.46 (dd, J = 1.5, 7.3 Hz, 1H),
7.36 (ddd, J = 1.5, 7.2, 8.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.69 (d,
J = 8.5 Hz, 2H), 4.08 (d, J = 15.0 Hz, 1H), 3.93 (d, J = 15.0 Hz, 1H),
3.64 (s, 3H), 3.47 (dd, J = 6.1, 7.3 Hz, 1H), 2.91 (dd, J = 6.1, 13.4 Hz,
1H), 2.86 (dd, J = 7.3, 13.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
175.0, 155.0, 149.0, 134.9, 133.3, 131.2, 130.4, 128.5, 128.2, 124.9,
115.5, 62.6, 52.0, 49.2, 38.8; HRMS (ESI) m/z [M + H]+ calcd for
S-(tert-Butyl) (2Z,4E,6E,8E,10E,12R,14R)-3-Hydroxy-4,10,12,14-
tetramethylhexadeca-2,4,6,8,10-pentaenethioate (9). Following a
general literature protocol,17 thioester 9 (236 mg, 95%) was prepared
from phosphonate 34 (289 mg, 889 μmol) and aldehyde 33 (140 mg,
635 μmol) as an orange-yellow oil and as a 2:3 keto/enol mixture; Rf
+
C17H19N2O5 331.1288, found 331.1284.
= 0.86 (10% EtOAc in hexane); [α]24 −43.2 ( c 0.50, CHCl3); IR
D
A solution of oNb-L-Tyr-OMe (610 mg, 1.85 mmol) in CH2Cl2 p.a.
(19 mL) was cooled to 0 °C and treated with imidazole (378 mg, 5.55
mmol) and TBSCl (613 mg, 4.07 mmol). The resulting mixture was
νmax 2960, 2923, 2871, 1688, 1651, 1614, 1586, 1456, 1376, 1364,
1311, 1250, 1163, 1100, 1062, 986, 907, 859, 797, 769, 652 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 12.96 (s, 1H), 7.15 (d, J = 11.0 Hz, 1H),
D
DOI: 10.1021/acs.joc.8b01530
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The Journal of Organic Chemistry
Article
7.11 (d, J = 11.0 Hz, 1H), 6.22−6.75 (m, 8H), 5.57 (s, 1H, HCCOS
enol), 5.41 (d, J = 9.8 Hz, 1H), 5.36 (d, J = 9.8 Hz, 1H), 3.88 (s, 2H,
H2CCOS keto), 2.56−2.69 (m, 2H), 1.92 (s, 3H), 1.86 (d, J = 0.9 Hz,
3H), 1.81 (d, J = 0.9 Hz, 3H), 1.80 (d, J = 0.9 Hz, 3H), 1.53 (s, 9H),
1.47 (s, 9H), 1.21−1.35 (m, 6H), 1.05−1.17 (m, 4H), 0.96 (d, J = 6.4
Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.80−0.88 (m, 12H); 13C NMR
(CDCl3, 125 MHz) δ 196.2, 193.6, 193.3, 169.6, 144.3, 143.2, 142.4,
141.8, 141.5, 139.9, 134.7, 132.6, 127.3, 127.2, 127.0, 126.4, 126.0,
98.1, 54.1, 49.0, 48.5, 45.0, 44.9, 32.5, 32.4, 30.84, 30.76, 30.35, 30.27,
30.25, 29.8, 21.63, 21.56, 19.2, 12.6, 12.4, 11.8, 11.5; HRMS (ESI) m
(R)-4-Benzyl-3-((R)-4-methylhexanoyl)oxazolidin-2-one (15). Ac-
cording to a literature procedure,9 compound 15 (526 mg, 88%) was
prepared from 14 (268 mg, 2.06 mmol), pivaloyl chloride (0.27 mL,
2.16 mmol), and (R)-benzyloxazolidin-2-one (383 mg, 2.16 mmol) as
a colorless solid; Rf = 0.64 (hexane/EtOAc 4:1); [α]24 −56.9 ( c
D
1.00, CHCl3) (lit.26 [α]27 −57.5 (c 1.00, CHCl3)); mp 36−37 °C;
D
IR νmax 2961, 2925, 2874, 1777, 1698, 1455, 1384, 1351, 1324, 1280,
1210, 1194, 1138, 1097, 1052, 1015, 761, 741, 700, 628, 595, 564
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.31−7.36 (m, 2H), 7.27−7.30
(m, 1H), 7.19−7.23 (m, 2H), 4.64−4.71 (m, 1H), 4.20 (dd, J = 7.6,
9.0 Hz, 1H), 4.16 (dd, J = 3.0, 9.0 Hz, 1H), 3.30 (dd, J = 3.3, 13.3 Hz,
1H), 2.99 (ddd, J = 5.4, 10.0, 16.7 Hz, 1H), 2.89 (ddd, J = 5.7, 9.8,
16.7 Hz, 1H), 2.76 (dd, J = 9.6, 13.3 Hz, 1H), 1.66−1.76 (m, 1H),
1.47−1.55 (m, 1H), 1.35−1.47 (m, 2H), 1.15−1.24 (m, 1H), 0.92 (d,
J = 6.4 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 173.9, 153.6, 135.5, 129.6, 129.1, 127.5, 66.3, 55.3, 38.1, 34.1,
33.5, 31.0, 29.4, 19.1, 11.5.
/z [M + Na]+ calcd for C24H38O NaS+ 413.2485, found 413.2482.
2
(4R,6R,E)-2,4,6-Trimethyloct-2-enal (10). A solution of alcohol 21
(1.60 g, 9.37 mmol) in CH2Cl2 p.a. (94 mL) was treated with MnO2
(29.48 g, 327.95 mmol), and the mixture was stirred at ambient
temperature for 18 h and then filtered over Celite. The filtrate was
concentrated in vacuo to give a clear liquid that was purified by flash
chromatography (silica gel, 10% ethyl acetate in hexane) to afford
(R)-4-Benzyl-3-((2R,4R)-2,4-dimethylhexanoyl)oxazolidin-2-one
(16). According to a literature procedure,9 compound 16 (5.63 g,
90%) was prepared from 15 (5.98 g, 20.65 mmol) as a colorless solid
aldehyde 10 (1.31 g, 83%) as a clear oil; Rf = 0.38 (6% ethyl acetate in
hexane); [α]24 −36.3 (c 1.00, CHCl3) (lit.20 [α]
−43 (c 0.75,
20
D
D
CHCl3)); IR νmax 2961, 2928, 2875, 2707, 1688, 1644, 1457, 1405,
1379, 1313, 1243, 1201, 1128, 1051, 1015, 874, 827, 805, 675 cm−1;
1H NMR (CDCl3, 500 MHz) δ 9.38 (s, 1H), 6.21 (dd, J = 1.2, 10.1
Hz, 1H), 2.75−2.86 (m, 1H), 1.72−1.78 (m, 3H), 1.10−1.39 (m,
5H), 1.03 (d, J = 6.7 Hz, 3H), 0.81−0.87 (m, 6H); 13C NMR
(CDCl3, 125 MHz) δ 195.8, 161.0, 138.0, 44.1, 32.5, 31.4, 30.1, 20.5,
19.2, 11.4, 9.5.
of mp 32−33 °C; Rf = 0.54 (hexane/EtOAc 7:1); [α]24 −66.6 (c
D
1.00, CHCl3) (lit.27 [α]27 −68.6 ( c 4.13, CHCl3)); IR νmax 2962,
D
2929, 2875, 1775, 1695, 1455, 1384, 1349, 1290, 1239, 1207, 1098,
1
1075, 1052, 1015, 971, 917, 761, 739, 701, 625, 593 cm−1; H NMR
(CDCl3, 500 MHz) δ 7.30−7.36 (m, 2H), 7.26−7.30 (m, 1H), 7.19−
7.24 (m, 2H), 4.65−4.71 (m, 1H), 4.20 (dd, J = 7.4, 9.0 Hz, 1H), 4.17
(dd, J = 2.8, 9.0 Hz, 1H), 3.82−3.92 (m, 1H), 3.26 (dd, J = 3.1, 13.3
Hz, 1H), 2.76 (dd, J = 9.6, 13.3 Hz, 1H), 1.85 (ddd, J = 5.5, 8.6, 13.2
Hz, 1H), 1.29−1.43 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 1.09−1.20 (m,
2H), 0.86 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 177.6, 153.2, 135.5, 129.6, 129.1, 127.5, 66.1,
55.5, 40.6, 38.0, 35.5, 32.4, 29.6, 19.5, 18.5, 11.4.
(S)-3,7-Dimethyloct-6-en-1-yl Methanesulfonate (12). According
to a literature procedure,21 compound 1222 (4.67 g, 100%) was
prepared from (S)-citronellol (11) (3.63 mL, 20.00 mmol), MsCl
(1.6 mL, 21.00 mmol), and NEt3 (2.9 mL, 21.00 mmol) as a yellow
oil; Rf = 0.55 (hexane/EtOAc 5:1); [α]24D −2.11 (c 1.00, CHCl 3); IR
νmax 2964, 2914, 2859, 1456, 1378, 1351, 1333, 1171, 1036, 973, 938,
(2R,4R)-2,4-Dimethylhexan-1-ol (17). According to a literature
procedure,28 alcohol 17 (2.11 g, 95%) was prepared from 16 (5.19 g,
17.10 mmol) and LiBH4 (4 M in THF, 4.9 mL, 19.67 mmol) as a
clear oil; Rf = 0.33 (hexane/EtOAc 5:1); [α]24D +4.7 (c 1.00, CHCl3)
(lit. [α]D +3.7 (c 1.67, CHCl3)); IR νmax 3342, 2959, 2915, 2875,
1
889, 818, 796, 730 cm−1; H NMR (CDCl3, 500 MHz) δ 5.04−5.11
(m, 1H), 4.21−4.32 (m, 2H), 3.00 (s, 3H), 1.90−2.07 (m, 2H),
1.75−1.85 (m, 1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.50−1.65 (m, 2H),
1.30−1.40 (m, 1H), 1.15−1.25 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ 131.8, 124.4, 68.7, 37.5, 36.9, 36.0, 29.1,
25.9, 25.4, 19.3, 17.8.
1
1462, 1378, 1028, 986, 612 cm−1; H NMR (CDCl3, 500 MHz) δ
3.48−3.56 (m, 1H), 3.34−3.42 (m, 1H), 1.66−1.76 (m, 1H), 1.40−
1.48 (m, 1H), 1.35−1.40 (m, 1H), 1.24−1.35 (m, 2H), 1.03−1.13
(m, 1H), 0.92 (d, J = 6.7 Hz, 3H), 0.90 (s, 1H), 0.87 (d, J = 6.5 Hz,
3H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 68.6,
40.7, 33.3, 31.7, 29.2, 19.9, 17.4, 11.3.
(R)-2,6-Dimethyloct-2-ene (13). According to a literature proto-
col,23 compound 13 (6.13 g, 100%) was prepared from 12 (10.30 g,
43.95 mmol) and LiAlH4 (3.34 g, 88.00 mmol) as a clear oil; Rf = 0.89
(hexane); [α]24 −6.2 (c 1.00, CHCl3) (lit.24 [α]25 −7.55 (neat));
D
D
1
IR νmax 2963, 2915, 2875, 2853, 1456, 1377, 833 cm−1; H NMR
(CDCl3, 500 MHz) δ 5.06−5.14 (m, 1H), 1.89−2.04 (m, 2H), 1.69
(s, 3H), 1.61 (s, 3H), 1.28−1.39 (m, 3H), 1.08−1.18 (m, 2H), 0.86
(d, J = 6.3 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 131.1, 125.3, 36.9, 34.2, 29.6, 25.9, 25.8, 19.3, 17.8, 11.5.
(R)-4-Methylhexanoic Acid (14). According to a modified
literature protocol,11 a solution of alkene 13 (6.15 g, 43.65 mmol)
in CH2Cl2 p.a. (130 mL) was treated with acetonitrile p.a. (130 mL),
H2O (170 mL), NaIO4 (37.35 g, 174.60 mmol), and RuCl3 × H2O
(181 mg, 873 μmol, 2 mol %), and the mixture was stirred at ambient
temperature for 18 h. Na2S2O3 (3 g) was added, and the mixture was
stirred for 15 min. The solids were filtered off, and the filtrate was
concentrated in vacuo. A 1 M aqueous NaOH (100 mL) solution was
added, and the resulting mixture was washed with diethyl ether (2 ×
200 mL). The aqueous phase was acidified with 1 M aqueous HCl
(175 mL), and the brown mixture was extracted with diethyl ether (3
× 200 mL). The combined organic phases were washed with aqueous
Na2S2O3 (20% wt, 2 × 150 mL) and brine (150 mL), dried
(Na2SO4), and concentrated in vacuo to give acid 14 (3.66 g, 64%) as
a brownish oil; Rf = 0.61 (hexane/EtOAc 4:1); [α]24D −10.9 ( c 1.00,
Triphenyl(1-ethoxycarbonylethyl)phosphorane (19). According
to literature procedure,29 ylide 1930 (10.13 g, 50.00 mmol, 64%) was
prepared as a beige solid from 2-bromoethyl propanoate (6.5 mL,
1
50.00 mmol) and PPh3 (13.12 g, 50.00 mmol); H NMR (CDCl3,
500 MHz) δ 7.44−7.63 (m, 15H), 3.56−4.00 (m, 2H), 1.61 (d, J =
13.7 Hz, 3H), 0.22−0.92 (m, 3H); 13C NMR (CDCl3, 125 MHz) δ
133.8, 133.7, 131.7, 128.6, 128.5, 57.6, 12.8; IR νmax 3055, 2979, 2927,
1626, 1589, 1571, 1484, 1435, 1381, 1365, 1310, 1298, 1185, 1158,
1087, 1071, 1029, 998, 950, 861, 773, 760, 747, 714, 692, 618, 576
cm−1.
Ethyl (4R,6R,E)-2,4,6-Trimethyloct-2-enoate (20). According to a
modified literature procedure,12 a cooled (−78 °C) solution of oxalyl
chloride (2.2 mL, 25.87 mmol) in CH2Cl2 (27 mL) was treated with a
solution of dimethyl sulfoxide (2.9 mL, 40.43 mmol) in CH2Cl2 (13.5
mL), and the mixture was stirred at −78 °C for 30 min. A solution of
alcohol 17 (2.11 g, 16.17 mmol) in CH2Cl2 (13.5 mL) was added,
and stirring was continued at −78 °C for 30 min. NEt3 (11.2 mL,
80.85 mmol) was added, and the mixture was stirred at −78 °C for 1
h before it was warmed to ambient temperature and stirred for 1 h.
Then 1 M aqueous HCl (100 mL) was added, and the mixture was
extracted with n-pentane (3 × 100 mL). The combined organic
phases were washed with H2O (100 mL), dried (Na2SO4), and
concentrated in vacuo to give aldehyde 18 as a pale-yellow liquid that
was used in the next step without purification.
CHCl3) (lit.25 [α]10 −10.1 (c 1.00, CHCl3)); IR νmax 3042, 2962,
D
2931, 2876, 2654, 1705, 1463, 1413, 1380, 1281, 1250, 1216, 936
1
cm−1; H NMR (CDCl3, 500 MHz) δ 11.45 (br. s, 1H), 2.27−2.44
(m, 2H), 1.63−1.74 (m, 1H), 1.40−1.50 (m, 1H), 1.30−1.40 (m,
2H), 1.12−1.22 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.3 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 180.6, 34.1, 32.0, 31.3, 29.2,
18.9, 11.4.
A solution of aldehyde 18 (2.07 g, 16.17 mmol) in CH2Cl2 p.a. (35
mL) was treated with Ph3PC(CH3)CO2Et (19) (8.79 g, 24.26
mmol), and the mixture was stirred at ambient temperature for 19 h.
E
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The solvent was removed in vacuo to give a brownish oil that was
purified by flash chromatography (silica gel, 2% diethyl ether in
hexane) to give ester 20 (2.41 g, 70% over two steps) as an 98:2
mixture of E/Z isomers as a pale yellow liquid; Rf = 0.34 (2% diethyl
ether in hexane); IR νmax 2961, 2929, 2875, 1710, 1650, 1462, 1367,
2,2-Dimethyl-5-(triphenylphosphoranylidene)acetyl-1,3-dioxan-
4,6-dione (26). According to a literature procedure,13 ylide 26 (2.31
g, 56%) was prepared as a colorless solid from Meldrum’s acid (1.32
g, 9.18 mmol) and ketenylidenetriphenylphosphorane (2.78 g, 9.18
mmol); IR νmax 3062, 2984, 1685, 1626, 1587, 1573, 1548, 1516,
1375, 1314, 1272, 1258, 1204, 1175, 1158, 1104, 1055, 1029, 996,
985, 935, 86, 798, 783, 757, 747, 723, 716, 692, 659, 651, 579 cm−1;
1H NMR (CDCl3, 500 MHz) δ 13.53 (dd, J = 0.8, 2.9 Hz, 1H), 7.60−
7.69 (m, 9H), 7.49−7.55 (m, 6H), 5.76 (dd, J = 2.9, 21.7 Hz, 1H),
1.70 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 175.9, 133.3 (d, J =
10.9 Hz), 133.0 (d, J = 2.7 Hz), 129.3 (d, J = 11.8 Hz), 124.9 (d, J =
91.7 Hz), 102.4, 57.0 (d, J = 108.1 Hz), 26.4.
1
1311, 1271, 1249, 1217, 1152, 1099, 1035, 991, 750 cm−1; H NMR
(CDCl3, 500 MHz) δ 6.50 (d, J = 9.8 Hz, 1H), 4.18 (q, J = 7.2 Hz,
2H), 2.56−2.64 (m, 1H), 1.84 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H),
1.20−1.34 (m, 3H), 1.08−1.18 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H),
0.80−0.87 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 168.7, 148.4,
126.3, 60.5, 44.3, 32.4, 31.0, 30.2, 20.7, 19.1, 14.4, 12.6, 11.4.
16
(4R,6R,E)-2,4,6-Trimethyloct-2-en-1-ol (21).
According to a
modified literature procedure,12 a cooled (−78 °C) solution of ester
20 (2.29 g, 10.79 mmol) in CH2Cl2 (36 mL) was treated with
DIBAL-H (1 M in hexane, 27 mL, 26.98 mmol) using a syringe pump
(2 mL/min). The mixture was stirred at −78 °C for 1 h, treated with
aqueous citric acid (20% wt, 150 mL), stirred at room temperature for
20 min, and then extracted with ethyl acetate (3 × 150 mL). The
combined organic phases were washed with aqueous citric acid (20%
wt, 100 mL) and brine (100 mL), dried (Na2SO4), and concentrated
in vacuo to give a clear oil which was purified by flash
chromatography (silica gel, 15% ethyl acetate in hexane) to afford
alcohol 21 (1.66 g, 90%) as a clear oil; Rf = 0.31 (16% ethyl acetate in
(5S,3Z)-5-(4-((tert-Butyldimethylsilyl)oxy)benzyl)-3-
((2E,4E,6E,8R,10R)-1-hydroxy-6,8,10-trimethyldodeca-2,4,6-trien-1-
ylidene)-1-(2-nitrobenzyl)pyrrolidine-2,4-dione (28a) and (5S,3Z)-
5-(4-((tert-Butyldimethylsilyl)oxy)benzyl)-1-(2,4-dimethoxybenzyl)-
3-((2E,4E,6E,8R,10R)-1-hydroxy-6,8,10-trimethyldodeca-2,4,6-trien-
1-ylidene)pyrrolidine-2,4-dione (28b). (A) A suspension of ylide 26
(790 mg, 1.77 mmol) and KOtBu (199 mg, 1.77 mmol) in THF (20
mL) was treated with a solution of aldehyde 25 (344 mg, 1.77 mmol)
in THF (15 mL), and the resulting mixture was heated at reflux for 22
h. It was concentrated in vacuo, and the remainder was taken up in
CH2Cl2 (150 mL) and sat. aqueous NaHCO3 (100 mL). The phases
were separated, and the organic one was washed with sat. aqueous
NaHCO3 (2 × 150 mL) and 1 M aqueous HCl (100 mL). The
organic phase was dried (Na2SO4) and concentrated in vacuo to give
an inseparable mixture of 42% of Meldrum’s acid derivative 8, 42%
PPh3O, and 16% residual ylide 26. It was taken up in acetonitrile p.a.
(30 mL), and the resulting solution was split in two 15 mL portions
which were used in the next step without further purification.
(B) The first 15 mL portion was treated with oNb-L-Tyr(OTBS)-
OMe 7a (326 mg, 734 μmol, 1.00 equiv), the resulting mixture was
heated at reflux for 1 h, and all volatiles were removed in vacuo to
leave an orange oil that was purified by flash chromatography (silica
gel, 30% EtOAc in hexane, Rf = 0.67) to give β-ketoamide 27a as a
yellow oil (161 mg, 30% over two steps) that was used in the next
step without further purification.
hexane); [α]24 −27.9 ( c 1.00, CHCl3); IR νmax 3315, 2959, 2923,
D
2871, 1457, 1378, 1010, 850, 618 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 5.12 (dd, J = 1.2, 9.5 Hz, 1H), 3.99 (d, J = 5.8 Hz, 2H), 2.43−2.55
(m, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.23−1.31 (m, 3H), 1.01−1.16 (m,
2H), 0.92 (d, J = 6.7 Hz, 3H), 0.80−0.86 (m, 6H); 13C NMR
(CDCl3, 125 MHz) δ 133.25, 133.16, 69.3, 44.9, 32.2, 30.2, 29.7, 21.8,
19.3, 14.0, 11.4.
Ethyl (2E,4E,6R,8R)-4,6,8-Trimethyldeca-2,4-dienoate (23). Ac-
cording to a literature procedure,12 compound 23 (990 mg, 68%) was
prepared from 10 (1.03 g, 6.09 mmol) and Ph3PCHCO2Et (22) (4.24
g, 12.18 mmol) as a colorless oil; Rf = 0.32 (6% ethyl acetate in
hexane); [α]24 −66.6 (c 1.00, CHCl3) (lit.12 [α]22.5 −41.8 (c 1.00,
D
D
CHCl3)); IR νmax 2961, 2926, 2874, 1713, 1623, 1461, 1393, 1366,
1
1289, 1260, 1239, 1162, 1131, 1096, 1033, 982, 846 cm−1; H NMR
The second 15 mL portion was reacted analogously with DMB-L-
Tyr(OTBS)-OMe 7b (381 mg, 829 μmol, 1.13 equiv) to give β-
ketoamide 27b as a yellow oil (120 mg, 25% over two steps) that was
also used in the next step without further purification; Rf = 0.57 (30%
EtOAc in hexane). (C) A solution of β-ketoamide 27a (161 mg, 228
μmol) in methanol p.a. (23 mL) was treated with sodium methoxide
(62 mg, 1.140 mmol), and the resulting mixture was stirred at
ambient temperature for 15 min. A 1 M aqueous HCl (15 mL)
solution and brine (10 mL) were added, and the mixture was
extracted with EtOAc (2 × 100 mL). The combined organic phases
were dried (Na2SO4) and concentrated in vacuo to afford tetramic
acid 28a as a foamy orange yellow solid (152 mg, quant); Rf = 0.15
(30% EtOAc in hexane); [α]24D −415 (c 0.50, CHCl3); IR νmax 2957,
2927, 2857, 1698, 1645, 1626, 1592, 1556, 1525, 1510, 1443, 1353,
1338, 1305, 1259, 1173, 1120, 1001, 920, 875, 857, 839, 809, 781,
(CDCl3, 500 MHz) δ 7.31 (d, J = 15.6 Hz, 1H), 5.78 (d, J = 15.6 Hz,
1H), 5.63 (d, J = 9.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.58−2.70
(m, 1H), 1.76−1.80 (m, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.19−1.35 (m,
3H), 1.07−1.17 (m, 2H), 0.96 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.3 Hz,
3H), 0.81 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 167.8,
150.1, 148.9, 131.3, 115.6, 60.3, 44.6, 32.5, 31.0, 30.3, 21.2, 19.2, 14.5,
12.4, 11.4.
(2E,4E,6R,8R)-4,6,8-Trimethyldeca-2,4-dien-1-ol (24). Analo-
gously to 21, alcohol 24 (383 mg, 98%) was prepared as a colorless
oil from ester 23 (477 mg, 2.00 mmol) and DIBAL-H (1 M in hexane,
5.0 mL, 5.00 mmol); Rf = 0.15 (16% ethyl acetate in hexane); [α]24
D
−40.3 (c 1.00, CHCl3) (lit.12 [α]22.5D −37.1 (c 1.00, CHCl3)); IR νmax
3313, 2960, 2923, 2871, 1651, 1457, 1377, 1097, 1024, 995, 964, 872,
772 cm−1; 1H NMR (CDCl3, 500 MHz) δ 6.25 (qd, J = 0.8, 15.6 Hz,
1H), 5.71 (td, J = 6.1, 15.6 Hz, 1H), 5.23 (d, J = 9.8 Hz, 1H), 4.20
(dd, J = 0.8, 6.1 Hz, 2H), 2.53−2.65 (m, 1H), 1.76 (d, J = 1.2 Hz,
3H), 1.36 (br. s, 1H), 1.20−1.32 (m, 3H), 1.03−1.18 (m, 2H), 0.93
(d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H), 0.81 (d, J = 6.41 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 140.7, 137.4, 131.3, 125.1, 64.2,
45.0, 32.4, 30.4, 30.3, 21.7, 19.2, 12.8, 11.5.
1
749, 727, 688, 608, 571 cm−1; H NMR (CDCl3, 500 MHz) δ 8.02
(dd, J = 1.2, 8.2 Hz, 1H), 7.58 (ddd, J = 1.2, 7.6, 7.6 Hz, 1H), 7.53
(dd, J = 11.3, 15.0 Hz, 1H), 7.44 (ddd, J = 1.2, 7.6, 8.2 Hz, 1H), 7.31
(dd, J = 1.2, 7.6 Hz, 1H), 7.17 (d, J = 15.0 Hz, 1H), 6.87 (d, J = 8.5
Hz, 2H), 6.69 (d, J = 15.3 Hz, 1H), 6.64 (d, J = 8.5 Hz, 2H), 6.43
(dd, J = 11.3, 15.3 Hz, 1H), 5.56 (d, J = 9.8 Hz, 1H), 5.22 (d, J = 17.1
Hz, 1H), 4.72 (d, J = 17.1 Hz, 1H), 4.00 (dd, J = 4.3, 5.2 Hz, 1H),
3.14 (dd, J = 4.3, 14.7 Hz, 1H), 3.04 (dd, J = 5.2, 14.7 Hz, 1H), 2.60−
2.71 (m, 1H), 1.82 (s, 3H), 1.20−1.36 (m, 3H), 1.08−1.17 (m, 2H),
0.97 (d, J = 6.4 Hz, 3H), 0.94 (s, 9H), 0.81−0.87 (m, 6H), 0.14 (s,
6H); 13C NMR (CDCl3, 125 MHz) δ 193.7, 174.6, 173.9, 154.8,
149.5, 148.3, 147.9, 146.6, 133.9, 132.9, 132.1, 130.3, 129.4, 128.6,
127.6, 125.4, 125.2, 120.2, 119.8, 99.7, 66.0, 44.7, 41.1, 35.0, 32.5,
31.1, 30.2, 25.8, 21.3, 19.2, 18.3, 12.5, 11.4, −4.4; HRMS (ESI) m /z
(2E,4E,6R,8R)-4,6,8-Trimethyldeca-2,4-dienal (25). Analogously to
10, aldehyde 25 (363 mg, 96%) was prepared as a colorless oil from
alcohol 24 (383 mg, 1.95 mmol) and MnO2 (3.39 g, 39.02 mmol); Rf
= 0.55 (16% ethyl acetate in hexane); [α]24 −47.3 (c 1.00, CHCl3)
D
(lit.12 [α]22.5 −61.4 (c 1.00, CHCl3)); IR νmax 2961, 2925, 2873,
D
2722, 1680, 1623, 1605, 1456, 1379, 1315, 1127, 1010, 969, 822, 595
cm−1. 1H NMR (CDCl3, 500 MHz) δ 9.55 (d, J = 7.9 Hz, 1H), 7.11
(d, J = 15.6 Hz, 1H), 6.09 (dd, J = 7.9, 15.6 Hz, 1H), 5.76 (d, J = 9.8
Hz, 1H), 2.62−2.74 (m, 1H), 1.83 (d, J = 1.2 Hz, 3H), 1.19−1.39 (m,
3H), 1.10−1.19 (m, 2H), 1.00 (d, J = 6.7 Hz, 3H), 0.85 (t, J = 7.3 Hz,
3H), 0.83 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 194.4,
158.4, 151.3, 132.0, 126.9, 44.5, 32.5, 31.3, 30.2, 21.1, 19.2, 12.6, 11.4.
[M + H]+ calcd for C39H53N O6Si+ 673.3667, found 673.3651.
2
Analogously, tetramic acid 28b (113 mg, quant) was obtained as a
solid yellow foam from β-ketoamide 27b (120 mg, 167 μmol) and
sodium methoxide (45 mg, 835 μmol); Rf = 0.41 (30% EtOAc in
F
DOI: 10.1021/acs.joc.8b01530
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The Journal of Organic Chemistry
Article
hexane); [α]24 −412 (c 0.50, CHCl3); IR νmax 2958, 2928, 2858,
(dd, J = 18.2, 7.3 Hz), 58.3, 49.2, 48.5, 47.2 (d, J = 126.3 Hz), 38.9 (d,
J = 135.3 Hz), 30.2, 29.7, 16.5 (d, J = 8.2 Hz), 12.7 (d, J = 5.4 Hz),
10.7 (d, J = 6.4 Hz).
D
1697, 1609, 1593, 1558, 1509, 1451, 1361, 1260, 1209, 1158, 1131,
1
1108, 1035, 1000, 915, 838, 782, 686, 610 cm−1; H NMR (CDCl3,
(5S,3Z)-5-(4-((tert-Butyldimethylsilyl)oxy)benzyl)-1-(2,4-dime-
thoxybenzyl)-3-((2E,4E,6E,8E,10R,12R)-1-hydroxy-2,8,10,12-tetra-
methyltetradeca-2,4,6,8-tetraen-1-ylidene)pyrrolidine-2,4-dione
(36). A mixture of thioester 9 (100 mg, 256 μmol), THF (3.2 mL),
and 4 Å molecular sieves (powdered, 40 mg) was cooled to 0 °C and
treated with a solution of DMB-L-Tyr(OTBS)-OMe 7b (130 mg, 282
μmol), NEt3 (0.14 mL, 1.024 mmol), and silver trifluoroacetate (113
mg, 512 μmol) in THF (3.2 mL). The mixture was stirred at 0 °C
under exclusion of light for 2.5 h, diluted with diethyl ether (100 mL),
and filtered over Celite. The filtrate was washed with sat. aqueous
NH4Cl (75 mL) and brine (75 mL), dried (Na2SO4), and
concentrated in vacuo to give an orange oil. It was purified by flash
chromatography (silica gel, 50% EtOAc in hexane; Rf = 0.76) to give
β-ketoamide 35 as a yellow oil (173 mg, 89%) that was used in the
next step without further purification. A solution of β-ketoamide 35
(159 mg, 209 μmol) in methanol (21 mL) was treated with sodium
methoxide (56 mg, 1.05 mmol), and the mixture was stirred at
ambient temperature for 20 min. Saturated aqueous NH4Cl (40 mL)
and 1 M aqueous HCl (30 mL) were added, the mixture was
extracted with EtOAc (100 mL), and the organic phase was dried
(Na2SO4) and concentrated in vacuo to give bisprotected
fumosorinone A (36) as a red gum (149 mg, quant); Rf = 0.56
500 MHz) δ 7.44 (dd, J = 11.3, 15.0 Hz, 1H), 7.06−7.12 (m, 2H),
6.96 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 15.3
Hz, 1H), 6.41−6.45 (m, 2H), 6.39 (dd, J = 11.3, 15.3 Hz, 1H), 5.51
(d, J = 9.8 Hz, 1H), 4.99 (d, J = 14.6 Hz, 1H), 4.19 (d, J = 14.6 Hz,
1H), 3.83−3.87 (m, 1H), 3.76−3.82 (m, 6H), 3.06−3.14 (m, 2H),
2.59−2.73 (m, 1H), 1.82 (s, 3H), 1.21−1.34 (m, 3H), 1.08−1.16 (m,
2H), 0.96 (d, J = 6.7 Hz, 3H), 0.94 (s, 9H), 0.80−0.86 (m, 6H), 0.14
(s, 6H); 13C NMR (CDCl3, 125 MHz) δ 194.8, 173.8, 173.1, 160.9,
158.7, 154.6, 148.5, 147.2, 145.3, 132.9, 131.5, 130.7, 128.1, 125.3,
120.3, 120.1, 116.4, 104.4, 100.6, 98.5, 65.1, 55.51, 55.48, 44.7, 38.4,
34.4, 32.5, 31.0, 30.2, 25.8, 21.4, 19.2, 18.3, 12.5, 11.4, −4.3; HRMS
(ESI) m/z [M + H]+ calcd for C41H58NO6Si+ 688.4028, found
688.4031.
Ethyl (2E,4E,6E,8R,10R)-6,8,10-Trimethyldodeca-2,4,6-trienoate
(31). According to a literature procedure,16 ester 31 (248 mg, 67%)
was prepared as a colorless oil from aldehyde 10 (235 mg, 1.394
mmol) and phosphonate 30 (1.12 g, 4.46 mmol); Rf = 0.40 (6%
EtOAc in hexane); [α]24D −51.7 (c 1.00, CHCl3) (lit.16 [α]19D −41.8
(c 1.00, CHCl3)); IR νmax 2960, 2925, 2872, 1710, 1613, 1457, 1392,
1367, 1329, 1304, 1256, 1234, 1201, 1178, 1136, 1096, 1039, 996,
1
861, 718 cm−1; H NMR (CDCl3, 500 MHz) δ 7.34 (dd, J = 11.0,
15.3 Hz, 1H), 6.56 (d, J = 15.3 Hz, 1H), 6.22 (dd, J = 11.0, 15.3 Hz,
1H), 5.85 (d, J = 15.3 Hz, 1H), 5.44 (d, J = 9.8 Hz, 1H), 4.20 (q, J =
7.0 Hz, 2H), 2.55−2.69 (m, 1H), 1.80 (d, J = 1.2 Hz, 3H), 1.29 (t, J =
7.0 Hz, 3H), 1.20−1.33 (m, 3H), 1.07−1.17 (m, 2H), 0.96 (d, J = 6.7
Hz, 3H), 0.80−0.87 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 167.5,
146.4, 145.6, 145.5, 132.3, 123.8, 119.6, 60.3, 44.8, 32.4, 30.8, 30.2,
21.5, 19.2, 14.5, 12.6, 11.4.
(50% EtOAc in hexane); [α]24 −367.1 (c 0.75, CHCl3); IR νmax
D
2958, 2928, 2859, 1652, 1611, 1590, 1544, 1508, 1452, 1389, 1361,
1255, 1209, 1171, 1158, 1119, 1034, 988, 913, 837, 807, 781, 725,
687, 640, 605, 578 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.74 (d, J =
11.6 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H),
6.68−6.75 (m, 3H), 6.57 (dd, J = 11.6, 14.3 Hz, 1H), 6.41−6.49 (m,
3H), 6.31 (dd, J = 10.7, 15.0 Hz, 1H), 5.40 (d, J = 9.5 Hz, 1H), 4.99
(d, J = 14.6 Hz, 1H), 4.24 (d, J = 14.6 Hz, 1H), 3.82−3.86 (m, 1H),
3.78−3.82 (m, 6H), 3.15 (dd, J = 4.6, 14.3 Hz, 1H), 3.10 (dd, J = 4.0,
14.3 Hz, 1H), 2.56−2.70 (m, 1H), 1.95 (s, 3H), 1.81 (s, 3H), 1.22−
1.35 (m, 3H), 1.06−1.17 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H), 0.95 (br.
s., 9H), 0.85 (dd, J = 7.0, 7.6 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H), 0.14
(s, 6H); 13C NMR (CDCl3, 125 MHz) δ 192.6, 182.7, 175.9, 160.9,
158.7, 154.6, 144.1, 143.2, 142.9, 142.6, 132.7, 131.5, 130.8, 128.21,
128.18, 126.9, 126.3, 120.1, 116.4, 104.4, 99.4, 98.5, 64.5, 55.51,
55.49, 44.9, 38.7, 34.5, 32.4, 30.8, 30.2, 25.8, 21.5, 19.2, 18.3, 12.64,
12.61, 11.4, −4.32, −4.34; HRMS (ESI) m /z [M + H]+ calcd for
(2E,4E,6E,8R,10R)-6,8,10-Trimethyldodeca-2,4,6-trien-1-ol (32).
Analogously to 21, alcohol 32 (179 mg, 85%) was prepared as a
colorless cloudy oil from ester 31 (226 mg, 948 μmol) and DIBAL-H
(1 M in hexane, 2.4 mL, 2.40 mmol) in 179 mg (85%); Rf = 0.19
(16% EtOAc in hexane); [α]24 −37.5 (c 1.00, CHCl3) (lit.16 [α]20
D
D
−28.8 (c 1.00, CHCl3)); IR νmax 3306, 3024, 2959, 2922, 2870, 1625,
1455, 1376, 1309, 1087, 982, 842 cm−1; 1H NMR (CDCl3, 500 MHz)
δ 6.10−6.33 (m, 3H), 5.82 (td, J = 6.1, 15.2 Hz, 1H), 5.25 (d, J = 9.5
Hz, 1H), 4.19 (d, J = 6.1 Hz, 2H), 2.54−2.65 (m, 1H), 1.77 (d, J =
1.2 Hz, 3H), 1.22−1.31 (m, 3H), 1.04−1.16 (m, 2H), 0.94 (d, J = 6.7
Hz, 3H), 0.79−0.86 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 141.3,
138.9, 132.7, 132.1, 130.6, 125.3, 63.8, 45.0, 32.4, 30.5, 30.3, 21.7,
19.2, 12.7, 11.5.
C44H62NO Si+ 728.4341, found 728.4340.
6
ASSOCIATED CONTENT
* Supporting Information
(2E,4E,6E,8R,10R)-6,8,10-Trimethyldodeca-2,4,6-trienal (33).
Analogously to 10, aldehyde 33 (150 mg, 92%) was prepared as a
yellowish oil from alcohol 32 (165 mg, 742 μmol) and MnO2 (1.29 g,
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01530.
14.84 mmol); Rf = 0.68 (16% EtOAc in hexane); [α]24 −49.4 ( c
D
0.50, CHCl3); IR νmax 2960, 2925, 2874, 2730, 1676, 1603, 1457,
1
1377, 1315, 1159, 1129, 1114, 1009, 984, 858, 647 cm−1; H NMR
NMR spectra of all compounds, HPLC chromatog-
ramms of target compounds 3 and 4, ECD spectrum of
compound 3 (PDF)
(CDCl3, 500 MHz) δ 9.55 (d, J = 7.9 Hz, 1H), 7.15 (dd, J = 11.0,
15.3 Hz, 1H), 6.68 (d, J = 15.3 Hz, 1H), 6.36 (dd, J = 11.0, 15.3 Hz,
1H), 6.16 (dd, J = 8.1, 15.1 Hz, 1H), 5.55 (d, J = 9.8 Hz, 1H), 2.60−
2.72 (m, 1H), 1.83 (d, J = 1.2 Hz, 3H), 1.21−1.35 (m, 3H), 1.09−
1.17 (m, 2H), 0.98 (d, J = 6.7 Hz, 3H), 0.80−0.88 (m, 6H); 13C
NMR (CDCl3, 125 MHz) δ 193.9, 153.5, 148.6, 147.5, 132.4, 130.5,
124.0, 44.7, 32.5, 31.0, 30.2, 21.4, 19.2, 12.6, 11.4; HRMS (ESI) m /z
AUTHOR INFORMATION
Corresponding Author
*E-mail: Rainer.Schobert@uni-bayreuth.de. Fax: +49 (0)921
552671.
■
+
[M + H]+ calcd for C15H25O 221.1900, found 221.1901.
S-tert-Butyl-4-(diethoxyphosphoryl)-3-oxopentanethioate (34).
According to a literature procedure,17 phosphonate 3431 (4.32 g,
59%) was prepared from bromopropionyl bromide (2.3 mL, 22.30
mmol) and Meldrum’s acid (2.900 g, 20.20 mmol) as a pale orange oil
and as a keto/enol mixture (5.6:1); IR νmax 2966, 1723, 1674, 1614,
1478, 1456, 1398, 1365, 1314, 1250, 1163, 1016, 959, 836, 789, 688,
ORCID
Rainer Schobert: 0000-0002-8413-4342
Notes
The authors declare no competing financial interest.
1
644, 591 cm−1; H NMR (CDCl3, 500 MHz) δ 13.01−13.06 (m,
1H), 5.42−5.47 (m, 1H), 4.06−4.16 (m, 4H), 4.03 (d, J = 15.3 Hz,
1H), 3.72 (d, J = 15.3 Hz, 1H), 3.46 (qd, J = 7.0, 26.2 Hz, 1H), 2.67
(qd, J = 7.3, 23.5 Hz, 1H), 1.41−1.50 (m, 9H), 1.35 (d, J = 7.0 Hz,
1H), 1.29−1.33 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 198.3 (d, J
= 4.5 Hz), 192.9, 171.6 (d, J = 6.4 Hz), 101.0 (d, J = 7.3 Hz), 62.9
ACKNOWLEDGMENTS
■
̈
We thank Prof. Dr. Birte Hocker and Sooruban Shanmugar-
atnam (all University of Bayreuth) for assistance with
measuring ECD spectra.
G
DOI: 10.1021/acs.joc.8b01530
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The Journal of Organic Chemistry
Article
(17) Loscher, S.; Schobert, R. Total Synthesis and Absolute
Configuration of Epicoccamide D, a Naturally Occurring Mannosy-
lated 3-Acyltetramic Acid. Chem. - Eur. J. 2013, 19, 10619−10624.
(18) Ley, S. V.; Smith, S. C.; Woodward, P. R. Further Reactions of
t-Butyl 3-Oxobutanthioate and t-Butyl 4-Diethyl-phosphono-3-
oxobutanthioate: Carbonyl Coupling Reactions, Amination, Use in
the Preparation of 3-Acyltetramic Acids and Application to the Total
Synthesis of Fuligorubin A. Tetrahedron 1992, 48, 1145−1174.
(19) Riache, N.; Bailly, C.; Deville, A.; Dubost, A.; Nay, B. Total
Synthesis of Tyrosine-Derived Tetramic Acid Pigments from a Slime
Mould. Eur. J. Org. Chem. 2010, 2010, 5402−5408.
(20) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.; Gademann,
K. A Unified Approach for the Stereoselective Total Synthesis of
Pyridone Alkaloids and their Neuritogenic Activity. Angew. Chem., Int.
Ed. 2011, 50, 4222−4226.
(21) Caporali, S.; Chiappe, C.; Ghilardi, T.; Iuliano, A.; Longhi, G.;
Margari, P.; Pomelli, C. S. Arrangements of Enantiopure and Racemic
Ionic Liquids at the Liquid/Air Interface: the Role of Chirality on
Self-assembly and Layering. RSC Adv. 2016, 6, 8053−8060.
(22) Dooley, D. J.; Taylor, C. P., Jr.; Thorpe, A. J.; Wustrow, D. J.
Preparation of Pregabalin Derivatives for the Treatment of
Fibromyalgia and Other Disorders. PCT Int. Appl. WO 2004054566
A1, July 1, 2004.
(23) Li, G.; Yang, X.; Zhai, H. Total Synthesis of (−)-5,6-
Dihydrocineromycin B. J. Org. Chem. 2009, 74, 1356−1359.
(24) Rossi, R.; Salvadori, P. A. Synthesis of Both Enantiomers of 6-
Methyl-3-octanone, a Component of the Alarm Pheromone of Ants in
the Genus Crematogaster. Synthesis 1979, 1979, 209−219.
(25) Song, S.; Zhu, S.-F.; Yu, Y.-B.; Zhou, Q.-L. Carboxy-Directed
Asymmetric Hydrogenation of 1,1-Diarylethenes and 1,1-Dialkyle-
thenes. Angew. Chem., Int. Ed. 2013, 52, 1556−1559.
(26) Mori, M.; Nakagawa, M.; Nishida, A.; Fuwa, M.; Saito, H.;
Matsunaga, T.; Takahashi, S.; Hasegawa, C. Preparation of Stereo-
isomeric 3-(4-Carboxyoxazol-5-yl)indole Compounds by Oxidative
Cyclization of N-acyl-l-tryptophan. PCT Int. Appl. WO 9912923 A1,
March 18, 1999.
REFERENCES
■
(1) Schmidt, K.; Gu
Hamburger, M. Militarinone A, a Neurotrophic Pyridone Alkaloid
from Paecilomyces militaris. Org. Lett. 2002, 4, 197−199.
(2) Schmidt, K.; Riese, U.; Li, Z.; Hamburger, M. Novel Tetramic
Acids and Pyridone Alkaloids, Militarinones B, C, and D, from the
Insect Pathogenic Fungus Paecilomyces militaris. J. Nat. Prod. 2003, 66,
378−383.
̈
nther, W.; Stoyanova, S.; Schubert, B.; Li, Z.;
(3) (a) Isaka, M.; Chinthanom, P.; Supothina, S.; Tobwor, P.;
Hywel-Jones, N. L. Pyridone and Tetramic Acid Alkaloids from the
Spider Pathogenic Fungus Torrubiella sp. BCC 2165. J. Nat. Prod.
2010, 73, 2057−2060. (b) Bruckner, S.; Bilitewski, U.; Schobert, R.
Synthesis and Antibacterial Activity of Four Stereoisomers of the
Spider-Pathogenic Fungus Metabolite Torrubiellone D. Org. Lett.
2016, 18, 1136−1139.
(4) (a) Cox, R. J.; O’Hagan, D. Synthesis of Isotopically Labelled 3-
Amino-2-phenylpropionic Acid and its Role as a Precursor in the
Biosynthesis of Tenellin and Tropic Acid. J. Chem. Soc., Perkin Trans.
1 1991, 1, 2537−2540. (b) Halo, L. M.; Heneghan, M. N.; Yakasai, A.
A.; Song, Z.; Williams, K.; Bailey, A. M.; Cox, R. J.; Lazarus, C. M.;
Simpson, T. J. Late Stage Oxidations during the Biosynthesis of the 2-
Pyridone Tenellin in the Entomopathogenic Fungus Beauveria
bassiana. J. Am. Chem. Soc. 2008, 130, 17988−17996. (c) Wasil, Z.;
Pahirulzaman, K. A. K.; Butts, C.; Simpson, T. J.; Lazarus, C. M.; Cox,
R. J. One Pathway, Many Compounds: Heterologous Expression of a
Fungal Biosynthetic Pathway Reveals its Intrinsic Potential for
Diversity. Chem. Sci. 2013, 4, 3845−3856.
(5) Zhang, J.; Meng, L.-L.; Wei, J.-J.; Fan, P.; Liu, S.-S.; Yuan, W.-Y.;
Zhao, Y.-X.; Luo, D.-Q. PTP1B Inhibitors from the Entomogenous
Fungi Isaria fumosorosea. Molecules 2017, 22, 2058−2512.
(6) van Huijsduijnen, R. H.; Sauer, W. H. B.; Bombrun, A.; Swinnen,
D. Prospects for Inhibitors of Protein Tyrosine Phosphatase 1B as
Antidiabetic Drugs. J. Med. Chem. 2004, 47, 4142−4146.
(7) Klaman, L. D.; Boss, O.; Peroni, O. D.; Kim, J. K.; Martino, J. L.;
Zabolotny, J. M.; Moghal, N.; Lubkin, M.; Kim, Y.-B.; Sharpe, A. H.;
Stricker-Krongrad, A.; Shulman, G. I.; Neel, B. G.; Kahn, B. B.
Increased Energy Expenditure, Decreased Adiposity, and Tissue-
Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-
Deficient Mice. Mol. Cell. Biol. 2000, 20, 5479−5489.
(27) Tokuyama, H.; Yamada, K.; Fujiwara, H.; Sakata, J.; Okano, K.;
Sappan, M.; Isaka, M. Structural Determination of (−)-SCH 64874
and Hirsutellomycin by Semisynthesis. J. Org. Chem. 2017, 82, 353−
371.
(8) Bruckner, S.; Haase, R. G.; Schobert, R. A Synthetic Route to β-
Hydroxytyrosine-Derived Tetramic Acids: Total Synthesis of the
Fungal Metabolite F-14329. Chem. - Eur. J. 2017, 23, 5692−5695.
(9) Haase, R. G.; Schobert, R. Synthesis of the Bioherbicidal Fungus
Metabolite Macrocidin A. Org. Lett. 2016, 18, 6352−6355.
(10) Nishida, A.; Fuwa, M.; Fujikawa, Y.; Nakahata, E.; Furuno, A.;
Nagagawa, M. First Total Synthesis of Martefragin A, a Potent
Inhibitor of Lipid Peroxidation Isolated from Sea Alga. Tetrahedron
Lett. 1998, 39, 5983−5986.
(11) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. A
Greatly Improved Procedure for Ruthenium Tetroxide Catalyzed
Oxidations of Organic Compounds. J. Org. Chem. 1981, 46, 3936−
3938.
(28) Organ, M.; Bilokin, Y.; Bratovanov, S. Approach toward the
Total Synthesis of Orevactaene. 2. Convergent and Stereoselective
Synthesis of the C18−C31 Domain of Orevactaene. Evidence for the
Relative Configuration of the Side Chain. J. Org. Chem. 2002, 67,
5176−5183.
(29) Isler, O.; Gutmann, H.; Montavon, M.; Ruegg, R.; Ryser, G.;
̈
Zeller, P. Synthesen in der Carotinoid-Reihe. 10. Mitteilung.
Anwendung der Wittig-Reaktion zur Synthese von Estern des Bixins
und Crocetins. Helv. Chim. Acta 1957, 40, 1242−1249.
̈
(30) Lang, R. W.; Hansen, H.-J. Eine einfache Allencarbonsaur-
eester-Synthese mittels der Wittig-Reaktion. Helv. Chim. Acta 1980,
63, 438−455.
(31) Burke, L. T.; Dixon, D. J.; Ley, S. V.; Rodriguez, F. Total
Synthesis of the Fusarium Toxin Equisetin. Org. Biomol. Chem. 2005,
3, 274−280.
(12) Ding, F.; Leow, M. L.; Ma, J.; William, R.; Liao, H.; Liu, X.-W.
Collective Synthesis of 4-Hydroxy-2-pyridone Alkaloids and Their
Antiproliferation Activities. Chem. - Asian J. 2014, 9, 2548−2554.
(13) Lovmo, K.; Dutz, S.; Harras, M.; Haase, R. G.; Milius, W.;
̈
Schobert, R. A Short Synthesis of 3-Enoyltetramic Acids Employing a
New Acyl Ylide Conjugate of Meldrum’s Acid. Tetrahedron Lett. 2017,
58, 4796−4798.
(14) Sengoku, T.; Nagae, Y.; Ujihara, Y.; Takahashi, M.; Yoda, H. A
Synthetic Approach to Diverse 3-Acyltetramic Acids via O- to C-Acyl
Rearrangement and Application to the Total Synthesis of Penicillenol
Series. J. Org. Chem. 2012, 77, 4391−4401.
(15) Kauhl, U.; Andernach, L.; Weck, S.; Sandjo, L. P.; Jacob, S.;
Thines, E.; Opatz, T. Total Synthesis of (−)-Hymenosetin. J. Org.
Chem. 2016, 81, 215−228.
(16) Dash, U.; Sengupta, S.; Sim, T. A Concise and Efficient Total
Synthesis of Militarinone D. Eur. J. Org. Chem. 2015, 2015, 3963−
3970.
H
DOI: 10.1021/acs.joc.8b01530
J. Org. Chem. XXXX, XXX, XXX−XXX