Synthesis of an Isomer of the Decalinoyltetramic Acid Methiosetin by a Stereocontrolled IMDA Reaction of a Metal-Chelated 3-Trienoyltetramate

Article abstract of DOI:10.1021/acs.joc.6b00750

An isomer of the 3-decalinoyltetramic acid methiosetin was synthesized for the first time. The decalin moiety was established by a late-stage intramolecular Diels-Alder cyclization catalyzed by Me₂AlCl or La(OTf)₃. Its high diastereoselectivity arose from stereoinduction by a well-defined metal O,O-chelate complex of the 3-acyltetramic acid moiety. The nature of the metal and the bulkiness of the residues at the tetramic acid chelator are decisive for the stereochemical outcome.

Full text of DOI:10.1021/acs.joc.6b00750

Article
pubs.acs.org/joc
Synthesis of an Isomer of the Decalinoyltetramic Acid Methiosetin by
a Stereocontrolled IMDA Reaction of a Metal-Chelated
3‑Trienoyltetramate
Markus Winterer,† Karl Kempf,† and Rainer Schobert*
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany
S
* Supporting Information
ABSTRACT: An isomer of the 3-decalinoyltetramic acid
methiosetin was synthesized for the first time. The decalin moiety
was established by a late-stage intramolecular Diels−Alder
cyclization catalyzed by Me2AlCl or La(OTf)3. Its high
diastereoselectivity arose from stereoinduction by a well-defined
metal O,O-chelate complex of the 3-acyltetramic acid moiety. The
nature of the metal and the bulkiness of the residues at the
tetramic acid chelator are decisive for the stereochemical outcome.
decalin like the one proposed for methiosetin (e.g., TA-289 4)
recently isolated by Atkinson et al. from an unidentified
Fusarium sp. fungus5 or the inverted configuration like JBIR-22
5.
INTRODUCTION
■
(+)-Methiosetin 1 is a 3-decalinoyltetramic acid1−3 with
antibacterial activity against Staphylococcus aureus and Haemo-
philus influenzae that was isolated in 2011 by Singh et al.4 from
a sooty mold Capnodium sp. This group also assigned the
relative configuration of the decalin moiety on grounds of
NMR studies and proposed the structure shown in Figure 1,
The majority of synthetic 3-decalinoyltetramic acids were
prepared by assembling the trans-decalin by an intramolecular
Diels−Alder (IMDA) reaction using auxiliaries or chiral
catalysts for stereocontrol. The tetramate ring was established
either prior to or following this IMDA cyclization. For instance,
Gao et al.6 prepared cryptocin 3 and derivatives of equisetin 6
and fusarisetin A by generating the tetramic acid according to
Ley et al.7,8 via aminolysis of a β-keto thioester, linked to the
full-fledged decalin, with the respective amino ester, followed
by a basic Dieckmann condensation of the resulting N-β-
ketoamino ester. Similarly, Opatz et al. synthesized hymeno-
setin 2 by first establishing an enantiopure decalin aldehyde by
IMDA reaction of a trienal derived from (+)-citronellal,
followed by attachement of an N-β-ketoacylthreoninate and
its Lacey-Dieckmann condensation.9 In contrast, Westwood
and Healy prepared highly enantioenriched diastereomers of
JBIR-22 5 by first attaching a trienoyl residue to a tetramic acid
via a Horner−Wadsworth−Emmons olefination and then
initiating the IMDA of this residue with an external magnesium
bisoxazoline complex as a catalyst.10 A third conceivable
approach to 3-decalinoyltetramic acids is the attachment of a
decalinoic acid to the respective preformed tetramic acid by
means of condensation agents such as DCC/DMAP (Yoshi11−
Yoda12 acylation) or BF3 etherate (Jones acylation).13
However, neutral condensation agents usually lead to the
formation of 4-O-decalinoyltetramic acids, which are difficult to
rearrange to the 3-decalinoyltetramates, and BF3 etherate may
lead to racemization at C-2 or C-5′.
Figure 1. Natural 3-decalinoyltetramic acids.
which leaves the absolute configurations at C-5′ and C-6′ of the
tetramic acid core unassigned. So far, there are examples known
of decalinoyltetramic acids derived from either L-threonine,
such as hymenositin 2, or L-allo-threonine, such as cryptocin 3
(Figure 1). Decalinoyltetramic acids lacking a methyl group at
C-2 are scarce. They may feature absolute configurations of the
Received: April 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00750
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Herein, we describe a conceptionally new approach to 3-
decalinoyltetramic acids which utilizes the attachment of an
unsaturated aldehyde to a tetramic acid bearing a 3-acyl ylide14
via a Wittig reaction, followed by an IMDA cyclization of the
unsaturated side chain, which is stereocontrolled not by an
external catalyst, as in the strategy of Westwood and Healy, but
by a metal chelate complex of the 3-acyltetramic acid itself.
IMDA precursor 15 in the presence of BF3 etherate led to
decomposition products. However, the use of 2 equiv of
Me2AlCl as a catalyst gave, after demetalation and deprotection,
one predominant methiosetin stereoisomer 1 in 29% yield with
separable trace amounts of a second one. With La(OTf)3 as the
catalysts, the same product was obtained even in 59% yield. A
conceivable explanation for this stereoinduction is offered by
the fact that 3-acyltetramic acids form chelate complexes with a
broad range of metals19 by engaging the exocyclic enol OH
group at C-1 and either the 4′-keto or the amide 2′-carbonyl
group of the heterocycle, depending on the metal. Both types of
chelate complexes are distinguishable by analyzing the 1700−
1500 cm−1 carbonyl region of their IR spectra.20,21 The IR
spectra of the complexes 16, recorded immediately after the
IMDA reaction, showed bands at 1694 and 1599 cm−1, typical
of metal coordination by the amide carbonyl (cf. the
Supporting Information, Figure S1). It is reasonable that the
IMDA precursor 15 showed the same sort of metal
coordination. The predominance of one product stereoisomer
may then be rationalized by the conformationally rigidifying
effect of the bulky TIPS group near the two stereocenters C-5′
and C-6′. Indirect proof for this rationale is provided by the fact
that TA-289 4, bearing a less bulky methyl residue at C-5′, was
not accessible diastereoselectively by this method, which
afforded only an inseparable 1:1.85 mixture of two major
endo-diastereoisomers. For the removal of the metal in the
presumed product complex 16a, the crude product was treated
first with BF3 etherate to substitute the metal for BF2 and then
with hot methanol to liberate the 3-acyltetramic acid 1.
Gratifyingly, the treatment with BF3 etherate led to a swift
cleavage of the TIPS protecting group but not to an undesired
subsequent elimination of water. The crude lanthanum complex
16b was deprotected and demetalated with HF in pyridine and
Et3SiH to give the same methiosetin isomer 1 in 59% yield.
For the stereochemical assignment of the decalin moiety of
our synthetic methiosetin isomer 1, we cleaved it oxidatively at
the formal double bond between C-1 and C-3′ under
conditions described by Opatz et al.9 for hymenosetin (Scheme
2, top row). The resulting decalinoic acid 17 showed a specific
RESULTS AND DISCUSSION
■
Synthesis of a Proposed Stereoisomer of Methiosetin.
We intended to attach a 3-trienoyl residue to an enantiopure
tetramic acid and then establish the decalin system via an
IMDA reaction stereocontrolled by the tetramate moiety. To
this end, TIPS-protected L-threonine-derived tetramic acid 12
was prepared as previously reported15,16 and acylated with the
cumulated phosphorus ylide Ph3PCCO 1314,17 to give the
stabilized ylide 14 in quantitative yield (Scheme 1). This was
Scheme 1. Synthesis of Methiosetin Isomer 1 via a Late-
a
Stage IMDA Reaction
24
optical rotation of [α]D −157.2 (c 0.50, CH2Cl2). For the
identification of its absolute configuration, we prepared it
independently according to a protocol by Paintner18 (Scheme
2).
Aldehyde 11 was olefinated with enantiopure amide ylide 18,
readily accessible by reaction of 4-benzyloxazolidin-2-one with
cumulated ylide 13 according to Boeckman et al.,22 to give an
IMDA precursor 19 in 57% yield. The latter was cyclized in the
presence of 2 equiv of Me2AlCl at −30 °C to give the decalin
derivative 20 with high endo-diastereoselectivity (endo/exo ≥
50:1) and in 99% yield. The absolute configuration of
compound 20 had been elucidated by Paintner et al.18 via
single-crystal X-ray diffraction analysis of its dibromo adduct
(CCDC199999). For the cleavage of the Evans auxiliary, the
IMDA product 20 was first converted quantitatively to the
thioester 21 with a mixture of propanethiol and n-BuLi
according to a general protocol by Damon et al.23 Since
Paintner had reported a partial epimerization upon basic
hydrolysis of this thioester, we now developed an epimeriza-
tion-free hydrolysis by means of silver nitrate in aqueous
dioxane, in analogy to a protocol by Gerlach et al.,24 which left
the acid 17 as a pure enantiomer in 93% yield. It showed a
specific optical rotation of [α]D20 −159.2 (c 0.97, CH2Cl2) and
was identical to the product obtained from oxidative cleavage of
a
Reagents and conditions: (i) Mg, THF, −40 °C, 1.5 h; (ii) 0.25 equiv
of CuBr(Me2S), −40 °C (3 h) → rt, 12 h, 78%; (iii) AcOH/THF/
H2O, 90 °C, 1.5 h, 97%; (iv) THF, reflux, 5 h, 99%; (v) CH2Cl2,
KOtBu, then 11, rt, 12 h, 81%; (vi) for 16a: 2 equiv of Me2AlCl,
CH2Cl2, rt, 3 days; for 16b: 1 equiv of La(OTf)3, CH2Cl2, rt, 2 days;
(vii) for 16a: BF3 × Et2O, CH2Cl2, rt, 12 h; for 16b: HF/pyridine,
THF, rt, 24 h; (viii) for 16a: MeOH, reflux, 2 h (29% over 3 steps); for
16b: Et3SiH, 30 min (59% over 3 steps).
deprotonated with KOtBu to afford an anionic ylide species
that underwent an E-selective olefination when treated with
decadienal 11 to give the immediate IMDA precursor 15 in
81% yield. The aldehyde 11 was synthesized in analogy to a
method by Paintner et al.18 starting with a copper-mediated
coupling reaction between the Grignard derivative 8 of
commercially available 2-(3-bromopropyl)-1,3-dioxolane 7
and (E2,E4)-hexadienyl acetate 9. By replacing Paintner’s
Li2CuCl4 with CuBr(Me2S), we increased the yield of product
dioxolane 10 by 10% to 78%. Its deprotection gave deca-6,8-
dienal 11 in near quantitative yield. An attempt to cyclize the
B
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of methiosetin isomers featuring the “enantiomeric” decalin
moiety. So far, no optimum catalyst of this type could be
identified. For instance, Cu(OAc)2 and MgCl2/MgBr2 mixtures
led to crude products whose IR spectra suggested a
predominant ketone coordination (cf. Supporting Information,
Figure S1). However, the reaction catalyzed by the former was
very slow, and the reaction with the latter resulted only in a 6:4
mixture of two diastereoisomers of methiosetin (cf. Supporting
Information). In addition, the counteranion of the metal
catalyst also played a role by influencing the IMDA reaction
rates and the stability of the TIPS protecting group. Table S3
shows the effect of various catalysts on the progress and
stereochemical outcome of the IMDA reaction.
Scheme 2. Oxidative Cleavage of Methiosetin Isomer 1 and
Synthesis of Decalinoic Acid 17
a
CONCLUSIONS
■
We synthesized the methiosetin stereoisomer 1 by controlling
the stereoselectivity of the IMDA reaction of the (E2,E8,E10)-
dodecatrienoyl residue of 15 via an aluminum or lanthanum (1-
O,2′-O)-chelate complex of its 3-acyltetramic acid core. This
stereoinduction relied on the presence of a bulky residue at C-
5′, apparent from the failure of a similar stereoinduction in the
case of the alanine-derived tetramic acid TA-289 4. We could
also assign the absolute configuration of methiosetin isomer 1.
Although it comprises a decalin residue which is configured as
was proposed for the natural isolate, it is not identical to it. The
most plausible explanation is a wrong stereochemical assign-
ment of the structure of the natural isolate. We provided
evidence for other metal catalysts, such as copper acetate or
magnesium halides, being able to induce the formation of a
decalin residue that is the enantiomer of that in isomer 1 and
thus probably the “natural” one. However, a large-scale
screening will be necessary to pinpoint suitable metal catalysts
that form exclusively tetramic acid chelate complexes employ-
ing the 4′-keto function and that give rise to a rapid IMDA
reaction.
a
Reagents and conditions: (i) toluene, 80 °C, 16 h, 57%; (ii) 2 equiv
of Me2AlCl, CH2Cl2, −30 °C, 12 h, 99%; (iii) propanethiol, n-BuLi,
THF, 0 °C, 10 min, 99%; (iv) AgNO3, dioxane/H2O (4:1), reflux, 2 h,
93%.
synthetic methiosetin isomer 1 also with respect to NMR and
MS analytics. As to the configuration of the tetramic acid
moiety of our synthetic methiosetin isomer 1, we assume it to
be (5′S,6′R) because we can exclude an allo-threonine
1
configuration from the H NMR coupling constants, which
are identical to those of the “L-threonine residue” of
hymenosetin,9 and because C-6′ is not prone to racemization
or inversion under the conditions of the IMDA reaction. Taken
together, our synthetic methiosetin isomer 1 features the
structure shown in Schemes 1 and 2.
However, the stereochemistry of the natural isolate remained
unclear. While the synthetic methiosetin isomer 1 showed a
EXPERIMENTAL SECTION
■
General Remarks. IR spectra were recorded with an FT-IR
spectrophotometer equipped with an ATR unit. Chemical shifts of
NMR signals are given in parts per million (δ) downfield from
tetramethylsilane for 1H and 13C. Mass spectra were obtained under EI
(70 eV) conditions. High-resolution mass spectra were obtained with a
UPLC/Orbitrap MS system in ESI mode. For chromatography silica
gel 60 (230−400 mesh) was used. HPLC was performed on Prontosil
RP 200-5-C18, 5 μm, 250 × 4 mm (analytic) and 250 × 20 mm
(preparative) columns.
24
specific optical rotation of [α]D −63 (c 1.0, MeOH), the
isolated natural product had [α]D23 +12.4 (c 1.0, MeOH). The
1H NMR shifts and coupling constants of both were in perfect
agreement when measured in methanol-d4 yet differed
somewhat when recorded in CDCl3. The 13C NMR shifts
were also a close match and differed by more than 0.2 ppm only
for carbon atoms 11, 4′, and 5′ (cf. the Supporting Information,
Tables S1 and S2). In conclusion, the natural isolate probably
featured a decalin moiety which is the enantiomer of our
synthetic methiosetin isomer 1. We can exclude that it had a
tetramic acid core derived from D-threonine since Opatz et al.9
demonstrated that the optical rotation changes dramatically by
more than 200° when going from L-threonine-derived to D-
threonine-derived hymenosetin. It is worth noting that
Westwood and Healy10 could also prove through their
synthetic studies that the decalin configuration of JBIR-22
had previously been assigned wrongly by Izumikawa et al.25
Stereoinduction by Other Metal 3-Acyltetramates. 3-
Acyltetramic acids may also coordinate to metals, such as
magnesium, via their exocyclic enol OH group and their 4′-keto
oxygen.20 Hence, we conducted IMDA reactions of 15 in the
presence of compounds of such metals, expecting the formation
2-(5E,7E)-Nona-5,7-diene-1-yl)-1,3-dioxolane 10. A suspen-
sion of magnesium (3.1 g, 142.5 mmol) in THF (17 mL) was treated
dropwise with a sixth of a solution of 2-(3-bromopropyl)-1,3-dioxolane
7 (13.9 g, 71.4 mmol) in THF (17 mL). Dibromoethane (0.25 mL,
0.25 mmol) was added to activate the metal, then the remaining
solution of 2-(3-bromopropyl)-1,3-dioxolane was added dropwise over
a period of 15 min. The resulting solution was stirred at 30 °C for 1.5
h and then added dropwise to a solution of sorbinic acetate 9 (8.84 g,
59.2 mmol) and CuBr−DMS complex (1.28 g, 18,0 mmol) in THF
(85 mL) and cooled to −40 °C. The resulting deep purple solution
was stirred at −40 °C for 3 h, allowed to warm to room temperature
overnight, and then quenched with saturated aqueous NH4Cl (170
mL). The mixture was extracted three times with diethyl ether, and the
combined organic layers were washed with brine, dried, and
concentrated. The residue was dissolved in a 3:1 mixture of MeOH/
THF (500 mL), NaOH (30 g) was added, and the mixture was stirred
for 1.5 h to hydrolyze residual sorbic acetate. Half-concentrated
aqueous NaHCO3 (400 mL) was added, the organic layer was
separated, and the aqueous one was extracted four times with diethyl
C
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ether. The combined organic layers were washed with brine, dried, and
concentrated. The remainder was purified by column chromatography
(cyclohexane/ethyl acetate 9:1, Rf 0.34) to leave 10 (9.0 g, 78%) as a
colorless oil: IR (ATR) νmax 3015, 2927, 2859, 1436, 1409, 1211, 1130,
149.4, 172.5, 174.4, 193.3; HRMS (ESI) m/z [M + H]+ calcd for
C28H48NO4Si+ 490.3347, found 490.3348; [M + H]+ calcd for
C28H48NaNO4Si+ 512.3166, found 512.3168; [M − H]− calcd for
C28H46NO4Si− 488.3202, found 488.3212.
1
1059, 1033, 986, 942, 863, 737, 709 cm−1; H NMR (CDCl3, 300
(R)-4-Benzyl-3-((2E,8E,10E)-dodeca-2,8,10-trienoyl)-
oxazolidin-2-one 19. A solution of (6E,8E)-deca-6,8-dienal 11 (0.97
g, 6.38 mmol) and ylide 1823 (4.47 g, 9.33 mmol) in toluene (100 mL)
was heated at 80 °C for 24 h. The remainder upon concentration was
purified by column chromatography (cyclohexane/ethyl acetate 3:1, Rf
MHz) δ 1.29−1.42 (m, 4 H), 1.52−1.62 (m, 2 H), 1.65 (d, J = 6.4 Hz,
3 H), 1.99 (dt, J = 6.1, 6.4 Hz, 2 H), 3.71−3.81 (m, 2 H), 3.82−3.91
(m, 2 H), 4.76 (t, J = 4.9 Hz, 1 H), 5.38−5.58 (m, 2 H), 5.86−6.10
(m, 2 H); 13C NMR (CDCl3, 75 MHz) δ 17.7, 23.5, 29.2, 32.3, 33.6,
64.6, 104.4, 126.5, 130.3, 131.4, 131.6; HRMS (ESI) m/z [M + H]+
20
0.47) to give 19 (1.3 g, 58%) as a colorless oil: [α]D −31.1 (c 1.0,
+
CH2Cl2); IR (ATR) νmax 3016, 2926, 2855, 1774, 1682, 1634, 1498,
calcd for C12H21O2 197.15361, found 197.15366.
1455, 1386, 1352, 1290, 1209, 1196, 1110, 1099, 1077, 1054, 987, 923,
(6E,8E)-Deca-6,8-dienal 11. A mixture of 10 (1.29 g, 6.55 mmol),
THF (19 mL), water (23 mL), and acetic acid (12 mL) was heated at
90 °C for 1.5 h. Due to identical Rf values of 10 and 11, the progress of
the reaction was controlled by gas chromatography. After completion,
the solution was cooled to room temperature, treated with saturated
NaHCO3 (50 mL), and extracted three times with hexanes. The
combined organic layers were washed with brine, dried over NaSO4,
and concentrated. The remainder was purified by column chromatog-
raphy (cyclohexane/ethyl acetate 9:1, Rf 0.34) to leave 11 (0.97 g,
97%) as a colorless oil: IR (ATR) νmax 3017, 2932, 2720, 1725, 1449,
1
851, 806, 761, 750, 731, 700 cm−1; H NMR (CDCl3, 300 MHz) δ
1.35−1.56 (m, 4 H), 1.71 (d, J = 6.2 Hz, 3 H), 2.10 (dt, J = 7.2, 14.2
Hz, 2 H), 2.28 (dt, J = 6.8, 13.0 Hz, 2 H), 2.77 (dd, J = 13.2, 9.6 Hz, 1
H), 3.32 (dd, J = 13.2, 3.2 Hz, 1 H), 4.11−4.22 (m, 2 H), 4.72 (ddd, J
= 3.4, 7.0, 13.1 Hz, 1H), 5.45−5.63 (m, 2 H), 5.92−6.06 (m, 2 H),
7.11−7.37 (m, 7 H); 13C NMR (CDCl3, 75 MHz) δ 17.9, 27.6, 28.9,
32.2, 32.5, 37.9, 55.3, 66.0, 120.0, 127.0, 127.3, 128.9, 129.4, 130.6,
131.4, 131.5, 135.4, 151.7, 153.4, 165.1; HRMS (ESI) m/z [M + H]+
calcd for C22H28O3N+ 354.20615, found 354.20605.
1
988 cm−1; H NMR (CDCl3, 300 MHz) δ 1.36−1.48 (m, 2 H), 1.64
(4R)-Benzyl-3-((1R,2R,4aS,8aR)-1,2,4a,5,6,7,8,8a-octahydro-
2-methylnaphthalene-1-carbonyl)oxazolidin-2-one 20. A sol-
ution of triene 19 (475 mg, 1.34 mmol) in CH2Cl2 (38 mL) was
cooled to −30 °C and treated dropwise with a 0.9 M solution of
Me2AlCl in hexane (3 mL, 2.69 mmol) over 10 min. The mixture was
stirred for another 4.5 h at −30 °C, treated with 1 M hydrochloric acid
(20 mL), and extracted four times with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated. The remainder was purified by column chromatography
(cyclohexane/ethyl acetate 4:1, Rf 0.63) to give 20 (474 mg, 99%) as a
colorless oil: [α]D20 −123 (c 0.98, CH2Cl2) (lit.18 [α]D20 −185 (c 0.96,
CH2Cl2)); IR (ATR) νmax 2926, 1776, 1694, 1449, 1384, 1372, 1349,
1322, 1292, 1261, 1234, 1215, 1194, 1148, 1101, 1087, 1049, 1020,
998, 909, 817, 792, 767, 729, 700 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 0.79−0.90 (m, 1 H), 0.95 (d, J = 7.2 Hz, 3 H), 1.00−1.22 (m, 1 H),
1.24−1.47 (m, 2 H), 1.52−1.67 (m, 1 H), 1.71−1.82 (m, 4 H), 1.86−
1.96 (m, 1 H), 2.63 (dd, J = 10.6, 13.1 Hz, 1 H), 2.73−2.88 (m, 1 H),
3.42 (dd, J = 3.3, 13.1 Hz, 1 H), 3.82 (dd, J = 5.9, 11.3 Hz, 1 H), 4.10−
4.19 (m, 2 H), 4.72 (ddd, J = 3.4, 7.0, 13.9 Hz, 1 H), 5.41 (br d, J = 9.9
Hz, 1 H), 5.58 (ddd, J = 2.6, 4.6, 9.9 Hz, 1 H), 7.21−7.37 (m, 5 H);
13C NMR (CDCl3, 75 MHz) δ 17.7, 26.5, 26.6, 30.0, 30.8, 33.1, 36.5,
(quint, J = 7.4 Hz, 2 H), 1.72 (d, J = 6.3 Hz, 3 H), 2.07 (dt, J = 7.4,
14.0 Hz, 2 H), 2.42 (dt, J = 1.8, 7.4 Hz, 2 H), 5.44−5.64 (m, 2 H),
5.92−6.07 (m, 2 H), 9.78 (t, J = 1.8 Hz, 1 H); 13C NMR (CDCl3, 75
MHz) δ 18.0, 21.6, 28.9, 32.2, 43.7, 127.2, 130.9, 131.0, 131.5, 202.7;
HRMS (ESI) m/z [M + H]+ calcd for C10H17O+ 153.12739, found
153.12739.
3-[(Triphenylphosphoranylidene)acetyl]-(5S)-((1′R)-1′-
triisopropylsilyloxyethyl)-1-methylpyrrolidine-2,4-dione 14. A
solution of tetramic acid 1215,16 (570 mg, 1.8 mmol) in THF (24 mL)
was treated with Ph3PCCO 13 (604 mg, 2.0 mmol) and refluxed for
12 h. Evaporation under reduced pressure afforded ylide 14
quantitatively as a brownish foam of mp 81 °C: IR (ATR) νmax
2941, 2864, 1656, 1612, 1550, 1463, 1437, 1190, 1103, 1067, 1015,
1
997, 882, 851, 783, 746, 719, 690, 570, 540 cm−1; H NMR (CDCl3,
300 MHz) δ 0.98−1.11 (m, 42 H), 1.39 (d, J = 6.6 Hz, 3 H), 1.44 (d, J
= 6.6 Hz, 3 H), 3.019 (s, 3 H), 3.023 (s, 3 H), 3.36 (d, J = 3.0 Hz, 1
H), 3.43 (d, J = 3.0 Hz, 1 H), 4.44 (qd, J = 6.6, 3.0 Hz, 1 H), 4.45 (qd,
J = 6.6, 3.0 Hz, 1 H), 5.23 (d, JP−H = 20.3 Hz, 1 H, fast H/D exchange
in CDCl3; signal disappears overnight), 7.45−7.53 (m, 12 H), 7.57−
7.68 (m, 18 H); 31P NMR (CDCl3, 161.7 MHz) (ylides/betaines
∼3:1) δ 14.8/14.9 (P=CHCOH), 21.4/21.9 (P+CH2CO−); 13C NMR
(CDCl3, 75.5 MHz) δ 12.2, 17.75/17.78, 21.8/22.3, 28.58/28.64, 51.2
(d, J = 109.9 Hz)/51.4 (d, J = 111.7 Hz), 67.7/68.3, 69.3/71.3, 91.1/
94.9 (d, J = 12.7 Hz), 119.0 (d, J = 88.1 Hz), 124.5/124.7 (d, J = 91.7
Hz), 128.1, 128.2, 128.3, 128.73, 128.76, 128.83, 128.9, 129.3, 129.4,
129.9, 130.0, 131.61, 131.63, 131.7, 132.47, 132.50, 132.55, 132.57,
132.70, 132.79, 132.84, 133.5, 133.6, 134.61, 134.63, 172.5/173.4,
172.3/177.1, 189.7/192.8; HRMS (ESI) m/z [M + H]+ calcd for
C36H47NO4PSi+ 616.3007, found 616.2998.
(5S)-((1R)-Triisopropylsilyloxyethyl)-1-methyl-3-((2E,8E,10E)-
dodecatrienoyl)-pyrrolidine-2,4-dione 15. A solution of ylide 14
(920 mg, 1.5 mmol) in CH2Cl2 (20 mL) was treated with KOtBu (180
mg, 1.6 mmol). After complete dissolution of the base, decadienal 11
(210 mg, 1.38 mmol) was added, and the mixture was stirred
overnight at room temperature and finally washed with 1 M aqueous
NaHSO4, dried over Na2SO4, and evaporated under reduced pressure.
The crude product was purified by reversed-phase column
chromatography (C-18, rinsing with 85% MeOH, 0.1% HCOOH in
the water fraction, elution of the product with pure MeOH) to afford
15 as a yellow oil (550 mg, 1.1 mmol, 81%): IR (ATR) νmax 2938,
2866, 1709, 1645, 1583, 1461, 1375, 1327, 1215, 1139, 1097, 1068,
986, 910, 882, 828, 782, 731, 677 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 0.75−1.10 (m, 21 H), 1.33−1.50 (m, 4H), 1.40 (d, J = 6.6 Hz, 3 H),
1.69 (d, J = 6.3 Hz, 3 H), 1.98−2.10 (m, 2 H), 2.21−2.35 (m, 2 H),
3.09 (s, 3 H), 3.47 (d, J = 1.4 Hz, 1 H), 4.52 (qd, J = 6.6, 1.4 Hz, 1 H),
5.32−5.63 (m, 2 H), 5.84−6.06 (m, 2 H), 6.98−7.17 (m, 2 H); 13C
NMR (CDCl3, 75.5 MHz) δ 12.5, 17.9, 18.0, 22.6, 27.7, 28.9, 29.1,
32.2, 32.9, 68.2, 72.3, 100.2, 113.7, 121.6, 126.8/130.6/131.2/131.5,
38.2, 41.8, 47.6, 55.3, 66.0, 127.2, 128.9, 129.3, 130.6, 130.8, 135.5,
153.0, 173.5; HRMS (ESI) m/z: [M + H]+ Calcd for C22H28O3N+
354.20637, found 354.20554.
(1R,2R,4aS,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2-methylnaph-
thalene-1-carboxylic acid thiopropyl ester 21. A solution of
oxazolidin-2-one 20 (50 mg, 0.14 mmol) and propanethiol (0.1 mL,
1.1 mmol) in THF (0.9 mL) was cooled to 0 °C and treated dropwise
with a 2.25 M solution of n-butyllithium in hexane (0.1 mL). The
mixture was stirred at 0 °C for 10 min, quenched with water (7.5 mL)
and extracted four times with t-butyl methyl ether. The combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated. The remainder was purified by column chromatography
(cyclohexane/ethyl acetate 3:1, Rf 0.7) to leave 21 (35 mg, 99%) as a
waxy solid; [α]20D − 41.9 (c 1.0, CH2Cl2). IR (ATR) νmax 2962, 2921,
2873, 2852, 1694, 1684, 1447, 1375, 1291, 1241, 1088, 1084, 1018,
1
998, 953, 913, 893, 862, 847, 824, 804, 788, 739, 721, 554 cm−1; H
NMR (CDCl3, 300 MHz) δ 0.78−0.93 (m, 1 H), 0.85 (d, J = 7.2 Hz, 3
H), 0.93 (t, J = 7.3 Hz, 3 H), 0.99−1.11 (m, 1 H), 1.20−1.34 (m, 2
H), 1.43−1.56 (m, 1 H), 1.55 (sex, J = 7.3, 2 H), 1.61−1.75 (m, 4 H),
1.77−1.87 (m, 1 H), 2.45−2.61 (m, 1 H), 2.70−2.91 (m, 1 H), 2.78
(q, J = 7.3, 2 H), 5.33 (br d, J = 9.9 Hz, 1 H), 5.49 (ddd, J = 2.6, 4.6,
9.9 Hz, 1 H); 13C NMR (CDCl3, 75 MHz) δ 13.3, 17.3, 23.2, 26.4,
26.6, 29.5, 30.5, 33.0, 33.5, 37.0, 42.4, 58.5, 130.8, 130.85, 200.3;
HRMS (ESI) m/z [M + H]+ calcd for C15H25OS+ 253.16206, found
253.16194.
(1R,2R,4aS,8aR)-1,2,4a,5,6,7,8,8a-Octahydro-2-methylnaph-
thalene-1-carboxylic Acid 17. A solution of thioester 21 (351 mg,
1.39 mmol) in 4:1 dioxane/water (30 mL) was treated with AgNO3
D
DOI: 10.1021/acs.joc.6b00750
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1500 mg, 8.83 mmol) and refluxed until no further starting material
could be detected by TLC. The suspension was extracted four times
with CH2Cl2, and the combined extracts were purified by suction over
a plug of Celite. Condensation of the filtrate and column
chromatography (cyclohexane/ethyl acetate 3:1, Rf 0.5) afforded 17
(251 mg, 93%) as a crystalline solid of mp 123.2 °C (from n-hexane):
130.9, 174.1, 191.1, 194.8; 1H NMR (MeOD, 500 MHz) δ 0.88 (dq, J
= 12.2, 2.5 Hz, 1 H), 0.92 (d, J = 7.0 Hz, 1 H), 1.05−1.14 (m, 1 H),
1.31 (d, J = 6.7 Hz, 3 H), 1.56 (qd, J = 11.3, 2.5 Hz, 1 H), 1.74−1.78
(m, 2 H), 1.85 (d, J = 11.6 Hz, 1 H), 2.53 (td, J = 6.1, 5.2 Hz, 1 H),
3.06 (s, 2 H), 3.71 (br s, 1 H), 3.77 (dd, J = 11.5, 5.5 Hz, 1 H), 4.16
(qd, J = 6.7, 3.4 Hz, 1 H), 5.41 (d, J = 9.8 Hz, 1 H), 5.56 (ddd, J =
10.1, 4.6, 2.5 Hz, 1 H); HRMS (ESI) m/z [M − H]− calcd for
20
[α]D −159.2 (c 0.97, CH2Cl2); IR (ATR) νmax 2929, 2852, 1703,
−
C19H26NO4 332.1856, found 332.1871.
1447, 1420, 1292, 1262, 1223, 1194, 948, 743, 717, 671, 582, 567
1
cm−1; H NMR (CDCl3, 300 MHz) δ 0.83−0.98 (m, 1 H), 0.98 (d, J
= 7.2 Hz, 3 H), 1.02−1.10 (m, 1 H), 1.19−1.46 (m, 4 H), 1.61−1.82
(m, 4 H), 1.95−2.06 (m, 1 H), 2.51−2.64 (m, 2 H), 5.37 (br d, J = 9.9
Hz, 1 H), 5.53 (ddd, J = 2.6, 3.9, 9.9 Hz, 1 H) 10.97 (br s, 1 H); 13C
NMR (CDCl3, 75 MHz) δ 17.6, 26.5, 26.6, 30.0, 32.1, 33.0, 36.2, 42.0,
49.5, 130.5, 131.0, 180.6; HRMS (ESI) m/z [M + H]+ calcd for
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00750.
■
S
−
C12H17O2 193.12231, found 193.12279.
NMR spectra of 1, 10, 11, 14, 15, 17, and 19−21; IR
spectra of Al and Cu chelate complexes of IMDA
precursor 15; chemical shifts of carbon and hydrogen
atoms of isolated natural methiosetin and synthetic 1;
influence of various metal catalysts on the IMDA
reaction of 15; HPLC chromatograms of IMDA products
of 15 catalyzed by various Lewis acids (PDF)
Carboxylic Acid 17 from Cleavage of Methiosetin Isomer 1.
A solution of methiosetin isomer 1 (30 mg, 0.09 mmol) in MeOH (1
mL) was treated with H2O2 (30% in H2O, 2 mL), 1 M NaOH solution
in H2O (1 mL), and H2O (5 mL) and stirred at room temperature.
After 4 and 8 h, the solution was treated once more with H2O2 (30%
in H2O, 1 mL) and 1 M NaOH solution in H2O (0.5 mL). After 24 h,
1 M hydrochloric acid was added to adjust a pH value of 1−2. The
resulting solution was extracted with CH2Cl2, and the combined
organic layers were dried over Na2SO4, filtered, and concentrated. The
remainder was purified by column chromatography (silica gel;
cyclohexane/ethyl acetate 3:1, Rf 0.5) to afford 17 (6 mg, 35%) as
colorless crystals: [α]D20 −157.2 (c 0.50, CH2Cl2). All other data were
identical to those of compound 17 obtained from thioester 21.
(5S)-((1′R)-Hydroxyethyl)-1-methyl-3-((1R,2R,4aS,8aR)-
1,2,4a,5,6,7,8,8a-octahydro-2-methylnaphthalene-1-
carbonyl)pyrrolidone-2,4-dione (Methiosetin) 1. Protocol A: A
solution of 3-dodecatrienoyltetramic acid 15 (200 mg, 0.4 mmol) in
CH2Cl2 (10 mL) was treated dropwise with a 1 M solution of Me2AlCl
in hexane (2 equiv, 0.8 mL) and then stirred for 3 days. The mixture
was washed with 1 M aqueous NaHSO4, dried over Na2SO4, and
evaporated under reduced pressure. The crude product was dissolved
in CH2Cl2 (10 mL) at room temperature and treated with BF3 × OEt2
(0.8 mmol, 211 μL, 48% in ether) under exclusion of air and moisture.
After being stirred overnight, the solution was washed with 1 M
aqeuous NaHSO4, dried over Na2SO4, and concentrated under
reduced pressure. The crude BF2 complex was hydrolyzed by boiling
in methanol for 2 h. The solvent was evaporated, and the residue was
taken up in ethyl acetate and washed with water. The organic layer was
dried over Na2SO4 and evaporated. The free 3-acyltetramic acid was
purified by preparative HPLC (Kinetex C-18, 5 μm, rinsing with 65%
MeOH, 0.1% HCO2H in the water fraction, elution of the product
with 77% MeOH) to afford 1 as a yellow oil (38 mg, 0.11 mmol, 29%).
Protocol B: A solution of tetramic acid 15 (274 mg, 0.56 mmol) in
CH2Cl2 (20 mL) was treated with La(OTf)3 (328.2 mg, 0.56 mmol)
and stirred at room temperature for 2 days. The mixture was washed
with 1 M aqueous NaHSO4, dried over Na2SO4, and concentrated
under reduced pressure. The remainder was dissolved in THF (1 mL)
in a plastic vial and was treated with HF (70% in pyridine, 100 μL, 3.6
mmol). After being stirred for 24 h, Et3SiH (573 μL, 3.6 mmol) was
added and the resulting mixture was stirred for another 30 min. The
solution was poured into methanol/water (65/35, 20 mL), and 3-
acyltetramic acid 1 was extracted and purified by preparative HPLC
(Kinetex C-18, 5 μm, rinsing with 65% MeOH, 0.1% HCO2H in the
water fraction, elution of the product with 77% MeOH) to afford pure
AUTHOR INFORMATION
Corresponding Author
*E-mail: rainer.schobert@uni-bayreuth.de.
■
Author Contributions
†M.W. and K.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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1644, 1606, 1485, 1449, 1394, 1374, 1333, 1281, 1257, 1212, 1124,
1088, 989, 946, 732 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.90 (qd, J
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J. Org. Chem. XXXX, XXX, XXX−XXX