Toward the macrocidins: Macrocyclization via williamson etherification of a phenolate

Article abstract of DOI:10.1021/jo101416x

The synthesis of macrocyclic 3-acyltetramic acids which are immediate precursors of the fungal herbicide macrocidin A (1) is reported. The crucial closure of the macrocycle was achieved in excellent yield by an unprecedented Williamson etherification of an ω-bromo phenolate generated in situ by a Pd-mediated O-deallylation.

Full text of DOI:10.1021/jo101416x

pubs.acs.org/joc
Toward the Macrocidins: Macrocyclization via
Williamson Etherification of a Phenolate
Bertram Barnickel and Rainer Schobert*
€
Organisch-chemisches Laboratorium der Universitat
Bayreuth, Geba€ude NW I, D-95440 Bayreuth, Germany
FIGURE 1. Macrocidins A (1) and B (2) and nor-macrocidin A (3).
rainer.schobert@uni-bayreuth.de
Received July 19, 2010
their complexity, they were also rarely chosen as synthetic
targets.4 The macrocidins are molecules worthy of synthesis
given their potential as a template for herbicide design.
Recently, Pfaltz et al. published the first total synthesis of 1
using a macrolactamization followed by a Lacey-Dieckmann
cyclization to install the pyrrolidine ring.5 The only other
reported attempt at a synthesis of 1 foundered on the epoxida-
tion of the alkene introduced by a ring-closing metathesis
(RCM) reaction.6
SCHEME 1. Retrosynthesis of Nor-macrocidin A (3)
The synthesis of macrocyclic 3-acyltetramic acids which
are immediate precursors of the fungal herbicide macro-
cidin A (1) is reported. The crucial closure of the macro-
cycle was achieved in excellent yield by an unprecedented
Williamson etherification of an ω-bromo phenolate
generated in situ by a Pd-mediated O-deallylation.
Herein, we describe an alternative approach toward the
core structure of the macrocidin family. We chose a simpli-
fied nor-macrocidin A (3) that features the most critical
structural hallmarks of 1, namely the formal 18-membered
ring, the epoxide, and the three stereogenic centers. The
synthesis is based on the 3-acylation of a tyrosine-derived
tetramic acid according to a protocol by Yoshii7 followed by
an intramolecular Williamson etherification (Scheme 1). The
latter was inspired by Ley’s synthesis of rapamycin which, to
the best of our knowledge, comprises the only other example
of a similar nondiaryl macroetherification.8 The epoxide
would be generated10 at a later stage from the deprotected
syn-diol9 group of 4 designated to be introduced as part
of the carboxylic acid required for the Yoshii acylation.
The macrocyclic 3-acyltetramic acids macrocidin A (1)
and B (2) (Figure 1) were extracted in 2003 by a Dow
AgroSciences group from field isolates of the pathogenic
fungus Phoma macrostoma Montagne dwelling on diseased
Canada thistles.1 They were found to induce chlorosis and
bleaching when tested postemergence on various green-
house-grown broadleaf weeds. Tetramic acids (i.e., pyrroli-
dine-2,4-diones) are a common structural motif found in
over 150 natural products many of which exhibit distinct
biological activities.2 While this substance class in general
has been receiving growing attention over the last 20 years,3
macrocyclic derivatives are still few and far between. Due to
(4) For recent examples, see: (a) Cramer, N.; Buchweitz, M.; Laschat, S.;
Frey, W.; Baro, A.; Mathieu, D.; Richter, C.; Schwalbe, H. Chem.;Eur. J.
2006, 12, 2488–2503. (b) Henderson, J. A.; Phillips, A. J. Angew. Chem., Int.
Ed. 2008, 47, 8499–8501.
(5) Yoshinari, T.; Ohmori, K.; Schrems, M. G.; Pfaltz, A.; Suzuki, K.
Angew. Chem., Int. Ed. 2010, 49, 881–885.
(6) Ramana, C. V.; Mondal, M. A.; Puranik, V. G.; Gurjar, M. K.
Tetrahedron Lett. 2006, 47, 4061–4064.
(7) (a) Hori, K.; Arai, M.; Nomura, K.; Yoshii, E. Chem. Pharm. Bull.
1987, 35, 4368–4371.
(8) Maddess, M. L.; Tackett, M. N.; Watanabe, H.; Brennan, P. E.;
Spilling, C. D.; Scott, J. S.; Osborn, D. P.; Ley, S. V. Angew. Chem., Int. Ed.
2007, 46, 591–597.
(9) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515–10530.
(10) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547.
(1) Graupner, P. R.; Carr, A.; Clancy, E.; Gilbert, J.; Bailey, K. L.; Derby,
J.-A.; Gerwick, B. C. J. Nat. Prod. 2003, 66, 1558–1561.
(2) For recent examples, see: (a) Wangun, H. V. K.; Dahse, H.-M.;
Hertweck, C. J. Nat. Prod. 2007, 70, 1800–1803. (b) Lang, G.; Cole, A. L. J.;
Blunt, J. W.; Munro, M. H. G. J. Nat. Prod. 2006, 69, 151–153. (c)
Ratnayake, A. S.; Davis, R. A.; Harper, M. K.; Veltri, C. A.; Andjelic,
C. D.; Barrows, L. R.; Ireland, C. M. J. Nat. Prod. 2005, 68, 104–107. (d)
Wang, C.-Y.; Wang, B.-G.; Wiryowidagdo, S.; Wray, V.; van Soest, R.;
Steube, K. G.; Guan, H.-S.; Proksch, P.; Ebel, R. J. Nat. Prod. 2003, 66, 51–
56. (e) Schmidt, K.; Riese, U.; Li, Z.; Hamburger, M. J. Nat. Prod. 2003, 66,
378–383.
(3) (a) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203–4221.
(b) Royles, B. J. L. Chem. Rev. 1995, 95, 1981–2001. (c) Henning, H.-G.;
Gelbin, A. Adv. Heterocycl. Chem. 1993, 57, 139–185. (d) Rosen, T. Drugs
Future 1989, 14, 153–163.
6716 J. Org. Chem. 2010, 75, 6716–6719
Published on Web 09/09/2010
DOI: 10.1021/jo101416x
r
2010 American Chemical Society

Barnickel and Schobert
JOCNote
SCHEME 2. Synthesis of Surrogate Tetramic Acids 8
SCHEME 3. Synthesis of Enantiopure Acid 17
The feasibility of a Williamson etherification for macrocycli-
zation was demonstrated by the synthesis of simplified
derivatives 8 lacking the epoxide group (Scheme 2).
SCHEME 4. Synthesis of Nor-macrocidin A Precursor (4)
Commercially available bisprotected tyrosine 5 was quan-
titatively converted with Meldrum’s acid to the correspond-
ing tetramic acid 6 according to a known general proce-
dure.11 3-Acylation of 6 with ω-bromo acids of different
chain length afforded 3-acyltetramic acids 7 in fair yields.7
These were deallylated under mild basic conditions and in the
presence of a catalytic amount of Pd(PPh3)4.12 Gratifyingly,
the so-formed phenolate intermediate underwent ring-clos-
ing etherification right away, leaving 16- and 18-membered
macrocycles 8a and 8b in very good yields. Control experi-
ments with previously deallylated 7b (obtained by applying
the same protocol as above, but at room temperature) in the
absence of Pd(PPh3)4 failed, which suggests that the catalyst
is requisite for the entire two-step sequence. We assume that
the phenolate remains coordinated to Pd until released
concomitantly with the base-induced elimination of the allyl
ligand. Since the rotational freedom of the 3-acyl residue is
restricted by the other ligands (Ph3P, allyl) on Pd, the like-
lihood of an intramolecular SN-reaction between phenolate
and bromide is increased. Although the analogous 20-mem-
bered macrolactam 8c could not be prepared in this way, this
is the first macrocyclizing Williamson reaction that shows
signs of generality. It is the more valuable from a practical
viewpoint, since alternative methods affording large rings,
such as RCM or lactonization/lactamization, require high-
dilution conditions as a rule.13
cedures.14 Protection of the alcohol as p-methoxybenzyl ether
1115 and AD-mix R dihydroxylation gave 12 as its 2R,3S
enantiomer with 95% ee.16 Formation of acetonide 13 and
reduction of its ester moiety to leave alcohol 14 both proceeded
with excellent yields. A two-step conversion of the alcohol into
the bromide 15 via the mesylate was necessary since all other
standard methods failed.17 PMB-cleavage with DDQ18 liber-
ated alcohol 16, which in turn was oxidized with PDC19 to
afford acid 17 in very good yield. Its reaction with tetramic acid
6 under Yoshii7 conditions led to 3-acyltetramic acid 18 in ca.
60% yield (Scheme 4), which we expected to be amenable to
cyclization under conditions as applied for the synthesis of 8.12
However, with K2CO3 as a base 18 was only deallylated and no
etherification of the phenol product took place. Employing
Cs2CO3 instead led to reductive dehalogenation of 18 as to
NMR spectra. Palladium-catalyzed reductions of halides are
quite rare and only known for aromatic systems. In these
rare cases, reduction takes place under basic conditions with
For the synthesis of nor-macrocidin A (3), the acetonide-
bearing ω-bromo acid 17 had to be prepared (Scheme 3).
Methyl (E)-8-hydroxy-oct-2-enoate 10 was obtained by reduc-
tion of ε-caprolactone 9 and subsequent Wittig alkenation of
the resulting lactol applying slightly modified literature pro-
(14) (a) Huang, Y. T.; Moeller, K. D. Tetrahedron 2006, 62, 6536–6550.
(b) Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. L. Can. J. Chem. 1987, 65,
1859–1866.
(15) (a) Wessel, H. P.; Iversen, T.; Bundel, D. R. J. Chem. Soc., Perkin
Trans. 1 1985, 2247–2250. (b) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu,
O. Tetrahedron Lett. 1988, 29, 4139–4142.
(16) According to chiral HPLC, when compared to a racemic sample
prepared using KMnO4.
(17) Such as: PBr3/pyridine; CBr4/PPh3; Br2/PPh3.
(18) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021–3028.
(19) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399–402.
(11) Jouin, P.; Castro, B.; Nisato, D. J. Chem. Soc., Perkin Trans. 1 1987,
1177–1182.
(12) Vutukuri, D. R.; Bharathi, P.; Yu, Z.; Rajasekaran, K.; Tran, M.-H.;
Thayumanavan, S. J. Org. Chem. 2003, 68, 1146–1149.
(13) For recent examples, see: Kiyota, H., Ed. Topics in Heterocyclic
Chemistry: Marine Natural Products 5; Springer-Verlag: Berlin, Heidelberg,
2006; pp 189-254.
J. Org. Chem. Vol. 75, No. 19, 2010 6717

Barnickel and Schobert
JOCNote
elemental analysis: Rf 0.38 (cyclohexane/ethanol 2:1); [R]26 75
D
(c 1.0, CHCl3); 1H NMR (300 MHz, MeOD-d4 only enol form is
observed) δ 1.60 (s, 9 H), 3.09 (dd, J = 14.0 Hz, 2.6 Hz, 1 H), 3.41
(dd, J = 14.0 Hz, 5.2 Hz, 1 H), 4.47 (ddd, J = 5.2 Hz, 1.6 Hz, 1.5
Hz, 2 H), 4.64 (dd, J= 5.2 Hz, 2.6 Hz, 1 H), 5.22 (ddt, J= 10.6 Hz,
1.6 Hz, 1.5 Hz, 1 H), 5.36 (ddt, J = 17.3 Hz, 1.6 Hz, 1.5 Hz, 1 H),
6.03 (ddt, J = 17.3 Hz, 10.6 Hz, 5.2 Hz, 1 H), 6.78 (d, J = 8.7 Hz, 2
H), 6.97 (d, J = 8.7 Hz, 2 H), enolic proton not observed; 13C
NMR (75 MHz, MeOD-d4 only enol form is observed) δ 28.5
(CH3), 35.0 (CH2), 62.5 (CH), 69.7 (CH2), 83.6 (Cq), 96.4 (CH),
115.3 (CH), 117.4 (CH2), 127.5 (Cq), 131.8 (CH), 135.0 (CH),
150.9 (Cq), 159.2 (Cq), 173.3 (Cq), 178.1 (Cq); IR (ATR) νmax 3166,
1754, 1610, 1511, 1362, 1150, 1077 cm-1; m/z (EI) 345 (4) [Mþ].
Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C,
65.77; H, 6.79; N, 4.43.
FIGURE 2. Assumed metal chelate complexes of 3-acyltetramic
acids.
methanol acting as the reductant.20 To preclude such a me-
chanism, we henceforth used tert-butyl alcohol, which is not
readily oxidized.
N-Boc-(5S)-3-(6-bromooctanoyl)-5-[4-(allyloxy)benzyl]pyrroli-
dine-2,4-dione (7b). A solution of 6 (345 mg, 1.0 mmol) in anhyd
CH2Cl2 (10 mL) was treated at 0 °C with DAMP (41 mg,
0.33 mmol), 8-bromooctanoic acid (245 mg, 1.1 mmol), and
DCC (250 mg, 1.2 mmol) and stirred at room temperature for
1.5 h. Anhydrous NEt3 (0.15 mL, 1.1 mmol) was added, and the
reaction mixture was stirred under reflux for 24 h and then
allowed to reach room temperature. Precipitated DHU was
removed by filtration and washed with diethyl ether (2 ꢀ
30 mL), and the combined filtrates were washed with aq KHCO3
(30 mL 10%) and 2 M HCl (2 ꢀ 30 mL). Drying over Na2SO4,
removal of the solvent under reduced pressure, and column
chromatography of the residue on silica gel (cyclohexane/ethyl
acetate 3:1 to cyclohexane/ethanol 1:2) yielded an unidentified
salt of the title compound. It was dissolved in ethyl acetate
(30 mL), and the resulting solution was washed with aq Na2ED-
TA (30 mL, 0.05M). Drying over Na2SO4 and removal of the
solvent under reduced pressure yielded 7b as viscous orange oil
(345 mg, 0.63 mmol, 63%): Rf 0.29 (cyclohexane/ethanol 4:1);
[R]25D -17 (c 1.0, CHCl3); mp 80 °C (potassium salt); 1H NMR
(300 MHz, MeOD-d4) δ 1.13-1.82 (m, 10 H), 1.62 (s, 9 H), 2.74
(t, J = 7.4 Hz, 2 H), 3.17 (dd, J = 13.9 Hz, 2.6 Hz, 1 H), 3.36 (dd,
J =13.9Hz, 5.2 Hz, 1 H), 3.43(t, J = 6.7 Hz, 2 H), 4.46 (ddd, J =
5.2 Hz, 1.7 Hz, 1.5 Hz, 2 H), 4.56 (dd, J = 5.2 Hz, 2.6 Hz, 1 H),
5.22 (ddt, J = 10.5 Hz, 1.5 Hz, 1.5 Hz, 1 H), 5.35 (ddt, J = 17.3
Hz, 1.7 Hz, 1.5 Hz, 1 H), 6.01 (ddt, J = 17.3 Hz, 10.5 Hz, 5.2 Hz,
The use of tert-butyl alcohol, K2CO3, and 18-crown-6
completely suppressed dehalogenation, while the macrocy-
clization still worked nicely (Scheme 4). However, the pur-
ification of tetramic acid 4 proved rather tedious and
intricate owing to the compound’s properties. Like most
3-acyltetramic acids, it showed a high affinity toward silica
gel and a pronounced tendency for metal chelate formation.21
We assume the formation of mixed metal chelates during
column chromatography on commercial silica gel containing
trace amounts of metal impurities, e.g., Mg2þ, Ca2þ, and Fe2þ
(Figure 2). These complexes not only hamper any chromato-
graphic purification but also cause significant signal broad-
ening in NMR spectra.
After extensive optimization testing a vast number of
solvent systems and common purification techniques, reversed-
phase column chromatography (Merck, LiChroprep RP18)
gave 4 in modest yield and still as mixed metal complexes. The
metals were removed by extraction with Na2EDTA solution
(0.05 M, pH ∼4.7) to finally yield the pure tetramic acid 4.
In summary, we have developed a new Pd-mediated one-
pot macrocyclization of p-(ω-bromoalkyl)phenyl allyl ethers
proceeding under mildly basic conditions. It comprises a
tandem deallylation-Williamson-type etherification. As ex-
emplified for the 18-membered ring system of the macrocidin
family, it works well at least for the synthesis of large rings
with extended planar, rigid segments. A thorough assess-
ment of the scope of this reaction and the role of palladium in
its mechanism is already under way as is an optimization of
the workup of the macrocidin precursor 4.
1 H), 6.76 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H); 13
C
NMR (75 MHz, MeOD-d4) δ 26.7 (CH2), 28.6 (CH3), 29.0, 29.5,
30.0, 34.0, 34.7, 34.8, 35.9 (CH2), 65.0 (CH), 69.8 (CH2), 84.9,
105.4 (Cq), 115.7 (CH), 117.6 (CH2), 127.5 (Cq), 132.0, 134.9
(CH), 150.8, 159.3, 177.5, 195.2, 195.3 (Cq); IR (ATR) νmax 1713,
1609, 1510, 1301, 1246, 1148 cm-1; m/z (EI) 451(10), 449(4) [M -
Boc]þ. Anal. Calcd for C27H35BrKNO6: C, 55.10; H, 5.99; N,
2.38. Found: C, 55.10; H, 6.10; N, 2.72.
(S)-7-Hydroxy-4-aza-15-oxa-5,21-dioxo-4-tert-butoxycarbo-
nyltricyclo[14.2.2.13,6]hencosa-1(19),6,16(20),17-tetraene (8b). A
solution of the potassium salt of 7b (295 mg, 0.50 mmol, obtained
by dissolving 7b in ethyl acetate followed by washing with aq
KHCO3 and drying over Na2SO4) in a mixture of anhyd THF/
methanol 5:1 (60 mL) was treated first with Pd(PPh3)4 (26 mg,
25 μmol, 5 mol %) and 5 min later with K2CO3 (208 mg, 1.50
mmol). The resulting mixture was heated under reflux for 27 h, the
volatiles were removed under reduced pressure, and the residue
thus obtained was dissolved in CH2Cl2 (50 mL) with addition of
2 M HCl (30 mL). The aqueous layer was extracted with CH2Cl2
(2 ꢀ 30 mL), and the combined organic phases were dried over
Na2SO4 and concentrated in vacuum. Column chromatography
on silica (cyclohexane/ethyl acetate 1:1 to cyclohexane/ethanol
1:1) yielded an unidentified salt of the title compound which was
dissolved in ethyl acetate (30 mL) and washed with aq Na2EDTA
(30 mL, 0.05M). Drying over Na2SO4 and removal of the solvent
under reduced pressure afforded compound 8b as a viscous yellow
oil (165 mg, 0.38 mmol, 76%): Rf 0.36 (cyclohexane/ethanol 2:1);
Experimental Section
N-Boc-(5S)-[4-(allyloxy)benzyl]pyrrolidine-2,4-dione (6). Boc-
allyl-L-tyrosine (3.21 g, 10.0 mmol) was dissolved in anhyd CH2Cl2
(40 mL), and Meldrum’s acid (1.59 g, 11.0 mmol), DCC (2.46 g,
12.0 mmol), and DMAP (2.44 g, 20.0 mmol) were added succes-
sively. After being stirred at room temperature for 2.5 h, the
precipitated DHU was removed by filtration and washed with
CH2Cl2 (2 ꢀ 20 mL), and the solvent was removed under reduced
pressure. The residue was dissolved in ethyl acetate (120 mL) and
washed with 2 M HCl (3 ꢀ 40 mL) and brine (40 mL), the organic
layer was heated under reflux for 1 h, and the solvent was removed
under reduced pressure. Tetramic acid 6 was obtained as a white
amorphous foam (3.45 g, 10.0 mmol, quant), pure by NMR and
(20) Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619–1620.
(21) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Morisaki, N.;
Hashimoto, Y. Chem. Pharm. Bull. 2001, 49, 206–212.
6718 J. Org. Chem. Vol. 75, No. 19, 2010

Barnickel and Schobert
JOCNote
[R]25D -5 (c 1.0, MeOH). Two isomers were visible in the NMR
spectra; * denotes signals of the major one: 1H NMR (300 MHz,
MeOD-d4) δ0.75-1.57 (m, 12 H), 1.62, 1.64* (s, 9 H), 2.24 (br. s, 1
H), 3.11 (dd, J = 14.1 Hz, 3.1 Hz, 1 H), 3.43 (dd, J = 14.1 Hz, 4.1
Hz, 1 H), 4.18 (t, J = 5.4 Hz, 2 H), 4.66 (dd, J = 4.1 Hz, 3.1 Hz,
1 H), 6.57-7.01 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 23.5,
23.7*, 24.7, 25.4*, 25.7, 26.2*, 26.6, 26.9*, 27.6*, 27.8 (10 ꢀ CH2),
28.1, 28.2* (2 ꢀ CH3), 32.4, 33.4* (2 ꢀ CH2), 34.5, 34.9* (2 ꢀ
CH2), 61.4, 62.3* (2 ꢀ CH2), 65.5, 67.1* (2 ꢀ CH2), 83.4*, 84.3
(2 ꢀ Cq), 103.0, 105.8* (2 ꢀ Cq), 115.7, 116.6 (2 ꢀ br. CH), 125.3*,
126.4 (2 ꢀ Cq), 130.6, 130.9 (2 ꢀ br CH), 148.8, 149.7* (2 ꢀ Cq),
155.9, 156.7* (2 ꢀ Cq), 164.4*, 173.8 (Cq), 191.6, 191.9, 195.9*,
197.8* (4 ꢀ Cq); IR (ATR) νmax 1608, 1509, 1347, 1300, 1247,
1146, 1024 cm-1; m/z (EI) 429 (25) [Mþ]; HRMS (EI) calcd for
[M - Boc] 329.1627, found 329.1630.
N-Boc-(5S)-3-[5-[(4S,5R)-5-bromomethyl-2,2-dimethyl-1,3-di-
oxolan-4-yl]-1-hydroxypent-1-ylidene]-5-[4-(allyloxy)benzyl]-
pyrrolidine-2,4-dione (18). To an ice-cooled solution of 6 (421
mg, 1.22 mmol) in anhyd CH2Cl2 (25 mL) were successively
added DMAP (49 mg, 0.40 mmol), DCC (301 mg, 1.46 mmol),
and 17 (397 mg, 1.34 mmol, dissolved in 5 mL anhyd CH2Cl2).
The reaction mixture was stirred at 0 °C for 10 min and then at
room temperature for 2 h. The mixture was cooled to 0 °C,
anhyd NEt3 (0.19 mL, 1.34 mmol) was added, and stirring was
continued at this temperature for a further 30 min. Finally, the
reaction was heated under reflux for 19 h. Workup analogous to
that of 7b yielded the compound 18 as a bright yellow amor-
phous solid (445 mg, 0.71 mmol, 58%): Rf 0.53 (cyclohexane/
ethanol 3:1) 0.27 (RP-C18, H2O/MeCN 2:1); [R]26D -22 (c 1.0,
MeOH); 1H NMR (300 MHz, MeOD-d4) δ 1.05-2.03 (m, 6 H),
1.37 (s, 6 H,), 1.61 (s, 9 H), 2.66-2.82 (m, 2 H), 3.17 (br. d, J =
13.6 Hz, 1 H), 3.35 (dd, J = 13.6 Hz, 4.0 Hz, 1 H), 3.48 (dd, J =
11.0 Hz, 4.9 Hz, 1 H), 3.54 (dd, J = 11.0 Hz, 4.4 Hz, 1 H), 3.83
(br. s, 2 H), 4.45 (d, J = 4.7 Hz, 2 H), 4.50 (br. s, 1 H), 5.21 (d,
J = 10.4 Hz, 1 H), 5.35 (d, J = 17.2 Hz, 1 H), 6.01 (ddt, J = 17.2
Hz, 10.5 Hz, 4.7 Hz, 1 H), 6.76 (d, J = 7.9 Hz, 2 H), 6.91 (d, J =
7.9 Hz, 2 H); 13C NMR (75 MHz, MeOD-d4) δ 26.3, 26.6, 26.8
(CH2), 27.5, 28.0, 28.6 (CH3), 33.4, 34.3 (CH2), 36.2 (CH2), 64.5
(CH), 69.7 (CH2), 81.0, 81.4 (CH), 84.3, 104.3, 110.2 (Cq), 115.3
(CH), 117.5 (CH2), 128.4 (Cq), 132.0, 135.0 (CH), 151.9, 158.9,
170.7, 194.3, 197.6 (br. Cq); IR (ATR) νmax 1626, 1510, 1366,
1300, 1244, 1151 cm-1; m/z (EI) 623 (3), 621 (2) [Mþ], 523 (6),
-
521 (6) [M - Boc]þ; HRMS (ESI) calcd for C30H39BrNO8
620.1865, found 620.1877
Macrocyclic Tetramic Acid 4. To a solution of 18 (125 mg,
0.20 mmol) in anhyd t-BuOH (24 mL), K2CO3 (83 mg, 0.60
mmol) were added 18-crown-6 (53 mg, 0.20 mmol) and Pd-
(PPh3)4 (11 mg, 10 μmol, 5 mol %). The resulting mixture was
stirred under reflux for 3 d, diethyl ether (80 mL) was added, and
the organic layer was washed with saturated aq NH4Cl (3 ꢀ
30 mL), dried over Na2SO4, and concentrated in vacuum. The
residue thus obtained was submitted to column chromatogra-
phy on Lichroprep RP-18 affording an unidentified salt of the
title compound which was dissolved in ethyl acetate (30 mL) and
washed with aq Na2EDTA (2 ꢀ 20 mL; 0.05 M). After being
dried over Na2SO4, the solution was concentrated under re-
duced pressure to leave tetramic acid 4 as a yellowish oil (25 mg,
50 μmol, 25%): Rf (RP-C18) 0.43 (H2O/MeCN 3:1); [R]24D -14
(c 1.0, CHCl3); 1H NMR (300 MHz, MeOD-d4) δ 1.06-1.20 (m,
1 H), 1.27-1.67 (m, 6 H), 1.36, 1.39 (s, 3 H), 1.80-1.90 (m, 1 H),
3.13 (dd, J = 14.0 Hz, 2.9 Hz, 1 H), 3.43 (dd, J = 14.0 Hz, 4.4
Hz, 1 H), 3.73-3.81 (m, 1 H), 3.90-3.98 (m, 1 H), 4.26-4.31 (m,
2 H), 4.62-4.68 (m, 1 H), 6.58-7.01 (m, 4 H); 13C NMR (75
MHz, MeOD-d4) δ 24.2 (CH2), 26.0, 26.7 (CH3), 27.2, 27.7
(CH2), 28.4 (CH3), 34.7, 35.8 (CH2), 63.9 (CH), 68.9 (CH2), 78.3,
79.1 (CH), 84.7 (Cq), 106.7, 109.4 (Cq), 116.1 (CH), 127.9 (Cq),
131.8 (br. CH), 150.9, 158.7, 177.4 (Cq), 195.6, 196.7 (br. Cq); IR
(ATR) νmax 3338, 1770, 1708, 1649, 1610, 1254, 1150 cm-1; m/z
(ESI-TOF, negative mode) 500 [M - H]-, 400 [M - Boc]-, 297;
HRMS (ESI) calcd for C27H34NO8- 500.2284, found 500.2259.
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft for financial support (Grant No.
Scho 402/9-2).
Supporting Information Available: Detailed experimental
procedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 19, 2010 6719