A Short Synthesis of the Mould Metabolite (R)-(+)-Carolinic Acid from (S)-Lactic Acid

Article abstract of DOI:10.1055/s-0035-1562625

(R)-(+)-Carolinic acid was prepared in seven steps and 59% yield from inexpensive benzyl l-lactate, the configuration of which was inverted by a Mitsunobu reaction with trifluoroacetate. The resulting benzyl d-lactate was cyclised by a domino addition-Wittig alkenation reaction with Ph₃PCCO. The product tetronic acid was acylated with a second equivalent of this ylide to give a 3-acylylidenetetronic acid, which was olefinated directly with tert-butyl glyoxylate. The product alkene was hydrogenated and deprotected to afford pure crystalline (R)-(+)-carolinic acid, which proved inactive against Staphylococcus aureus and Escherichia coli mutant D21f2.

Full text of DOI:10.1055/s-0035-1562625

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–E
A
paper
Synthesis
D. Linder, R. Schobert
Paper
A Short Synthesis of the Mould Metabolite (R)-(+)-Carolinic Acid
from (S)-Lactic Acid
David Linder
O
O
OH
O
O
Rainer Schobert
2 Ph3PCCO
PPh3 OHC–CO2t-Bu
*
O
O
CO2H
OBn
S
R
Organisch-chemisches Laboratorium der Universität Bayreuth,
Gebäude NW I, 95440 Bayreuth, Germany
Rainer.Schobert@uni-bayreuth.de
OH
O
OH
(
R)-(+)-carolinic acid
Received: 25.07.2016
O
O
O
O
Accepted after revision: 27.07.2016
Published online: 02.09.2016
DOI: 10.1055/s-0035-1562625; Art ID: ss-2016-t0388-op
3
OH
O
O
5
HO2C
OH
OH
Abstract (R)-(+)-Carolinic acid was prepared in seven steps and 59%
yield from inexpensive benzyl L-lactate, the configuration of which was
inverted by a Mitsunobu reaction with trifluoroacetate. The resulting
benzyl D-lactate was cyclised by a domino addition–Wittig alkenation
carlosic acid [(S)-1]
carolic acid [(R)-2]
O
O
O
CO2H
reaction with Ph PCCO. The product tetronic acid was acylated with a
3
second equivalent of this ylide to give a 3-acylylidenetetronic acid,
which was olefinated directly with tert-butyl glyoxylate. The product
alkene was hydrogenated and deprotected to afford pure crystalline
OH
carolinic acid [(R)-3]
Figure 1 Tetronic acids produced by Penicillium charlesii G. Smith
(R)-(+)-carolinic acid, which proved inactive against Staphylococcus au-
reus and Escherichia coli mutant D21f2.
Herein, we report an expeditious synthesis of the natu-
ral (R)-(+)-enantiomer of carolinic acid starting from inex-
Key words tetronic acids, carolinic acid, Wittig reaction, natural prod-
ucts, stereoinversion
pensive L-lactic acid, which utilises the cumulated ylide
17,18
Ph P=C=C=O
for both the closure of the five-membered
3
Over 100 naturally occurring tetronic acids are known
to date, a good deal of them featuring a 3-acyl residue and
exhibiting biological activities associated with their metal
affinity and stereoelectronic resemblance to inorganic
ring and the 3-acylation reaction.
Given that L-lactic acid 4 is much cheaper than its D-en-
antiomer, which is required for the synthesis of the natural
(R)-carolinic acid 3, we inverted the configuration of its
benzyl ester (S)-5 in two steps and 91% yield (Scheme 1).
Mitsunobu esterification with trifluoroacetic acid afforded
diester 6, which was selectively hydrolysed with lithium
carbonate in aqueous methanol to leave benzyl lactate (R)-
5. This was cyclised with ketenylidenetriphenylphos-
phosphate. Although tetronic acids have been known6–8
since the 1880’s they were not identified as part of natural
products until 1934 when Clutterbuck et al. isolated five
closely related 5-substituted derivatives from the mould
1–5
9
Penicillium charlesii G. Smith grown on glucose. Amongst
10
them were carlosic acid (1), which is also an intermediate
phorane, Ph PCCO, under pH-neutral, non-racemizing con-
3
in the biosynthesis of penicillic acid, as well as carolic acid
ditions to furnish tetronate 7 in 92% yield. This domino re-
action proceeds through addition of the OH-group of (R)-5
across the C=C bond of the starting ylide to give a new sta-
bilised ester ylide, which undergoes an intramolecular ole-
11,12
(
2)
and carolinic acid (3) (Figure 1). The absolute config-
13
uration of 2 and 3 was elucidated by Boll et al. in 1968. Ra-
cemic carolinic acid 3 was synthesised by Haynes et al.,
14
Svendsen and Boll,15 and Ley et al. The first two syntheses
cyclised a γ-halo-β-ketoester with the required succinyl
residue already attached to the α-carbon atom, whereas the
Ley group obtained 3 by Pd-catalysed succinylation of
methyl 3-stannyltetronate.
16
fination of its ester carbonyl group. Tetronic acid 8 was
18
then liberated by catalytic hydrogenolysis of tetronate 7.
The 3-acylation of tetronic acids can be achieved in various
ways, e.g., by reaction with the respective acyl chlorides
19
and BF -diethyl etherate according to Jones, or with car-
3
boxylic acids and various condensation agents according to
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

B
Synthesis
D. Linder, R. Schobert
Paper
Yoshii,20 Yoda,21 or Moloney,22 or with the ylide Ph PCCO.23
3
O
O
OH
(
iii)
In the latter case, stabilised phosphorus ylides such as 9 re-
sult in quantitative yield. They can be deprotonated by po-
tassium tert-butoxide in tetrahydrofuran (THF) to give an
anionic species that undergoes Wittig alkenation reactions
OR
Ot-Bu
RO
t-BuO
47%
O
OH
O
1
1
0: R = H
(i)
85%
13
1: R = Me
(iv)
9%
(ii)
56%
24
12: R = t-Bu
9
with aldehydes.
O
Ot-Bu
O
H
O
O
O
(
ii)
OBn
CF3
(iii)
1
4
OR
OH
OBn
93%
O
98%
OH
O
OH
O
O
OH
O
PPh3
(v) t-BuOK
vi) 14
2%
Ot-Bu
4
: R = H
S)-5: R = Bn
(i)
6
(R)-5
O
(
(
78%
O
8
O
O
O
O
OH
9
15α
(
iv) Ph3PCCO
2%
(vi) Ph3PCCO
99%
PPh3
O
O
9
O
O
O
O
O
OR
O
(vii)
Ot-Bu
O
CO2R
7
8
: R = Bn
: R = H
(v)
99%
9α
93%
O
OH
OH
O
O
16: R = t-Bu
(viii)
94%
15β
(R)-3: R = H
PPh3
O
Scheme 2 Reagents and conditions: (i) H SO , MeOH, reflux, 2 h;
H
H
2
4
(
ii) BuLi, t-BuOH, THF, r.t., 2.5 h; (iii) KMnO , t-BuOH, r.t., 0.5 h; (iv)
O
4
9β
Pb(OAc) , THF, r.t., 0.5 h; (v) t-BuOK, THF, reflux, 20 min; (vi) 14, THF,
4
Scheme 1 Inversion of benzyl L-lactate 5 and synthesis of 3-[(triphen-
ylphosphoranylidene)acetyl]tetronic acid 9. Reagents and conditions: (i)
reflux, 2 h; (vii) 5% Pd/C, H
0 °C, 6 h.
2
(1 bar), EtOAc, r.t., 0.5 h; (viii) TFA, CH Cl ,
2
2
(
a) KOH, DMF, 100 °C, 1 h; (b) BnBr, DMF, 100 °C, 17 h; (ii) diisopropyl
azodicarboxylate (DIAD), TFA, Ph P, THF, r.t., 7 h; (iii) Li CO , MeOH/H O
3
2
3
2
(
8:1), r.t., 20 min; (iv) Ph PCCO, benzoic acid, THF, reflux, 48 h; (v) 5%
against Gram-positive Staphylococcus aureus (DSM346) and
the drug-sensitive, Gram-negative Escherichia coli mutant
D21f2 at concentrations as high as 20 μg/mL.
3
Pd/C, H (1 bar), MeOH, r.t., 1.5 h; (vi) Ph PCCO, THF, reflux, 14 h.
2
3
To obtain carolinic acid in this way, ylide 9 was prepared
in situ, deprotonated, and immediately reacted with tert-
butyl glyoxylate 14, which was accessible in four steps and
Melting points (uncorrected) were obtained with an Electrothermal
9100 apparatus. Optical rotations were obtained with a Perkin–Elmer
polarimeter 241 (λ = 589 nm, 546 nm). IR spectra were obtained with
a Perkin–Elmer Spectrum One FTIR spectrophotometer with ATR
sampling unit. NMR spectra were obtained with a Bruker Avance 300
spectrometer, chemical shifts are reported in ppm (δ) downfield from
TMSint. Mass spectra were obtained with a Varian MAT 8500 (EI,
70 eV). High-resolution mass spectra were obtained with a Thermo
22% yield by an optimised literature procedure starting
from fumaric acid 10 (Scheme 2).
Fumaric acid 10 was converted into its methyl ester 11,
which was transesterified with n-butyllithium and tert-bu-
25,26
tyl alcohol to afford di-tert-butyl ester 12.
This was oxi-
dised with KMnO and the resulting tartrate 13 was treated
4
+
–
with lead tetraacetate to furnish the Criegee cleavage prod-
Fisher Scientific Q Exactive in ESI ESI mode. Chiral HPLC column was
a Macherey-Nagel Nucleodex beta-OH. For flash chromatography
Merck silica gel 40–60 (230–400 mesh) was used.
27
uct 14. Its Wittig olefination with the anion generated in
situ by treating ylide 9, freshly prepared from tetronic acid
8
and Ph PCCO, with potassium tert-butoxide, afforded 3-
3
(
S)-Benzyl 2-Hydroxypropionate [(S)-5]
enoyltetronic acid 15 in 82% yield and as a mixture of iso-
mers/tautomers, two of which were observable in the NMR
spectra. Hydrogenation of the alkene 15 and subsequent
cleavage of the product ester 16 left optically pure carolinic
acid (R)-(+)-3 in 59% overall yield with respect to starting
A solution of L-(+)-lactic acid 4 (5.0 g, 55.5 mmol) in DMF (200 mL)
was heated to 100 °C, treated with KOH (3.74 g, 66.6 mmol), and
stirred for 1 h. Benzyl bromide (7.6 mL, 63.8 mmol) was added and
the mixture was stirred and heated at 100 °C for another 16 h. After
cooling to r.t., the solvent was evaporated under reduced pressure.
The residue was taken up in CH Cl (200 mL), washed with H O (200
mL), and the aqueous phase was extracted with CH
combined organic phases were dried over MgSO and the crude prod-
uct was purified by column chromatography (silica gel 60; hex-
anes/EtOAc, 4:1) to give (S)-5.
25
benzyl L-lactate. Its specific optical rotation was [α]
+23
D
2
2
2
25
9
(
c 0.33, H O) and [α]546 +53 [Lit. +60 (c 0.33, H O)]. The
2
Cl
2
(200 mL). The
2
2
stereochemical purity of the synthesised product was addi-
tionally confirmed by chiral HPLC analysis. In preliminary
tests, the synthetic (R)-(+)-carolinic acid proved inactive
4
Yield: 6.94 g (78%); colourless oil; R = 0.59 (hexanes/EtOAc, 2:1);
f
25
28
[α]D –14.4 (c 4.0, MeOH) [Lit. –15.9 (c 4.0, MeOH)].
IR (ATR): 3424, 1731, 1198, 1122, 1043, 735, 696 cm–1
.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

C
Synthesis
D. Linder, R. Schobert
Paper
1
13
H NMR (300 MHz, CDCl ): δ = 1.34 (d, J = 6.9 Hz, 3 H, CH ), 3.45 (s,
C NMR (75.5 MHz, CDCl ): δ = 17.8 (5-Me), 74.3 (OCH ), 75.4 (C5),
3
3
3
2
q
1
5
H, OH), 4.19–4.30 (m, 1 H, CH), 5.10 (s, 2 H, OCH ), 7.21–7.29 (m,
89.0 (C3), 127.8, 128.7, 128.9 (Ar-CH), 133.8 (Ar-C ), 172.3 (C2), 182.0
(C4).
2
H, Ar-CH).
1
3
+
C NMR (75.5 MHz, CDCl ): δ = 20.0 (C3), 66.6 (C2), 66.7 (OCH ),
HRMS: m/z [M + H] calcd for C12H13O : 205.08592; found: 205.08575.
3
2
3
q
1
27.9, 128.1, 128.3 (Ar-CH), 135.1 (Ar-C ), 175.1 (C1).
+
MS (EI, 70 eV): m/z (%) = 180 (3) [M ], 108 (4), 91 (100), 89 (3), 77 (6),
(R)-4-Hydroxy-5-methylfuran-2(5H)-one (8)
65 (12), 51 (2), 46 (3).
Compound 7 (2.03 g, 9.94 mmol) was dissolved in MeOH (50 mL), 5%
Pd on charcoal (102 mg) was added, and the resulting mixture was
(R)-Benzyl 2-Trifluoroacetopropionate (6)
purged with hydrogen gas and kept under an H atmosphere (1 bar)
2
for 1.5 h while stirring. After filtration over a pad of Celite, the solvent
was removed in vacuo to leave 8 as a 85:15 mixture of enol and diketo
tautomers.
Yield: 1.12 g (99%); yellow solid; mp 107 °C [Lit.30 118 °C for enantio-
A solution of (S)-5 (6.50 g, 36.07 mmol) in THF (150 mL) was treated
with Ph P (11.35 g, 43.28 mmol), TFA (3.3 mL, 43.28 mmol), and DIAD
3
(8.5 mL, 43.28 mmol), and stirred at r.t. for 7 h. The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography (silica gel 60; hexanes/EtOAc, 8:1) to give
mer of unspecified enol/diketo ratio]; R = 0.38 tailing (acetone/CH Cl ,
f
2
2
25
30
6
.
1:1); [α]D +10.8 (c 1.22, MeOH) [Lit. +20.4 (c 1.22, MeOH) for enan-
tiomer of unspecified enol/diketo ratio].
Yield: 9.18 g (93%); colourless oil; R = 0.53 (hexanes/EtOAc, 6:1);
f
25
[α]D +38 (c 1.0, MeOH).
IR (ATR): 2940, 2689, 1704, 1587, 1235, 1163, 1074, 1046, 960, 905,
–
1
8
07 cm .
IR (ATR): 1790, 1749, 1672, 1547, 1199, 1151, 1125, 1090, 734,
−1
1
696 cm
.
H NMR (300 MHz, acetone-d ): δ = 1.41 (d, J = 6.2 Hz, 3 H, CH ), 4.86
6 3
1
(q, J = 6.2 Hz, 1 H, CHCH ), 4.91 (s, 1 H, 3-H), 11.14 (s, 1 H, OH). Dike-
3
H NMR (300 MHz, CDCl ): δ = 1.64 (d, J = 7.2 Hz, 3 H, CH ), 5.23 (s,
3
3
tone: 1.41 (d, J = 6.2 Hz, 3 H, CH ), 3.27–3.34 (m, 2 H, CH ), 4.91 (q,
2
H, OCH ), 5.32 (q, J = 7.2 Hz, 1 H, CH), 7.32–7.44 (m, 5 H, Ar-CH).
3
2
2
J = 6.2 Hz, 1 H, CHCH3).
13
C NMR (75.5 MHz, CDCl ): δ = 16.4 (C3), 67.7 (OCH ), 71.7 (C2),
3
2
13C NMR (75.5 MHz, acetone-d
): δ = 18.1 (CH ), 75.9 (C5), 89.0 (C3),
3
q
6
1
14.2 (q, J = 283.8 Hz, CF ), 128.4, 128.5 (Ar-CH), 134.7 (Ar-C ), 156.8
3
168.4 (C4), 182.9 (C2).
(q, J = 42.5 Hz, CCF ), 168.2 (C1).
3
+
+
MS (EI, 70 eV): m/z (%) = 114 (14) [M ], 86 (14), 43 (100).
HRMS: m/z [M] calcd for C12H11F O : 276.0609; found: 276.0607.
3
4
Dimethyl Fumarate (11)
(R)-Benzyl 2-Hydroxypropionate [(R)-5]
A mixture of fumaric acid 10 (5.0 g, 43.08 mmol), MeOH (70 mL), and
A solution of Li CO (23 mg, 0.31 mmol) in H O (5 mL) was added to a
2
3
2
H SO (1.72 mL, 32.31 mmol) was stirred and heated to reflux for 2 h,
solution of 6 (1.09 g, 3.93 mmol) in MeOH (40 mL). After stirring for
0 min at r.t., the mixture was washed with brine, extracted with
2
4
then cooled to r.t., and neutralized with 10% aq Na CO solution. The
2
2
3
precipitate was filtered off to give 11.
Yield: 5.24 g (85%); white solid; mp 102 °C [Lit.25 102 °C]; R = 0.37
EtOAc (3 × 50 mL) and dried over MgSO . The organic phase was con-
4
centrated to give (R)-5.
f
(
hexanes/EtOAc, 95:5).
Yield: 641 mg (98%); colourless oil; R = 0.36 (hexanes/EtOAc, 4:1);
f
25
29
IR (ATR): 3077, 2964, 1706, 1439, 1295, 1154, 990, 881, 774, 672 cm–1
.
[α]D +13.3 (c 0.72, MeOH) [Lit. +13.2 (c 0.72, MeOH)].
IR (ATR): 3440, 1732, 1199, 1122, 1043, 735, 696 cm–1
.
1
H NMR (300 MHz, CDCl ): δ = 3.80 (s, 6 H, OCH ), 6.86 (s, 2 H, CH).
3
3
1
13
H NMR (300 MHz, CDCl ): δ = 1.44 (d, J = 6.9 Hz, 3 H, CH ), 3.51 (s,
C NMR (75.5 Hz, CDCl ): δ = 52.5 (OCH ), 133.7 (CH), 165.5 (CO).
3 3
3
3
1
H, OH), 4.32 (q, J = 6.9 Hz, 1 H, CH), 5.21 (s, 2 H, OCH ), 7.33–7.40
2
(
1
m, 5 H, Ar-CH).
Di-tert-butyl Fumarate (12)
3
C NMR (75.5 MHz, CDCl ): δ = 20.3 (C3), 66.9 (C2), 67.2 (OCH ),
A mixture of t-BuOH (1.30 mL) and THF (20 mL) was cooled to 0 °C
and treated first dropwise with BuLi (5.55 mL, 13.88 mmol), and after
15 min with 11 (1.00 g, 6.94 mmol). Stirring was continued for 1 h at
3
2
q
1
28.2, 128.5, 128.6 (Ar-CH), 135.3 (Ar-C ), 175.5 (C1).
+
MS (EI, 70 eV): m/z (%) = 180 (2) [M ], 108 (3), 91 (100), 89 (4), 77 (6),
6
0
°C and then at r.t. for 1 h. The reaction was quenched with NH Cl
5 (15), 51 (2), 46 (3).
4
and the mixture was extracted with EtOAc (3 × 50 mL). The organic
phases were washed with brine, dried over MgSO4 and purified by
column chromatography (silica gel 60; hexanes/EtOAc, 19:1) to give
(
R)-4-Benzyloxy-5-methylfuran-2(5H)-one (7)
A mixture of (R)-5 (2.17 g, 12.05 mmol), anhydrous THF (60 mL),
Ph PCCO (4.74 g, 15.67 mmol), and a catalytic amount of benzoic acid
was heated to reflux for 48 h. The volatiles were removed in vacuo
and the residue was purified by column chromatography (silica gel
6
12.
3
Yield: 886 mg (3.88 mmol); white solid; mp 69 °C [Lit.26 69 °C]; R =
f
0
.88 (hexanes/EtOAc, 8:1).
0; hexanes/EtOAc, 3:1) to give 7.
IR (ATR): 2982, 2940, 1703, 1368, 1138, 974, 846, 777, 767, 673 cm–1
.
3
0
1
Yield: 2.04 g (92%); white solid; mp 74 °C [Lit. 84 °C for enantio-
H NMR (300 MHz, CDCl ): δ = 1.50 (s, 18 H, CH ), 6.67 (s, 2 H, CH).
3
3
25
mer]; R = 0.65 (hexanes/EtOAc, 2:1); [α]
+11.8 (c 1.33, CHCl3).
13
f
D
C NMR (75.5 Hz, CDCl ): δ = 28.1 (CH ), 81.6 (C(CH ) ), 134.7 (CH),
3 3 3 3
IR (ATR): 3122, 1745, 1617, 1349, 1294, 1235, 1162, 1077, 1059, 943,
164.7 (CO).
–1
916, 902, 858, 815, 757, 709, 699, 659 cm
.
HRMS: m/z [M + Na]+ calcd for C12H20O Na: 251.12521; found:
251.12538.
4
1
H NMR (300 MHz, CDCl ): δ = 1.47 (d, J = 7.0 Hz, 3 H, CH ), 4.85 (q, J =
3
3
7
.0 Hz, 1 H, CHCH ), 5.04 (s, 2 H, OCH ), 5.10 (s, 1 H, 3-H), 7.31–7.43
3
2
(m, 5 H, Ar-CH).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

D
Synthesis
D. Linder, R. Schobert
Paper
Di-tert-butyl Tartrate (13)
(R)-3-[3′-(tert-Butoxycarbonyl)propanoyl]-5-methyltetronic Acid
(16)
A solution of 12 (5.15 g, 22.55 mmol) in t-BuOH (100 mL) was treated
with a solution of KMnO (5.35 g, 33.83 mmol) in H O (100 mL). The
Compound 15 (832 mg, 3.10 mmol) was dissolved in anhydrous
4
2
mixture was stirred for 30 min and then extracted with Et O (3 × 100
EtOAc (30 mL), 5 % Pd on charcoal (42 mg) was added, and the result-
2
mL). The organic phases were washed with H O (3 × 60 mL), dried
ing mixture was purged with hydrogen gas and kept under a H atmo-
2
2
over MgSO , and diluted with n-hexane to precipitate 13.
sphere (1 bar) for 30 min while stirring. After filtration over a pad of
4
Yield: 2.74 g (10.45 mmol); colourless needles; mp 83 °C [Lit.27 84–
Celite, the solvent was removed in vacuo to give 16.
8
5 °C]; R = 0.49 (hexanes/EtOAc, 5:1).
Yield: 778 mg (93%); yellow oil; R = 0.29 (CH Cl /MeOH, 9:1);
f
f
2
2
25
IR (ATR): 3481, 2975, 1731, 1367, 1248, 1091, 853, 755, 603 cm–1
.
[α]
D
+6.3 (c 1.0, MeOH).
1
IR (ATR): 2980, 1762, 1726, 1653, 1599, 1366, 1236, 1148, 1047, 1005,
H NMR (300 MHz, CDCl ): δ = 1.52 (s, 18 H, CH ), 3.08 (d, J = 7.0 Hz,
H, CHOH), 4.37 (d, J = 7.0 Hz, 2 H, OH).
3
3
–1
8
45 cm
1H NMR (300 MHz, CDCl
H, CHCH ), 2.61 (t, J = 6.2 Hz, 2 H, CH CO ), 3.18 (t, J = 6.2 Hz, 2 H,
.
2
13
): δ = 1.42 [s, 9 H, (CH ) ], 1.53 (d, J = 7.0 Hz,
3 3 3
C NMR (75.5 Hz, CDCl ): δ = 28.1 (CH ), 72.5 (CH), 83.6 (CCH ), 171.1
3
3
3
3
(CO).
3
2
2
CH -CH CO ), 4.88 (q, J = 7.0 Hz, 1 H, CHCH ), 11.78 (br. s, 1 H, OH).
2
2
2
3
HRMS: m/z [M + Na]+ calcd for C12H22O Na: 285.13086; found:
2
6
1
3
C NMR (75.5 MHz, CDCl ): δ = 17.1 (5-Me), 28.1 [(CH ) ], 29.0
85.13043.
3
3 3
(
CH -CH CO ), 32.6 (CH CO ), 75.2 (C5), 81.2 [C(CH ) ], 100.7 (C3),
2 2 2 2 2 3 3
1
67.8 (CH CO ), 171.2 (C2), 196.7 [3-C(O)CH ], 198.1 (C4).
2
2
2
tert-Butyl 2-Oxoacetate (14)
HRMS (ESI): m/z [M + Na]+ calcd for C13H18O Na: 293.09956; found:
6
A mixture of 13 (147 mg, 0.56 mmol), THF (6 mL), and Pb(OAc) (274
mg, 0.62 mmol) was stirred at r.t. for 30 min. The reaction mixture
was passed through a syringe filter and the filtrate was used directly
4
293.09877.
(R)-(+)-Carolinic Acid [(R)-3]
for the next reaction step without further purification; R 0.28 (hex-
f
31,32
anes/EtOAc, 3:1).
A solution of ester 16 (176 mg, 0.65 mmol) in CH Cl (12 mL) was
2
2
cooled to 0 °C and treated with TFA (1.3 mL). After stirring for 6 h, the
solvent was removed at 0 °C in vacuo to leave (R)-(+)-carolinic 3 acid
as a light-yellow solid.
(
R)-3-[3′-(tert-Butoxycarbonyl)prop-(2′E)-enoyl]-5-methyltetron-
ic Acid (15)
A boiling solution of tetronic acid 8 (277 mg, 2.43 mmol) in THF (20
Yield: 131 mg (94%); recrystallised from acetonitrile to afford white
15
mL) was slowly treated over 20 min with a solution of Ph PCCO (733
crystals; mp 141 °C (Lit. 141–142 °C); R
f
9
= 0.20 (CH
2
Cl
O) [Lit. [α]546 +60 (c 0.33, H
2
2
/MeOH, 9:1);
3
25
25
mg, 2.43 mmol) in the same solvent (7 mL). Heating was continued
for a further 14 h, then t-BuOK (269 mg, 2.40 mmol) was added and
heating to reflux was continued for 30 min. tert-Butyl glyoxylate 14
[α]
D
+23 / [α]546 +53 (c 0.33, H
2
O)].
IR (ATR): 3279, 2443, 1745, 1729, 1652, 1594, 1374, 1229, 1158, 1056,
–1
1021, 954, 825, 793, 771, 671, 588 cm
.
(236 mg; 1.441 mmol), as obtained from the Criegee cleavage of 13,
1
H NMR (DMSO-d ): δ = 1.35 (d, J = 6.8 Hz, 3 H, 5-Me), 2.43 (t, J =
6
was added dropwise by using a syringe and the reaction mixture was
6
.8 Hz, 2 H, CH CH CO ), 2.96 (t, J = 6.8 Hz, 2 H, CH CH CO ), 4.81 (q,
31
2 2 2 2 2 2
stirred until completeness was indicated by P NMR spectroscopic
J = 6.8 Hz, 1 H, 5-H).
analysis (ca. 2 h). The reaction was quenched with KHSO and the sol-
4
13
C NMR (75.5 MHz, DMSO-d ): δ = 17.5 (5-Me), 27.6 (CH CH CO ),
vent was removed in vacuo. The residue was dissolved in CH Cl (60
6
2
2
2
2
2
3
5.0 (CH CH CO ), 74.1 (C5), 98.9 (C3), 170.4 (C2), 174.0 (CH CH CO ),
mL) and the pH was adjusted to 8.5 with aq NaHCO to allow the te-
2
2
2
2
2
2
3
1
90.5 [3-C(O)CH ], 193.0 (C4).
tronate salt to accumulate in the aqueous layer. After separation of
the phases, the aqueous layer was acidified with 1 M HCl to liberate
the tetronic acid, which was extracted with several portions of dieth-
2
–
HRMS: m/z [M–H] calcd for C H O : 213.03936; found: 213.03999.
9
9
6
yl ether (70 mL). These extracts were dried with MgSO and concen-
4
trated in vacuum to afford 15.
Acknowledgment
Yield: 524 mg (82%); yellow solid; 1:1 mixture of diketo and enol tau-
2
5
We thank Prof. Dr. Ursula Bilitewski and Sonja M. Höhmann (Helm-
holtz Centre for Infection Research, Braunschweig, Germany) for pre-
liminary antibacterial tests.
tomers; mp 80 °C; R = 0.29 (CH Cl /MeOH, 9:1); [α]
+11.5 (c 1.0,
f
2
2
D
MeOH).
IR (ATR): 3090, 3057, 2988, 2940, 1761, 1670, 1652, 1571, 1390, 1369,
–1
1311, 1154, 1087, 1051, 1026, 1000, 810, 690, 599 cm .
1
H NMR (300 MHz, CDCl ): δ = 1.53 [s, 9 H, C(CH ) ], 1.55 (d, J = 6.8 Hz,
3
3
3
Supporting Information
3
H, CHCH ), 4.77 (q, J = 6.8 Hz, 1 H, CHCH ), 7.00 (d, J = 15.7 Hz, 1 H,
3
3
CHCOO), 7.94 (d, J = 15.7 Hz, 1 H, CHCHCOO). δ (enol) = 1.53 [s, 9 H,
C(CH ) ], 1.54 (d, J = 7.2 Hz, 3 H, CHCH ), 4.85 (q, J = 7.2 Hz, 1 H,
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562625.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
3
3
3
CHCH ), 7.02 (d, J = 15.8 Hz, 1 H, CHCHOO), 7.95 (d, J = 15.8 Hz, 1 H,
3
CHCHCOO).
13
References
C NMR (75.5 MHz, CDCl ): δ = 16.7 (5-Me), 27.9 [C(CH ) ], 82.1 (C5),
3
3 3
8
2.5 [C(CH ) ], 98.0 (C3), 130.3 (=CHCO ), 136.4 (CH=CHCO ), 163.3
3
3
2
2
(
(
(
(
1) Haynes, L. J.; Plimmer, J. R. Q. Rev., Chem. Soc. 1960, 14, 292.
2) Tejedor, D.; Garcia-Tellado, F. Org. Prep. Proced. Int. 2004, 36, 35.
3) Zografos, A. L.; Georgiadis, D. Synthesis 2006, 3157.
(=CHCO ), 174.0 (COH), 175.3 (C2), 194.5 (C4). δ (enol) = 16.7 (5-Me),
2
27.9 [C(CH ) ], 77.8 (C5), 82.5 [C(CH ) ], 99.9 (C3), 130.7 (CH=CHCO ),
3 3 3 3 2
136.9 (=CHCO ), 166.5 (=CHCO ), 175.3 (C2), 177.8 (CCOC), 203.6 (C4).
2
2
4) Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203.
HRMS: m/z [M + Na]+ calcd for C13H16O Na: 291.08391; found:
6
(5) Georgiadis, D. Tetronic Acids, In Natural Lactones and Lactams;
Janecki, T., Ed.; Wiley-VCH: Weinheim, 2013.
291.08352.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

E
Synthesis
D. Linder, R. Schobert
Paper
(
(
(
(
6) Demarcay, E. Ann. Chim. Phys. 1880, 20, 422.
7) Wolff, L. Justus Liebigs Ann. Chem. 1896, 291, 226.
8) Benary, E. Ber. Dtsch. Chem. Ges. 1907, 1079.
9) (a) Clutterbuck, P. W.; Haworth, W. N.; Raistrick, H.; Smith, G.;
Stacey, M. Biochem. J. 1934, 28, 94. (b) Clutterbuck, P. W.;
Raistrick, H.; Reuter, F. Biochem. J. 1935, 29, 300.
(19) Jones, R. C. F.; Begley, M. J.; Peterson, G. E.; Sumaria, S. J. Chem.
Soc., Perkin Trans. 1 1990, 1959.
(20) Hori, K.; Arai, M.; Nomura, K.; Yoshii, E. Chem. Pharm. Bull. 1987,
35, 4368.
(21) Sengoku, T.; Wierzejska, J.; Takahashi, M.; Yoda, H. Synlett 2010,
2944.
(
10) For syntheses of carlosic acid, see: (a) Bloomer, J. L.; Kappler, F.
E. J. Org. Chem. 1974, 39, 113. (b) Svendsen, A.; Boll, P. M. J. Org.
Chem. 1975, 40, 1927. (c) Svendsen, A.; Boll, P. M. Tetrahedron
Lett. 1974, 2821. (d) Booth, P. M.; Fox, C. M. J.; Ley, S. V. Tetrahe-
dron Lett. 1983, 24, 5143. (e) Booth, P. M.; Fox, C. M. J.; Ley, S. V.
J. Chem. Soc., Perkin Trans. 1 1987, 121. (f) Mitsos, C. A.;
Zografos, A. L.; Igglessi-Markopoulou, O. J. Org. Chem. 2000, 65,
(22) Jeong, Y.-C.; Moloney, M. G. J. Org. Chem. 2011, 76, 1342.
(23) Schobert, R.; Siegfried, S.; Nieuwenhuyzen, M.; Milius, W.;
Hampel, F. J. Chem. Soc., Perkin Trans. 1 2000, 1723.
(24) (a) Schlenk, A.; Diestel, R.; Sasse, F.; Schobert, R. Chem. Eur. J.
2010, 16, 2599. (b) Harras, M.; Bauer, T.; Kempe, R.; Schobert, R.
Tetrahedron 2013, 69, 3677.
(25) Tapaswi, P. K.; Choi, M.-C.; Jung, Y. S.; Cho, H. J.; Seo, D. J.; Ha, C.-
S. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2316.
(26) Geny, A.; Agenet, N.; Iannazzo, L.; Malacria, M.; Aubert, C.;
Gandon, V. Angew. Chem. Int. Ed. 2009, 48, 1810.
(27) Blake, J.; Tretter, J. R.; Juhasz, G. J.; Bonthrone, W.; Rapoport, H.
J. Org. Chem. 1966, 4061.
5852. (g) Schobert, R.; Jagusch, C. Synthesis 2005, 2421.
(
(
(
(
11) For a structural elucidation of carolic acid, see: Simonsen, O.;
Reffstrup, T.; Boll, P. M. Tetrahedron 1979, 36, 795.
12) For the biosynthesis of 1 and 2, see also: Bentley, R.; Bhate, D. S.;
Keil, J. G. J. Biol. Chem. 1962, 237, 859.
13) Boll, P. M.; Sorensen, E.; Balieu, E. Acta Chem. Scand. 1968, 22,
251.
14) (a) Haynes, L. J.; Plimmer, J. R.; Stanners, A. H. J. Chem. Soc. 1956,
661. (b) Haynes, L. J.; Plimmer, J. R. Chem. Ind. 1954, 37, 1147.
(28) Shin, I.; Lee, J.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem. 2000, 65,
7667.
(29) Zhu, S.-F.; Chen, C.; Cai, Y.; Zhou, Q.-L. Angew. Chem. Int. Ed.
2008, 47, 932.
3
4
(
15) Svendsen, A.; Boll, P. M. Tetrahedron 1973, 29, 4251.
(30) Schobert, R.; Stehle, R.; Walter, H. Tetrahedron 2008, 64, 9401.
(31) For the synthesis of 14 by means of periodate, see: Våbenø, J.;
Brisander, M.; Lejon, T.; Luthman, K. J. Org. Chem. 2002, 67,
9186.
(32) For a synthesis of 14 through ozonolysis, see: Bishop, J. E.;
O’Connell, J. F.; Rapoport, H. J. Org. Chem. 1991, 56, 5079.
(16) Ley, S. V.; Trudell, M. L.; Wadsworth, D. J. Tetrahedron 1991, 47,
8
285.
17) Bestmann, H. J.; Sandmeier, D. Angew. Chem., Int. Ed. Engl. 1975,
4, 634.
18) (a) Löffler, J.; Schobert, R. J. Chem. Soc., Perkin Trans. 1 1996,
(
(
1
2799. (b) Schobert, R.; Gordon, G. J. Curr. Org. Chem. 2002, 6,
1181. (c) Schobert, R.; Boeckman, R. K. Jr.; Pero, J. E. Org. Synth.
2005, 82, 140.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E