Asymmetric synthesis of monocyclic β-lactams from l-cysteine using photochemistry

Article abstract of DOI:10.1016/j.tetlet.2011.07.085

An asymmetric method to synthesize cis-configured β-lactams using photochemistry has been developed. Aerobic photo-oxidation of l-cysteine-derived thiazolidine hydroxamate esters afforded C-3 hydroxylated products which when cyclized and deprotected gave

Full text of DOI:10.1016/j.tetlet.2011.07.085

Tetrahedron Letters 52 (2011) 5051–5054
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Tetrahedron Letters
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Asymmetric synthesis of monocyclic b-lactams from L-cysteine
using photochemistry
Xiao Lu a, Timothy E. Long a,b,
⇑
a Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA
b Center for Drug Discovery, University of Georgia, Athens, GA 30602, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric method to synthesize cis-configured b-lactams using photochemistry has been developed.
Received 5 July 2011
Revised 18 July 2011
Accepted 20 July 2011
Available online 27 July 2011
Aerobic photo-oxidation of L-cysteine-derived thiazolidine hydroxamate esters afforded C-3 hydroxyl-
ated products which when cyclized and deprotected gave the corresponding N-protio monocyclic
b-lactams.
Published by Elsevier Ltd.
Keywords:
Photo-oxidation
Pummerer rearrangement
b-Lactams
Thiazolidines
Hydroxamates
1. Introduction
H
H
N
H
H
N
S
S
RCOHN
RCOHN
For over 60 years, b-lactam antibacterials have been mainstays
as first-line treatments for infection due to their therapeutic effi-
cacy and inherent safety profile. Penicillins (e.g., ampicillin), ceph-
alosporins (e.g., cephalexin), and carbapenems (e.g., meropenem)
comprise the vast majority of b-lactams in clinical use today
(Fig. 1) and like many mechanistic classes of drugs, their biological
activity is predicated by the stereochemistry. As acylating agents of
bacterial cell wall transpeptidases, each family member functions
R'
CO2H
O
O
CO2H
penicillins
cephalosporins
H
H
N
HO
H
RCOHN
H
SR
N
O
as a suicide substrate by mimicking the D-configured peptides in
O
SO3H
CO2H
carbapenems
peptidoglycan. To date, a limited number of asymmetric methods
to synthesize a b-lactam nucleus with a proper configuration for
antibacterial activity have been reported. The most commonly em-
ployed is Miller’s biomimetic approach utilizing hydroxamate es-
monobactams
Figure 1. Families of b-lactam antibacterials used in therapy.
ters of L-serine and L
-threonine.1 The efficiency of this method
aided the development of aztreonam,2 a monobactam (Fig. 1) used
in the treatment of life-threatening Gram-negative infections such
as chronic pneumonia by Pseudomonas aeruginosa in cystic fibrosis
patients.
DMAD,4 NBS,3c or benzoyl peroxide.3a,b,5 The stereospecific reac-
tions generated predominately trans products that enabled subse-
quent cyclization to cis-configured b-lactams via intramolecular
SN2 substitution at the amide nitrogen.
Prior to 1980, L-cysteine was the amino acid of choice to prepare
An alternative approach we envisioned that could be used to
generate chiral b-lactams is to install a hydroxyl group at the C-3
methylene of L-cysteine-derived thiazolidines by aerobic photo-
oxidation (Scheme 2). The Pummerer-type rearrangement (i.e.,
lacks use of an acid/anhydride activator) described previously by
Ando6 offers a facile route to access an array of highly functional-
izable cis-configured b-lactams when merged with the cyclization
strategy by Miller. Herein, this Letter details the first asymmetric
synthetic penicillins,3 cephalosporins,4 and nocardicins.5 Each
respective b-lactam nucleus was constructed from N-protected
2,2-dimethylthiazolidines (e.g., 1, Scheme 1) and the ensuing func-
tionalizations at the C-3 methylene were accomplished with either
⇑
Corresponding author. Tel.: +1 706 542 8597; fax: +1 706 542 5358.
E-mail address: tlong@rx.uga.edu (T.E. Long).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.07.085

5052
X. Lu, T. E. Long / Tetrahedron Letters 52 (2011) 5051–5054
Table 1
O
Isolated yields of photo-oxidation products 3a–h
1. dry acetone
.
N
L
-Cys HCl
S
3
R
Entry
R
R0
Solvent
Product
Yield (%)
rfx, 2-5 h, 63%
2. ref. 7
1
2
Ph
Ph
Me
Bn
THF
THF
THF
PhH
MeCN
THF
THF
THF
THF
THF
3a
3b
3c
3c
3c
3d
3e
3f
80
68–73
48
HO2C
1
3
4
5
6
7
8
9
10
H
H
H
Ph
Bn
Bn
Bn
37
35
R=H, Ph, tBuO,
BnO, PhOCH2
CH2CO2Bn
CH2CO2Bn
CH2CO2Bn
CH2CO2tBu
Ac
67–84
58–73
53
60–68
44
tBuO
BnO
PhOCH2
PhOCH2
O
i
BuO2CCl, NMM
3g
3h
N
R
S
DCM, 0.5 h, 0oC
then NH2OR'
O
NHOR'
useful in the synthesis of cephalosporins,4 monobactams,2 and pen-
ems10 (entries 1–5), oxamazins11 (entries 6–9), and monosulfac-
tams12 (entry 10) were evaluated in the reaction. The photo-
oxidations were monitored by TLC, however, the hydroperoxide
intermediates were often indiscernible on the plates. This issue
was resolved by co-spotting with Me2S which converted the hydro-
peroxide to thiohemiacetal 3 on the TLC plate and allowing the
chemically stable product to be readily detected at a lower Rf value.
The reaction scales ranged from 0.4 to 2.0 g with a slight to moderate
decrease in the resulting yields (entries 2, 6–8) when over 1.0 g of
hydroxamate ester 2 was used. In many instances, the yields after
purification were P60%, with the highest consistently observed
for thiazolidines bearing an N-benzoyl protecting group.
The photo-oxidation products were next cyclized to the fused
thiazolidine b-lactam 4 (Scheme 3) using Miller’s strategy which
capitalizes on the acidity of hydroxamate esters. Unlike standard
amides (pKa P20) that require a strong base for lactam ring
formation,3–5 hydroxamate ester anions (pKa 610) can be readily
generated with mild tertiary amines to effect the cyclization. When
the method was applied to the synthesis of bicyclic lactams 4a and b,
the reaction was easily accomplished when MsCl and Et3N were
combined with the hydroxamate ester 3 in DCM and left overnight
in a ꢀ20 °C freezer.13 Alternatively at 0 °C, cyclization to O-methyl
lactam 4a was complete in less than 10 min while several hours
were required for the more sterically hindered O-benzyl analog 4b.
Regardless of the time and temperature, both reactions resulted in
yields of about 40%. This moderately low outcome was attributed
to the decomposition of the constrained lactams during isolation
as only trace impurities were observed in the 1H NMR spectra of
the crude reaction mixtures before silica gel chromatography.
2a
R=Ph, R'=Me, 80%
2b R=Ph, R'=Bn, 68%
2c
2d
R=H, R'=Bn, 48%
R=Ph, R'=CH2CO2Bn, 67%
2e R=tBuO, R'=CH2CO2Bn, 58%
2f
R=BnO, R'=CH2CO2Bn, 53%
t
2g R=PhOCH2, R'=CH2CO2 Bu, 60%
Scheme 1. Synthesis of thiazolidine hydroxamate esters 2.
O
O
1. O2, hv, TPP
N
N
S
S O
OH
R
R
THF, -10-0 oC
1.5-2 h
O
O
NHOR'
NHOR'
2
Pummerer-type
rearrangment
O
O
[-O]
N
S
N
S
R
R
2. Me2S, rt
2-3 h
O
OH
O
OOH
NHOR'
NHOR'
3
Scheme 2. Photo-oxidation of thiazolidine hydroxamate esters 2.
synthesis of N-protio monocyclic b-lactams from L-cysteine that is
facilitated by the aerobic photo-oxidation of thiazolidine hydroxa-
mate esters.
Bz
Bz
O
N
S
N
S
MsCl, Et3N
DCM, -20 oC
2. Results and discussion
H
H
N
OH
The hydroxamate esters (i.e., 2) screened in the photo-oxidation
O
OR
NHOR
reactions were prepared from
dimethylthiazolidine-4-carboxylates
previously described methods,7
-cysteine was first converted to
L
-cysteine via N-protected 2,2-
4a: R=Me, 38-41%
3
1
(Scheme 1). Following
4b:
R=Bn, 34-41%
1. SmI2, DCM
L
the corresponding 2,2-dimethylthiazolidine HCl salt under acetone
reflux. Various carbonyl protecting groups were then attached to
the ring nitrogen to afford acid 1. Conversion to hydroxamate
esters 2a–g was next achieved by the N-acylation of different
alkoxyamines8 via the isobutyl anhydride of acid 1. In comparison,
when the HOBt and NHS esters of acid 1 were used, multiple
products of similar polarities resulted that led to purified yields
of less than 30%.
The photo-oxidation of thiazolidines 2 (Scheme 2) was next
examined using singlet O2 generated from triplet O2 via a 500 W
halogen lamp in the presence of a photosensitizer, tetraphenylpor-
phyrin (TPP).9 Various hydroxamate esters (Table 1) that would be
ClSCO2Me
56-95%
2. ClSCO2Me
40%
AcOH, TFA
NaOAc, DMF
65%
H H
H H
BzHN
BzHN
SSCO2Me
SSCO2Me
4
N
N
O
H
O
OBn
5
6
Scheme 3. Synthesis of monocyclic b-lactams from thiohemiacetal 3b.

X. Lu, T. E. Long / Tetrahedron Letters 52 (2011) 5051–5054
5053
3. (a) Baldwin, J. E.; Christie, M. A.; Haber, S. B.; Kuse, I. K. J. Am. Chem. Soc. 1976,
98, 3045–3047; (b) Baldwin, J. E.; Au, A.; Christie, M. A.; Haber, S. B.; Hessan, H.
J. Am. Chem. Soc. 1975, 97, 5957–5958; (c) Nakatsuka, S.; Tanino, H.; Kishi, Y. J.
Am. Chem. Soc. 1975, 97, 5008–5010.
4. (a) Woodward, R. B. Science 1966, 153, 487–493; (b) Woodward, R. B.; Heusler,
K.; Gosteli, J.; Naegeli, J.; Oppolzer, W.; Ramage, R.; Ranganathan, S.;
Vorbrüggen, H. J. Am. Chem. Soc. 1966, 88, 852–853.
The conversion to monocyclic b-lactams was subsequently
examined by screening methods to cleave the thiazolidine with
mineral acids and mercury salts. In most instances, lactam 4b
was unreactive or the azetidinone ring could not tolerate the con-
ditions applied. Attention was then turned to the use of meth-
oxycarbonylsulfenyl (Scm) chloride which has served as
a
5. Koppel, G. A.; McShane, L.; Jose, F.; Cooper, R. D. G. J. Am. Chem. Soc. 1978, 100,
3933–3935.
deprotecting reagent of the thiazolidine rings in cysteine-contain-
ing peptides.14 Under the standard conditions with AcOH as the
solvent/catalyst, DMF to solubilize the peptide, water to promote
the hydrolysis, and NaOAc as a Clꢀ scavenger, the cleavage was
found to be slow and incomplete after 18 h. The problem was re-
solved by supplementing the reaction with a stronger acid catalyst
(i.e., TFA) and the monocyclic b-lactam 5 was obtained as a tritura-
ble white solid in 65% yield (Scheme 3).15
6. (a) Takata, T.; Hoshino, K.; Takeuchi, E.; Tamura, Y.; Ando, W. Tetrahedron Lett.
1984, 25, 4767–4770; (b) Takata, T.; Tamura, Y.; Ando, W. Tetrahedron 1985, 41,
2133–2137; (c) Takata, T.; Ishibashi, K.; Ando, W. Tetrahedron Lett. 1985, 26,
4609–4612; (d) Takata, T.; Huang, L.; Ando, W. Chem. Lett. 1985, 1705–1708;
(e) Takata, T.; Ando, W. Tetrahedron Lett. 1986, 27, 1591–1594; (f) Takata, T.;
Ando, W. Bull. Chem. Soc. Jpn. 1986, 59, 1275–1276.
7. (a) Iwakawa, M.; Pinto, B. M.; Szarek, W. A. Can. J. Chem. 1978, 56, 329–335; (b)
Sheehan, J. C.; Yang, D. H. J. Am. Chem. Soc. 1958, 80, 1158–1164; (c) Suaifan, G.
A. R.; Mahon, M. F.; Arafat, T.; Threadgill, M. D. Tetrahedron 2006, 62, 11245–
11266.
In the final stage of the reaction sequence to produce N-protio
monocyclic b-lactams, cleavage of the benzyloxy group was at-
tempted using a range of reducing agents (e.g., LAH, NaBH4, Zn
dust, and SmI2); however, the N-1/C-4 bond of lactam 5 proved
to be too labile in the reactions. With this impasse, it was realized
that removal of the alkoxy group before conversion to the monocy-
clic ring would be required for entry to N-protio b-lactams. Thus,
SmI2-mediated scission of the N–O bond16 followed by cleavage
of the thiazolidine successfully afforded the N-protio monocyclic
b-lactam 617 (Scheme 3) possessing the cis-configured azetidinone
nucleus of penicillins and cephalosporins.
8. (a) Shepherd, A.; Miller, M. J. J. Chem. Soc., Perkin Trans. 1 1990, 2519–2525; (b)
Shin, I.; Park, K. Org. Lett. 2002, 4, 869–872.
9. Photo-oxidation of thiazolidines 2; general procedure: To a 500 mL jacketed
beaker equipped with
tetraphenylporphyrin (17 mg, 28
a
circulating ꢀ10 to 0 °C bath was added
l
mol) and hydroxamate ester 2 (2.8 mmol)
in dry THF (55 mL). A 500 W halogen lamp was illuminated ca. 1 inch above the
beaker for 1.5 h while a stream of purified oxygen was bubbled into the
solution. Methyl sulfide (520 lL, 7.0 mmol) was next added and the solution
was left at rt until conversion to the thiohemiacetal was complete (2–3 h). The
solvent was then evaporated and the oil was purified by silica gel
chromatography using a 10–70% gradient of EtOAc in hexanes to afford the
product.
(4R,5S)-3-Benzoyl-N-(benzyloxy)-5-hydroxy-2,2-dimethylthiazolidine-4-car-
boxamide (3b): Yield: 68–73%; pale solid, mp: 64–66 °C; TLC (SiO2) Rf 0.28 (1:1
hexanes/EtOAc); ½a D28
ꢁ
: ꢀ58 (c 1, CHCl3); 1H NMR (500 MHz, DMSO-d6) d 11.20
(s, 1H), 7.46–7.28 (m, 10H), 6.64 (d, 1H, J = 3.0 Hz), 5.27 (d, 1H, J = 3.0 Hz), 4.72
3. Conclusion
and 4.62 (ABq, 2H,
Dv = 40.5 Hz, J = 11.0 Hz), 4.52 (s, 1H), 2.08–1.93 (m, 6H);
13C NMR (125 MHz, DMSO-d6) d 169.4, 165.4, 142.3, 139.4, 136.1, 129.5, 129.4,
128.9, 128.8, 128.7, 125.9, 78.9, 77.0, 75.2, 73.7, 32.3, 28.5.
10. Pfaendler, H. R.; Gosteli, J.; Woodward, R. B. J. Am. Chem. Soc. 1979, 101, 6306–
6310.
In summary, a new method to synthesize monocyclic b-lactams
from L-cysteine has been achieved with the use of photochemistry.
The aerobic photo-oxidations were scalable to at least 2 g and a
diversity of hydroxamate esters could be employed in the reac-
tions. Subsequent cyclizations to bicyclic b-lactams were found
to be clean and facile, though the stability of the constrained rings
likely had an adverse effect on the isolated yields. Evidence for this
was observed during our efforts to deprotect lactam 4 which fre-
quently resulted in the regeneration of the hydroxamate ester. Re-
moval of the N-alkoxy group prior to thiazolidine ring cleavage
successfully afforded the N-protio monocyclic b-lactam capable
of further elaboration into biologically active antibacterials.
11. (a) Woulfe, S. R.; Miller, M. J. Tetrahedron Lett. 1984, 25, 3293–3296; (b) Woulfe,
S. R.; Miller, M. J. J. Med. Chem. 1985, 28, 1447–1453; (c) Boyd, D. B.; Eigenbrot,
C.; Indelicato, J. M.; Miller, M. J.; Pasini, C. E.; Woulfe, S. R. J. Med. Chem. 1987,
30, 528–536.
12. (a) Gordon, E. M.; Ondetti, M. A.; Pluscec, J.; Cimarusti, C. M.; Bonner, D. P.;
Sykes, R. B. J. Am. Chem. Soc. 1982, 104, 6053–6060; (b) Agenoa, G.; Banfia, L.;
Casciob, G.; Guanti, G.; Manghisib, E.; Riva, R.; Roccaa, V. Tetrahedron 1995, 51,
8121–8134.
13. Cyclization of thiohemiacetals 3; general procedure: Thiohemiacetal
3
(2.0 mmol), mesyl chloride (318 L, 4.0 mmol) and Et3N (1.14 mL, 8.2 mmol)
l
were combined in 16 mL of DCM at 0 °C. The flask was capped and placed
overnight in a ꢀ20 °C freezer. The brown solution was then transferred to a
separatory funnel with 10 mL of DCM, washed with brine, dried over MgSO4,
filtered, and concentrated. Purification by silica gel chromatography using a 6–
50% gradient afforded the bicyclic b-lactam product.
Acknowledgments
(1R,5R)-2-Benzoyl-6-(benzyloxy)-3,3-dimethyl-4-thia-2,6-diazabicyclo[3.2.0]-
heptan-7-one (4b): Yield: 34–41%; white solid, mp: 104–106 °C; TLC (SiO2) Rf
0.26 (4:1 hexanes/EtOAc); ½a D28
ꢁ
: ꢀ122 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) d
The authors thank the American Foundation for Pharmaceutical
Education for its generous financial support of this research. Spe-
cial thanks are also given to the UGA College of Pharmacy and
Department of Pharmaceutical and Biomedical Sciences.
7.60–7.56 (m, 2H), 7.46–7.39 (m, 8H), 5.27 (d, 1H, J = 5.0 Hz), 5.17 (d, 1H,
J = 5.0 Hz), 5.09 and 5.03 (ABq, 2H,
Dv = 40.5 Hz, J = 11.0 Hz), 2.05 (s, 3H), 1.97
(s, 3H); 13C NMR (125 MHz, CDCl3) d 169.2, 162.6, 136.9. 134.0, 130.0, 129.2,
129.0, 128.8, 128.6, 126.8, 78.5, 76.8, 72.2, 69.3, 31.4, 29.9.
14. (a) Kemp, D. S.; Carey, Robert I. J. Org. Chem. 1989, 54, 3640–3646; (b) Yang, H.;
Sheng, X. C.; Harrington, E. M.; Ackermann, K.; Garcia, A. M.; Lewis, M. D. J. Org.
Chem. 1999, 64, 242–251.
Supplementary data
15. Thiazolidine ring cleavage of b-lactam 4b: Methoxycarbonylsulfenyl chloride
(57
l
L, 0.69 mmol) was added dropwise into an ice-chilled solution of b-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.085.
lactam (169 mg, 0.46 mmol) and NaOAc (76 mg, 0.92 mmol) in
a
12:2:1
solution of AcOH/DMF/TFA (2.25 mL). The solution was stirred at 0 °C for 1.5 h,
and then added with distilled water. The yellow solution was then transferred
to a separatory funnel with 10 mL of EtOAc, washed three times with distilled
water. The organic layer was then dried over MgSO4, filtered, and concentrated
giving a yellow solid which was triturated in a 4:1 solution of hexanes/EtOAc
to afford the monocyclic b-lactam product (125 mg, 0.29 mmol).
References and notes
1. (a) Mattingly, P. G.; Kerwin, J. F.; Miller, M. J. J. Am. Chem. Soc. 1979, 101, 3983–
3985; (b) Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin, J. F. J. Am. Chem.
Soc. 1980, 102, 7026–7032; (c) Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1980,
45, 410–415; (d) Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1981, 46, 1557–
1564; (e) Miller, M. J.; Biswas, A.; Krook, M. A. Tetrahedron 1983, 39, 2571–
2575; (f) Krook, M. A.; Miller, M. J. J. Org. Chem. 1985, 50, 1126–1128.
2. (a) Sykes, R. B.; Cimarusti, C. M.; Bonner, D. P.; Bush, K.; Floyd, D. M.;
Georgopapadakou, N. H.; Koster, W. M.; Liu, W. C.; Parker, W. L.; Principe, P. A.;
Rathnum, M. L.; Slusarchyk, W. A.; Trejo, W. H.; Wells, J. S. Nature (London)
1981, 291, 489–491; (b) Floyd, D. M.; Fritz, A. W.; Plusces, J.; Weaver, E. R.;
Cimarusti, C. M. J. Org. Chem. 1982, 47, 5160–5167; (c) Floyd, D. M.; Fritz, A. W.;
Cimarusti, C. M. J. Org. Chem. 1982, 47, 176–178; (d) Cimarusti, C. M.;
Applegate, H. E.; Chang, H. W.; Floyd, D. M.; Koster, W. H.; Slusarchyk, W. A.;
Young, M. G. J. Org. Chem. 1982, 47, 179–180.
SS-((2R,3R)-3-Benzamido-1-(benzyloxy)-4-oxoazetidin-2-yl) O-methyl carbon-
(dithioperoxoate) (5): Yield: 65%; white solid, mp: 139–141 °C; TLC (SiO2) Rf
0.12 (2:1 hexanes/EtOAc); ½a D28
ꢁ
: ꢀ16 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) d
7.82 (d, 2H, J = 7.5 Hz), 7.69 (1H, d, J = 7.0 Hz), 7.54–7.43 (m, 7H), 7.30 (s, 1H),
5.43 (m, 1H), 5.15 (s, 2H), 4.99 (d, 1H, J = 4.5 Hz), 3.85 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 169.3, 167.8, 161.7, 134.1, 132.9, 132.2, 129.5, 129.4, 128.8,
128.6, 127.5.
16. Keck, G. E.; Wager, T. T.; McHardy, S. F. Tetrahedron 1999, 55, 11755–11772.
17. Conversion to N-protio monocyclic b-lactam 6: To a stirring solution of b-lactam
4b (48 mg, 0.13 mmol) in dry DCM (1 mL) under Ar was added SmI2 in THF
(4.6 mL, 0.32 mmol). After 15 min, the reaction was quenched with 5% Na2S2O3
(1 mL) and 5% NaHCO3 (5 mL). The product was extracted with DCM, dried over

5054
X. Lu, T. E. Long / Tetrahedron Letters 52 (2011) 5051–5054
MgSO4, filtered, and evaporated. Purification by silica gel chromatography
using an 8–66% EtOAc in hexanes gradient afforded the N-protio bicyclic b-
lactam as colorless oil. Methoxycarbonylsulfenyl chloride (12 L,
and evaporated. Purification by silica gel chromatography using an 8–66%
EtOAc in hexanes gradient afforded the monocyclic b-lactam product (12 mg,
0.04 mmol).
a
l
0.145 mmol) was next added dropwise to an ice-chilled solution of the b-
lactam (25.5 mg, 0.096 mmol) and NaOAc (15.8 mg, 0.192 mmol) in a 12:2:1
mixture of AcOH/DMF/TFA (1 mL). The ice bath was removed and the solution
was stirred at rt for 15 min. Distilled water (2 mL) was then added and the
cloudy solution was transferred to a separatory funnel. The product was
extracted with EtOAc, washed with distilled water, dried over MgSO4, filtered,
SS-((2R,3R)-3-Benzamido-4-oxoazetidin-2-yl) O-methyl carbon-(dithioper-
oxoate) (6): Yield: 40%; white solid, mp: 161–163 °C; TLC (SiO2) Rf 0.18
(1:1 hexanes/EtOAc); ½a D22
ꢁ
: ꢀ16 (c 0.5, MeOH); 1H NMR (500 MHz, CD3OD) d
7.90 (d, 2H, J = 7.5 Hz), 7.57 (d, 1H, J = 7.5 Hz), 7.49 (t, 2H, J = 7.5 Hz), 5.49 (d,
1H, J = 4.5 Hz), 5.16 (d, 1H, J = 4.5 Hz), 3.87 (s, 3H); 13C NMR (125 MHz,
CD3OD) d 170.8, 170.7, 168.8, 134.8, 133.4, 129.8, 128.8, 69.8, 63.2, 56.6.