Duffy et al.
SCHEME 19. Total Synthesis of (+)-Maculalactone (45)
stereochemical integrity during this concise three-step sequence
to a tetronic acid from an acid chloride; however, a final
challenging coupling step led to erosion of enantiopurity of the
final product. Given the demonstrated rich reactivity of these
spiroheterocycles, further utilization of these novel intermediates
will likely continue to expand in the future and even more so
if practical methods for heteroketene dimer synthesis can be
developed.
Experimental Section
(R,Z)-3-Benzyl-4-(2-phenylethylidene)oxetan-2-one (11c): To
a solution of O-TMS-quinine (413 mg, 1.00 mmol) and diisopro-
pylethylamine (3.30 mL, 20.0 mmol) in CH2Cl2 (185 mL, 0.1 M)
at 22 °C was added hydrocinnamoyl chloride (3.52 g, 20.0 mmol)
over 10 min via syringe. After stirring for 6 h, the light yellow
solution was concentrated in vacuo to 35 mL (∼1/5 original
volume), and 200 mL of pentane was added to precipitate the
ammonium salts. After filtration through Whatmann filter paper,
the solution was concentrated and purified by flash chromatography
on SiO2 elution with 1:50 EtOAc/hexanes, giving dimer 11c (1.70
CH2Cl2); natural: [R]25D +70.2 (c ) 0.37, CH2Cl2).44 However,
the high enantiopurity of the initial dimerization and subsequent
Mosher ester analysis of the tetronic acid intermediate 45
verified that the reduced enantiopurity of maculalactone was
due to the triflation step when (i-Pr)2NEt was used (see Scheme
14). Epimerization could be avoided during triflation by use of
pyridine as base to give triflate (+)-46 in high optical purity
(97% ee, chiral HPLC) and improved yield. However, epimer-
ization during the final coupling step was not easily suppressed.
Indeed, the enantiomeric excess of synthetic maculalactone was
determined to be 75% ee by chiral HPLC, which is consistent
with measured rotation values. Interestingly, (+)-maculalactone
is isolated as a partially racemized natural product (85-95%
ee), and Brown and co-workers rigorously determined that this
was not due to the isolation procedure.35
g, 60%) as a pale yellow oil: Rf 0.40 (1:9 EtOAc/hexanes); [R]19
D
+13.5 (c ) 1.2, CH2Cl2); IR (thin film) νmax 1859, 1723, 1353,
1217 cm-1; 1H NMR (500 MHz, benzene-d6) δ 7.15-7.11 (m, 2H),
7.07-6.97 (m, 6H), 6.88-6.86 (m, 2H), 4.36 (t, J ) 10 Hz, 1H),
3.47 (t, J ) 5.0 Hz, 1H), 3.24 (d, J ) 5.0 Hz, 2H), 2.54 (dd, J )
14.5, 6.5 Hz, 1H), 2.45 (dd, J ) 14.5, 7.5 Hz, 1H); 13C NMR (125
MHz, benzene-d6) δ 167.9, 145.8, 140.0, 136.5, 129.1 (2), 128.7
(2), 128.6 (2), 128.5, 128.2, 127.1, 126.4, 101.0, 54.8, 33.0, 31.0.
LRMS calcd for C18H16O2Li [M + Li] 271, found 271. (Satisfactory
HRMS could not be obtained for ketene dimers).
Conclusions
(2S,3R,6R)-2,6-Dibenzyl-1,4-dioxaspiro[2.3]hexan-5-one (10c):
To a solution of (R,Z)-3-benzyl-4-(2-phenylethylidene)oxetan-2-
one (112 mg, 0.424 mmol) in CH2Cl2 (30 mL) at 0 °C were added
MgSO4 (25.0 mg, 0.83 mmol, ∼0.50 equiv) and an acetone solution
of DMDO14 (14 mL, 0.076 M, ∼2.5 equiv) in one portion to give
a pale yellow slurry which was warmed to 23 °C and stirred for
5 h. The reaction mixture was then filtered through a pad of MgSO4,
and the volatiles were removed by rotary evaporation. Purification
by flash chromatography (1:5 Et2O/hexanes) afforded spiroepoxy-
ꢀ-lactone 10c (68 mg, 57%, 24:1) as a clear oil: Rf 0.25 (1:5 Et2O/
hexanes); [R]23D -26.6 (c ) 1.0, CH2Cl2); IR (thin film) νmax 1854
Epoxidation of several functionalized ketene dimers leading
to novel spiroepoxy-ꢀ-lactones, oxaspiro[2.3]hexan-5-ones, was
accomplished by using the mild, neutral, and non-nucleophilic
oxidizing agent DMDO in moderate to good yields. An X-ray
crystal structure of a bis-cyclohexyl spiroepoxy-ꢀ-lactone
revealed several interesting physical characteristics and sug-
gested that a double anomeric effect may be operative, which
may explain the unexpected stability of these spirocycles. In
general, we found that cleavage of spiroepoxy-ꢀ-lactones
proceeds via two principal pathways involving attack at the distal
epoxide C-O bond and the ꢀ-lactone acyl C-O bond with no
evidence to date for nucleophilic additions to the ketal carbon.
Although the initial reaction manifold that was sought for
spiroepoxy-ꢀ-lactones has remained elusive to date, we found
a number of interesting reactions that reveal the unique reactivity
of these novel spiroheterocycles. We demonstrated the utility
of spiroepoxy-ꢀ-lactones as intermediates toward a number of
functional arrays but most notably the propensity of these
systems to rearrange to tetronic acids. The latter reaction was
applied to the enantioselective total synthesis of (+)-macula-
lactone A, and this synthesis demonstrated the ability to maintain
1
cm-1; H NMR (500 MHz, benzene-d6) δ 7.09-7.00 (m, 3H),
6.99-6.89 (m, 5H), 6.71-6.67 (m, 2H), 3.46 (dd, J ) 6.5, 8.0 Hz,
1H), 2.87 (app t, J ) 6.5 Hz, 1H), 2.72 (dd, J ) 6.5, 14.5 Hz, 1H),
2.55 (dd, J ) 6.5, 14.5 Hz, 1H), 2.41 (dddd, J ) 6.5, 8.0, 8.0, 15.5
Hz, 2H); 13C NMR (125 MHz, benzene-d6) δ 166.5, 136.1, 136.0,
129.1, 129.0(2), 128.8, 128.6(2), 127.2(2), 127.2(2), 90.8, 59.2, 54.3,
34.6, 31.0; HRMS (ESI) calcd for C18H16O3Li [M + Li] 287.1259,
found 287.1262.
(S)-(+)-3,5-Dibenzyl-4-hydroxyfuran-2(5H)-one (45): To a solu-
tion of spiroepoxy-ꢀ-lactone 10c (0.60 g, 2.1 mmol) in CH2Cl2 (40
mL, 0.05 M) was added N,O-dimethylhydroxylamine (0.23 mL,
3.1 mmol) and stirred at 23 °C for 6 h at which time the solution
had copious amounts of white solid. The suspension was concen-
trated to give tetronic acid 45 as a white solid. Purification by
recrystallization (1:10 EtOAc/Et2O) provided tetronic acid 45 (86%,
0.49 g) as white crystals: mp (159-162 °C); Rf 0.10 (8:2 EtOAc/
(43) Synthetic (+)-maculalactone was tested for its ability to inhibit the
formation of bacterial biofilms. For Gram-positive bacteria, modest anti-biofilm
activity was noted against vancomycin-resistant Enterococcus facium (VRE,
ATCC #51559) and methicillin-resistant Staphylococcus aureus (MRSA, ATCC
#BAA-44). A dose response study revealed IC50 values of 210 and 290 mM
against VRE and MRSA, respectively. Growth curves of each bacterial strain
grown in the presence or absence of (+)-maculalactone were identical, thus
indicating that activity was driven by a non-microbicidal mechanism. Macula-
lactone was also screened for its ability to inhibit biofilm development of two
Gram-negative strains of bacteria, Pseudomonas aeruginosa (PAO1) and multi-
drug-resistant Acinetobacter baumannii (ATCC #BAA-1605). However, no anti-
biofilm activity was noted.
hexanes); [R]20 +20.0 (c ) 1.00, CH3OH); IR (thin film) νmax
D
1715, 1650 cm-1; 1H NMR (500 MHz, CD3OD) δ 7.25-7.20 (m,
5H), 7.13-7.05 (m, 3H), 6.76 (d, J ) 7.5 Hz, 2H), 5.05 (t, J ) 4.3
Hz, 1H), 3.43-3.28 (obs, 2H), 3.01 (dd, J ) 5.0, 14.5 Hz, 1H);
13C NMR (125 MHz, CD3OD) δ 176.3, 175.8, 138.8, 134.8,
129.8(2), 128.1(2), 128.0(2), 127.7(2), 126.9, 125.6, 100.5, 78.3,
36.8, 26.3; HRMS (ESI) calcd for C18H16O3Na [M + Na] 303.0997,
found 303.0989.
(S)-2,4-Dibenzyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethane-
sulfonate (46): To a solution of tetronic acid 45 (31 mg, 0.11 mmol)
(44) Tsui, W.-Y.; Williams, G. A.; Brown, G. D. Phytochemistry 1996, 43,
1083.
4780 J. Org. Chem. Vol. 74, No. 13, 2009