Biomimetic synthesis of functionalized γ-resorcylates from dioxinone derivatives

Article abstract of DOI:10.1002/ejoc.201402473

Biomimetic syntheses of functionalized γ-resorcylates from 2,2,6-trimethyl-4H-1,3-dioxin-4-one derivatives are reported. Cross metathesis of 2,2-dimethyl-6-vinyl-4H-1,3-dioxin-4-one with homoallylic esters or aldol reactions of tert-butyl or benzyl esters with 1-(2,2-dimethyl-4-oxo-4H-1,3- dioxin-6-yl)-acetone and related ketones followed by aromatization under mild Appel-type reaction conditions gave a range of γ-resorcylates.

Full text of DOI:10.1002/ejoc.201402473

FULL PAPER
DOI: 10.1002/ejoc.201402473
Biomimetic Synthesis of Functionalized γ-Resorcylates from Dioxinone
Derivatives
Peter S. Blencowe[a] and Anthony G. M. Barrett*[a]
Keywords: Biomimetic synthesis / Natural products / Cyclization / Metathesis / Acylation
Biomimetic syntheses of functionalized γ-resorcylates from
2,2,6-trimethyl-4H-1,3-dioxin-4-one derivatives are reported.
Cross metathesis of 2,2-dimethyl-6-vinyl-4H-1,3-dioxin-4-
one with homoallylic esters or aldol reactions of tert-butyl
or benzyl esters with 1-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-
yl)-acetone and related ketones followed by aromatization
under mild Appel-type reaction conditions gave a range of
γ-resorcylates.
We sought to extend our biomimetic syntheses of β-re-
sorcylates and salicylates, utilizing dioxinone compounds as
masked triketo and diketo esters, for flexible syntheses of
γ-resorcylates.[5] We considered that, akin to the Paquette
intramolecular C-acylation of dihydrofuran 3 (Scheme 1),
comparable reaction of dioxinone carboxylic acid 6 should
provide functionalized γ-resorcylates 5.[6] Alternatively, de-
hydrative cyclization of β-hydroxy acid 7 should also pro-
vide other γ-resorcylates 5 (Scheme 2). Herein we report the
syntheses and aromatization reactions of dioxinone deriva-
tives 6 and 7 with variation of the three R1, R2 and R3
substituents providing diverse γ-resorcylates 5.
Introduction
γ-Resorcylates (2,6-dihydroxybenzoates) have found use
in medicine, polymer science, dye synthesis and as ligands
for metal–organic chemistry.[1,2] Specifically, 3,5-Di-tert-
butyl-γ-resorcylic acid and its ester derivatives have shown
effectiveness against platelet aggregation and atherosclerosis
whereas the naturally occurring γ-resorcylate penicillide
and its derivatives have shown biological activity including
inhibition of cholesterol ester transfer protein and oxytocin
antagonism.[2] Efficient syntheses of functionalized resor-
cinols from resorcinol (1,3-hydroxybenzene) can be prob-
lematical and, as such, syntheses from non-aromatic precur-
sors may be used as alternatives.[3] Such syntheses of γ-re-
sorcylates are currently limited but an example from the
work of Doyle is summarized in Scheme 1.[4]
Scheme 2. Retrosynthetic analysis for the biomimetic synthesis of
γ-resorcylate 5.
Results and Discussion
Scheme 1. Doyle and Paquette syntheses of γ-and α-resorcylate de-
rivatives from non-aromatic precursors. Reagents and conditions:
(a) 10 mol-% NaOH in H2O, CH2Cl2, 2 h, 83 %; (b) (COCl)2,
CH2Cl2, reflux, 1.5 h, n = 1: 85%, n = 2: 77%.
Cross metathesis reaction of known vinyl dioxinone 9a,[7]
with tert-butyl ester 8a[8] in dichloromethane at reflux gave
unsaturated ester 10a in 82% yield (Table 1, Entry 1). Ester
deprotection of 10a with trifluoroacetic acid (TFA) gave
carboxylic acid 6a in 95% yield as a single regioisomer. In
contrast, attempted cross metathesis of vinyl dioxinone 9a
with ester 8b in dichloromethane was unsuccessful. How-
ever, reaction in perfluorotoluene as solvent at 70 °C with
[a] Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, England
E-mail: agm.barrett@imperial.ac.uk
www3.imperial.ac.uk/people/agm.barrett
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402473.
4844
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4844–4853

Biomimetic Synthesis of Functionalized γ-Resorcylates
Table 1. Synthesis of substrates 2a–c by cross-metathesis. Reagents and conditions: (a) see below; (b) CF3CO2H, CH2Cl2, 25 °C, 1.5–6 h.
Entry
8
9
R1
R2
R3
Cross metathesis conditions
10 [%]
6 [%]
1[a]
2[a]
3[a]
4[b]
5[b]
6[b]
7[b]
a
b
b
b
c
d
a
a
a
a
a
a
a
b
H
H
H
H
H
H
Me
H
H
H
H
H
Ph
H
H
11a[c], CH2Cl2, 2.5 h, 40 °C
11a[c], CH2Cl2, 2.5 h, 40 °C
11a[d], C6F5CF3, 16 h, 70 °C
11a[d], C6F5CF3, 2 h, 70 °C
11a[d], C6F5CF3, 2 h, 70 °C
11a,b or c[d] , C6F5CF3, 14 h, 70 °C
11a,b or c[d] , C6F5CF3, 16 h, 70 °C
10a (82)
10b (0)
6a (95)
6b (97)
Me
Me
Me
Bn
H
10b (43)
10b (68)
10c (61)
6c (96)
n/a
n/a
[e]
–
–
[e]
H
[a] 1:1.5 ratio of vinyl dioxinone 8/ester 9 used. [b] 1:3 ratio of vinyl dioxinone 8/ester 9 used. [c] 5 mol-% catalyst used. [d] 10 mol-%
catalyst used. [e] No cross-metathesis products observed.
catalyst 11a gave desired product 10b in 43% yield as a of 14a with TFA however, gave a complex mixture. As an
mixture of regioisomers (Table 1, Entry 3).[9] The use of alternative, dehydration of 14a–e using the Burgess reagent
3 equiv. of vinyl dioxinone 9a gave ester 10b in 68% yield gave esters 10d–h, all as mixtures of regioisomers, which
(Table 1, Entry 4). These reaction conditions were sub- were deprotected using TFA to provide the carboxylic acids
sequently applied to the cross metathesis of vinyl dioxinone 6d–g (Table 2). One exception was the reaction of tert-butyl
9a with ester 8c giving desired alkene 10c in 61% yield as a ester 10h with TFA, which gave pyrone 15 possibly due to
mixture of regioisomers (Table 1, Entry 5). The use of di- more rapid unsaturated ketene formation (Scheme 3).
substituted alkenes 8d and 9b, in cross metathesis reactions
with 9a and 8a respectively, was attempted (Table 1, Entries
6 and 7). However, none of the desired cross metathesis
products were formed, even when using metathesis catalysts
11b or 11c.[10] Deprotection of tert-butyl esters 10b and 10c
with TFA gave carboxylic acids 6b and 6c in 97 and 96%
yields respectively.
Scheme 3. Formation of pyrone 15. Reagents and conditions: (a)
CF3CO2H, CH2Cl2, 25 °C, 2 h, 74% yield.
Since highly substituted analogues of carboxylic acids 6
were not available using cross metathesis, an alternative
Aldol reaction of benzyl esters 16a–c with dioxinone
route was examined. Aldol reaction of dioxinone ketones ketones 12a–c gave expected aldol adducts and these were
12a–c with tert-butyl esters 13a–c gave corresponding β- directly hydrogenolyzed to give required carboxylic acids
hydroxy esters 14a–e (Table 2).[11] Attempted dehydration 7a–e directly (Table 3).
Table 2. Synthesis of carboxylic acids 6d–g via sequential aldol and dehydration reactions. Reagents and conditions: (a) LiN(iPr)2, THF,
–78 °C, 0.25 h; (b) Et3N+SO2N–CO2Me (Burgess reagent), MeCN, 70 °C, 2–4 h; (c) CF3CO2H, CH2Cl2, 25 °C, 0.5–2.5 h.
Entry
12
13
R1
R2
R3
14 [%]
10 [%]
6 [%]
1
2
3
4
5
12a
12a
12a
12b
12c
13a
13b
13c
13b
13a
H
H
H
Bn
H
Me
Me
Me
Me
H
14a 48
14b 50
14c 42
14d 50
14e 52
10d 77
10e 77
10f 75
10g 82
10h 81
6d 76
6e 97
6f 98
6g 85
–
Me
Ph
Me
H
p-C6H4OMe
Eur. J. Org. Chem. 2014, 4844–4853
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P. S. Blencowe, A. G. M. Barrett
FULL PAPER
Table 3. Synthesis of substrates 7a–e using an aldol addition–
hydrogenolysis sequence. Reagents and conditions: (a) LiN(iPr)2,
THF, –78 °C, 0.25 h; (b) H2, Pd/C (10%), THF, 25 °C, 0.5 h.
Table 4. Cyclization reactions of 6 and 7. Reagents and conditions:
(a) 6a–g, CCl4 (1.2 equiv.), PPh3 (1.5 equiv.), CH2Cl2, reflux, 3 h;
(b) 7a–e, [CCl4 (2.5 equiv.)], PPh3 (3.0 equiv.), CH2Cl2, reflux, 3 h.
Entry 12
16
R1
R2
R3
7 [%]
1
3
5
2
4
12a
16a
16a
16a
16b
16c
H
Bn
H
Bn
H
Me
Me
p-MeO-C6H4
Me
Me
H
H
H
Me
Ph
7a 38
7b 56
7c 43
12b
12c
12b
12a
7d 41
7e[12] 19
With a range of dioxinone carboxylic acids 6 and 7 in
hand, conditions for their aromatization were developed.
Using carboxylic acid 6a as a test substrate, various reac-
tion conditions were examined to activate the carboxylic
acid moiety for dioxinone C-5 acylation to provide γ-resor-
cylate 5a (see Supporting Information Table S1). The use
of Paquette’s reaction conditions with oxalyl chloride in
dichloromethane at reflux gave γ-resorcylate 5a but only in
9% yield accompanied by decomposition. In contrast, for-
mation of the acid chloride under Appel type reaction con-
ditions with triphenylphosphine (1.5 equiv.) and carbon
tetrachloride (1.2 equiv.) in dichloromethane at reflux gave
γ-resorcylate 5a (76%). These reaction conditions were
applied for the aromatization of substrates 6 and 7
(Table 4).
The aromatization of carboxylic acids 6a–f and 7a–c to
give γ-resorcylates 5a–f, 5h and 5i proceeded in good yields
and gave the corresponding substituted aromatic com-
pounds. Generally speaking, aromatization proceeded as
expected except for in a few instances. When applied to car-
boxylic acid 6e, heating at 70 °C was necessary to achieve
an acceptable yield of γ-resorcylate, presumably due to
steric hindrance.[13] When the aromatization conditions
were applied to the even more sterically demanding carbox-
ylic acid 6g, desired hexa-substituted resorcylate 5g was not
produced but only decomposition of the material was ob-
served. Targeting resorcylate 5g again, but from β-hydroxy
acid 7d, β-lactone 17a was produced in 62% yield. Forma-
tion of β-lactones appeared to be preferred over aromatiza-
tion when utilizing β-hydroxy acids 7 substituted in the α-
position since reaction of carboxylic acid 7e under aromati-
zation conditions gave rise to corresponding β-lactone 17b
in 31% yield.[14] However, desired gamma resorcylate 5f was
synthesized from carboxylic acid 6f where β-lactone forma-
tion posed a reduced risk.
Direct comparison of the efficiency of aromatization of
unsaturated acids 6 and β-hydroxy acids 7 is possible for
carboxylic acids 6d and 7a, which both gave γ-resorcylate
5d in 67 and 42% yields respectively. The lower yield for
[a] 1,2-Dichloroethane used as solvent at 70 °C.
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Eur. J. Org. Chem. 2014, 4844–4853

Biomimetic Synthesis of Functionalized γ-Resorcylates
General Procedure A for the Cross Metathesis of Alkenes 8a–8c with
Alkenes 9a–9b: Catalyst 11a (5–10 mol-%) was added with stirring
to vinyl dioxinone 9a (1.5–3 equiv.) and homoallylic ester (8a–8c,
0.15 m) in CH2Cl2 at reflux or C6F5CF3 at 70 °C and heating was
continued for 2–2.5 h. The mixture was rotary evaporated and
chromatographed to give dioxinone (10a–c).
aromatization of hydroxy-acid 7a may have been the result
of a competitive acid catalyzed retro-aldol reaction. The
routes developed for the aromatization reactions of carbox-
ylic acids 6 and 7 are complimentary to each other in that
they allow the synthesis of differentially substituted γ-resor-
cylates; use of cross metathesis allowed generation of resor-
cylates 5b–c bearing an R3 substituent wherein R1 and R2
= H. Conversely, the use of aldol additions to dioxinone
ketones 12a–c generated 5d–f, 5h and 5i and stipulates that
a substituent at R2 is always present (i.e. R2 ϶ H) although
R1 or R3 could be incorporated. When resorcylate 5i was
inaccessible from 10h due to formation of pyrone 15, syn-
thesis of requisite hydroxy acid 7c and its aromatization was
possible. Additionally, γ-resorcylate 5f was available from
carboxylic acid 6f when attempted cyclization of the corre-
sponding hydroxy-acid 7e gave rise to the β-lactone 17b.
General Procedure B for Deprotection of the tert-Butyl Esters 10a–
h: CF3CO2H (10 equiv.) was added with stirring to ester (10a–h,
0.4 m) in CH2Cl2 at 25 °C. After 0.5–6 h, the resulting mixture was
rotary evaporated and the residue dissolved in diethyl ether (10 mL)
and extracted with saturated aqueous NaHCO3 (5ϫ 5 mL). The
aqueous layer was acidified to pH 1 using 3 m aqueous HCl and
the mixture extracted with EtOAc (3ϫ 20 mL). The combined
EtOAc layers were washed with brine, dried (MgSO4), and rotary
evaporated to give carboxylic acids 6a–g and 15.
General Procedure C for Aldol Reaction of Esters 13a–c with
Ketones 12a–c: nBuLi in hexanes (2.5 m, 1.2 equiv.) was added
dropwise with stirring to (iPr)2NH (1.2 equiv.) in THF (10 mL) at
0 °C. After 15 min, the mixture was cooled to –78 °C and ester
(13a–c, 1.0 equiv.) in THF (5 mL) was added dropwise. After an-
other 1 h, dioxinone ketone (12a–c, 1.0 equiv.) in THF (5 mL) was
added dropwise. After a further 15 min, AcOH (1.3 equiv.) in THF
(5 mL) was added dropwise. Water (20 mL) was added and the mix-
ture extracted with EtOAc (3ϫ 40 mL). The combined organic ex-
tracts were washed with brine, dried (MgSO4), rotary evaporated,
and chromatographed to give the corresponding esters 14a–e.
Conclusions
Three complimentary routes for the synthesis of substi-
tuted γ-resorcylates have been developed. The methods pro-
vide a versatile modular approach for the synthesis of acids
6 and 7, which undergo aromatization under mild condi-
tions to give γ-resorcylates selectively incorporating up to 2
alkyl and/or aryl substituents. This method also provides
access to 4-substituted γ-resorcylates not previously readily
available.
General Procedure D for Dehydration of β-Hydroxy Esters 14a–e:
Et3N+SO2N–CO2Me (Burgess reagent) (1.5 equiv.) was added with
stirring to β-hydroxy-ester (14a–e, 0.2 m) in MeCN at 70 °C and
heating continued for 2–4 h. The residue was rotary evaporated and
chromatographed to give the corresponding esters 10d–10h.
General Procedure E for Aldol Reaction of Esters 16a–c with
Ketones 12a–c Followed by Hydrogenolysis: nBuLi in hexanes
(2.5 m, 1.2 equiv.) was added dropwise with stirring to (iPr)2NH
(1.2 equiv.) in THF (10 mL) at 0 °C. After 15 min, the mixture was
cooled to –78 °C and ester 16a–c (1.0 equiv.) in THF (5 mL) was
added dropwise. After a further 1 h, dioxinone ketone 12a–c
(1.0 equiv.) in THF (5 mL) was added dropwise. After another
15 min, AcOH (1.3 equiv.) in THF (5 mL) was added dropwise.
Water (20 mL) was added and the mixture was extracted with
EtOAc (3ϫ 40 mL) and the combined organic extracts were
washed with brine, dried (MgSO4), the solvent evaporated under
vacuum and the residue dissolved in THF (20 mL). N2 was bubbled
through the mixture for 5 min, when Pd/C (10% by wt.) was added
and H2 was bubbled through the mixture for 5 min, which was
stirred under an H2 atmosphere for 30 min. The mixture was fil-
tered through celite, rotary evaporated and the residue worked up
as in general procedure B to give carboxylic acids 7a–e.
Experimental Section
General Methods: All reactions were carried out in oven-dried
glassware under N2, using commercially supplied solvents and
reagents unless otherwise stated. CH2Cl2 was redistilled from CaH2
and THF was redistilled from Na–benzophenone ketyl. Flash
chromatography was carried out on silica gel (eluents are given in
parentheses). Analytical TLC was performed using pre-coated sil-
ica gel F254 aluminum plates with visualization under UV light and
by staining with acidic vanillin or acidic potassium permanganate
solutions. Melting points were determined using a hot-stage micro-
scope. IR spectra are recorded as thin films. 1H and 13C NMR
spectra were recorded at 400 and 101 MHz respectively, with the
solvent used in each case specified and spectra referenced to resid-
ual solvent peaks. Where mixtures of regioisomers (rr = re-
gioisomer ratio) have been characterized together integrals are
normalized to the major isomer.
General Procedure F for the Aromatization of Carboxylic Acids 6 or
7: CCl4 (1.2 equiv. for 6, 2.5 equiv. for 7) was added with stirring
to Ph3P (1.5 equiv. for 6, 3.0 equiv. for 7) and carboxylic acid 6a–
g or 7a–e (0.5 m) in CH2Cl2 and the mixture heated at reflux for
3 h. The mixture was rotary evaporated and chromatographed to
give γ-resorcylates 5a–5f, 5h and 5i or β-lactones 17a and 17b.
Esters 13a–b and 16a–c were available from commercial suppliers.
Homoallylic ester 8a was prepared as described previously from
crotonoyl chloride and tert-butanol.[8] Homoallylic esters 8b[15] and
8c[16] were prepared from tert-butyl crotonate by deconjugative alk-
ylation.[17] Homoallylic ester 8d[18] was prepared by a Horner–
Wadsworth Emmons reaction of tert-butyl diethyl phosphonoacet-
ate with acetophenone followed by deconjugative deprotonation
and reprotonation. Dioxinones 9a,[7] 12a[19] and 12c[19] were pre-
pared following literature procedures. Dioxinone 9b was prepared
from tert-butyl 4-methyl-3-oxopent-4-enoate by condensation with
acetone.[20] tert-butyl phenylacetate 13c was prepared from the 1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) mediated
coupling of phenylacetic acid and tert-butyl alcohol.[21]
2,2-Dimethyl-6-(prop-1-en-2-yl)-4H-1,3-dioxin-4-one (9b): (CF3-
CO)2O (5.72 mL, 37.4 mmol), CF3CO2H (28.4 mL, 370 mmol) and
Ac2O (4.4 mL, 47 mmol) were added dropwise with stirring to tert-
butyl 4-methyl-3-oxopent-4-enoate in Me2CO at –78 °C and the
mixture was warmed to 25 °C. After 14 h, the mixture was poured
into cold saturated aqueous NaHCO3 (800 mL) and extracted with
EtOAc (2ϫ 100 mL). The combined organic phases were dried
Eur. J. Org. Chem. 2014, 4844–4853
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4847

P. S. Blencowe, A. G. M. Barrett
FULL PAPER
(MgSO4), filtered, rotary evaporated and chromatographed (pent-
(1.504 g, 5.61 mmol) for 2 h gave carboxylic acid 6a (1.130 g, 95%)
ane/Et2O, 95:5 to 90:10) to give dioxinone 9b (353 mg, 33%) as a
as an amorphous tan solid. IR: ν = 1743, 1682, 1621, 1586, 1399,
˜
yellow oil. IR: ν = 1721, 1635, 1593, 1391 1369, 1283, 1253, 1202,
1379, 1277, 1264, 1201, 1136, 1096, 1024, 979, 938, 909, 859, 834,
˜
1
1146, 1016, 998, 921, 903, 887, 820, 754, 617 cm–1. 1H NMR
797, 752, 681 cm–1. H NMR (400 MHz, CDCl3): δ = 9.94 (br. s,
(400 MHz, CDCl3): δ = 5.80 (s, 1 H), 5.47 (s, 1 H), 5.37–5.40 (m, 1 H), 6.61 (dt, J = 15.6, 7.3 Hz, 1 H), 6.06 (d, J = 15.6 Hz, 1 H),
1 H), 1.92 (s, 3 H), 1.70 (s, 6 H) ppm. 13C NMR (101 MHz,
5.34 (s, 1 H), 3.31 (d, J = 7.3 Hz, 2 H), 1.72 (s, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 175.6, 162.3, 162.0, 131.8, 126.0, 106.7,
CDCl3): δ = 164.5, 162.0, 135.3, 121.1, 106.2, 92.8, 24.9, 18.1 ppm.
MS (ESI): m/z = 210 [M + MeCN + H]+, 169 [M + H]+. HR-MS 94.9, 37.2, 25.0 ppm. MS (ESI: m/z = 213 [M + H]+. HR-MS (ESI)
(ESI): m/z calcd. for C9H13O3: 169.0865 [M + H]+, found 169.0869.
m/z calcd. for C10H13O5: 213.0763 [M + H]+, found 213.0753.
(E)-tert-Butyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)but-3-eno-
ate (10a): According to general procedure A, cross metathesis of
ester 8a (615 mg, 4.33 mmol) and dioxinone 9a (1.00 g, 6.49 mmol)
with catalyst 11a (136 mg, 0.217 mmol) in CH2Cl2 (30 mL) at re-
flux for 2.5 h and chromatography (pentane/Et2O, 9:1 to 4:1) gave
dioxinone ester 10a (948 mg, 82%) as a pale yellow solid; m.p. 112–
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-methylbut-3-enoic
Acid (6b): According to general procedure B, deprotection of ester
10b (108 mg, 0.383 mmol) for 1.5 h gave carboxylic acid 6b (84 mg,
97%, 1.0:0.9 rr) as a brown oil. IR: ν = 1698, 1649, 1591, 1458,
˜
1391, 1376, 1273, 1200, 1125, 1097, 1015, 970, 903, 857, 805, 744,
683, 614 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.78 (br. s, 1.9
H), 6.86 (t, J = 7.3 Hz, 1 H), 6.63 (dd, J = 15.7, 7.8 Hz, 0.9 H),
6.04 (d, J = 15.6 Hz, 0.9 H), 5.36 (s, 0.9 H), 5.32 (s, 1 H), 3.34–
3.38 (m, J = 7.1 Hz, 0.9 H), 3.16 (d, J = 7.3 Hz, 2 H), 1.89 (s, 3
H), 1.72 (m, 11.4 H), 1.40 (d, J = 6.8 Hz, 2.7 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 178.6, 172.1, 167.9, 162.5, 161.0, 140.0,
138.3, 134.9, 131.2, 123.9, 106.9, 106.6, 94.9, 94.1, 42.3, 32.9, 25.0,
24.9, 16.5, 12.3 ppm. MS (ESI: m/z = 225 [M – H]–. HR-MS (ESI)
m/z calcd. for C11H13O5: 225.0763 [M – H]–, found 225.0762.
114 °C (CH Cl /pentane). IR: ν = 1715, 1656, 1592, 1388, 1374,
˜
2
2
1365, 1278, 1258, 1215, 1203, 1180, 1144, 1092, 973, 948, 935, 904,
870, 841, 796, 765, 750 cm–1. 1H NMR (400 MHz, CDCl3): δ =
6.61 (dt, J = 15.6, 7.3 Hz, 1 H), 5.99 (dt, J = 15.7, 1.5 Hz, 1 H),
5.28 (s, 1 H), 3.16 (dd, J = 7.3, 1.5 Hz, 2 H), 1.70 (s, 6 H), 1.46 (s,
9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.4, 162.5, 161.7,
133.5, 125.2, 106.4, 94.4, 81.6, 38.8, 28.0, 25.0 ppm. MS (ESI) m/z
269 [M + H]+. HR-MS (ESI) m/z calcd. for C14H21O5: 269.1389
[M + H]+, found 269.1384.
(؎)-2-Benzyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)but-3-enoic
Acid (6c): According to general procedure B, deprotection of ester
10c (120 mg, 0.335 mmol) for 6 h gave carboxylic acid 6c (97 mg,
tert-Butyl (؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-meth-
ylbut-3-enoate (10b): According to general procedure A, cross me-
tathesis of ester 8b (80 mg, 0.51 mmol) and dioxinone 9a (237 mg,
1.54 mmol) with catalyst 11a (32 mg, 0.05 mmol) in C6F5CF3
(3 mL) at 70 °C for 2 h and chromatography (pentane/Et2O, 95:5
to 17:3) gave dioxinone ester 10b (98 mg, 68 %, 1:0.75 rr) as a
96%, 1.0:0.8 rr) as a brown oil. IR: ν = 1707, 1649, 1592, 1391,
˜
1377, 1275, 1255, 1200, 1101, 1017, 968, 905, 857, 803, 738,
698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.37 (br. s, 1.8 H),
7.12–7.36 (m, 9 H), 7.03 (t, J = 7.6 Hz, 0.8 H), 6.53 (dd, J = 15.7,
8.8 Hz, 1 H), 5.89 (d, J = 15.6 Hz, 1 H), 5.27 (s, 1 H), 5.26 (s, 0.8
H), 3.73 (s, 1.6 H), 3.40–3.57 (m, 1.8 H), 3.15–3.26 (m, 1.8 H),
2.88–2.97 (m, 1 H), 1.72 (s, 6 H), 1.69 (s, 4.8 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 177.2, 171.6, 167.6, 162.2, 161.9, 161.0,
138.1, 137.3, 136.8, 136.4, 134.2, 129.0, 128.7, 128.6, 128.1, 127.0,
126.6, 125.4, 107.0, 106.7, 95.1, 94.4, 50.5, 38.2, 33.2, 32.1, 25.0,
25.0 ppm. MS (ESI: m/z = 320 [M + NH4]+, 303 [M + H]+. HR-MS
(ESI) m/z calcd. for C17H19O5: 303.1232 [M + H]+, found 303.1239.
brown oil. IR: ν = 1724, 1653, 1637, 1595, 1458, 1390, 1369, 1271,
˜
1252, 1202, 1149, 1125, 1065, 1015, 966, 901, 846, 804, 743 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.57–6.64 (m, 1.75 H), 5.96 (dd,
J = 15.7, 1.0 Hz, 1 H), 5.30 (s, 1 H), 5.27 (s, 0.75 H), 3.14–3.24 (m,
1 H), 3.08 (d, J = 7.3 Hz, 1.5 H), 1.83 (s, 2.25 H), 1.72 (s, 6 H), 1.70
(s, 4.5 H), 1.50 (s, 6.75 H), 1.46 (s, 9 H), 1.31 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 172.4, 168.5, 166.4,
162.8, 161.8, 161.0, 140.0, 133.7, 130.9, 123.1, 106.8, 106.5, 94.5,
93.9, 81.3, 80.8, 43.6, 32.8, 28.1, 28.0, 25.1, 25.0, 16.9, 12.7 ppm.
MS (ESI: m/z = 283 [M + H]+. HR-MS (ESI) m/z calcd. for
C15H23O5: 283.1545 [M + H]+, found 283.1550.
4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-methylbut-3-enoic Acid
(6d): According to general procedure B, deprotection of ester 10d
(440 mg, 1.56 mmol) for 0.5 h gave carboxylic acid 6d (268 mg,
tert-Butyl (؎)-2-Benzyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-
but-3-enoate (10c): According to general procedure A, cross a
metathesis of ester 8c (150 mg, 0.647 mmol) and dioxinone 9a
(299 mg, 1.94 mmol) with catalyst 11a (41 mg, 0.07 mmol) in
C6F5CF3 (4 mL) at 70 °C for 2.5 h and chromatography (pentane/
Et2O, 19:1 to 4:1) gave dioxinone ester 10c (142 mg, 61%, 1:0.25
76%, 1.0:0.6:0.5:0.4 rr) as a brown gum. IR: ν = 1698, 1642, 1582,
˜
1561, 1391, 1375, 1275, 1251, 1201, 1163, 1015, 969, 902, 856, 827,
805, 752, 694, 639, 612 cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.01 (br. s, 2.5 H), 6.09 (s, 1 H), 5.83 (s, 0.4 H), 5.79 (s, 1 H), 5.34–
5.36 (m, 1 H), 5.33 (s, 1 H), 5.21 (s, 0.6 H), 5.18 (s, 0.6 H), 3.56 (s,
1.2 H), 3.21 (s, 2 H), 3.17 (s, 1.2 H), 3.13 (s, 1 H), 3.08 (s, 0.8 H),
2.22 (s, 1.2 H), 2.18 (s, 1.5 H), 2.15 (s, 3 H), 1.64–1.80 (m,
15 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 176.3, 175.5, 172.6,
171.0, 169.0, 167.4, 164.4, 162.9, 162.4, 161.6, 161.1, 156.3, 155.7,
154.5, 154.2, 144.1, 134.7, 121.5, 121.0, 119.7, 119.2, 112.1, 108.8,
107.0, 106.8, 106.4, 95.5, 95.2, 95.1, 94.3, 93.9, 46.1, 44.7, 40.9,
40.1, 39.3, 38.9, 37.1, 27.2, 25.1, 24.9, 21.4, 19.6, 19.0 ppm. MS
(ESI: m/z = 249 [M + Na]+, 227 [M + H]+. HR-MS (ESI) m/z
calcd. for C11H15O5: 227.0919[M + H]+, found 227.0930.
rr) as a brown oil. IR: ν = 1720, 1651, 1593, 1496, 1478, 1455,
˜
1391, 1369, 1273, 1250, 1202, 1144, 1018, 970, 902, 843, 806, 740,
699 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.12–7.32 (m, 6.25 H),
6.77 (t, J = 7.3 Hz, 0.25 H), 6.55 (dd, J = 15.7, 8.8 Hz, 1 H), 5.87
(d, J = 15.7 Hz, 1 H), 5.25 (s, 1.25 H), 3.67 (s, 0.5 H), 3.31–3.40
(m, 1 H), 3.06–3.17 (m, 1.5 H), 2.82–2.92 (m, 1 H), 1.71 (s, 6 H),
1.68 (s, 1.5 H), 1.41 (s, 9 H), 1.36 (s, 2.25 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 171.3, 168.2, 166.0, 162.5, 161.7, 160.8,
138.9, 138.1, 137.8, 136.6, 132.5, 129.1, 128.5, 128.4, 128.1, 126.7,
126.3, 124.4, 106.8, 106.5, 94.7, 94.1, 81.6, 81.1, 51.7, 38.7, 32.9,
32.6, 27.9 27.9, 25.0, 25.0 ppm. MS (ESI: m/z = 376 [M + NH4]+,
359 [M + H]+. HR-MS (ESI) m/z calcd. for C21H27O5: 359.1858
[M + H]+, found 359.1865. C21H26O5 (358.43): calcd. C 70.37, H
7.31; found C 70.26, H 7.38.
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2,3-dimethylbut-3-
enoic Acid (6e): According to general procedure B, deprotection of
ester 10e (550 mg, 1.86 mmol) for 1 h gave carboxylic acid 6e
(433 mg, 97%, 1.0:0.5:0.5 rr) as a yellow oil. IR: ν = 1718, 1642,
˜
1
1579, 1392, 1377, 1276, 1204, 1078, 1018, 905, 810 cm–1. H NMR
(E)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)but-3-enoic Acid (6a):
According to general procedure B, deprotection of ester 10a
(400 MHz, CDCl3): δ = 8.61 (br. s, 2 H), 6.04 (s, 0.5 H), 5.78 (s,
1 H), 5.33 (s, 0.5 H), 5.32 (s, 1 H), 5.23 (s, 0.5 H), 5.14 (s, 0.5 H),
4848
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4844–4853

Biomimetic Synthesis of Functionalized γ-Resorcylates
3.52 (s, 1 H), 3.27 (q, J = 6.8 Hz, 1 H), 3.20 (q, J = 7.2 Hz, 0.5 H), (pentane/Et2O, 4:1 to 3:2) to give dioxinone ketone 12b (663 mg,
3.02–3.11 (m, 1 H), 2.13 (s, 1.5 H), 2.07 (s, 3 H), 2.04 (s, 1.5 H),
1.73 (s, 9 H), 1.67–1.68 (m, 3 H), 1.32–1.38 (m, 4.5 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 179.1, 178.3, 173.0, 169.3, 164.6,
164.0, 162.3, 161.5, 152.0, 149.8, 149.5, 140.3, 120.1, 119.8, 117.1,
109.9, 106.7, 106.3, 95.6, 94.3, 49.6, 44.9, 39.2, 38.7, 25.2, 25.1,
25.0, 24.8, 19.5, 17.3, 15.8, 15.4, 12.2 ppm. MS (ESI: m/z = 241 [M
+ H]+. HR-MS (ESI) m/z calcd. for C12H17O5: 241.1076 [M + a
H]+, found 241.1087. C12H16O5 (240.26): calcd. C 59.99, H 6.71;
found C 59.87, H 6.63.
45%) as a pale yellow oil. IR: ν = 1718, 1627, 1497, 1455, 1390,
˜
1375, 1358, 1271, 1253, 1200, 1151, 1079, 1009, 968, 901, 854, 810,
747, 699, 612 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.12–7.34
(m, 5 H), 5.32 (s, 1 H), 3.57–3.64 (m, 1 H), 3.23 (dd, J = 14.2,
6.8 Hz, 1 H), 2.95 (dd, J = 14.2, 8.3 Hz, 1 H), 2.19 (s, 3 H), 1.61 (s,
6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 202.5, 166.8, 160.4,
137.4, 128.7, 127.0, 107.0, 96.0, 59.0, 33.8, 29.5, 25.0, 24.8 ppm.
MS (ESI: m/z = 292 [M + NH4]+, 275 [M + H]+. HR-MS (ESI)
m/z calcd. for C16H19O4: 275.1283 [M + H]+, found 275.1291.
C16H18O4 (274.32): calcd. C 70.06, H 6.61; found C 70.16, H 6.73.
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-methyl-2-phenyl-
but-3-enoic Acid (6f): According to general procedure B, deprotec-
tion of ester 10f (470 mg, 1.31 mmol) for 2.5 h gave carboxylic acid
tert-Butyl (؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-
hydroxy-3-methylbutanoate (14a): According to general procedure
C, aldol reaction of ester 13a (731 μL, 5.43 mmol) and dioxinone
ketone 12a (1.00 g, 5.43 mmol) gave, after chromatography (pent-
ane/Et2O, 7:3 to 3:2), dioxinone ester 14a (775 mg, 48%) as a yel-
6f (390 mg, 98%, 1.0:1.0:0.8 rr) as a yellow gum. IR: ν = 1710,
˜
1631, 1581, 1494, 1455, 1390, 1375, 1274, 1254, 1200, 1165, 1078,
1017, 984, 963, 904, 875, 807, 783, 752, 699, 640, 617 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 9.93 (br. s, 2.8 H), 7.18–7.46 (m,
14 H), 6.19 (s, 0.8 H), 5.79 (s, 1 H), 5.31 (s, 1 H), 5.24–5.29 (m,
3 H), 4.46 (s, 1 H), 4.40 (s, 1 H), 3.60 (s, 1.6 H), 3.02 (d, J =
15.7 Hz, 1 H), 2.90 (d, J = 15.7 Hz, 1 H), 2.04–2.08 (m, 5.4 H), 1.72
(s, 10.8 H), 1.66 (s, 3 H), 1.65 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 176.7, 176.1, 172.7, 168.9, 164.4, 162.7, 162.1, 161.4,
153.8, 151.3, 147.9, 139.1, 135.1, 134.9, 133.4, 129.8, 128.9, 128.8
128.8, 128.4, 128.1, 124.8, 120.6, 118.3, 109.9, 106.7, 106.4, 95.9,
94.5, 61.0, 56.7, 39.4, 38.8, 25.1, 25.0, 24.9, 24.8, 20.4, 18.8 ppm.
MS (ESI: m/z = 320 [M + NH4]+, 303 [M + H]+. HR-MS (ESI)
m/z calcd. for C17H19O5: 303.1232 [M + H]+, found 303.1235.
low oil. IR: ν = 1713, 1629, 1390, 1369, 1273, 1249, 1202, 1150,
˜
116, 1091, 1014, 963, 901, 814 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 5.31 (s, 1 H), 4.06 (s, 1 H), 2.40–2.53 (m, 4 H), 1.70 (s, 3 H),
1.70 (s, 3 H), 1.48 (s, 9 H), 1.30 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 172.0, 168.0, 160.9, 106.5, 96.2, 82.1, 70.5, 45.4, 45.3,
28.0, 27.4, 25.2, 25.1 ppm. MS (ESI: m/z = 623 [M2 + Na]+, 601
[M2 + H]+. HR-MS (ESI) m/z calcd. for C30H49O12: 601.3224 [M2
+ H]+, found 601.3231.
tert-Butyl (؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-
hydroxy-2,3-dimethylbutanoate (14b): According to general pro-
cedure C, aldol reaction of ester 13b (820 μL, 5.43 mmol) and diox-
inone ketone 12a (1.00 g, 5.43 mmol) gave, after chromatography
(pentane/Et2O, 7:3 to 1:1), dioxinone ester 14b (845 mg, 50 %,
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-methyl-3-methyl-
ene-5-phenylpentanoic Acid (6g): According to general procedure B,
deprotection of ester 10g (300 mg, 0.777 mmol) for 2 h gave carbox-
1.0:0.6 dr) as a yellow oil. IR: ν = 1721, 1630, 1458, 1390, 1368,
˜
1273, 1255, 1204, 1148, 1008, 1076, 1013, 933, 901, 847, 811 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.32 (s, 1.0 H), 5.31 (s, 0.6 H),
3.91 (br. s, 0.6 H), 3.55 (br. s, 1.0 H), 2.41–2.53 (m, 3.8 H), 2.33 (d,
J = 13.7 Hz, 1.0 H), 1.70 (s, 9.6 H), 1.46–1.48 (m, 14.4 H), 1.29 (s,
3 H), 1.19–1.22 (m, 6.6 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 176.0, 175.3, 168.3, 168.2, 160.9, 106.5, 106.4, 96.4, 96.2, 81.9,
81.8, 72.7, 72.5, 48.7, 47.5, 45.3, 42.4, 28.0, 26.0, 25.2, 25.0, 23.9,
12.4, 12.3 ppm. MS (CI: m/z = 332 [M + NH4]+, 315 [M + H]+.
HR-MS (CI) m/z calcd. for C16H30NO6: 332.2073 [M + NH4]+,
found 332.2070. C16H26O6 (314.38): calcd. C 61.13, H 8.34; found
C 60.95, H 8.45.
ylic acid 6g (217 mg, 85%) as a yellow oil. IR: ν = 1702, 1455,
˜
1391, 1377, 1273, 1201, 1166, 1076, 1018, 905, 854, 810, 731, 698,
1
647, 606 cm–1. H NMR (400 MHz, CDCl3): δ = 9.90 (br. s, 1 H),
7.05–7.33 (m, 5 H), 5.37 (s, 1 H), 5.35 (s, 1 H), 5.26 (s, 1 H), 3.36
(m, 1 H), 3.17 (q, J = 7.3 Hz, 1 H), 2.97–3.09 (m, 2 H), 1.60 (s, 3
H), 1.55 (s, 3 H), 1.24 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 179.1, 170.9, 161.7, 144.3, 138.0, 128.8,
128.4, 126.7, 115.7, 106.7, 94.1, 49.8, 45.2, 37.4, 25.0, 24.5,
15.9 ppm. MS (ESI: m/z = 348 [M + NH4]+, 331 [M + H]+. HR-MS
(ESI) m/z calcd. for C19H23O5: 331.1545 [M + H]+, found 331.1541.
C19H22O5 (330.38): calcd. C 69.07, H 6.71; found C 69.20, H 6.63.
tert-Butyl (؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-
hydroxy-3-methyl-2-phenylbutanoate (14c): According to general
procedure C, aldol reaction of ester 13c (1.04 g, 5.43 mmol) and di-
oxinone ketone 12a (1.00 g, 5.43 mmol) gave, after chromatography
(pentane/Et2O, 9:1 to 1:1), dioxinone ester 14c (853 mg, 42%, 1:0.8
2-[4-(4-Methoxyphenyl)-2-oxo-2H-pyran-6-yl]acetic Acid (15): Ac-
cording to general procedure B, reaction of ester 10h (329 mg,
0.880 mmol) for 2 h gave pyrone 15 (206 mg, 74%) as a yellow so-
lid; decomposition (-CO ) 148 °C (MeOH). IR: ν = 1729, 1671,
˜
2
1619, 1598, 1580, 1544, 1517, 1433, 1401, 1323, 1314, 1291, 1272,
1248, 1186, 1146, 1122, 1055, 1019, 1006, 895, 862, 846, 827, 802,
dr) as a colorless gum. IR: ν = 1721, 1630, 1455, 1390, 1369, 1273,
˜
1251, 1203, 1146, 1088, 1014, 955, 900, 863, 808, 754, 701,
622 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.29–7.41 (m, 9 H),
5.34 (s, 0.8 H), 5.26 (m, 1 H), 4.42 (s, 0.8 H), 3.97 (s, 1 H), 3.57 (s,
1 H), 3.54 (s, 0.8 H), 2.62 (d, J = 13.7 Hz, 0.8 H), 2.57 (d, J =
13.7 Hz, 0.8 H), 2.36 (d, J = 14.2 Hz, 1 H), 2.13 (d, J = 13.7 Hz,
1 H), 1.75 (s, 2.4 H), 1.74 (s, 2.4 H), 1.71 (s, 3 H), 1.70 (s, 3 H),
1.40–1.42 (m, 19.2 H), 1.04 (s, 2.4 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 173.6, 173.0, 168.4, 168.1, 160.9, 160.9, 134.7, 134.6,
129.7, 129.5, 128.4, 128.4, 127.8, 127.7, 106.6, 106.4, 96.6, 96.4,
82.5, 82.3, 73.4, 73.2, 60.4, 59.0, 46.1, 42.9, 27.9, 26.6, 25.3, 25.2,
25.1, 24.8 ppm. MS (CI: m/z = 394 [M + NH4]+, 376 [M]+. HR-
MS (CI) m/z calcd. for C21H32NO6: 394.2230[M + NH4]+, found
394.2219. C21H28O6 (376.45): calcd. C 67.00, H 7.50; found C
66.73, H 7.64.
1
741, 730, 712, 694, 640, 624 cm–1. H NMR (400 MHz, CD3OD):
δ = 7.36–7.44 (m, 2 H), 6.69–6.78 (m, 2 H), 6.34 (d, J = 1.5 Hz,
1 H), 6.07 (d, J = 1.5 Hz, 1 H), 3.56 (s, 3 H), 3.27 (s, 2 H) ppm. 13
C
NMR (101 MHz, CD3OD): δ = 151.3, 144.6, 143.9, 140.9, 136.0,
110.8, 110.4, 97.0, 89.6, 86.4, 37.4, 21.5 ppm. MS (ESI: m/z = 302
[M + MeCN + H]+, 261 [M + H]+. HR-MS (ESI) m/z calcd. for
C14H13O5: 261.0763 [M + H]+, found 261.0779. C14H12O5 (260.25):
calcd. C 64.61, H 4.65; found C 64.46, H 4.74.
(؎)-2,2-Dimethyl-6-(3-oxo-1-phenylbutan-2-yl)-4H-1,3-dioxin-4-one
(12b): PhCH2Br (711 μL, 5.98 mmol) was added with stirring to
dioxinone ketone 12a (1.00 g, 5.43 mmol) and iPr2NH (845 μL,
5.98 mmol) in THF (5.5 mL). After 14 h, the mixture was acidified
to pH 1 with 1 m aqueous HCl and extracted with EtOAc (2ϫ
20 mL). The combined organic extracts were washed with brine,
dried (MgSO4), filtered, rotary evaporated and, chromatographed
tert-Butyl (؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-
hydroxy-2,3-dimethyl-5-phenylpentanoate (14d): According to gene-
Eur. J. Org. Chem. 2014, 4844–4853
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4849

P. S. Blencowe, A. G. M. Barrett
FULL PAPER
ral procedure C, aldol reaction of ester 13b (341 μL, 2.26 mmol)
and dioxinone ketone 12b (620 mg, 2.26 mmol) gave, after
chromatography (pentane/Et2O, 4:1 to 13:7), dioxinone ester 14d
(d, J = 6.8 Hz, 3.6 H), 1.23 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 172.7, 172.1, 169.3, 164.7, 164.0, 161.9,
161.8, 161.1, 150.8, 150.4, 141.4, 119.5, 118.9, 115.7, 106.5, 106.2,
106.1, 95.2, 95.1, 94.4, 81.1, 80.9, 80.8, 50.8, 45.9, 42.9, 39.3, 28.1,
27.9, 25.1, 24.9, 24.9, 21.2, 17.3, 16.0, 15.6, 15.3 ppm. MS (ESI:
m/z = 314 [M + NH4]+, 297 [M + H]+. HR-MS (ESI) m/z calcd. for
(452 mg, 50%) as a colorless gum. IR: ν = 1731, 1699, 1629, 1494,
˜
1456, 1392, 1374, 1366, 1345, 1320, 1291, 1272, 1258, 1203, 1160,
1141, 1095, 1069, 1018, 972, 944, 900, 855, 845, 832, 809, 753, 736,
702, 983, 658, 615 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.22– C16H25O5: 297.1702 [M + H]+, found 297.1704. C16H24O5 (296.36):
7.29 (m, 2 H), 7.10–7.21 (m, 3 H), 5.06 (s, 1 H), 4.29 (s, 1 H), 3.30–
3.42 (m, 1 H), 2.75–2.83 (m, 2 H), 2.49 (q, J = 7.3 Hz, 1 H), 1.55
(s, 3 H), 1.52 (s, 3 H), 1.48 (s, 9 H), 1.30 (d, J = 7.3 Hz, 3 H), 1.22
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 177.0, 170.0,
160.5, 139.3, 128.7, 128.4, 126.4, 106.4, 96.7, 82.2, 74.3, 55.9, 46.1,
32.7, 27.9, 25.0, 20.1, 12.9 ppm. MS (CI: m/z = 405 [M + H]+.
HR-MS (CI) m/z calcd. for C23H33O6: 405.2277 [M + H]+, found
405.2267. C23H32O6 (404.50): calcd. C 68.29, H 7.97; found C
68.44, H 8.11.
calcd. C 64.84, H 8.16; found C 64.91, H 8.20.
(؎)-tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-methyl-
2-phenylbut-3-enoate (10f): According to general procedure D, de-
hydration of β-hydroxy ester 14c (750 mg, 1.99 mmol) for 3.5 h and
chromatography (pentane/Et2O, 17:3 to 3:1) gave dioxinone ester
10f (532 mg, 75%, 1.0:1.0:0.7 rr) as a yellow oil. IR: ν = 1721,
˜
1640, 1601, 1583, 1495, 1455, 1390, 1369, 1311, 1272, 1250, 1202,
1138, 1079, 1014, 967, 901, 875, 854, 806, 754, 699, 626 cm–1. H
1
NMR (400 MHz, CDCl3): δ = 7.10–7.34 (m, 13.5 H), 5.76 (s,
tert-Butyl (؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3- 0.7 H), 5.61 (s, 1 H), 5.47 (s, 0.7 H), 5.25 (s, 0.7 H), 5.18 (s, 1 H),
hydroxy-3-(4-methoxyphenyl)butanoate (14e): According to general
procedure C, aldol reaction of ester 13a (729 μL, 5.43 mmol) and
dioxinone ketone 12c (1.50 g, 5.43 mmol) gave, after chromatog-
raphy (pentane/Et2O, 4:1 to 3:1), dioxinone ester 14e (1.10 g, 52%)
5.16 (s, 1 H), 5.08-5.11 (m, 2 H), 4.24 (s, 1 H), 4.17 (s, 1 H), 2.92
(d, J = 15.7 Hz, 1 H), 2.80 (d, J = 14.7 Hz, 1 H), 1.97 (s, 3 H), 1.76
(s, 2.1 H), 1.67 (s, 2.1 H), 1.62–1.66 (m, 8.1 H), 1.57–1.61 (m, 6 H),
1.42 (s, 6.3 H), 1.37–1.40 (m, 18 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 170.6, 170.2, 169.0, 164.6, 163.7, 161.8, 161.7, 161.1,
149.2, 148.9, 140.3, 137.2, 136.2, 136.0, 128.8, 128.8, 128.8, 128.7,
as a yellow gum. IR: ν = 1721, 1644, 1583, 1458, 1390, 1369, 1319,
˜
1373, 1251, 1203, 1147, 1084, 1047, 1015, 901, 877, 848, 805, 744,
605 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.29–7.35 (m, 2 H), 128.6, 128.3, 127.7, 127.6, 127.2, 120.5, 120.1, 117.4, 106.5, 106.4,
6.82–6.88 (m, 2 H), 5.14 (s, 1 H), 4.61 (s, 1 H), 3.80 (s, 3 H), 2.88
(d, J = 15.2 Hz, 1 H), 2.79 (d, J = 15.7 Hz, 1 H), 2.68 (s, 2 H),
1.56 (s, 3 H), 1.51 (s, 3 H), 1.29 (s, 9 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.5, 167.4, 161.0, 158.8, 135.9, 126.3, 113.4, 106.4,
96.5, 82.2, 74.2, 55.3, 46.7, 46.2, 27.8, 25.0, 24.9 ppm. MS (CI: m/z
= 410 [M + NH4]+. HR-MS (CI) m/z calcd. for C21H32NO7:
410.2179 [M + NH4]+, found 410.2171. C21H28O7 (392.45): calcd.
C 64.27, H 7.19; found C 64.19, H 7.30.
106.1, 95.6, 95.6, 94.5, 81.9, 81.7, 81.5, 77.3, 77.2, 76.7, 62.2, 57.8,
54.1, 39.5, 28.0, 27.9, 25.2, 25.1, 25.0, 24.8, 23.1, 18.9 ppm. MS
(ESI: m/z = 376 [M + NH4]+, 359 [M + H]+. HR-MS (ESI) m/z
calcd. for C21H27O5: 359.1858 [M + H]+, found 359.1866.
C21H26O5 (358.43): calcd. C 70.39, H 7.31; found C 70.26, H 7.45.
(؎)-tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2-methyl-
3-methylene-5-phenylpentanoate (10g): According to general pro-
cedure D, dehydration of β-hydroxy ester 14d (404 mg, 1.00 mmol)
tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-methylbut- for 2 h and chromatography (pentane/Et2O, 4:1) gave dioxinone es-
3-enoate (10d): According to general procedure D, dehydration of
β-hydroxy ester 14a (726 mg, 2.42 mmol) for 2.5 h and chromatog-
raphy (pentane/Et2O, 3:1 to 7:3) gave dioxinone ester 10d (527 mg,
ter 10g (317 mg, 82%) as a yellow oil. IR: ν = 1724, 1626, 1456,
˜
1390, 1369, 1345, 1271, 1250, 1202, 1145, 1095, 1075, 1017, 901,
847, 810, 745, 699 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.11–
7.32 (m, 5 H), 5.27 (s, 2 H), 5.21 (s, 1 H), 3.34 (t, J = 7.8 Hz, 1 H),
2.95–3.06 (m, 3 H), 1.59 (s, 3 H), 1.55 (s, 3 H), 1.42 (s, 9 H), 1.21
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 172.8,
170.7, 161.1, 145.5, 138.3, 128.6, 128.4, 126.6, 114.0, 106.5, 94.5,
80.9, 50.4, 46.1, 37.2, 27.9, 25.2, 24.5, 16.3 ppm. MS (ESI: m/z =
387 [M + H]+. HR-MS (ESI) m/z calcd. for C23H31O5: 387.2171
77%, 1.0:0.4:0.4:0.3 rr) as a yellow oil. IR: ν = 1721, 1649, 1584,
˜
1458, 1389, 1368, 1322, 1272, 1250, 1202, 1139, 1014, 956, 901,
1
874, 851, 804, 753, 695, 657 cm–1. H NMR (400 MHz, CDCl3): δ
= 5.79 (s, 1 H), 5.66–5.72 (m, 0.8 H), 5.25–5.30 (m, 2.1 H), 5.09 (d,
J = 12.7 Hz, 0.6 H), 3.61 (s, 0.4 H), 3.37 (s, 1.2 H), 3.02–3.09 (m,
2.2 H), 2.98 (d, J = 4.4 Hz, 1 H), 2.14 (d, J = 1.5 Hz, 0.6 H), 2.08
(d, J = 1.0 Hz, 1.8 H), 1.98 (d, J = 1.0 Hz, 3 H), 1.69–1.73 (m, [M + H]+, found 387.2175. C23H30O5 (386.49): calcd. C 71.48, H
8.4 H), 1.67 (s, 3.6 H), 1.48 (s, 1.8 H), 1.44–1.46 (m, 17.7 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 169.9, 169.3, 169.1, 169.0, 167.9,
164.4, 163.9, 161.9, 149.1, 148.7, 145.3, 145.0, 136.0, 121.8, 121.7,
120.7, 120.3, 118.5, 106.7, 106.5, 106.2, 106.1, 95.2, 94.9, 94.9, 94.4,
93.7, 81.4, 81.2, 81.1, 80.3, 47.9, 44.5, 42.4, 40.9, 40.1, 36.6, 28.2,
28.1, 28.0, 28.0, 26.9, 25.1, 25.0, 24.9, 19.5, 18.4 ppm. MS (ESI:
m/z = 305 [M + Na]+, 283 [M + H]+. HR-MS (ESI) m/z calcd. for
C15H23O5: 283.1545 [M + H]+, found 283.1547.
7.82; found C 71.56, H 7.93.
tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-(4-methoxy-
phenyl)but-2-enoate (10h): According to general procedure D, de-
hydration of β-hydroxy ester 14e (486 mg, 1.24 mmol) for 4 h and
chromatography (pentane/Et2O, 4:1 to 7:3) gave dioxinone ester
10h (376 mg, 81%, 1:0.4 rr) as a yellow oil. IR: ν = 1725, 1702,
˜
1624, 1602, 1513, 1390, 1369, 1274, 1250, 1203, 1180, 1139, 1029,
1012, 970, 901, 877, 832, 804, 731 cm–1 1H NMR (400 MHz,
.
(؎)-tert-Butyl 4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-2,3-di- CDCl3): δ = 7.37–7.39 (m, 2 H), 7.11–7.13 (m, 0.8 H), 6.89–6.91
methylbut-3-enoate (10e): According to general procedure D, de-
hydration of β-hydroxy ester 14b (815 mg, 2.60 mmol) for 2 h and
chromatography (pentane/Et2O, 4:1 to 3:1) gave dioxinone ester 10e
(m, 2 H), 6.84–6.86 (m, 0.8 H), 6.17 (s, 1 H), 5.94 (s, 0.4 H), 5.42
(s, 1 H), 5.14 (s, 0.4 H), 3.83 (s, 5 H), 3.81 (s, 1.2 H) 3.35 (0.8 H),
1.76 (s, 6 H), 1.44 (s, 2.4 H), 1.40 (s, 9 H), 1.33 (s, 3.6 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 169.6, 169.3, 165.5, 164.2, 161.8,
161.3, 160.3, 159.5, 148.7, 144.9, 133.8, 132.0, 127.9, 127.8, 120.6,
(590 mg, 77%, 1.0:0.6:0.6 rr) as a yellow oil. IR: ν = 1721, 1644,
˜
1583, 1458, 1390, 1369, 1318, 1271, 1250, 1202, 1145, 1085, 1014,
900, 875, 848, 804, 744 cm–1. 1H NMR (400 MHz, CDCl3): δ = 119.8, 114.1, 114.0, 106.6, 106.4, 96.1, 93.8, 81.3, 80.6, 55.3, 55.3,
5.71 (s, 1.0 H), 5.69 (s, 0.6 H), 5.31 (s, 0.6 H), 5.30 (s, 0.6 H), 5.26
(s, 1.0 H), 5.13 (s, 0.6 H), 5.04 (s, 0.6 H), 3.11 (q, J = 7.2 Hz, 1.0 H),
2.96–3.06 (m, 2.4 H), 2.01–2.02 (m, 3 H), 1.86 (d, J = 1.0 Hz,
39.2, 34.1, 28.2, 27.9, 25.1, 24.8 ppm. MS (ESI: m/z = 392 [M +
NH4]+, 375 [M + H]+. HR-MS (ESI) m/z calcd. for C21H26O6:
375.1808 [M + H]+, found 375.1820. C21H26O6 (374.43): calcd. C
1.8 H), 1.71 (s, 9.6 H), 1.66–1.67 (m, 3.6 H), 1.43 (s, 19.8 H), 1.26 67.36, H 7.00; found C 67.21, H 7.09.
4850 Eur. J. Org. Chem. 2014, 4844–4853
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Biomimetic Synthesis of Functionalized γ-Resorcylates
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxy-3-methyl-
butanoic Acid (7a): According to general procedure E, aldol reac-
tion of dioxinone ketone 12a (1.00 g, 5.43 mmol) and benzyl acet-
ate 16a (815 mg, 5.43 mmol) gave, after hydrogenolysis, carboxylic
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxy-3-methyl-
2-phenylbutanoic Acid (7e): According to general procedure E,
aldol reaction of dioxinone ketone 12a (1.00 g, 5.43 mmol) and
benzyl phenylacetate 16c (1.23 g, 5.43 mmol) gave, after
hydrogenolysis, carboxylic acid 7e (325 mg, 19%, 1.0:0.8 dr) as a
yellow oil. Alternatively, carboxylic acid 7e was synthesized by ad-
dition of the dianion derived from PhCH2CO2H to dioxinone
ketone 12a. nBuLi in hexanes (13.6 mL, 32.6 mmol) was added
dropwise with stirring to (iPr)2NH (4.61 mL, 32.6 mmol) in THF
(30 mL) at 0 °C. After 15 min, PhCH2CO2H (2.22 g, 16.3 mmol) in
acid 7a (500 mg, 38%) as a yellow gum. IR: ν = 1714, 1658, 1624,
˜
1501, 1463, 1435, 1419, 1390, 1378, 1326, 1289, 1258, 1205, 1188,
1159, 1116, 1098, 1052, 1021, 972, 964, 928, 905, 886, 865, 848,
1
821, 790, 754, 698, 677, 621 cm–1. H NMR (400 MHz, CDCl3): δ
= 6.00 (br. s, 1 H), 5.39 (s, 1 H), 2.69 (d, J = 17.1 Hz, 1 H), 2.62
(d, J = 16.1 Hz, 1 H), 2.56 (s, 2 H), 1.73 (s, 3 H), 1.72 (s, 3 H), 1.39
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 175.6, 167.8, THF (20 mL) was added dropwise with stirring. After 30 min, the
161.2, 106.8, 96.5, 70.5, 45.4, 44.2, 27.6, 25.1, 25.1 ppm. MS (CI:
m/z = 262 [M + NH4]+, 245 [M + H]+. HR-MS (CI) m/z calcd. for
C11H20NO6: 262.1291 [M + NH4]+, found 262.1285.
solution was heated at 50 °C for 2 h. After cooling to –78 °C, dioxi-
none ketone 12a (3.00 g, 16.3 mmol) in THF (10 mL) was added
dropwise. After a further 20 min, AcOH (2.42 mL, 42.3 mmol) in
THF (10 mL) was added dropwise. Water (100 mL) was added and
the mixture extracted with EtOAc (3ϫ 100 mL). The combined
organic extracts were washed with brine, dried (MgSO4), rotary
evaporated, and chromatographed (CH2Cl2/MeOH/AcOH,
99:0.9:0.1 to 95:4.9:0.1) to give carboxylic acid 7e (2.00 g, 38%,
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxy-3-methyl-
5-phenylpentanoic Acid (7b): According to general procedure E,
aldol reaction of dioxinone ketone 12b (204 mg, 0.745 mmol) and
benzyl acetate 16a (112 mg, 0.745 mmol) gave, after hydrogenolysis,
carboxylic acid 7b (140 mg, 56%, 1.0:0.4 dr) as a colorless gum.
1.0:0.8 dr) as a yellow oil. IR: ν = 1702, 1626, 1497, 1455, 1390,
˜
IR: ν = 1702, 1623, 1497, 1456, 1391, 1377, 1272, 1255, 1200, 1120,
˜
1375, 1275, 1257, 1200, 1175, 1088, 1016, 906, 810, 725, 700, 644,
1075, 1020, 956, 858, 811, 731, 699, 647 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.12–7.29 (m, 7.0 H), 5.23 (s, 0.4 H), 5.21 (s, 1.0 H),
3.25 (dd, J = 13.4, 3.2 Hz, 1.0 H), 3.14 (d, J = 11.7 Hz, 0.4 H),
2.60–2.93 (m, 5.6 H), 1.49–1.54 (m, 8.4 H), 1.45 (s, 1.2 H), 1.41 (s,
3.0 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 176.2, 176.1, 170.0,
161.2, 138.5, 138.2, 128.7, 128.5, 126.7, 126.6, 106.8, 97.1, 96.7,
72.2, 55.7, 55.4, 43.3, 43.0, 32.8, 32.3, 25.8, 25.2, 25.1, 24.8, 24.7,
24.5 ppm. MS (ESI: m/z = 376 [M + MeCN + H]+, 352 [M +
NH4]+, 335 [M + H]+. HR-MS (ESI) m/z calcd. for C18H23O6:
335.1495 [M + H]+, found 335.1507.
1
624 cm–1. H NMR (400 MHz, CDCl3): δ = 7.32–7.44 (m, 9.0 H),
5.40 (s, 1.0 H), 5.29 (s, 0.8 H), 3.75 (s, 0.8 H), 3.72 (s, 1.0 H), 2.59
(s, 2.0 H), 2.49 (d, J = 14.2 Hz, 0.8 H), 2.16–2.22 (m, 0.8 H), 1.72
(s, 3 H), 1.71 (s, 3 H), 1.69, (s, 2.4 H) 1.68 (s, 2.4 H), 1.42 (s, 2.4
H), 1.11 (s, 3.0 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 177.3,
177.0, 168.3, 168.1, 161.6, 161.4, 133.9, 133.8, 129.8, 129.7, 128.7,
128.6, 128.3, 128.2, 106.9, 106.7, 96.6, 96.6, 73.5, 73.2, 59.9, 58.6,
45.8, 42.6, 26.5, 25.2, 25.0, 24.7 ppm. MS (ESI: m/z = 362 [M +
+
M
e
C
N
+
H
]
,
3
3
8
[
M
+
NH4]+, 321 [M + H]+. HR-MS (ESI) m/z calcd. for C17H21O6:
321.1338 [M + H]+, found 321.1365.
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxy-3-(4-meth-
oxyphenyl)butanoic Acid (7c): According to general procedure E,
aldol reaction of dioxinone ketone 12c (1.00 g, 5.43 mmol) and
benzyl acetate 16a (815 mg, 5.43 mmol) gave, after hydrogenolysis,
5-Hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (5a):[22] Ac-
cording to general procedure F, aromatization of acid 6a (100 mg,
0.472 mmol) and chromatography (pentane/Et2O, 95:5) gave resor-
cylate 5a (70 mg, 76%) as a colorless solid; m.p. 63–64 °C (CH2Cl2/
carboxylic acid 7c (784 mg, 43%) as a yellow gum. IR: ν = 1712,
˜
1680, 1621, 1586, 1515, 1461, 1430, 1393, 1375, 1332, 1288, 1257,
1200, 1168, 1122, 1101, 1046, 1022, 936, 907, 889, 846, 829, 817,
pentane). IR: ν = 1687, 1631, 1584, 1469, 1385, 1343, 1277, 1249,
˜
1205, 1167, 1151, 1079, 1056, 1047, 970, 920, 850, 803, 778, 688,
775, 754, 717, 701, 677, 637, 616 cm–1 1H NMR (400 MHz,
.
1
666, 631, 620 cm–1. H NMR (400 MHz, CDCl3): δ = 10.35 (s, 1
CDCl3): δ = 7.28–7.34 (m, 2 H), 6.83–6.90 (m, 2 H), 5.15 (s, 1 H),
3.80 (s, 3 H), 2.89–3.05 (m, 2 H), 2.69–2.80 (m, 2 H), 1.51, (s, 3 H),
1.50 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 176.0, 167.3,
161.3, 159.0, 135.4, 126.1, 113.7, 106.6, 96.6, 74.0, 55.2, 46.4, 44.9,
24.9, 24.8 ppm. (ESI: m/z = 354 [M + NH4]+, 336 [M + H]+. HR-
MS (ESI) m/z calcd. for C17H21O7: 337.1287 [M + H]+, found
337.1304.
H), 7.42 (t, J = 8.3 Hz, 1 H), 6.64 (dt, J = 8.3, 1.0 Hz, 1 H), 6.45
(dd, J = 7.8, 1.0 Hz, 1 H), 1.76 (s, 6 H) ppm. 13C NMR (101 MHz
CDCl3): δ = 165.5, 161.4, 155.6, 137.9, 110.8, 107.2, 107.1, 99.3,
25.7 ppm. MS (CI: m/z = 195 [M + H]+. HR-MS (CI) m/z calcd.
for C10H11O4: 195.0657 [M + H]+, found 195.0654. The data are
in agreement with literature values.[22]
5-Hydroxy-2,2,6-trimethyl-4H-benzo[d][1,3]dioxin-4-one (5b): Ac-
cording to general procedure F, aromatization of acid 6b (67 mg,
0.30 mmol) and chromatography (hexanes/Et2O, 98:2 to 98:5) gave
resorcylate 5b (30 mg, 49 %) as a colorless solid; m.p. 70–73 °C
(؎)-4-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxy-2,3-di-
methyl-5-phenylpentanoic Acid (7d): According to general pro-
cedure E, aldol reaction of dioxinone ketone 12b (204 mg,
0.745 mmol) and benzyl propanoate 16b (122 mg, 0.745 mmol)
gave, after hydrogenolysis, carboxylic acid 7d (106 mg, 41%, 1.0:0.4
(CH Cl /pentane). IR: ν = 1739, 1681, 1598, 1473, 1421, 1395,
˜
2
2
1304, 1269, 1248, 1199, 1074, 992, 972, 940, 882, 798, 779,
704 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.55 (s, 1 H), 7.27 (d,
J = 8.3 Hz, 1 H), 6.37 (d, J = 8.3 Hz, 1 H), 2.20 (s, 3 H), 1.74 (s,
6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 165.9, 159.3, 153.4,
138.5, 119.7, 107.2, 106.3, 98.8, 25.6, 14.8 ppm. MS (CI: m/z = 226
[M + NH4 ]+ , 209 [M + H]+ . HR-MS (CI) m/z calcd. for
C11H16NO4: 226.1079 [M + NH4]+, found 226.1079. C11H12O4
(208.21): calcd. C 63.45, H 5.81; found C 63.38, H 5.92.
dr) as a colorless gum. IR: ν = 1702, 1622, 1497, 1456, 1391, 1377,
˜
1273, 1255, 1200, 1101, 1074, 1019, 905, 859, 810, 730, 699,
648 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.46 (br. s, 0.4 H),
7.11–7.29 (m, 7.0 H), 5.20 (s, 1.0 H), 5.16 (s, 0.4 H), 3.94 (br. s,
0.4 H), 3.26–3.38 (m, 1.4 H), 2.67–2.91 (m, 5.2 H), 1.52–1.57 (m,
4.2 H), 1.46–1.49 (m, 4.2 H), 1.41 (s, 1.2 H), 1.33–1.39 (m, 5.2 H),
1.28 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 180.1, 179.8,
170.2, 169.8, 161.3, 160.9, 138.7, 128.9, 128.7, 128.5, 126.6, 106.8,
106.7, 96.7, 96.6, 74.5, 73.5, 55.2, 52.7, 46.6, 45.3, 32.6, 32.4, 25.4, 6-Benzyl-5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (5c):
25.1, 24.7, 24.5, 23.1, 20.4, 12.8, 11.9 ppm. MS (ESI: m/z = 390 [M
+ MeCN + H]+, 366 [M + NH4]+, 349 [M + H]+. HR-MS (ESI)
m/z calcd. for C19H25O6: 349.1651 [M + H]+, found 349.1643.
According to general procedure F, aromatization of acid 6c (82 mg,
0.27 mmol) and chromatography (pentane/Et2O, 90:10) gave resor-
cylate 5c (45 mg, 58 %) as a colorless solid; m.p. 100–103 °C
Eur. J. Org. Chem. 2014, 4844–4853
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4851

P. S. Blencowe, A. G. M. Barrett
FULL PAPER
(CH Cl /pentane). IR: ν = 1692, 1631, 1498, 1446, 1390, 1379,
(s, 3 H), 1.64 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
165.7, 159.4, 153.2, 149.1, 140.0, 128.3, 128.0, 126.0, 118.0, 112.2,
107.1, 97.3, 30.7, 25.5, 20.9 ppm. MS (ESI: m/z = 299 [M + H]+.
HR-MS (ESI) m/z calcd. for C18H19O4: 299.1283 [M + H]+, found
˜
2
2
1352, 1272, 1241, 1205, 1093, 927, 809, 699, 631 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 10.66 (s, 1 H), 7.17–7.35 (m, 6 H), 6.39 (d,
J = 8.3 Hz, 1 H), 3.95 (s, 2 H), 1.75 (s, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 165.8, 159.0, 153.8, 140.1, 138.4, 128.9, 299.1280.
128.4, 126.2, 123.1, 107.3, 106.6, 99.0, 34.7, 25.6 ppm. MS (ESI:
5-Hydroxy-7-(4-methoxyphenyl)-2,2-dimethyl-4H-benzo[d][1,3]-
m/z = 285 [M + H]+. HR-MS (ESI) m/z calcd. for C17H17O4:
285.1127 [M + H]+, found 285.1130. C17H16O4 (284.31): calcd. C
71.82, H 5.67; found C 71.92, H 5.77.
dioxin-4-one (5i): According to general procedure F, aromatization
of acid 7c (300 mg, 0.893 mmol) and chromatography (pentane/
Et2O, 7:3 to 1:1) gave resorcylate 5i (102 mg, 38%) as a colorless
5-Hydroxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one (5d): Ac-
cording to general procedure F, aromatization of acid 6d (192 mg,
0.850 mmol) and chromatography (pentane/Et2O, 49:1 to 19:1) gave
resorcylate 5d (110 mg, 62%) as a colorless solid. Alternatively, ac-
cording to general procedure F, aromatization of acid 7a (100 mg,
0.410 mmol) and chromatography (pentane/Et2O, 19:1) gave resor-
cylate 5d (36 mg, 42 %) as a colorless solid; m.p. 97–100 °C
solid; m.p. 108–110 °C (CH Cl /pentane). IR: ν = 1676, 1634, 1604,
˜
2
2
1583, 1563, 1518, 1499, 1489, 1459, 1444, 1389, 1375, 1341, 1312,
1289, 1272, 1256, 1207, 1183, 1117, 1094, 1060, 1046, 1028, 967,
926, 855, 841, 824, 733, 718, 698, 666, 625, 603 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 10.33 (s, 1 H), 7.52–7.57 (m, 2 H), 6.93–
7.01 (m, 2 H), 6.85 (d, J = 1.5 Hz, 1 H), 6.67 (d, J = 1.5 Hz, 1 H),
3.87 (s, 3 H), 1.78 (s, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 165.4, 161.4, 160.5, 155.7, 150.6, 131.4, 128.3, 114.3, 108.5, 107.2,
105.3, 97.5, 55.4, 25.7 ppm. MS (ESI: m/z = 301 [M + H]+. HR-MS
(ESI) m/z calcd. for C17H17O5: 301.1076 [M + H]+, found 301.1084.
C17H16O5 (300.31): calcd. C 67.99, H 5.37; found C 67.85, H 5.47.
(CH Cl /pentane). IR: ν = 1689, 1643, 1585, 1466, 1381, 1361,
˜
2
2
1273, 1204, 1059, 1091, 996, 964, 906, 831, 797, 707, 677, 627 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.24 (s, 1 H), 6.46 (s, 1 H), 6.28
(s, 1 H), 2.32 (s, 3 H), 1.74 (s, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 165.4, 161.1, 155.3, 150.0, 111.2, 108.0, 107.0, 96.9,
25.6, 22.5 ppm. MS (CI: m/z = 226 [M + NH4]+, 209 [M + H]+.
HR-MS (CI) m/z calcd. for C11H13O4: 209.0814[M + H]+, found
229.0808.
(؎)-6-[1-(2,3-Dimethyl-4-oxooxetan-2-yl)-2-phenylethyl]-2,2-dimeth-
yl-4H-1,3-dioxin-4-one (17a): According to general procedure F, at-
tempted aromatization of carboxylic acid 7d (85 mg, 0.24 mmol)
and chromatography (pentane/Et2O, 7:3 to 1:1) gave β-lactone 17a
(50 mg, 62 %, 1.0:0.15 dr) as a colorless solid; decomposition
5-Hydroxy-2,2,6,7-tetramethyl-4H-benzo[d][1,3]dioxin-4-one (5e):
According to general procedure F, aromatization of acid 6e
(100 mg, 0.417 mmol) and chromatography (pentane/Et2O, 90:10)
gave resorcylate 5e (40 mg, 43%) as a colorless solid; m.p. 94–97 °C
(-CO ) 104 °C (CH Cl /pentane). IR: ν = 1815, 1723, 1634, 1499,
˜
2
2
2
1454, 1376, 1273, 1253, 1199, 1041, 1014, 958, 901, 809, 744, 721,
700, 649, 616 cm–1. 1H NMR (400 MHz, CDCl3): δ = (data for
major diastereoisomer only): δ = 7.19–7.32 (m, 3 H), 7.13–7.18 (m,
2 H), 5.19 (s, 1 H), 3.66 (q, J = 7.8 Hz, 1 H), 3.04–3.15 (m, 1 H),
2.86–2.97 (m, 2 H), 1.58 (s, 6 H), 1.58 (s, 3 H), 1.30 (d, J = 7.8 Hz,
3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = (data for major dia-
stereoisomer only): δ = 170.7, 167.2, 160.0, 137.2, 128.7, 128.5,
127.0, 107.0, 97.0, 81.4, 55.4, 52.1, 32.5, 25.3, 24.6, 17.7, 9.2 ppm.
MS (ESI: m/z = 372 [M + MeCN + H]+, 348 [M + NH4]+, 331 [M
+ H]+. HR-MS (ESI) m/z calcd. for C19H23O5: 331.1545 [M +
H]+, found 331.1544.
(CH Cl /pentane). IR: ν = 1678, 1630, 1580, 1536, 1505, 1453,
˜
2
2
1418, 1393, 1377, 1354, 1318, 1269, 1200, 1180, 1134, 1099, 1047,
1021, 993, 966, 907, 865, 849, 816, 797, 734, 695, 651, 638,
608 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.54 (s, 1 H), 6.29 (s,
1 H), 2.27 (s, 3 H), 2.11 (s, 3 H), 1.72 (s, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 165.9, 158.8, 152.7, 148.3, 118.1, 108.2,
106.9, 96.8, 25.6, 21.1, 10.5 ppm. MS (ESI: m/z = 222 [M + H]+.
HR-MS (ESI) m/z calcd. for C12H15O4: 223.0970 [M + H]+, found
223.0972. C12H14O4 (222.24): calcd. C 64.85, H 6.35; found C
64.96, H 6.46.
(؎)-2,2-Dimethyl-6-[(2-methyl-4-oxo-3-phenyloxetan-2-yl)methyl]-
4H-1,3-dioxin-4-one (17b): According to general procedure F, at-
tempted aromatization of carboxylic acid 7e (547 mg, 1.71 mmol)
and chromatography (pentane/Et2O, 1:1 to 0:1) gave β-lactone 17b
5-Hydroxy-2,2,7-trimethyl-6-phenyl-4H-benzo[d][1,3]dioxin-4-one
(5f): According to general procedure F, aromatization of acid 6f
(137 mg, 0.454 mmol) and chromatography (pentane/Et2O, 90:10)
gave resorcylate 5f (68 mg, 53%) as a colorless solid; m.p. 148–
(160 mg, 31%, 1.0:0.25 dr) as a yellow oil. IR: ν = 1818, 1722,
˜
150 °C (CH Cl /pentane). IR: ν = 1719, 1672, 1636, 1577, 1509,
˜
1633, 1496, 1455, 1392, 1378, 1343, 1327, 1303, 1279, 1252, 1202,
1174, 1149, 1111, 1075, 1041, 1014, 972, 948, 905, 848, 831, 802,
729, 699, 648 cm–1. 1H NMR (400 MHz, CDCl3): δ = (data for
major diastereoisomer only): δ = 7.37–7.43 (m, 3 H), 7.20–7.25 (m,
2 H), 5.45 (s, 1 H), 4.88 (s, 1 H), 2.93–2.94 (m, 2 H), 1.76 (s, 3 H),
1.73 (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
(data for major diastereoisomer only): δ = 167.9, 165.4, 160.2,
130.5, 129.1, 128.6, 128.3, 107.3, 97.1, 80.7, 63.5, 44.6, 25.4, 24.8,
21.4 ppm. MS (ESI): m/z = 344 [M + MeCN + H]+, 320 [M +
NH4]+, 303 [M + H]+. HR-MS (ESI) m/z calcd. for C17H19O5:
303.1232 [M + H]+, found 303.1236.
2
2
1490, 1455, 1436, 1388, 1377, 1364, 1319, 1308, 1290, 1259, 1236,
1202, 1189, 1143, 1088, 1052, 1031, 1020, 998, 968, 910, 860, 842,
808, 798, 758, 742, 722, 703, 670, 641, 611 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 10.54 (s, 1 H), 7.36–7.49 (m, 3 H), 7.24–
7.29 (m, 2 H), 6.43 (s, 1 H), 2.13 (s, 3 H), 1.80 (s, 6 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 165.6, 158.5, 154.1, 148.2, 135.3,
130.1, 128.4, 127.4, 124.3, 108.4, 107.2, 97.0, 25.7, 21.6 ppm. MS
(ESI: m/z = 285 [M + H]+. HR-MS (ESI) m/z calcd. for C17H17O4:
285.1127 [M + H]+, found 285.1138. C17H16O4 (284.31): calcd. C
71.82, H 5.67; found C 71.73, H 5.85.
8-Benzyl-5-hydroxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one
(5h): According to general procedure F, aromatization of acid 7b
(121 mg, 0.362 mmol) and chromatography (pentane/Et2O, 9:1)
gave resorcylate 5h (50 mg, 46%) as a colorless solid; m.p. 80–81 °C
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new compounds.
Acknowledgments
(CH Cl /pentane). IR: ν = 1688, 1634, 1585, 1494, 1481, 1453,
˜
2
2
1390, 1379, 1364, 1338, 1264, 1247, 1208, 1097, 1071, 1040, 1075,
1002, 980, 903, 849, 823, 792, 727, 697, 646, 616 cm–1. 1H NMR
The authors would like to thank GlaxoSmithKline for the generous
(400 MHz, CDCl3): δ = 10.23 (s, 1 H), 7.24–7.29 (m, 2 H), 7.17– endowment (to A. G. M. B) and the Thorpe Bequest (Imperial Col-
7.22 (m, 1 H), 7.08–7.12 (m, 2 H), 6.54 (s, 1 H), 3.93 (s, 2 H), 2.27 lege, London) for studentship support (to P. S. B). The authors also
4852
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4844–4853

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Received: April 23, 2014
Published Online: June 24, 2014
Eur. J. Org. Chem. 2014, 4844–4853
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4853