Total synthesis of 7-deoxy-6-o-methylfusarentin featuring a chelation-controlled 1,3-reetz-keck-type allylation

Article abstract of DOI:10.1021/jo301167a

The total synthesis of 7-deoxy-6-O-methylfusarentin (1) and a formal synthesis of 7-deoxy-6,8-O-dimethylfusarentin (2) has been successfully achieved in 10 steps. The described tactic underscores a diastereoselective strategy which incorporates a single acyclic reaction based on the initial stereocenter by means of a 1,3-chelation-controlled Reetz-Keck-type allylation.

Full text of DOI:10.1021/jo301167a

Note
pubs.acs.org/joc
Total Synthesis of 7‑Deoxy-6‑O‑methylfusarentin Featuring a
Chelation-Controlled 1,3-Reetz−Keck-Type Allylation
Timothy N. Trotter, Aymara M. M. Albury, and Michael P. Jennings*
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States
S
* Supporting Information
ABSTRACT: The total synthesis of 7-deoxy-6-O-methylfusar-
entin (1) and a formal synthesis of 7-deoxy-6,8-O-
dimethylfusarentin (2) has been successfully achieved in 10
steps. The described tactic underscores a diastereoselective
strategy which incorporates a single acyclic reaction based on
the initial stereocenter by means of a 1,3-chelation-controlled
Reetz−Keck-type allylation.
iologically active and structurally intriguing natural
products have been isolated from a diverse set of both
B
marine- and terrestrial-based organisms and plant sources.1
Along this line, Isaka and co-workers isolated in 2010 an
antimycobacterial cyclodepsipeptide, termed cordycommunin,
along with two unnamed dihydroisocoumarin natural products
from the extracts of the entomopathogenic fungus Ophiocordy-
ceps communis BCC 16475.2 While the two dihydroisocoumar-
ins are known in the literature via a synthetic approach to
fusaretin methyl ethers by Simpson, the Isaka disclosure
represents the first time they have been isolated as natural
products.3 Recently, Reddy reported a synthetic approach to
compounds 1 and 2 but incorrectly named the molecules with
respect to the fusarentin family.4 After an agreeable discussion
with the isolation chemist and in an effort to facilitate
communication of the given structures, we have renamed
natural products 1 and 2 as 7-deoxy-6-O-methylfusarentin and
7-deoxy-6,8-O-dimethylfusarentin, respectively, in accordance
with the parent fusarentin skeleton as shown in Figure 1.
We were drawn to the structures based on our previous
interest in both the aigialomycin and pochonin families of
similar compounds.5 As shown in Figure 1, compounds 1 and 2
add to a significant family of such smaller natural products that
have varied biologically relevant profiles. For example,
fusarentin methyl ethers have shown antifungal, insecticidal,
and phytotoxic activities.6 In addition, both cladosporin and
isocladosporin have exhibited significant activity as antifungal
antibiotics and plant growth inhibitors.7,8 Although 1 and 2
have not shown considerable biological activity, it is worth
noting that they have only been tested against a few cancer cell
lines.2 On the basis of the structural similarity to that of both
cladosporin and fusarentin, one might anticipate that 1 and 2
will indeed possess biological activity.
Figure 1. Structural similarities between a selected series of
isocoumarin natural products.
envisioned a chelation controlled 1,3-anti allylation by means of
Lewis acid activation of the aldehyde resident in compound 5.
Lastly, oxidative cleavage of the terminal alkene of the
previously reported compound 6 should readily afford aldehyde
5.
With this general synthetic blueprint in hand, the first order
of business was the completion of homoallylic alcohol 11 as
described in Scheme 2. Thus, the synthesis of olefin 6 started
from commercially available 5,7-dihydroxy-2,2-dimethyl-4H-
1,3-benzodioxin-4-one (7). The hydroxy group para to the
carbonyl moiety resident in 7 was chemoselectively protected
under Mitsunobu conditions9 using DIAD and PPh3 in the
presence of methanol and afforded 8 in 88% yield. Ensuing
treatment of 8 with Tf2O and pyridine readily provided the
corresponding triflate 9 in 80% yield.9 The resulting triflate 9
As shown in Scheme 1, our initial approach to the syntheses
of both 1 and 2 was based on a late-stage lactonization under
basic conditions from diol 3. In turn, compound 3 was
envisaged to be derived from 4 via concomitant olefin
reduction and hydrogenolysis of the benzyl ether protecting
group. As the key stereochemical sequence leading to 4, we
Received: June 5, 2012
Published: August 13, 2012
© 2012 American Chemical Society
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Note
the homoallylic alcohol 11(as a 7.3:1 er based on 19F NMR
analysis of the crude Mosher esters, see the Supporting
Information) after basic oxidation with the standard reagents
(NaOH and H2O2) in 80% yield.11
Scheme 1. Retrosynthetic Analysis of 7-Deoxy-6-O-
methylfusarentin and 7-Deoxy-6,8-O-dimethylfusarentin
With the initial chiral center in place, the stage was set for the
key diastereoselective chelation-controlled 1,3-anti-allylation in
hopes of providing the final stereocenter en route to 1 and 2 as
delineated in Scheme 3. In order to investigate such a directed
Scheme 3. Completion of 7-Deoxy-6-O-methylfusarentin and
7-Deoxy-6,8-O-dimethylfusarentin
Scheme 2. Synthesis of Homoallylic Alcohol 11
reaction process, we required protection of the secondary
alcohol 11 as a benzyl ether as noted by Reetz and Keck.12,13
Unfortunately, benzylation under basic conditions (BnBr, NaI,
and NaH) did not provide the desired compound 12 but
instead furnished the δ lactone via an intramolecular trans-
esterfication. In addition, attempted etherification under acidic
conditions with the benzyl trichloroacetimidate reagent
[CCl3C(NH)OCH2C6H5] failed to provide the desired
benzyl ether 12 and led to the decomposition of homoallylic
alcohol 11. Much to our delight, treatment of 11 with the
Dudley reagent coupled with MgO afforded the benzyl ether 12
albeit with a modest yield of 41% with the remaining material
balance as the undesired lactone.14 With 12 in hand, an ensuing
oxidative cleavage of the terminal alkene was accomplished with
smoothly underwent a Suzuki cross-coupling reaction with the
allyl pinacol boronate reagent in the presence of Pd(PPh3)4 and
CsF to furnish the substituted allyl benzene derivative 6 in 82%
yield.10 Subsequent oxidative cleavage of the terminal alkene of
6 by means of O3 followed by a reductive quench of the
ozonide intermediate with PPh3 provided aldehyde 10 in 91%
yield. With aldehyde 10 in hand, asymmetric allylboration with
(+)-Ipc2Ballyl under the reported Brown procedure afforded
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Note
mmol) in pyridine (9.00 mL) was added Tf2O (1.86 g, 6.60 mmol,
1.09 mL) at 0 °C and the reaction was allowed to stir for 24 h at the
same temperature. The reaction mixture was then diluted with EtOAc,
washed with saturated aqueous CuSO4, water, and brine, dried over
anhydrous Na2SO4, concentrated in vacuo, and purified on silica (10%
EtOAc in Hexane) to yield 9 as a yellow amorphous solid (1.3 g,
O3 followed by a reductive workup of the intermediate ozonide
with PPh3 furnished aldehyde 5 in 99% yield and set the stage
for the chelation controlled allylation. Thus, pretreatment of
aldehyde 5 with the oxophilic Lewis acid TiCl4 presumably
formed the six-membered chelated intermediates 13 and 14
followed by an ensuing addition of the allylstannane reagent
(Bu3Snallyl) led to the formation of the anti-1,3-homoallylic
alcohol 4 with a diastereomeric ratio of 4.5:1 for the desired
stereochemistry in 80% yield.
1
80%): H NMR (500 MHz, CDCl3) δ 6.53 (d, J = 2.2 Hz, 1H), 6.48
(d, J = 2.5 Hz, 1H), 3.88 (s, 3H), 1.74 (s, 6H).9
5-Allyl-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-
one (6). A two-necked round-bottom flask was charged with 9 (1.50 g,
4.21 mmol), CsF (2.47 g, 16.3 mmol), and Pd(PPh3)4 (0.486 g, 0.421
mmol) in THF (260 mL) and stirred for 30 min. Allyl boronic acid
pinacol ester (15.1 mmol, 2.83 mL) was added, and the resulting
reaction mixture was heated to reflux for 24 h. Upon completion of the
reaction, the mixture was diluted with petroleum ether, followed by
H2O. The layers were extracted with petroleum ether. The combined
organic layers were washed with H2O and brine and dried with
Na2SO4. The crude product was purified on silica (5% EtOAc in
Based on the final product ratio of 4, one might suggest that
two potential reactive conformations 13 and 14 were in
operation (assuming that the allylation process proceeds
through a chelated six-membered chairlike transition state).
The data suggest that conformer 14 was preferred as all
substituents were placed into equatorial positions and readily
allowed for the axial approach of the nucleophilic allylstannane
reagent en route to the 1,3-anti adduct (i.e., compound 4). On
the other hand, conformer 13 would have placed both the
benzyl moiety and large aromatic group 1,2-diaxial to one
another, which would presumably lead to a higher energy
conformation. It is worth noting that within conformer 13 a
third chelation between the Ti metal and the carbonyl resident
within the aromatic portion would be possible. One could
suggest that chelation might help to stabilize the conformer;
however, axial approach of the allylstannane would be severely
hindered. Ultimately, 13 would not be preferred which we
presume furnished the minor amount of the 1,3-syn product.
With the requisite stereochemistry in place, concomitant
hydrogenation/hydrogenolysis of both the terminal alkene
and benzyl ether resident in compound 4 with 1 atm of H2 and
10% Pd(OH)2 in MeOH readily proceeded to afford diol 3 in
76% yield. Subsequent treatment of 3 with NaH in a 1:1 DMF/
THF solution furnished 7-deoxy-6-O-methylfusarentin (1) via
an intramolecular trans-esterification in 75% yield. The spectral
data (1H NMR, 500 MHz; 13C NMR, 125 MHz), optical
rotation ([α]23 −18.3, c 0.060 CHCl3, lit. value [α]26 −14, c
1
hexane) to yield 6 as a white amorphous solid (0.860 g, 82%): H
NMR (500 MHz, CDCl3) δ 6.51 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 2.2
Hz, 1H), 6.02 (m, 1H), 5.07 (m, 2H), 3.86 (d, J = 6.6 Hz), 3.83 (s,
3H), 1.69 (s, 6H).10
2-(7-Methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-
yl)acetaldehyde (10). A solution of 6 (0.860 g, 3.46 mmol)
dissolved in CH2Cl2 (28.0 mL) and MeOH (10.0 mL) was cooled to
−78 °C, and O3 was bubbled through the solution until the starting
material was consumed as indicated by TLC. The solution was then
sparged with O2, and the reaction was quenched via portionwise
addition of PPh3 (2.73 g, 10.4 mmol) and stirred for 4 h. The resulting
mixture was concentrated in vacuo and purified by flash chromatog-
raphy (25% EtOAc in hexane) to yield 10 as a white amorphous solid
(0.791 g, 91%): TLC Rf = 0.12 in 15% EtOAc/hexane; 1H NMR (500
MHz, CDCl3) δ 9.80 (t, J = 0.9 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.40
(d, J = 2.5 Hz, 1H), 4.14 (bs, 2H), 3.84 (s, 3H), 1.72 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 198.1, 165.2, 159.2, 138.9, 114.2, 105.6,
105.2, 100.7, 55.7, 49.2, 25.6; IR (neat) 3425, 2943, 1719, 1612, 1578,
1285, 1201, 1160 cm−1; HRMS (EI) calcd for C13H16O4 [M − CH3]
221.0184 found 221.0185.
(R)-5-(2-Hydroxypent-4-en-1-yl)-7-methoxy-2,2-dimethyl-
4H-benzo[d][1,3]dioxin-4-one (11). To a flame-dried round-
bottom flask under argon was added allylmagnesium bromide (1.0
M solution in ether, 4.08 mL) dropwise into a solution of
(+)-Ipc2BOMe (1.38 g, 4.35 mmol) in anhydrous ether (6.80 mL)
at 0 °C. The reaction mixture was allowed to stir for 1 h at room
temperature before being cooled to −78 °C. A solution of 10 (681 mg,
2.88 mmol) in ether (2.0 mL) was added dropwise into the borane
solution and allowed to stir for 1 h at −78 °C and then warmed slowly
to room temperature during 1 h. An aqueous solution of pH 7 buffer
(1.94 mL) was added, followed by slow addition of a 30% H2O2
solution (3.63 mL). The mixture was allowed to stir overnight. The
biphasic solution was separated, and the aqueous layer was extracted
with EtOAc (3 × 20 mL). The organic layers were combined, dried
over MgSO4, concentrated in vacuo, and purified on silica (27%
EtOAc/hexane) to yield 11 as a white amorphous solid (639 mg,
80%): TLC Rf = 0.09 in 15% EtOAc/hexane; [α]23D= −14.2 (c 0.491,
D
D
0.13 CHCl3) and HRMS data of synthetic 1 was in agreement
with the natural sample.2 In addition, the completion of 1 also
constitutes a formal synthesis of 2 as previously described by
Isaka and co-workers.2
In summary, the total synthesis of 7-deoxy-6-O-methylfusar-
entin (1) and a formal synthesis of 7-deoxy-6,8-O-dimethylfu-
sarentin (2) has been successfully achieved in 10 steps from the
commercially available compound 7. The described tactic
underscores a diastereoselective strategy which incorporates a
single acyclic reaction with modest dr based on the initial
stereocenter of alcohol 11. The prospect of a late stage addition
to the terminal alkene of 4 can also allow for the synthesis of
additional natural products that possess the dihydroisocoumar-
in substructure, such as ent-cladosporin and isocladosporin.
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 6.52 (d, J = 2.5 Hz, 1H),
6.34 (d, J = 2.5 Hz, 1H), 5.92 (m, 1H), 5.16 (m, 2H), 3.92 (m, 1H),
3.83 (s, 3H), 3.30 (dd, J = 13.2, 3.8 Hz, 1H), 3.12 (dd, J = 12.9, 8.5 Hz
1H), 2.41 (m, 1H) 2.34 (m, 1H), 1.70 (s, 3H), 1.68 (s, 3H); 13C NMR
(125 Hz, CDCl3) δ 164.9, 159.4, 145.9, 134.9, 117.8, 113.7, 105.1,
100.1, 72.1, 55.6, 42.1, 41.3, 25.8, 25.3; IR (neat) 3452, 3075, 2935,
1723, 1609, 1578, 1282, 1206, 1159, 1065, 913 cm−1; HRMS (EI)
calcd for C16H20O5 [M − H2O] 274.1205, found 274.1204.
(R)-5-(2-(Benzyloxy)pent-4-en-1-yl)-7-methoxy-2,2-dimeth-
yl-4H-benzo[d][1,3]dioxin-4-one (12). A mixture of 2-benzyloxy-1-
methylpyridinium triflate (823 mg, 2.36 mmol), benzene (2.40 mL),
MgO (95.1 mg, 2.36 mmol), and 11 (333 mg, 1.14 mmol) was heated
to 83 °C for 24 h. The reaction mixture was allowed to cool to rt and
filtered through Celite. The filtrate was concentrated under vacuum
pressure and purified on silica (7% EtOAc/hexane) to yield 12 as a
EXPERIMENTAL SECTION
■
5-Hydroxy-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]-
dioxin-4-one (8). To a solution of 7 (4.13 g, 19.1 mmol) in THF
(40.1 mL) were added MeOH (0.850 mL) and Ph3P (5.51 g, 21.0
mmol) sequentially at 0 °C. After being stirred for 5 min at the same
temperature, DIAD (4.25 g, 21.0 mmol) was added dropwise to the
reaction mixture and stirred for an additional 4 h at 0 °C. The reaction
mixture was concentrated in vacuo and chromatographed on silica gel
(10% EtOAc in hexane) to give 8 as a white amorphous solid (3.75 g,
1
88%): H NMR (500 MHz, CDCl3) δ 10.45 (s, 1H), 6.15 (d, J = 2.2
Hz, 1H), 6.00 (d, J = 2.5 Hz, 1H), 3.82 (s, 3H), 1.73 (s, 6H).9
7-Methoxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl
Trifluoromethanesulfonate (9). To a solution of 8 (1.00 g, 4.46
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Note
colorless oil (161 mg, 41%): TLC Rf = 0.78 in 30% EtOAc/hexane;
3H), 1.69 (s, 3H), 1.52 (m, 1H), 1.44 (m, 2H), 1.36 (m, 1H), 0.92 (t,
J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 164.9, 161.5, 159.2,
145.8, 113.7, 105.4, 105.2, 100.1, 70.7, 69.1, 55.6, 43.0, 42.3, 39.7, 25.7,
25.4, 18.9,14.4; IR (neat) 3403, 2927, 1723, 1612, 1578, 1281, 1205,
1160, 1061 cm−1; HRMS (EI) calcd for C18H26O6 [M] 338.1729,
found 338.1717; calcd for C18H26O6 [M − H2O] 320.1624, found
320.1633.
1
[α]23 = −50.7 (c 1.610, CH2Cl2); H NMR (500 MHz, CDCl3) δ
D
7.21 (m, 5H), 6.56 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.95
(m, 1H), 5.10 (m, 2H), 4.52 (d, J = 11.7 Hz, 1H), 4.33 (d, J = 11.7 Hz,
1H), 3.79 (s, 3H), 3.40 (dd, J = 12.9, 4.7 Hz, 1H), 3.14 (dd, J = 12.9,
7.8 Hz, 1H), 2.39 (m, 2H), 1.65 (s, 3H), 1.64 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 164.5, 160.3, 158.9, 146.2, 138.8, 135.0, 128.1, 127.6,
127.3, 117.0, 113.0, 104.9, 100.2, 79.1, 71.7, 55.5, 40.0, 39.1, 25.8, 25.4;
IR (neat) 2938, 1725, 1612, 1577, 1434, 1282, 1205, 1159, 1062, 914
cm−1; HRMS (EI) calcd for C23H26O5 [M] 382.1780, found 382.1794.
(S)-3-(Benzyloxy)-4-(7-methoxy-2,2-dimethyl-4-oxo-4H-
benzo[d][1,3]dioxin-5-yl)butanal (5). A solution of 12 (161 mg,
0.421 mmol) dissolved in CH2Cl2 (3.50 mL) and MeOH (1.00 mL)
was cooled to −78 °C, and O3 was bubbled through the solution until
the starting material was consumed as indicated by TLC. The solution
was then sparged with O2, and the reaction was quenched via
portionwise addition of PPh3 (331 mg, 1.26 mmol) and stirred for 4 h.
The resulting mixture was concentrated in vacuo and purified by flash
chromatography (24% EtOAc/hexane) to yield 5 as a colorless oil
(160 mg, 99%): TLC Rf = 0.13 in 20% EtOAc/hexane; [α]23D = −3.4
7-Deoxy-6-O-methylfusarentin (1). To a solution of 3 (10.0 mg,
0.0209 mmol) in THF (0.600 mL) and DMF (0.600 mL) at 0 °C was
added sodium hydride (0.700 mg, 0.0290 mmol). The solution was
allowed to stir at 0 °C until complete consumption of starting material
as indicated by TLC (3 h). The reaction mixture was quenched with
5% HCl (5 mL) and extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with NaHCO3 and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (25% EtOAc/hexanes) to give 1 as a
white amorphous solid (6 mg, 75%): TLC Rf = 0.20 in 25% EtOAc/
hexane; [α]23 = −18.3 (c 0.060, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 11.19 (s, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.25 (m, 1H), 4.84
(m, 1H), 4.05 (bs, 1H), 3.82 (s, 3H), 1.97 (ddd, J = 14.5, 9.5, 2.2 Hz,
1H), 1.69 (ddd, J = 14.5, 10.4, 3.2 Hz, 1H), 1.48 (m, 3H), 0.95 (t, J =
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.7, 165.8, 164.6,
1
(c 0.460, CH2Cl2); H NMR (500 MHz, CDCl3) δ 9.76 (dd, J = 2.8,
1.9 Hz, 1H), 7.28 (m, 5H), 6.54 (d, J = 2.5 Hz, 1H), 6.38 (d, J =.5 Hz,
1H), 4.60 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.31 (m,
1H); 3.82 (s, 3H), 3.56 (dd, J = 12.6, 6.6 Hz, 1H), 3.24 (dd, J = 12.6,
5.9 Hz, 1H), 2.69 (ddd, J = 16.1, 7.9, 2.8 Hz, 1H), 2.60 (ddd, J = 16.1,
4.4, 1.9 Hz, 1H), 1.70 (s, 3H), 1.69 (s, 3H), 13C NMR (125 MHz,
CDCl3) δ 201.4, 164.7, 159.2, 144.5, 138.2, 128.2, 127.8, 127.6, 114.2,
105.1, 104.9, 100.4, 74.8, 71.8, 55.5, 48.5, 39.9, 25.7, 25.4; IR (neat)
2940, 2848, 1718, 1610, 1576, 1281, 1203, 1162, 1061 cm−1; HRMS
(EI) calcd for C22H24O6 [M] 384.1573, found 384.1568.
141.1, 106.2, 101.7, 99.5, 76.2, 67.2, 55.5, 42.3, 40.2, 33.8, 18.7, 13.9;
cm‑1
IR (neat)
3425, 3205, 1639, 1373, 1255, 1198; HRMS (EI) calcd
for C15H20O5 [M] 280.1311, found 280.1308.
ASSOCIATED CONTENT
* Supporting Information
Full spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
5-((2S,4S)-2-(Benzyloxy)-4-hydroxyhept-6-en-1-yl)-7-me-
thoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (4). To a
stirring solution of 5 (45.0 mg, 0.117 mmol) in CH2Cl2 (0.600 mL)
at −78 °C was added TiCl4 (0.141 mL, 0.141 mmol, 1 M in CH2Cl2),
and the resulting yellow solution was allowed to stir for 10 min. To
this solution was added allyltributylstannae (77.6 mg, 0.0720 mL,
0.234 mmol) dissolved in CH2Cl2 (0.200 mL) over a period of 15 min.
The resulting solution was allowed to stir until completion (∼3 h).
The reaction was then quenched with saturated NaHCO3 (0.418 mL)
and allowed to warm to room temperature. The reaction was diluted
with CH3CN (1.90 mL), and KF (90.0 mg) was added. The reaction
was then allowed to stir for 24 h. The reaction mixture was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography (20%
AUTHOR INFORMATION
Corresponding Author
*E-mail: jenningm@bama.ua.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this project was provided by the National Science
Foundation CAREER program under CHE-0845011. We thank
Dr. Masahiko Isaka for fruitful discussions with respect to the
naming of compounds 1 and 2.
EtOAc/hexanes) to give 4 as a pale yellow oil (39.9 mg, 80%): TLC Rf
REFERENCES
1
= 0.19 in 20% EtOAc/hexane; [α]23 = −2.0 (c 0.390, CH2Cl2); H
■
D
(1) (a) Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.;
Prinsep, M. R. Nat. Prod. Rep. 2012, 29, 144. (b) Cragg, G. M.;
Newman, D. J. Pure Appl. Chem. 2005, 77, 7.
(2) Haritakun, R.; Sappan, M.; Suvannakad, S.; Tasanathai, K.; Isaka,
M. J. Nat. Prod. 2010, 73, 75.
NMR (500 MHz, CDCl3) δ 7.25 (m, 5H), 6.52 (d, J = 2.5 Hz, 1H),
6.34 (d, J = 2.5 Hz, 1H), 5.81 (m, 1H), 5.06 (m, 2H), 4.56 (d, J = 11.4
Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 3.99 (m, 2H), 3.80 (s, 3H), 3.44
(dd, J = 12.6, 7.3 Hz, 1H), 3.26 (dd, J = 12.6, 5.7 Hz, 1H), 2.21 (m,
2H), 1.70 (m, 2H), 1.66 (s, 6H), 1.32 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 164.6, 160.4, 159.1, 145.6, 138.4, 135.0, 128.3, 127.9, 117.3,
114.2, 104.9, 104.8, 100.2, 71.7, 68.0, 55.5, 42.1, 39.9, 25.9, 25.3; IR
(neat) 3414, 2929, 1724, 1612, 1577, 1282, 1205, 1160, 1062 cm−1;
HRMS (EI) calcd for C25H30O6 [M] 426.2042, found 426.2029; calcd
for C25H30O6 [M − H2O] 408.1937, found 408.1937.
5-((2S,4S)-2,4-Dihydroxyheptyl-7-methoxy-2,2-dimethyl-4H-
benzo[d][1,3]dioxin-4-one (3). To a solution of 4 (39.9 mg, 0.0940
mmol) in EtOH (1.00 mL) was added Pd(OH)2 (39.9 mg) in one
portion. The reaction vessel was evacuated under vacuum and placed
under atmospheric H2 balloon pressure. The reaction mixture was
allowed to stir at rt for 3 h until complete consumption of the starting
material as indicated by TLC. The reaction was filtered through Celite
and concentrated in vacuo. Purification by flash chromatography (35%
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EtOAc/hexane) yielded 3 as a colorless oil (23.6 mg, 76%): TLC Rf =
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1
0.23 in 40% EtOAc/hexane; [α]23 = −5.4 (c 0.160, CH2Cl2); H
D
NMR (500 MHz, CDCl3) δ 6.52 (d, J = 2.2 Hz, 1H), 6.34 (d, J = 2.5
Hz, 1H), 4.16 (m, 1H), 3.98 (m, 1H), 3.83 (s, 3H), 3.26 (dd, J = 12.9,
4.1 Hz, 1H), 3.18 (dd, J = 13.2, 8.2 Hz, 1H), 1.74 (m, 2H), 1.70 (s,
7691
dx.doi.org/10.1021/jo301167a | J. Org. Chem. 2012, 77, 7688−7692

The Journal of Organic Chemistry
Note
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7692
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