Synthesis of the purported ent -pochonin J structure featuring a stereoselective oxocarbenium allylation

Article abstract of DOI:10.1021/jo200332d

The synthesis of the alleged natural product pochonin J is presented. Key steps of this convergent synthesis include a chemoselective Wacker oxidation, and an Evans anti-reduction of the resulting ketone. Upon ozonolysis, this intermediate undergoes a 6-e

Full text of DOI:10.1021/jo200332d

ARTICLE
pubs.acs.org/joc
Synthesis of the Purported ent-Pochonin J Structure Featuring
a Stereoselective Oxocarbenium Allylation
Dionicio Martinez-Solorio, Kenneth A. Belmore, and Michael P. Jennings*
Department of Chemistry, The University of Alabama, 250 Hackberry Lane, Tuscaloosa, Alabama 35487-0336, United States
S Supporting Information
b
ABSTRACT: The synthesis of the alleged natural product
pochonin J is presented. Key steps of this convergent synthesis
include a chemoselective Wacker oxidation, and an Evans’ anti-
reduction of the resulting ketone. Upon ozonolysis, this inter-
mediate undergoes a 6-exo-trig cyclization to give a hemiketal
intermediate, the key oxocarbenium precursor. The construc-
tion of the R-C-glycoside subunit is highlighted by a mis-
matched oxocarbenium cation formation/allylation sequence. An olefin metathesis afforded the 14-membered macrolactone,
and final oxidation provided the “desired” compound that does not spectroscopically correlate to the initially described natural
product.
’ INTRODUCTION
Terrestrially derived sources have long since been a repository
for biologically relevant natural products.1 In 2009, Shinonaga
and co-workers disclosed four unique pochonin family structures
(pochonins GꢀJ) from the culture broth of Pochonia chlamydos-
poria var. chlamydosporia.2 These compounds were isolated via
bioassay-guided fractionation against WNT-5A expression in
search of novel hair-growth stimulants. The structures of pocho-
nins GꢀJ were elucidated by means of a combination of 1D and
2D spectroscopic techniques. The entire family of pochonin
natural products (AꢀP) has been shown to share a common
structural motif of a 14-membered macrocyclic resorcylic acid
lactone core. In addition, all pochonins except F and J are
chlorinated at C13 of the aromatic ring analogous to radicicol
and monorden.3 Similarly, pochonins J (1) and F demonstrate
Figure 1. Resorcylic macrolide natural products.
more semblances to the aigialomycin family of natural products
and hypothemycin, due in part to the lack of C13 chlorination as
shown in Figure 1.4,5 Because of their diverse biological functions
and curious skeletal connectivities, members of these families of
natural products have been met with interest giving rise to
innovative synthetic approaches toward their assembly.6
determination of the correct structure. Surprisingly, these errors
were not limited to molecules of great complexity as one would
initially surmise, but include compounds of varying degrees of
size and stereochemical complexity. Thus, total synthesis con-
tinues to play a very important role in structure elucidation of
chemical entities by overcoming the gaps in technology that exist
in the current state of spectroscopy.
As part of a research program aimed at expanding the diversity
of RALs beyond the naturally occurring compounds, efforts made by
the Winssinger group have also yielded significant contributions to
the syntheses and biological studies of RALs. They have successfully
synthesized aigialomycin D, pochonin A, C, and D, and through the
application of solid-state chemistry, a library of pochonin and
aigialomycin analogues that have been crucial in gaining valuable
insight into their biological profiles.9 Our attraction to 1 initially arose
’ RESULTS AND DISCUSSION
Resorcylic acid lactones (RALs) of the type shown in Figure 1
are secondary metabolites that have been known since 1953 with
the isolation of radicicol.7 Despite great leaps forward in structure
elucidation and characterization provided by NMR spectroscopy
and other analytical methods, it is not uncommon to find errors
in structure assignment. Nicolaou and Snyder reported the
existence of over 300 structural revisions in the literature
published between January 1990 and April 2004.8 In over half
of these cases, total synthesis of the presumed structure was
required to identify a discrepancy and ultimately allowed for the
Received: February 15, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Scheme 1. First Generation Retrosynthetic Analysis of ent-Pochonin J
Scheme 2. Synthesis of Aromatic Subunit via a Wacker
Oxidation
from the inclusion of an R-C-glycoside subunit in the 14-membered
macrocyclic structure. Such structural motifs are extremely rare and
have only been seen in aspergillide B and C.10 On the basis of our
previous synthetic work on resorcylic macrolides (i.e., aigialomycin
D) and the synthesis of aspergillide B, we sought to merge our
interests and investigate the synthesis of 1.11,12 Since we were
uncertain of the absolute stereochemistry of 1 and considering its
similarity to aigialomycin D, we initiated the synthetic venture toward
1 with the (S)-TBDPS protected glycidol starting chiral synthon
(similar to our synthetic work with aigialomycin D). We were
cognizant that the chiral starting material might lead to the enantio-
mer of 1 based on the initial disclosure by Shinogaga and co-workers.
Initial Retrosynthetic Analysis of ent-Pochonin J (1). Our
initial retrosynthetic analysis of ent-1 envisioned a late stage
oxocarbenium cation formation, followed by intramolecular
diastereoselective axial attack by the tethered TMS kinetic
enolate 2 derived in situ from ketone 3 as delineated in Scheme 1.
This approach was particularly attractive considering that for-
mation of a stereogenic center to forge the R-C-glycoside moiety
along with concomitant generation of the macrocyle could be
theoretically achieved. If successful this strategy would further
extend the scope of our oxocarbenium protocols as well as
provide an alternative methodology for macrocyle construction.
With this in mind, the macrocyclic/oxocarbenium precursor 3
was expected to arise from a trans-esterification reaction of the
aromatic subunit 4 with methoxy ketal 7. Aromatic precursor 4
was envisioned to be the product of a Wacker oxidation of the
terminal alkene 5. In turn, terminal alkene 5 would arise from the
previously reported aromatic subunit 6 by means of a Pd-
catalyzed cross coupling. The required methoxy ketal 7 could,
in principle, be derived from reductive cleavage of the terminal
alkene resident in triol 8, leading to a 6-exo-trig cyclization
followed by treatment with PPTS in MeOH. Compound 8
would be ultimately derived from diol 9 via a chemoselective
Wacker oxidation of the least sterically hindered olefin and a
subsequent intramolecular 1,3-anti-reduction of the correspond-
ing ketone moiety. In turn, diol 9 would be the result of an
asymmetric allylboration of an aldehyde intermediate resulting
from TBDPS ether 10. Lastly, 10 would arise from the union of
the prenyl derived Grignard reagent 11 and TBDPS protected
(S)-glycidol 12.
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With the original retrosynthetic blueprint in mind, our initial focus
was on the construction of aromatic subunit 4, which commenced
with acetonide formation of commercially available 2,4,6-trihydrox-
ybenzoic acid 13 in the presence of SOCl2, DMAP, and acetone to
tionality not present in the substrates studied by Yoshifuji or
Kozlowski. As shown in Scheme 3, one could envision a scenario
where deprotonation at the more acidic benzylic position would
lead to a lithium-stabilized six-membered chelate intermediate,
somewhat similar to the one proposed during our synthesis of
brussonol.18 In addition to this stabilization, the generated anion
might also be significantly delocalized given that the ester carbonyl
group π-bond is aligned with the π-orbitals of the aromatic ring.
Unfortunately, TMS enol ether 17 eluded all attempts toward its
synthesis and we were forced to abandon our initial synthetic
strategy. Thus, we redesigned a second synthetic blueprint, this time
taking advantage of a highly diastereoselective intermolecular oxo-
carbenium allylation reaction, which has been successfully employed
in numerous synthetic ventures from our laboratory.19
Second-Generation Retrosynthetic Analysis of Pochonin J
(1). Disappointed, yet undaunted by the failure to obtain the key
kinetic siyl enol ether 17, we proceeded to revise our synthetic
strategy. The second-generation retrosynthetic analysis envi-
sioned a late stage alcohol oxidation of 18 that would be derived
from the macrocyclic olefin 19 as delineated in Scheme 4.
Synthesis of macrocycle 19 would be obtained from a ring-
closing metathesis reaction of the acyclic diene 20, followed by
MOM protection of the free phenol moeity. In turn, a trans-
esterification of the aromatic subunit 21 with R-C-glycoside 22
should provide diene 20. Aromatic subunit 21 should be accessed
starting from the previously synthesized aryl triflate 15 via a Pd-
catalyzed coupling with potassium vinyl trifluoroborate. The
give aryl acetonide 6 in 84% yield as shown in Scheme 2.13
A
subsequent chemoselective protection of the more reactive phenol
moiety as a MOM ether by employing MOMCl and K2CO3 afforded
the desired product 14 in 86% yield. Next, aryl triflate 15 was obtained
in near quantitative yield, and an ensuing Pd-catalyzed Suzukiꢀ
Miyaura allylation provided aromatic subunit 5 in a 92% yield.14
Lastly, treatment of 5 under modified Wacker conditions, employing
50 mol % of PdCl2 and excess quantities of CuCl (2.0 equiv) under an
atmosphere of O2 provided the desired aryl ketone 4 in 72% yield.15
Prior to the attempted unification of fragments 4 and 7, en route to
the coveted trimethylsilyl enol ether 2 intermediate, we chose to
explore conditions that would hopefully lead to the desired kinetic
silyl enol ether 17 from ketone 4. On the basis of early studies on
the kinetic deprotonation of benzyl methyl ketone conducted by
Yoshifuji and co-workers, we reasoned that it might be possible to
obtain kinetic silyl enol ether 17 by using a sterically hindered
lithium base, such as 1-lithio-2,4,6-tri-tert-butylbenzene, at low
temperatures.16 More recently, Kozlowski’s group has also
demonstrated that kinetic enolization at the least hindered
position of highly substituted benzyl methyl ketones was indeed
possible utilizing sterically hindered LiHMDS/Ph3N adducts in
toluene at ꢀ78 °C.17 Despite the initial promise provided by
these examples, careful implementation of literature procedures
lead exclusively to the undesired thermodynamic silyl enol ether
16. Summarized in Table 1 are the various attempts made to
attain the required kinetic silyl enol ether 17.
Scheme 4. Second Generation Synthetic Blueprint of Po-
chonin J
In retrospect, aryl ketone 4 possesses a carbonyl moiety that is
locked in position through the cyclic acetonide subunit, a func-
Table 1. Attempted Kinetic Enolization of Aromatic Ketone
time
base
additive
(equiv)
TMSCl
entry solvent (h)
(equiv)
(equiv) 16:17
1
2
3
4
5
6
7
THF
0.5 ArLi (1.2)
NEt3 (2.3)
NEt3 (6.0)
2
5
3
4
5
5
5
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
THF
1
1
1
1
1
1
ArLi (1.5)
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
LiHMDS (1.25) Ph3N (5.0)
LiHMDS (1.25) Ph3N (10.0)
LiHMDS (1.5) Ph3N (10.0)
LiHMDS (1.25) Ph3N (40.0)
LiHMDS (1.25) Ph3N (80.0)
Scheme 3. Rationale for the Thermodynamic Enolate Formation of 16
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Scheme 5. Synthesis of Substituted Styrene 21 via Suzuki
Cross-Coupling
Scheme 7. Synthesis of R-C-Glycoside 22
Scheme 6. Synthesis of Triol 8 via Wacker Oxidation
With the aromatic segment 21 readily in hand, we proceeded to the
synthesis of the R-C-glycoside segment of ent-1. Thus, the addition
of prenyl derived Grignard reagent 11 to TBDPS protec-
ted (S)-glycidol 12 readily proceeded with a catalytic amount of
Li2CuCl4 to provide diol 10 in virtually a quantitative yield as shown
in Scheme 6. An ensuing protection of the free hydroxyl moiety as a
MOM ether utilizing standard conditions (MOMCl, DMAP, and
DIPEA) followed by fluorine mediated desilylation of the corre-
sponding primary TBDPS ether furnished monoprotected diol 24
in 88% yield over two steps from 10. Subsequent oxidation of the
primary alcohol with TPAP afforded the requisite aldehyde, and a
matched asymmetric allylation with Brown’s (þ)-Ipc2Ballyl reagent
provided homoallylic alcohol 9 in 57% yield over the two-step
sequence with a >20:1 dr for the desired diastereomer.21
At this point in the synthesis, we deemed it prudent to verify
the 1,2-anti relationship of the diol moiety resident in 9. Thus,
removal of the MOM ether with LiBF4 furnished the free diol.
This compound was immediately submitted to acetonide forma-
tion utilizing 2,2-dimethoxypropane (DMP) and CSA to afford
compound 28 in 74% yield over the two steps. As depicted in
Scheme 6, we observed very strong NOE crosspeak signals
between the hydroxyl-methine signals and the axial methyl
group, which strongly supports the notion that the stereochem-
istry of the 1,2-diol was indeed anti as expected. With 9 in hand,
the stage was set for what we envisioned would be a chemose-
lective Wacker oxidation of the terminal olefin in the presence of
the trisubstituted alkene. Initial attempts at terminal alkene
oxidation in the presence of a free secondary alcohol, led to
diminished yields of the desired product (∼10%). Along this line,
the hydroxyl group of 9 was protected as a TES ether under
standard silylation conditions (TESCl, imidazole, and DMAP)
and furnished 25 in 90% yield. Much to our delight, treatment of
25 with 10 mol % of PdCl2 and 0.2 equiv of Cu(OAc)2 under an
atmosphere of O2 chemoselectively provided the desired TES
protected β-hydroxy ketone 26 in 77% yield. Removal of the TES
required alcohol 22 could, in principle, be derived from a highly
stereoselective oxocarbenium allylation reaction process be-
tween precursor 23 and allyl trimethylsilane. Thus, acetal 23
would be envisioned to arise from an oxidative cleavage of the
olefin resident in 8 followed by cyclization and capping of both
hydroxy moieties with acetic anhydride.
As presented in Scheme 5, our revised synthetic blueprint
required the synthesis of substituted styrene 21. By analogy to
our previous synthesis of epi-aigialomycin D, treatment of aryl
triflate 15 with potassium trifluoroborate and Pd(dppf)Cl2 under
conditions reported by Molander, readily provided compound
21 in 96% yield.11,20
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protecting group was readily accomplished with TBAF and
afforded ketone 27. An ensuing hydroxyl directed intramolecular
1,3-anti reduction of 27 with NMe4þH(OAc)3Bꢀ provided the
MOM protected triol 8 with a dr of >20:1 in 76% yield over two
steps from ketone 26.22
Scheme 8. Synthesis of the Proposed Structure of ent-Po-
chonin J
With triol 8 readily in hand, we were in position to proceed and
cyclize the linear fragment through an oxidative cleavage reaction
process as shown in Scheme 7. Hence, treatment of 8 under
standard ozonolysis conditions allowed for oxidative cleavage of
the alkene moiety followed by a 6-exo-trig cyclization of the
corresponding bis-hydroxy aldehyde intermediate to afford the
resultant hemiacetal product, which when directly treated with
excess acetic anhydride and pyridine with catalytic amounts of
DMAP provided the desired bis-acetyl hemiketal 23 as a mixture of
diastereomers in a yield of 79% over two steps from triol 8. With 23
in hand, addition of BF3 OEt2 at ꢀ78 °C readily generated the
3
endocyclic oxocarbenium cation and stereoselective allylation of
reactive intermediate conformer 30 with allyltrimethylsilane pro-
vided the desired R-C-glycoside 31 in 87% yield as a single
diastereomer. Presumably, alkylations of oxocarbenium cations
occur through a stabilized chairlike transition state via axial addition
of the allyl silane to afford the R-C-glycoside.23 Of two possible
reactive conformers (29 and 30) and based on the isolated R-C-
glycoside, the proposed conformer 30 placed the substituents at C4
and C5 into pseudoequatorial positions. During our prior examina-
tion of stereoselective endocyclic oxocarbenium alkylation with
respect to the synthesis of aspergillide B, the C4 hydroxyl moiety
was placed in the axial position and the C5 substituent in the pseudo
equatorial geometry and the allylation took only 1 h for
completion.12 Based on Woerpel’s observations and in conjunction
with our prior investigations, these C4 axial and C5 pseudoequatorial
oxocarbenium conformations tend to represent a “matched”
geometry.12,24 However, the current reactive oxocarbenium confor-
mer 30 placed the C4 and C5 substituents in the pseudoequatorial
positions. Interestingly, the highly stereoselective oxocarbenium for-
mation/alkylation reaction required ∼6 h for completion at ꢀ78 °C.
Hence, it is alleged that conformer 30 represents a “mismatched”
geometry for a highly stereoselective oxocarbenium allylation. Once
again, the current results would suggest that the C5 substituent plays a
dominant role with respect to reactive oxocarbenium conformation
preference during an alkylation and/or reduction process.24 Final
hydrolysis of the acetate resident in 31 with K2CO3 and MeOH
provided the requisite aliphatic portion (22) of ent-1 in nearly
quantitative yield as delineated in Scheme 7.
mixture of CH2Cl2 and 1 M aqueous solution of NaHCO3, stereo-
selectively oxidized the olefin to afford epoxide 34 in a good yield of
82% as a single diastereomer. Although the generation of this
stereogenic center is extraneous, as it is later oxidized to the requisite
ketone, it is noteworthy that the epoxidation took place with such
remarkable stereoselectivity. After meticulous experimentation and
optimization of reaction parameters, reductive benzylic hydrogeno-
lysis of the oxirane moiety of 34 with H2 and 10% Pd/C in MeOH
furnished the homobenzylic alcohol 18 in 70% yield. The stereo-
chemistry of the secondary alcohol moiety resident in 18 was
determined via NOE correlation spectroscopy, thus leading us to
infer the epoxide stereochemistry as shown in Scheme 8. Initial
screening of several oxidants (TPAP, IBX, and Swern) failed to
provide the ketone and led only to starting material decomposition.
Fortunately, the DessꢀMartin periodinane reagent proved compe-
tent for the required oxidation of the secondary alcohol. Ensuing
global deprotection of the three MOM acetal groups with LiBF4
provided ent-1 in 78% yield over two steps from 18. Unfortunately,
the spectral (1H NMR, 500 MHz; 13C NMR, 125 MHz) and optical
rotation data of synthetic (þ)-pochonin J did not agree with the
With the aliphatic R-C-glycoside subunit 22 readily in hand, our
focus turned toward the completion of ent-1 as summarized in
Scheme 8. Consequently, convergent transesterification of 21 with
the alkoxide anion derived from the treatment of 22 with NaH in a
1:1 THF/DMF solvent mixture proceeded to provide diene 20 in
77% yield. Similar to our previous work on aigialomycin D, we
envisaged a macrocyclization to the 14-membered ring via a ring-
closing metathesis at C10ꢀC11.11
Thus, treatment of 20 with Grubbs’ second generation catalyst
(32) in refluxing CH2Cl2 led to the formation of the desired 14-
membered macrocycle 33 in 97% yield. With the crude framework in
place, we sought to install the final carbonꢀoxygen bond by means of
an m-CPBA mediated epoxidation of the newly formed olefin in 33.
Since epoxidation of this intermediate proved problematic and led
only to degradation of the starting material, we chose to protect the
free phenol of 33 as a MOM acetal, and said reaction furnished the
fully protected macrocycle 19 in 96% yield. Much to our surprise,
treatment of 19 with m-CPBA, buffered in a 1:1 biphasic solvent
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1
Table 2. HNMR chemical shift comparison of natural vs
on either a 360 or 500 MHz spectrometer. 1H NMR spectra were obtained
using CDCl3 as the solvent with either tetramethylsilane (TMS, 0 ppm) or
chloroform (CHCl3, 7.26 ppm) as the internal standard. Column chroma-
tography was performed using 60ꢀ200 μm silica gel. Analytical thin layer
chromatography was performed on silica-coated glass plates with F-254
indicator. Visualization was accomplished by UV light (254 nm), KMnO4,
or ceric sulfate-PMA stain. All starting materials and solvents were
commercially available and were used without further purification. Com-
pounds 6 and 12 have been previously reported.13,25
1-(tert-Butyl-diphenyl-silanyloxy)-6-methyl-hept-5-en-
2-ol (10). 1-Chloro-3-methyl-2-butene (1.10 mL, 9.60 mmol, 3.00
equiv) was added dropwise to a stirred suspension of preactivated Mg
powder (466 mg, 19.2 mmol, 6.00 equiv) in THF (9.60 mL) at 0 °C
under Ar and stirred for 1.5 h. Meanwhile to a solution of 12 (1.00 g,
3.20 mmol, 1.00 equiv) in THF (16.0 mL) at ꢀ40 °C under Ar was
added Li2CuCl4 (0.10 M solution in THF, 0.16 mmol, 0.05 equiv). The
previously made Grignard reagent was then added dropwise to the
reaction mixture and allowed to stir for 1 h at ꢀ40 °C, at which time the
reaction temperature was warmed to 0 °C and quenched with satd
NH4Cl (50.0 mL). The reaction mixture was then allowed to reach rt.
The aqueous layer was extracted with EtOAc (3 ꢁ 30.0 mL), and the
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 2% ethyl acetate in hexanes)
afforded 10 as a clear viscous oil (1.21 g, 99% yield): Rf at 5% ethyl
acetate in hexanes 0.30; 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 4H),
7.44 (m, 6H), 5.13 (m, 1H), 3.77 (m, 1H), 3.71 (dd, 1H, J = 10.1,
3.5 Hz), 3.55 (dd, 1H, J = 10.1, 7.3 Hz), 2.11 (m, 2H), 1.71 (s, 3H), 1.62
(s, 3H), 1.54 (m, 1H), 1.46 (m, 1H), 1.12 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 135.5, 135.5, 133.2, 133.1, 131.8, 129.7, 127.7, 123.9, 71.4,
synthetic pochonin Ja in CD3OD
natural pochonin
synthetic ent-pochonin
J ppm, mult, J in Hz
J ppm, mult, J in Hz
carbon
1.34, d, (6.7)
5.32, m
1
1.34, d, (6.0)
5.27, m
2
2.18, dd, (15.5, 2.4)
1.58, ddd, (15.5, 7.3, 4.3)
3.42, ddd, (10.0, 7.3, 2.4)
3.58, m
3a
3b
4
2.04, m
1.93, m
3.81, m
5
3.31, m
2.05, m
6a
6b
7a
7b
8
1.96, m
1.94, m
1.77, m
1.91, m
1.83, m
1.74, m
1.68, m
4.38, m
4.33, m
2.65, dd, (15.5, 10.0)
2.40, dd, (15.5, 4.0)
4.27, d, (18.3)
3.85, d, (18.3)
5.98, d, (2.4)
9a
9b
11a
11b
13
15
3.21, dd, (13.9, 11.9)
2.34, dd, (13.9, 3.8)
4.44, d, (18.9)
4.27, d, (18.9)
6.11, d, (2.5)
6.26, d, (2.5)
68.0, 32.8, 26.8, 25.6, 24.0, 19.2, 17.6. IR (CH2Cl2) 610, 703, 736, 825,
6.14, d, (2.4)
a Reference peak = 3.31 ppm.
ꢀ1
1006, 1109, 1427, 1471, 2857, 2928, 3050, 3068, 3456, 3578 cm
.
[R]20 = þ17.8 (c 0.40, CH2Cl2). HRMS (EI) calcd for C24H34O2Si
D
(M ꢀ C4H9) 325.1624, found 325.1623.
natural sample.2 The key NOE enhancements in Scheme 8 strongly
suggest that ent-1 is indeed an R-C-glycoside and the C1 methyl
group has the presumed stereochemistry as illustrated. As shown in
Table 2, many of the signals of ent-1 in the 1H NMR do not match
that of the reported structure. A couple of significant H NMR
discrepancies lie at both C9 and C11 and these results might provide
valuable insight into the true structure of pochonin J.
2-Methoxymethoxy-6-methyl-hept-5-en-1-ol (24). To a
stirred solution of 10 (300 mg, 0.78 mmol, 1.00 equiv) in CH2Cl2
(4.00 mL) were added DMAP (29 mg, 0.24 mmol, 0.30 equiv), DIPEA
(0.68 mL, 3.92 mmol, 5.00 equiv), and MOMCl (0.18 mL, 2.35 mmol,
3.00 equiv) at 0 °C under Ar. The reaction mixture was stirred for 18 h at
rt, at which time the temperature was lowered to 0 °C. The reaction was
quenched with a saturated aqueous solution of NaHCO3 (10.0 mL) and
deionized H2O (10.0 mL) and then allowed to reach rt. The aqueous
layer was extracted with Et2O (3 ꢁ 20.0 mL), and the organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography (silica, 1% ether in hexanes) afforded the MOM
protected diol as a light yellow oil (304 mg, 91% yield): Rf at 1% ether
in hexanes 0.30.;
1
’ CONCLUSION
In summary, an efficient synthesis of ent-1 has been achieved
but unfortunately does not match the spectroscopic data of
pochonin J as initially reported. The construction of the
R-C-glycoside subunit is highlighted by a highly diastereoselec-
tive oxocarbenium cation formation/allylation sequence of a
hemiketal intermediate. Convergent union of the elaborated
subunits, through a trans-esterification and subsequent RCM
reaction, forged the 14-membered macrolactone. Final oxidation
of the resulting alkene provided “pochonin J”, which did not
spectroscopically correlate to the initially disclosed natural
product. Further attempts at the structural verification of
pochonin J are ongoing and will be reported in due course.
To a solution of the MOM-protected diol (1.60 g, 3.75 mmol, 1.00
equiv) in THF (18.8 mL) was added TBAF (1.00 M solution in THF,
5.63 mmol, 1.50 equiv) at 0 °C under Ar. The reaction mixture was
stirred for 6 h at rt, at which time the reaction temperature was lowered
to 0 °C. The reaction was quenched with deionized H2O (50.0 mL) and
then allowed to reach rt. The aqueous layer was extracted with EtOAc
(3 ꢁ 25.0 mL), and the organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. Flash chromatography (silica, 20% ethyl
acetate in hexanes) afforded 24 as a yellow viscous oil (680 mg, 97%
1
yield): Rf at 20% ethyl acetate in hexanes 0.20; H NMR (500 MHz,
CDCl3) δ 5.08 (m, 1H), 4.74 (d, 1H, J = 6.9 Hz), 4.68 (d, 1H, J = 6.9
Hz), 3.54 (m, 3H), 3.43 (s, 3H), 3.13 (dd, 1H, J = 3.20, 8.8 Hz), 2.07
and 2.04 (ABq, 2H, J = 7.3 Hz), 1.68 (s, 3H), 1.60 (s, 3H), 1.56 (m, 1H),
1.46 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 132.2, 123.6, 97.1, 82.0,
65.8, 55.6, 31.7, 25.7, 23.9, 17.7. IR (CH2Cl2) 833, 917, 1035, 1105,
’ EXPERIMENTAL SECTION
General Procedure. All of the reactions were performed under an
inert atmosphere of Ar in flame-dried glassware. Anhydrous tetrahydrofuran
(THF) and dimethoxyethane (DME) were obtained from commercial
sources and used without purification. Deuterated chloroform (CDCl3) was
stored over molecular sieves (4 Å). All of the NMR spectra were recorded
1146, 1213, 1375, 1453, 2932, 3445 cm ꢀ1. [R]20 = þ228 (c 0.33,
D
CH2Cl2). HRMS (EI) calcd for C10H20O3 (M - H) 187.1334, found
187.1335.
3903
dx.doi.org/10.1021/jo200332d |J. Org. Chem. 2011, 76, 3898–3908

The Journal of Organic Chemistry
ARTICLE
5-Methoxymethoxy-9-methyl-deca-1,8-dien-4-ol (9). To a
stirred solution of 24 (2.00 g, 10.6 mmol, 1.00 equiv) in CH2Cl2
(106 mL) containing preactivated 4 Å molecular sieves (1.00 g/mmol)
were added NMO (3.74 g, 31.9 mmol, 3.00 equiv) and TPAP (374 mg,
1.06 mmol, 0.10 equiv) at rt under Ar. The reaction mixture was allowed
to stir for 1 h at rt, at which time the mixture was filtered through a plug
of silica (ca. 3 mm) to afford the corresponding aldehyde as a clear oil
(1.60 g, 81% yield): Rf at 40% ethyl acetate in hexanes 0.85.
(m, 1H), 0.93 (t, 9H, J = 7.9 Hz), 0.59 (q, 6H, J = 8.1 Hz). 13C NMR
(125 MHz, CDCl3) δ 207.5, 132.1, 123.9, 96.5, 80.7, 71.1, 55.7, 46.5,
31.6, 31.4, 25.6, 24.4, 17.7, 6. 8, 6.5, 5.8, 4.8. IR (CH2Cl2) 736, 839, 1032,
1098, 1150, 1239, 1357, 1375, 1412, 1460, 1719, 2880, 2912, 2957,
3438 cm ꢀ1. [R]20D = ꢀ76.9 (c 0.13, CH2Cl2). HRMS (EI) calcd for
C19H38O4Si (Mþ) 358.2539, found 358.2556.
4-Hydroxy-5-methoxymethoxy-9-methyl-dec-8-en-2-one
(27). To a solution of 26 (480 mg, 1.34 mmol, 1.00 equiv) in THF
(14.0 mL) was added TBAF (1.00 M solution in THF, 1.34 mmol, 1.00
equiv) at 0 °C under Ar. The reaction mixture was stirred for 6 h at rt, at
which time the reaction temperature was lowered to 0 °C. The reaction
was quenched with deionized H2O (25.0 mL) and then allowed to reach
rt. The aqueous layer was extracted with EtOAc (3 ꢁ 25.0 mL), and the
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 25% ethyl acetate in hexanes)
afforded 27 as a clear viscous oil (297 mg, 91% yield): Rf at 25% ethyl
acetate in hexanes 0.20; 1H NMR (500 MHz, CDCl3) δ 5.04 (m, 1H),
4.69 (d, 1H, J = 6.6 Hz), 4.58 (d, 1H, J = 6.6 Hz), 4.02 (m, 1H), 3.52 (m,
1H), 3.37 (s, 3H), 2.59 (dd, 1H, J = 16.7, 9.20 Hz), 2.52 (dd, 1H, J = 16.7,
3.20 Hz), 2.20 (s, 3H), 2.07 (m, 1H), 1.99 (m, 1H), 1.63 (s, 3H), 1.56 (s,
3H), 1.50 (m, 1H), 1.38 (m, 1H). 13C NMR (125 MHz, CDCl3) δ
208.6, 131.9, 123.5, 97.1, 82.1, 69.4, 55.6, 45.2, 31.1, 30.5, 25.4, 23.8,
17.4. IR (CH2Cl2) 921, 1032, 1073, 1150, 1213, 1265, 1361, 1375, 1442,
1712, 2924, 3449 cm ꢀ1. [R]20D = þ277 (c 0.14, CH2Cl2). HRMS (EI)
calcd for C13H24O4 (Mþ) 244.1675, found 244.1668.
To a stirred solution of (þ)-Ipc2BOMe (9.51 g, 30.1 mmol, 1.40
equiv) in Et2O (75.0 mL) at ꢀ78 °C under Ar was added allylmagne-
sium bromide (1.00 M solution in Et2O, 27.9 mmol, 1.30 equiv). The
reaction mixture was allowed to reach rt and stirred for 1 h, after which
time the mixture was recooled to ꢀ78 °C. The previously synthesized
aldehyde (4.00 g, 21.5 mmol, 1.00 equiv) was then added dropwise to
the reaction mixture, which was allowed to stir for 2 h. The reaction was
warmed to 0 °C. To this mixture were added 3 M NaOH (7.50 mL), 30%
aqueous H2O2 (15.0 mL), and deionized H2O (50.0 mL) sequentially.
The reaction mixture was allowed to stir at rt for 6 h, after which the
aqueous layer was extracted with Et2O (3 ꢁ 50.0 mL). The organic
extracts were dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography (silica, 10% ethyl acetate in hexanes) afforded 9
as a clear oil (3.43 g, 70% yield): Rf at 10% ethyl acetate in hexanes 0.20;
1H NMR (500 MHz, CDCl3) δ 5.87 (m, 1H), 5.10 (m, 3H), 4.72 (d, 1H,
J = 6.6 Hz), 4.62 (d, 1H, J = 6.9 Hz), 3.64 (m, 1H), 3.54 (m, 1H), 3.42 (s,
3H), 2.85 (m, 1H), 2.22 (m, 2H), 2.11 (m, 1H), 2.02 (m, 1H), 1.67 (s,
3H), 1.62 (m, 1H), 1.56 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 135.4,
132.1, 123.8, 117.1, 97.4, 83.2, 72.5, 55.8, 36.5, 30.6, 25.6, 24.2, 17.6. IR
5-Methoxymethoxy-9-methyl-dec-8-ene-2,4-diol (8). To a
solution of tetramethylammonium triacetoxyborohydride (11.8 g, 44.6
mmol, 10.0 equiv) in anhydrous CH3CN (25.0 mL) was added
anhydrous HOAc (25.0 mL), and the mixture was stirred at rt for 0.5 h
under Ar. The mixture was cooled to ꢀ40 °C, and a solution of 27
(1.09 g, 4.46 mmol, 1.00 equiv) in anhydrous CH3CN (45.0 mL) was
added dropwise. The reaction mixture was then allowed to stir at ꢀ20 °C
for 48 h. The reaction was quenched with a 0.5 M aqueous solution of
sodium potassium tartrate (25.0 mL), and the mixture was allowed to
warm to rt. The reaction mixture was then carefully neutralized with a
saturated aqueous solution of NaHCO3 (100 mL) at 0 °C and then
allowed to warm to rt. The aqueous layer was extracted with CH2Cl2
(3 ꢁ 50.0 mL), and the organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. Flash chromatography (silica, 40% ethyl
acetate in hexanes) afforded 8 as a clear viscous oil (910 mg, 83% yield):
Rf at 40% ethyl acetate in hexanes 0.20; 1H NMR (500 MHz, CDCl3) δ
5.00 (m, 1H), 4.65 (d, 1H, J = 6.9 Hz), 4.53 (d, 1H, J = 6.6 Hz), 4.01 (m,
1H), 3.79 (m, 1H), 3.67 (d, 1H, J = 6.9 Hz), 3.44 (m, 1H), 3.32 (s, 3H),
3.22 (m, 1H), 2.02 (m, 1H), 1.94 (m, 1H), 1.59 (s, 3H), 1.51 (s, 3H),
1.50 (m, 2H), 1.37 (m, 2H), 1.14 (d, 3H, J = 6.3 Hz). 13C NMR (125
MHz, CDCl3) δ 131.8, 123.7, 97.3, 83.8, 69.7, 64.5, 55.6, 39.3, 30.8, 25.5,
24.1, 23.5, 17.5. IR (CH2Cl2) 833, 917, 1035, 1150, 1209, 1375, 1446,
1642, 1723, 2924, 3408 cm ꢀ1. [R]20D = þ115 (c 0.28, CH2Cl2). HRMS
(EI) calcd for C13H26O4 (Mþ) 246.1831, found 246.1831.
(CH2Cl2) 735, 915, 1033, 1263, 1446, 1641, 1686, 2927, 3060, 3438 cm ꢀ1
.
[R]20D = þ150 (c 0.14, CH2Cl2). HRMS (EI) calcd for C13H24O3 (Mþ)
228.1725, found 228.1728.
(1-Allyl-2-methoxymethoxy-6-methyl-hept-5-enyloxy)-trieth-
yl-silane (25). To a solution of 9 (400 mg, 1.74 mmol, 1.00 equiv) in
DMF (8.60 mL) were added DMAP (65 mg, 0.52 mmol, 0.30 equiv),
imidazole (475 mg, 6.95 mmol, 4.00 equiv), and TESCl (0.75 mL,
4.34 mmol, 2.50 equiv) at 0 °C under Ar. The reaction mixture was stirred
for 24 h at rt, at which time the reaction temperature was lowered to 0 °C
and quenched with deionized H2O (50.0 mL) and then allowed to reach
rt. The aqueous layer was extracted with Et2O (3 ꢁ 25.0 mL), and the
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 1% ether in hexanes) afforded 25 as
a light yellow oil (540 mg, 90% yield): Rf at 1% ether in hexanes 0.35; 1H
NMR (500 MHz, CDCl3) δ 5.83 (m, 1H), 5.11 (m, 1H), 5.05 (m, 2H),
4.76 (d, 1H, J = 6.6 Hz), 4.62 (d, 1H, J = 6.6 Hz), 3.73 (m, 1H), 3.51 (m,
1H), 3.39 (s, 3H), 2.26 (m, 2H), 2.13 (m, 1H), 2.02 (m, 1H), 1.68 (s,
3H), 1.61 (s, 3H), 1.58 (m, 1H), 1.47 (m, 1H), 0.95 (t, 9H, J = 7.6 Hz),
0.59 (q, 6H, J = 7.8 Hz). 13C NMR (125 MHz, CDCl3) δ 135.7, 131.7,
124.3, 116.7, 96.3, 80.2, 74.4, 55.7, 37.7, 30.8, 25.6, 24.5, 17.7, 6.9, 5.1. IR
(CH2Cl2) 738, 915, 1006, 1036, 1102, 1150, 1238, 1381, 1414, 1458,
1642, 2880, 2912, 2953 cm ꢀ1. [R]20D = ꢀ133 (c 0.33, CH2Cl2). HRMS
(EI) calcd for C19H38O3Si (Mþ) 342.2590, found 342.2595.
4-Allyl-2,2-dimethyl-5-(4-methyl-pent-3-enyl)-[1,3]dioxolane
(28). To a solution of 9 (67.0 mg, 0.29 mmol, 1.00 equiv) in a 95:5
solvent mixture of CH3CN/H2O (5.87 mL) was added LiBF4 (1.0 M
solution in CH3CN, 2.93 mmol, 10.0 equiv). The reaction mixture was
then heated to reflux (75 °C) and allowed to stir for 1 h. After cooling,
the reaction was quenched with a saturated aqueous solution of
NaHCO3 (10.0 mL). The aqueous layer was extracted with EtOAc
(3 ꢁ 10.0 mL), and the organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. Flash chromatography (silica, 15% ethyl
acetate in hexanes) afforded the corresponding diol as a white crystalline
solid (48.0 mg, 89% yield): Rf at 20% ethyl acetate in hexanes 0.20.
To a stirred solution of the synthesized diol (25.0 mg, 0.14 mmol,
1.00 equiv) in THF (2.70 mL) were added CSA (3.20 mg, 0.02 mmol,
0.10 equiv) and 2,2-dimethoxypropane (0.17 mL, 1.36 mmol, 10.0
equiv) at 0 °C under Ar. The reaction mixture was allowed to stir at rt for
4-Hydroxy-5-methoxymethoxy-9-methyl-dec-8-en-2-one
(26). To a solution of 25 (75.0 mg, 0.22 mmol, 1.00 equiv) in DMF/
H2O (2.20 mL, 7:1) were added PdCl2 (4.00 mg, 0.02 mmol, 0.10 equiv)
and Cu(OAc)2 (8.00 mg, 0.04 mmol, 0.20 equiv). The reaction mixture
was allowed to stir under O2 (1 atm) at rt for 48 h. The reaction was then
diluted with EtOAc (10.0 mL) and water (20.0 mL). The aqueous layer
was extracted with EtOAc (3 ꢁ 15.0 mL), and the organic extracts were
dried over MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography (silica, 10% ethyl acetate in hexanes) afforded 26 as a yellow oil
(60 mg, 77% yield): Rf at 10% ethyl acetate in hexanes 0.20; 1H NMR
(500 MHz, CDCl3) δ 5.10 (m, 1H), 4.80 (d, 1H, J = 6.3 Hz), 4.64 (d,
1H, J = 6.3 Hz), 4.23 (m, 1H), 3.53 (m, 1H), 3.39 (s, 3H), 2.70 (dd, 1H,
J = 16.4, 7.6 Hz), 2.49 (dd, 1H, J = 16.4, 3.8 Hz), 2.16 (s, 3H), 2.11
(m, 1H), 2.02 (m, 1H), 1.68 (s, 3H), 1.61 (s, 3H), 1.48 (m, 1H), 1.37
3904
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The Journal of Organic Chemistry
ARTICLE
5 h, at which time the reaction was quenched with a saturated aqueous
solution of NaHCO3 (5.00 mL). The aqueous layer was extracted with
Et2O (3 ꢁ 5.00 mL), and the organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography (silica, 1%
ether in hexanes) afforded 28 as a yellow oil (25.0 mg, 83% yield): Rf at
1% ether in hexanes 0.40; 1H NMR (500 MHz, CDCl3) δ 5.84 (m, 1H),
5.10 (m, 3H), 4.08 (m, 2H), 2.28 (m, 1H), 2.18 (m, 2H), 2.04 (m, 1H),
1.69 (s, 3H), 1.62 (s, 3H), 1.57 (m, 1H), 1.45 (s, 3H), 1.40 (m, 1H), 1.34
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 134.9, 132.3, 123.7, 117.0,
107.6, 77.4, 77.3, 34.6, 29.8, 28.5, 25.9, 25.7, 24.7, 17.7. IR (CH2Cl2)
[R]20D = þ288 (c 0.40, CH2Cl2). HRMS (EI) calcd for C15H26O5 (M ꢀ
C3H5) 245.1389, found 245.1397.
1-(6-Allyl-3-methoxymethoxy-tetrahydro-pyran-2-yl)-propan-
2-ol(22). To a stirred solution of 31 (300 mg, 1.05 mmol, 1.00 equiv) in
MeOH (21.0 mL) was added K2CO3 (872 mg, 6.29 mmol, 6.00 equiv)
in four portions at 5 min intervals at 0 °C. The reaction mixture was
allowed to stir at rt for 5 h, at which time the reaction was quenched with
deionized H2O (50.0 mL) and then allowed to reach rt. The aqueous
layer was extracted with EtOAc (3 ꢁ 75.0 mL), and the organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography (silica, 30% ethyl acetate in hexanes) afforded 22 as a
clear viscous oil (250 mg, 98% yield): Rf at 30% ethyl acetate in hexanes
0.20; 1H NMR (500 MHz, CDCl3) δ 5.80 (m, 1H), 5.08 (m, 2H), 4.72
(d, 1H, J = 6.9 Hz), 4.62 (d, 1H, J = 6.9 Hz), 4.03 (m, 1H), 3.88 (m, 1H),
3.80 (m, 1H), 3.39 (m, 1H), 3.36 (s, 3H), 2.60 (broad s, 1H), 2.51 (m,
1H), 2.19 (m, 1H), 1.92 (m, 1H), 1.76 (m, 2H), 1.65 (m, 3H), 1.20 (d,
3H, J = 6.3 Hz). 13C NMR (125 MHz, CDCl3) δ 135.2, 117.0, 94.8, 73.9,
71.4, 70.8, 64.6, 55.5, 39.0, 36.9, 26.4, 24.5, 23.3. IR (CH2Cl2) 917, 1035,
911, 1059, 1214, 1377, 1449, 1639, 1729, 2858, 2927 cm ꢀ1. [R]20
=
D
þ56.7 (c 0.03, CH2Cl2). HRMS (EI) calcd for C14H24O2 (Mþ)
224.1776, found 224.1781.
Acetic Acid 6-(2-Acetoxy-propyl)-5-methoxymethoxy-tetra-
hydro-pyran-2-yl Ester (23). A stream of ozone was bubbled through
a solution of 8 (750 mg, 3.05 mmol, 1.00 equiv) dissolved in CH2Cl2
(60.0 mL) at ꢀ78 °C until complete consumption of starting material
was observed by TLC analysis (30 min). To the reaction mixture was
added PPh3 (4.00 g, 15.3 mmol, 5.00 equiv) at ꢀ78 °C, and the resulting
mixture was stirred initially for 0.5 h and then for an additional 2.5 h at rt.
The solution was concentrated in vacuo, and flash chromatography
(silica, 70% ethyl acetate in hexanes) afforded the hemiacetal as a clear
viscous oil (535 mg, 80% yield): Rf at 70% ethyl acetate in hexanes 0.20.
To a solution of the synthesized hemiacetal (700 mg, 3.18 mmol, 1.00
equiv) in CH2Cl2 (16.0 mL) were added DMAP (117 mg, 0.95 mmol,
0.30 equiv), pyridine (0.78 mL, 9.54 mmol, 3.00 equiv), and Ac2O
(0.75 mL, 7.95 mmol, 2.50 equiv) at 0 °C under Ar. The reaction mixture
was stirred for 12 h at rt, at which time the reaction temperature was
lowered to 0 °C. The reaction was quenched with saturated aqueous
solution of NaHCO3 (25.0 mL) and then allowed to warm to rt. The
aqueous layer was extracted with EtOAc (3 ꢁ 25.0 mL), and the organic
extracts were dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography (silica, 20% ethyl acetate in hexanes) afforded 23
as a yellow oil (765 mg, 79% yield): Rf at 20% ethyl acetate in hexanes
1102, 1220, 1368, 1446, 1642, 2355, 2942, 3083, 3430 cm ꢀ1. [R]20
=
D
þ242 (c 0.60, CH2Cl2). HRMS (EI) calcd for C13H24O4 (M - OH)
227.1647, found 227.1646.
5-Hydroxy-7-methoxymethoxy-2,2-dimethyl-benzo[1,3]-
dioxin-4-one (14). To a stirred solution of 5,7-dihydroxy-2,2-dimeth-
yl-4H-benzo[d][1,3]dioxin-4-one (6) (2.10 g, 10.1 mmol, 1.00 equiv) in
anhydrous acetone (50.0 mL) were added K2CO3 (4.17 g, 30.1 mmol,
3.00 equiv) and MOMCl (1.53 mL, 20.1 mmol, 2.00 equiv) at 0 °C
under Ar. The reaction mixture was stirred for 18 h at rt, at which time
the reaction temperature was lowered to 0 °C and quenched with a
saturated aqueous solution of NaHCO3 (50.0 mL) and then allowed to
reach rt. The aqueous layer was extracted with EtOAc (3 ꢁ 50.0 mL),
and the organic extracts were dried over MgSO4, filtered, and concen-
trated in vacuo. Flash chromatography (silica, 5% ethyl acetate in
hexanes) afforded 14 as a white crystalline solid (2.30 g, 90% yield):
Rf at 5% ethyl acetate in hexanes 0.20; 1H NMR (500 MHz, CDCl3) δ
10.4 (s, 1H), 6.28 (d, 1H J = 2.2 Hz), 6.12 (d, 1H, J = 2.2 Hz), 5.17 (s,
2H), 3.47 (s, 3H), 1.73 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 165.2,
165.1, 162.8, 156.8, 119.9, 106.9, 97.9, 95.8, 94.1, 93.7, 56.4, 25.6. IR
(CH2Cl2) 747, 847, 906, 1142, 1279, 1320, 1512, 1627, 1678, 2337,
2362, 2954, 3001, 3105 cm ꢀ1. HRMS (EI) calcd for C12H14O6 (Mþ)
254.0790, found 254.0799.
1
0.20; H NMR (500 MHz, CDCl3), Minor diastereomer: δ 5.59 (dd,
1H, J = 8.5, 1.3 Hz), 5.04 (m, 1H), 4.59 (d, 2H, J = 6.9 Hz), 3.45 (m, 1H),
3.34 (d, 3H, J = 1.0 Hz), 3.26 (m, 1H), 2.21 (m, 1H), 2.08 (m, 1H), 1.99
(s, 3H), 1.98 (s, 3H), 1.78 (m, 2H), 1.53 (m, 2H), 1.20 (d, 3H, J = 6.30
Hz). Major diastereomer: δ 5.99 (s, 1H), 5.05 (m, 1H), 4.70 (dd, 2H, J =
6.9, 1.0 Hz), 3.64 (t, 1H, J = 10.1 Hz), 3.36 (d, 3H, J = 1.0 Hz), 3.26 (m,
2H), 2.08 (m, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.78 (m, 2H), 1.53 (m,
2H), 1.19 (d, 3H, J = 6.3 Hz). 13C NMR (125 MHz, CDCl3) δ 142.8,
138.5, 128.3, 127.8, 127.6, 112.9, 76.8, 71.3, 65.9, 46.3, 40.1, 35.9, 22.4,
18.6, 14.2. IR (CH2Cl2) 944, 1043, 1109, 1249, 1374, 1443, 1737, 2938,
Trifluoro-methanesulfonic Acid 7-Methoxymethoxy-2,2-
dimethyl-4-oxo-4H-benzo[1,3]dioxin-5-yl Ester (15). To a
stirred solution of 14 (2.14 g, 8.42 mmol, 1.00 equiv) in anhydrous
pyridine (42.0 mL) was added Tf2O (2.13 mL, 12.6 mmol, 1.50 equiv) at
0 °C under Ar. The reaction mixture was stirred for 18 h at rt, at which
time the reaction temperature was lowered to 0 °C and quenched with a
saturated aqueous solution of NaHCO3 (50.0 mL) and deionized H2O
(50.0 mL) and then allowed to reach rt. The aqueous layer was extracted
with EtOAc (3 ꢁ 75.0 mL), and the combined organic extracts were
washed with a saturated aqueous solution of CuSO4 (300 mL) to
remove excess pyridine, dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 15% ethyl acetate in hexanes)
afforded 15 as a white crystalline solid (3.22 g, 99% yield): Rf at 15%
ethyl acetate in hexanes 0.20; 1H NMR (500 MHz, CDCl3) δ 6.67 (d,
1H, J = 2.2 Hz), 6.64 (d, 1H, J = 2.2 Hz), 5.21 (s, 2H), 3.49 (s, 3H), 1.73
(s, 6H). 13C NMR (125 MHz, CDCl3) δ 163.2, 158.5, 157.0, 149.6, (q,
CF3, J = 321 Hz), 106.5, 118.4, 106.3, 103.6, 101.5, 94.6, 56.5, 25.3. IR
(CH2Cl2) 588, 731, 815, 863, 1010, 1083, 1138, 1201, 1377. 1428, 1572,
1627, 1737, 2835, 2960, 3008, 3100 cm ꢀ1. HRMS (EI) calcd for
C13H13O8F3S (Mþ) 386.0283, found 386.0274.
3452 cm ꢀ1. [R]20 = þ463 (c 0.40, CH2Cl2). HRMS (EI) calcd for
D
C14H24O7 (Mþ) 305.1600, found 305.1602.
Acetic Acid 2-(6-Allyl-3-methoxymethoxy-tetrahydro-pyran-
2-yl)-1-methyl-ethyl Ester (31). To a stirred solution of 23 (550 mg,
1.81 mmol, 1.00 equiv) in CH2Cl2 (11.0 mL) were added allylTMS
(1.20 mL, 7.24 mmol, 4.00 equiv) and BF3 OEt2 (0.45 mL, 3.62 mmol,
3
2.00 equiv) at ꢀ78 °C under Ar. The reaction mixture was stirred for 3 h,
at which time the reaction was quenched with a saturated aqueous
solution of NaHCO3 (25.0 mL) at ꢀ78 °C and slowly allowed to reach
rt. The aqueous layer was extracted with CH2Cl2 (3 ꢁ 25.0 mL), and the
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 10% ethyl acetate in hexanes)
afforded 31 as a light yellow oil (440 mg, 87% yield): Rf at 10% ether in
hexanes 0.20; 1H NMR (500 MHz, CDCl3) δ 5.76 (m, 1H), 5.02 (m,
3H), 4.71 (d, 1H, J = 6.9 Hz), 4.63 (d, 1H, J = 6.9 Hz), 3.68 (m, 2H), 3.37
(s, 3H), 3.32 (m, 1H), 2.40 (m, 1H), 2.16 (m, 1H), 2.00 (s, 3H), 1.86
(m, 2H), 1.69 (m, 2H), 1.61 (m, 2H), 1.24 (d, 3H, J = 6.3 Hz). 13C NMR
(125 MHz, CDCl3) δ 170.3, 134.8, 116.5, 94.7, 73.9, 70.6, 70.3, 67.8,
5-Allyl-7-(methoxymethoxy)-2,2-dimethyl-4H-benzo[d][1,3]-
dioxin-4-one (5). To a stirred solution of 15 (5.73 g, 14.8 mmol, 1.00
equiv) in THF (926 mL) were added CsF (4.50 g, 29.7 mmol, 2.00
equiv), Pd(PPh3)4 (1.72 g, 1.48 mmol, 0.10 equiv), and stirred for
55.3, 37.3, 37.2, 26.0, 24.3, 21.1, 20.5. IR (CH2Cl2) 607, 917, 1035,
ꢀ1
1106, 1150, 1242, 1375, 1442, 1642, 1734, 2935, 3072, 3534 cm
.
3905
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30 min at room temperature under Ar. Allyl boronic acid pinacol ester
(5.60 mL, 29.7 mmol, 2.00 equiv) was then added and the reaction
mixture was stirred for 18 h at reflux (40 °C) and allowed to reach rt, at
which time the reaction was quenched with deionized H2O (400 mL).
The aqueous layer was extracted with EtOAc (3 ꢁ 250 mL), and the
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 1% ethyl ether in hexanes) afforded
5 as a white solid (3.80 g, 92% yield): Rf at 1% ethyl ether in hexanes
0.35; 1H NMR (500 MHz, CDCl3) δ 6.59 (d, 1H, J = 2.52 Hz), 6.49 (d,
1H, J = 2.52 Hz), 6.00 (m, 1H), 5.18 (s, 2H), 5.07 (m, 1H), 5.05 (m,
1H), 3.85 (s, 1H), 3.84 (s, 1H), 3.47 (s, 3H), 1.68 (s, 6H). 13C NMR
(125 MHz, CDCl3) δ 162.5, 159.9, 158.9, 147.2, 136.4, 116.2, 113.4,
105.6, 104.9, 101.8, 94.1, 56.4, 38.4, 25.6. IR (CH2Cl2) 858, 910, 1017,
1079, 1147, 1209, 1279, 1438, 1580, 1612, 1734, 2828, 2943, 2998,
3080 cm ꢀ1. HRMS (EI) calcd for C15H18O5 (Mþ) 278.1154, found
278.1161.
7-(Methoxymethoxy)-2,2-dimethyl-5-(2-oxopropyl)-4H-benzo-
[d][1,3]dioxin-4-one (4). To a solution of 5 (300 mg, 1.08 mmol, 1.00
equiv) in DMF/H2O (10.8 mL, 7:1) were added PdCl2 (48.0 mg, 0.27
mmol, 0.50 equiv) and CuCl (160 mg, 1.62 mmol, 2.00 equiv). The
reaction mixture was allowed to stir under O2 (1 atm) at rt for 48 h. The
reaction was then diluted with EtOAc (10.0 mL) and water (20.0 mL).
The aqueous layer was extracted with EtOAc (3 ꢁ 15.0 mL), and the
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 10% ethyl acetate in hexanes)
afforded 4 as a pale yellow solid (230 mg, 72% yield): Rf at 10% ethyl
acetate in hexanes 0.30; 1H NMR (360 MHz, CDCl3) δ 6.51 (s, 1H),
6.47 (s, 1H), 5.15 (s, 2H), 4.09 (s, 2H), 3.44 (s, 3H), 2.27 (s, 3H), 1.67
(s, 6H). 13C NMR (125 MHz, CDCl3) δ 204.8, 201.4, 162.5, 160.6,
158.6, 140.6, 115.1, 105.4, 102.6, 94.1, 56.3, 49.2, 30.0, 25.5 IR (CH2Cl2)
727, 913, 1010, 1081, 1153, 1209, 1286, 1353, 1442, 1581, 1611, 1723,
2252, 2826, 2941, 2997 cm ꢀ1. HRMS (EI) calcd for C15H18O6 (Mþ)
294.1103, found 294.1117.
EtOAc (3 ꢁ 75.0 mL), and the organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography (silica, 15%
ethyl acetate in hexanes) afforded 20 as a yellow viscous oil (425 mg,
77% yield): Rf at 15% ethyl acetate in hexanes 0.20; 1H NMR (500 MHz,
CDCl3) δ 11.7 (s, 1H), 7.30 (dd, 1H, J = 17.1, 10.7 Hz), 6.56 (s, 2H),
5.72 (m, 1H), 5.41 (d, 1H, J = 17.1 Hz), 5.30 (m, 1H), 5.20 (m, 1H),
5.18 (s, 2H), 4.95 (m, 2H), 4.71 (d, 1H, J = 6.9 Hz), 4.61 (d, 1H, J = 6.9
Hz), 3.74 (m, 2H), 3.46 (s, 3H), 3.36 (s, 3H), 3.32 (m, 1H), 2.40 (m,
1H), 2.09 (m, 2H), 1.89 (m, 1H), 1.75 (m, 1H), 1.64 (m, 3H), 1.38 (d,
3H, J = 6.3 Hz). 13C NMR (125 MHz, CDCl3) δ 170.4, 164.5, 161.4,
143.8, 138.7, 134.8, 116.7, 115.4, 109.0, 105.2, 102.9, 94.8, 93.9, 74.2,
70.7, 70.3, 70.1, 56.2, 55.4, 37.5, 36.8, 26.3, 24.5, 20.8. IR (CH2Cl2) 813,
921, 1024, 1146, 1261, 1323, 1375, 1571, 1612, 1652, 2938, 3397 cm ꢀ1
.
[R]20 = þ288 (c 0.08, CH2Cl2). HRMS (EI) calcd for C24H34O8
D
(Mþ) 450.2254, found 450.2265.
7,9,16-Tris-methoxymethoxy-13-methyl-12,19-dioxa-tricyclo-
[13.3.1.05,10]nonadeca 3,5,7,9-tetraen-11-one (33). To a refluxing
solution of 20 (310 mg, 0.69 mmol, 1.00 equiv) in CH2Cl2 (68.8 mL,
40 °C) under Ar was added a solution of Grubbs’ second-generation
catalyst (32) (59.0 mg, 0.07 mmol, 0.10 equiv) in CH2Cl2 (7.00 mL)
dropwise over a period of 2 h. The reaction mixture was allowed to stir at
40 °C for 18 h, at which time the reaction was concentrated in vacuo.
Flash chromatography (silica, 15% ethyl acetate in hexanes) afforded 33
as a viscous oil (280 mg, 97% yield): Rf at 15% ethyl acetate in hexanes
0.15; 1H NMR (500 MHz, CDCl3) δ 11.2 (s, 1H), 6.83 (d, 1H, J = 15.5
Hz), 6.49 (d, 1H, J = 2.5 Hz), 6.41 (d, 1H, J = 2.5 Hz), 5.63 (dd, 1H, J =
10.4, 4.1 Hz), 5.28 (m, 1H), 5.15 (s, 2H), 4.75 (d, 1H, J = 6.9 Hz), 4.61
(d, 1H, J = 6.9 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 3.43 (s, 3H), 3.38 (s,
3H), 3.25 (m, 1H), 2.91 (q, 1H, J = 12.3 Hz), 2.09 (m, 1H), 2.00 (m,
1H), 1.90 (m, 3H), 1.72 (m, 1H), 1.59 (m, 1H), 1.37 (d, 3H, J = 6.3 Hz).
13C NMR (125 MHz, CDCl3) δ 170.7, 163.8, 161.3, 143.8, 134.6, 127.9,
108.6, 106.0, 102.2, 95.2, 93.9, 76.0, 71.3, 70.2, 67.7, 56.1, 55.6, 37.7,
33.4, 27.6, 25.9, 19.9. IR (CH2Cl2) 736, 851, 950, 1028, 1146, 1213,
1261, 1317, 1453, 1575, 1612, 1649, 2935 cm ꢀ1. [R]20 = ꢀ44.0 (c
D
7-Methoxymethoxy-2,2-dimethyl-5-vinyl-benzo[1,3]dioxin-
4-one (21). To a stirred solution of 15 (3.08 g, 8.03 mmol, 1.00 equiv)
in EtOH (54.0 mL) were added Et3N (1.45 mL, 10.4 mmol, 1.30 equiv),
0.25, CH2Cl2). HRMS (EI) calcd for C22H30O8 (Mþ) 422.1941, found
422.1945.
7,9,16-Tris-methoxymethoxy-13-methyl-12,19-dioxa-tricyclo-
[13.3.1.05,10]nonadeca-3,5,7,9-tetraen-11-one (19). To a stirred
solution of 33 (43.0 mg, 0.11 mmol, 1.00 equiv) in CH2Cl2 (1.00 mL)
were added TBAI (8.00 mg, 0.02 mmol, 0.20 equiv), DIPEA (0.06 mL,
0.31 mmol, 3.00 equiv), and MOMCl (0.02 mL, 0.21 mmol, 2.00 equiv)
at 0 °C under Ar. The reaction mixture was stirred for 24 h at rt, at which
time the reaction temperature was lowered to 0 °C and quenched with a
saturated aqueous solution of NaHCO3 (5.00 mL) and deionized H2O
(5.00 mL) and then allowed to reach rt. The aqueous layer was extracted
with CH2Cl2 (3 ꢁ 10.0 mL), and the organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. Flash chromatography
(silica, 25% ether in hexanes) afforded 19 as a light yellow oil (45.0 mg,
96% yield): Rf at 25% ethyl acetate in hexanes 0.15; 1H NMR (500 MHz,
CDCl3) δ 6.69 (d, 1H, J = 2.2 Hz), 6.50 (m, 1H), 5.89 (dd, 1H, J = 10.7,
2.8 Hz), 5.41 (m, 1H), 5.19 (d, 1H, J = 6.6 Hz), 5.13 (s, 3H), 4.69 (d, 1H,
J = 6.9 Hz), 4.56 (d, 1H, J = 6.9 Hz), 4.13 (m, 1H), 3.56 (m, 1H), 3.46 (s,
3H), 3.44 (s, 3H), 3.34 (s, 3H), 3.18 (m, 1H), 2.76 (m, 1H), 2.30 (m,
1H), 2.15 (m, 1H), 2.04 (m, 1H), 1.84 (m, 1H), 1.69 (m, 1H), 1.48 (m,
2H), 1.26 (d, 3H, J = 6.3 Hz), 1.25 (m, 1H). 13C NMR (125 MHz,
CDCl3) δ 167.2, 158.3, 155.6, 138.5, 131.1, 130.3, 118.2, 108.6, 102.6,
95.2, 94.8, 94.3, 77.4, 69.1, 66.9, 66.7, 56.2, 56.1, 55.5, 39.2, 34.8, 27.6,
25.2, 20.8. IR (CH2Cl2) 925, 977, 1032, 1098, 1150, 1223, 1267, 1447,
1597, 1723, 2935, 3430 cm ꢀ1. [R]20D = þ120 (c 0.40, CH2Cl2). HRMS
(EI) calcd for C24H34O9 (Mþ) 466.2203, found 466.2192.
PdCl2(dppf) CHCl3 (655 mg, 0.81 mmol, 0.10 equiv), and potassium
3
vinyltrifluoroborate (1.20 g, 8.83 mmol, 1.10 equiv) at rt under Ar. The
reaction mixture was stirred for 18 h at reflux (75 °C) at which time the
reaction was concentrated in vacuo. The crude solid was redissolved in
EtOAc (50.0 mL) and deionized H2O (50.0 mL) and allowed to stir for
30 min at rt. The aqueous layer was then extracted with EtOAc (3 ꢁ
50.0 mL), and the organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography (silica, 2% ethyl acetate in
hexanes) afforded 21 as a white solid (2.08 g, 98% yield): Rf at 2% ethyl
acetate in hexanes 0.25; 1H NMR (500 MHz, CDCl3) δ 7.63 (dd, 1H, J =
17.3, 10.7 Hz), 6.83 (d, 1H, J = 1.9 Hz), 6.49 (d, 1H, J = 2.5 Hz), 5.63
(dd, 1H, J = 17.3, 1.26 Hz), 5.33 (dd, 1H, J = 11.1, 1.26 Hz), 5.15 (s, 2H),
3.42 (s, 3H), 1.64 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 162.5, 160.1,
158.4, 144.0, 135.3, 117.7, 109.8, 105.1, 104.7, 102.9, 94.1, 56.4, 25.6. IR
(CH2Cl2) 862, 910, 988, 1039, 1150, 1209, 1275, 1386, 1430, 1575,
1605, 1730, 2828, 2994, 3090 cm ꢀ1. HRMS (EI) calcd for C14H16O5
(Mþ) 264.0998, found 264.0989.
2-Hydroxy-4-methoxymethoxy-6-vinyl-benzoic Acid 2-(6-Al-
lyl-3-methoxymethoxy tetrahydro-pyran-2-yl)-1-methyl-ethyl
Ester (20). To a stirred solution of 22 (300 mg, 1.23 mmol, 1.00 equiv)
in a 1:1 mixture of DMF/THF (54.0 mL) was added NaH (60%
dispersion in mineral oil, 210 mg, 4.30 mmol, 3.50 equiv) at 0 °C under
Ar. To this mixture was added 21 (422 mg, 1.60 mmol, 1.25 equiv), and
the resulting mixture was allowed to stir at rt. At 5 h intervals, additional
(4 times) 21 (80 mg, 0.31 mmol, 0.25 equiv) was added to the reaction
mixture. After 30 h, the resulting suspension was cooled to 0 °C and
quenched with deionized H2O (100 mL). The mixture was allowed to
stir at rt for 30 min, at which time the aqueous layer was extracted with
Epoxy-macrocycle (34). To a stirred solution of 19 (260 mg,
0.56 mmol, 1.00 equiv) in a 1:1 biphasic mixture of CH2Cl2 (5.60mL) anda
1 M NaHCO3 aqueous solution (5.60 mL) was added mCPBA (77% max.,
275 mg, 1.12 mmol, 2.00 equiv) at 0 °C under Ar. The reaction mixture
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was stirred for 3 h at rt, at which time the reaction temperature was
quenched with saturated aqueous solutions of NaHCO3 (10.0 mL) and
Na2S2O3 (10.0 mL). The aqueous layer was extracted with CH2Cl2 (3 ꢁ
25.0 mL), and the organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography (silica, 35% ethyl acetate
in hexanes) afforded 34 as a clear viscous oil (220 mg, 82% yield): Rf at
35% ethyl acetate in hexanes 0.20; 1H NMR (500 MHz, CDCl3) δ 6.78
(d, 1H, J = 2.2 Hz), 6.71 (d, 1H, J = 2.2 Hz), 5.17 (m, 5H), 4.73 (d, 1H,
J = 6.6 Hz), 4.60 (d, 1H, J = 6.9 Hz), 4.11 (m, 1H), 4.04 (s, 1H), 3.69 (m,
1H), 3.49 (s, 3H), 3.44 (s, 3H), 3.38 (s, 3H), 3.26 (m, 1H), 2.89 (m,
1H), 2.02 (m, 4H), 1.90 (m, 2H), 1.61 (m, 2H), 1.37 (d, 3H, J = 6.3 Hz).
13C NMR (125 MHz, CDCl3) δ 165.6, 159.6, 156.9, 138.9, 116.3, 105.9,
103.9, 95.3, 95.2, 94.2, 76.3, 70.4, 69.3, 67.9, 60.6, 57.6, 56.3, 56.2, 55.6,
37.3, 33.6, 27.9, 25.5, 20.0. IR (CH2Cl2) 732, 921, 1032, 1150, 1265,
1446, 1605, 1723, 2935, 3527 cm ꢀ1. [R]20D = þ278 (c 0.04, CH2Cl2).
HRMS (EI) calcd for C24H34O10 (Mþ) 482.2152, found 482.2151.
3-Hydroxy-7,9,16-tris-methoxymethoxy-13-methyl-12,19-di-
oxa-tricyclo[13.3.1.05,10]nonadeca-5,7,9-trien-11-one (18). To a
solution of 34 (65.0 mg, 0.14 mmol, 1.00 equiv) in MeOH (13.5 mL)
was added 10% Pd/C (20.0 mg). The reaction vessel was evacuated
under vacuum and placed under atmospheric H2 balloon pressure. The
reaction mixture was allowed to stir at rt for 12 h, at which time
additional 10% Pd/C (20.0 mg) was added. After 12 h, additional 10%
Pd/C (20.0 mg) was added and the suspension was stirred for 12 h. The
reaction was then filtered through a plug of Celite and concentrated in
vacuo. Flash chromatography (silica, 60% ethyl acetate in hexanes)
afforded 18 as a clear viscous oil (45.0 mg, 70% yield): Rf at 60% ethyl
acetate in hexanes 0.25; 1H NMR (500 MHz, CDCl3) δ 6.71 (d, 1H, J =
2.2 Hz), 6.54 (d, 1H, J = 2.2 Hz), 5.35 (m, 1H), 5.15 (s, 4H), 4.71 (d, 1H,
J = 6.9 Hz), 4.61 (d, 1H, J = 6.9 Hz), 4.09 (m, 2H), 3.83 (m, 1H), 3.47
(m, 6H), 3.37 (m, 4H), 3.07 (dd, 1H, J = 13.9, 6.0 Hz), 2.92 (dd, 1H, J =
13.9, 8.5 Hz), 2.25 (broad s, 1H), 2.10 (m, 2H), 1.88 (m, 1H), 1.81 (dd,
1H, J = 8.8, 2.5 Hz), 1.68 (m, 2H), 1.60 (m, 2H), 1.38 (d, 3H, J = 6.3 Hz).
13C NMR (125 MHz, CDCl3) δ 167.8, 158.7, 155.9, 138.6, 118.9, 111.4,
102.1, 94.9, 94.8, 94.4, 75.7, 69.2, 69.0, 68.8, 68.6, 56.2, 56.1, 55.5, 42.5,
37.9, 35.7, 26.9, 25.4, 19.7. IR (CH2Cl2) 843, 924, 1035, 1150, 1265,
1438, 1605, 1719, 2938, 3430 cm ꢀ1. [R]20D = þ205 (c 0.10, CH2Cl2).
HRMS (EI) calcd for C24H36O10 (Mþ) 484.2308, found 484.2320.
ent-Pochonin J (ent-1). To a stirred solution of 18 (33.0 mg, 0.07
mmol, 1.00 equiv) in CH2Cl2 (1.00 mL) was added DessꢀMartin period-
inane (58.0 mg, 0.14 mmol, 2.00 equiv) at 0 °C. The reaction mixture was
allowed to stir at rt for 5 h, at which time the reaction was quenched with
saturated aqueous solutions of NaHCO3 (5.00 mL) and Na2S2O3
(5.00 mL). The aqueous layer was extracted with CH2Cl2 (3 ꢁ
10.0 mL), and the organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography (silica, 40% ethyl acetate in
hexanes) afforded the ketone macrocycle as a light yellow oil (28.0 mg, 91%
yield): Rf at 50% ethyl acetate in hexanes 0.25.
(CH2Cl2) 1026, 1255, 1373, 1453, 1646, 1730, 2832, 2946, 3376 cm ꢀ1
[R]20D = þ144 (c 0.08, MeOH). HRMS (EI) calcd for C18H22O7 (Mþ)
350.1366, found 350.1375.
.
’ ASSOCIATED CONTENT
Supporting Information. Full characterization (1H and
S
b
13C NMR) data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jenningm@bama.ua.edu.
’ ACKNOWLEDGMENT
Support for this project was provided by the University
of Alabama and the National Science Foundation CAREER
program under CHE-0845011.
’ REFERENCES
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To a stirred solution of the corresponding ketone (30.0 mg, 0.06 mmol,
1.00 equiv) in a 95:5 solvent mixture of CH3CN/H2O (1.30 mL) was
added LiBF4 (1.0 M solution in CH3CN, 1.25 mmol, 20.0 equiv). The
reaction mixture was then heated to reflux (75 °C) and allowed to stir for
1.5 h. After cooling, the reaction was quenched with a saturated aqueous
solution of NaHCO3 (10.0 mL). The aqueous layer was extracted with
EtOAc (3 ꢁ 10.0 mL), and the organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography (silica, 60% ethyl
acetate in hexanes) afforded ent-1 as a white solid (19.0 mg, 86% yield): Rf at
70% ethyl acetate in hexanes 0.25; 1H NMR (500 MHz, CD3OD) δ 6.26
(d, 1H, J = 2.5 Hz), 6.11 (d, 1H, J = 2.5 Hz), 5.27 (m, 1H), 4.44 (d, 2H, J =
18.9 Hz), 4.35 (m, 1H), 4.27 (d, 2H, J = 18.9 Hz), 3.81 (m, 1H), 3.31 (m,
1H), 3.21 (dd, 1H, J = 13.9, 11.9 Hz), 2.34 (dd, 1H, J = 14.2, 3.80 Hz), 1.97
(m, 3H), 1.83 (m, 1H), 1.76 (m, 1H), 1.68 (m, 1H), 1.34 (d, 3H, J = 6.0
Hz). 13C NMR (125 MHz, CD3OD) δ 210.1, 173.6, 166.8, 164.6, 140.7,
114.3, 108.5, 103.7, 73.6, 72.9, 71.4, 71.1, 52.3, 46.0, 37.1, 29.8, 29.3, 20.0. IR
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