Total synthesis of cephalosporolide E via a tandem radical/polar crossover reaction. The use of the radical cations under nonoxidative conditions in total synthesis

Article abstract of DOI:10.1021/jo502757c

The present work reports the first example of the use of the chemistry of radical cations under nonoxidative conditions in total synthesis. Using a late-stage tandem radical/polar crossover reaction, a highly stereoselective total synthesis of cephalospor

Full text of DOI:10.1021/jo502757c

Article
pubs.acs.org/joc
Total Synthesis of Cephalosporolide E via a Tandem Radical/Polar
Crossover Reaction. The Use of the Radical Cations under
Nonoxidative Conditions in Total Synthesis
Omar Cortezano-Arellano, Leticia Quintero, and Fernando Sartillo-Piscil*
Centro de Investigacion
Claudio, Col. San Manuel, 72570, Puebla, Mex
́
de la Facultad de Ciencias Químicas, Benemer
́ ́
ita Universidad Autonoma de Puebla (BUAP), 14 Sur Esq. San
́
ico
S
* Supporting Information
ABSTRACT: The present work reports the first example of the use of the chemistry of radical cations under nonoxidative
conditions in total synthesis. Using a late-stage tandem radical/polar crossover reaction, a highly stereoselective total synthesis of
cephalosporolide E (which is typically obtained admixed with cephalosporolide F) was accomplished. The reaction of a
phthalimido derivative with triphenyltin radical in refluxing toluene engenders a contact ion-pair (radical cation) that leads, in the
first instance, to the cephalosporolide F, which is transformed into the cephalosporolide E via a stereocontrolled spiroketal
isomerization promoted by the diphenylphosphate acid that is formed during the tandem transformation.
Scheme 1 (eq 3), wherein a stereocontrolled attack of the
hydroxyl group on the intermediate A, on the opposite face to
that shielded by the phosphate ion, gave exclusively a single
stereoisomer (Scheme 2). Although this methodology appears
as an attractive solution for overcoming the problem of the
stereoselective construction of 5,5-spiroketal centers, no
synthetic application has been reported yet. On this basis, we
believe that this tandem transformation can be utilized as an
expedient chemical transformation for the total synthesis of
compounds that contain the 5,5-spiroketal moiety.
Among the wide variety of 5,5-spiroketal-containing natural
products, chalcogran sex-pheromones9 and cephalosporolides10
have received special attention due to their biological
importance and structural complexity, especially the latter,
because of the lack of stereocontrolled methods for the
formation of the spiroketal center (Figure 1).11
Unlike the 5,6- or 6,6-spiroketal compounds, the 5,5-
spiroketal analogues are weakly dependent on the anomeric
effect;12 therefore, the classical acid-catalyzed method generally
provides unpredictable mixtures of spiroketals. Consequently,
all of the total syntheses of cephalosporolides have required
separation from their respective spiro-diastereoisomers.13
Moreover, an interesting approach for the stereocontrolled
synthesis of cephalosporolides H14 and E11 was reported. This
INTRODUCTION
■
Unlike conventional olefin radical cations, which are formed by
one-electron oxidation of an olefin in high polar media (eq 1),1
the nonoxidative radical cations are similar charged species
generated by a C−O bond heterolysis (even in nonpolar
media) of a suitable leaving group placed at the β-position of an
alkyl free radical (eq 2).2 Despite that this C−O bond
heterolysis was first reported in 1972 by Norman and co-
workers,3 it was not until the beginning of this century that the
nature of this heterolysis was fully recognized.4 In conjunction
with the physical organic chemical studies of these species,4
synthetic applications were documented, wherein an intra-
molecular nucleophilic attack to the cation by heteroatoms like
oxygen and nitrogen has permitted the development of new
methodologies for the synthesis of lactones,5 tetrahydrofur-
ans,5,6 pyranes,5 and pyrrolidines,5,7 with moderate and good
yields, and also acceptable stereoselectivities (eq 3). The origin
of the stereoselectivities is generally explained in terms of a
stereocontrolled nucleophilic attack on the contact ion-pair, on
the opposite side of the leaving group (eq 3, Scheme 1).5,7
Inspired by the synthetic sequence described in eq 3, we
developed a tandem radical/polar crossover reaction for the
synthesis of a carbohydrate-derived spiroketal (Scheme 2).8a
Accordingly, when phthalimide derivative 1 was treated with
Ph3SnH/AIBN in refluxing benzene, spiroketal 2 was obtained
in 70% yield. The stereochemical outcome of the reaction was
rationalized based on the contact ion-pair model described in
Received: December 5, 2014
© XXXX American Chemical Society
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a
Scheme 1. Radical Cations: Conventional (eq. 1) and Nonclassical (Nonoxidative, eqs 2 and 3)
a
Abbreviations: LG = leaving group; Nu = nucleophile.
a
Scheme 2. Synthesis of a Carbohydrate-Derived Spiroketal 2 under Nonoxidizing Conditions
a
Abbreviation: AIBN = azobisisobutyronitrile; Et = ethyl.
stereoselective total synthesis of cephalosporolide F, an
interesting and unexpected behavior during the tandem
radical/polar reaction (vide infra) led to the direct stereo-
controlled total synthesis of cephalosporolide E. In order to
avoid isomerization in the spiroketal center at earlier stages of
the total synthesis, we planned to perform the tandem radical/
polar reaction at the late stage of the total synthesis.
RESULTS AND DISCUSSION
■
Our retrosynthetic plan focused on the stereoselective
construction of the bicyclic furan-γ-lactone framework (I)
from the xylofuranose derivative II via a sequential procedure,
which includes the stereoselective nucleophilic substitution at
the anomeric position (NSAP).15 We planned to use the
stereoselective Corey−Bakshi−Shibata (CBS) reduction16 to
install the correct stereochemistry of the hydroxyl group at the
C9 position ((S)-alcohol IV from α,β-unsaturated ketone III).
Then, after introduction of the N-hydroxyphthalimide group
under Mitsunobu conditions17 and phosphorylation at the C5
position, the radical precursor V could be obtained. Finally,
after the reaction of V with Ph3SnH and AIBN,18 the direct
stereocontrolled total synthesis of cephalosporolide F is
expected to be completed (Scheme 3).
Figure 1. Representative 5,5-spiroketal-containing natural products.
approach is based on the use of zinc salts as key reagents for the
formation of the spiro-center via either steric biases or chelation
control. Although certainly this zinc-mediated isomerization
represents an attractive strategy for the total synthesis of
cephalosporolides H and E, the crucial step for the construction
of the 5,5-spiroketal center is not stereoselective; an additional
step is required.
With this background in mind, we envisioned that our
stereocontrolled tandem radical/polar crossover reaction might
conduct to the first direct synthesis of a single cephalosporolide.
Although the present work was designed to achieve the direct
This total synthesis began with the transformation of
xylofuranose derivative 319 into allylated product 4 via the
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a
Scheme 3. Retrosynthetic Plan for the First Total Synthesis of Cephalosporolide F
a
Abbreviations: NPht = phthalimide; Ph = phenyl; Pg1 = protecting group 1; Pg2 = protecting group 2.
NSAP reaction;15 however, under standard reaction conditions
(allyltrimethylsilane/BF3·OEt2 in CH2Cl2 at 0 °C), the
expected product 4 was obtained in low yield (24%) along
with desylilated and debenzylated byproducts. This forced us to
prepare another xylofuranose derivative (5) with a more robust
protecting group at the C5 position. To this end, diacetone-D-
glucose 6 was benzylated and transformed into xylofuranose
derivative 7 by using the Robins’s dehomologation protocol
(H5IO6 in ethyl acetate, then NaBH4 in ethanol at room
temperature).20 Xylofuranose derivative 5 was obtained by
simple acetylation of 7. Then, compound 5 was submitted to
NSAP under the same reaction conditions as for compound 3,
and allylated product 8 was stereoselectivelly obtained in 82%
yield. The stereochemical outcome of the reaction can be
rationalized based on the Woerpel’s “inside attack” model,21
which predicts the formation of the 1,3-cis stereoisomer as the
major product. Deprotection of 8 with K2CO3 in methanol and
reprotection with TBSCl gave 4 (94% yield from 8).
Mesylation of the secondary hydroxyl group afforded
compound 9 (85% yield).
Conversion of 9 to the bicyclic furan-γ-lactone 10 was
accomplished by transforming the double bond into a
carboxylic acid in three sequential steps ((1) OsO4/NMO;
(2) NaIO4; (3) NaClO2, 11 in 75% overall yield), followed by
an intramolecular SN2 substitution with triethylamine at the
reflux temperature of the solvent (Scheme 4). Compound 10
was transformed into the α,β,-unsaturated ketone 12 by
applying another sequential three-steps reaction: silyl depro-
tection with BF3·OEt2, then oxidation of the respective primary
hydroxyl group with Dess−Martin perioidinane,22 and finally
trans-selective Wittig olefination at −45 °C with the
commercially available 1-(triphenylphosphoranylidene)-2-pro-
nanone (60% overall yield). Since the absolute stereochemistry
at the C9 position of the cephalosporolides E and F is R, and
the incorporation of the N-hydroxyphthalimide would occur
with inversion of the configuration, then the stereoselective
reduction of the unsaturated ketone 12 would have to provide
the corresponding S-stereoisomer. Therefore, the stereo-
selective keto reduction was conducted with the appropriate
Corey−Bakshi−Shibata (CBS) catalyst.16 After screening
reaction conditions, it was found that the use of 0.6 equiv of
the (R)-MeCBS and 1.0 equiv of BH3·SMe2 at −50 °C
provided the best yield and stereoselectivity (70%, dr = 9:1,
respectively). Allylic alcohol 13 was subjected to Mitsunobu
conditions17 with N-hydroxyphthalimide, DIAD, and triphenyl
phosphine; its corresponding N-phthalimido derivative 14 was
obtained in 60% yield. The reduction of the double bond and
removal of the benzyl group was conducted simultaneously
over Pd(OH)2 in 40% (by weight) and H2 during 14 h. Finally,
phosphorylation of 15 with phenyldichloro phosphate in the
presence of 4-dimethylamino pyridine gave the radical
precursor 16 (Scheme 4).
With the radical precursor 16 in hand, we proceeded to test
the crucial tandem radical polar crossover reaction. The slow
addition of Ph3SnH (45 min) in the presence of AIBN at
vigorous toluene reflux23 led to the exclusive formation of
cephalosporolide E in 72% yield, and no traces of the
cephalosporolide F was observed (Scheme 5). Evidently, this
unexpected result seems to be at odds with the radical cation/
ion-pair model proposed in Scheme 2. However, a likely
explanation would be that the cephalosporolide F is actually
formed according to the predicted ion-pair model, and the
formation of the cephalosporolide E is the result of an acid
isomerization of the cephalosporolide F by the presence of
phenylphosphate acid, which is formed during the tandem
radical/polar crossover reaction. If this is true, then the
isomerization process would be decreased by conducting the
radical reaction under basic conditions, and thus to observe the
presence of cephalosporolide F. Having this in mind, we
proceeded to perform the reaction in the presence of a suitable
base. Among the studied bases, we found that both triethyl-
amine and imidazole are compatible with the substrate and the
reaction conditions.
When the radical reaction was performed with 3 equiv of
triethylamine, a mixture of cephalosporolides E/F (85/15) was
observed. A slightly increase of the cephalosporolide F (i.e.,
∼75/25) is detected when either 6 or 8 equiv of triethylamine
was used. Moreover, a more significant decrease of cepha-
losporolide E at the expense of the formation of cephalospor-
olide F (i.e., ∼51/49) was achieved when either 6 or 8 equiv of
imidazole was employed (Scheme 5). Unfortunately, further
addition of imidazole did not improve the formation of
cephalosporolide F, but degradation of the starting material was
observed.
It is worth to remark the extraordinary effectiveness of the
phenylphosphate acid for promoting the stereoselective
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a
Scheme 4. Synthesis of Precursor of the Cephalosporolide E (16)
a
Abbreviations: TBS = tert-butyldimethylsilyl; Bn = benzyl; Ac = acetyl; Ms = methanesulfonyl; DIAD = diisopropyl azodicarboxylate; NMO = N-
methylmorpholine-N-oxide; CBS = Corey−Bakshi−Shibata; 4-DMAP = 4-dimethylaminopyridine; THF = tetrahydrofuran; dr = diastereomeric
ratio.
formation of cephalosporolide E from its stereoisomer
congener, since as above-mentioned, similar stereocontrol was
only achieved when ZnCl2 is used as catalyst. Also, the presence
of a hydroxyl group either protected or unprotected close to the
spiroketal nucleus is required.11,14 Since, in our case, the
presence of an additional stereochemical element is not needed
for the stereochemical control of the cephalosporolide E, but
the presence of phenylphosphate acid and the toluene refluxing
temperature, we propose that the cephalosporolide E is the
thermodynamic product and the cephalosporolide F the
kinetic.24 Further experimental and theoretical studies in
order to prove this proposal are currently underway and will
be reported soon.
CONCLUSION
■
By using the Chiron Approach and featuring our tandem
radical/polar reaction for the synthesis of 5,5-spiroketals, the
total synthesis of cephalosporolide E was accomplished in 20
steps with 4% overall yield from commercially available
diaceton-D-glucose. As in the previous total synthesis of
cephalosporolides E and F has required the use of either
chromatographic purifications from its diastereoisomer con-
gener or the use of an additional step for equilibration to the
“apparent” thermodynamic cephalosporolide E, the present
work should be considered as the first direct diastereoselective
total synthesis of cephalosporolide E. Therefore, the present
D
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Scheme 5. Synthesis of Cephalosporolide E through a Tandem Radical/Polar Crossover Reaction/Acid-Catalyzed Spiro-
isomerization. Evidence of Formation of Cephalosporolide E from Cephalosporolide F via an Ion-Pair Contact Intermediary
a
a
Abbreviations: NPht = phthalimide; AIBN = azobisisobutyronitrile; NMR = nuclear magnetic resonance.
carefully quenched with H2O (5 mL) on a bath of ice. The solvent was
evaporated, and the residue was diluted with EtOAc (180 mL), washed
with brine (60 mL), dried with Na2SO4, and evaporated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (eluent Hexane/EtOAc: 2/1) to give 525 (9.0 g, 85% yield) as a
work represents an attractive approach for the total synthesis of
other natural products that contain the 5,5-spiroketal nucleus.
EXPERIMENTAL SECTION
■
1
yellow oil. H NMR (400 MHz, CDCl3) δ: 7.33 (m, 5H, CH arom.),
General. All reagents were obtained from commercial sources and
used without purification. Solvents were used as technical grade, and
freshly distilled prior to use. NMR studies were carried out with 500,
5.97 (d, 1H, CH, J = 3.6 Hz), 4.69 (d, 1H, OCH2Ph, J = 12.0 Hz), 4.63
(d, 1H, CH, J = 4.0 Hz), 4.48 (d, 1H, OCH2Ph, J = 12.0 Hz), 4.37 (m,
2H, CH2−CH), 4.28 (m, 1H, CH2), 3.96 (d, 1H, CH, J = 2.8 Hz), 2.05
(s, 3H, CH3), 1.49 (s, 3H, CH3), 1.33 (s, 3H,CH3). 13C NMR (100
MHz, CDCl3) δ: 171.1 (COOCH3), 137.0 (C arom.), 128.5, 128.0,
127.7 (CH arom.), 105.2 (C), 81.9 (CH), 81.5 (CH), 78.0 (CH), 71.8
(CH2), 62.3 (CH), 26.7 (CH3), 26.2 (CH3), 20.9 (CH3). IR (ATR)
νmax 2932, 1738, 1371, 1229 cm−1.
1
400, and 300 MHz equipment. Internal references (TMS) for H and
13C chemical shifts are stated in parts per million. COSY, HSQC, and
1
NOESY experiments have been carried out in order to assign the H
and 13C NMR spectra completely. IR spectra were recorded on an FT/
IR spectrophotometer (ATR method). High-resolution mass spectra
(HRMS, ESI-TOF ion mode).
((2S,3S,4R,5R)-2-Allyl-4-(benzyloxy)-5((acetoxy)methyl))-
tetrahydrofuran-3-ol (8). To an ice-cooled solution of 5 (2.13 g, 6.6
mmol) and allyltrimethylsilane (5.32 mL, 33.0 mmol) in dry CH2Cl2
(133 mL) was dropwise added BF3·OEt2 (2.5 mL, 20.0 mmol). The
reaction mixture was warmed to room temperature and allowed to
react for 30 h. The resulting mixture was treated with saturated
aqueous solution of NaHCO3 to adjust pH ∼ 7 and then extracted
with CH2Cl2 (3 × 30 mL), dried with Na2SO4, and evaporated under
reduced pressure. Purification by flash chromatography (eluent
hexane/EtOAc: 2/1) to afford the 8 (1.65 g, 82% yield) as a yellow
oil. [α]2D0 = +10.54° (c = 1.1, CHCl3). 1H NMR (300 MHz, CDCl3) δ:
7.31 (m, 5H, CH arom.), 5.84 (dddd, 1H, CHCH2, J = 17.0, 10.0,
7.5, 7.0 Hz), 5.11 (m, 2H, CHCH2), 4.64 (d, 1H, OCHPh, J = 11.7
Hz), 4.51 (d, 1H, OCHPh, J = 11.7 Hz), 4.39 (dd, 1H, CH, J = 10.2,
2.4 Hz), 4.21 (m, 2H, CH, CH), 4.05 (m, 1H, CH), 3.92 (dd, 1H, CH,
J = 4.8, 2.7 Hz), 3.76 (ddd, 1H, CH, J = 6.6, 6.2, 4.2 Hz), 2.44 (m, 3H,
CH2, OH), 2.05 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ: 171.1
(COOCH3), 137.5 (C arom.), 133.9 (CH), 128.3, 127.7, 127.4 (CH
arom.), 117.5 (CH2), 85.0 (CH), 84.0 (CH), 78.4 (CH), 77.6 (CH),
71.7 (CH2), 63.6 (CH2), 37.7 (CH2), 20.8 (CH3). IR (ATR) νmax
3419, 2905, 1717, 1641, 1234, 1041 cm−1. (HRMS, ESI-TOF) m/z
307.1535 [M + H]+ calcd for C17H23O5: 307.1525.
(2S,3S,4R,5R)-2-Allyl-4-(benzyloxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)tetrahydrofuran-3-ol (4). A solution of 8 (2.1 g,
6.85 mmol) and K2CO3 (4.7 g, 34.25 mmol) in MeOH (69 mL) was
stirred at room temperature for 2 h. The solvent was evaporated, and
the residue was diluted with 60 mL of a mixture of EtOAc/H2O (10/5
mL). The mixture was neutralized (pH ∼ 7) with HCl (20% aqueous
solution) and extracted with EtOAc (3 × 20 mL). The combined
organic extracts were dried with Na2SO4 and concentrated under
reduced pressure. The residue was dissolved in dry CH2Cl2 (69 mL) at
5-O-Acetyl-3-O-benzyl-1,2-O-isopropylidene-α-D-xylo-
furanose (5). To a solution of DAG (6) (10 g, 38.4 mmol) and NaH
(3.07 g, 128 mmol, 60% dispersion in oil) in dry THF (192 mL) was
added BnBr (5.5 mL, 46.3 mmol) at 0 °C. The mixture was warmed
up to room temperature and kept stirring for 2 h. The resulting
reaction was carefully quenched with H2O (10 mL) at 0 °C, and the
solvent was evaporated under vacuum. The residue was diluted with
EtOAc (120 mL), washed with brine (30 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent hexane/ethyl
acetate: 5/1) to give 7 (12.8 g, 95% yield) as a yellow oil. To a solution
of protected product 7 (12.8 g, 36.5 mmol) in EtOAc (256 mL) under
an argon atmosphere was added H5IO6 (10 g, 43.9 mmol) portion-
wise at 0 °C. The reaction mixture was warmed up to room
temperature and kept stirring for 2 h.The formed solids were filtered
off and washed with ethyl acetate, and the organic phase was
evaporated under reduced pressure. The residue was dissolved in
methanol (365 mL) and NaBH4 (2.76 g, 73 mmol) was added in small
portions with vigorous stirring at 0 °C. The reaction mixture was
stirred for 2 h at room temperature. The reaction was carefully
quenched with H2O (10 mL) on a bath of ice, the solvent was
evaporated, and the residue was diluted with H2O (50 mL), extracted
with EtOAc (3 × 50 mL), dried with Na2SO4, and concentrated under
reduced pressure. The crude was purified by flash column
chromatography on silica gel (eluent hexane/EtOAc: 3/1) to give
the corresponding alcohol (9.2 g, 90% yield over 2 steps) as a colorless
oil. This alcohol (9.2 g, 32.82 mmol) was dissolved in dry THF under
an inert atmosphere and added NaH (2.62 g, 109.15 mmol, 60%
dispersion in oil) at 0 °C, followed by the dropwise addition of AcCl
(4.63 mL, 65.55 mmol). The resulting mixture was warmed up to
room temperature and kept stirring for 3 h. Finally, the reaction was
E
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0 °C, and imidazole (560 mg, 8.22 mmol) was added. The reaction
mixture was stirred for 10 min before adding TBSCl (1.13 g, 7.53
mmol). The mixture was warmed to room temperature for 2 h, and 10
mL of water was added, followed by extraction with CH2Cl2 (3 × 20
mL). The organic phase was dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography on silica (eluent hexane/EtOAc: 3/1) to give 4
(2.4 g, 94% yield) as a colorless oil. [α]2D0 = −21.0° (c = 1, CHCl3). 1H
NMR (400 MHz, CDCl3) δ: 7.31 (m, 5H, CH arom.), 5.85 (dddd,
1H, CHCH2, J = 17.2, 9.6, 7.2, 7.0 Hz), 5.10 (m, 2H, CH2), 4.65 (d,
1H, OCHPh, J = 12.4 Hz), 4.61 (d, 1H, OCHPh, J = 12.0 Hz), 4.07
(dd, 1H, CH, J = 10.8, 5.2 Hz), 4.03 (dd, 1H, CH, J = 4.4, 2.4 Hz),
3.90 (m, 2H, CH2−CH), 3.78 (dd, 1H, CH2, J = 10.4, 5.2 Hz), 3.70
(dd, 1H, CH, J = 11.4, 6.6 Hz), 2.46 (m, 1H, CH2), 2.38 (m, 1H,
CH2), 1.73 (br, 1H, OH), 0.9 (s, 9H, (CH3)3), 0.06 (s, 6H, (CH3)2).
13C NMR (100 MHz, CDCl3) δ: 138.2 (C arom.), 134.4 (CH), 128.3,
(apparent d, 2H, CH−CH2−CO, J = 7.6 Hz), 0.89 (s, 9H, (CH3)3),
0.056 (s, 3H, CH3), 0.053 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3) δ: 175.8 (COOH), 137.2 (C arom.), 128.5, 128.0, 127.8 (CH
arom.), 84.7 (CH), 81.8 (CH), 81.3 (CH), 78.5 (CH), 72.7 (CH2),
60.8 (CH2), 38.3 (CH3), 37.8 (CH2), 25.8 (CH3)3, 18.2 (C), −5.3
(CH3), −5.4 (CH3). IR (ATR) νmax 3167, 1715, 1354, 1174, 1254, 833
cm−1.
(3aS,5R,6S,6aR)-6-(Benzyloxy)-5-(((tert-butyldimethylsilyl)-
oxy)methyl)tetrahydrofuro[3,2-b]furan-2(3H)-one (10). A sol-
ution of acid 11 (1.7 g, 3.7 mmol) and NEt3 (1.1 mL, 7.4 mmol) in
CH3CN (74 mL) under an inert atmosphere was refluxed for 1 h and
then partitioned between H2O−EtOAc and extracted. The organic
phase was dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel using
(eluents hexane/EtOAc: 3/1) to give the γ-lactone 10 (1.2 g, 90%
yield) as a yellow oil. [α]2D0 = −74.4° (c = 1, CHCl3). H NMR (400
1
MHz, CDCl3) δ: 7.32 (m, 5H, CH arom.), 5.03 (dd, 1H, CH, J = 6.6,
4.6 Hz), 4.79 (d, 1H, OCHPh, J = 11.6 Hz), 4.7 (ddd, 1H, CH, J = 7.0,
7.0, 4.4 Hz), 4.49 (d, 1H, OCHPh, J = 11.6 Hz), 4.13 (apparent t, 1H,
CH, J = 4.4 Hz), 3.92 (m, 2H, CH, CH2a), 3.76 (dd, 1H, CH2b, J =
10.2, 6.2 Hz), 2.73 (dd, 1H, CH2a, J = 16.2, 7.2 Hz), 2.72 (dd, 1H,
CH2b, J = 16.4, 4.4 Hz), 0.89 (s, 9H, (CH3)3), 0.058 (s, 3H, CH3),
0.055 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ: 175.2 (COO),
137.3 (C arom.), 128.3, 128.0, 127.9 (CH arom.), 82.7 (CH), 82.2
(CH), 77.0 (CH), 75.8 (CH), 73.6 (CH2), 61.5 (CH2), 36.2 (CH2),
25.8 (CH3)3, 18.3 (C), −5.3 (CH3), −5.4 (CH3). IR (ATR) νmax 2931,
2857, 1782, 1253, 834 cm−1. (HRMS, ESI-TOF) m/z 379.1934 [M +
H]+ calcd for C20H31O5Si: 379.1940.
127.6, 127.4, 127.3 (CH arom.), 117.3 (CH2), 84.8 (CH), 83.8 (CH),
80.8 (CH), 79.2 (CH), 72.0 (CH2), 61.3 (CH2), 38.0 (CH2), 25.9
(CH3)3, 18.3 (C), −5.3 (CH3), −5.4 (CH3). IR (ATR) νmax 3423,
1641, 1253, 1087, 835 cm−1. (HRMS, ESI-TOF) m/z 379.2296 [M +
H]+ calcd for C21H35O4Si: 379.2304.
(2S,3S,4S,5R)-2-Allyl-4-(benzyloxy)-5-(((tert-butyldimethyl-
silyl)oxy)methyl)tetrahydrofuran-3-yl Methanesulfonate (9).
To a solution of alcohol 4 (1.8 g, 4.75 mmol) and NEt3 (3.97 mL,
28.48 mmol) at 0 °C in dry CH2Cl2 (95 mL) under an argon
atmosphere was added MsCl (0.8 mL, 10.55 mmol). The reaction
mixture was warmed to room temperature and stirred for 3 h before
adding 10 mL of H2O, followed by extraction with CH2Cl2 (3 × 20
mL), and dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (eluent
hexane/EtOAc: 6/1) to give 9 (1.8 g, 85% yield) as a yellow pale oil.
(3aS,5R,6S,6aR)-6-(Benzyloxy)-5-((E)-3-oxobut-1-en-1-yl)-
tetrahydrofuro[3,2-b]furan-2(3H)-one (12). To solution of lactone
10 (1.0 g, 2.6 mmol,) in anhydrous CH2Cl2 (53 mL) at 0 °C and
under an argon atmosphere was slowly added BF3·OEt2 (0.34 mL, 2.6
mmol). After stirring at 0 °C for 1 h, the mixture was treated with a
saturated aqueous solution of K2CO3 to adjust the pH ∼ 7. Extraction
with CH2Cl2, followed by drying with Na2SO4 and concentrating
under reduced pressure, gave the corresponding deprotected alcohol
as a yellow oil, which was dissolved in dry CH2Cl2 (53 mL) at room
temperature and treated with Dess−Martin periodinane (3.3 g, 7.9
mmol). After 3 h of stirring, the reaction was quenched with 20%
aqueous Na2SO3·5H2O (30 mL) at 0 °C, and the resulting mixture
was extracted with CH2Cl2. The organic phase was washed with
saturated aqueous NaCl, dried with Na2SO4, and concentrated under
reduced pressure. The crude aldehyde was directly used for olefination
without further purification. To a solution of phosphorus ylide (1.0 g,
3.2 mmol) in anhydrous THF (13 mL) was slowly transferred a
solution of the aldehyde in dry THF (40 mL), and the reaction
mixture was stirred 14 h at −45 °C. Finally, the reaction mixture was
warmed to room temperature for 2 h and partitioned between H2O−
EtOAc and extracted. The organic phase was dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (eluent hexane/EtOAc/MeOH: 75/20/
5) to afford 12 (480 mg, 60% yield) as a yellow oil. [α]2D0 = −41.0° (c
[α]2D0 = −34.0° (c = 1, CHCl3). H NMR (400 MHz, CDCl3) δ: 7.31
1
(m, 5H, CH arom.), 5.82 (dddd, 1H, CHCH2, J = 17.2, 10.0, 6.8,
6.8 Hz), 5.15 (dd, 1H, CH, J = 1.6, 1.2 Hz), 5.11 (apparent d, 1H, CH,
J = 9.4), 4.84 (dd, 1H, CH, J = 2.8, 1.6 Hz), 4.69 (d, 1H, OCHPh, J =
12.0 Hz), 4.61 (d, 1H, OCHPh, J = 12.0 Hz), 4.15 (dd, 1H, CH, J =
2.8, 1.4 Hz), 4.01 (m, 2H, 2(CH)), 3.88 (dd, 1H, CH, J = 10.2, 6.6
Hz), 3.81 (dd, 1H, CH, J = 10.2, 5.4 Hz), 2.95 (s, 3H, CH3), 2.47 (m,
2H, CH2), 0.89 (s, 9H, (CH3)3), 0.06 (s, 3H, CH3), 0.05 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3) δ: 137.4 (C arom.), 133.5 (CH), 128.4,
127.8, 127.7 (CH arom.), 118.1 (CH2), 84.6 (CH), 82.1 (2(CH)),
81.4 (CH), 72.2 (CH2), 60.7 (CH2), 38.4 (CH2), 37.6 (CH3), 25.8
(CH3)3, 18.2 (C), −5.3 (CH3), −5.4 (CH3). IR (ATR) νmax 1641,
1355, 1176, 1253, 1087, 833 cm−1. (HRMS, ESI-TOF) m/z 457.2067
[M + H]+ calcd for C22H37O6SSi: 457.2080.
2-((2S,3S,4S,5R)-4-(Benzyloxy)-5-(((tert-butyldimethylsilyl)-
oxy)methyl)-3-((methylsulfonyl)oxy)tetrahydrofuran-2-yl)-
acetic Acid (11). To a solution of allylated compound 9 (2.4 g, 5.26
mmol) in a mixture of acetone/H2O 10/1 (58 mL) were added N-
methylmorpholine N-oxide (1.23 g, 10.5 mmol) and OsO4 (4.2 mL,
0.1 M solution in tert-butanol). The reaction mixture was stirred at
room temperature for 3 h. Then, an aqueous solution of NaIO4 (2.25
g, 10.5 mmol in 5 mL of water) was added slowly, and the resulting
suspension was allowed to react at room temperature for 1 h. Then, a
mixture of tert-butanol/H2O 7/3 (53 mL) was added, followed by the
addition of NaH2PO4·H2O (7.26 g, 52.6 mmol) and NaClO2 (3.8 g,
42.1 mmol). The reaction mixture was stirred at room temperature for
2 h at room temperature before adding 20 mL of water and 50 mL of
ethyl acetate. The organic phase was separated, and the aqueous phase
was extracted with ethyl acetate (3 × 50 mL). Both organic phases
were dried Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (eluent hexane/
EtOAc: 1/1) to give the acid 11 (1.8 g, 75% yield) as a yellow pale oil.
This product is itself somewhat unstable; therefore, only NMR
1
= 0.4, CHCl3). H NMR (500 MHz, CDCl3) δ: 7.34 (m, 5H, CH
arom.), 6.8 (dd, 1H, CH, J = 16.0, 5.2 Hz), 6.24 (dd, 1H, CH, J = 16.2,
1.8 Hz), 5.03 (dd, 1H, CH, J = 6.0, 4.4 Hz), 4.80 (d, 1H, OCHPh, J =
12.0 Hz), 4.79 (ddd, 1H, CH, J = 6.0, 5.8, 4.0 Hz), 4.56 (ddd, 1H, CH,
J = 4.8, 4.6, 1.7 Hz), 4.52 (d, 1H, OCHPh, J = 11.6 Hz), 4.21 (dd, 1H,
CH, J = 5.6, 4.8 Hz), 2.79 (apparent d, 1H, CH2a, J = 1.6 Hz), 2.77
(apparent s, 1H, CH2b), 2.27 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3) δ: 198.0 (COCH3), 174.7 (COO), 141.4 (CHCHCOCH3),
136.8 (C arom.), 131.7 (CHCHCOCH3), 128.5, 128.3, 128.3,
128.2, 128.0 (CH arom.), 81.6 (CH), 79.9 (CH), 78.8 (CH), 76.5
(CH), 73.3 (CH2), 36.6 (CH2), 27.1 (CH3). IR (ATR) νmax 2933,
1779, 1728, 1255, 1152, 914 cm−1. (HRMS, ESI-TOF) m/z 303.1230
[M + H]+ calcd for C17H19O5: 303.1232.
1
characterization was possible. H NMR (400 MHz, CDCl3) δ: 7.32
(m, 5H, CH arom.), 4.95 (apparent t, 1H, CH, J = 2.2 Hz), 4.69 (d,
1H, OCHPh, J = 11.6 Hz), 4.62 (d, 1H, OCHPh, J = 12.0 Hz), 4.36
(ddd, 1H, CH, J = 7.2, 7.2, 2.8 Hz), 4.19 (dd, 1H, CH, J = 4.2, 2.2 Hz),
4.12 (m, 1H, CH), 3.83 (dd, 1H, O−CH2CH, J = 10.4, 6.0 Hz), 3.78
(dd, 1H, O−CH2CH, J = 10.2, 5.6 Hz), 3.02 (s, 3H, CH3), 2.82
(3aS,5R,6S,6aR)-6-(Benzyloxy)-5-((S,E)-3-hydroxybut-1-en-1-
yl)tetrahydrofuro[3,2-b]furan-2(3H)-one (13). To a solution of
unsaturated ketone 12 (200 mg, 0.66 mmol) and (R)-CBS catalyst
(110 mg, 0.4 mmol) in dry THF (7 mL) at −50 °C was added BH3·
SMe2 (75 μL, 0.79 mmol) dropwise. The reaction mixture was stirred
F
DOI: 10.1021/jo502757c
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The Journal of Organic Chemistry
Article
overnight before quenching with 0.1 mL of methanol and warming to
room temperature. The mixture was diluted with EtOAc and washed
with NH4Cl saturated, and the combined organic phases were washed
with brine, dried (Na2SO4), and concentrated. The residue was
purified by flash chromatography on silica gel (eluents hexane/EtOAc:
phate (16). To a mixture of alcohol 15 (63 mg, 0.17 mmol) and
DMAP (128 mg, 1.0 mmol) in dry CH2Cl2 (3 mL) under an inert
atmosphere at 0 °C was added dropwise (PhO)2POCl (109 μL, 0.52
mmol). The reaction was allowed to warm at room temperature and
was stirred for 3 h before adding a saturated aqueous NH4Cl solution
(1 mL), followed by extraction with CH2Cl2 (2 × 3 mL). The organic
phase was washed with brine (2 mL), dried (Na2SO4), and evaporated.
The residue was purified by flash chromatography on silica gel (eluent
CH2Cl2/EtOAc 1/1) to afford the phosphorylated product 16 (85 mg,
85% yield) as a yellow oil. [α]2D0 = −28.0° (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3) δ: 7.81 (m, 2H, CH arom.), 7.45 (m, 2H, CH
arom.), 7.29 (m, 8H, CH arom.), 7.17 (m, 2H, CH arom.), 5.12 (m,
2H, 2(CH)), 4.67 (ddd, 1H, CH, J = 7.2, 7.2, 3.6 Hz), 4.29 (dd, 1H,
CH, J = 11.6, 6.2 Hz), 3.95 (m, 1H, CH), 2.74 (dd, 1H, CH2a, J = 18.5,
7.2 Hz), 2.72 (dd, 1H, CH2b, J = 18.4, 3.6 Hz), 1.79 (m, 4H, CH2−
CH2), 1.27 (d, 3H, CH3, J = 6.3 Hz). 13C NMR (75 MHz, CDCl3) δ:
174.4 (COO), 164.2 (2(CON)), 150.4 (2(C arom.)), 134.4, 129.8,
129.7 (CH arom.), 129.0 (2(C arom.)), 125.5, 125.4, 123.4, 120.2,
120.18, 120.10 (CH arom.), 83.9 (CH), 81.4 (CH), 81.3 (CH), 77.5
(CH), 75.4 (CH), 35.8 (CH2), 31.0 (CH2), 24.7 (CH2), 18.7 (CH3).
31P NMR (121 MHz, CDCl3) δ: −10.74. IR (ATR) νmax 2926, 1781,
1721, 1485, 1194, 923 cm−1. ESI-HRMS m/z 594.1540 [M + H]+
calcd for C30H29NO10P: 594.1529.
1/2) to give the alcohol 13 (141 mg, 70% yield) as a yellow oil. [α]D20
=
1
−47.5° (c = 1.2, CHCl3). H NMR (500 MHz, CDCl3) δ: 7.66 (m,
1H, CH arom.), 7.49 (m, 1H, CH arom.), 7.33 (m, 3H, CH arom.),
5.87 (dd, 1H, CH, J = 15.6, 5.2 Hz), 5.83 (ddd, 1H, CH, J = 15.2, 15.2,
5.6 Hz), 5.0 (apparent t, 1H, CH, J = 5.2 Hz), 4.77 (d, 1H, OCHPh, J
= 12.0 Hz), 4.74 (dd, 1H, CH, J = 10.0, 4.8 Hz), 4.56 (d, 1H, OCHPh,
J = 11.6 Hz), 4.42 (apparent t, 1H, CH, J = 5.4 Hz), 4.32 (quin, 1H,
CH, J = 6.4 Hz), 4.08 (apparent t, 1H, CH, J = 5.2 Hz), 2.74 (apparent
d, 2H, CH2, J = 4.8 Hz), 1.25 (d, 3H, CH3, J = 6.4 Hz). 13C NMR (125
MHz, CDCl3) δ: 175.6 (COO), 137.9 (CHCHCOCH3), 137.1 (C
arom.), 132.1 (CHCHCOCH3), 128.46, 128.43, 128.0, 127.9, 125.6
(CH arom.), 81.9 (CH), 80.1 (CH), 78.8 (CH), 76.0 (CH), 73.0
(CH2), 68.2 (CH), 37.1 (CH2), 22.7 (CH3). IR (ATR) νmax 3454,
2968, 1777, 1267, 1143, 1051, 974 cm−1. (HRMS, ESI-TOF) m/z
305.1399 [M + H]+ calcd for C17H21O5: 305.1389.
2-(((R,E)-4-((2R,3S,3aR,6aS)-3-(Benzyloxy)-5-oxohexa-
hydrofuro[3,2-b]furan-2-yl)but-3-en-2-yl)oxy)isoindoline-1,3-
dione (14). To a mixture of alcohol 13 (153 mg, 0.5 mmol), PPh3
(236 mg, 0.9 mmol), and N-hydroxyphthalimide (163 mg, 1 mmol) in
dry THF (10 mL) at 0 °C was added dropwise DIAD (178 μL, 0.9
mmol). The reaction was allowed to warm at room temperature and
stirred overnight. The mixture was partitioned between H2O−EtOAc,
and the organic phase was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by flash chromatography on silica
gel (eluent from hexane/EtOAc: 2/1 to 1/1) to provide the
Mitsunobu product 14 (135 mg, 60% yield) as a white solid. mp =
(+)-Cephalosporolide E. A solution of radical precursor 16 (20
mg, 0.03 mmol) and AIBN (1.6 mg) in dry toluene (5 mL) was
refluxed for 5 min under an argon atmosphere. Then, a solution of
Ph3SnH (24 mg, 0.06 mmol) and a catalytic amount of AIBN (1.6 mg)
in dry/degassed toluene (5 mL) was slowly added to the refluxing
solution (45 min). When the starting material was completely
consumed (2 h), the mixture was cooled to room temperature; the
solvent was evaporated under reduced pressure. The reaction crude
was dissolved in 5 mL of CH3CN and extracted with hexane to remove
tin residues. The acetonitrile phase was evaporated under reduced
pressure and purified by flash column chromatography on silica gel
(eluent hexane/EtOAc/NEt3, 60/10/07 to 40/10/0.5) to provide the
110−112 °C. [α]2D0 = −28.7° (c = 0.8, CHCl3). H NMR (300 MHz,
1
CDCl3) δ: 7.75 (m, 2H, CH arom.), 7.66 (m, 2H, CH arom.), 7.23 (m,
3H, CH arom.), 7.10 (m, 2H, CH arom.), 5.95 (dd, 1H, CH, J = 15.9,
8.1 Hz), 5.90 (dd, 1H, CH, J = 15.6, 6.0 Hz), 4.90(dd, 1H, CH, J = 6.0,
4.8 Hz), 4.83 (m, 1H, CH), 4.68 (ddd, 1H, CH, J = 6.3, 6.3, 3.6 Hz),
4.47 (d, 1H, OCHPh, J = 11.4 Hz), 4.34 (apparent t, 1H, CH, J = 5.4
Hz), 4.14 (d, 1H, OCHPh, J = 11.7 Hz), 3.95 (apparent t, 1H, CH, J =
cephalosporolide E (4.2 mg, 72% yield) as a colorless oil. [α]D20
=
+21.5° (c = 0.25, CHCl3); lit.13e = +27.3 (c 0.41 in CHCl3). 1H NMR
(300 MHz, CDCl3) δ: 5.16 (t, 1H, CH, J = 6.0 Hz), 4.92−4.87 (m,
1H, CH), 4.23−4.11 (m, 1H, CH), 2.74 (dd, 1H, CH2a, J = 18.6, 7.8
Hz), 2.68 (dd, 1H, CH2b, J = 18.6, 2.1 Hz), 2.45 (d, 1H, CH2c, J = 14.1
Hz), 2.17−2.00 (m, 4H, CH2d, CH2e, CH2), 1.50−1.42 (m, 1H, CH2f),
1.20 (d, 3H, CH3, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3) δ: 175.8
(COO), 115.08 (C), 83.3 (CH), 77.4 (CH), 75.1 (CH), 41.6 (CH2),
37.5 (CH), 34.2 (CH2), 31.3 (CH2), 20.9 (CH3).
4.8 Hz), 2.69 (m, 2H, CH2a, CH2b), 1.5 (d, 3H, CH3, J = 6.6 Hz). 13
C
NMR (75 MHz, CDCl3) δ: 174.9 (COO), 163.9 (2(CON)), 136.8 (C
arom.), 134.3, 128.7, 128.3, 127.8, 127.6, 123.3 (CH arom.), 133.3
(CHCHCOCH3), 131.0 (CHCHCOCH3), 84.4 (CH), 81.9
(CH), 80.6 (CH), 78.7 (CH), 76.0 (CH), 73.0 (CH2), 36.6 (CH2),
19.0 (CH3). IR (ATR) νmax 2923, 1783, 1725, 1459, 1262, 1122, 970
cm−1. (HRMS, ESI-TOF) m/z 450.1538 [M + H]+ calcd for
C25H24NO7: 450.1552.
ASSOCIATED CONTENT
■
2-(((R)-4-((2R,3S,3aS,6aS)-3-Hydroxy-5-oxohexahydrofuro-
[3,2-b]furan-2-yl)butan-2yl)oxy)isoindoline-1,3-dione (15). A
suspension of benzyl ether 14 (81 mg, 0.18 mmol) and Pd(OH)2
(32 mg, 40 wt %) in EtOAc (4 mL) was stirred under a H2 atmosphere
(1 atm) at room temperature. When the starting material was
completely consumed (12 h), the mixture was filtered through a
neutral alumina pad and washed with EtOAc, and the solvent was
evaporated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent from hexane/EtOAc: 2/1 to 1/2)
to provide the reduced product 15 (46 mg, 70% yield) as a white solid.
mp = 150−152 °C). [α]D20 = −25.2° (c = 1.8, CHCl3). 1H NMR (300
MHz, CDCl3) δ: 7.83 (m, 2H, CH arom.), 7.75 (m, 2H, CH arom.),
5.0 (dd, 1H, CH, J = 11.5, 5.5 Hz), 4.6 (ddd, 1H, CH, J = 6.0, 6.0, 3.3
Hz), 4.36 (m, 2H, 2(CH), 3.84 (ddd, 1H, CH, J = 5.7, 5.7, 3.6 Hz),
2.79 (d, 1H, CH2a, J = 18.2, 6.3 Hz), 2.72 (d, 1H, CH2b, J = 18.0, 3.1
Hz), 2.43 (br, 1H, OH), 1.89 (m, 4H, CH2−CH2), 1.36 (d, 3H, CH3, J
= 6.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 175.3 (COO), 164.4
(2(CON)), 134.4 (CH arom.), 128.9 (C arom.), 123.5 (CH arom.),
84.5 (CH), 83.0 (2(CH)), 75.5 (CH), 71.2 (CH), 35.8 (CH2), 31.5
(CH2), 24.4 (CH2), 18.9 (CH3). IR (ATR) νmax 3449, 2923, 1783,
1723, 1460, 1269, 1113 cm−1. (HRMS, ESI-TOF) m/z 362.1233 [M +
H]+ calcd for C18H20NO7: 362.1239.
S
* Supporting Information
1H NMR and 13C NMR spectra of 4, 5, 8, 9, 10, 11, 12, 13, 14,
15, 16, and cephalosporolide E. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Telephone: +52 222 2955500, ext. 7391. Fax: + 52 222
2454972. E-mail: fernando.sartillo@correo.buap.mx (F.S.-P.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dra. Evelyn Paz-Morales for her help in initial
experiments and Dr. Alejandro Cordero-Vargas for revision of
this manuscript. Financial support from CONACyT (project
́ ́
number: 179074), and Benemerita Universidad Autonoma de
Puebla (BUAP-VIEP). O.C.-A thanks CONACyT for a
postdoctoral fellowship.
(2R,3S,3aR,6aS)-2-((R)-3-((1,3-Dioxoisoindolin-2-yl)oxy)-
butyl)-5 oxohexahydrofuro[3,2-b]furan-3-yl Diphenyl Phos-
G
DOI: 10.1021/jo502757c
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(15) (a) García-Tellado, F.; De Armas, P.; Marrero-Tellado, J. J.
DEDICATION
■
Angew. Chem., Int. Ed. 2000, 39, 2727−2729. (b) Sartillo-Melen
C.; Cruz-Gregorio, S.; Quintero, L.; Sartillo-Piscil, F. Lett. Org. Chem.
2006, 3, 504−509. (c) Romero, M.; Hernandez, L.; Quintero, L.;
́
dez,
We respectfully dedicate this manuscript to the 43 missing
students of Ayotzinapa. Our prayers and thoughts are with all of
them.
́
Sartillo-Piscil, F. Carbohydr. Res. 2006, 341, 2883−2890. (d) Hernan
́
-
dez-García, L.; Quintero, L.; Hopfl, H.; Sosa, M.; Sartillo-Piscil, F.
̈
Tetrahedron 2009, 65, 139−144. (e) Paz-Morales, E.; Melendres, R.;
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H
DOI: 10.1021/jo502757c
J. Org. Chem. XXXX, XXX, XXX−XXX