Methyl-α-D-2-selenonyl Pent-2-enofuranoside: A Reactive Selenosugar for the Diversity Oriented Synthesis of Enantiomerically Pure Heterocycles, Carbocycles, and Isonucleosides

Article abstract of DOI:10.1021/acs.joc.5b01192

The construction of vinyl selenone on a furanoside led to a highly reactive synthetic intermediate methyl-α-d-2-selenonyl pent-2-enofuranoside composed of a masked aldehyde, an electron-deficient double bond along with an excellent leaving group. This new

Full text of DOI:10.1021/acs.joc.5b01192

Note
pubs.acs.org/joc
Methyl-α‑D‑2-selenonyl Pent-2-enofuranoside: A Reactive
Selenosugar for the Diversity Oriented Synthesis of Enantiomerically
Pure Heterocycles, Carbocycles, and Isonucleosides
Atanu Bhaumik and Tanmaya Pathak*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
S
* Supporting Information
ABSTRACT: The construction of vinyl selenone on a furanoside led to
a highly reactive synthetic intermediate methyl-α-D-2-selenonyl pent-2-
enofuranoside composed of a masked aldehyde, an electron-deficient
double bond along with an excellent leaving group. This new Michael
acceptor on reactions with different nucleophiles afforded bicyclic
azasugars, cyclopropanated carbohydrate, dihydrofuran- and dihydroi-
soxazole- substituted furanosides, and isonucleosides in moderate to
good yields. Hydrolysis of the hemiacetal linkage of some of these
modified carbohydrates afforded enantiopure aziridines, nitrocyclopro-
pane, and dihydrofuran.
inyl sulfones have been used as Michael acceptors and 2π
selenone-modified carbohydrates would be excellent synthetic
intermediates for generating skeletal complexity along with
stereochemical diversity. In order to initiate a study with this
class of hitherto unknown Michael acceptors, we selected
methyl-α-D-2-selenonyl pent-2-enofuranoside 1 (Scheme 1),
V
partners in organic synthesis.1 We have extensively
employed vinyl sulfone-modified carbohydrates for accessing
a wide range of modified carbohydrates as well as enantiopure
carbocycles and heterocycles.1b,2 In most of the cases, it is
necessary to remove the sulfone group after the synthetic
transformation. In general, several methodologies are available
for the desulfonylation, although Na−Hg- and Mg/MeOH-
mediated reductions are the most widely used methods for the
desulfonylation of organic molecules.3 Attempted desulfonyla-
tion of furanosides using many of these reagents led to the
extensive degradation of starting materials.4,5 We reintroduced
the Mg-NiBr2-MeOH3 reagent systems for the synthesis of
various 2,3-dideoxy-2-alkylamino furanosides via desulfonyla-
tion. However, none of these reagents were efficient enough to
desulfonylate modified carbohydrates3 including nucleosides.6
Since desulfonylation of vinyl sulfone-modified carbohy-
drates remains an unsolved problem to date, we looked for
alternative Michael acceptors (and a 2π partner) derived from
carbohydrates. Vinyl selenones have been used in simple
systems in the past to fulfill both the requirements.7 Although
vinyl selenone functionality has been effectively used in more
complex nucleoside chemistry for accessing a plethora of
modified nucleosides,8 vinyl selenones derived from carbohy-
drates have rarely been utilized partly because the stability of
carbohydrate selenones or selenoxides is notoriously unpre-
dictable.2e,9 Nevertheless, we have designed strategies for the
synthesis of stable vinyl selenone-modified furanosides and
showed their applications as 2π partners by synthesizing a wide
range of triazoles.2e
Scheme 1. Reaction Patterns of Methyl-α-D-2-selenonyl
Pent-2-enofuranoside
which was easily synthesized in relatively large scale from D-
xylose.2e We presumed that a single starting material like 1
composed of a masked aldehyde, an electron-deficient double
bond along with the excellent leaving ability of the selenone
group would easily generate enantiomerically pure cyclic
structures depicted in Scheme 1.
Initial studies indicated that vinyl selenone 1 on reaction with
potassium hydroxide or sodium sulfide in water at room
temperature afforded a diastereomeric mixture of oxiranes
It should be noted that in recent time, we have utilized the
vinyl sulfone-modified carbohydrates as efficient Michael
acceptors in diversity oriented synthesis (DOS) to generate
complex molecular scaffolds.2b,c We presumed that vinyl
Received: May 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01192
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The Journal of Organic Chemistry
Note
6a10/6b11 (1:1) and thiiranes 7a/7b (1:1), respectively
(Scheme 2). Although the expected products were obtained
Scheme 4. Synthesis of Isomeric Aziridinated Carbohydrate
Scheme 2. Synthesis of Oxirane and Thiirane Derivatives
from Selenosugar 1
to presume that the C-3 position of 1 was attacked from the α-
face of 1 because of the least stereoelectronic hindrance
(Scheme 3). This assumption is supported by the fact that
smaller nucleophiles in Scheme 2 did not differentiate between
the two faces and produced diastereomeric mixtures.
Vinyl selenone 1 also efficiently reacted with nitromethane,
malononitrile, and dimethyl malonate in the presence of tBuOK
in THF at room temperature to afford single diastereomeric
cyclopropanated sugar derivatives 12a−c, respectively, in good
yields (Scheme 5).13 The stereochemistry at C-2 and C-3
as mixtures, these reactions established the expected reaction
pattern of 1, which prompted us to utilize this molecule as a
synthetic intermediate for the diversity oriented synthesis of a
wide range of molecules. Thus, compound 1 on treatment with
aqueous methylamine in DMF at room temperature afforded a
single diastereomeric aziridine 8a (Scheme 3) Cyclohexyl-
Scheme 5. Synthesis of Cyclopropanated Carbohydrates
from Selenosugar 1
Scheme 3. Synthesis of Aziridinated Carbohydrates from
a
Selenosugar 1
centers of 12a−c have been determined by 1D 1H NOE
difference spectroscopic technique (Figures S1 and S2, see SI).
Structural features of these compounds are comparable to those
of aziridines 8a−e. Ambident nucleophiles such as acetyl
acetone and ethyl acetoacetate on reactions with 1 in the
a
Reagents and conditions: 8a: 40% methylamine, DMF (2 h, 78%);
8b: neat cyclohexylamine (2 h, 81%); 8c: neat isopropylamine (2 h,
85%) ; 8d: neat 2-amino-2-methyl-1-propanol (4 h, 80%); 8e: glycine
ethylester hydrochloride, DMSO, Et3N (3 h, 85%); 8f: TMG, DMF,
(10 h, 65%).
t
presence of BuOK in THF at room temperature afforded
single diastereomeric dihydrofuran derivatives 13a−b, respec-
amine, isopropylamine, and 2-amino-2-methyl-1-propanol on
reaction with 1 at room temperature afforded single
diastereomeric aziridine derivatives 8b−d, respectively. Glycine
ethyl esterhydrochloride reacted with 1 in the presence of
Et3N/DMSO at room temperature to afford the aziridine
derivative 8e.12 The powerful Michael acceptor 1 even reacts
with an organic base tetramethylguanidine (TMG) to afford an
urea derivative 8f (Scheme 3). The structure of the aziridines
was established by synthesizing the diastereomer of 8b in an
alternative pathway. Thus, the known ribo-epoxide 9 was
opened by cyclohexylamine at C-2 position following the
known pattern2e to produce aminoalcohol 10, which was
converted to the corresponding N-alkylaziridin 11 under
Mitsunobu conditions (Scheme 4). The lyxo-aziridin 11 was
not identical to 8b obtained from vinyl selenone 1 (Scheme 3),
which indicated the D-ribo configuration of 8b. It is also logical
tively.14 Similarly, ethyl nitroacetate on treatment with 1 in the
t
presence of BuOK in THF produced single diastereomeric
dihydroisoxazole derivative 14 in excellent yield (Scheme 6).15
The structure of compound 14 has been unambiguously
secured by X-ray diffraction of its single crystal (Figure S3, see
SI).
The smaller nucleophiles like KO− or NaS− attack C-3 of 1
from the α- as well as β-faces generating the intermediate 1A
(Scheme 2), which afforded the mixtures of epoxides/thiiranes
6 and 7 after instantaneous elimination. The stereoelectronic
repulsion of CH2OBn attached to C-4 of 1 is not sufficient to
block the attack of small nucleophiles like KO− or NaS− at C-3
of 1 from the β-face.
This was also observed in case of 5′-monomethoxytritylated
vinylselenone-modified uridine, which afforded a mixture ribo-
and lyxo-thioepoxides.8 Even a larger group like C-5′
B
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Scheme 6. Synthesis of Dihydrofurans and Dihydroisoxazole
from Selenosugar 1
Scheme 7. Synthesis of Densely Functionalized Enantiopure
Aziridines, Nitrocyclopropane, and Dihydrofuran
Since vinyl selenone 1 was capable of affording C-3-
substituted isonucleosides,19 different planar heterocycles,
such as pyrrole, imidazole, 1,2,4-triazole, 1-H-tetrazole, and
the nucleobase thymine, were reacted with the Michael
acceptor, but the reaction conditions caused exhaustive
elimination to afford furan-linked heterocycles 20a−e,
respectively (Scheme 8).20 It is probable that planar hetero-
Scheme 8. Synthesis of Furan-Linked Heterocycles from
a
Selenosugar 1
CH2OMMTr could not block the nucleophilic addition of
NaS− to the vinyl selenone bond from the β-face. However, the
stereoelectronic repulsion imposed by CH2OBn moiety was
sufficient to force nucleophiles attached to a small methyl (in
case of MeNH2; Scheme 3) or nitro (in case of MeNO2;
Scheme 5) group to attack the C-3 position exclusively from
the α-face of 1. Thus, all alkyl amines, including TMG, afforded
the final products 8 via the intermediate 1B (Scheme 3).
Although the formation of 8f from 1 was unexpected, the
product formation may be explained by the nucleophilic attack
of TMG’s NH group at the C-3 position followed by the
addition of a molecule of water and elimination of one of the
−NMe2 groups (Scheme 3). The adducts of active methylene
compounds 1C, however, required the 1,3-shift of the residual
acidic hydrogen to afford 1D; the carbanion, thus generated,
attacked the C-2 position to displace the selenonyl group to
afford cyclopropanated carbohydrates 12 (Scheme 5). Similar
shift of negative charge generated the intermediates 1E and 1F
from the adducts of 1 and acetylacetone and ethylnitroacetate,
respectively; dispersion of negative charge generated the more
stable oxygen nucleophiles in both cases and the intramolecular
attack at C-2 afforded compounds 13 and 14 (Scheme 6).
To establish the strategy for the synthesis of enantiopure and
densely functionalized aziridine,16 cyclopropane,17 and dihy-
drofuran18 articulated in Scheme 1, compounds 8a−c were
treated with 80% aqueous TFA at 70 °C followed by NaBH4
reduction; and the products were isolated as alcohols 15a−c,
respectively. Using the same methodology, cyclopropane 16
and densely substituted dihydrofuran 17 were synthesized from
12a and 13b, respectively (Scheme 7).
a
t
Reagents and conditions: 20a: pyrrole, BuOK, THF, rt (1 h, 73%);
20b: imidazole, H2O, 80 °C (6 h, 86%); 20c: 1,2,4-triazole, K2CO3,
THF, rt (2 h, 80%); 20d: 1-H-tetrazole, K2CO3, THF, 70 °C (10 h,
76%); 20e: RH = thymine, BuOK, THF, rt (10 h, 64%).
t
cycles first reacted with 1 to produce intermediates 18a−e
followed by elimination of phenyl seleninic acid (PhSeO2H) to
produce intermediates 19a−e. Concomitant elimination of
methanol from 19a−e afforded isonucleosides 20a−e,
respectively (Scheme 8). In order to avoid the double
elimination we opted for an organic base TMG. For pyrrole,
imidazole, 1,2,4-triazole, and 1-H-tetrazole the base reacted
directly with 1 to afford 8f. However, instead of reacting with 1,
the same base TMG efficiently deprotonated thymine and
uracil, respectively, to afford the O-anhydroisonucleosides 22a−
b, respectively, in good yields (Scheme 9). Due to the
electronic repulsion between nucleobase and anomeric
methoxy group, nucleobases first attacked from the β-face of
C-3 centers of 1 to form intermediates 21a−b which
C
DOI: 10.1021/acs.joc.5b01192
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Note
residue. The residue thus obtained was purified over silica gel column
to afford compounds 7a (0.042 g, 34%) and 7b (0.04 g, 32%).
Compound 7a: [Eluent: EtOAc:pet ether (1:4)] Yellowish gum:
[α]D26 +42.2 (c 0.90 in CHCl3); 1H NMR (400 MHz, CDCl3): δ 3.35
(d, 1H, J = 4.8 Hz), 3.43 (s, 3H), 3.56 (dd, 1H, J = 2.2, 4.6 Hz), 3.58−
3.65 (m, 2H), 4.48−4.51 (m, 1H), 4.59 (q, 2H, J = 12.0 Hz), 4.99 (s,
1H), 7.30−7.36 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 38.8, 39.8,
55.8, 71.8 (CH2), 73.8 (CH2), 76.0, 105.1, 128.0, 128.7, 138.1; HRMS
[ES+, (M + Na)+] for C13H16O3SNa found 275.0723, calcd 275.0718.
Compound 7b: [Eluent: EtOAc:pet ether (1:2)] Yellowish gum:
[α]D26 +36.2 (c 1.00 in CHCl3); 1H NMR (400 MHz, CDCl3): δ 3.38
(dd, 1H, J = 0.8, 5.2 Hz), 3.54−3.65 (m, 6H), 4.39 (t, 1H, J = 3.0 Hz),
4.57 (q, 2H, J = 12.0 Hz), 5.43 (s, 1H), 7.31−7.39 (m, 5H); 13C NMR
(50 MHz, CDCl3): δ 39.0, 40.4, 57.9, 72.5(CH2), 73.6(CH2), 79.1,
104.4, 127.6, 128.0, 128.7, 138.0; HRMS [ES+, (M + Na)+] for
C13H16O3SNa found 275.0711, calcd 275.0718.
General Procedure for Synthesis of N-alkyl Aziridines 8b−d
from Vinyl Selenone 1. A mixture of vinyl selenone 1(1 equiv) and
appropriate amine (5 equiv) was stirred at room temperature. After
completion of reaction (TLC), the mixture was partitioned between
EtOAc and satd. aq. NH4Cl solution. Organic layers were pooled
together, dried over anhyd. Na2SO4, and filtered, and the filtrate was
concentrated under reduced pressure to get a residue. The residue was
purified by column chromatography over silica gel to give the
corresponding product.
Compound 8a. To a well-stirred solution of vinyl selenone 1 (0.15
g, 0.36 mmol) in DMF (10 mL) 40% methylamine (2 mL) was added,
and the mixture was stirred at room temperature for 2 h. After
completion of reaction (TLC), the mixture was partitioned between
EtOAc (3 × 15 mL) and satd. aq. NH4Cl solution (50 mL). Organic
layers were pooled together, dried over anhyd. Na2SO4, and filtered,
and the filtrate was concentrated under reduced pressure to get a
residue. The residue was purified by column chromatography to give
8a (0.072 g, 78%). [Eluent: EtOAc:pet ether (1:1)] Yellowish gum;
[α]D26 +15.6 (c 1.03 in CHCl3); 1H NMR (400 MHz, CDCl3): δ 2.24
(d, 1H, J = 4.8 Hz), 2.31−2.34 (m, 4H), 3.40−3.49 (m, 5H), 4.28 (t,
1H, J = 4.6 Hz), 4.52 (d, 2H, J = 2.8 Hz), 5.05 (s, 1H), 7.29−7.35 (m,
5H); 13C NMR (50 MHz, CDCl3): δ 44.6, 46.2, 46.5, 57.2, 71.4
(CH2), 73.5 (CH2), 78.6, 104.1, 127.6, 127.7, 128.4, 138.1; HRMS
[ES+, (M + H)+] for C14H20NO3 found 250.1428, calcd 250.1443.
Compound 8b. Following the general procedure, cyclohexylamine
(0.2 mL, 1.8 mmol) was reacted with 1 (0.15 g, 0.36 mmol) for 2 h to
afford 8b (0.099 g, 81%). [Eluent: EtOAc:pet ether (1:2)] Yellowish
gum; [α]D26 +25.0 (c 1.14 in CHCl3); 1H NMR (400 MHz, CDCl3): δ
1.07−1.77 (m, 11H), 2.31 (d, 1H, J = 5.2 Hz), 2.36 (dd, 1H, J = 1.6,
4.8 Hz), 3.41−3.50 (m, 5H), 4.23−4.25 (m, 1H), 4.52 (q, 2H, J = 12.0
Hz), 5.04 (d, 1H, J = 1.6 Hz), 7.24−7.34 (m, 5H); 13C NMR (50
MHz, CDCl3): δ 25.0 (2 × CH2), 26.0 (CH2), 32.4 (CH2), 43.6, 44.2,
57.2, 66.0, 71.6 (CH2), 73.5 (CH2), 78.7, 104.3, 127.5, 127.7, 128.4,
138.2; HRMS [ES+, (M + H)+] for C19H28NO3 found 318.2049, calcd
318.2069.
Scheme 9. O-Anhydro Isonucleosides from Selenosugar 1
underwent intramolecular nucleophilic displacement of PhO2Se
group by the attack of C-2 oxygen of nucleobases to form 22a−
b. The anhydroisonucleoside 22a was shown to be a key
intermediate for the synthesis of the corresponding 3-deoxy-3-
isonucleoside by regio- and stereospecific ring-opening of the
tricyclic system.19 Structures of 20e and 22a have been
established by X-ray diffraction of their single crystals (Figures
S4 and S5, see SI). A plausible mechanism for the formation of
22a−b is delineated in Scheme 9.
In summary, we have introduced a densely functionalized
Michael acceptor, namely vinyl selenone-modified carbohydrate
1 composed of a masked aldehyde, an electron-deficient double
bond attached to selenone, and an excellent leaving group.
Using the DOS strategy, this synthetic intermediate was reacted
with a wide range of nucleophiles to afford a variety of
products. Most of the compounds are reported for the first
time. The strategy opens up a new avenue for the synthesis of
different classes of enantiopure products starting from a single
intermediate.
EXPERIMENTAL SECTION
■
General methods: Carbohydrates and other fine chemicals were
obtained from commercial suppliers and used without purification.
Solvents were dried and distilled following the standard procedures.
TLC was carried out on precoated plates (Merck silica gel 60, f254),
and the spots were visualized with UV light or by charring the plates
dipped in 5% H2SO4-MeOH solution. Column chromatography was
performed on silica gel (230−400 mesh). 1H and 13C NMR for
compounds were recorded at 400 MHz instrument and 50.3 MHz
instrument, respectively, using either CDCl3 as the solvent unless
stated otherwise. DEPT experiments were carried out to identify the
methylene carbons. High-resolution mass spectra were recorded using
QTOF mass analyzer. Optical rotations were recorded at 589 nm.
Compounds 6a10 and 6b.11 Potassium hydroxide (0.082 g, 1.47
mmol) was added to a well-stirred mixture of vinyl selenone 1 (0.2 g,
0.49 mmol) in water (4 mL) at room temperature for 2 h. The mixture
was partitioned between EtOAc (3 × 15 mL) and satd. aq. NH4Cl
solution (50 mL). Organic layers were pooled together, dried over
anhyd. Na2SO4, and filtered, and the filtrate was evaporated to dryness
to get a residue. The residue thus obtained was purified over silica gel
column to afford compounds 6a (0.043 g, 37%) and 6b (0.041 g,
35%). Compound 6a: [Eluent: EtOAc:pet ether (1:5)] Colorless
Compound 8c. Following the general procedure, isopropylamine
(0.15 mL, 1.8 mmol) was reacted with 1 (0.15 g, 0.36 mmol) for 2 h to
afford 8c (0.087 g, 85%). [Eluent: EtOAc:pet ether (1:2)] Yellowish
gum; [α]D26 +35.9 (c 0.62 in CHCl3); 1H NMR (400 MHz, CDCl3): δ
1.12 (d, 6H, J = 6.4 Hz), 1.49−1.54 (m, 1H), 2.29 (d, 1H, J = 5.2 Hz),
2.34−2.36 (m, 1H), 3.41−3.50 (m, 5H), 4.23−4.25 (m, 1H), 4.52 (q,
2H, J = 12.0 Hz), 5.04 (s, 1H), 7.24−7.34 (m, 5H); 13C NMR (50
MHz, CDCl3): δ 21.9, 44.3, 45.0, 57.3, 58.0, 71.6 (CH2), 73.5 (CH2),
78.7, 104.3, 127.6, 127.7, 128.5, 138.2; HRMS [ES+, (M + H)+] for
C16H24NO3 found 278.1781, calcd 278.1756.
Compound 8d. Following the general procedure 2-amino-2-
methyl-1-propanol (0.17 mL, 1.8 mmol) was reacted with 1 (0.15 g,
0.36 mmol) for 4h to afford 8d (0.09 g, 80%). [Eluent: EtOAc:pet
ether (1:1)] Yellowish gum; [α]D26 +22.7 (c 1.08 in CHCl3); 1H NMR
(400 MHz, CDCl3): δ 0.72 (s, 3H), 1.03 (s, 3H), 2.53 (d, 1H, J = 4.8
Hz), 2.75 (dd, 1H, J = 1.8, 5.0 Hz), 3.12 (bs, 1H), 3.29 (d, 1H, J = 11.2
Hz), 3.42−3.54 (m, 6H), 4.20−4.22 (m, 1H), 4.53 (q, 2H, J = 12.2
Hz), 5.05 (d, 1H, J = 1.2 Hz), 7.27−7.35 (m, 5H); 13C NMR (50
MHz, CDCl3): δ 17.5, 23.8, 37.3, 39.7, 55.4, 57.5, 71.5 (CH2), 72.0
1
gum: H NMR (400 MHz, CDCl3): δ 3.42 (s, 3H), 3.65−3.67 (m,
3H), 3.77 (d, 1H, J = 2.8 Hz), 4.21 (t, 1H, J = 6.2 Hz), 4.60 (q, 2H, J =
12.0 Hz), 4.95 (s, 1H), 7.26−7.36 (m, 5H). Compound 6b: [Eluent:
EtOAc: pet ether (1:2)] Yellowish gum: 1H NMR (400 MHz,
CDCl3): δ 3.52 (s, 3H), 3.58−3.60 (m, 2H), 3.70 (d, 1H, J = 2.8 Hz),
3.76 (d, 1H, J = 2.8 Hz), 4.39 (t, 1H, J = 3.6 Hz), 4.55 (q, 2H, J = 12.0
Hz), 5.19 (s, 1H), 7.30−7.38 (m, 5H).
Compounds 7a and 7b. Sodium sulfide (0.076 g, 0.98 mmol) was
added to a well-stirred mixture of vinyl selenone 1 (0.2 g, 0.49 mmol)
in water (4 mL) at room temperature for 2 h. The mixture was
partitioned between EtOAc (3 × 15 mL) and satd. aq. NH4Cl solution
(50 mL). Organic layers were pooled together, dried over anhyd.
Na2SO4, and filtered, and the filtrate was evaporated to dryness to get a
D
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(CH2), 73.5 (CH2), 79.8, 104.6, 127.6, 127.7, 128.5, 138.1; HRMS
[ES+, (M + H)+] for C17H26NO4 found 308.1875, calcd 308.1862.
Compound 8e. To the glycine ethyl ester hydrochloride (0.1 g,
0.72 mmol) in dry DMSO was added triethylamine (0.15 mL, 1.08
mmol) at room temperature. After 10 min vinyl selenone 1 (0.15 g,
0.36 mmol) was added to the solution, and stirring was continued for
3 h. The mixture was partitioned between EtOAc (3 × 10 mL) and
satd. aq. NaHCO3 solution (50 mL). Organic layers were pooled
together, dried over anhyd. Na2SO4, and filtered, and the filtrate was
evaporated to get a residue. The residue was purified over silica gel
column to afford 8e (0.1 g, 85%). [Eluent: EtOAc:pet ether (1:1)]
Yellowish gum; [α]D26 +33.6 (c 1.18 in CHCl3); 1H NMR (400 MHz,
CDCl3): δ 1.19−1.23 (m, 3H), 2.44 (d, 1H, J = 4.8 Hz), 2.53 (d, 1H, J
= 3.6 Hz), 2.93 (d, 1H, J = 16.0 Hz), 3.22 (d, 1H, J = 16.0 Hz), 3.45−
3.51 (m, 5H), 4.12 (q, 2H, J = 7.2 Hz), 4.35 (t, 1H, J = 4.0 Hz), 4.50
(q, 2H, J = 12.2 Hz), 5.10 (s, 1H), 7.22−7.32 (m, 5H); 13C NMR
(100 MHz, CDCl3): δ 14.0, 45.2, 45.3, 57.1, 58.0 (CH2), 60.7 (CH2),
71.3 (CH2), 73.3 (CH2), 78.6, 104.0, 127.4, 127.6, 128.3, 137.9, 169.5;
HRMS [ES+, (M + H)+] for C17H24NO5 found 322.1650, calcd
322.1654.
Compound 8f. To the solution of vinyl selenone 1 (0.1 g, 0.24
mmol), TMG (0.048 g, 0.38 mmol) was added, and the mixture was
stirred at room temperature for 10 h. The mixture was partitioned
between EtOAc(3 × 15 mL) and satd. aq. NH4Cl solution (60 mL).
The organic layers were pooled together, dried over anhyd. Na2SO4,
and filtered, and the filtrate was evaporated to get a residue. The
residue was purified by column chromatography over silica gel to
afford 8f (0.049 g, 65%). [Eluent: EtOAc:pet ether (1:1)] Yellowish
gum; [α]D26 −35.7 (c 1.0 in CHCl3); 1H NMR (200 MHz, CDCl3): δ
2.91 (s, 3H), 3.16 (s, 3H), 3.26 (dd, 1H, J = 1.6, 5.2 Hz), 3.37 (d, 1H, J
= 5.0 Hz), 3.50 (s, 3H), 3.56 (d, 2H, J = 3.8 Hz), 4.38 (t, 1H, J = 3.8
Hz), 4.53 (d, 2H, J = 4.0 Hz), 5.19 (d, 1H, J = 1.4 Hz), 7.27−7.34 (m,
5H); 13C NMR (50 MHz, CDCl3): δ 36.6, 37.0, 43.5, 45.1, 57.7, 71.4
(CH2), 73.6 (CH2), 78.6, 104.2, 127.6, 127.9, 128.6, 138.1, 163.2;
HRMS [ES+, (M + H)+] for C16H23N2O4 found 307.1638, calcd
307.1658.
Compound 10. To a solution of the oxirane 9 (0.15 g, 0.64 mmol)
and LiClO4 (0.136 g, 1.28 mmol) in MeCN (10 mL), cyclohexylamine
(0.146 mL, 1.28 mmol) was added. Then the mixture was heated
under stirring at 80 °C for 24 h. Volatile matters were evaporated
under vacuum, and the residue was partitioned between EtOAc (3 ×
15 mL) and satd. aq. NH4Cl solution (50 mL). Organic layers were
pooled together, dried over anhyd. Na2SO4, and filtered, and the
filtrate was evaporated to dryness under reduced pressure. The residue
was purified by silica column chromatography to afford 10 (0.163 g,
77%). [Eluent: EtOAc:pet ether (3:2)] Yellowish gum; [α]D26 +11.2 (c
1.00 in CHCl3); 1H NMR (400 MHz, CDCl3): δ 0.96−1.82 (m, 11H),
2.83−2.89 (m, 1H), 3.20−3.24 (m, 1H), 3.45 (s, 3H), 3.69 (s, 1H),
3.79−3.88 (m, 2H), 4.33 (d, 1H, J = 2.0 Hz), 4.41 (s, 1H), 4.57 (s,
2H), 5.25 (s, 1H), 7.32−7.42 (m, 5H); 13C NMR (50 MHz, CDCl3):
δ 24.3 (CH2), 24.6 (CH2), 29.3 (CH2), 29.4 (CH2), 30.7 (CH2), 55.7,
56.9, 65.1, 69.8 (CH2), 74.0, 74.6 (CH2), 85.2, 104.8, 128.9, 129.2,
136.2; HRMS [ES+, (M + H)+] for C19H30NO4 found 336.2158, calcd
336.2175.
General Procedure for Synthesis of Cyclopropanes 12a−c,
Dihydrofurans 13a−b, and Dihydrooxazole 14 from Vinyl
Selenone 1. Active methylene compound (1.6 equiv) was added to a
t
suspension of BuOK (1.2 equiv) in dry THF (20 mL/mmol vinyl
selenone) at ambient temperature, and the resulting solution was
stirred for 0.5 h at this temperature under nitrogen. A solution of vinyl
selenone 1 (1 equiv) in dry THF was added dropwise to the reaction
mixture, and the resulting solution was stirred at appropriate
temperature. After completion of the reaction (TLC), volatile matters
were evaporated under vacuum, and the residue was partitioned
between EtOAc and satd. aq. NH4Cl solution. Organic layers were
pooled together, dried over anhyd. Na2SO4, and filtered, and the
filtrate was evaporated to dryness under reduced pressure to get a
residue. The residue was purified by column chromatography over
silica gel to give the corresponding product.
Compound 12a. Following the general procedure, nitromethane
(0.031 mL, 0.57 mmol) was treated with 1 (0.15 g, 0.36 mmol) in the
presence of tBuOK (0.049 g, 0.44 mmol) at room temperature for 3 h
to afford 12a (0.078 g, 76%). [Eluent: EtOAc:pet ether (1:5)]
Colorless gum: [α]D26 +30.9 (c 1.10 in CHCl3); 1H NMR (400 MHz,
CDCl3): δ 2.69 (dd, 1 H, J = 1.4, 7.8 Hz), 2.92 (d,1 H, J = 7.6 Hz),
3.44 (s, 3 H), 3.52 (d, 2 H, J = 4.0 Hz), 4.38 (t, 1 H, J = 4.0 Hz), 4.44
(s, 1 H), 4.57 (q, 2 H, J = 12.0 Hz), 5.36 (d, 1 H, J = 2.8 Hz), 7.32−
7.40 (m, 5 H); 13C NMR (50 MHz, CDCl3): δ 31.9, 33.6, 57.3, 59.3,
72.2 (CH2), 73.7 (CH2), 79.7, 105.6, 127.7, 128.1, 128.7, 137.9;
HRMS [ES+, (M + H)+] for C14H18NO5 found 280.1178, calcd
280.1185.
Compound 12b. Following the general procedure, malononitrile
(0.037 g, 0.57 mmol) was treated with 1 (0.15 g, 0.36 mmol) in the
presence of tBuOK (0.049 g, 0.44 mmol) at room temperature for 2 h
to afford 12b (0.077 g, 74%). [Eluent: EtOAc:pet ether (1:3)]
26
1
Yellowish gum: [α]D +5.2 (c 1.10 in CHCl3); H NMR (400 MHz,
CDCl3): δ 2.72 (d, 1 H, J = 6.8 Hz), 2.90 (dd,1 H, J = 2.4, 6.8 Hz),
3.51 (s, 3 H), 3.59 (excess malononitrile) 3.61−3.69 (m, 2 H), 4.50−
4.62 (m, 3 H), 5.54 (d, 1 H, J = 2.8 Hz), 7.28−7.40 (m, 5 H);13C
NMR (50 MHz, CDCl3): δ 8.8 (excess malononitrile) 6.5, 35.8, 37.6,
57.9, 71.6 (CH2), 73.6 (CH2), 77.9, 104.9, 109.3 (excess
malononitrile), 111.7, 114.2, 127.7, 128.2, 128.7, 137.5; HRMS [ES+,
(M + H)+] for C16H17N2O3 found 285.1236, calcd 285.1239.
Compound 12c. Following the general procedure, dimethyl
malonate (0.065 mL, 0.57 mmol) was treated with 1 (0.15 g, 0.36
t
mmol) in the presence of BuOK (0.049 g, 0.44 mmol) at room
temperature for 3 h to afford 12c (0.12 g, 93%). [Eluent: EtOAc:pet
ether (1:3)] Yellowish gum: [α]D26 +5.2 (c 1.10 in CHCl3); 1H NMR
(400 MHz, CDCl3): δ 2.24 (d, 1 H, J = 7.2 Hz), 2.66 (dd, 1 H, J = 2.8,
7.2 Hz), 3.42 (s, 3 H), 3.52−3.61 (m, 2 H), 3.70 (s, 3 H), 3.77 (s, 3
H), 4.55 (q, 2 H, J = 12.0 Hz), 4.71 (t, 1 H, J = 4.0 Hz), 5.43 (d, 1 H, J
= 2.8 Hz), 7.26−7.37 (m, 5 H);13C NMR (50 MHz, CDCl3): δ 33.0,
33.9, 34.7, 52.1, 52.7, 57.4, 72.1 (CH2), 73.1 (CH2), 76.4, 105.5, 127.3,
127.5, 127.7, 128.2, 137.8, 166.3, 169.2; HRMS [ES+, (M + Na)+] for
C18H22O7Na found 373.1257, calcd 373.1263.
Compound 13a. Following the general procedure, acetylacetone
(0.058 mL, 0.57 mmol) was treated with 1 (0.15 g, 0.36 mmol) in the
presence of tBuOK (0.049 g, 0.44 mmol) at room temperature for 4 h
to afford 13a (0.103 g, 88%). [Eluent: EtOAc:pet ether (1:3)]
26
1
Compound 11. To a chilled solution of compound 10 (0.15 g,
0.45 mmol) and TPP (0.236 g, 0.9 mmol) in dry THF (15 mL), DIAD
(0.177 mL, 0.9 mmol) was added dropwise with stirring. The solution
was heated at 70 °C for 2 h, cooled, and then evaporated under
reduced pressure to give a thick residue. The residue was purified by
column chromatography over silica gel to afford 11 (0.102 g, 68%).
[Eluent: EtOAc:pet ether (1:3)] Yellowish gum; [α]D26 −31.5 (c 1.00
in CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.12−1.76 (m, 11H), 2.36
(d, 1H, J = 5.2 Hz), 2.41 (dd, 1H, J = 1.8, 5.0 Hz), 3.37 (s, 3H), 3.63
(d, 2H, J = 6.4 Hz), 4.13−4.17 (m, 1H), 4.57 (q, 2H, J = 11.8 Hz),
4.82 (s, 1H), 7.28−7.35 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 24.8
(CH2), 26.2 (CH2), 32.5 (CH2), 32.7 (CH2), 42.1, 44.8, 55.2, 64.9,
69.9 (CH2), 73.9 (CH2), 76.0, 104.1, 127.9, 128.2, 128.6, 138.3;
HRMS [ES+, (M + H)+] for C19H28NO3 found 318.2055, calcd
318.2069.
Yellowish gum: [α]D +8.7 (c 1.00 in CHCl3); H NMR (400 MHz,
CDCl3): δ 2.27−2.33 (m, 6 H), 3.42 (s, 3 H), 3.72−3.78 (m, 2 H),
3.93 (dd, 1 H, J = 1.8, 10.4 Hz), 4.14−4.16 (m, 1 H), 4.61 (q, 2 H, J =
12.2 Hz), 4.98 (dd, 1 H, J = 4.6, 10.6 Hz), 5.15 (d, 1 H, J = 4.8 Hz),
7.26−7.35 (m, 5 H); 13C NMR (50 MHz, CDCl3): δ 15.4, 29.2, 48.1,
55.6, 71.8 (CH2), 73.5 (CH2), 83.5, 84.4, 103.7, 116.7, 127.6, 128.3,
138.3, 168.3, 193.5; HRMS [ES+, (M + H)+] for C18H23O5 found
319.1554, calcd 319.1545.
Compound 13b. Following the general procedure, ethyl
acetoacetate (0.072 mL, 0.57 mmol) was treated with 1 (0.15 g,
t
0.36 mmol) in the presence of BuOK (0.049 g, 0.44 mmol) at room
temperature for 4 h to afford 13b (0.097 g, 76%). [Eluent: EtOAc:pet
ether (1:9)] Yellowish gum: [α]D26 +33.9 (c 0.62 in CHCl3); 1H NMR
(400 MHz, CDCl3): δ 1.15 (t, 3 H, J = 7.2 Hz), 2.33 (s, 3 H), 3.40 (s,
3 H), 3.61−3.68 (m, 2 H), 3.87 (d, 1 H; J = 10.4 Hz), 4.02−4.10 (m, 2
E
DOI: 10.1021/acs.joc.5b01192
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
H), 4.18−4.21 (m, 1 H), 4.60 (s, 2 H), 5.00 (dd, 1 H, J = 4.4, 10.8
Hz), 5.13 (d, 1 H, J = 5.2 Hz), 7.26−7.34 (m, 5 H); 13C NMR (50
MHz, CDCl3): δ 14.1, 14.3, 47.2, 55.4, 59.5 (CH2), 71.3 (CH2), 73.5
(CH2), 83.5, 84.8, 103.5, 104.1, 127.7, 128.3, 138.2, 165.6, 170.0;
HRMS [ES+, (M + H)+] for C19H25O6 found 349.1644, calcd
349.1651.
73.8 (CH2), 128.1, 128.3, 128.8, 137.4; HRMS [ES+, (M + Na)+] for
C13H17NO5Na found 290.1003, calcd 290.1004.
Compound 17. Following the general procedure, compound 13b
(0.07 g, 0.2 mmol) was converted to 17 (0.039 g, 58% in two steps).
26
[Eluent: EtOAc:pet ether (3:2)] Colorless gum: [α]D +26.2 (c 1.00
in CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.23−1.28 (m, 3 H), 2.20
(s, 3 H), 3.20 (t, 1 H, J = 8.0 Hz), 3.36 (dd, 1 H, J = 3.2, 9.2 Hz),
3.46−3.72 (m, 3 H), 3.93 (dd, 1 H, J = 5.4, 12.4 Hz), 4.02−4.07 (m, 2
H), 4.11−4.17 (m, 2 H), 4.52 (s, 2 H), 4.62−4.68 (m, 1 H), 7.29−7.37
(m, 5 H); 13C NMR (50 MHz, CDCl3): δ 14.5, 14.9, 46.5, 60.0 (CH2),
60.4 (CH2), 69.8, 72.8 (CH2), 73.7 (CH2), 86.1, 104.0, 128.0, 128.1,
128.7, 137.8, 166.2, 170.9; HRMS [ES+, (M + Na)+] for C18H24O6Na
found 359.1460, calcd 359.1470.
Compound 14. Following the general procedure, ethyl nitro-
acetate (0.063 mL, 0.57 mmol) was treated with 1 (0.15 g, 0.36 mmol)
t
in the presence of BuOK (0.049 g, 0.44 mmol) at room temperature
for 4 h to afford 14 (0.12 g, 94%). [Eluent: EtOAc:pet ether (1:3)]
26
1
White solid: mp 103 °C; [α]D +62.4 (c 1.33 in CHCl3); H NMR
(400 MHz, CDCl3): δ 1.25 (t, 3 H, J = 7.0 Hz), 3.44 (s, 3 H), 3.73
(dd, 1 H, J = 3.6, 10.8 Hz), 3.85 (dd, 1 H, J = 1.8, 10.6 Hz), 4.17−4.27
(m, 3 H), 4.39 (s, 1 H), 4.62 (q, 2 H, J = 12.0 Hz), 4.93 (dd, 1 H, J =
4.2, 11.0 Hz), 5.16 (d, 1 H, J = 4.0 Hz), 7.30−7.36 (m, 5 H); 13C
NMR (50 MHz, CDCl3): δ 14.0, 46.7, 55.3, 61.9 (CH2), 69.8 (CH2),
73.7 (CH2), 76.5, 81.3, 103.1, 108.8, 127.7, 127.8, 128.4, 137.8, 158.8;
HRMS [ES+, (M + Na)+] for C17H21NO7Na found 374.1218, calcd
374.1216.
General Procedure for Synthesis of Furans 20a and 20e
from Vinyl Selenone 1. To a solution of pyrrole or thymine (2
t
equiv) in THF (20 mL/mmol vinyl selenone), BuOK (2 equiv) was
added, and the mixture was stirred at room temperature for 10 min.
Vinyl selenone 1 (1 equiv) was added to the solution and stirred at
appropriate temperature. After completion of reaction (TLC) volatile
matter was evaporated under vacuum, and the residual mixture was
partitioned between EtOAc and satd. aq. NH4Cl solution. Organic
layers were pooled together, dried over anhyd. Na2SO4, and filtered,
and the filtrate was evaporated to dryness to give a residue. The
residue was purified over silica gel column to afford corresponding
product.
General Procedure for Synthesis of Furans 20c and 20d
from Vinyl Selenone 1. To a solution of 1,2,4-triazole or 1-H-
tetrazole (2 equiv) in THF (20 mL/mmol vinyl selenone), K2CO3 (2
equiv) was added, and the mixture was stirred at room temperature for
10 min. Vinyl selenone 1 (1 equiv) was added to the solution and
stirred at appropriate temperature. After completion of the reaction
(TLC) volatile matter was evaporated under vacuum, and the residual
mixture was partitioned between EtOAc and satd. aq. NH4Cl solution.
Organic layers were pooled together, dried over anhyd. Na2SO4, and
filtered, and the filtrate was evaporated to dryness to give a residue.
The residue was purified over silica gel column to afford corresponding
product.
General Procedure for Opening of Sugar Ring. TFA (80%, 2
mL) was added to the compound (1 mmol), and the mixture was
stirred at 70 °C. After completion of reaction (3 h), the mixture was
partitioned between EtOAc and satd. aq. NaHCO3 solution. The
organic layers were pooled together, dried over anhyd. Na2SO4, and
filtered, and the filtrate was evaporated to dryness to get a residue. To
the solution of residue in ethanol (10 mL/mmol compound), NaBH4
(2 mmol) was added, and the mixture was stirred at room temperature
for 2 h. The volatile matters were evaporated under vacuum, and the
residue was partitioned between EtOAc and satd. aq. NH4Cl solution.
Organic layers were pooled together, dried over anhyd. Na2SO4, and
filtered, and the filtrate was evaporated to dryness. The residue thus
obtained was purified over silica gel column to afford corresponding
products.
Compound 15a. Following the general procedure, compound 8a
(0.1 g, 0.4 mmol) was converted to 15a (0.051 g, 54% in two steps).
26
[Eluent: EtOAc:pet ether (1:1)] Colorless gum; [α]D −12.7 (c 1.00
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 0.87 (bs, 1H), 1.25 (s,
Compound 20a. Following the general procedure, pyrrole (0.05
mL, 0.72 mmol) was reacted with 1 (0.15 g, 0.36 mmol) in the
presence of tBuOK (0.123 g, 0.72 mmol) at room temperature for 1 h
to afford 20a (0.067 g, 73%). [Eluent: EtOAc:pet ether (1:5)]
Brownish gum; 1H NMR (400 MHz, CDCl3): δ 4.54 (s, 2H), 4.57 (s,
2H), 6.29−6.30 (m, 2H), 6.52 (d, 1H, J = 1.6 Hz), 6.92−6.93 (m,
2H), 7.29−7.36 (m, 5H), 7.39 (d, 1H, J = 2.0 Hz); 13C NMR (50
MHz, CDCl3): δ 61.9 (CH2), 72.5 (CH2), 108.2, 110.0, 121.6, 128.1,
128.3, 128.7, 137.8, 142.2, 142.4; HRMS [ES+, (M + Na)+] for
C16H15NO2Na found 276.1018, calcd 276.1000.
1H), 1.56 (t,1H,J = 7.2 Hz), 1.78−1.83 (m, 1H), 2.33 (s, 3H), 3.48−
3.72 (m, 4H), 3.89−3.93 (m, 1H), 4.59 (q, 2H, J = 12.0 Hz), 7.30−
7.34 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 45.3, 45.5, 47.2, 61.6
(CH2), 70.1, 73.1 (CH2), 73.7 (CH2), 128.0, 128.1, 128.7, 137.9;
HRMS [ES+, (M + H)+] for C13H20NO3 found 238.1470, calcd
238.1443.
Compound 15b. Following the general procedure, compound 8b
(0.1 g, 0.31 mmol) was converted to 15b (0.048 g, 50% in two steps).
[Eluent: EtOAc:pet ether (2:3)] Yellowish gum; [α]D26 −3.2 (c 0.66 in
1
CHCl3); H NMR (400 MHz, CDCl3): δ 1.13−1.33 (m, 6H), 1.58−
Compound 20b. A mixture of vinyl selenone 1 (0.15 g, 0.36
mmol) and imidazole (0.075 g, 1.1 mmol) in water (10 mL) was
heated at 80 °C for 6 h. The reaction mixture was partitioned between
EtOAc (3 × 15 mL) and satd. aq. NH4Cl solution (50 mL). Organic
layers were pooled together, dried over anhyd. Na2SO4, and filtered,
and the filtrate was evaporated to dryness to give a residue. The
residue was purified over silica gel column to afford 20b (0.08 g, 86%).
[Eluent: EtOAc:pet ether (1:1)] Colorless gum; 1H NMR (400 MHz,
CDCl3): δ 4.46 (s, 2H), 4.54 (s, 2H), 6.50 (d, 1H, J = 2.0 Hz), 7.14 (d,
2H, J = 8.4 Hz), 7.26−7.35 (m, 5H), 7.42 (d, 1H, J = 2.0 Hz), 7.71 (s,
1H); 13C NMR (50 MHz, CDCl3): δ 61.3 (CH2), 72.6 (CH2), 108.0,
119.8, 124.0, 128.0, 128.5, 129.9, 137.3, 142.7, 143.5; HRMS [ES+, (M
+ H)+] for C15H15N2O2 found 255.1130, calcd 255.1134.
Compound 20c. Following the general procedure, 1,2,4-triazole
(0.051 g, 0.72 mmol) was reacted with 1 (0.15 g, 0.36 mmol) in the
presence of K2CO3 (0.1 g, 0.72 mmol) at room temperature for 2 h to
afford 20c (0.075 g, 80%). [Eluent: EtOAc:pet ether (1:5)] White
solid; mp 120 °C; 1H NMR (400 MHz, CDCl3): δ 4.52 (s, 2H), 4.58
(s, 2H), 6.64 (d, 1H, J = 1.6 Hz), 7.23−7.30 (m, 5H), 7.40 (d, 1H, J =
2.0 Hz), 8.01 (s, 1H), 8.35 (s, 1H); 13C NMR (50 MHz, CDCl3): δ
61.9 (CH2), 72.7 (CH2), 107.2, 124.1, 128.1, 128.7, 137.4, 142.9,
143.5, 152.7; HRMS [ES+, (M + H)+] for C14H14N3O2 found
256.1085, calcd 256.1086.
1.77 (m, 8H), 1.85−1.90 (m, 1H), 3.53−3.63 (m, 3H), 3.73 (dd, 1H, J
= 2.4, 8.8 Hz), 3.84−3.88 (m, 1H), 4.58 (q, 2H, J = 11.6 Hz), 7.30−
7.38 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 24.9 (CH2), 26.1
(CH2), 32.6 (CH2), 32.8 (CH2), 43.0, 43.2, 61.8 (CH2), 68.1, 70.1,
72.8 (CH2), 73.8 (CH2), 128.1, 128.7, 137.9; HRMS [ES+, (M + H)+]
for C18H28NO3 found 306.2081, calcd 306.2069.
Compound 15c. Following the general procedure, compound 8c
(0.1 g, 0.36 mmol) was converted to 15c (0.047 g, 49% in two steps).
26
[Eluent: EtOAc:pet ether (1:1)] Yellowish gum; [α]D −8.0 (c1.2 in
1
CHCl3); H NMR (400 MHz, CDCl3): δ 1.02 (d, 3H, J = 6.4 Hz),
1.09 (d, 3H, J = 6.0 Hz), 1.57−1.70 (m, 3H), 1.85−1.90 (m, 1H),
2.00−2.05 (m, 1H), 3.53−3.65 (m, 3H), 3.72−3.75 (m, 1H), 3.85−
3.90 (m, 1H), 4.58 (q, 2H, J = 11.6 Hz), 7.29−7.37 (m, 5H); 13C
NMR (50 MHz, CDCl3): δ 22.0, 22.2, 43.7, 43.9, 60.4, 61.7 (CH2),
70.0, 72.9 (CH2), 73.8 (CH2), 128.1, 128.7, 137.9; HRMS [ES+, (M +
H)+] for C15H24NO3 found 266.1784, calcd 266.1756.
Compound 16. Following the general procedure, compound 12a
(0.07 g, 0.25 mmol) was converted to 16 (0.041 g, 61% in two steps).
26
[Eluent: EtOAc:pet ether (3:2)] Colorless gum: [α]D −42.2 (c 1.00
in CHCl3); 1H NMR (400 MHz, CDCl3)δ 2.30−2.36 (m, 1 H), 2.48−
2.53 (m, 1 H), 3.29 (bs, 1H), 3.40−3.73 (m, 5 H), 4.02−4.07 (m, 1
H), 4.13−4.16 (m, 1 H), 4.57 (s, 2 H), 7.30−7.39 (m, 5 H); 13C NMR
(50 MHz, CDCl3): δ 30.2, 31.1, 59.0 (CH2), 61.7, 68.3, 73.1 (CH2),
F
DOI: 10.1021/acs.joc.5b01192
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Compound 20d. Following the general procedure, 1-H-tetrazole
(0.051 g, 0.72 mmol) was reacted with 1 (0.15 g, 0.36 mmol) in the
presence of K2CO3 (0.1 g, 0.72 mmol) at 70 °C for 10 h to afford 20d
ACKNOWLEDGMENTS
■
A.B. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India for a fellowship. Financial support by
the Council of Scientific and Industrial Research (CSIR), New
Delhi, India is gratefully acknowledged. The Department of
Science and Technology, New Delhi, India is also thanked for
the creation of 400 MHz facility under IRPHA program and
DST-FIST for single crystal X-ray facility.
1
(0.071 g, 76%). [Eluent: EtOAc:pet ether (1:5)] Yellowish gum; H
NMR (400 MHz, CDCl3): δ 4.61 (s, 2H), 4.94 (s, 2H), 7.00 (s, 1H),
7.26−7.31 (m, 5H), 7.52 (s, 1H), 8.61 (s, 1H); 13C NMR (50 MHz,
CDCl3): δ 62.2 (CH2), 73.0 (CH2), 106.4, 128.1, 128.6, 137.7, 143.3,
144.4, 153.0; HRMS [ES+, (M + H)+] for C13H13N4O2 found
257.1054, calcd 257.1039.
Compound 20e. Following the general procedure, thymine (0.092
g, 0.72 mmol) was reacted with 1 (0.15 g, 0.36 mmol) in the presence
of tBuOK (0.082 g, 0.72 mmol) at room temperature for 10 h to afford
20e (0.073 g, 64%). [Eluent: EtOAc:pet ether (2:3)] White solid; mp
REFERENCES
■
(1) (a) Simpkins, N. S. Chem. Soc. Rev. 1990, 19, 335. (b) Pathak, T.
Tetrahedron 2008, 64, 3605. (c) El-Awa, A.; Noshi, M. N.; du Jourdin,
X. M.; Fuchs, P. L. Chem. Rev. 2009, 109, 2315. (d) Alba, A.-N. R.;
Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018.
(2) For selected recent references, see: (a) Atta, A. K.; Pathak, T. Eur.
J. Org. Chem. 2010, 872. (b) Manna, C.; Pathak, T. Eur. J. Org. Chem.
2013, 6084. (c) Manna, C.; Sahu, D.; Ganguly, B.; Pathak, T. Eur. J.
Org. Chem. 2013, 8197. (d) Sahu, D.; Dey, S.; Pathak, T.; Ganguly, B.
Org. Lett. 2014, 16, 2100. (e) Bhaumik, A.; Samanta, S.; Pathak, T. J.
Org. Chem. 2014, 79, 6895.
1
106 °C; H NMR (400 MHz, CDCl3): δ 1.88 (s, 3H), 4.46 (s, 2H),
4.55 (s, 2H), 6.50 (s, 1H), 7.13 (s, 1H), 7.29−7.33 (m, 5H), 7.42 (s,
1H), 9.13 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 12.4, 62.0 (CH2),
73.0 (CH2), 110.1, 111.2, 124.3, 128.1, 128.3, 128.7, 137.4, 141.4,
142.5, 146.6, 150.0, 164.2; HRMS [ES+, (M + H)+] for C17H17N2O4
found 313.1204, calcd 313.1188.
General Procedure for Synthesis of Isonucleosides 22a and
22b from Vinyl Selenone 1. To the solution of thymine or uracil (2
equiv) in DMF (15 mL/mmol vinyl selenone), TMG (1.6 equiv) was
added, and the mixture was stirred at room temperature for 10 min.
Vinyl selenone 1 (1 equiv) was added to the solution and stirred for 2
h at the same temperature. The mixture was partitioned between
EtOAc and satd. aq. NH4Cl solution. The organic layers were pooled
together, dried over anhyd. Na2SO4, and filtered, and the filtrate was
evaporated to get a residue. The residue was purified by column
chromatography over silica gel to afford the corresponding product.
(3) Das, I.; Pathak, T. Org. Lett. 2006, 8, 1303 and references cited
therein..
(4) (a) Pasetto, P.; Walczak, M. C. Tetrahedron 2009, 65, 8468.
(b) Lewis, F. W.; McCabe, T. C.; Grayson, D. H. Tetrahedron 2011,
67, 7517.
(5) (a) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura,
S.; Toru, T. Angew. Chem., Int. Ed. 2006, 45, 4973. (b) Das, I.; Pal, T.
K.; Pathak, T. J. Org. Chem. 2007, 72, 9181.
.
19
Compound 22a Following the general procedure, thymine
(0.061 g, 0.48 mmol) was reacted with 1 (0.1 g, 0.24 mmol) in the
presence of TMG (0.048 g, 0.38 mmol) to afford 22a (0.054 g, 64%).
(6) Wu, J.-C.; Pathak, T.; Tong, W.; Remaud, G.; Chattopadhyaya, J.
Tetrahedron 1988, 44, 6705.
1
[Eluent: EtOAc:pet ether (1:1)] White solid; H NMR (400 MHz,
(7) (a) Posner, G. H.; Hulce, M.; Mallamo, J. P. J. Org. Chem. 1981,
46, 5246. (b) Ando, R.; Sugawara, T.; Kuwazima, I. J. Chem. Soc.,
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Catal. 2009, 351, 1801. (e) Sternativo, S.; Marini, F.; Verme, F. D.;
Calandriello, A.; Testaferri, L.; Tiecco, M. Tetrahedron 2010, 66, 6851.
(f) Bagnoli, L.; Scarponi, C.; Rossi, M. G.; Testaferri, L.; Tiecco, M.
Chem. - Eur. J. 2011, 17, 993. (g) Sternativo, S.; Calandriello, A.;
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Ed. 2013, 52, 12714. (i) Buyck, T.; Wang, Q.; Zhu, J. J. Am. Chem. Soc.
2014, 136, 11524.
CDCl3): δ1.91 (s, 3H), 3.39 (s, 3H), 3.49 (s, 1H), 3.84 (dd, 1H, J =
4.4, 9.6 Hz), 4.37−4.41 (m, 1H), 4.56 (q, 2H, J = 11.4 Hz), 4.90 (dd,
1H, J = 4.0, 7.2 Hz), 5.17−5.19 (m, 2H), 7.26 (s, 1H overlap), 7.33−
7.41 (m, 5H).
Compound 22b. Following the general procedure, uracil (0.054 g,
0.48 mmol) was treated with 1 (0.1 g, 0.24 mmol) in the presence of
TMG (0.048 g, 0.38 mmol) to afford 22b (0.05 g, 63%). [Eluent:
26
EtOAc:pet ether (3:2)] White solid; mp 132 °C; [α]D +18.2 (c1.00
1
in CHCl3); H NMR (400 MHz, CDCl3): δ 2.70 (bs, 1H), 3.34 (s,
3H), 3.36−3.39 (m, 1H), 3.73−3.77 (m, 1H), 4.33−4.37 (m, 1H),
4.51 (q, 2H, J = 12.0 Hz), 5.02−5.05 (m, 1H), 5.11 (s, 1H), 5.21 (d,
1H, J = 7.2 Hz), 5.80 (d, 1H, J = 7.2 Hz), 7.26−7.36 (m, 5H); 13C
NMR (50 MHz, CDCl3): δ 55.2, 63.3, 66.0 (CH2), 74.1 (CH2), 76.9,
86.0, 105.5, 109.1, 128.3, 128.5, 128.8, 136.6, 137.3, 160.8, 172.0;
HRMS [ES+, (M + H)+] for C17H19N2O5 found 331.1273, calcd
331.1294.
(8) Tong, W.; Xi, Z.; Gioeli, C.; Chattopadhyaya, J. Tetrahedron
1991, 47, 3431 and references cited therein..
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(11) Wright, J. A.; Taylor, N. F.; Fox, J. J. J. Org. Chem. 1969, 34,
2632.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01192.
(12) Selected references on carbohydrate derived aziridines:
(a) Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R. H. J. Org. Chem.
1994, 59, 434. (b) Hofmann, B.; Dauban, P.; Biron, J. P.; Potier, P.;
Dodd, R. H. Heterocycles 1997, 46, 473. (c) Ogawa, S.; Ashiura, M.;
Uchida, C. Carbohydr. Res. 1998, 307, 83. (d) Lorpitthaya, R.;
Suryawanshi, S. B.; Wang, S.; Pasunooti, K. K.; Cai, S.; Ma, J.; Liu, X.-
W. Angew. Chem., Int. Ed. 2011, 50, 12054. (e) Ahmed, M. F.; Lowary,
T. L. Tetrahedron 2013, 69, 4276. (f) Okazaki, H.; Hanaya, K.; Shoji,
M.; Hada, N.; Sugai, T. Tetrahedron 2013, 69, 7931. (g) Di Bussolo,
V.; Frau, I.; Crotti, S.; Uccello-Barretta, G.; Balzano, F.; Pineschi, M.;
Crotti, P. Org. Lett. 2013, 15, 6026.
(CIF)
(CIF)
(CIF)
Additional information, NMR spectra, and crystal
structures; COSY and 1D NOE experiments for
structure determination of 12a (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: tpathak@chem.iitkgp.ernet.in.
Notes
(13) For reviews on cyclopropanated carbohydrates: (a) Cousins, G.
S.; Hoberg, J. O. Chem. Soc. Rev. 2000, 29, 165. (b) Reissig, H. U.;
Zimmer, R. Chem. Rev. 2003, 103, 1151. (c) Yin, J.; Linker, T. Org.
Biomol. Chem. 2012, 10, 2351.
■
(14) There are very few examples on the synthesis of carbohydrate-
The authors declare no competing financial interest.
derived substituted dihydrofurans, see: refs 2b and 2c.
G
DOI: 10.1021/acs.joc.5b01192
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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́
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DOI: 10.1021/acs.joc.5b01192
J. Org. Chem. XXXX, XXX, XXX−XXX