Synthesis of enantiomerically pure highly functionalized furanoid glycal and 2,5-Dihydrofuran building blocks

Article abstract of DOI:10.1002/ejoc.200801226

Differently protected enantiomerically pure furanoid glycals (5a-d) and highly functionalized 2,5-dihydrofurans (6a-b) were synthesized from their respective 2,3,4-trisubstituted tetrahydrofurans. These furanoid glycals were identified as 1,4-anhydro-2-de

Full text of DOI:10.1002/ejoc.200801226

FULL PAPER
DOI: 10.1002/ejoc.200801226
Synthesis of Enantiomerically Pure Highly Functionalized Furanoid Glycal and
2,5-Dihydrofuran Building Blocks[‡]
Pinki Pal,[a] Brijesh Kumar,[b] and Arun K. Shaw*[a]
Dedicated to Professor Dr. Ralf Miethchen[‡‡]
Keywords: Alcohols / Glycals / Elimination / Oxygen heterocycles / Allylic compounds
Differently protected enantiomerically pure furanoid glycals
(5a–d) and highly functionalized 2,5-dihydrofurans (6a–b)
were synthesized from their respective 2,3,4-trisubstituted
tetrahydrofurans. These furanoid glycals were identified as
ene-3-O-benzyl-
5,6-O-isopropylidene-3-O-benzyl-
1,4-anhydro-2-deoxy-5,6-O-isopropylidene-3-O-benzyl-
abino-hex-1-enitol, respectively.
L
-ribo-hex-1-enitol, 1,4-anhydro-2-deoxy-
-ribo-hex-1-enitol and
-ar-
D
D
1,4-anhydro-2-deoxy-5,6-O-isopropylidene-3-O-benzyl-L-ar- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
abino-hex-1-enitol, 1,4-anhydro-2-deoxy-5,6-O-isopropylid-
Germany, 2009)
(iv) Elimination from 2-deoxypentofuranose derivatives
such as 1-O-mesylates,[6] nucleosides[7] and 1,2-diols.[8]
(v) Oxidative elimination of 1-phenylselenenylfuranosides
and 2-phenylselenenyl-1,4-anhydroalditols,[9] and very re-
cently, reaction of furanosyl sulfoxides with nBuLi in THF
at –78 °C.[10] Similarly, the stereoselective synthesis of func-
tionalized 2,5-dihydrofurans has also been reported due to
their importance as structural motifs and presence in a wide
variety of natural products exhibiting various biological ac-
tivities.[11–13] As mentioned above, several methods are
available for synthesis of furanoid glycals or 4,5-dihydrofu-
rans but difficulties are generally encountered with the for-
mation of unstable glycal,[2] usage of expensive starting ma-
terials[7] and, in some cases, low yields of the desired prod-
ucts; that is why improvements in the existing methods are
still desirable. To overcome all these limitations, herein we
wish to describe a simple protocol for the synthesis of ste-
reochemically different furanoid glycals 5a (1,4-anhydro-2-
deoxy-5,6-O-isopropylidene-3-O-benzyl--arabino-hex-1-en-
itol), 5b (1,4-anhydro-2-deoxy-5,6-O-isopropylidene-3-O-
benzyl--ribo-hex-1-enitol), 5c (1,4-anhydro-2-deoxy-5,6-O-
isopropylidene-3-O-benzyl--ribo-hex-1-enitol),[14a] 5d (1,4-
anhydro-2-deoxy-5,6-O-isopropylidene-3-O-benzyl--arab-
ino-hex-1-enitol)[3c,14] and also highly functionalized 2,5-di-
hydrofurans 6a,b (Figure 1) from easily accessible enantio-
merically pure 2,3,4-trisubstituted THF scaffolds (2a–d).
The synthesis of these THF building blocks was recently
reported from our laboratory.[15] Subsequently, their utility
was exemplified by achieving the syntheses of jaspine B,[16a]
enantiomerically pure γ-azidotetrahydrofuran carboxylic
acids[16b] and oxybiotin, an oxygen analogue of biotin.[16c]
Further utilization of versatile THF scaffolds 2 to obtain
Introduction
A great deal of interest has been devoted in recent years
towards the synthesis of furanoid glycals, owing to the fact
that they have been used as key intermediates in the prepa-
ration of structurally diverse compounds with various bio-
logical activities such as polyether antibiotics,[1a] 6-epi-leu-
kotrienes C & D,[1b] palladium-mediated coupling reaction
leading to C-nucleosides,[1c] antiviral and antitumour C-nu-
cleosides,[1d] α-arabino nucleosides,[1e] 2Ј,3Ј-dideoxynucleos-
ides[1f] and more recently 2Ј-deoxynuleosides.[1g] The first
known glycal derivative with a furanose structure, namely,
1,4-anhydro-3,5-di-O-benzoyl-2-deoxy--erythro-pent-1-en-
itol, was synthesized by Ness and Fletcher in 1963, but sev-
eral protection and deprotection steps were necessary for
the synthesis of the appropriate precursor 3,5-di-O-benzoyl-
2-O-p-nitrophenylsulfonyl-β--ribosyl bromide.[2] Over the
years, different methodologies for the synthesis of furanoid
glycals have been reported: (i) Reduction of protected gly-
cosyl halides with reducing agents like lithium in liquid am-
monia (Ireland’s method) and Na-naphthalene.[3] (ii) Reac-
tion of glycosyl phenyl sulfones with samarium(II) iodide
in THF.[4] (iii) Molybdenum-catalyzed alkynol cyclization.[5]
[‡] CDRI communication no. 7628.
[a] Division of Medicinal and Process Chemistry, Central Drug Re-
search Institute,
Lucknow-226 001, India
E-mail: akshaw55@yahoo.com
[b] Division of Sophisticated Analytical Instrument Facility, Cen-
tral Drug Research Institute,
Lucknow-226 001, India
[‡‡]University of Rostock, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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P. Pal, B. Kumar, A. K. Shaw
FULL PAPER
title compounds 5a–d and 6a,b of different configurations
The free hydroxy group in 2a was protected with meth-
at all the chiral centres with ethylene glycol chain is re- anesulfonyl chloride[16a,16b] in the presence of triethylamine
ported herein. To the best of our knowledge, no examples to afford corresponding mesyl derivative 3a. OMs-protected
of the synthesis of enantiomerically pure furanoid glycals THF 3a in dry DMF was subjected to a thermal elimi-
5a,b and functionalized 2,5-dihydrofurans 6a,b have been nation reaction for 8 h in the presence of DBU[19] to furnish
reported so far.
furanoid glycal 5a (52%) as a single product. The regiose-
lective elimination of MsOH in this case presumably re-
sulted from the antiperiplanar arrangement of the OMs
leaving group at C4 and one of the hydrogen atoms at C5
(Scheme 2). However, a similar experiment with DBU in
refluxing dry toluene or dry DCM did not afford the elimi-
nation product.
Having this result in hand, we extended our study of the
elimination reaction to other mesylated THFs (3b–d) pre-
pared from their respective THF scaffolds (2b–d) to obtain
furanoid glycals (5b–d). When mesylated THF 3b was
heated at reflux with DBU in dry DMF for 8 h, a mixture
of two compounds was formed. Column chromatographic
purification of the mixture led to the isolation of 5b and 6a
in 34 and 19% yield, respectively. Whereas C3 had opposite
stereochemistry in 3a and 3b, the stereochemistry of C4 in
3b was the same as that in 3a, and therefore, the formation
of glycal 5b was quite obvious. The formation of more sub-
stituted olefin 6a was also possible in this case as the leaving
groups to be eliminated were in the antiperiplanar arrange-
ment.
Here, we thought that the formation of olefin 6a could
be also possible from 2a via an intermediate where H3 and
the leaving group should be antiperiplanar. The formation
of this pivotal intermediate required SN2 displacement of
the secondary hydroxy group at C4 in 2a by an appropriate
leaving group followed by its elimination along with H3 in
an E2 fashion. Thus, when stereochemically inverted iodide
4a prepared by Garegg–Samuelsson reaction[20] from 2a
was heated at reflux with DBU in dry DMF for 5 h, trisub-
stituted olefin 6a was obtained as a single product in 67%
yield. However, the regioselective elimination of HI from 4b
prepared from 2b, following the above reaction conditions,
gave glycal 5b as a single product in 54% yield (Scheme 3).
Our study on the elimination reaction was further ex-
tended to other mesylated THF scaffolds. Thus, when mes-
ylate 3c, prepared from 2c, in dry DMF was heated at reflux
with DBU furanoid glycal 5c was obtained as a single prod-
uct in 52% yield. In contrast, thermal elimination of MsOH
in 3d obtained from THF scaffold 2d furnished a mixture
Figure 1. Structures of furanoid glycals and highly functionalized
2,5-dihydrofurans.
Results and Discussion
Our approach to obtain a family of furanoid glycals (5a–
d) of different configurations at the 3-, 4- and 5-positions
and functionalized 2,5-dihydrofurans (6a,b) of different
configurations at the 2- and 1Ј-positions from enantiopure
THF scaffolds (2a–d) is outlined in Scheme 1.
Scheme 1. General strategy for the synthesis of furanoid glycals 5a–
d and functionalized 2,5-dihydrofurans 6a,b.
Scheme 2. Synthesis of furanoid glycals 5a,b and functionalized 2,5-dihydrofuran 6a.
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Functionalized Furanoid Glycal and 2,5-Dihydrofuran Building Blocks
Noteworthy is that when 3d or 4d was heated at reflux
with DBU in dry DMF C3 was epimerized in either case,
resulting in the formation of an inseparable isomeric mix-
ture of furanoid glycals containing 5c and 5d. Unfortu-
nately, we do not have a suitable explanation for this.
Castillón and Kassou[9] reported the synthesis of dif-
ferently protected erythro- and threo-configured furanoid
glycals by oxidative elimination of their respective dia-
stereomeric 2-deoxy-2-phenylselenenyl-1,4-anhydroalditols
in the presence of tBuOOH, Ti(O-iPr)4 and EtiPr2N in re-
fluxing CH2Cl2 or C2H4Cl2 for 36–48 h (Scheme 6). In their
study, the stereochemical requirement to obtain furanoid
glycal exclusively was 1,2-syn elimination of PhSeOH. Here,
both epimers at C2 showed identical regioselective outcome,
as no 2,3-syn elimination of PhSeOH was observed to pro-
duce 2,5-dihydrofuran. On the contrary, in our above-de-
scribed study, the stereochemical requirement was anti eli-
mination of MsOH or HI to furnish either furanoid glycals
or 2,5-dihydrofurans.
Scheme 3. Synthesis of furanoid glycal 5b and functionalized 2,5-
dihydrofuran 6a.
of products, whose chromatographic purification led to the
isolation of functionalized 2,5-dihydrofuran 6b as the major
product in 61% yield and an inseparable mixture of fu-
ranoid glycals 5d and 5c as minor products in a combined
5% yield. 1H NMR spectroscopic analysis of the glycal mix-
ture demonstrated that it contained 5d and 5c in a 1:0.2
ratio (Scheme 4).
Whereas iodo derivative 4c, derived from 2c, afforded
functionalized 2,5-dihydrofuran 6b as the major product in
64% yield and furanoid glycal 5c in 29% yield upon ther-
mal elimination, stereoisomer 4d, obtained from 2d, under
Scheme 6. Synthesis of differently protected erythro and threo fu-
ranoid glycals from diastereomeric 2-deoxy-2-phenylselenenyl-1,4-
the identical reaction conditions furnished a product (single anhydroalditols.
spot on TLC) that was purified by column chromatography
1
in 67% yield. Its H NMR spectrum identified it as an in-
From the above study, it can be concluded that the prod-
separable mixture of glycals 5d and 5c in a 1:0.2 ratio uct distribution in each case was governed essentially by the
(Scheme 5).
relative disposition of the groups (mesyl or iodine at C4 and
Scheme 4. Synthesis of furanoid glycals 5c,d and functionalized 2,5-dihydrofuran 6b.
Scheme 5. Synthesis of furanoid glycals 5c,d and functionalized 2,5-dihydrofuran 6b.
Eur. J. Org. Chem. 2009, 2179–2184
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P. Pal, B. Kumar, A. K. Shaw
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neighbouring H atoms) to be eliminated. In the formation ring compounds or molecules of various biological interest.
of either glycal or olefin, the E2 elimination took place Work in this direction is currently ongoing in our labora-
most readily when the hydrogen atom and the leaving group tory.
were in an antiperiplanar arrangement. Further, it can be
argued that E2 elimination of MsOH from 3b leading to
the formation of two products in which furanoid glycal 5b
(Hofmann product) was formed predominantly over Saytz-
eff product 6a (more substituted olefin) may be attributed
to the involvement of a conformation in which the leaving
group, 4-OMs, and one of the hydrogen atoms at C5
adopted a relatively higher degree of antiperiplanar ar-
rangement relative to the antiperiplanar arrangement of 4-
OMs and H3. In contrast, the formation of Saytzeff prod-
Experimental Section
General Methods: Organic solvents were dried by standard meth-
ods. All products were characterized by H, 13C, 2D homonuclear
1
COSY (correlation spectroscopy) for compound 5b, heteronuclear
single quantum coherence (HSQC), IR, MS (ESI) and HRMS (EI;
C, H, O). Analytical TLC was performed by using 2.5ϫ5 cm plates
coated with a 0.25 mm thickness of silica gel (60F-254), visualiza-
tion was accomplished with CeSO4 (1% in 2.0  H2SO4) and subse-
uct 6b as the major product and a mixture of glycals 5c,d quent charring over a hot plate. Column chromatography was per-
formed by using silica gel (60–120 mesh). NMR spectra were re-
corded with a Bruker Avance 300 (300 MHz for 1H and 75 MHz
for 13C). Experiments were recorded in CDCl3 or CDCl3 + CCl4
(1:1) at 25 °C. Chemical shifts are given on the δ scale and are
referenced to TMS at δ = 0.00 ppm for proton and 0.00 ppm for
as the minor product, both from 3d, could be attributed to
the comparable torsion angles subtended by the OMs group
and the H atom across the C4–C3 and C4–C5 bond, respec-
tively. Similarly, E2 elimination of HI from 4c gave expected
Saytzeff product 6b as the major product over furanoid gly-
cal 5c as a result of the same reason described in the case
of E2 elimination of MsOH from 3d.
carbon. For 13C NMR, reference CDCl3 appeared at
δ =
77.00 ppm. For 13C NMR in CDCl3 + CCl4, CCl4 appeared at δ =
96.2 ppm. IR spectra were recorded with Perkin–Elmer 881 and
FTIR-8210 PC Shimadzu Spectrophotometers. Mass spectra were
recorded with a JEOL JMS-600H high-resolution spectrometer by
using EI mode at 70 eV. Optical rotations were determined with an
Autopol III polarimeter by using a 1 dm cell at 25–29 °C in chloro-
form as the solvent; concentrations mentioned are in g/100 mL.
Conclusions
In summary, we have discussed the synthesis of highly
functionalized furanoid glycals (4,5-dihydrofurans) 5a–d
and 2,5-dihydrofurans 6a,b, which all have an ethylene
glycol chain. The construction of the double bonds, which
is the main topic of the present work, was accomplished by
carrying out a base-induced E2 elimination of enantiomer-
ically pure C4 mesylate or iodo THF scaffolds (3 or 4) by
utilizing inexpensive reagents with a simple experimental
and workup procedure. The reaction conditions (DBU, dry
DMF, reflux) employed to obtain the title chiral building
blocks were optimized depending on the stereochemistry of
the starting materials. We also showed that furanoid glycals
5a and 5c or functionalized 2,5-dihydrofurans 6a and 6b
can be synthesized exclusively or in major quantity from
the same 2,3,4-trisubstituted THF scaffolds 2a and 2c,
respectively, by changing the leaving group at C4. Further-
more, it can be emphasized that our present study provides
two pairs of enantiomeric furanoid glycals (4,5-dihydrofu-
rans) 5a, 5d and 5b, 5c and one pair of enantiomeric 2,5-
dihydrofurans 6a, 6b (Figure 1). These furanoid glycals and
functionalized 2,5-dihydrofurans have various sites of diver-
sification (Figure 2) and, therefore, they may find wide syn-
thetic applications as important chiral building blocks for
the generation of structurally diverse compounds. They
could also be utilized for the synthesis of naturally occur-
General Procedure for the Preparation of 4-Iodo THF Scaffolds: A
stirred solution of 2a (110 mg, 0.37 mmol) in dry toluene (10 mL)
was treated with PPh3 (196 mg, 0.748 mmol), imidazole (108 mg,
1.49 mmol) and iodine (190 mg, 0.748 mmol). The reaction mixture
was heated at reflux at 110 °C for 4 h until completion of the reac-
tion (TLC control) and then cooled to room temperature. After-
wards, the reaction mixture was diluted with EtOAc (5 mL), and
the solvent was removed under reduced pressure. The excess
amount of iodine in the residue obtained was quenched with a
saturated aqueous Na2S2O7 solution (5 mL), and the aqueous layer
was extracted with EtOAc (3ϫ5 mL). The combined organic layer
was dried with anhydrous Na2SO4, filtered and concentrated to
afford the crude product that was purified by column chromatog-
raphy (60–120 mesh silica gel) to furnish pure 4a (61 mg, 40%).
Similar reaction protocol was adopted for the synthesis of 4b, 4c
and 4d.
General Procedure for the Preparation of Furanoid Glycals from Me-
sylated THF Scaffolds: To a stirred solution of mesylate 3a
(100 mg, 0.268 mmol) in dry DMF (5 mL) was added DBU
(0.1 mL, 0.672 mmol), and the mixture was stirred under reflux for
8 h until completion of the reaction (TLC control). The resulting
reaction mixture was cooled to room temperature and water (5 mL)
was added. Afterwards, the aqueous layer was extracted with
EtOAc (3ϫ5 mL). The combined organic extracts were dried with
anhydrous Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by column chromatography (60–
120 mesh silica gel) to furnish pure furanoid glycal 5a (39 mg,
52%). Similar reaction protocol was adopted for the synthesis of
compounds 5b, 5c and 5d.
General Procedure for the Preparation of Furanoid Glycals from 4-
Iodo THF Scaffolds: To a solution of compound 4b (46 mg,
0.114 mmol) in dry DMF (5 mL) was added DBU (0.04 mL,
0.284 mmol), and the mixture was stirred under reflux for 5 h until
completion of the reaction (TLC control). The resulting reaction
Figure 2. Sites of diversification.
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Functionalized Furanoid Glycal and 2,5-Dihydrofuran Building Blocks
mixture was cooled to room temperature and diluted with water
(5 mL). Afterwards, the aqueous layer was extracted with EtOAc
(3ϫ5 mL). The combined organic layer was dried with anhydrous
Na2SO4, filtered and concentrated. Purification of the residue by
column chromatography (60–120 mesh silica gel) furnished pure fu-
ranoid glycal 5b (17 mg, 54%).
27.0 (CH3), 67.2 (CH2), 72.7 (CH2Ph), 73.4 (CH), 76.4 (CH2), 80.7
(CH), 86.9 (CH), 108.9 (Cq), 127.8 (ArC), 128.1 (ArC), 128.5
(ArC), 137.5 (ArCq) ppm. MS (ESI): m/z = 405 [M + H]+. HRMS
(EI): calcd. for C15H18IO4 [M – CH3]+ 389.0250; found 389.0249.
Compound 5a: Colourless oil; yield: 39 mg (52%) from 3a. Eluent
for column chromatography: EtOAc/hexane (1:49). [α]2D5 = +95.29
General Procedure for the Preparation of Functionalized 2,5-Dihy-
drofurans (6a,b) either from Mesylated or 4-Iodo THF Scaffolds:
General procedure to obtain functionalized 2,5-dihydrofurans was
similar to the general procedure followed for the preparation of
furanoid glycals.
(c = 0.58, CHCl ). R = 0.68 (EtOAc/hexane, 1:4). IR (neat): ν
˜
3
f
= 732, 1065, 1260, 1352, 1461, 1595, 2856, 2926 cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.39 (s, 3 H, CH3), 1.48 (s, 3 H,
CH3), 3.99 (dd, J = 6.4, 8.7 Hz, 1 H, 6a-H), 4.11 (dd, J = 6.7,
8.6 Hz, 1 H, 6b-H), 4.44 (dd, J = 5.1, 7.0 Hz, 1 H, 4-H), 4.49–4.62
(m, 3 H, 5-H, CH2Ph), 4.63–4.67 (m, 1 H, 3-H), 5.29 (t, J = 2.6 Hz,
1 H, 2-H), 6.63 (d, J = 2.7 Hz, 1 H, 1-H), 7.30–7.37 (m, 5 H, ArH)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 25.2 (CH3), 26.5
(CH3), 65.9 (CH2), 71.0 (CH2Ph), 73.1 (CH), 79.2 (CH), 84.1 (CH),
101.9 (CH), 108.7 (Cq), 127.5 (ArC), 127.6 (ArC), 128.4 (ArC),
138.4 (ArCq), 150.6 (CH) ppm. MS (ESI): m/z = 299 [M + Na]+.
HRMS (EI): calcd. for C16H20O4 [M]+ 276.1362; found 276.1361.
Compound 4a: Light yellow oil; yield: 61 mg (40%). Eluent for col-
umn chromatography: EtOAc/hexane (1:49). [α]2D5 = +3.28 (c =
0.19, CHCl ). R = 0.59 (EtOAc/hexane, 1:4). IR (neat): ν = 697,
˜
3
f
1
1061, 1250, 1637, 2922 cm–1. H NMR (300 MHz, CDCl3, 25 °C):
δ = 1.35 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 3.91–4.13 (m, 6 H, 2Ј-
H, 2-H, 3-H, 5-H), 4.19–4.34 (m, 2 H, 1Ј-H, 4-H), 4.72 (d, J =
10.5 Hz, 1 H, CH2Ph), 4.87 (d, J = 10.5 Hz, 1 H, CH2Ph), 7.30–
7.45 (m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
22.8 (CH), 25.4 (CH3), 26.8 (CH3), 67.2 (CH2), 73.7 (CH), 74.5
(CH2Ph), 74.6 (CH2), 79.4 (CH), 81.4 (CH), 109.0 (Cq), 127.9
(ArC), 128.3 (ArC), 128.4 (ArC), 137.6 (ArCq) ppm. MS (ESI): m/z
= 405 [M + H]+. HRMS (EI): calcd. for C15H18IO4 [M – CH3]+
389.0250; found 389.0255.
Compound 5b: Colourless oil; yield: 25 mg (34%) from 3b, 17 mg
(54%) from 4b. Eluent for column chromatography: EtOAc/hexane
(1:49). [α]2D5 = –40.0 (c = 0.09, CHCl3). Rf = 0.7 (EtOAc/hexane,
1:4). IR (neat): ν = 738, 1069, 1213, 1372, 1457, 1615, 2341, 2370,
˜
1
2855, 2923 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.36 (s,
3 H, CH3), 1.49 (s, 3 H, CH3), 3.84–3.90 (m, 1 H, 5-H), 3.96 (dd,
J = 4.8, 8.6 Hz, 1 H, 6a-H), 4.09 (dd, J = 6.3, 8.7 Hz, 1 H, 6b-H),
4.38 (dd, J = 2.4, 8.2 Hz, 1 H, 4-H), 4.51 (d, J = 11.7 Hz, 1 H,
CH2Ph), 4.59 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.73–4.76 (m, 1 H, 3-
H), 5.18 (t, J = 2.6 Hz, 1 H, 2-H), 6.55 (dd, J = 0.7, 2.6 Hz, 1 H,
1-H), 7.29–7.35 (m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3
+ CCl4, 25 °C): δ = 25.4 (CH3), 27.0 (CH3), 67.3 (CH2), 69.6
(CH2Ph), 74.2 (CH), 82.5 (CH), 86.7 (CH), 101.0 (CH), 109.7 (Cq),
127.6 (ArC), 127.8 (ArC), 128.4 (ArC), 138.4 (ArCq), 149.9 (CH)
ppm. MS (ESI): m/z = 277 [M + H]+, 299 [M + Na]+. HRMS (EI):
calcd. for C16H20O4 [M]+ 276.1362; found 276.1359.
Compound 4b: Light yellow oil; yield: 91 mg (60%). Eluent for col-
umn chromatography: EtOAc/hexane (1:49). [α]2D5 = +6.47 (c =
0.17, CHCl ). R = 0.65 (EtOAc/hexane, 1:4). IR (neat): ν = 752,
˜
3
f
1072, 1265, 1517, 1650, 2919 cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.37 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 3.78 (dd, J =
3.1, 7.8 Hz, 1 H, 3-H), 3.93 (dd, J = 4.9, 8.6 Hz, 1 H, 2aЈ-H), 4.06–
4.19 (m, 3 H, 2bЈ-H, 5-H), 4.23–4.26 (m, 1 H, 4-H), 4.29–4.35 (m,
1 H, 1Ј-H), 4.48–4.49 (m, 1 H, 2-H), 4.62 (d, J = 11.8 Hz, 1 H,
CH2Ph), 4.67 (d, J = 11.8 Hz, 1 H, CH2Ph), 7.31–7.39 (m, 5 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 23.9 (CH),
25.2 (CH3), 26.8 (CH3), 67.4 (CH2), 72.2 (CH2Ph), 76.3 (CH2), 76.6
(CH), 86.3 (CH), 89.1 (CH), 109.7 (Cq), 127.9 (ArC), 128.0 (ArC),
128.5 (ArC), 137.5 (ArCq) ppm. MS (ESI):m/z = 405 [M + H]+.
HRMS (EI): calcd. for C15H18IO4 [M – CH3]+ 389.0250; found
389.0242.
Compound 5c: Colourless oil; yield: 39 mg (52%) from 3c, 9 mg
(29%) from 4c. Eluent for column chromatography: EtOAc/hexane
(1:49). [α]2D5 = +98.6 (c = 0.60, CHCl3). Rf = 0.71 (EtOAc/hexane,
1:4). IR (neat): ν = 738, 1068, 1216, 1376, 1457, 1613, 2366,
˜
2927 cm–1. 1H NMR (300 MHz, CDCl3 + CCl4, 25 °C): δ = 1.34
(s, 3 H, CH3), 1.46 (s, 3 H, CH3), 3.77–3.84 (m, 1 H, 5-H), 3.93
(dd, J = 4.8, 8.6 Hz, 1 H, 6a-H), 4.06 (dd, J = 6.4, 8.5 Hz, 1 H,
6b-H), 4.32 (dd, J = 2.3, 8.5 Hz, 1 H, 4-H), 4.48 (d, J = 11.8 Hz,
1 H, CH2Ph), 4.58 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.71 (br. s, 1 H,
3-H), 5.13 (t, J = 2.5 Hz, 1 H, 2-H), 6.50 (d, J = 2.5 Hz, 1 H, 1-
H), 7.25–7.31 (m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 25.2 (CH3), 26.8 (CH3), 67.1 (CH2), 69.6 (CH2Ph), 74.2
(CH), 82.4 (CH), 86.5 (CH), 101.0 (CH) 109.7 (Cq), 127.6 (ArC),
127.8 (ArC), 128.4 (ArC), 138.3 (ArCq), 150.0 (CH) ppm. MS
(ESI): m/z = 277 [M + H]+. HRMS (EI): calcd. for C16H20O4
[M]+ 276.1362; found 276.1363.
Compound 4c: Light yellow oil; yield: 66 mg (44%). Eluent for col-
umn chromatography: EtOAc/hexane (1:49). [α]2D5 = +26.9 (c =
0.19, CHCl ). R = 0.58 (EtOAc/hexane, 1:4). IR (neat): ν = 631,
˜
3
f
1
1098, 1237, 1517, 2919 cm–1. H NMR (300 MHz, CDCl3, 25 °C):
δ = 1.32 (s, 3 H, CH3), 1.40 (s, 3 H, CH3), 3.70–3.83 (m, 2 H, 2aЈ-
H, 3-H), 3.89–4.05 (m, 4 H, 1Ј-H, 2bЈ-H, 2-H, 5a-H), 4.15–4.22
(m, 2 H, 4-H, 5b-H), 4.57 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.68 (d,
J = 11.7 Hz, 1 H, CH2Ph), 7.27–7.41 (m, 5 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 24.9 (CH), 25.5 (CH3), 26.5
(CH3), 66.2 (CH2), 72.2 (CH2Ph), 74.9 (CH2), 75.7 (CH), 78.9
(CH), 82.8 (CH), 109.7 (Cq), 127.9 (ArC), 128.2 (ArC), 128.4
(ArC), 137.2 (ArCq) ppm. MS (ESI): m/z = 405 [M + H]+. HRMS
(EI): calcd. for C15H18IO4 [M – CH3]+ 389.0250; found 389.0260.
Compounds 5d+5c: Inseparable diastereomeric mixture (5d/5c,
1:0.2); colourless oil; yield: 4 mg (5%) from 3d, 21 mg (67%) from
4d. Eluent for column chromatography: EtOAc/hexane (1:49). Rf =
0.71 (EtOAc/hexane, 1:4). 1H NMR (300 MHz, CDCl3 + CCl4,
25 °C): δ = 1.34 (s, 0.7 H, CH3D), 1.37 (s, 3 H, CH3), 1.44 (s, 3 H,
Compound 4d: Light yellow oil; yield: 95 mg (63%). Eluent for col-
umn chromatography: EtOAc/hexane (1:49). [α]2D5 = +2.41 (c =
0.27, CHCl ). R = 0.68 (EtOAc/hexane, 1:4). IR (neat): ν = 754,
˜
3
f
1071, 1215, 1376, 1634, 2375, 2922 cm–1. 1H NMR (300 MHz, CH3), 1.46 (s, 0.7 H, CH3D), 3.79–3.84 (m, 0.2 H, 5-HD), 3.95 (dd,
CDCl3, 25 °C): δ = 1.35 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 3.89– J = 6.3, 8.6 Hz, 1 H, 6a-H), 4.07 (dd, J = 6.5, 8.6 Hz, 1 H, 6b-H),
3.97 (m, 1 H, 2aЈ-H), 4.01–4.16 (m, 2 H, 2bЈ-H, 5a-H), 4.19–4.25
(m, 1 H, 4-H), 4.28–4.36 (m, 3 H, 1Ј-H, 2-H, 3-H), 4.50 (dd, J =
5.1, 10.5 Hz, 1 H, 5b-H), 4.60 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.66
(d, J = 11.7 Hz, 1 H, CH2Ph), 7.31 (br. s, 5 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3 + CCl4, 25 °C): δ = 23.6 (CH), 25.6 (CH3),
4.31 (d, J = 2.5 Hz, 0.1 H, 4-HD), 4.35 (t, J = 6.3 Hz, 1 H, 4-H),
4.47–4.57 (m, 4 H, 5-H, CH2Ph, CH2PhD), 4.61 (dd, J = 2.3,
7.1 Hz, 1 H, 3-H), 4.71–4.72 (m, 0.2 H, 3-HD), 5.13 (t, J = 2.7 Hz,
0.2 H, 2-HD), 5.24 (t, J = 2.5 Hz, 1 H, 2-H), 6.49 (d, J = 2.5 Hz,
0.2 H, 1-HD), 6.58 (d, J = 2.6 Hz, 1 H, 1-H) ppm. 13C NMR
Eur. J. Org. Chem. 2009, 2179–2184
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2183

P. Pal, B. Kumar, A. K. Shaw
FULL PAPER
[3] a) R. E. Ireland, C. S. Wilcox, S. Thaisrivongs, J. Org. Chem.
1978, 43, 786–787; b) R. E. Ireland, D. W. Norbeck, G. S. Man-
del, N. S. Mandel, J. Am. Chem. Soc. 1985, 107, 3285–3294; c)
C. Kim, R. Hoang, E. A. Theodorakis, Org. Lett. 1999, 1,
1295–1297.
[4] R. Pontikis, J. Wolf, C. Monneret, J.-C. Florent, Tetrahedron
Lett. 1995, 36, 3523–3526.
[5] F. E. McDonald, M. M. Gleason, J. Am. Chem. Soc. 1996, 118,
6648–6659.
[6] J. A. Walker II, J. J. Chen, D. S. Wise, L. B. Townsend, J. Org.
Chem. 1996, 61, 2219–2221.
[7] a) E. Larsen, P. T. Jørgensen, M. A. Sofan, E. B. Pederson,
Synthesis 1994, 1037–1038; b) M. A. Cameron, S. B. Cush,
R. P. Hammer, J. Org. Chem. 1997, 62, 9065–9069; c) I. Singh,
O. Seitz, Org. Lett. 2006, 8, 4319–4322.
[8] a) R. R. Diaz, C. R. Melgarejo, I. I. Cubero, M. T. P. López-
Espinosa, Carbohydr. Res. 1997, 300, 375–380; b) Z.-X. Wang,
L. I. Wiebe, J. Balzarini, E. De Clercq, E. E. Knaus, J. Org.
Chem. 2000, 65, 9214–9219.
[9] a) M. Kassou, S. Castillón, Tetrahedron Lett. 1994, 35, 5513–
5516; b) F. Bravo, M. Kassou, S. Castillón, Tetrahedron Lett.
1999, 40, 1187–1190; c) F. Bravo, M. Kassou, Y. Díaz, S. Cas-
tillón, Carbohydr. Res. 2001, 336, 83–97.
[10] A. M. Gómez, M. Casillas, A. Barrio, A. Gawel, J. C. López,
Eur. J. Org. Chem. 2008, 3933–3942.
[11] A. Hoffmann-Röder, N. Krause, Org. Lett. 2001, 3, 2537–2538.
[12] a) For selected reviews on polyether antibiotics, see: M. M.
Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407–2473; marine
polyethers: J. J. Fernández, M. L. Souto, M. Norte, Nat. Prod.
Rep. 2000, 17, 235–246; marine natural products: J. W. Blunt,
B. R. Copp, M. H. G. Munro, P. T. Northcote, M. R. Prinsep,
Nat. Prod. Rep. 2006, 23, 26–78; b) A. Buzas, F. Istrate, F.
Gagosz, Org. Lett. 2006, 8, 1957–1959.
[13] M. Brasholz, H.-U. Reissig, Synlett 2007, 1294–1298.
[14] a) S. J. Eitelman, R. H. Hall, A. Jordaan, J. Chem. Soc. Perkin
Trans. 1 1978, 595–600; b) G. V. M. Sharma, K. Krishnudu,
Carbohydr. Res. 1995, 268, 287–293; c) T. Oishi, K. Ando, N.
Chida, Chem. Commun. 2001, 1932–1933 and references cited
therein.
(75 MHz, CDCl3 + CCl4, 25 °C): δ = 25.4 (CH3D), 25.5 (CH3), 26.7
(CH3), 27.0 (CH3D), 66.2 (CH2), 67.2 (CH2D), 69.6 (CH2PhD), 71.0
(CH2Ph), 73.0 (CH), 74.2 (CHD), 79.3 (CH), 82.5 (CHD), 84.3
(CH), 86.7 (CHD), 101.0 (CHD), 102.0 (CH), 108.8 (Cq), 127.5,
127.6, 127.8, 128.4 (ArC, ArCD), 138.5 (ArCq), 149.9 (CHD), 150.5
(CH) ppm. MS (ESI): m/z = 299 [M + Na]+. HRMS (EI): calcd.
for C16H20O4 [M]+ 276.1362; found 276.1357.
Compound 6a: Colourless oil; yield: 14 mg (19%) from 3b, 21 mg,
(67%) from 4a. Eluent for column chromatography: EtOAc/hexane
(1:24). [α]2D5 = –14.2 (c = 0.12, CHCl3). Rf = 0.48 (EtOAc/hexane,
1:4). IR (neat): ν = 765, 1072, 1222, 1375, 1654, 2363, 2858,
˜
1
2926 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.37 (s, 3 H,
CH3), 1.46 (s, 3 H, CH3), 3.89–3.97 (m, 2 H, 2Ј-H), 4.35 (td, J =
2.9, 6.9 Hz, 1 H, 1Ј-H), 4.65–4.67 (m, 2 H, 5-H), 4.78 (d, J =
1.6 Hz, 1 H, 4-H), 4.80–4.85 (m, 1 H, 2-H), 4.87 (br. s, 2 H,
CH2Ph), 7.32–7.40 (m, 5 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 25.4 (CH3), 26.3 (CH3), 64.3 (CH2), 72.3
(CH2Ph), 73.7 (CH2), 77.3 (CH), 80.7 (CH), 93.0 (CH), 109.5 (Cq),
127.3 (ArC), 128.2 (ArC), 128.6 (ArC), 136.1 (ArCq), 154.3 (Cq)
ppm. MS (ESI): m/z = 299 [M + Na]+. HRMS (EI): calcd. for
C16H20O4 [M]+ 276.1362; found 276.1370.
Compound 6b: Colourless oil; yield: 45 mg (61%) from 3d, 20 mg
(64%) from 4c. Eluent for column chromatography: EtOAc/hexane
(1:24). [α]2D5 = +18.2 (c = 0.17, CHCl3). Rf = 0.41 (EtOAc/hexane,
1:4): IR (neat): ν = 767, 1071, 1218, 1662, 2854, 2923 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 1.38 (s, 3 H, CH3), 1.46 (s, 3 H,
CH3), 3.89–3.97 (m, 2 H, 2Ј-H), 4.35 (td, J = 2.9, 6.9 Hz, 1 H, 1Ј-
H), 4.66–4.68 (m, 2 H, 5-H), 4.78 (d, J = 1.5 Hz, 1 H, 4-H), 4.81–
4.84 (m, 1 H, 2-H), 4.87 (br. s, 2 H, CH2Ph), 7.31–7.41 (m, 5 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 25.4 (CH3),
26.3 (CH3), 64.2 (CH2), 72.3 (CH2Ph), 73.7 (CH2), 77.3 (CH), 80.7
(CH), 93.0 (CH), 109.4 (Cq), 127.3 (ArC), 128.2 (ArC), 128.6
(ArC), 136.1 (ArCq), 154.2 (Cq) ppm. MS (ESI): m/z = 299 [M
+ Na]+. HRMS (EI): calcd. for C16H20O4 [M]+ 276.1362; found
276.1352.
[15] a) R. Sagar, L. V. R. Reddy, M. Saquib, B. Kumar, A. K. Shaw,
Tetrahedron: Asymmetry 2006, 17, 3294–3299; b) L. V. R.
Reddy, A. D. Roy, R. Roy, A. K. Shaw, Chem. Commun. 2006,
3444–3446.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all new compounds.
[16] a) L. V. R. Reddy, P. V. Reddy, A. K. Shaw, Tetrahedron: Asym-
metry 2007, 18, 542–546; b) P. V. Reddy, L. V. R. Reddy, B. Ku-
mar, R. Kumar, P. R. Maulik, A. K. Shaw, Tetrahedron 2008,
64, 2153–2159; c) L. V. R. Reddy, G. N. Swamy, A. K. Shaw,
Tetrahedron: Asymmetry 2008, 19, 1372–1375.
[17] a) F. Gonzalez, S. Lesage, A. S. Perlin, Carbohydr. Res. 1975,
42, 267–274; b) R. Sagar, R. Pathak, A. K. Shaw, Carbohydr.
Res. 2004, 339, 2031–2035; c) M. Saquib, R. Sagar, A. K. Shaw,
Carbohydr. Res. 2006, 341, 1052–1056.
Acknowledgments
We are thankful to the Sophisticated Analytical Instrument Facil-
ity, CDRI, for providing spectroscopic data and Mr. A. K. Pandey
for technical assistance. P.P. thanks CSIR New Delhi for financial
support.
[18] R. Sagar, L. V. R. Reddy, A. K. Shaw, Tetrahedron: Asymmetry
2006, 17, 1189–1198.
[1] a) R. E. Ireland, S. Thaisrivongs, N. Vanier, C. S. Wilcox, J.
Org. Chem. 1980, 45, 48–61; b) E. J. Corey, G. Goto, Tetrahe-
[19] J. S. Yadav, I. Prathap, B. P. Tadi, Tetrahedron Lett. 2006, 47,
3773–3776.
dron Lett. 1980, 21, 3463–3466; c) U. Hacksell, G. D. Daves Jr., [20] a) P. J. Garegg, B. Samuelsson, J. Chem. Soc. Perkin Trans. 1
J. Org. Chem. 1983, 48, 2870–2876; d) U. Hacksell, G. D.
Daves Jr., Prog. Med. Chem. 1985, 22, 1–65; e) K. Chow, S.
Danishefsky, J. Org. Chem. 1990, 55, 4211–4214; f) C. U. Kim,
P. F. Misco, Tetrahedron Lett. 1992, 33, 5733–5736; g) A. El-
Laghdach, Y. Diáz, S. Castillón, Tetrahedron Lett. 1993, 34,
2821–2822.
1980, 2866–2869; b) K. K. Schumacher, J. Jiang, M. M. Joullié,
Tetrahedron: Asymmetry 1998, 9, 47–53; c) I. Nowak, J. F. Can-
non, M. J. Robins, J. Org. Chem. 2007, 72, 532–537; d) I.
Nowak, M. J. Robins, J. Org. Chem. 2007, 72, 3319–3325; e) I.
Izquierdo, M. T. Plaza, V. Yáñez, Tetrahedron 2007, 63, 1440–
1447.
[2] R. K. Ness, H. G. Fletcher Jr., J. Org. Chem. 1963, 28, 435–
Received: December 10, 2008
Published Online: March 10, 2009
437.
2184
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2179–2184