A Concise Synthesis of the Key Tetrahydrofuran Moieties of Caruifolin A and EBC-342

Article abstract of DOI:10.1002/ejoc.202000513

A common strategy for the concise synthesis of the key tetrahydrofuran moieties of caruifolin A and EBC-342 is presented. Asymmetric dihydroxylation and intramolecular S_N2-cyclization are key strategic reactions for the synthesis of the furan f

Full text of DOI:10.1002/ejoc.202000513

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A Concise Synthesis of the Key Tetrahydrofuran Moieties of
Caruifolin A and EBC-342
Authors: Rodney Agustinho Fernandes and Venkati Bethi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000513
Link to VoR: https://doi.org/10.1002/ejoc.202000513
01/2020

10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
A Concise Synthesis of the Key Tetrahydrofuran Moieties of
Caruifolin A and EBC-342
Rodney A. Fernandes,*[a] and Venkati Bethi[a]
Dedication ((optional))
Abstract: A common strategy for the concise synthesis of the key
tetrahydrofuran moieties of caruifolin A and EBC-342 is presented.
Asymmetric dihydroxylation and intramolecular SN2-cyclization are
key strategic reactions for the synthesis of the furan fragments.
cyclopropane ring adding two chiral centres. The 14-membered
macrocycle also contain a conjugated enone with -hydroxy
group. There are no reports on the synthetic studies of these
molecules.[4] Thus, we took up the preparation of the key THF
moieties 3a and 3b based on asymmetric dihydroxylation and
intramolecular SN2-cyclization for THF synthesis.
Introduction
Results and Discussion
Caruifolin A (1a, Figure 1), a germacranolide was isolated from
the aerial part of Artemisia caruifolia Buch.-Ham. ex Roxb.
(Asteraceae) by Hattori and co-workers.[1] This herb is one of the
botanical sources of the Chinese herbal drug “Qing Hao”, that has
been used for the treatment of infectious diseases.[2] Caruifolin A
showed 22-46% HIV-1 protease inhibition at 100 g/mL
concentration.[1] The structure of caruifolin A (1a) features the 10-
membered carbocyclic skeleton, which includes a tetrahydrofuran
(THF) moiety with three asymmetric centers. A -methyl--
butyrolactone is appended through the C7−C8 bond and adds
three more asymmetric centers. The relative stereochemistry was
established by NOESY and molecular modelling studies.
Recently, a related THF containing casbane, EBC-342 (1b,
Figure 1) has been isolated by Williams and co-workers[3] from the
Australian rain forest plant Croton insularis. The structure was
established through extensive NMR studies and the
configurational assignment has been proposed based on
measured CD spectra and comparison with the quantum
chemical calculations-based spectrum. The THF moiety present
in 1b is diastereomeric to that in 1a, but has a similar substitution
pattern. Compound 1b also features gem-dimethyl containing
The envisaged retrosynthetic strategy for caruifolin A (1a) and
EBC-342 (1b) is depicted in Scheme 1.
A ring-closing
metathesis[5] of 2 and C-2 inversion would lead to 1a. The THF
unit 3a and the -lactone 4 can be combined through cross-
metathesis[6] toward the synthesis of 2. The THF 3a was planned
through asymmetric dihydroxylation[7] of 5a with intramolecular
SN2 displacement of correctly placed mesyl group. Compound 5a
can be traced back to intermediate 6a that can be obtained by
diastereoselective allylation of the aldehyde from benzyl
protected (S)-lactate 7. The diastereomer 3b would be an
intermediate toward the synthesis of recently isolated EBC-342
(1b), also requiring the inversion of configuration at the C-2
hydroxy group. The former can be traced similarly to 5b and then
to the diastereomer of 6a that will be formed during allylation. The
relative configuration at C-1 and C-2 positions in the THF moieties
Figure 1. Caruifolin A (1a) with substituted tetrahydrofuran and -methyl--
lactone units and related molecule EBC-342 (1b).
[a]
Prof. Dr. R. A. Fernandes and Dr. V. Bethi
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400076, Maharashtra, India
Fax: (+91)-22-25767152
E-mail: rfernand@chem.iitb.ac.in
Homepage: http://ether.chem.iitb.ac.in/~rfernand/default.htm
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. Retrosynthetic analysis.
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10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
of both 1a and 1b are identical and have anti-placement of the
oxygen atoms, while they differ at the C-4 position (and hence are
diastereomeric). It also infers from this analysis and the
retrosynthesis (Scheme 1) that these configurations can be
directly set if a cis-olefin corresponding to 5a or 5b is used in
asymmetric dihydroxylation. However, cis-olefins and that too
trisubstituted and electron deficient are sluggish and known to
give lower enantio- or diastereoselectivity in asymmetric
dihydroxylation.[7b] Since the absolute stereochemistry of 1a and
1b is not established by synthesis and that the C-2 position can
be easily inverted under Mitsunobu conditions,[8] we planned at
this stage to execute the asymmetric dihydroxylation and SN2-
cyclization strategy as depicted in Scheme 1.
diastereomers 13a (60%) and 13b (30%). The stereochemical
assignment is based on conversion to compound 3a and NMR
studies (see further below). Thus, major compound 13a was
protected as TBS ether 14a (72%) and then DIBAL-H reduction of
ester to aldehyde and one carbon Wittig olefination led to the
THF-moiety 3a in 65% yield over two steps. The C-2 hydroxy in
caruifolin A (1a) has opposite stereochemistry with respect to that
in compound 3a. Inversion of this center at latter part of the
synthesis could be envisaged.
Following a similar strategy, the minor diastereomer syn-
9b was carried forward to the synthesis of an intermediate
3b (for EBC-342) and also to the diastereomer of 3a, i.e. 3c
(
3c can be considered as enantiomer to 3a, as the benzyloxy
The synthesis of THF moiety 3a commenced from ethyl (S)-
lactate 7 (Scheme 2) that was first protected as benzyl ether 8
(76% yield). Further, the partial reduction of ester to aldehyde and
subsequent zinc-mediated allylation[9] gave a separable mixture
of homoallyl alcohols anti-9a (54%) and syn-9b (27%) in 2:1 ratio.
The latter syn-compound is normally obtained as major product in
other allylation reactions (9:1 to 97:3, syn/anti).[10] The anti-alcohol
9a was subjected to ozonolysis followed by Wittig olefination of
the aldehyde with stable ylide 10 to afford the (E)-,-unsaturated
ester 11a in 77% yield. The later on treatment with
methanesulfonyl chloride furnished the mesylate 5a in 79% yield.
Subsequent asymmetric dihydroxylation using the (DHQ)2-PHAL
ligand provided the diastereomeric mixture of diols 12a in 2:1 ratio
(1H NMR), which on further intramolecular cyclization through SN2
displacement of mesylate gave a separable mixture of THF
chirality will be eventually a double bond or Sp2 carbon and
hence is inconsequential) (Scheme 3). Ozonolytic cleavage
of 9b to aldehyde and Wittig olefination led to the ester 11b
(70%). Conversion of free hydroxy to mesylate (5b, 94%),
asymmetric dihydroxylation (to 12b) and SN2-cyclization led
to two diastereomers 13c (27%) and 13d (55%) that were
easily separated by column chromatography. The minor
diastereomer 13c on TBS protection to 14b (70%) and
further ester reduction/Wittig olefination provided compound
3c (61%). The major diastereomer 13d on TBS protection
gave the intermediate 3b (72%) representing the THF core
of EBC-342 (1b), considering a possible C-2 hydroxy
inversion later.[11] The minor diastereomer 13b (Scheme 2)
and the major diastereomer 3b (Scheme 3) are available to
be carried forward if need be while establishing the absolute
stereochemistry for the natural product 1a. The strategy is
Scheme 3. Synthesis of tetrahydrofuran moieties 3b and 3c.
Scheme 2. Synthesis of tetrahydrofuran moiety 3a.
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10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
also flexible to shift the diastereoselectivity by changing ligand to
(DHQD)2-PHAL in asymmetric dihydroxylation in Schemes 2 and
3.
asymmetric dihydroxylation and intramolecular SN2-
cyclization as key steps. The strategy is flexible and
diastereoselectivity can be reversed based on change in
stereochemistry at the asymmetric dihydroxylation step. This
will help in establishing the absolute stereochemistry of the
The stereochemical assignment for compounds 3a and 3c was
considered by 1H NMR study (Figure 2). The stereochemical
relationship among Ha, Hb, Hc, Me and olefin C-H is ascertained
by JH-H coupling constants, H-1H-COSY and NOE experiments
on 3a and 3c as depicted in Figure 2. H-1H-COSY experiment
natural product. Further synthesis of compound
4 for the
1
cross-metathesis toward the total synthesis of caruifolin A is
underway in our laboratory.
1
shows the relationship between the adjacent protons in
compound 3a and 3c.[12] Whereas, NOE experiment study
accomplished the spacial relationship of assigned protons with
others. For example, in compound 3a, irradiation of Ha shows Me
and Hb are in same plane and there is no relation with Hc.
Whereas irradiation of Hb proton in 3c shows Ha, Hb, Hc are in
same plane and also with one of the olefin C-H (J = 17.5, 2.0 Hz).
Similarly, the irradiation of Hc shows special relationship with Hb.
Thus, the stereochemistry for compounds 3a and 3c is as
depicted. This also establishes the stereochemistry in other
isomers 13b and 3b, working backward.
Experimental section
General Information
Flasks were oven or flame dried and cooled in a desiccator.
Dry reactions were carried out under an atmosphere of Ar or
N2. Solvents and reagents were purified by standard
methods. Thin-layer chromatography was performed with
EM 250 Kieselgel 60 F254 silica gel plates. The spots were
visualized by staining with KMnO4 or under UV lamp. 1H and
13C NMR spectra were recorded with a Bruker, AVANCE III
400 spectrometer and the chemical shifts are calculated
1
relative to the tetramethylsilane peak at
NMR and CDCl3 peak at

= 0.00 pm for H

= 77.00 ppm (t) for 13C NMR
spectra. IR spectra were obtained with a Perkin–Elmer
Spectrum One FT–IR spectrometer and samples were
prepared by evaporation from CHCl3 on CsBr plates. Optical
rotations were measured with a Jasco P-2000 digital
polarimeter. High-resolution mass spectra (HRMS) were
obtained by using positive electrospray ionization and by
TOF method
.
(S)-Ethyl 2-(benzyloxy)propanoate (8):
To a stirred solution of (S)-ethyl lactate
7
(2.0 g, 16.93 mmol)
in dry THF (50 mL), was added oil free NaH (0.487 mg, 20.32
mmol, 1.2 equiv.) at 0 C, and the mixture was stirred for 20

min. BnBr (2.4 mL, 20.316 mmol, 1.2 eqiuv.) was added and
the reaction mixture was slowly warmed to room temperature
and stirred for 12 h. It was then quenched with water (10 mL)
and the solution extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed with water, brine,
dried (Na2SO4) and concentrated. The residue was purified
by silica gel column chromatography with petroleum
ether/EtOAc (95:5) as eluent to give
colorless oil. [ D
25 = −5.8 (c = 10.0, CHCl3); IR (CHCl3): max
8
[13] (2.68 g, 76%) as a
]
= 3088, 3064, 3031, 2984, 2938, 2873, 1746, 1496, 1454,
1396, 1372, 1301, 1271, 1200, 1143, 1065, 1025, 907, 860,
698, 609 cm-1; 1H NMR (400 MHz, CDCl3):
 = 7.39−7.27 (m,
5H), 4.69 (d, J = 11.6 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H),
4.25−4.19 (m, 2H), 4.05 (q, J = 6.8 Hz, 1H), 1.44 (d, J = 6.8
Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3):
 = 173.2, 137.6, 128.4, 127.9, 127.8, 74.0, 71.9,
60.8, 18.7, 14.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C12H16O3Na 231.0992, found 231.0981.
(2S,3R)-2-(Benzyloxy)hex-5-en-3-ol (9a) and (2S,3S)-2-
(Benzyloxy)hex-5-en-3-ol (9b)[9]:
Figure 2. NOE experiments for 3a and 3c.
To a stirred solution of
8 (2.0 g, 9.60 mmol) in dry CH2Cl2 (30
Conclusion
mL) at –78 C was added DIBAL-H (8.3 mL, 14.41 mmol, 1.5

In summary, we have synthesized the tetrahydrofuran
equiv., 1.75 M solution in toluene) drop wise over 25 min
moieties 3a, 3b and 3c from (S)-lactate 7 using Sharpless
under a N2 atmosphere. The reaction mixture was stirred for
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10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
1 h and then quenched with saturated aq. Rochelle’s salt
solution (4.0 mL) and stirred vigorously at room temperature
for 1 h. The aqueous layer was separated and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated
to give the corresponding aldehyde (1.58 g), which was used
directly in the next reaction.
(4:1) as an eluent to afford the compound 11a (109 mg, 77%)
25
as colorless oil. [ D
]
= +1.5 (c = 1.0, CHCl3); IR (CHCl3):
max = 3469, 3064, 2981, 2933, 2873, 1705, 1651, 1496,
1454, 1390, 1369, 1326, 1279, 1205, 1095, 1029, 915, 869,
699, 667, 608 cm-1; 1H NMR (400 MHz, CDCl3):
 =
7.51−7.28 (m, 5H), 6.83 (td, J = 7.1, 1.4 Hz, 1H), 4.63 (d, J =
11.7 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.18 (q, J = 5.2 Hz,
2H), 3.88−3.84 (m, 1H), 3.56−3.54 (m, 1H), 2.39−2.33 (m,
2H), 2.11 (s, 1H, OH), 1.85 (d, J = 1.2 Hz, 3H), 1.29 (t, J =
7.2 Hz, 3H), 1.20 (d, J = 6.2 Hz, 3H) ppm; 13C{1H} NMR (100
To a stirred suspension of zinc dust (942.3 mg, 14.41
mmol, 1.5 equiv.) in THF (20 mL) was added allylbromide
(1.3 mL, 14.41 mmol, 1.5 equiv.) at 0 C followed by 4 drops
of saturated aq. NH4Cl. The mixture was stirred for 20 min
and a solution of the above aldehyde (1.58 g) in THF (3 mL)
was added. It was warmed to room temperature and stirred
for 8 h and then quenched with saturated aq. NH4Cl solution.
The mixture was extracted with EtOAc (3 × 10 mL) and the
combined organic layers were washed with water, brine,
dried (Na2SO4) and concentrated. The residue was purified
by silica gel column chromatography with petroleum
ether/EtOAc (9:1) as an eluent to afford the syn-9b (534 mg,
27%) and further elution gave anti-9a (1.07 g, 54%) as
colorless oils.
MHz, CDCl3):  = 167.9, 138.3, 138.0, 129.7, 128.4, 127.7,
127.6, 77.3, 72.6, 70.8, 60.5, 31.7, 14.2, 13.8, 12.6 ppm;
HRMS (ESI-TOF) m/z: [M + K]+ calcd for C17H24O4K
331.1306, found 331.1304.
(5R,6S,E)-Ethyl 6-(benzyloxy)-2-methyl-5-
(methylsulfonyloxy)hept-2-enoate (5a):
To a stirred solution of 11a (1.0 g, 3.42 mmol) in dry CH2Cl2
(15 mL), was added triethylamine (0.95 mL, 6.841 mmol, 2.0
equiv.) and methanesulfonyl chloride (0.4 mL, 5.13 mmol,
1.5 equiv.) at 0 C. The reaction mixture was slowly warmed
Characteristic data for compound anti-9a: []D
25 = +3.9 (c
to room temperature and stirred for 12 h. It was then
quenched with water (5 mL) and the solution extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated.
The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (85:15) as
= 2.3, CHCl3); IR (CHCl3): max = 3457, 3067, 3030, 2979,
2933, 2874, 1641, 1496, 1454, 1382, 1330, 1284, 1090,
1
1073, 1028, 995, 916, 871, 698, 667 cm-1; H NMR (400
MHz, CDCl3):
 = 7.38−7.27 (m, 5H), 5.89−5.78 (m, 1H),
5.17−5.10 (m, 2H), 4.62 (d, J = 11.7 Hz, 1H), 4.51 (d, J =
11.7 Hz, 1H), 3.81−3.76 (m, 1H), 3.58−3.50 (m, 1H),
2.30−2.22 (m, 2H), 1.96 (br s, 1H, OH), 1.20 (d, J = 6.3 Hz,
eluent to give 5a (1.0 g, 79%) as a colorless oil. [ D
(c = 5.0, CHCl3); IR (CHCl3): max = 3031, 2982, 2938, 1709,
1653, 1455, 1353, 1280, 1219, 1174, 1133, 1101, 1028, 956,
]
25 = +0.2

3H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
 = 138.4, 134.9,
1
921, 795, 700, 529 cm-1; H NMR (400 MHz, CDCl3):
 =
128.3, 127.7, 127.6, 117.4, 77.3, 72.5, 70.6, 36.9, 13.7 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H18O2Na
229.1199, found 229.1191.
7.50−7.28 (m, 5H), 6.72 (t, J = 7.3 Hz, 1H), 4.86−4.82 (m,
1H), 4.58 (d, J = 6.0 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H),
3.73−3.69 (m, 1H), 3.0 (s, 3H), 2.74−2.66 (m, 1H), 2.56−2.49
(m, 1H), 1.86 (s, 3H), 1.31−1.24 (m, 6H) ppm; 13C{1H} NMR
Characteristic data for compound syn-9b[10]
: []D
25 = +2.2
(c = 3.25, CHCl3); IR (CHCl3): max = 3442, 3067, 3030, 2976,

2932, 2872, 1641, 1497, 1454, 1394, 1375, 1333, 1281,
(100 MHz, CDCl3):
 = 167.5, 137.7, 134.8, 131.2, 128.4,
1
1261, 1207, 1071, 1028, 992, 914, 870, 608 cm-1; H NMR
127.8, 127.76, 83.4, 75.2, 71.3, 60.7, 38.7, 30.2, 14.7, 14.2,
12.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H26O6SNa 393.1342, found 393.1343.
(400 MHz, CDCl3):  = 7.38−7.27 (m, 5H), 5.93−5.83 (m, 1H),
5.13−5.07 (m, 2H), 4.66 (d, J = 11.5 Hz, 1H), 4.45 (d, J =
11.5 Hz, 1H), 3.59−3.51 (m, 1H), 3.45 (q, J = 6.1 Hz, 1H),
2.39−2.32 (m, 1H), 2.25−2.17 (m, 1H), 2.08 (br s, 1H, OH),
(2R,3S,5S)-Ethyl 5-[(S)-1-(benzyloxy)ethyl]-3-hydroxy-2-
methyltetrahydrofuran-2-carboxylate (13a) and (2S,3R,5S)-
Ethyl 5-[(S)-1-(benzyloxy)ethyl]-3-hydroxy-2-
1.20 (d, J = 6.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):

= 138.3, 134.8, 128.5, 127.8, 127.7, 117.2, 77.5, 74.2, 71.0,
37.5, 15.4 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C13H18O2Na 229.1199, found 229.1186.
methyltetrahydrofuran-2-carboxylate (13b):
To a mixture of K3Fe(CN)6 (1.33 g, 4.05 mmol, 3.0 equiv.),
K2CO3 (0.56 g, 4.050 mmol, 3.0 equiv.), MeSO2NH2 (0.257
g, 2.7 mmol, 2.0 equiv.), (DHQ)2-PHAL (10.5 mg, 0.0135
mmol, 1.0 mol%) and K2OsO4
0.4 mol%), t-BuOH (4 mL) and water (5 mL) were added. The
mixture was stirred for 5 min and cooled to 0 C in an ice
bath. To the cooled mixture, a solution of the -unsaturated
ester 5a (0.5 g, 1.35 mmol) in t-BuOH (1 mL) was added. The
reaction mixture was stirred at 0 C for 6 h and at room
(5R,6S,E)-Ethyl 6-(benzyloxy)-5-hydroxy-2-methylhept-2-
enoate (11a)
·2H2O (2.0 mg, 0.0054 mmol,
Ozone in oxygen gas was bubbled through a stirred and
cooled (−78 C) solution of homoallyl alcohol 9a (100 mg,
0.485 mmol, 1.0 eqiuv.) in CH2Cl2 (5 mL) until blue color
persisted (30 min). Nitrogen gas was then passed through

,
the solution for 15 min at −78 C to remove any excess

ozone. Then, PPh3 (190.8 mg, 0.727 mmol, 1.5 equiv.) was
added, and the solution was stirred at room temperature for
30 min. To the reaction mixture was added
triphenylphosphorane 10 (211 mg, 0.582 mmol, 1.2 equiv.)
and refluxed for 12 h. The reaction mixture was concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography with petroleum ether/EtOAc
temperature for 24 h and then quenched with solid Na2SO3
(1.0 g) and stirred for 30 min. The solution was extracted with
CH2Cl2 (3 × 50 mL) and the combined organic layers were
washed with 1M KOH (50 mL), water (50 mL), brine, dried
(Na2SO4) and concentrated to give the corresponding
inseparable diastereomeric mixture of diol 12a (437 mg)
which was used directly in the next reaction.
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10.1002/ejoc.202000513
European Journal of Organic Chemistry
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To the above crude diol 12a (437 mg), was added 2,6-
[(2S,3S,5S)-5-[(S)-1-(Benzyloxy)ethyl]-2-methyl-2-
lutidine (2 mL) and the resulting mixture was heated at 120
vinyltetrahydrofuran-3-yloxy](tert-butyl)dimethylsilane 3a:

C for 6 h. It was then concentrated under reduced pressure
To a stirred solution of 14a (100 mg, 0.237 mmol) in dry
CH2Cl2 (10 mL) at –78 C was added DIBAL-H (0.2 mL,
and the residue was purified by silica gel column
chromatography with CH2Cl2/EtOAc (95:5) as an eluent to
afford the compound 13b (125 mg, 30%) as colorless oil.
Further elution gave compound 13a (250 mg, 60%) as
colorless oil.
Characteristic data for compound 13a:
4.0, CHCl3); IR (CHCl3): max = 3458, 3065, 2981, 2935,
1732, 1496, 1455, 1390, 1373, 1300, 1283, 1112, 1069,
1025, 964, 914, 861, 698, 667 cm-1; H NMR (400 MHz,
0.355 mmol, 1.5 equiv., 1.75M solution in toluene) dropwise
under N2 atmosphere. The reaction mixture was stirred for 1
h and then quenched with saturated aq. Rochelle’s salt
solution (3 mL) and stirred vigorously at room temperature
for 1 h. The aqueous layer was separated and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4) and concentrated
to give the corresponding aldehyde (80 mg), which was used
directly in the next reaction.
25
[
]D
= +1.5 (c =
1
CDCl3):  = 7.37−7.24 (m, 5H), 4.66 (d, J = 12.0 Hz, 1H), 4.58
(d, J = 12.0 Hz, 1H), 4.46−4.40 (m, 1H), 4.30−4.18 (m, 3H),
3.63−3.55 (m, 1H), 2.14−2.03 (m, 1H), 1.99−1.90 (m, 1H),
1.45 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3):
128.1, 127.5, 127.3, 87.1, 81.4, 78.1, 75.8, 71.0, 61.1, 34.9,
23.4, 15.1, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C17H24O5Na 331.1516, found 331.1514.
Characteristic data for compound 13b:
3.4, CHCl3); IR (CHCl3): max = 3461, 3067, 2986, 2937,
1735, 1498, 1460, 1395, 1367, 1312, 1285, 1118, 1071,
1035, 974, 924, 867, 687, 667 cm-1; H NMR (400 MHz,
CDCl3):  = 7.34−7.27 (m, 5H), 4.72 (d, J = 11.8 Hz, 1H), 4.46
To a stirred suspension of methyltriphenylphosphonium
bromide (169.3 mg, 0.474 mmol, 2.0 equiv.) in dry THF (10
mL) was added n-BuLi (0.3 mL, 0.474 mmol, 2.0 equiv., 1.6M
 = 173.5, 138.6,
solution in hexane) at 0 C. The mixture was stirred for 1 h
and a solution of the above aldehyde (80 mg) in THF (3 mL)
was added. It was warmed to room temperature and stirred
for 8 h and then quenched with saturated aq. NH4Cl solution.
The mixture was extracted with EtOAc (3 × 10 mL) and the
combined organic layers were washed with water, brine,
dried (Na2SO4) and concentrated. The residue was purified
by silica gel column chromatography with petroleum
25
[
]D
= +2.8 (c =
1
ether/EtOAc (9:1) as an eluent to afford olefin 3a (58 mg,
(d, J = 11.8 Hz, 1H), 4.28−4.10 (m, 3H), 4.06 (dd, J = 5.5, 1.2
Hz, 1H), 3.50 (qd, J = 9.5, 2.8 Hz, 1H), 2.46−2.35 (m, 1H),
1.84 (dd, J = 3.2, 1.3 Hz, 1H), 1.39−1.34 (m, 6H), 1.26 (t, J =
25
65%) as a colorless oil. [ D
]
= +2.3 (c = 2.5, CHCl3); IR
(CHCl3): max = 2933, 2861, 2328, 1612, 1462, 1375, 1256,
1188, 1134, 1027, 839, 776, 758, 666, 607, 551, 499 cm-1;
7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
 = 171.9,
1H NMR (400 MHz, CDCl3):
 = 7.37−7.25 (m, 5H), 6.00 (dd,
137.4, 128.4, 128.2, 127.9, 88.6, 81.0, 77.3, 75.5, 70.9, 60.8,
35.3, 22.0, 15.3, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
calcd C17H24O5Na 331.1516, found 331.1516.
J = 17.5, 10.8 Hz, 1H), 5.30 (dd, J = 17.5, 2.0 Hz, 1H), 5.11
(dd, J = 10.8, 2.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.56 (d,
J = 12.0 Hz,1H), 4.23−4.18 (m, 1H), 3.93 (t, J = 7.0 Hz, 1H),
3.55−3.52 (m, 1H), 2.00−1.94 (m, 1H), 1.81−1.74 (m, 1H),
1.26 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
(2R,3S,5S)-Ethyl 5-[(S)-1-(benzyloxy)ethyl]-3-(tert-
butyldimethylsilyloxy)-2-methyltetrahydrofuran-2-
carboxylate (14a):
3H), 0.04 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
139.7, 139.0, 128.2, 127.6, 127.4, 112.5, 84.0, 78.6, 78.1,
 =
To a stirred solution of 13a (0.27 g, 0.875 mmol) in dry
CH2Cl2 (10 mL) was added 2,6-lutidine (0.2 mL, 1.75 mmol,
2.0 eqiuv.) and TBDMSOTf (0.347 g, 1.314 mmol, 1.5 equiv.)
76.4, 71.2, 35.3, 25.7, 25.0, 18.0, 15.1,
−4.7, −5.03 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H36O3SiNa
399.2326, found 399.2323.
at 0 C. The reaction mixture was stirred at room temperature
for 12 h. It was then diluted with CH2Cl2 (10 mL) and H2O (10
mL). The solution was extracted with CH2Cl2 (3 × 20 mL) and
the combined organic phases were washed with water, brine,
dried (Na2SO4) and concentrated. The residue was purified
by silica gel column chromatography with petroleum
(5S,6S,E)-Ethyl 6-(benzyloxy)-5-hydroxy-2-methylhept-2-
enoate (11b):
The titled compound was prepared from 9b (100 mg, 0.485
mmol, 1.0 eqiuv.) following similar procedure as described
for 11a to give 11b (99.2 mg, 70%) as a colorless oil. [ D
25
]
ether/EtOAc (95:5) as eluent to afford 14a (0.266 g, 72%) as
= +1.6 (c = 2.5, CHCl3); IR (CHCl3):

max = 3472, 3064, 3031,
25
a colorless oil. [ D
]
= +1.8 (c = 1.45, CHCl3); IR (CHCl3):
2979, 2932, 2903, 1707, 1649, 1496, 1454, 1391, 1369,
1278, 1205, 1129, 1094, 1029, 916, 871, 699 cm-1; 1H NMR
max = 3065, 3030, 2955, 2931, 2858, 2899, 1738, 1496,
1471, 1463, 1455, 1372, 1252, 1193, 1127, 1066, 1028, 939,
914, 862, 837, 777, 698, 672, 597 cm-1; 1H NMR (400 MHz,
(400 MHz, CDCl3):
 = 7.37−7.27 (m, 5H), 6.85 (td, J = 7.2,
1.1 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 4.43 (d, J = 11.4 Hz,
1H), 4.18 (q, J = 7.1 Hz, 2H), 3.61 (q, J = 6.0 Hz, 1H), 3.45
(q, J = 6.0 Hz, 1H), 2.45−2.32 (m, 2H), 1.85 (s, 3H), 1.75 (br
s, 1H, OH), 1.28 (t, J = 7.1 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H)
CDCl3):
 = 7.34−7.27 (m, 5H), 4.67 (d, J = 12.0 Hz, 1H),
4.60−4.49 (m, 2H), 4.29−4.18 (m, 1H), 4.14 (t, J = 5.5 Hz,
1H), 4.11−4.01 (m, 1H), 3.56 (q, J = 5.6 Hz, 1H), 2.06−1.92
(m, 2H), 1.43 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.3
Hz, 3H), 0.85 (s, 9H), 0.03 (s, 6H) ppm; 13C{1H} NMR (100
ppm; 13C{1H} NMR (100 MHz, CDCl3):
 = 167.9, 138.1,
137.8, 129.4, 128.4, 127.7 (2C), 77.3, 74.0, 70.9, 60.4, 32.4,
15.5, 14.2, 12.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C17H24O4Na 315.1567, found 315.1569.
MHz, CDCl3):
81.4, 79.2, 76.0, 71.2, 60.6, 35.9, 25.6, 23.0, 17.8, 15.1, 14.2,
4.8,
5.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C23H38O5SiNa 445.2381, found 445.2381.
 = 172.9, 138.9, 128.3, 127.6, 127.4, 87.3,
−
−
(5S,6S,E)-Ethyl 6-(benzyloxy)-2-methyl-5-
(methylsulfonyloxy)hept-2-enoate (5b)
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10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
The titled compound was prepared from 11b (0.6 g, 2.052
CDCl3):

= 7.33−7.25 (m, 5H), 4.62 (d, J = 7.0 Hz, 2H), 4.41
mmol, 1.0 eqiuv.) following similar procedure as described
(td, J = 7.2, 3.2 Hz, 1H), 4.28−4.21 (m, 1H), 4.19−4.14 (m,
1H), 4.09−4.01 (m, 1H), 3.78−3.71 (m, 1H), 2.25−2.16 (m,
1H), 1.95−1.87 (m, 1H), 1.43 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H),
1.13 (d, J = 6.4 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s,
25
for 5a to give 5b (0.715 g, 94%) as a colorless oil. [ D
]
=
+0.6 (c = 3.45, CHCl3); IR (CHCl3):

max = 3030, 2982, 2938,
2902, 2875, 1709, 1455, 1355, 1281, 1255, 1218, 1175,
1
1135, 1099, 1028, 966, 923, 862, 802, 700, 528 cm-1; H
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
128.3, 128.25, 127.7, 127.5, 127.3, 87.5, 83.0, 79.2, 75.8,
 = 172.9, 139.1,
NMR (400 MHz, CDCl3):
 = 7.36−7.27 (m, 5H), 6.73 (t, J =
7.0 Hz, 1H), 4.69 (q, J = 5.8 Hz, 1H), 4.64 (d, J = 11.5 Hz,
1H), 4.47 (d, J = 11.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.77
(q, J = 6.1 Hz, 1H), 2.93 (s, 3H), 2.77−2.62 (m, 1H),
2.61−2.2.54 (m, 1H), 1.86 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H),
1.25 (d, J = 6.3 Hz, 3H) ppm; 13C{1H} NMR (100 MHz,
71.9, 60.7, 34.3, 25.6, 23.2, 17.9, 16.7, 14.2, −4.8, −5.1;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H38O5SiNa
445.2381, found 445.2383.
[(2R,3R,5R)-5-[(S)-1-(Benzyloxy)ethyl]-2-methyl-2-
vinyltetrahydrofuran-3-yloxy](tert-butyl)dimethylsilane 3c:
CDCl3):  = 167.5, 137.7, 134.8, 131.2, 128.4, 127.84, 127.8,
83.1, 74.8, 71.5, 60.7, 38.4, 29.7, 15.0, 14.2, 12.7 ppm;
HRMS (ESI-TOF) ) m/z: [M + Na]+ calcd for C18H26O6SNa
393.1342, found 393.1338.
The titled compound was prepared from 14b (100 mg, 0.237
mmol, 1.0 eqiuv.) following similar procedure as described
25
for 3a to give 3c (54.4 mg, 61%) as a colorless oil. [ D
]
=
−1.7 (c = 2.2, CHCl3); IR (CHCl3): max = 3064, 3028, 2955,
2929, 2887, 2858, 1734, 1710, 1471, 1463, 1454, 1404,
1369, 1258, 1216, 1121, 1071, 1036, 997, 920, 902, 871,
837, 777, 753, 734, 697, 668, 542 cm-1; 1H NMR (400 MHz,
(2S,3R,5R)-Ethyl 5-[(S)-1-(benzyloxy)ethyl]-3-hydroxy-2-
methyltetrahydrofuran-2-carboxylate (13c) and (2R,3S,5R)-
Ethyl 5-[(S)-1-(benzyloxy)ethyl]-3-hydroxy-2-
methyltetrahydrofuran-2-carboxylate (13d):
CDCl3):
 = 7.36−7.27 (m, 5H), 6.01 (dd, J = 17.5, 10.8 Hz,
The titled compounds were prepared from 5b (0.5 g, 1.35
mmol, 1.0 eqiuv.) following similar procedure as described
for 13a and 13b to give 13c (112.4 mg, 27%) and 13d (229
1H), 5.30 (dd, J = 17.5, 2.0 Hz, 1H), 5.10 (dd, J = 10.8, 2.0
Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H),
4.08−4.03 (m, 1H), 3.96 (t, J = 7.1 Hz, 1H), 3.64−3.58 (m,
1H), 2.13−2.07 (m, 1H), 1.79−1.72 (m, 1H), 1.26 (s, 3H), 1.14
(d, J = 6.3 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H)
mg, 55%) as colorless oils.
Characteristic data for compound 13c:
25
[
]D
= +1.4 (c =
2.5, CHCl3); IR (CHCl3): max = 3454, 3061, 2978, 2931,
ppm; 13C{1H} NMR (100 MHz, CDCl3):
128.2, 127.5, 127.3, 112.5, 83.8, 79.5, 78.5, 76.7, 71.7, 34.2,
 = 139.7, 139.2,
1736, 1485, 1465, 1385, 1383, 1305, 1284, 1112, 1055,
1
1023, 970, 917, 872, 698, 667 cm-1; H NMR (400 MHz,
25.7, 24.9, 18.0, 16.6, −4.7, −5.0 ppm; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C22H36O3SiNa 399.2326, found
CDCl3):

= 7.33−7.19 (m, 5H), 4.61 (dd, J = 15.0, 11.8 Hz,
2H), 4.36−4.31 (m, 1H), 4.29−4.19 (m, 3H), 3.79−3.74 (m,
1H), 2.33−2.26 (m, 1H), 1.96−1.90 (m, 1H), 1.45 (s, 3H), 1.30
(t, J = 7.1 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR
399.2325.
(2R,3S,5R)-Ethyl 5-[(S)-1-(benzyloxy)ethyl]-3-(tert-
butyldimethylsilyloxy)-2-methyltetrahydrofuran-2-
carboxylate 3b:
(100 MHz, CDCl3):
 = 173.7, 138.9, 128.2, 127.5, 127.4,
87.2, 82.8, 78.3, 75.4, 71.9, 61.3, 33.3, 23.5, 16.6, 14.2 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H24O5Na
The titled compound was prepared from 13d (80 mg, 0.259
331.1516, found 331.1515.
Characteristic data for compound 13d:
mmol, 1.0 eqiuv.) following similar procedure as described
25
25
[
]D
= −1.9 (c =
for 14a to give 3b (79 mg, 72%) as a colorless oil. [ D
]
=
2.2, CHCl3); IR (CHCl3): max = 3455, 3068, 2983, 2938,
−1.7 (c = 2.2, CHCl3); IR (CHCl3): max = 3030, 2956, 2931,
2886, 2858, 1737, 1496, 1472, 1463, 1454, 1370, 1254,
1193, 1072, 1028, 964, 914, 838, 777, 698, 671, 612 cm-1;
1735, 1491, 1460, 1393, 1375, 1303, 1273, 1115, 1063,
1
1033, 961, 698, 667 cm-1; H NMR (400 MHz, CDCl3):
 =
1H NMR (400 MHz, CDCl3):
 = 7.36−7.24 (m, 5H), 4.66 (d,
7.32−7.16 (m, 5H), 4.69 (dd, J = 17.2, 11.3 Hz, 2H),
4.36−4.29 (m, 1H), 4.26−4.14 (m, 2H), 4.13−4.06 (m, 1H),
4.04−3.97 (m, 1H), 3.85 (qd, J = 6.5, 2.2 Hz, 1H), 2.38−2.26
(m, 1H), 1.95 (dd, J = 14.2, 2.8 Hz, 1H), 1.29 (s, 3H), 1.21 (t,
J = 7.1 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H) ppm; 13C{1H} NMR
J = 11.7 Hz, 1H), 4.53 (d, J = 11.7 Hz, 1H), 4.28−4.13 (m,
2H), 4.09−3.99 (m, 1H), 3.95 (q, J = 7.0 Hz, 1H), 3.85−3.76
(m, 1H), 2.31 (q, J = 6.5 Hz, 1H), 2.16−2.08 (m, 1H), 1.42 (s,
3H), 1.32 (d, J = 6.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.86
(s, 9H), 0.06 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3):
172.3, 138.9, 128.2, 127.7, 127.4, 87.2, 81.5, 79.8, 77.3,

=
(100 MHz, CDCl3):
 = 171.6, 137.4, 128.4, 128.1, 127.8,
89.1, 81.3, 76.5, 75.9, 72.4, 60.9, 32.4, 21.8, 16.5, 14.2 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H24O5Na
331.1516, found 331.1516.
70.9, 60.6, 37.0, 25.6, 22.7, 17.8, 16.9, 14.1,
−4.7, −5.2;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C23H38O5SiNa
445.2381, found 445.2383.
(2S,3R,5R)-Ethyl 5-[(S)-1-(Benzyloxy)ethyl]-3-(tert-
butyldimethylsilyloxy)-2-methyltetrahydrofuran-2-
carboxylate (14b):
Acknowledgements
The titled compound was prepared from 13c (0.160 g, 0.52
We thank DST-SERB New Delhi (EMR/2017/000499) for financial
support. V.B. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for research fellowship.
mmol, 1.0 eqiuv.) following similar procedure as described
25
for 14a to give 14b (0.154 g, 70%) as a colorless oil. [ D =
]
−1.7 (c = 2.2, CHCl3); IR (CHCl3): max = 3058, 3032, 2968,
2928, 2874, 1743, 1486, 1466, 1373, 1343, 1280, 1090,
1
1073, 1030, 997, 869, 698, 667 cm-1; H NMR (400 MHz,
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10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
Keywords: Allylation • chiral pool • germacranolide • asymmetric
dihydroxylation • cyclization • natural products
ORCID
Rodney A. Fernandes: 0000-0001-8888-0927
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Org. Biomol. Chem. 2017, 15, 7102
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[11] For similar inversion of secondary alcohol centre on a THF ring,
−
11370; b) S. J. Connon, S. Blechert,
−
1923; c) A. H. Hoveyda, P.
−
−
,
−
−
213; b) C. H. Kolb, M.
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,
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see: a) Y. Mori, T. Sawada, H. Furukawa, Tetrahedron Lett. 1999
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−
−
−
−
.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000513
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
A common strategy for the synthesis
of substituted tetrahydrofuran moieties
of caruifolin A and EBC-342 has been
developed based on asymmetric
dihydroxylation and intramolecular
SN2-cyclization
Tetrahydrofuran
Rodney A. Fernandes* and Venkati
Bethi
Page No. – Page No.
A Concise Synthesis of the Key
Tetrahydrofuran Moieties of
Caruifolin A and EBC-342
*Diastereoselective synthesis
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