General Asymmetric Synthetic Strategy for the α-Alkylated 2,5,6-Trisubstituted Pyran of Indanomycin and Related Natural Products

Article abstract of DOI:10.1002/ejoc.202000156

A general synthetic strategy for convergent asymmetric synthesis of C1–C10 fragment of tetraene-containing natural product indanomycin was achieved starting from 2-(benzyloxy)acetaldehyde which in turn was obtained from very inexpensive material cis-1,4-butene-diol. Key steps include Evans' aldol reaction, HWE olefination, iodine-catalyzed tandem isomerization followed by C–O and C–C bond formation similar to our earlier report in constructing the trans-2,6-disubstituted dihydropyran ring and Evans' asymmetric alkylation.

Full text of DOI:10.1002/ejoc.202000156

A Journal of
Accepted Article
Title: General Asymmetric Synthetic Strategy for α-Alkylated 2,5,6-
Trisubstituted Pyran of Indanomycin and Related Natural
Products
Authors: Ravishetty Padma, Beduru Srinivas, Jhillu S. Yadav, and
Debendra Kumar Mohapatra
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000156
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000156
Supported by

10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
General Asymmetric Synthetic Strategy for α-Alkylated 2,5,6-
Trisubstituted Pyran of Indanomycin and Related Natural
Products
Ravishetty Padma,[a] Beduru Srinivas,[a] Jhillu S. Yadav,[a,b] and Debendra K. Mohapatra*[a]
Abstract: A general synthetic strategy for convergent asymmetric
synthesis of C1−C10 fragment of tetraene-containing natural product
indanomycin was achieved starting from 2-(benzyloxy)acetaldehyde
which in turn was obtained from very inexpensive material cis-1,4-
butene-diol. Key steps include Evans' aldol reaction, HWE
olefination, iodine-catalyzed tandem isomerization followed by C−O
and C−C bond formation similar to our earlier report in constructing
the trans-2,6-disubstituted dihydropyran ring and Evans' asymmetric
alkylation.
The pyrrolocarbonyl functionality is found in only few other
ionophore
O
6
11
13
15
19
9
3
21
O
7
HN
26
COOH
27
25
Tetraene Biosynthetic Intermediate of Indanomycin (1)
H
N
O
H
O
Introduction
COOH
H
Et
OH
Indanomycin (2)
For decades polyoxygenated ionophore-containing natural
products have been of significant interest for not only their
architectural complexity but also for interesting biological
properties (Figure 1). These polyketides are imperative natural
products synthesized by diverse organisms in retort to
environmental stress and hence been studied for their antibiotics,
immunosuppressant and antitubercular properties.[1] The
commercial ionophore compounds possessing antifungal and
antibiotic properties affect the ion-exchange processes of
monovalent cations such as Li+, Na+, and K+, and divalent
cations such as Ca2+ and Rb2+ across all cell membranes by
making lipophilic complexes with the cations.[2] In addition, some
of the ionophores displayed anticancer activity further attracting
the attention.[3,4] In 1978, a new polyether ionophore antibiotic
indanomycin (2) was isolated from the fermentation broth of
Streptomyces antibioticus by chemists at Hoffmann-La Roche,
Nutley, NJ, that exhibited potent antibiotic activity against gram-
positive bacteria.[5] Indanomycin has the unique ability to
transport divalent cations, such as Ca2+ and Rb2+ which usually
is displayed by carboxylic acid ionphores that include lasolocid,
calcimycin, ionomycin and lysocellin. Indanomycin also shows
antitumor and antihypertensive activities, and is useful as a
growth promotant for ruminants increasing the feed utilization of
these animals.[6] The relative and absolute configuration was
determined by X-ray crystallographic analysis of a crystal of the
derived (R)-(+)-1-(4-bromophenyl)ethane salt. In 2011, Kelly et
al., isolated a carboxylic pyrrole ether antibiotic ionophore
tetraene containing intermediate (1) of the indanomycin from the
fermentation culture broth of Streptomyces antibioticus DOH1.[7]
O
OH OH OH
HO
O
Zincophorin (3)
OH
O
Et
OH
O
O
O
Et
OH
OH
Et
HOOC
Ferensimycin B (4)
OH
Et
OH
O
O
HOOC
HOOC
O
O
O
O
Et
OH
Narasin (5)
OH
Et
OH
O
O
O
O
O
O
Et
OH
Salinomycin (6)
Figure 1. Representatives structures of natural products containing α-alkylated
3,6,7-trisubstituted pyrans.
of the calcimycin type molecules which also show particular
specificity and transport ability for divalent cations. Ionophores
(1) and (2) display appreciable antibacterial activity against
Escherichia coli (E. coli), a Bacillus sp., methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus faecium (VREF). It enjoys an array of rather rare
and challenging structural features, including a substituted trans-
tetrahydropyran ring system, a linear tetraene moiety, and a
ketopyrrole group. The complete molecular structure, including
absolute stereochemistry has been determined through
spectroscopic techniques by Kelly's group.[7] The presence of a
tetraene system in the biosynthetic intermediate of indanomycin
facilitates a convergent synthesis of 1 via coupling of left-hand
portion containing the four asymmetric centers of the
tetrahydropyrenyl-2-acetic acid moiety and N-protected right-
[a]
[b]
Department of Organic Synthesis and Process Chemistry, CSIR-
Indian Institute of Chemical Technology, Hyderabad 500 007, India.
E-mail: mohaptra@iict.res.in
Homepage: www.iictindia.org
School of Science, Indrashil University, Kadi, Gujarat, India.
Supporting information for this article is given via a link at the end of
the document (1H, 13C, 2D NMR and HPLC chromatogram)
hand fragment bearing one asymmetric center by
a
stereoselective Witting olefination followed by deprotection of
the pyrrole nitrogen.
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10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
Since several polyketide antibiotics contain the left-hand
substituted trans-tetrahydropyran ring system as a common
scaffold, herein, we report a successful general synthetic
strategy for the stereoselective synthesis of the C1-C10
fragment of linear tetraene containing biosynthetic intermediate
of indanomycin (1).
aldol adduct as its TBS ether 16 was obtained using tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) in the
presence of 2,6-lutidine in CH2Cl2 with 93 % yield.[10] Reductive
cleavage[11] of the chiral auxiliary with DIBAL-H at –78 °C
followed by two carbon homologation using Horner-Wadsworth-
Emmons olefination[12] with triethyl phosphonoacetate in
presence of NaH furnished the α,β-unsaturated ester 17 in 90 %
isolated yield (E:Z > 95:05) over two steps(Scheme 2). The ester
functionality present in 17 was reduced by treating with DIBAL-H
in CH2Cl2 at –78 °C and the acid-mediated deprotection of TBS
group from the corresponding allylic alcohol produced the
desired diol in 90 % yield.[13]
As per the retrosynthetic analysis (Scheme 1), compound 1 was
disconnected at the C10−C11 bond to reveal two key fragments
as left-hand fragment 7 (C1−C10) and right-hand fragment 8
(C11−C25). It was anticipated that the Wittig reaction could be
employed to stitch both these fragments with ease as depicted
in Scheme 1. We initially focused on the synthesis of the left-
hand fragment (C1−C10) 7 which could be synthesized from 9.
General protocol of alkylation would be achieved through Evans
asymmetric alkylation protocol starting from compound 9.
Compound 10 could be prepared from δ-hydroxy-α,β-
unsaturated aldehyde by utilizing iodine-catalyzed tandem
isomerization followed by C−O and C−C bond forming reactions
developed by our group. Utilizing a substrate controlled Evans
syn-aldol reaction between Evans oxazolidinone with aldehyde
11 followed by few standard synthetic procedures could provide
δ-hydroxy-α,β-unsaturated aldehyde.
O
O
OH
O
Ref. 9a
OBn
N
BnO
O
H
11
14
Ph
O
O
OTBS
TBSOTf
2,6-lutidine
i) DIBAL-H, CH2Cl2
-78 oC, 30 min
OBn
N
O
CH2Cl2, 0 oC
30 min, 93%
ii) (EtO)2P(O)CH2CO2Et
NaH, THF, 0 oC to rt,
5 h, 90%
16
Ph
i) DIBAL-H
CH2Cl2, -78 oC
Evans syn aldol reaction
Asymmetric alkylation
O
OTBS
OBn
OH
O
Wittig reaction
30 min, 95%
O
EtO
H
ii) CSA, MeOH
0 oC,1 h, 90%
O
OBn
17
18
O
HN
HO
O
Iodine-Catalyzed
Isomerization/C-O/C-C
iii) TEMPO, BAIB
CH2Cl2,0 o
C
Tetraene Biosynthetic Intermediate of Indanomycin (1)
O
3 h, 94%
N
O
SiMe
3, I2, THF
OBn
O
O
10
0 oC to rt,1 h, 90%
(R)-15
+
O
Ph3P
Br
OPMB
OPMB
3
Ph
O
O
7
8
Scheme 2. Synthesis of pyran fragment 10.
Ph
The primary alcohol was oxidized in the presence of BAIB and
OBn
O
HO
catalytic amount of TEMPO to obtain the required (E)-α,β-
3
N
%
yield.[14] The tandem
O
unsaturated aldehyde 18 in 94
O
12
9
isomerization and cyclization protocol was performed by
subjecting 18 to our optimized reaction conditions
(allyltrimethylsilane and iodine), to afford stereoselective trans-
dihydropyran 10 as the sole product in 90 % yield.[15]
Next, the synthesis of the acid fragment 20 was initiated as
depicted in Scheme 3. The selective one-pot oxidative cleavage
of the terminal double bond in 10 was performed by using OsO4,
2,6-lutidine and NaIO4 following Jin's protocol[16] to furnish the
corresponding aldehyde 19 in 80 % yield, which on further
oxidation under Pinnick conditions[17] provided the corresponding
acid 20 in 93 % yield.
O
O
O
N
OPMB
O
3
OBn
O
10
13
Ph
O
BnO
11
Scheme 1. Retrosynthetic analysis
Following the Evans’ protocol, chiral amide 9 was prepared
starting with the acid 20 and by amide formation with chiral
oxazolidinone 21 following a mixed anhydride protocol using
pivaloyl chloride.[18] Now, the stage is ready for the crucial
alkylation at C-2 position without epimerizing at the C-3
stereocenter. Several conditions were investigated, including
LDA and LiHMDS. However, these attempts were met with
limited success and the major product obtained was
Results and Discussion
The synthesis began with an asymmetric aldol reaction of the
aldehyde 11[8] with boron enolate derived from oxazolidinone
(R)-15 to give aldol adduct 14 in 96 % yield with a 96:4
diastereomeric ratio (as analyzed by HPLC).[9] The protection of
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10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
dihydropyran ring opening product. It was ultimately discovered
α,β-unsaturated aldehyde 7 in 64 % yield[28] with a 95:5
diastereomeric ratio (crude NMR spectra showed 6:1 ratio). The
spectral (1H and 13C NMR) and analytical data for compound 7
were in good agreement with the reported data.[26c]
that the deprotonation of compound
9
with sodium
bis(trimethylsilylamide) followed by highly diastereoselective
alkylation of the resulting chiral imide enolate with iodomethane
smoothly promoted methylation 22 in 80 % yield with a 97:3
diastereomeric ratio (as analyzed by HPLC) and without C-3
epimerization.[19] Reductive removal of the oxazolidinone
auxiliary with lithium borohydride produced the corresponding
alcohol 23 in 88 % yield.[20] At this stage, the 3,7-trans
orientation at the pyran ring of compound 23 was confirmed
through 2D NOE experiments. The hydroxyl group present in
compound 23 was protected as its TBDPS ether with TBDPSCl
and imidazole in CH2Cl2 to get TBDPS ether compound in 95 %
yield.[21] One-pot hydrogenation of the double bond and
deprotection of the benzyl group was achieved under hydrogen
atmosphere in the presence of a catalytic amount of palladium
on activated carbon to furnish the tetrahydropyran derivative 24
in 93 % yield.[22] The resulting alcohol 24 was oxidized with
Dess−Martin periodinane[23] to obtain the corresponding
aldehyde in 90 % yield. Aldehyde was then
i) TBDPSCl, Imidazole
CH2Cl2, 0 oC
2 h, 95%
OBn
OH
O
O
ii) Pd/C-H2, EtOAc
rt, 12 h, 93%
OH
OTBDPS
23
24
i) DMP, NaHCO3
CH2Cl2, 0 oC
2 h, 90%
TBAF
THF
OH
OH
O
O
0 oC, 1 h
92%
ii) EtMgBr
Toluene
-78 oC, 1 h
86%
OH
OTBDPS
26
25
i) Jones reagent
Acetone
-40oC to -20 oC
MgBr, THF
O
O
-78 oC, 1 h
95%
OsO4, NaIO4
2,6-lutidine
ii) CH2N2
Diethyl ether
0 oC, 3 h
84%
O
O
27
OBn
OBn
O
O
O
dioxane:H2O
(3:1), rt, 4 h
80%
10
19
PCC
CH2Cl2
OH
NaClO2, NaH2PO4
2-methyl-2-butene
21, n-BuLi
Piv-Cl, Et3N
O
O
O
O
40 oC, 5 h
64%
O
O
OBn
O
O
THF, -78 oC
2 h, 90%
28
t-BuOH:H2O (1:1) HO
0 oC, 2 h, 93%
O
7
20
Scheme 4. Synthesis of α,β-unsaturated aldehyde fragment 7.
NaHMDS
MeI
Ph
Ph
O
O
Conclusions
THF, -78 oC
2 h, 80%
N
OBn
N
OBn
O
O
9
22
O
O
O
In summary, we have developed a general synthetic strategy
for C1−C10 fragment of recently isolated tetraene containing
intermediate of the indanomycin starting from cis-1,4-butene-diol.
The key steps in the synthesis involved Evans aldol reaction,
iodine-catalyzed tandem isomerization followed by C−O and
C−C bond forming reaction developed by our group, Evans
asymmetric alkylation reaction and rearrangement of tertiary
alcohol to α,β-unsaturated aldehyde. Further work towards the
total synthesis of tetraene containing product of the indanomycin
and transformation to indanomycin is currently in progress and
will be reported in due course.
O
Ph
LiBH4, MeOH, THF
0 oC, 3 h, 88%
NH
O
OBn
O
O
21
HO
23
Scheme 3. Synthesis of fragment 23.
subjected to the Grignard reaction with ethyl magnesium
bromide to furnish alcohol 25 as a diastereomeric mixture in
86
%
yield.[24] Without further purification, the mixture of
secondary alcohols 25 was treated with TBAF in THF to afford
26 in 92 % yield.[25] Diol compound 26 was subjected to Jones
oxidation in acetone followed by treatment of the resulting acid
with CH2N2 in diethyl ether afforded methyl ester 27 in 84 %
yield over two steps (Scheme 4). The spectral (1H and 13C NMR)
and analytical data for compound 27 were in good agreement
with the data reported.[26] Addition of vinyl magnesium bromide
(1.5 equiv, THF, −78 °C) to the ketone 27 to afford alcohol 28
Experimental Section
General Information: Air and/or moisture sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon or
nitrogen in an oven or flame-dried glassware. All starting materials and
reagents were obtained from commercial producers and are used without
further purification. All anhydrous solvents were distilled prior to use: THF
from Na and benzophenone; CH2Cl2, DMF, hexane from CaH2; MeOH
from Mg cake. Column chromatography was carried out by using silica
gel (60–120 mesh and 100-200 mesh). Reactions were monitored by
TLC on silica gel GF254 (0.25 mm). Specific optical rotations [α]D were
(stereochemistry not assigned) in 95
%
yield.[27]
Finally,
rearrangement of the tertiary alcohol was carried out using
pyridinium chlorochromate (PCC) in dichloromethane to furnish
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10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
given in 10−1 degdm−1cm3g−1
.
Infrared spectra were recorded in
under reduced pressure to obtain crude product, which upon purification
by silica gel column chromatography (ethyl acetate/hexane = 1:19) to
furnish the desired TBS ether 16 (18.10 g, 93 %) as a yellowish oil. Rf
0.63 (ethyl acetate/hexane = 1:9); [α]D20 = −36.0 (c = 1.0, CHCl3); IR
(CHCl3) νmax 1777, 1696, 1461, 1382, 1214, 1107, 743 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.33–7.21 (m, 8H), 7.16–7.12 (m, 2H), 4.45 (dd, J =
30.7, 11.5 Hz, 2H), 4.27 (ddt, J = 9.6, 8.0, 3.0 Hz, 1H), 4.20 (td, J = 7.1,
5.2 Hz, 1H), 4.02 (p, J = 6.9 Hz, 1H), 3.91 (dd, J = 8.9, 2.7 Hz, 1H), 3.59
(dd, J = 9.6, 5.3 Hz, 1H), 3.53 (obscured t, J = 8.3 Hz, 1H), 3.47 (dd, J =
9.6, 7.0 Hz, 1H), 3.18 (dd, J = 13.4, 3.3 Hz, 1H), 2.67 (dd, J = 13.4, 9.6
Hz, 1H), 1.24 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.09 (d, J = 5.2 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 175.4, 153.2, 138.2, 135.4, 129.3,
128.7, 128.2, 127.5, 127.1, 74.3, 73.2, 71.9, 65.6, 55.2, 42.0, 37.8, 25.7,
18.0, 14.1, −4.4, −4.9 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C28H40NO5Si: 498.2676, Found: 498.2688.
CHCl3/neat (as mentioned) and reported in wave number (cm−1). HRMS
spectra were obtained using a TOF spectrometer. 1H and 13C NMR
chemical shifts were reported in ppm downfield from tetramethylsilane
and coupling constants (J) were reported in hertz (Hz). The following
abbreviations were used to designate signal multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad.
2-(Benzyloxy) acetaldehyde (11): To a stirred solution of (Z)-1,4-
bis(benzyloxy)but-2-ene (15.0 g, 56.0 mmol) in CH2Cl2/MeOH (3:1) at
−78 °C, was bubbled with a stream of ozone until the color turned blue
(~4 h). The excess ozone was removed by
a nitrogen stream
(disappearance of the blue color) and then dimethyl sulfide (16.5 mL,
223.8 mmol) was added at −78 °C. The reaction mixture was warmed to
ambient temperature and stirred for additional 4 h. The solvents were
removed under reduced pressure and the crude product was purified by
silica gel column chromatography (ethyl acetate/hexane = 3:17) to furnish
aldehyde 11 (16.6 g, 99 %) as a colorless oil. that was immediately used
after purification. Rf 0.52 (ethyl acetate/hexane = 3:7); IR (CHCl3) νmax
3026, 2858, 1736, 1452, 1376, 1120, 745, 699 cm−1; H NMR (400 MHz,
CDCl3) δ 9.73 (t, J = 0.8 Hz, 1H), 7.39–7.31 (m, 5H), 4.63 (s, 2H), 4.10 (d,
J = 0.8 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ 200.4, 136.9, 128.6,
128.2, 128.1, 75.3, 73.6 ppm.
(2R,3R)-4-(Benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2-methyl
butanal (16a): To a stirred solution of silyl ether 16 (16.0 g, 32.2 mmol)
in CH2Cl2 (150 mL) at −78 °C, was added DIBAL-H (1.4 M in hexane,
32.2 mL, 45.0 mmol) dropwise until the yellow color disappeared. The
reaction was immediately quenched by the addition of a saturated
aqueous sodium potassium tartrate solution and then warmed to room
temperature with vigorous stirring. After dispersion of the emulsion, the
layers were separated and the aqueous layer was extracted with CH2Cl2
(3 × 120 mL). The combined organic extracts were dried with Na2SO4
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (ethyl acetate/hexane =
1:19) to afford the aldehyde 16a (9.3 g, 95 %) as a colorless liquid. Rf
0.48 (ethyl acetate/hexane = 1:9); [α]D20 = −12.5 (c = 1.0, CHCl3); IR
(CHCl3) νmax 2939, 2861, 1725, 1253, 1100, 1037, 837, 777, 741 cm−1; 1H
NMR (400 MHz, CDCl3) δ 9.74 (d, J = 0.9 Hz, 1H), 7.37–7.27 (m, 5H),
4.56–4.46 (m, 2H), 4.31 (ddd, J = 6.4, 5.3, 3.9 Hz, 1H), 3.48 (dd, J = 9.5,
5.2 Hz, 1H), 3.42 (dd, J = 9.5, 6.4 Hz, 1H), 2.60 (qdd, J = 6.9, 3.9, 0.8 Hz,
1H), 1.06 (d, J = 7.1 Hz, 3H), 0.85 (s, 9H), 0.04 (d, J = 3.0 Hz, 6H) ppm;
13C NMR (100 MHz, CDCl3) δ 204.1, 137.8, 128.3, 127.6, 127.5, 73.3,
71.7, 70.4, 49.9, 25.6, 17.9, 7.5, −4.3, −5.1 ppm; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C18H30O3NaSi : 345.1862, Found: 345.1866.
1
(R)-4-Benzyl-3-((2R,3R)-4-(benzyloxy)-3-hydroxy-2-methylbutanoyl)
oxazolidin-2-one (14): To a cooled (0 °C) solution of the oxazolidinone
15 (15.0 g, 64.3 mmol) in CH2Cl2 (120 mL) added a solution of Bu2BOTf
in CH2Cl2 (1 M, 77.2 mL), followed by addition of Et3N (11.4 mL, 83.6
mmol). After stirring at 0 °C for 1 h, the solution was cooled to −78 °C,
The above obtained aldehyde 11 (11.6 g, 77.2 mmol) in CH2Cl2 (100 ml)
was added. Stirring was continued for 30 min at −78 °C and then stirred
for 1 h at 0 °C. Upon completion (monitored by TLC), the reaction was
quenched with a mixture of pH 7.0 phosphate buffer (15 ml), followed by
addition of a mixture of 30 % aqueous H2O2 (15 ml) and CH3OH (30 ml).
After stirring at 0 °C for 1 h, organic solvent was removed under reduced
pressure and the mixture was diluted with CH2Cl2 and water. Organic
layer was separated and the aqueous layer was extracted with CH2Cl2 (3
× 100 mL). The combined organic extracts were washed with brine, dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:9) to afford the aldol adduct 14 (28.4 g, 96 %) as a
light yellow liquid with a 95:5 diastereomeric ratio. Rf 0.65 (ethyl
Ethyl-(4S,5R,E)-6-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-4-
methylhex-2-enoate (17): Triethyl phosphonoacetate (16.6 mL, 83.8
mmol) was added dropwise at 0 °C to a slurry of NaH (1.7 g, 41.9 mmol)
in THF (60 mL). After 30 min at 0 °C, the mixture was stirred at room
temperature for an additional 30 min and cooled again to 0 °C, after
which the aldehyde 16a (9.0 g, 27.9 mmol) in THF (70 mL) was added.
The reaction mixture was stirred at 0 °C for 4 h and then quenched with a
saturated aqueous solution of NH4Cl (60 mL), diluted with water (30 mL)
and extracted with ethyl acetate (2 × 80 mL). The combined organic
layers were washed with brine (60 mL), dried over anhydrous Na2SO4
and concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:39) to afford α,β-unsaturated
20
acetate/hexane = 3:7); [α]D = –56.2 (c = 1.0, CHCl3); IR (CHCl3) νmax
3503, 3022, 2920, 1777, 1695, 1453,1381, 1210, 1105, 746, 702 cm−1
;
1H NMR (500 MHz, CDCl3) δ 7.36–7.26 (m, 8H), 7.20–7.17 (m, 2H), 4.59
(ddt, J = 9.6, 7.8, 3.1 Hz, 1H), 4.54 (s, 2H), 4.17 (dd, J = 10.8, 5.4 Hz,
1H), 4.13 (dd, J = 9.0, 2.7 Hz, 1H ), 4.08 (obscured t, 1H), 3.94 (qd, J =
7.0, 5.0 Hz, 1H), 3.57–3.52 (m, 2H), 3.23 (dd, J = 13.4, 3.3 Hz, 1H), 2.76
(dd, J = 13.4, 9.5 Hz, 1H), 1.29 (d, J = 7.1 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 175.9, 152.8, 137.8, 134.9, 129.2, 128.7, 128.2, 128.1,
127.6, 127.1, 73.1, 71.7, 70.6, 65.9, 54.9, 40.1, 37.5, 12.1 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C22H25NO5Na: 406.1630, Found:
406.1638.
ester 17 (10.4 g, 95 %) as
a
colorless liquid. Rf 0.48 (ethyl
acetate/hexane = 1:19); [α]D = −15.8 (c = 1.0, CHCl3); IR (CHCl3) νmax
3023, 2941, 2861, 1711, 1216, 744, 669 cm−1 1H NMR (400 MHz,
20
;
CDCl3) δ 7.36–7.27 (m, 5H), 6.98 (dd, J = 15.7, 7.7 Hz, 1H), 5.81 (dd, J =
15.7, 1.3 Hz, 1H), 4.49 (dd, J = 16.3, 11.9 Hz, 2H), 4.18 (qd, J = 14.3,
7.1, 1.7 Hz , 2H), 3.82 (dd, J = 10.1, 5.6 Hz, 1H), 3.39 (ddd, J = 22.4, 9.7,
5.7 Hz, 2H), 2.60 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.8 Hz,
3H), 0.87 (s, 9H), 0.03 (d, J = 1.4 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) δ 166.6, 151.8, 138.1, 128.3, 127.6, 127.5, 120.8, 73.8, 73.3,
72.5, 60.1, 39.8, 25.8, 18.1, 14.2, 13.1, −4.3, −4.9 ppm; HRMS (ESI-
(R)-4-Benzyl-3-((2R,3R)-4-(benzyloxy)-3-((tert-butyldimethylsilyl)
oxy)-methylbutanoyl)- oxazolidin-2-one (16): To a stirred solution of
alcohol 14 (15.0 g, 39.2 mmol) in CH2Cl2 (120 mL) under nitrogen
atmosphere was added 2,6-lutidine (9.1 mL, 78.3 mmol) followed by
TBSOTf (12.3 mL, 46.9 mmol) dropwise at 0 °C and the mixture was
allowed to stir for 30 min. After completion of the reaction (monitored by
TLC), it was quenched with water (100 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 100 mL) and washed with 1 N HCl (2 × 75 mL)
to remove excess 2,6-lutidine. The organic layer was washed with brine
(2 × 90 mL), dried over anhydrous Na2SO4 and evaporated to dryness
TOF) m/z: [M
415.2282.
+
Na]+ calcd for C22H36O4NaSi: 415.2281, Found:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
(4S,5R,E)-6-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-4-methylhex
-2-en-1-ol (17a): To a stirred solution of α,β-unsaturated ester 17 (8.5 g,
21.6 mmol) in CH2Cl2 (90 mL) was added DIBAL-H (1.4 M hexane, 38.7
mL, 54.2 mmol) at −78 °C, the resulting mixture was stirred at −78 °C for
30 min. Upon completion (monitored by TLC), the reaction was quenched
by the slow addition of CH3OH (10 mL) followed by a saturated solution
of Rochelle salt (120 mL). The reaction mixture was warmed to room
temperature and then stirred vigorously until the resulting white slurry
was completely dissolved. The organic layer was separated and aqueous
layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic
extracts were washed with water and brine (75 mL), dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (ethyl acetate/hexane =
(2R,3S,6S)-6-Allyl-2-((benzyloxy)methyl)-3-methyl-3,6-dihydro-2H-
pyran (10): Iodine (0.48 g, 1.9 mmol) was added at 0 °C to a stirred
solution of δ-hydroxy α,β-unsaturated aldehyde 18 (3.0 g, 12.8 mmol)
and allyltrimethylsilane (3.06 mL, 19.2 mmol) in THF (30 mL), the
resulting mixture was allowed to warm to room temperature and stirred
for 45 min. After completion of the reaction (monitored by TLC), it was
quenched by the addition of a saturated aqueous solution of Na2S2O3 (35
mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic
extracts were washed with water and brine (30 mL), dried with anhydrous
Na2SO4, concentrated under reduced pressure to give a pale yellow oil,
which was purified by column chromatography on silica gel (ethyl
acetate/hexane = 1:39) to give the cyclized product 10 (2.97 g, 90 %) as
20
a pale yellow liquid. Rf 0.56 (ethyl acetate/hexane = 1:19); [α]D = +42.4
1:9) to furnish the allylic alcohol 17a (7.2 g, 95 %) as a colorless liquid. Rf
(c = 0.5, CHCl3); IR (CHCl3) νmax 2922, 2857, 1727, 1456, 1077, 750
20
0.50 (ethyl acetate/hexane = 1:4); [α]D
= −6.1 (c = 1.0, CHCl3); IR
cm−1 1H NMR (400 MHz, CDCl3) δ 7.43–7.26 (m, 5H), 5.96–5.78 (m,
;
(CHCl3) νmax 3416, 2931, 2859, 1460, 1252, 1092, 832, 769, 743 cm−1
;
2H), 5.66 (ddd, J = 10.2, 2.8, 1.1 Hz, 1H), 5.15–5.04 (m, 2H), 4.57 (dd, J
= 44.7, 12.0 Hz, 2H), 4.21 (m, 1H), 4.03 (m, 1H), 3.57 (dd, J = 9.9, 7.1
Hz, 1H), 3.48 (dd, J = 9.9, 5.6 Hz, 1H), 2.45 (m, 1H), 2.27 (m, 1H), 2.18
(m, 1H), 0.92 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
138.3, 134.9, 130.8, 128.3, 127.9, 127.6, 127.5, 116.9, 73.3, 72.7, 70.5,
69.7, 38.5, 30.6, 13.3 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H22O2Na: 281.1517, Found: 281.1521.
1H NMR (400 MHz, CDCl3) δ 7.38–7.27 (m, 5H), 5.73–5.58 (m, 2H),
4.54–4.45 (m, 2H), 4.08 (brs, 2H), 3.72 (dd, J = 10.7, 5.0 Hz, 1H), 3.44
(dd, J = 9.7, 4.9 Hz, 1H), 3.36 (dd, J = 9.7, 5.7 Hz, 1H), 2.43 (m, 1H),
0.99 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3) δ 138.3, 135.6, 128.6, 128.2, 127.6, 127.4, 74.8, 73.2, 72.9,
63.7, 39.7, 25.8, 18.1, 14.5, −4.2, −4.8 ppm; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C20H34O3NaSi: 373.2175, Found: 373.2179.
2-((2S,5S,6R)-6-((Benzyloxy)methyl)-5-methyl-5,6-dihydro-2H-pyran-
2-yl)acetaldehyde (19): To a stirred solution of cyclized compound 10
(2.0 g, 7.7 mmol) in 1,4-dioxane (30 mL), were added 2,6-lutidine (3.6
mL, 31.0 mmol), NaIO4 (6.6 g, 31.0 mmol) (dissolved in 10 mL distilled
water) and OsO4 (1 M in toluene, 0.8 mL, 0.8 mmol). The reaction
mixture was stirred at room temperature for 4 h. After completion of the
reaction (monitored by TLC), it was quenched by the addition of solid
NaHSO3. The organic solvent was removed under reduced pressure,
water (25 mL) was added to the residue and the aqueous layer was
extracted with ethyl acetate (3 × 40 mL). The combined organic layer was
washed with 1 N HCl (2 × 50 mL) to remove the excess 2,6-lutidine, dried
with anhydrous Na2SO4 and concentrated under reduced pressure. The
crude aldehyde was purified by silica gel column chromatography (ethyl
acetate/hexane = 1: 9) to give the desired aldehyde 19 (1.6 g, 80 %) as a
(4S,5R,E)-6-(Benzyloxy)-4-methylhex-2-ene-1,5-diol (17b): To
a
stirred solution of the allylic alcohol 17a (6.5 g, 18.5 mmol) in MeOH (60
mL) was added CSA (0.86 g, 3.7 mmol). The resulting mixture was
stirred until the starting material was completely consumed, then the
reaction was quenched by the addition of Et3N (3 mL). The solvent was
removed under reduced pressure and the crude residue was directly
purified by column chromatography on silica gel (ethyl acetate/hexane =
3:7) to afford the diol 17b (3.9 g, 90 %) as a colorless liquid. Rf 0.53
20
(ethyl acetate/hexane = 1:1); [α]D = −24.4 (c = 1.0, CHCl3); IR (CHCl3)
νmax 3395, 2919, 2863, 1454, 1370, 1081, 980, 746, 698 cm−1 1H NMR
;
(500 MHz, CDCl3) δ 7.39–7.27 (m, 5H), 5.71–5.57 (m, 2H), 4.54 (dd, J =
18.1, 11.9 Hz, 2H), 4.09 (d, J = 4.9 Hz, 2H), 3.65 (td, J = 7.2, 2.9 Hz, 1H),
3.54 (dd, J = 9.5, 3.1 Hz, 1H), 3.39 (dd, J = 9.4, 7.7 Hz, 1H), 2.43–2.32
(m, 2H), 1.39 (brs, 1H), 1.08 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 137.8, 134.1, 129.6, 128.4, 127.8, 127.7, 73.5, 73.3, 72.5,
63.4, 39.5, 15.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C14H20O3Na: 259.1310, Found: 259.1312.
20
colorless liquid. Rf 0.52 (ethyl acetate/hexane = 1:4); [α]D = +27.0 (c =
0.5, CHCl3); IR (CHCl3) νmax 2922, 2857, 1719, 1456, 1272, 1215, 1099,
751 cm−1 1H NMR (400 MHz, CDCl3) δ 9.83 (dd, J = 2.5, 1.8 Hz, 1H),
;
7.38–7.27 (m, 5H), 5.89 (ddd, J = 10.2, 5.5, 2.2 Hz, 1H), 5.64 (ddd, J =
10.2, 2.9, 1.3 Hz, 1H), 4.77 (brs, 1H), 4.54 (dd, J = 33.0, 11.9 Hz, 2H),
3.98 (ddd, J = 9.0, 5.7, 3.3 Hz, 1H), 3.54 (dd, J = 9.9, 6.9 Hz, 1H), 3.48
(dd, J = 9.9, 5.6Hz, 1H), 2.82 (ddd, J = 16.2, 8.8, 2.7Hz, 1H), 2.54 (ddd, J
(4S,5R,E)-6-(Benzyloxy)-5-hydroxy-4-methylhex-2-enal (18): To
a
stirred solution of allylic alcohol 17b (3.5 g, 14.8 mmol) in CH2Cl2 (40
mL), were added iodobenzene diacetate (5.71 g, 17.7 mmol) and
TEMPO (0.44 g, 2.9 mmol) at 0 °C, the resulting mixture was stirred at
ambient temperature for 3 h. After complete conversion of the primary
alcohol into the aldehyde (monitored by TLC), the reaction was quenched
by the addition of a saturated solution of Na2S2O3 (40 mL). The organic
layer was separated and the aqueous layer was extracted with CH2Cl2 (3
× 40 mL). The combined organic layers were dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The crude aldehyde
was purified by column chromatography on silica gel (ethyl
acetate/hexane = 3:17) to afford the α,β-unsaturated aldehyde 18 (3.3 g,
94 %) as a colorless viscous liquid. Rf 0.42 (ethyl acetate/hexane = 3:7);
= 16.2, 4.7, 1.8 Hz, 1H), 2.22 (m, 1H), 0.93 (d, J = 7.0 Hz, 3H) ppm; 13
C
NMR (100 MHz, CDCl3) δ 201.0, 138.2, 131.9, 128.4, 127.6, 126.8, 73.4,
70.2, 70.1, 68.3, 47.5, 30.5, 13.3 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C16H20O3Na: 283.1310, Found: 283.1311.
2-((2S,5S,6R)-6-((Benzyloxy)methyl)-5-methyl-5,6-dihydro-2H-pyran-
2-yl)acetic acid (20): To a stirred solution of aldehyde 19 (1.5 g, 5.7
mmol) in t-BuOH (20 mL), was added 2-methyl-2-butene (1 M in THF,
11.5 mL, 11.5 mmol) at room temperature. NaH2PO4 (2.7 g, 17.3 mmol)
and NaClO2 (0.77 g, 8.64 mmol) dissolved in water (10 mL) were added
at 0 °C. The resulting reaction mixture was stirred at room temperature
for 2 h. After completion of the reaction (monitored by TLC), it was diluted
with water (25 mL) and ethyl acetate (40 mL). The organic layer was
separated and the aqueous layer was extracted with ethyl acetate (2 × 30
mL). The combined organic extracts were washed with brine (50 mL),
dried with anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatography
20
[α]D = −21.2 (c = 1.0, CHCl3); IR (CHCl3) νmax 3019, 2925, 1689, 1216,
1100, 743, 667 cm−1 1H NMR (500 MHz, CDCl3) δ 9.50 (d, J = 7.8 Hz,
;
1H), 7.39 – 7.28 (m, 5H), 6.83 (dd, J = 15.8, 7.6 Hz, 1H), 6.13 (ddd, J =
15.8, 7.8, 1.0 Hz, 1H), 4.54 (dd, J = 8.5,4.7 Hz, 2H), 3.80 (td, J = 6.9, 3.2
Hz, 1H), 3.53 (dd, J = 9.5, 3.2 Hz, 1H), 3.39 (dd, J = 9.5, 7.3 Hz, 1H),
2.68 (m, 1H), 2.44 (brs, 1H), 1.17(d, J = 6.8 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 194.1, 159.5, 137.5, 132.6, 128.5, 128.0, 127.8, 73.5,
72.8, 72.0, 40.1, 14.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C14H18O3Na: 257.1154, Found: 257.1157.
(ethyl acetate/hexane = 1:3) to afford the acid compound 20 (1.48 g, 93
20
%) as a colorless liquid. Rf 0.36 (ethyl acetate/hexane = 1:1); [α]D
=
+79.0 (c = 1.0, CHCl3); IR (CHCl3) νmax 3021, 1716, 1214, 1089, 743
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 5H), 5.91 (ddd, J =
64.7, 54.4, 39.4, 36.8, 29.6, 13.1, 12.2 ppm; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C27H31NO5Na: 472.2100, Found: 472.2101.
10.2, 5.7, 2.1 Hz, 1H), 5.63 (ddd, J = 10.2, 2.9, 1.2 Hz, 1H), 4.66 (m, 1H),
4.56 (dd, J = 40.8, 12.0 Hz, 2H), 4.00 (ddd, J = 7.8, 4.8, 3.2 Hz, 1H), 3.56
(dd, J = 9.8, 7.6 Hz, 1H), 3.49 (dd, J = 9.9, 4.9 Hz, 1H), 2.75 (dd, J =
15.5, 10.0 Hz, 1H), 2.49 (dd, J = 15.5, 4.1 Hz, 1H), 2.18 (m, 1H), 0.92 (d,
J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.4, 138.0, 132.1,
128.4, 127.7, 127.7, 126.5, 73.4, 70.2, 70.1, 69.6, 38.5, 30.4, 13.2 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H20O4Na: 299.1259,
Found: 299.1264.
(S)-2-((2R,5S,6R)-6-((Benzyloxy)methyl)-5-methyl-5,6-dihydro-2H-
pyran-2-yl)propan-1-ol (23): To a stirred solution of compound 22 (0.5
g, 1.11 mmol) in MeOH (0.32 mL) and THF (8 mL), was added LiBH4
portion wise (49 mg, 2.2 mmol) at 0 oC. The resulting mixture was
warmed to room temperature and stirred for 3 h. After completion of the
reaction (monitored by TLC), it was quenched with saturated aqueous
Rochelle’s salt, the resulting residue was diluted with water and extracted
with ethyl acetate (3 ×15 mL). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure after which the
crude product was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:9) to furnish the alcohol 23 (0.27 g, 88 %) as a
(R)-4-Benzyl-3-(2-((2S,5S,6R)-6-((benzyloxy)methyl)-5-methyl-5,6-
dihydro-2H-pyran-2-yl)acetyl)oxazolidin-2-one (9): To
a
stirred
solution of acid compound 20 (0.8 g, 2.9 mmol) and Et3N (0.80 mL, 5.8
mmol) in THF (12 mL), was added pivaloyl chloride (0.4 mL, 3.2 mmol) at
−78 oC. After the resultant white suspension was stirred for 10 min at −78
oC and 30 min at 0 oC, it was cooled to −78 oC then added a solution of
lithiated oxazolidinone, which was prepared by the addition of n-BuLi
(1.27 mL, 3.2 mmol) at −78 oC to oxazolidone 21 (0.56 g, 3.2 mmol) in
THF (8 mL) was added via cannula. The reaction mixture was stirred for
an additional 30 min at 0 oC. After completion of the reaction (monitored
by TLC), it was quenched with saturated aqueous NH4Cl solution (15
mL). The residue was extracted with ethyl acetate (3 × 25 mL) and the
combined organic layers were washed with brine (40 mL), dried over
Na2SO4 and concentrated under reduced pressure. The crude product
obtained was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:9) to afford compound 9 (1.13 g, 90 %) as a pale
yellow liquid. Rf 0.65 (ethyl acetate/hexane = 1:4); [α]D20 = +11.1 (c = 1.0,
CHCl3); IR (CHCl3) νmax 2966, 2919, 1777, 1698, 1367, 1206, 1082, 745,
705 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36–7.17 (m, 10H), 5.92 (ddd, J
= 10.1, 5.7, 2.1 Hz, 1H), 5.70 (ddd, J = 10.2, 3.0, 1.1 Hz, 1H), 4.84 (m,
1H), 4.62 (m, 1H), 4.52 (dd, J = 31.5, 12.1 Hz, 2H), 4.07 (m, 1H), 4.03
(dd, J = 9.0, 2.5 Hz, 1H), 3.90 (t, J = 8.3 Hz, 1H), 3.67 (dd, J = 15.4, 10.0
Hz, 1H), 3.54 (dd, J = 9.9, 7.2 Hz, 1H), 3.45 (dd, J = 9.9, 5.4 Hz, 1H),
3.30 (dd, J = 13.4, 3.2 Hz, 1H), 2.89 (dd, J = 15.2, 3.9 Hz, 1H), 2.73 (dd,
J = 13.4, 9.7 Hz, 1H), 2.15 (m, 1H), 0.92 (d, J = 7.0 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 170.7, 153.6, 138.5, 135.4, 131.9, 129.5,
128.9, 128.3, 127.6, 127.5, 127.3, 127.1, 73.3, 70.8, 70.2, 69.8, 66.0,
55.3, 38.9, 37.8, 30.5, 13.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C26H29NO5Na: 458.1943, Found: 458.1948.
20
colorless liquid. Rf 0.46 (ethyl acetate/hexane = 1:4); [α]D = +20.4 (c =
1.0, CHCl3); IR (CHCl3) νmax 3449, 2924, 2858, 1722, 1216, 1076, 750,
667 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 5.85 (ddd, J
= 10.4, 5.2, 1.8 Hz, 1H), 5.79 (ddd, J = 10.3, 2.8, 0.8 Hz, 1H), 4.58 (dd, J
= 46.8, 12.2 Hz, 2H), 4.09 (dt, J = 8.8, 3.1 Hz, 1H), 3.93 (m, 1H), 3.74
(dd, J = 11.3, 8.2 Hz, 1H), 3.58 – 3.47 (m, 2H), 3.44 (dd, J = 9.8, 3.0 Hz,
1H), 2.14 – 2.01 (m, 2H), 0.89 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz,
3H) ppm; 13C NMR (125 MHz, CDCl3) δ 137.7, 130.9, 128.4, 127.8,
127.7, 126.7, 79.7, 73.5, 71.1, 70.2, 69.2, 38.8, 30.4, 13.9, 13.5 ppm;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H24O3Na: 299.1623,
Found: 299.1627.
((S)-2-((2R,5S,6R)-6-((Benzyloxy)methyl)-5-methyl-5,6-dihydro-2H-
pyran-2-yl)propoxy) (tert-butyl)diphenylsilane (23a): To
a stirred
solution of compound 23 (0.15 g, 0.54 mmol) in CH2Cl2 (4 mL), was
added imidazole (55 mg, 0.81 mmol) followed by TBDPSCl (0.16 mL,
0.65 mmol) at 0 oC under N2 atmosphere and allowed to stir for 2 h. After
completion of the reaction (monitored by TLC), it was quenched with
water (8 mL) and diluted with CH2Cl2 (10 mL). The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (2 ×10 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and
evaporated to dryness under reduced pressure. The crude product
obtained was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:39) to furnish the silyl ether 23a (0.265 g, 95 %) as a
20
colorless liquid. Rf 0.56 (ethyl acetate/hexane = 1:19); [α]D = +53.0 (c =
1.0, CHCl3); IR (CHCl3) νmax 3016, 2925, 2863, 1719, 1461, 1216, 1098,
(R)-4-Benzyl-3-((R)-2-((2R,5S,6R)-6-((benzyloxy)methyl)-5-methyl-5,6-
dihydro-2H-pyran-2-yl)propanoyl)oxazolidin-2-one (22): To a stirred
solution of compound 9 (1.0 g, 2.3 mmol) in THF (10 mL), was added
sodium bis(trimethylsilyl)amide (4.6 mL, 1 M solution in THF, 4.6 mmol)
at −78 oC. The reaction mixture was stirred for 45 min at −78 oC. The
reaction mixture was treated with CH3I (0.74 mL, 11.4 mmol) and stirred
for 1 h at −78 oC. After completion of the reaction (monitored by TLC), it
was quenched with aqueous NH4Cl solution (20 mL) and diluted with
ethyl acetate (30 mL). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3 × 25 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude product, which on purification by silica gel
column chromatography (ethyl acetate/hexane = 1:19) to obtain the
methylated product 22 (0.82 g, 80 %) as a pale yellow liquid. Rf 0.54
746, 702 cm−1 1H NMR (500 MHz, CDCl3) δ 7.72–7.65 (m, 4H), 7.41–
;
7.32 (m, 6H), 7.31–7.23 (m, 5H), 5.83 (ddd, J = 10.3, 5.1, 2.0 Hz, 1H),
5.75 (ddd, J = 10.3, 2.8, 1.2 Hz, 1H), 4.45 (dd, J = 42.1, 12.0 Hz, 2H),
4.05 (d, J = 8.9 Hz, 1H), 3.89 (td, J = 6.4, 3.4 Hz, 1H), 3.82 – 3.70 (m,
2H), 3.39 (dd, J = 6.5, 2.4 Hz, 2H), 2.15 (brs,1H), 2.01 (brs, 1H), 1.05 (s,
9H), 1.01 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 138.4, 135.7, 135.6, 134.1, 134.0, 131.1, 129.5,
129.4, 128.3, 127.6, 127.5, 127.5, 126.9, 74.0, 73.4, 70.4, 70.2, 65.7,
39.3, 30.5, 26.9, 19.4, 13.6, 13.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C33H43O3Si: 515.2981, Found: 515.2987.
((2R,3S,6R)-6-((S)-1-((tert-Butyldiphenylsilyl)oxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)methanol (24): Pd/C (10%) (10 mg)
was added to a stirred solution of compound 23a (0.15 g, 0.29 mmol) in
ethyl acetate (5 mL) at room temperature under hydrogen atmosphere.
The mixture was stirred for 12 h at room temperature. After complete
consumption of starting material (monitored by TLC), the reaction mass
was filtered through a pad of Celite and then thoroughly washed with
ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced
pressure and purified by silica gel column chromatography (ethyl
acetate/hexane = 1:19) to furnish the desired alcohol 24 (115 mg, 93 %)
20
(ethyl acetate/hexane = 1:9); [α]D = +3.5 (c = 1.0, CHCl3); IR (CHCl3)
1
νmax 2923, 2859, 1778, 1699, 1382, 1211, 1076, 756, 707 cm−1; H NMR
(400 MHz, CDCl3) δ 7.34 – 7.14 (m, 10H), 5.92 (ddd, J = 10.2, 5.5, 1.7
Hz, 1H), 5.83 (dd, J = 10.4, 1.9 Hz, 1H), 4.55 – 4.38 (m, 5H), 4.04 (m,
1H), 3.84 (dd, J = 8.9, 2.3 Hz, 1H), 3.52 – 3.44 (m, 2H), 3.39 (dd, J =
10.1, 3.5 Hz, 1H), 3.24 (dd, J = 13.3, 3.1 Hz, 1H), 2.71 (dd, J = 13.3, 9.7
Hz, 1H), 2.07 (brs, 1H), 1.21 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 174.6, 152.4, 137.3, 134.5, 131.6,
128.4, 127.8, 127.3, 126.5, 126.5, 126.1, 123.8, 74.5, 72.2, 70.7, 69.4,
20
as a colorless liquid. Rf 0.46 (ethyl acetate/hexane = 1:9); [α]D = −18.7
(c = 1.0, CHCl3); IR (CHCl3) νmax 3512, 3015, 2940, 1624, 1465, 1216,
;
1074, 750 cm−1 1H NMR (400 MHz, CDCl3) δ 7.70–7.61 (m, 4H), 7.46–
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
7.33 (m, 6H), 3.97–3.79 (m, 3H), 3.60–3.52 (m, 2H), 3.42 (dd, J = 11.1,
3.6 Hz, 1H), 1.95 (m, 1H), 1.77–1.59 (m, 4H), 1.35–1.26 (m, 2H), 1.07 (s,
9H), 0.83 (t, J = 6.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 135.8,
135.7, 133.7, 129.6, 127.7, 127.6, 76.6, 69.6, 65.3, 57.4, 39.8, 31.6,
27.7, 27.5, 27.0, 19.3, 16.3, 13.5 ppm; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C26H38O3NaSi: 449.2488, Found: 449.2495.
67.5, 35.4, 29.6, 26.8, 25.7, 23.4, 14.3, 13.7, 9.8 ppm; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C12H24O3Na: 239.1623, Found: 239.1626.
Methyl (R)-2-((2R,5S,6R)-5-methyl-6-propionyltetrahydro-2H-pyran-2
yl)propanoate (27): The diol compound 26 (20 mg, 0.09 mmol) was
dissolved in acetone (3 mL) and cooled to −40 oC under Argon. A
solution of Jones reagent (0.1 mL of 1.87 M solution) (prepared from 0.28
g of CrO3, 1.13 mL of H2O and 0.23 mL of con. H2SO4) was added
dropwise and the reaction mixture was stirred at −20 oC for 2 h. Upon
completion (monitored by TLC), excess ethereal diazomethane was
added until gas evolution ceased and the excess diazomethane was
removed by bubbling Argon through the solution. The mixture was diluted
with ether (10 mL) and the organic phase was washed with 20% NaHSO3
solution (2 × 6 mL), water (6 mL), brine (10 mL) and dried over Na2SO4.
The crude product was purified by silica gel column chromatography
(ethyl acetate/hexane = 1:19) to afford methyl ester 27 (19.0 mg, 84 %)
as a colorless liquid. Rf 0.56 (ethyl acetate/hexane = 1:9); (Identical in all
respects with the degradation product.) [α]D20 = −19.5 (c = 0.7, CHCl3); IR
(CHCl3) νmax 2926, 2858, 1740, 1720, 1461, 1350, 1264, 1164, 1084,
1-((2R,3S,6R)-6-((S)-1-((tert-Butyldiphenylsilyl)oxy)propan-2-yl)-3-
methyltetrahydro-2H-pyran-2-yl)propan-1-ol (25): To a stirred solution
of alcohol 24 (80 mg, 0.18 mmol) and solid anhydrous NaHCO3 (47 mg,
0.56 mmol) in CH2Cl2 (5 mL), was added Dess-Martin periodinane (120
mg, 0.28 mmol) at 0 oC under nitrogen atmosphere and allowed to stir for
2 h at same temperature. After completion of the reaction (monitored by
TLC), it was quenched with aqueous saturated NaHCO3 solution (6 mL)
and diluted with CH2Cl2 (5 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude product which on purification by short
flash column chromatography over silica gel (ethyl acetate/hexane =
1:19) furnished the aldehyde 24a (72 mg, 90 %) as a colorless liquid
which was immediately taken to the next step {Rf 0.62 (ethyl
acetate/hexane = 1:9)}.
972, 766 cm−1 1H NMR (400 MHz, CDCl3) δ 4.16 (d, J = 4.2 Hz, 1H),
;
3.71 (m, 1H), 3.68 (s, 3H), 2.72 (dq, J = 9.6, 7.0 Hz, 1H), 2.57 (dq, J =
14.5, 7.3 Hz, 1H), 2.39 (dq, J = 14.5, 7.3 Hz, 1H), 2.01 (m, 1H), 1.83 (m,
1H), 1.72–1.65 (m, 2H), 1.34 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H), 1.02 (t, J
= 7.4 Hz, 3H), 0.97 (d, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3)
δ 211.5, 175.4, 79.4, 75.3, 51.6, 43.3, 33.5, 31.4, 26.0, 25.1, 15.0, 13.6,
7.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H22O4Na:
265.1416, Found: 265.1421.
Aldehyde 24a (70 mg, 0.16 mmol) was dissolved in dry toluene (1.5 mL)
under an Argon atmosphere and cooled to −78 oC. Ethylmagnesium
bromide (0.33 mL of 1 M solution in THF, 0.33 mmol) was added and the
stirring was continued for 1 h at −78 oC and gradually increased to −30
oC. After completion of the reaction (monitored by TLC), it was quenched
with saturated aqueous NH4Cl (3 mL) and the reaction mixture was
extracted with ethyl acetate (3 × 10 mL), washed with brine (15 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure to get crude product which on
purification by column chromatography over silica gel (ethyl
acetate/hexane = 1:19) furnished diastereomeric mixture of alcohol 25
(65 mg, 86 %) as a colorless liquid. Rf 0.55 (ethyl acetate/hexane = 1:9);
Methyl-(2R)-2-((2R,5S,6R)-6-(3-hydroxypent-1-en-3-yl)-5-methyltetra
hydro-2H-pyran-2-yl)propanoate (28): To
a
stirred solution of
compound 27 (18 mg, 0.07 mmol) in THF (2 mL) added vinyl magnesium
bromide (0.1 mL, 1 M solution in THF, 0.11 mmol) at −78 oC. The
reaction mixture was stirred at the same temperature for 1 h. After
completion of the reaction (monitored by TLC), it was quenched with
aqueous NH4Cl (2 mL). The reaction mixture was extracted with ethyl
acetate (3 × 5 mL), washed with brine (8 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude product which on purification by column
chromatography over silica gel (ethyl acetate/hexane = 1:19) afforded
diastereomeric mixture of alcohol 28 (19.0 mg, 95 %) as a colorless
liquid. Rf 0.48 (ethyl acetate/hexane = 1:9); [α]D20 = –6.2 (c = 1.0, CHCl3);
IR (CHCl3) νmax 3533, 2926, 2856, 1740, 1461, 1269, 1166, 1058, 918,
20
[α]D = –26.8 (c = 1.0, CHCl3); IR (CHCl3) νmax 3456, 3060, 2928, 2863,
1462, 1100, 1072, 751, 701 cm−1 1H NMR (400 MHz, CDCl3) δ 7.70–
;
7.64 (m, 4H), 7.45–7.33 (m, 6H), 3.72 (dd, J = 9.8, 3.8 Hz, 1H), 3.63–
3.51 (m, 2H), 3.35 (td, J = 9.0, 2.9 Hz, 1H), 3.18 (dd, J = 7.9, 3.0 Hz, 1H),
2.20 (m, 1H), 1.93 (m, 1H), 1.82 (m, 1H), 1.72 (m, 1H), 1.62–1.49 (m,
2H), 1.47–1.37 (m, 2H), 1.06 (s, 9H), 1.01 (d, J = 7.0 Hz, 3H), 0.95 (d, J
= 6.7 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
135.7, 135.7, 134.1, 133.9, 129.5, 129.5, 127.6, 74.7, 74.7, 72.9, 65.6,
34.3, 28.5, 26.9, 26.5, 26.4, 21.2, 19.3, 14.1, 13.3, 9.9 ppm; HRMS (ESI-
1
757 cm−1; H NMR (500 MHz, CDCl3) δ 5.68 (dd, J = 17.2, 10.6 Hz, 1H),
5.24 (dd, J = 17.1, 1.6 Hz, 1H), 5.09 (dd, J = 10.6, 1.6 Hz, 1H), 4.04 (dd,
J = 11.1, 6.1 Hz, 1H), 3.67 (s, 3H), 3.57 (d, J = 2.5 Hz, 1H), 3.11 (dq, J =
11.0, 6.9 Hz, 1H), 2.15 (brs, 1H), 2.01–1.93 (m, 2H), 1.64–1.57 (m, 2H),
1.46–1.37 (m, 3H), 1.12 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 0.82
(t, J = 7.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 175.4, 143.5,
113.0, 77.4, 76.2, 76.0, 51.7, 39.6, 29.7, 28.1, 27.2, 19.1, 15.0, 13.7, 7.5
ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H26O4Na: 293.1729,
Found: 293.1735.
TOF) m/z: [M
477.2806.
+
Na]+ calcd for C28H42O3NaSi: 477.2801, Found:
1-((2R,3S,6R)-6-((S)-1-Hydroxypropan-2-yl)-3-methyltetrahydro-2H-
pyran-2-yl)propan-1-ol (26): To a stirred solution of compound 25 (55
mg, 0.12 mmol) in 2 mL of THF added TBAF (0.24 ml of 1 M solution in
THF, 0.24 mmol) at 0 °C temperature. The reaction mixture was stirred
for 1 h. After completion of the reaction (monitored by TLC), it was
quenched with water. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3 × 4 mL). The combined organic
layers were dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude product was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:4) to afford diastereomeric
mixture of alcohol 26 (24 mg, 92 %) as a colorless liquid. Rf 0.62 (ethyl
Methyl-(R)-2-((2R,5S,6R)-5-methyl-6-((E)-1-oxopent-2-en-3-yl)tetra
hydro-2H-pyran-2-yl)propanoate (7): To a stirred solution of compound
28 (16 mg, 0.06 mmol) in CH2Cl2 (2 mL), was added PCC (64 mg, 0.29
mmol) at room temperature. The reaction mixture was heated to 60 oC
and allowed to stir for 5 h. After completion of the reaction (monitored by
TLC), it was filtered through a small pad of Celite. The filtrate was dried
over anhydrous Na2SO4 and evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography (ethyl
acetate/hexane = 1:19) to afford the α,β-unsaturated aldehyde 7 (10.1
mg, 64 %) as a white amorphous solid. Rf 0.40 (ethyl acetate/hexane
20
acetate/hexane = 2:3); [α]D = –26.4 (c = 1.0, CHCl3); IR (CHCl3) νmax
3402, 2924, 2859, 1460, 1377, 1218, 1058, 976, 762 cm−1; 1H NMR (400
MHz, CDCl3) δ 3.72–3.64 (m, 3H), 3.60–3.53 (m, 2H), 2.94 (s, 1H), 2.13
(m, 1H), 1.92–1.72(m, 4H), 1.63−1.36 (m, 4H), 1.03–0.94 (m, 6H), 0.83
(d, J = 6.9 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 77.9, 76.2, 72.8,
20
=1:9); Mp. 70−71 oC; [α]D = −35.2 (c = 0.3, CHCl3); IR (CHCl3) νmax
2923, 2856, 1728, 1660, 1456, 1369, 1212, 1165, 1076, 843, 759 cm−1
;
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10.1002/ejoc.202000156
European Journal of Organic Chemistry
FULL PAPER
1H NMR (500 MHz, CDCl3) δ 10.04 (d, J = 8.2 Hz, 1H), 6.02 (dd, J = 8.1,
1.4 Hz, 1H), 4.42 (brs, 1H), 3.98 (dd, J = 10.9, 5.3 Hz, 1H), 3.60 (s, 3H),
3.11 (m, 1H), 2.76 (m, 1H), 2.21 (m, 1H), 2.03 (m, 1H), 1.96–1.90 (m,
2H), 1.63 (m, 1H), 1.45 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H), 1.09 (d, J = 7.0
Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
191.3, 175.3, 167.2, 125.2, 76.3, 73.2, 51.7, 39.8, 29.9, 26.0, 21.6, 19.6,
15.4, 14.2, 12.3 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H25O4:
269.1753, Found: 269.1765
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The authors thank Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for financial support as part of the XII Five Year Plan
Programme under the title ORIGIN (CSC-0108). We are thankful to the
Director, CSIR-IICT for his support and providing research facility
(Manuscript Communication Number IICT/Pubs/2020/031). R.P. and B.S.
thank UGC and CSIR, New Delhi, India, for financial assistance in the
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European Journal of Organic Chemistry
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FULL PAPER
General
Asymmetric
A general synthetic strategy for
Synthetic Strategy for
convergent
asymmetric
α-Alkylated
2,5,6-
synthesis of C1−C10 fragment
Trisubstituted Pyran of
of tetraene-containing natural
Indanomycin
Related
Products
and
Natural
product
indanomycin
was
achieved starting from 2-
(benzyloxy)acetaldehyde which
was readily prepared using
very inexpensive material cis-
1,4-butene-diol.
Ravishetty Padma,[a]
Beduru Srinivas,[a] J. S.
Yadav,[a,b] and Debendra
K. Mohapatra*[a]
Page No. – Page No.
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