Stereoselective total synthesis of 10-epi-tirandamycin E

Article abstract of DOI:10.1016/j.tet.2017.01.057

A stereoselective total synthesis of 10-epi-tirandamycin E is described, employing desymmetrization protocol, ring-closing metathesis (RCM), acid-catalyzed ketalization, substrate controlled dihydroxylation and Horner-Wadsworth-Emmons olefination as key r

Full text of DOI:10.1016/j.tet.2017.01.057

Tetrahedron xxx (2017) 1e9
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective total synthesis of 10-epi-tirandamycin E
Jhillu S. Yadav**, Santu Dhara, Debendra K. Mohapatra*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective total synthesis of 10-epi-tirandamycin E is described, employing desymmetrization
protocol, ring-closing metathesis (RCM), acid-catalyzed ketalization, substrate controlled dihydrox-
ylation and Horner-Wadsworth-Emmons olefination as key reactions.
Received 29 August 2016
Received in revised form
16 January 2017
Accepted 23 January 2017
Available online xxx
© 2017 Published by Elsevier Ltd.
Keywords:
Tirandamycins
Desymmetrization protocol
Ring-closing metathesis
Acid catalyzed ketalization
Substrate-controlled dihydroxylation
Horner-Wadsworth-Emmons olefination
1. Introduction
dioxabicyclononane skeleton. In the tirandamycin family, two
types of 2,6-dioxabicyclononane structures are known. One is the
The tirandamycins belong to a small group of naturally occur-
ring dienoyl tetramic acids with diverse molecular architecture, are
an important class of compounds in medicinal chemistry. Com-
pounds containing a tetramic acid structural unit exhibit broad
biological activities such as antibacterial, antiviral, anti-HIV-1,
cytotoxicity, mycotoxicity, antitumor, and antimicrobial activities.1
In 1970s tirandamycin A (1) and tirandamycin B (2), two of the
more well-known members of this family, were isolated from
Streptomyces species (Fig. 1).2 In 2011, tirandamycin G (6), a novel
dienoyl tetramic acid with inhibitory activity against the B. Malayi
AsnRS was isolated by Shen and co-workers3 from Streptomyces sp.;
17944 along with two known tirandamycin A (1) and tirandamycin
B (2). Tirandamycins also exhibited antibacterial activity against
Gram-positive bacteria and in vitro activity against bacterial DNA-
directed RNA polymerase.4 Previously, tirandamycins have not
been identified for the use in the prevention and treatment of
lymphatic filariasis (LF). Consequently, tirandamycins represent a
new lead structure for the discovery and development of antifilarial
drugs. In addition to the dienoyl tetramic acid moiety, tirandamy-
cins possess another fascinating structural element, the 2,6-
oxabicyclononane structure with an epoxy ketone moiety (tiran-
damycin A and B) and the other incorporates a double bond
(tirandamycin C, D and E),5 but tirandamycin G contains vicinal
dihydroxy in 2,6-dioxabicyclononane skeleton (Fig. 1).
The complex molecular architecture and potent pharmacolog-
ical properties render this family of antibiotics worthy targets for
their biosynthetic6 and synthetic exploration.7 The most significant
challenging feature of the tirandamycins synthesis is the anti, anti-
dipropionate stereotriad unit which is used for the construction of
2,6-dioxabicyclononane skeleton. Recently, we have successfully
employed our own developed desymmetrization protocol for the
synthesis of 2,6-dioxabicyclononane skeleton of tirandamycin C
(3).8 To further demonstrate the utility of desymmetrization pro-
tocol, we tried to synthesize tirandamycin G that led to the syn-
thesis of 10-epi-tirandamycin E, which is described in this
manuscript.
Our retrosynthetic analysis for the synthesis of tirandamycin G
(6) is illustrated in Scheme 1. We envisioned that tirandamycin G
(6) could be assembled from the bicyclic aldehyde 7 and Schles-
singer's phosphonate 87a,7c via Horner-Wadsworth-Emmons olefi-
nation. Aldehyde 7 in turn could be accessible from an advanced
2,6-dioxabicyclononane intermediate 9 via substrate controlled
dihydroxylation. The bicyclic framework of 9 could be prepared by
elaboration of lactone 10, which in turn would arise from esterifi-
cation of acid 12 with diol 11, followed by ring-closing metathesis
* Corresponding author.
** Corresponding author.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
http://dx.doi.org/10.1016/j.tet.2017.01.057
0040-4020/© 2017 Published by Elsevier Ltd.
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10.1016/j.tet.2017.01.057

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J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
Fig. 1. Structures of tirandamycins (1e6).
Scheme 2. Synthesis of the fragment 11.
(RCM) reaction. Diol 11 in turn could be achieved from a known
bicyclic lactone 13.9
90% yield. The conversion of triol 17 to PMB acetal 18 was carried
out using anisaldehyde dimethyl acetal11 and substoichiometric
amount of camphorsulfonic acid (CSA). The primary hydroxyl group
of compound 18 was protected as pivaloyl ester with PivCl and Et3N
in anhydrous CH2Cl2 to obtain compound 19 in good yield. Regio-
selectively reductive opening of PMB acetal with BH3.THF and
Bu2BOTf led to the primary alcohol 20.12 The hydroxy was con-
verted to its iodo, followed by elimination with t-BuOK in THF
smoothly afforded olefin 21 (80% yield over two steps). The di-PMB
protecting group in the resulted olefin 21 were removed using TFA
in CH2Cl2 at room temperature to furnish the diol 11 in good yield
(Scheme 2).
2. Result and discussion
Our first objective focused on the stereoselective synthesis of
the 2,6-dioxabicyclic skeleton 9. As outlined in Scheme 2, the
fragment 11 was prepared following a desymmetrization of bicylic
olefin 15 using Brown's chiral hydroboration followed by oxidation
via known lactone 13, which was widely used as a building block for
the synthesis of polypropionated natural products in our group.10
Lithium aluminum hydride reduction of 13 afforded triol 17 in
Preparation of the acid 12 began with protection of the Roche's
ester as its TBDPS ether with TBDPS-Cl and imidazole in CH2Cl2 at
0
ꢀC. DIBAL-H reduction of 22 afforded corresponding alcohol
which on treatment with the Dess-Martin periodinane13 reagent
gave aldehyde. The aldehyde was immediately subjected to Wittig
olefination with benzyltriphenylphosphonium bromide and n-BuLi
in benzene at 0 ꢀC to furnish olefin 24 as a 10:1 ratio of E/Z isomers
(53% yield over three steps). The TBDPS group present in compound
24 was deprotected with CSA in MeOH to obtain alcohol 25.
TEMPO-BAIB14 mediated oxidation of the resulting alcohol in
CH2Cl2-water (3:1) afforded the acid 12 in 88% yield (Scheme 3).
Having diol 11 and acid fragment 12 in hand, our next objective
was to couple both the fragments. Initially, esterification of acid 12
with alcohol 11 was performed activatin with dicyclohexyl carbo-
diimide (DCC) and a catalytic amount of 4-dimethylaminopyridine
Scheme 1. Retrosynthetic analysis.
Scheme 3. Synthesis of the fragment 12.
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J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
3
(DMAP) in CH2Cl2 to afford ester as an inseparable mixture of
regioisomers (1:1) in good yield. To improve the selectivity for the
required regioisomer 26, the esterification was examined at low
temperature and at high dilution conditions using dicyclohexyl
carbodiimide (DCC) and catalytic amount of 4-dimethylami-
nopyridine (DMAP) in CH2Cl2 at ꢁ40 ꢀC which resulted better
selectivity towards allylic hydroxy to afford required ester 26 along
with unrequired regioisomer 27 as an inseparable mixture (26/
27 ¼ 4:1) (Scheme 4). The ester 26 along with its regioisomer 27,
were subjected to ring-closing metathesis reaction using Grubbs II
generation15 catalyst in refluxing toluene to furnish lactone 10 (59%
for two steps). The regioisomer 27 did not participate in the ring-
closing metathesis reaction and thus got separated during the pu-
rification by silica gel column chromatography. Lactone 10 was
converted to Weinreb amide16 28 by using methoxymethylamine
hydrochloride and trimethylaluminum in anhydrous CH2Cl2 at 0 ꢀC
with good yield. The resulting Weinreb amide 28 was treated with
excess methyllithium17 (4 equiv.) in THF to convert it to the cor-
responding methyl ketone followed by deprotection of pivaloyl
group to afford triol. The crude triol was subjected to acid-catalyzed
intramolecular ketalization using CSA in CH2Cl2 to form the crucial
2,6-dioxabicyclononane skeleton 9 in 80% yield over two steps.
Having successfully constructed the advanced 2,6-dioxabi-
Fig. 2. NOE correlations of compound 30.
(32)19 to obtain
a,b-unsaturated aldehyde 7 as E/Z isomers (20:1) in
good yield. Coupling of the potassium dianion of Schlessinger's
phosphonate (8)7a,7c with bicyclic aldehyde 7 under Horner-
Wadsworth-Emmons olefination conditions furnished acetonide
and N-dimethoxybenzyl-protected tirandamycin G 33 in 80% yield
(Scheme 5).
To achieve the total synthesis of tirandamycin G (6), depro-
tection of the acetonide on the hydroxy at C10 and C11 and N-
dimethoxybenzyl (DMB) protecting group was planned. For the
same, compound 33 was treated with TfOH and thioanisole in
CH2Cl2 which resulted in complete decomposition of starting ma-
terial. Again, compound 33 was treated with TFA in CH2Cl2 (1:1) to
get the desired tirandamycin G (6) instead 10-epi-tirandamycin E
(5′) was obtained (Table 1).6 The formation of 10-epi-tirandamycin
cyclononane skeleton, diastereoselective dihydroxylation of
9
from the exo face of the 2,6-dioxabic-yclooctane skeleton under
Upjohn conditions18 afforded vicinal diols 29 in moderate yield
(dr ꢂ 99 by HPLC). The assignment of vicinal diol stereochemistry
was confirmed by NOE experiment in the next step. The vicinal
dihydroxy of 29 was protected as its acetonide 30 by using 2,2-
dimethoxypropane (2,2-DMP) in CH2Cl2 in presence of catalytic
amount of CSA (Scheme 4). In the NOESY spectrum of compound
30, the NOE interactions between H-10 and H-7 and C-18 methyl
(Fig. 2) supported the assigned relative stereochemistry of the
acetonide protected vicinal diol 30.
E (5′) was confirmed by comparing thoroughly with the 1H and 13
C
NMR data of the tirandamycin E (5). The plausible pathways for the
formation of the 10-epi-tirandamycin E (5′) was explained in Fig. 3.
In the presence of TFA in CH2Cl2 (1:1), the 2,6-dioxabicyclononane
skeleton opens up to afford keto diol intermediate 34, followed by
deprotonation and deprotection of the acetonide group forms the
stable
a,b-unsaturated keto intermediate 35. The acid-catalyzed
intramolecular ketalization of 35 with TFA in CH2Cl2 reoccurs to
form the crucial 2,6-dioxabicyclononane skeleton present in 5′
followed by deprotection of the DMB group furnishes 10-epi-
tirandamycin E.
Hydroxy compound 30 was then oxidized with Dess-Martin
periodinane13 followed by Wittig olefination with PPh3C(Me)CHO
Next, it was attempted initially to remove the acetonide pro-
tecting group only under mild conditions to avoid the elimination.
Accordingly, when compound 33 was treated with 2 N HCl, it ended
up with intractable mixture of compounds. Moreover, treatment of
compound 33 in CSA-MeOH and CuCl2eCH3CN conditions also led
to decomposition of the starting material (Table 1).
Scheme 4. Synthesis of 2,6-dioxabicyclononane skeleton 30.
Scheme 5. Synthesis of bicylic acetonide and DMB protected tirandamycin G (33).
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J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
Moreover, deprotection of N-dimethoxybenzyl (DMB) protect-
ing group under DDQ conditions also led to an intractable mixture
of compounds.
Fig. 3. Plausible pathways for the formation of 10-epi-tirandamycin E (5′).
reported in hertz (Hz). High resolution mass spectra were run by
the electron impact mode (ESIMS, 70 eV) or by the FAB mode (m-
nitrobenzyl alcohol matrix), using an orbitrap mass analyzer. IR
data were measured with oily films on NaCl plates (oils) or KBr
pellets (solids) and are given only for molecules with relevant
3. Conclusion
In summary, we have made an effort towards the total synthesis
of tirandamycin G, which resulted in the total synthesis of 10-epi-
tirandamycn E (5′). We have developed a stereoselective route for
the total synthesis of 10-epi-tirandamycin E employing desym-
metrization protocol, ring-closing metathesis, acid-catalyzed
ketalization, substrate controlled dihydroxylation and Horner-
Wadsworth-Emmons olefination as key reactions. The total syn-
thesis of tirandamycin G is in progress by changing the protecting
groups and will be reported in due course of time.
functional groups (OH, C]O). Specific optical rotations [
a]
are
D
given in 10ꢁ1 deg cm2gꢁ1 and were measured at 25 ꢀC. The
following abbreviations are used to designate signal multiplicity:
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, quin ¼ quintet,
m ¼ multiplet, br ¼ broad.
4.2. (S)-Methyl 3-(tert-butyldiphenylsilyloxy)-2-methylprop-
4. Experimental section
anoate (22)
4.1. General remarks
To an ice cooled solution of Roche's ester (14) (5.0 g,
42.37 mmol) and imidazole (5.76 g, 84.74 mmol), was added
TBDPSCl (14.5 ml, 55.09 mmol) in CH2Cl2 (80 mL). The reaction
mixture was stirred at 0 ꢀC for 1 h and quenched with aqueous
NH4Cl solution (30 mL). The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (3 ꢃ 40 mL). The combined
organic layer was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography utilizing ethyl acetate and hexane
Experiments which required an inert atmosphere were carried
out under argon in flame-dried glassware. Et2O and THF were
freshly distilled from sodium/benzophenone ketyl and transferred
via syringe. Dichloromethane was freshly distilled from CaH2. Ter-
tiary amines were freshly distilled over KOH. Commercially avail-
able reagents were used as received. Unless detailed otherwise,
“work-up” means pouring the reaction mixture into brine, followed
by extraction with the solvent indicated in parenthesis. If the re-
action medium was acidic (basic), an additional washing with 5%
aqueous NaHCO3 (aqueous NH4Cl) was performed. Washing with
brine, drying over anhydrous Na2SO4 and evaporation of the sol-
vent under reduced pressure followed by chromatography on a
silica gel column (60e120 mesh) with the indicated eluent fur-
nished the corresponding products. Where solutions were filtered
through a Celite pad, the pad was additionally washed with the
same solvent used, and the washings incorporated to the main
organic layer. 1H and 13C NMR chemical shifts are reported in ppm
downfield from tetramethylsilane and coupling constants (J) are
(1:25) as mobile phase to afford silyl ether 22 (14.3 g, 95%) as a
29
colorless liquid. Rf (5% ethyl acetate/hexane) 0.5; [
(c ¼ 1.16, CHCl3); IR (neat):
1255, 1199, 1109, 1027 cmꢁ1
a
]
þ13.6
D
n
3070, 2935, 2859, 1741, 1466, 1429,
;
1H NMR (300 MHz, CDCl3):
d
7.68e7.62 (m, 4H), 7.45e7.35 (m, 6H), 3.38 (dd, J ¼ 9.8, 6.8 Hz,
1H), 3.73 (dd, J ¼ 9.8, 5.2 Hz, 1H), 3.68 (s, 3H), 2.72 (m, 1H), 1.16
(d, J ¼ 6.8 Hz, 3H), 1.03 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3):
d
175.2, 135.5, 133.4, 129.6, 127.6, 65.9, 51.4, 42.3, 26.7, 19.2,
13.4 ppm; HRMS (ESI) m/z calc. for C21H28O3NaSi [M þ Na]þ:
379.1699, found: 379.1700.
4.3. (R)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropan-1-ol (23)
Table 1
A stirred solution of ester 22 (10.0 g, 28.08 mmol) in anhydrous
CH2Cl2 (100 mL), was treated with DIBAL-H (44.15 mL of 1.4 M
solution in toluene, 61.8 mmol) at ꢁ78 ꢀC and stirred for 2 h. The
reaction was quenched with MeOH (5 mL) and saturated aqueous
sodium potassium tartrate solution (50 mL). The reaction mixture
was warmed to room temperature and stirred for 5 h. The organic
layer was separated and the aqueous layer extracted with CH2Cl2
(2 ꢃ 50 mL). Combined organic layers were dried over Na2SO4,
concentrated under reduced pressure. The crude product was
Different deprotection conditions.
Entry
Reaction conditions
Duration (h)
Results
1
2
TfOH, thioanisole CH2Cl2, rt
TFA, CH2Cl2 (1:1), rt
12 h
1 h
Decomposed
10-epi-Tirandamycin
E (60% yield)
Intractable mixture
Decomposed
Decomposed
3
4
5
6
2 N HCl, MeOH, rt
CSA, MeOH, rt
CuCl2, CH3CN, rt
DDQ, CH2Cl2, H2O, rt
4 h
6 h
3 h
2 h
Intractable mixture
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J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
5
purified by silica gel column chromatography using ethyl acetate
6.8 Hz, 1H), 3.53 (dd, J ¼ 10.2, 6.7 Hz, 1H), 2.55 (m, 1H), 1.12 (d,
and hexane (1:10) as mobile phase to afford alcohol 23 (8.29 g, 90%)
J ¼ 6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 137.1, 132.4, 130.9,
29
as a colorless liquid. Rf (15% ethyl acetate/hexane) 0.45; [
(c ¼ 1.0, CHCl3); IR (neat):
1389, 1107, 1037, 701 cmꢁ1; 1H NMR (300 MHz, CDCl3):
a
]
þ5.1
128.5, 127.2, 126.1, 67.3, 40.1, 16.4 ppm; HRMS (EI) m/z calc. for
D
n
3435, 3056, 2956, 2861, 1466, 1426,
7.74e7.63
C
11H14O [M]þ: 162.1043, found: 162.1045.
d
(m, 4H), 7.49e7.34 (m, 6H), 3.73 (dd, J ¼ 10.5, 4.5 Hz, 1H), 3.70e3.65
4.6. (R,E)-2-Methyl-4-phenylbut-3-enoic acid (12)
(m, 2H), 3.59 (dd, J ¼ 9.8, 7.5 Hz, 1H), 2.00 (m, 1H), 1.06 (s, 9H), 0.83
(d, J ¼ 7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d
135.5, 133.2,
To a stirred solution of alcohol 25 (1.75 g, 10.8 mmol) in
dichloromethane-water (30 mL, 2:1 ratio), was added bis(acetoxy)
iodobenzene (BAIB) (8.7 g, 27.0 mmol), 2,2,6,6-tetramethy-
lpiperidine 1-oxyl (TEMPO) (810 mg, 5.4 mmol) sequentially and
stirred for 6 h at room temperature. After completion of the reac-
tion (monitored by TLC), it was quenched with saturated aqueous
solution of Na2S2O7 and stirred for 10 min. The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3 ꢃ 30 mL).
The combined organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was pu-
rified by silica gel column chromatography using ethyl acetate and
hexane (3:7) as mobile phase to afford acid 12 (1.67 g, 88%) as a
129.7, 127.7, 68.5, 67.4, 37.3, 26.8, 19.1, 13.1 ppm; HRMS (ESI) m/z
calc. for C20H28O2NaSi [M þ Na]þ: 351.1750, found: 351.1755.
4.4. (R,E)-tert-butyl(2-methyl-4-phenylbut-3-enyloxy)diphen-
ylsilane (24)
To a stirred solution of primary alcohol 23 (7.5 g, 22.86 mmol)
and solid anhydrous NaHCO3 (5.76 g, 68.58 mmol) in CH2Cl2
(75 mL) at 0 ꢀC, was added Dess-Martin periodinane (14.6 g,
34.3 mmol). The resulting reaction mixture was stirred at 0 ꢀC to
room temperature for 2 h. After completion of the reaction
(monitored by TLC), the reaction was quenched with saturated
aqueous solution of Na2S2O3 (50 mL) and saturated aqueous so-
lution of NaHCO3 (30 mL) and stirred for 15 min. The organic layer
was separated and the aqueous layer extracted with CH2Cl2
(3 ꢃ 50 mL). The combined organic layer was dried over anhy-
drous Na2SO4, concentrated under reduced pressure and filtered
through a small pad of silica gel to give aldehyde (6.78 g, 91%) as
colorless oil which was used for the next step without further
purification.
yellow oil. Rf (40% ethyl acetate/hexane) 0.60; [
CHCl3); IR (neat):
1031, 971 cmꢁ1 1H NMR (300 MHz, CDCl3):
a
]
29 ꢁ30.0 (c ¼ 1.05,
D
n
2974, 2931, 1710, 1627, 1450, 1398, 1230, 1137,
;
d
7.43e7.18 (m, 5H),
6.51 (d, J ¼ 15.8 Hz, 1H), 6.28 (dd, J ¼ 15.8, 8.3 Hz, 1H), 3.34 (m, 1H),
1.40 (d, J ¼ 6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 180.9,
136.7, 131.6, 128.5, 127.9, 127.6, 126.3, 43.0, 17.1 ppm; HRMS (EI) m/z
calc. for C11H12O2 [M]þ: 176.0832, found: 176.0838.
4.7. (3R,4S,5R,6R)-5-(4-methoxybenzyloxy)-4,6-dimethyl hep-
To a solution of benzyltriphenylphosphonium bromide (10.8 g,
24.95 mmol) in anhydrous benzene (75 mL) at 0 ꢀC, was added n-
BuLi (15.6 mL, 24.59 mmol, 1.6 M in hexane) dropwise and the
resulting solution was warmed to room temperature then stirred
for 1 h. The solution was cooled to 0 ꢀC and treated with a solution
of aldehyde (6.78 g, 20.79 mmol) in anhydrous benzene (15 mL).
The reaction mixture was warmed to room temperature and stirred
for 5 h. The reaction mixture was quenched with saturated aqueous
solution of NH4Cl (100 mL) and extracted with diethyl ether
(3 ꢃ 75 mL). Combined extracts were washed with brine (100 mL),
dried over anhydrous Na2SO4, concentrated under reduced pres-
sure. The crude product was purified by silica gel column chro-
matography using ethyl acetate and hexane (1:49) as mobile phase
tane-1,3,7-triol (17)
To an ice cooled suspension of LAH (3.72 g, 98.0 mmol) in THF
(150 mL), was added a solution of lactone 13 (10.0 g, 32.6 mmol) in
THF (50 mL) under nitrogen atmosphere. The reaction mixture was
stirred for 2 h at room temperature. After complete consumption of
starting material (monitored by TLC), it was quenched with satu-
rated aqueous solution of NH4Cl (100 mL) and the formed precip-
itate was filtered off on a pad of Celite using ethyl acetate. The
filtrate was concentrated under reduced pressure to get the crude
triol which was purified by column chromatography over silica gel
ethyl acetate and hexane (3:2) as mobile phase to afford triol 17
(9.17 g, 90%) as a viscous liquid. Rf (pure ethyl acetate) 0.55;
to afford E-olefin 24 (5.4 g, 65%) as a colorless oil. Rf (5% ethyl ac-
[a
]
29 þ6.7 (c ¼ 1.1, CHCl3); IR (neat):
n
3412, 2935, 1612, 1513, 1461,
7.30e7.24 (m, 2H),
D
29
etate/hexane) 0.7; [
a
]
þ12.1 (c ¼ 1.0, CHCl3); IR (neat):
n
3020,
1248, 1034 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
D
2960, 2940, 2860, 1430, 1200, 1120, 960 cmꢁ1; 1H NMR (300 MHz,
CDCl3):
6.88 (d, J ¼ 9.0 Hz, 2H), 4.62 (s, 2H), 4.25 (m, 1H), 3.85e3.67 (m, 4H),
3.80 (s, 3H), 3.48 (dd, J ¼ 8.3, 3.7 Hz, 1H), 2.05 (m, 1H), 1.89 (m, 1H),
1.73 (m, 1H), 1.44 (m, 1H), 1.12 (d, J ¼ 7.5 Hz, 3H), 0.99 (d, J ¼ 6.8 Hz,
d
7.70e7.63 (m, 4H), 7.44e7.26 (m, 11H), 6.40 (d, J ¼ 15.8 Hz,
1H), 6.15 (dd, J ¼ 15.8, 7.5 Hz, 1H), 3.66e3.56 (m, 2H), 2.56 (m, 1H),
1.12 (d, J ¼ 6.8 Hz, 3H), 1.06 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3):
3H) ppm; 13C NMR (75 MHz, CDCl3):
d 159.5, 129.6, 114.0, 88.1, 75.6,
d
137.8, 135.6, 134.8, 133.3, 129.5, 128.4, 127.6, 126.9, 126.0, 68.6,
70.5, 65.1, 61.7, 55.2, 39.2, 37.8, 36.5, 15.0, 11.9 ppm; HRMS (ESI) m/z
39.7, 26.9, 19.3, 16.6 ppm; HRMS (ESI) m/z calc. for C27H32ONaSi
calc. for C17H28O5Na [M þ Na]þ: 335.1829, found: 335.1831.
[M þ Na]þ: 423.2115, found: 423.2108.
4.8. (2R,3R,4S)-3-(4-methoxybenzyloxy)-4-((4R)-2-(4-meth-
4.5. (R,E)-2-Methyl-4-phenylbut-3-en-1-ol (25)
oxyphenyl)-1,3-dioxan-4-yl)-2-methyl pentan-1-ol (18)
To a solution of compound 24 (5.0 g, 12.5 mmol) in MeOH
(50 mL), camphoresulphonic acid (0.58 g, 2.50 mmol) was added at
room temperature and stirred for 6 h. After completion of the re-
action (monitored by TLC), it was quenched with Et3N (10 mL). The
reaction mass was concentrated under reduced pressure to afford
the crude product, which on purification by silica gel column
chromatography using ethyl acetate and hexane (1:5) as the mobile
phase afforded the alcohol 25 (1.92 g, 95%) as a colorless oil. Rf (20%
To a stirred solution of triol 17 (8.0 g, 25.6 mmol) in anhydrous
CH2Cl2 (75 mL), anisaldehye dimethyl acetal (5.23 mL, 30.7 mmol)
was added followed by catalytic amount of camphorsulfonic acid
(580 mg) at 0 ꢀC. The reaction mixture was stirred at room tem-
perature for 1 h and then quenched with saturated aqueous solu-
tion of NaHCO3 (30 mL). The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (3 ꢃ 50 mL). The combined
organic layer was washed with brine (100 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The crude
product was purified on silica gel column chromatography using
ethyl acetate and hexane (1:4) as mobile phase to afford compound
18 (10.0 g, 91%) as pale yellow liquid. Rf (50% ethyl acetate/hexane)
ethyl acetate/hexane) 0.65; [
a
]
D
29 þ26.1 (c ¼ 1.1, CHCl3); IR (neat):
n
3383, 3060, 3027, 2960, 2930, 2874, 1492, 1453,1378, 1274, 1032,
970 cmꢁ1; 1H NMR (500 MHz, CDCl3):
J ¼ 16.0 Hz, 1H), 6.10 (dd, J ¼ 16.0, 8.0 Hz, 1H), 3.60 (dd, J ¼ 10.3,
d 7.39e7.20 (m, 5H), 6.50 (d,
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6
J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
0.5; [
a]
29 ꢁ52.4 (c ¼ 1.3, CHCl3); IR (neat):
n
3453, 2961, 2929, 1613,
7.42 (d,
4.11. (2R,3R,4S,5R)-3,5-bis(4-methoxybenzyloxy)-2,4-dime-
thylhept-6-enyl pivalate (21)
D
1514, 1461, 1248, 1033 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
J ¼ 9.0 Hz, 2H), 7.24 (d, J ¼ 9.0 Hz, 2H), 6.94e6.85 (m, 4H), 5.41 (s,
1H), 4.54 (q, J ¼ 11.3 Hz, 2H), 4.32e4.19 (m, 2H), 4.00e3.85 (m, 2H),
3.81 (s, 3H), 3.80 (s, 3H), 3.59e3.51 (m, 2H), 2.17e2.01 (m, 2H),
1.97e1.81 (m, 2H), 1.20 (d, J ¼ 6.8 Hz, 3H), 1.01 (d, J ¼ 6.8 Hz, 3H)
To a stirred solution of alcohol 20 (5.0 g, 9.69 mmol) in anhy-
drous THF (75 mL) were added imidazole (1.3 g, 19.40 mmol), tri-
phenyl phosphine (TPP) (4.9 g, 19.37 mmol) and iodine (4.92 g,
19.40 mmol) separately at 0 ꢀC under nitrogen. After 30 min the
reaction was quenched by an aqueous saturated hypo solution
(30 mL) and the organic layer was separated. The aqueous layer was
extracted with ethyl acetate (2 ꢃ 50 mL). The combined organic
layer was washed with brine (100 mL), dried over anhydrous
Na2SO4, concentrated under reduced pressure and filtered through
a small pad of silica gel to give iodo compound (5.58 g, 92%) as a
yellow oil which was used for the next step without further
purification.
ppm; 13C NMR (75 MHz, CDCl3):
d 159.7, 159.2, 131.4, 130.2, 129.3,
127.2, 113.8, 113.4, 100.8, 85.4, 75.7, 75.3, 67.2, 64.2, 55.1, 41.0, 35.9,
28.5, 16.1, 10.9 ppm; HRMS (ESI) m/z calc. for C25H34O6Na [M þ
Na]þ: 453.2247, found: 453.2244.
4.9. (2R,3R,4S)-3-(4-methoxybenzyloxy)-4-((4R)-2-(4-meth-
oxyphenyl)-1,3-dioxan-4-yl)-2-methylpentyl pivalate (19)
To a stirred solution of alcohol 18 (5.0 g, 15.5 mmol) in CH2Cl2
(70 mL), was added triethyl amine (6.5 mL, 46.5 mmol), pivaloyl
chloride (2.88 mL, 23.3 mmol) and DMAP (0.19 g, 1.55 mmol) at 0 ꢀC
under N2 atmosphere. The reaction mixture was allowed to come to
room temperature and continued for additional 1 h. The reaction
was quenched by addition of H2O (50 mL) and the organic layer was
separated. The aqueous layer was extracted with CH2Cl2
(2 ꢃ 50 mL) and the combined organic layer was washed with brine
(100 mL), dried over anhydrous Na2SO4, concentrated under
reduced pressure and purified by silica gel column chromatography
using ethyl acetate and hexane (1:19) as the mobile phase to afford
To a stirred solution of iodo compound (5.58 g, 8.91 mmol) in
anhydrous THF (100 mL) was added tBuOK (1.24 g, 11.14 mmol) at
0
ꢀC under nitrogen. The reaction mixture was stirred at ꢁ20 ꢀC
for 15 min. After complete consumption of the starting
material (monitored by TLC), it was quenched with saturated
aqueous ammonium chloride solution (100 mL). The organic
layer was separated and the aqueous layer extracted with ethyl
acetate (2 ꢃ 50 mL). The combined organic layer was washed
with brine (100 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography using ethyl acetate
and hexane (1:20) as mobile phase to afford olefin 21 (3.86 g,
pivalate ester 19 (5.31 g, 89%) as a colorless liquid. Rf (15% ethyl
29
acetate/hexane) 0.45; [
a
]
ꢁ22 (c ¼ 1.0, CHCl3); IR (neat):
n
3424,
1H NMR
7.42 (d, J ¼ 8.6 Hz, 2H), 7.28e7.24 (m, 2H),
D
87%) as a colorless oil. Rf (10% ethyl acetate/hexane) 0.55;
2964, 2928, 1725, 1613, 1514, 1248, 1163, 1034, 980 cmꢁ1
(300 MHz, CDCl3):
;
29
[
a
]
ꢁ21.1 (c ¼ 1.0, CHCl3); IR (neat):
n 3427, 2971, 2837, 1725,
D
d
1611, 1513, 1462, 1397, 1285, 1248, 1167, 1085, 1035 cmꢁ1; 1H NMR
(500 MHz, CDCl3):
6.93e6.84 (m, 4H), 5.40 (s, 1H), 4.52 (ABq, dA 4.55, dB 4.49,
J ¼ 10.7 Hz, 2H), 4.32e4.18 (m, 3H), 3.98e3.87 (m, 2H), 3.81 (s, 3H),
3.80 (s, 3H), 3.47 (dd, J ¼ 9.6, 2.4 Hz,1H), 2.25e2.00 (m, 3H),1.82 (m,
1H), 1.19 (s, 9H), 1.10 (d, J ¼ 6.9 Hz, 3H), 1.04 (d, J ¼ 6.8 Hz, 3H) ppm;
d
7.28e7.25 (m, 2H), 7.19 (d, J ¼ 8.7 Hz, 2H),
6.88e6.84 (m, 4H), 5.84 (m, 1H), 5.28e5.23 (m, 2H), 4.53 (d,
J ¼ 11.3 Hz, 1H), 4.38 (ABq, dA 4.43, dB 4.33 J ¼ 10.8 Hz, 2H),
4.27e4.13 (m, 3H), 3.94 (dd, J ¼ 10.8, 7.8 Hz, 1H), 3.80 (s, 3H), 3.78
(s, 3H), 3.45 (dd, J ¼ 8.8, 3.0 Hz, 1H), 2.17 (m, 1H), 1.87 (m, 1H),
1.18 (s, 9H), 1.06 (d, J ¼ 7.0 Hz, 3H), 0.98 (d, J ¼ 7.0 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3):
d 178.6, 159.8, 159.1, 131.6, 130.9, 129.1,
127.3, 113.8, 113.5, 100.9, 82.8, 75.8, 75.0, 67.3, 65.7, 55.3, 40.8, 38.7,
34.9, 27.2, 27.0, 16.1, 10.9 ppm; HRMS (ESI) m/z calc. for C30H42O7Na
[M þ Na]þ: 537.2822, found: 537.2825.
13C NMR (75 MHz, CDCl3):
d 178.5, 158.9, 138.1, 131.0, 129.0, 128.8,
117.0, 113.6, 82.8, 79.3, 74.2, 69.5, 65.9, 55.1, 41.7, 38.7, 34.8, 27.1,
15.9, 10.3 ppm; HRMS (ESI) m/z calc. for C30H42O6Na [M þ Na]þ:
521.2859, found: 521.2860.
4.10. (2R,3R,4S,5R)-7-Hydroxy-3,5-bis(4-methoxybenzyloxy)-2,4-
dimethylheptyl pivalate (20)
Compound 19 (5.0 g, 9.72 mmol) was dissolved in a solution of
BH3.THF complex (1 M in THF, 48.5 mL). After the mixture was
stirred at 0 ꢀC for 5 min, dibutylboron triflate (1 M in CH2Cl2,
9.72 mL) was added dropwise, and the reaction mixture was stirred
at 0 ꢀC for another 1 h. Subsequently, triethylamine (1.5 mL) and
methanol (1.5 mL) were added until the evolution of H2 gas had
ceased. The solvents were concentrated under reduced pressure,
and the residue was co-evaporated with methanol (3 ꢃ 50 mL). The
residue was purified by silica gel column chromatography using
ethyl acetate and hexane (1:4) as the mobile phase to afford the
4.12. (2R,3R,4S,5R)-3,5-dihydroxy-2,4-dimethylhept-6-enyl
pivalate (11)
To a stirred solution of di-PMB protected olefin 21 (3.75 g,
7.53 mmol) in anhydrous CH2Cl2 (20 mL), was added CF3CO2H
(10 mL). The resulting wine red solution was stirred at room
temperature for 3 h and then quenched with ice pieces. The light
yellow solution was extracted with CH2Cl2 (3 ꢃ 30 mL), com-
bined extracts were washed with saturated aqueous solution of
sodium bicarbonate and dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography using ethyl acetate
primary alcohol 20 (4.10 g, 82%) as a colorless oil. Rf (50% ethyl
29
acetate/hexane) 0.5; [
a]
ꢁ9.5 (c ¼ 1.0, CHCl3); IR (neat):
n 3446,
D
2964, 2932, 1725, 1612, 1585, 1513, 1461, 1398, 1286, 1248, 1167,
and hexane (1:4) as mobile phase to afford diol 11 (1.65 g, 85%) as
1035 cmꢁ1 1H NMR (500 MHz, CDCl3):
;
d
7.24e7.20 (m, 4H),
colorless oil. Rf (50% ethyl acetate/hexane) 0.65; [
(c ¼ 1.2, CHCl3); IR (neat):
1399, 1287, 1164, 1032 cmꢁ1
a
]
þ6.7
29
D
6.87e6.84 (m, 4H), 4.52e4.48 (m, 2H), 4.45e4.38 (m, 2H), 4.27 (dd,
J ¼ 10.8, 4.9 Hz, 1H), 4.0 (dd, J ¼ 10.8, 7.6 Hz, 1H), 3.87 (td, J ¼ 6.4,
2.6 Hz, 1H), 3.79 (s, 6H), 3.76e3.66 (m, 2H), 3.39 (dd, J ¼ 7.8, 3.9 Hz,
1H), 2.20 (m, 1H), 1.99e1.88 (m, 2H), 1.73 (m, 1H), 1.20 (s, 9H), 1.07
(d, J ¼ 7.0 Hz, 3H), 1.03 (d, J ¼ 7.0 Hz, 3H) ppm; 13C NMR (125 MHz,
n
3444, 2972, 2933, 1724, 1645, 1460,
;
1H NMR (500 MHz, CDCl3):
d
5.90
(m, 1H), 5.30 (m, 1H), 5.20 (m, 1H), 4.49 (m, 1H), 4.27 (dd, J ¼ 11.1,
5.6 Hz, 1H), 4.19 (dd, J ¼ 11.1, 4.6 Hz, 1H), 3.44 (m, 1H), 2.09 (m,
1H), 1.89 (m, 1H), 1.22 (s, 9H), 1.00 (d, J ¼ 7.0 Hz, 3H), 0.99 (d,
CDCl3):
d
178.6,159.0,130.9,130.8,129.1,129.0,113.7, 83.7, 76.7, 74.4,
J ¼ 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 179.0, 138.7,
71.2, 66.0, 60.4, 55.2, 39.8, 38.8, 35.2, 35.0, 27.2, 15.8, 11.5 ppm;
HRMS (ESI) m/z calc. for C30H44O7Na [M þ Na]þ: 539.2974, found:
539.2976.
115.1, 77.5, 73.6, 66.3, 38.9, 38.6, 36.0, 27.2, 14.6, 11.8 ppm; HRMS
(ESI) m/z calc. for C14H26O4Na [M þ Na]þ: 281.1723, found:
281.1725.
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J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
7
4.13. (2R,3R,4R)-3-Hydroxy-2-methyl-4-((2R,5R)-5-methyl-6-oxo-
4.15. (R)-2-((1R,3R,4S,5R,8S)-1,4,8-Trimethyl-2,9-dioxabicy- clo
5,6-dihydro-2H-pyran-2-yl)pentyl pivalate (10)
[3.3.1]non-6-en-3-yl)propan-1-ol (9)
To a stirred solution of carboxylic acid 12 (681 mg, 3.87 mmol)
and diol 11 (1.0 g, 3.87 mmol) in anhydrous CH2Cl2 (20 mL)
at ꢁ40 ꢀC, were added a solution of 1,3-dicyclohexylcarbodiimide
(DCC) (985 mg, 4.65 mmol) in anhydrous dichloromethane
(10 mL) and 4-dimethylaminopyridine (DMAP) (47 mg,
0.38 mmol) in anhydrous dichloromethane (5 mL). The
reaction mixture was gradually warmed to room temperature in
4 h. After completion of the reaction (monitored by TLC), the
precipitate of dicyclohexyl urea was filtered off and the
filtrate washed with saturated aqueous ammonium chloride so-
lution (20 mL) and then water (20 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated under reduced
pressure and filtered through a small pad of silica gel to give
mixture of ester 26 and 27 (1.41 g, 88%) as (4:1) inseparable regio
isomer of ester which was used for the next step without further
purification.
To a stirred solution of hydroxy amide 28 (350 mg, 0.94 mmol)
in anhydrous THF (10 mL), MeLi (2.51 mL, 1.5 M in diethyl ether,
3.76 mmol) was added dropwise at ꢁ78 ꢀC under argon. After
10 min, the reaction mixture was warmed to 0 ꢀC, stirred for 15 min,
and then quenched with saturated aqueous solution of NH4Cl
(5 mL). Organic layer was separated, and the aqueous phase
extracted with diethyl ether (2 ꢃ 10 mL). The combined organic
layers were washed with brine (15 mL), dried over MgSO4, and
concentrated under reduced pressure. The resulting crude hemi-
ketal was dissolved in dichloromethane (25 mL) and treated with
CSA (22 mg, 0.094 mmol) at room temperature. After 2 h, the re-
action was quenched with triethylamine (0.5 mL) and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography using ethyl acetate and hexane (1:4) as
mobile phase to obtain bicyclic compound 9 (170 mg, 80%) as
colorless oil; Rf (30% ethyl acetate/hexane) 0.4; [
CHCl3); IR (neat):
1118, 1072, 1040 cmꢁ1
a
]
29 þ41.2 (c ¼ 1.0,
D
To a solution of mixture of ester 26 and 27 (1.41 g, 3.38 mmol)
was added Grubbs II catalyst (286 mg, 0.338 mmol) in toluene
(338 mL, 0.01 M) and heated at 110 ꢀC for 12 h. After completion
of the reaction, toluene was removed under reduced pressure
and the residue was purified by silica gel column chromatog-
raphy using ethyl acetate and hexane (2:3) as mobile phase to
n 3451, 2963, 2926, 1636, 1455, 1375, 1223, 1176,
;
1H NMR (300 MHz, CDCl3):
d 5.89 (dd,
J ¼ 10.5, 3.0 Hz, 1H), 5.75 (m, 1H), 4.30 (m, 1H), 4.00 (dd, J ¼ 11.3,
3.0 Hz, 1H), 3.83 (dd, J ¼ 10.5, 2.2 Hz, 1H), 3.35 (m, 1H), 2.85 (m, 1H),
2.52 (m, 1H), 2.24 (m, 1H), 1.75 (m, 1H), 1.35 (s, 3H), 1.18 (d,
J ¼ 7.5 Hz, 3H), 1.07 (d, J ¼ 7.5 Hz, 3H), 0.70 (d, J ¼ 6.8 Hz, 3H) ppm;
afford lactone 10 (720 mg, 59% for two steps) as yellow oil. Rf
13C NMR (75 MHz, CDCl3):
d 133.8, 123.2, 98.0, 78.5, 71.6, 64.0, 38.4,
29
(50% ethyl acetate/hexane) 0.3; [
(neat):
1028 cmꢁ1
a
]
ꢁ19 (c ¼ 1.0, CHCl3); IR
34.1, 33.7, 27.4, 15.0, 14.1, 12.7 ppm; HRMS (ESI) m/z calc. for
D
n
3444, 2960, 2931, 1719, 1464, 1386, 1109, 1078,
C
13H22O3Na [M þ Na]þ: 249.1466, found: 249.1472.
;
1H NMR (300 MHz, CDCl3):
d
5.82 (m, 1H), 5.68 (m,
1H), 5.52 (m, 1H), 4.28 (dd, J ¼ 11.3, 5.3 Hz, 1H), 3.97 (dd, J ¼ 11.3,
6.8 Hz, 1H), 3.70 (m, 1H), 3.06 (m, 1H), 2.12 (m, 1H), 1.93 (m, 1H),
1.40 (d, J ¼ 7.5 Hz, 3H), 1.21 (s, 9H), 1.08 (d, J ¼ 6.8 Hz, 3H), 0.92
4.16. (1S,3R,4R,5S,6R,7R,8S)-3-((R)-1-Hydroxypropan-2-yl)-1,4,8-
trimethyl-2,9-dioxabicyclo-[3.3.1]- nonane-6,7-diol (29)
(d, J ¼ 6.8 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d
178.5,
To a solution of olefin 9 (150 mg, 0.664 mmol) in acetone-H2O
(3:1, 10 mL) at 0 ꢀC, was added a solution of OsO4 (1.32 mL, 0.025 M
in toluene, 0.033 mmol) followed by the addition of NMO (225 mg,
1.66 mmol). The reaction mixture was stirred at 0 ꢀC for 2 h and at
room temperature for 2 days. The reaction mixture was diluted
with EtOAc (10 mL), quenched with Na2S2O3 (2.0 M, 5.0 mL). The
organic layer was separated and the aqueous layer extracted with
EtOAc (3 ꢃ 10 mL). The combined organic layers were washed with
brine (20 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography using ethyl acetate and hexane (1:1) as
172.8, 128.9, 125.9, 78.9, 74.2, 64.9, 40.6, 38.7, 34.4, 34.3, 27.1, 17.5,
15.6, 9.7 ppm; HRMS (ESI) m/z calc. for C17H28O5Na [M þ Na]þ:
335.1829, found: 335.1831.
4.14. (2R,3R,4S,5R,8R,Z)-3,5-dihydroxy-9-(methoxy (methyl)
amino)-2,4,8-trimethyl-9-oxonon-6-enyl pivalate (28)
To
(419 mg, 4.32 mmol) in anhydrous dichloromethane (10 mL) at
ꢀC, was added dropwise trimethylaluminum (2.0 M in hexane,
a suspension of methoxymethylamine hydrochloride
0
mobile phase to obtain triol 29 (132 mg, 76%) as colorless oil. Rf
29
2.16 mL, 4.32 mmol). When complete dissolution was observed,
the solution was transferred via cannula to a solution of lactone
10 (450 mg, 1.44 mmol) in anhydrous dichloromethane (10 mL)
at 0 ꢀC. The reaction mixture was stirred at 0 ꢀC for 1 h before
being quenched with saturated Rochelle's salts (10 mL) and
extracted with dichloromethane (3 ꢃ 20 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The crude product was purified
by silica gel column chromatography using ethyl acetate and
hexane (1:1) as mobile phase to afford hydroxy amide 28
(pure ethyl acetate) 0.3; [
a
]
ꢁ16.1 (c ¼ 1.1, CHCl3); IR (neat):
n
D
3429, 2916, 2927, 2876, 1726, 1612, 1513, 1459, 1249, 1037 cmꢁ1; 1H
NMR (500 MHz, CDCl3):
d
4.11 (dd, J ¼ 6.4, 2.1 Hz, 1H), 3.93 (dd,
J ¼ 11.3, 3.2 Hz, 1H), 3.88 (m, 1H), 3.76 (dd, J ¼ 10.3, 3.8 Hz, 1H),
3.59e3.52 (m, 2H), 2.41 (m, 1H), 1.82e1.75 (m, 2H), 1.36 (s, 3H), 1.17
(d, J ¼ 7.1 Hz, 3H), 1.13 (d, J ¼ 6.8 Hz, 3H), 0.86 (d, J ¼ 7.1 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3):
d 99.2, 80.8, 76.0, 70.7, 67.1, 63.2,
44.2, 35.7, 31.2, 27.1, 15.3, 12.6, 12.4 ppm; HRMS (ESI) m/z calc. for
C
13H24O5Na [M þ Na]þ: 283.1516, found: 283.1514.
(473 mg, 88%) as colorless liquid. Rf (pure ethyl acetate) 0.3;
4.17. (R)-2-((3aR,4S,5S,7R,8R,9S,9aS)-2,2,4,5,8-Pentamethyl
hexahydro-3aH-5,9-epoxy[1,3]dioxolo[4,5-d]oxocin-7-yl)pro-pan-
1-ol (30)
29
[
a
]
ꢁ16.2 (c ¼ 1.3, CHCl3); IR (neat):
n
3440, 2969, 2932, 1725,
;
D
1639, 1459, 1392, 1285, 1163, 1086 cmꢁ1
CDCl3):
1H NMR (500 MHz,
d
5.65 (dd, J ¼ 11.0, 8.4 Hz, 1H), 5.56 (m, 1H), 4.80 (dd,
J ¼ 8.2, 1.3 Hz, 1H), 4.27e4.20 (m, 2H), 3.93 (m, 1H), 3.74 (s, 3H),
3.47 (m, 1H), 3.19 (s, 3H), 2.09 (m, 1H), 1.88 (m, 1H), 1.22 (s, 9H),
1.21 (d, J ¼ 6.0 Hz, 3H), 1.03 (d, J ¼ 7.2 Hz, 3H), 1.02 (d, J ¼ 6.7 Hz,
To a stirred solution of diol 29 (120 mg, 0.461 mmol) in anhy-
drous dichloromethane (5 mL), was added 2,2-dimethoxy- propane
(0.6 mL, 4.61 mmol) followed by a catalytic amount of CSA (20 mg)
at 0 ꢀC. The reaction mixture was stirred for 1 h at room temper-
ature. After completion of the reaction (monitored by TLC), it was
quenched with NEt3 (2.0 mL). The reaction mixture was concen-
trated to dryness under reduced pressure and purified by silica gel
3H) ppm; 13C NMR (125 MHz, CDCl3):
d 178.6, 170.9, 131.1, 130.7,
76.9, 68.8, 65.8, 60.1, 39.1, 38.5, 35.6, 34.4, 26.9, 17.8, 14.5,
11.9 ppm; HRMS (ESI) m/z calc. for C19H35NO6Na [M þ Na]þ:
396.2358, found: 396.2363.
Please cite this article in press as: Yadav JS, et al., Stereoselective total synthesis of 10-epi-tirandamycin E, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.01.057

8
J.S. Yadav et al. / Tetrahedron xxx (2017) 1e9
column chromatography using ethyl acetate and hexane (1:5) as
mobile phase to afford compound 30 (126 mg, 91%) as colorless oil.
(42 mg, 80%) as a pale yellow oil: Rf (50% ethyl acetate/hexane)
0.25; [
a]
29 þ3.5 (c ¼ 0.7, CHCl3); IR (neat):
n
3451, 2924, 2853, 1704,
D
Rf (50% ethyl acetate/hexane) 0.55; [
(neat):
1H NMR (400 MHz, CDCl3):
a
]
29 þ43.5 (c ¼ 1.2, CHCl3); IR
1617, 1572, 1466, 1375, 1294, 1237, 1211, 1160, 1037 cmꢁ1
;
1H NMR
D
n
3435, 2961, 1739, 1663, 1456, 1413, 1374, 1165, 1040 cmꢁ1
;
(500 MHz, CDCl3):
d
7.54 (d, J ¼ 15.8 Hz, 1H), 7.18 (d, J ¼ 8.7 Hz, 1H),
d
4.26 (d, J ¼ 5.0 Hz, 1H), 4.10 (d,
7.11 (d, J ¼ 15.8 Hz, 1H), 6.46 (s, 2H), 6.21 (d, J ¼ 10.1 Hz, 1H), 4.58 (s,
2H), 4.19 (d, J ¼ 5.0 Hz, 1H), 4.04 (m, 1H), 4.03 (m, 1H), 3.82 (s, 3H),
3.80 (s, 3H), 3.66 (s, 2H), 3.14 (d, J ¼ 10.8 Hz, 1H), 2.78 (m, 1H), 1.96
(m, 1H), 1.90 (s, 3H), 1.87 (m, 1H), 1.53 (s, 3H), 1.37 (s, 3H), 1.36 (s,
3H),1.10 (d, J ¼ 6.9 Hz, 3H), 1.06 (d, J ¼ 6.9 Hz, 3H),0.80 (d, J ¼ 7.2 Hz,
J ¼ 5.8 Hz, 1H), 4.02 (m, 1H), 3.93 (dd, J ¼ 10.8, 3.3 Hz, 1H), 3.54 (dd,
J ¼ 10.8, 3.3 Hz, 1H), 3.22 (dd, J ¼ 10.8, 1.7 Hz, 1H), 2.37 (m, 1H),
1.88e1.76 (m, 2H), 1.51 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H), 1.15 (d,
J ¼ 6.7 Hz, 3H), 1.05 (d, J ¼ 7.5 Hz, 3H), 0.87 (d, J ¼ 6.7 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3):
d
108.2, 99.1, 81.0, 77.3, 73.2, 70.3, 63.1,
3H) ppm; 13C NMR (125 MHz, CDCl3):
d 192.1, 173.8, 173.4, 160.9,
44.1, 35.0, 32.7, 28.2, 27.2, 26.3, 15.1, 14.5, 13.1 ppm; HRMS (ESI) m/z
158.6, 149.2, 144.5, 134.2, 131.2, 116.4, 116.0, 108.1, 104.3, 100.8, 98.7,
98.5, 78.6, 72.9, 70.4, 55.6, 55.3, 44.2, 40.0, 35.1, 33.1, 28.2, 26.9,
26.3, 17.0, 14.5, 12.9, 12.2 ppm; HRMS (ESI) m/z calc. for
calc. for C16H29O5 [M þ H]þ: 301.2009, found: 301.2011.
4.18. (R,E)-2-Methyl-4-((3aR,4S,5S,7R,8R,9S,9aS)-2,2,4,5,8-
pentamethylhexahydro-3aH-5,9-epoxy[1,3] dioxolo[4,5-d]oxo-cin-
7-yl)pent-2-enal (7)
C
34H45NO9Na [M þ Na]þ: 634.2986, found: 634.2989.
4.20. 10-epi-tirandamycin E (50)
To a stirred solution of primary alcohol 30 (100 mg, 0.33 mmol)
and solid anhydrous NaHCO3 (125 mg, 1.50 mmol) in CH2Cl2
(10 mL) at 0 ꢀC, was added Dess-Martin periodinane (284 mg,
0.66 mmol). The resulting reaction mixture was stirred at 0 ꢀC to
room temperature for 2 h. After completion of the reaction
(monitored by TLC), the reaction was quenched with saturated
aqueous solution of Na2S2O3 (5 mL) and saturated aqueous solution
of NaHCO3 (5 mL) and stirred for 15 min. The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3 ꢃ 10 mL).
The combined organic layer was dried over anhydrous Na2SO4,
concentrated under reduced pressure and filtered through a small
pad of silica gel to give aldehyde 31 (85 mg, 86%) as a colorless oil
which was used for the next step without further purification.
The resulting aldehyde 31 (85 mg, 0.285 mmol) and ylide 32
(110 mg, 0.342 mmol) were dissolved in toluene (15 mL) and heated
at 110 ꢀC for 12 h. Toluene was removed under reduced pressure
and the residue was purified by silica gel column chromatography
To a stirred solution of acetonide and dimethoxybenzyl (DMB)
protected tirandamycin G 33 (20 mg, 0.032 mmol) in anhydrous
CH2Cl2 (1.0 mL), was added CF3CO2H (1.0 mL). The resulting wine
red solution was stirred at room temperature for 1 h and then
quenched with ice pieces. The light yellow solution was extracted
with CH2Cl2 (3 ꢃ 10 mL). The combined extracts were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography to
give 10-epi-tirandamycin E (5′) (7.8 mg, 60%) as yellow oil. Rf (10%
29
MeOH/CH2Cl2) 0.6; [
a]
þ8.1 (c ¼ 0.1, CHCl3); IR (neat):
n 3445,
D
3425, 2948, 2914, 2851, 1619, 1578, 1464, 1379, 1291, 1247, 1115,
1030 cmꢁ1 1H NMR (500 MHz, CDCl3):
;
d
7.62 (d, J ¼ 15.6 Hz, 1H),
7.15 (d, J ¼ 15.6 Hz, 1H), 6.30 (d, J ¼ 9.8 Hz, 1H), 5.93 (br s, 1H), 3.94
(m, 1H), 3.82 (s, 2H), 3.77 (d, J ¼ 5.0 Hz, 1H), 3.37 (d, J ¼ 10.8 Hz, 1H),
3.13 (m, 1H), 2.80 (m, 1H), 1.91 (s, 3H), 1.88 (m, 1H), 1.68 (s, 3H), 1.45
(s, 3H),1.04 (d, J ¼ 6.8 Hz, 3H), 0.77 (d, J ¼ 6.8 Hz, 3H) ppm; 13C NMR
(125 MHz, CDCl3):
d 192.5, 176.5, 175.3, 150.4, 146.3, 136.5, 134.3,
using ethyl acetate and hexane (1:9) as mobile phase to afford
a,b-
125.1, 116.0, 99.8, 95.4, 78.4, 77.6, 76.4, 51.6, 34.5, 33.3, 24.1, 18.2,
17.0, 12.7, 12.2 ppm; HRMS (ESI) m/z calc. for C22H29NO6Na [M þ
Na]þ: 426.1918, found: 426.1922.
unsaturated aldehyde 7 (86 mg, 89%) as a 20:1 E/Z isomers. Rf (30%
29
ethyl acetate/hexane) 0.4; [
3450, 2929, 2860, 1686, 1538, 1457, 1376, 1217, 1186, 1138,
1051 cmꢁ1 1H NMR (500 MHz, CDCl3):
9.45 (s, 1H), 6.68 (dd,
a
]
þ30.1 (c ¼ 1.0, CHCl3); IR (neat):
n
D
;
d
Acknowledgements
J ¼ 10.7, 1.2 Hz, 1H), 4.21 (d, J ¼ 5.3 Hz, 1H), 4.10 (d, J ¼ 6.0 Hz, 1H),
4.04 (dd, J ¼ 7.6, 6.1 Hz, 1H), 3.20 (dd, J ¼ 11.3. 1.7 Hz, 1H), 2.91 (m,
1H), 1.94 (m, 1H), 1.89 (m, 1H), 1.78e1.77 (m, 3H), 1.53 (s, 3H), 1.39
(s, 3H), 1.37 (s, 3H), 1.16 (d, J ¼ 7.0 Hz, 3H), 1.08 (d, J ¼ 7.0 Hz, 3H),
The authors thank CSIR, New Delhi for financial support as part
of XII Five Year plan programme under title ORIGIN (CSC-0108). S.D.
is thankful to the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for the financial assistance in the form of
fellowship.
0.83 (d, J ¼ 7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 195.4,
153.7, 139.4, 108.2, 98.8, 78.3, 77.4, 72.9, 70.3, 44.2, 35.0, 33.3, 28.2,
26.9, 26.3, 16.5, 14.5, 12.9, 9.3 ppm; HRMS (ESI) m/z calc. for
C
19H31O5 [M þ H]þ: 339.2166, found: 339.2173.
Appendix A. Supplementary data
4.19. Acetonide and N-DMB protected tirandamycin G (33)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.01.057.
To flame-dried, 25-mL two-nacked round bottom flask
a
equipped with a rubber septum and argon inlet needle was charged
with KO-t-Bu (69 mg, 0.616 mmol) and anhydrous THF (10 mL). A
solution of phosphonate 8 (114 mg, 0.264 mmol) in anhydrous THF
(5.0 mL) was added and the mixture was stirred at 0 ꢀC for 30 min.
A solution of aldehyde 7 (30 mg, 0.0 88 mmol) in anhydrous THF
(5.0 mL) was added dropwise and the mixture was stirred at room
temperature for 12 h. The reaction was quenched by addition of
saturated aqueous NH4Cl solution (10 mL). The organic layer was
separated and the aqueous layer extracted with EtOAc (3 ꢃ 10 mL).
The combined organic extracts were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography using
ethyl acetate and hexane (2:3) as mobile phase to give acetonide
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